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Immunogenic Effect of Hyperthermia on Enhancing Radiotherapeutic Efficacy.
Sep. 2018 | Lee, Sungmin; Son, Beomseok; Park, Gaeul; Kim, Hyunwoo; Kang, Hyunkoo; Jeon, Jaewan; Youn, HyeSook; Youn, BuHyun
Hyperthermia is a cancer treatment where tumor tissue is heated to around 40 °C. Hyperthermia shows both cancer cell cytotoxicity and immune response stimulation via immune cell activation. Immunogenic responses encompass the innate and adaptive immune systems, involving the activation of macrophages, natural killer cells, dendritic cells, and T cells. Moreover, hyperthermia is commonly used in combination with different treatment modalities, such as radiotherapy and chemotherapy, for better clinical outcomes. In this review, we will focus on hyperthermia-induced immunogenic effects and molecular events to improve radiotherapy efficacy. The beneficial potential of integrating radiotherapy with hyperthermia is also discussed. PMID 30227629

Enhancement of Radiation Effectiveness in Cervical Cancer Cells by Combining Ionizing Radiation with Hyperthermia and Molecular Targeting Agents.
Aug. 2018 | IJff, Marloes; van Oorschot, Bregje; Oei, Arlene L; Krawczyk, Przemek M; Rodermond, Hans M; Stalpers, Lukas J A; Kok, H Petra; Crezee, Johannes; Franken, Nicolaas A P
Hyperthermia (HT) and molecular targeting agents can be used to enhance the effect of radiotherapy (RT). The purpose of this paper is to evaluate radiation sensitization by HT and different molecular targeting agents (Poly [ADP-ribose] polymerase 1 inhibitor, PARP1; DNA-dependent protein kinase catalytic subunit inhibitor, DNA-PKcs- and Heat Shock Protein 90 inhibitor, HSP90) in cervical cancer cell lines. Survival curves of SiHa and HeLa cells, concerning the combined effects of radiation with hyperthermia and PARP1, DNA-PKcs or HSP90, were analyzed using the linear-quadratic model: S(D)/S(0) = exp - (αD + βD²). The values of the linear-quadratic (LQ) parameters α and β, determine the effectiveness at low and high doses, respectively. The effects of these sensitizing agents on the LQ parameters are compared to evaluate dose-dependent differences in radio enhancement. Combination of radiation with hyperthermia, PARP1 and DNA-PKcs significantly increased the value of the linear parameter α. Both α and β were significantly increased for HSP90 combined with hyperthermia in HeLa cells, though not in SiHa cells. The Homologous Recombination pathway is inhibited by hyperthermia. When hyperthermia is combined with DNA-PKcs and PARP1, the Non-Homologous End Joining or Alternative Non-Homologous End Joining pathway is also inhibited, leading to a more potent radio enhancement. The observed increments of the α value imply that significant radio enhancement is obtained at clinically-used radiotherapy doses. Furthermore, the sensitizing effects of hyperthermia can be even further enhanced when combined with other molecular targeting agents. PMID 30115874

Chemotherapy Sensitizes Therapy-Resistant Cells to Mild Hyperthermia by Suppressing Heat Shock Protein 27 Expression in Triple-Negative Breast Cancer.
Juni 2018 | Mu, Chaofeng; Wu, Xiaoyan; Zhou, Xinyu; Wolfram, Joy; Shen, Jianliang; Zhang, Dechen; Mai, Junhua; Xia, Xiaojun; Holder, Ashley M; Ferrari, Mauro; Liu, Xuewu; Shen, Haifa
Triple-negative breast cancer (TNBC) is a clinically aggressive disease with poor prognosis. Conventional chemotherapeutics are generally able to shrink the tumor mass, but often fail to completely eradicate cancer stem-like cells (CSCs) that are responsible for high risk of relapse and frequent metastases. In this study, we examined thermal sensibility of CSCs, developed an approach that enabled concurrent elimination of both the bulk of cancer cells and CSCs, and investigated the underlying mechanism. We designed a platform consisting of gold nanoparticle-coated porous silicon microparticle (AuPSM) that was also loaded with docetaxel micelles (mDTXs) to enable concurrent killing of the bulk of cancer cells by released mDTX and CSCs by mild hyperthermia upon stimulation of AuPSM with near infrared. In addition, we examined the role of heat shock proteins in sensitizing CSC killing. Finally, we applied mDTX-loaded AuPSM to treat mice with SUM159 and 4T1 orthotopic tumors and evaluated tumor growth and tumor metastasis. MDA-MB-231 and SUM159 TNBC cells treated with mDTX-loaded AuPSM and mild hyperthermia displayed significantly reduced efficiencies in mammosphere formation than those treated with mDTX alone or mild hyperthermia alone. Combination treatment also completely inhibited SUM159 orthotopic tumor growth and 4T1 tumor metastasis. Mechanistically, DTX treatment suppressed expression of heat shock protein 27 in cancer cells including the CSCs, rendering cells sensitive to mild hyperthermia. Our results indicate that chemotherapy sensitizes CSC to mild hyperthermia. We have developed an effective therapeutic approach to eliminate therapy-resistant cells in TNBC. The current study offers a novel approach to eliminate therapy-resistant cells in breast cancer and uncovers the underlying mechanism of action. PMID 29921732

Integrated Cancer Treatment in the Course of Metastatic Pancreatic Cancer: Complete Resolution in 2 Cases.
Feb. 2018 | Bonucci, Massimo; Pastore, Carlo; Ferrera, Vincenzo; Fiorentini, Carla; Fabbri, Alessia
Pancreatic cancer (PC) has a very low average survival, but its prognosis is further reduced in the case of metastatic spread. Medical therapy in these cases is the only applicable methodology in the international guidelines. During anticancer treatments, common side effects are nausea, vomiting, arthralgia, neuropathy, and alopecia as well as a myelosuppressive effect. The toxicity of various drugs not only affects the quality of life of the patient, but often its severity requires a reduction in if not the termination of drug administration. Scientific studies have shown that a combined use of chemotherapy and certain natural substances, in the form of standardized extracts, can lead to an enhancement of the action of the chemotherapy. Here, we describe 2 cases of metastatic PC. The first case concerns the integrated treatment of a patient with cancer of the pancreas tail with metastatic involvement ab initio of peripancreatic lymph nodes and liver parenchyma, with numerous secondary lesions greater than 9.5 cm. The second case concerns the integrated treatment of a patient with cancer of the pancreatic body with metastatic involvement of the liver parenchyma, with a small secondary lesion. In both cases, an integrated cancer treatment approach, combining chemotherapy with natural remedies, extracts, and hyperthermia, induced a notable remission of primary and metastatic lesions. PMID 29478350

Non-Invasive Radiofrequency Field Treatment of 4T1 Breast Tumors Induces T-cell Dependent Inflammatory Response.
Feb. 2018 | Newton, Jared M; Flores-Arredondo, Jose H; Suki, Sarah; Ware, Matthew J; Krzykawska-Serda, Martyna; Agha, Mahdi; Law, Justin J; Sikora, Andrew G; Curley, Steven A; Corr, Stuart J
Previous work using non-invasive radiofrequency field treatment (RFT) in cancer has demonstrated its therapeutic potential as it can increase intratumoral blood perfusion, localization of intravenously delivered drugs, and promote a hyperthermic intratumoral state. Despite the well-known immunologic benefits that febrile hyperthermia can induce, an investigation of how RFT could modulate the intra-tumoral immune microenvironment had not been studied. Thus, using an established 4T1 breast cancer model in immune competent mice, we demonstrate that RFT induces a transient, localized, and T-cell dependent intratumoral inflammatory response. More specifically we show that multi- and singlet-dose RFT promote an increase in tumor volume in immune competent Balb/c mice, which does not occur in athymic nude models. Further leukocyte subset analysis at 24, 48, and 120 hours after a single RFT show a rapid increase in tumoral trafficking of CD4+ and CD8+ T-cells 24 hours post-treatment. Additional serum cytokine analysis reveals an increase in numerous pro-inflammatory cytokines and chemokines associated with enhanced T-cell trafficking. Overall, these data demonstrate that non-invasive RFT could be an effective immunomodulatory strategy in solid tumors, especially for enhancing the tumoral trafficking of lymphocytes, which is currently a major hindrance of numerous cancer immunotherapeutic strategies. PMID 29472563

Effect of Neoadjuvant Chemotherapy Plus Regional Hyperthermia on Long-term Outcomes Among Patients With Localized High-Risk Soft Tissue Sarcoma: The EORTC 62961-ESHO 95 Randomized Clinical Trial.
Feb. 2018 | Issels, Rolf D; Lindner, Lars H; Verweij, Jaap; Wessalowski, Rüdiger; Reichardt, Peter; Wust, Peter; Ghadjar, Pirus; Hohenberger, Peter; Angele, Martin; Salat, Christoph; Vujaskovic, Zeljko; Daugaard, Soeren; Mella, Olav; Mansmann, Ulrich; Dürr, Hans Roland; Knösel, Thomas; Abdel-Rahman, Sultan; Schmidt, Michael; Hiddemann, Wolfgang; Jauch, Karl-Walter; Belka, Claus; Gronchi, Alessandro; ,
Patients with soft tissue sarcoma are at risk for local recurrence and distant metastases despite optimal local treatment. Preoperative anthracycline plus ifosfamide chemotherapy improves outcome in common histological subtypes. PMID 29450452

The effect of modulated electro-hyperthermia on temperature and blood flow in human cervical carcinoma.
Jan. 2018 | Lee, Sun-Young; Kim, Jong-Hun; Han, Yeon-Hee; Cho, Dong-Hyu
Mild hyperthermia has been known to enhance the response of tumours to radiotherapy or chemotherapy by increasing tumour blood flow, thereby increasing tumour oxygenation or drug delivery. The purpose of this study was to assess the changes in temperature and blood flow in human cervical cancer in response to regional heating with modulated electro-hyperthermia (mEHT). PMID 29297234

Hyperthermia enhances radiosensitivity of colorectal cancer cells through ROS inducing autophagic cell death.
Dez. 2017 | Ba, Ming-Chen; Long, Hui; Wang, Shuai; Wu, Yin-Bing; Zhang, Bo-Huo; Yan, Zhao-Fei; Yu, Fei-Hong; Cui, Shu-Zhong
Hyperthermia (HT) enhances the anti-cancer effects of radiotherapy (RT), but the precise biochemical mechanisms involved are unclear. This study was aim to investigate if mild HT sensitizes colorectal cancer cells to RT through reactive oxygen species (ROS)-inducing autophagic cell death in a mice model of HCT116 human colorectal cancer. HCT116 mice model were randomly divided into five groups: mock group, hyperthermia group (HT), radiotherapy group (RT), HT + RT group, and HT + RT +N-acetyl L-cysteine (NAC) group (HT + CT + NAC). After four weeks of treatment, cancer growth inhibition, rate and mitochondrial membrane potential were measured with MTT and JC-1 assays, respectively, while ROS were estimated fluorimetrically. The relationship of these parameters to expressions of autophagy-related genes Beclin1, LC3B, and mTOR was analyzed. Gene expression was measured by Real-Time polymerase chain reaction (RT-PCR). There were significant increases in ROS levels and mitochondrial membrane potential in the HT + RT group. ROS levels in the HT + RT group increased more significantly than in any other group. In contrast, ROS levels in the HT + RT + NAC group were significantly decreased relative to the HT + RT group. The number of autophagic bodies in HT + RT group was higher than that of mock group. There were significant increases in the expression of Beclin1 and LC3B genes, while mTOR expression was significantly decreased in the HT + CT group. Treatment with NAC reversed the pattern of these changes. These results indicate that HT enhances the radiosensitivity of colorectal cancer cells to RT through ROS inducing autophagic cell death. PMID 29240246

The clinical benefit of hyperthermia in pancreatic cancer: a systematic review.
Nov. 2017 | van der Horst, Astrid; Versteijne, Eva; Besselink, Marc G H; Daams, Joost G; Bulle, Esther B; Bijlsma, Maarten F; Wilmink, Johanna W; van Delden, Otto M; van Hooft, Jeanin E; Franken, Nicolaas A P; van Laarhoven, Hanneke W M; Crezee, Johannes; van Tienhoven, Geertjan
In pancreatic cancer, which is therapy resistant due to its hypoxic microenvironment, hyperthermia may enhance the effect of radio(chemo)therapy. The aim of this systematic review is to investigate the validity of the hypothesis that hyperthermia added to radiotherapy and/or chemotherapy improves treatment outcome for pancreatic cancer patients. PMID 29168401

Patient With Unresectable Cholangiocarcinoma Treated With Radiofrequency Hyperthermia in Combination With Chemotherapy: A Case Report.
Juli 2017 | Ryu, Juyoung; Lee, Kangwook; Joe, Changmug; Joo, JongCheon; Lee, Namhun; Yoo, Hwa-Seung
Hyperthermia, which is a noninvasive treatment that causes tumor cells to become heated and that works in synergy with anticancer drugs and radiation therapy, is emerging as a promising treatment for patients with cancer. The purpose of this study is to report the efficacy of hyperthermia combined with chemotherapy (gemcitabine/cisplatin) for the treatment of a patient with unresectable cholangiocarcinoma. A 54-year-old man was diagnosed as hilar cholangiocarcinoma (Klatskin tumor) and was administered neoadjuvant and preoperative radiation with chemotherapy. However, because the treatment with radiation and chemotherapy was not successful, he decided to undergo hyperthermia combined with chemotherapy as a second treatment option. He was suffering from fatigue, dyspepsia, epigastralgia, and jaundice. Hyperthermia combined with chemotherapy was administered 32 times over a period of 4 months. The patient experienced no critical complications, and the patient's condition improved, with the carbohydrate antigen 19-9 (CA 19-9) and the total bilirubin levels being relatively lowered. In addition, the computed tomography scan showed that the cholangiocarcinoma had not progressed. In conclusion, this case report suggests radiofrequency hyperthermia combined with chemotherapy may be a promising treatment option for patients with unresectable cholangiocarcinoma. PMID 28745084

Treatment outcome analysis of chemotherapy combined with modulated electro-hyperthermia compared with chemotherapy alone for recurrent cervical cancer, following irradiation.
Juli 2017 | Lee, Sun Young; Lee, Na Ri; Cho, Dong-Hyu; Kim, Jung Soo
The survival of patients with recurrent cervical cancer following irradiation remains poor. Chemotherapy combined with hyperthermia has been demonstrated to improve the response rate. The present study was performed to evaluate the effect of modulated electro-hyperthermia combined with conventional chemotherapy compared with chemotherapy alone on recurrent cervical cancer previously treated with irradiation. A total of 20 patients were treated with chemotherapy alone, and 18 were treated with chemotherapy combined with modulated electro-hyperthermia. A single patient was treated with chemo-radiotherapy as primary treatment and then relapsed; the tumor was inoperable and radio-refractory upon recurrence. Local metastases, including metastasis of the para-aortic lymph nodes and adjacent pelvic lymph nodes were included, but distant metastases were excluded. Modulated electro-hyperthermia was performed three times per week beginning at chemotherapy initiation, and patients underwent a total of 36 sessions. The overall response (complete remission + partial remission + stable disease/progressive disease) to treatment was significantly greater in the group of patients who underwent chemotherapy combined with modulated electro-hyperthermia (P=0.0461), and at the evaluation conducted at the last follow-up visit, the response rate was significantly higher (P=0.0218). Additionally, severe complications were not reported. In the present study, of patients with recurrent cervical cancer previously treated with irradiation, the overall response rate for patients treated with chemotherapy combined with modulated electro-hyperthermia was significantly greater than that for those treated with chemotherapy alone. PMID 28693137

Treatment outcomes of concurrent hyperthermia and chemoradiotherapy for pancreatic cancer: Insights into the significance of hyperthermia treatment.
Juni 2017 | Maebayashi, Toshiya; Ishibashi, Naoya; Aizawa, Takuya; Sakaguchi, Masakuni; Sato, Tsutomu; Kawamori, Jiro; Tanaka, Yoshiaki
Patients with locally advanced unresectable pancreatic cancer (LAUPC) have a poor prognosis. In addition their quality of life impaired by cancer pain and biliary tract infections. Therefore, multimodality therapy and selection of optimal treatment methods are essential for achieving prolonged survival. The present study investigated the significance of using hyperthermia concurrently with multimodality therapy to improve treatment outcomes in patients with LAUPC. In total, 13 patients receiving concurrent hyperthermia and chemoradiotherapy (HCR) or chemoradiotherapy (CR) alone for LAUPC between 2002 and 2013 were analyzed retrospectively. Of the 13 patients, 5 received concurrent HCR and 8 received CR. The chemotherapy regimens were 5-fluorouracil (5-FU) in 5 patients and gemcitabine hydrochloride (GEM) in the other 8. Patients who gave consent for hyperthermia treatment received GEM plus CR. The median overall survival period for all patients was 12 months and the 1-year survival rate was 55%; the corresponding values were 12 months and 57% in the GEM CR group, and 15 months and 80% in the HCR group. Univariate analyses was perfomed to identify factors predicting recurrence after treatment. The potential prognostic factors analyzed were: Age, sex, performance status, location, tumor size, the tumor marker CA 19-9, total radiation dose, chemotherapy and hyperthermia. Univariate analysis for factors associated with outcomes revealed a significant difference favoring the HCR group [relative risk=15.97 (95% confidence interval: 12.87-19.83) P=0.021]. In conclusion, hyperthermia merits active recommendation to pancreatic cancer patients who have a positive attitude toward this treatment and whose performance status is satisfactory. PMID 28588736

The effect of thermal dose on hyperthermia-mediated inhibition of DNA repair through homologous recombination.
Juni 2017 | van den Tempel, Nathalie; Laffeber, Charlie; Odijk, Hanny; van Cappellen, Wiggert A; van Rhoon, Gerard C; Franckena, Martine; Kanaar, Roland
Hyperthermia has a number of biological effects that sensitize tumors to radiotherapy in the range between 40-44 °C. One of these effects is heat-induced degradation of BRCA2 that in turn causes reduced RAD51 focus formation, which results in an attenuation of DNA repair through homologous recombination. Prompted by this molecular insight into how hyperthermia attenuates homologous recombination, we now quantitatively explore time and temperature dynamics of hyperthermia on BRCA2 levels and RAD51 focus formation in cell culture models, and link this to their clonogenic survival capacity after irradiation (0-6 Gy). For treatment temperatures above 41 °C, we found a decrease in cell survival, an increase in sensitization towards irradiation, a decrease of BRCA2 protein levels, and altered RAD51 focus formation. When the temperatures exceeded 43 °C, we found that hyperthermia alone killed more cells directly, and that processes other than homologous recombination were affected by the heat. This study demonstrates that optimal inhibition of HR is achieved by subjecting cells to hyperthermia at 41-43 °C for 30 to 60 minutes. Our data provides a guideline for the clinical application of novel combination treatments that could exploit hyperthermia's attenuation of homologous recombination, such as the combination of hyperthermia with PARP-inhibitors for non-BRCA mutations carriers. PMID 28574821

Hyperthermia enhances bortezomib-induced apoptosis in human white blood cancer cells.
Mai 2017 | Saliev, Timur; Feril, Loreto B; Begimbetova, Dinara; Baiskhanova, Dinara; Klodzinskyi, Anton; Bobrova, Xeniya; Aipov, Rassulbek; Baltabayeva, Tolkyn; Tachibana, Katsuro
At present, the current therapeutic strategy for apoptosis induction mainly relies on the administration of pharmacological apoptotic modulators. Apart from that, apoptosis can be induced by various external stimuli such as hyperthermia, ionizing radiation, and electric fields. Despite advantages, both physical and pharmacological approaches bear some limitations as well. The rationale of this study was to overcome the limitations by combining hyperthermia and apoptotic modulator 'bortezomib' (Velcade). Two types of human blood cancer cell lines were utilized: human leukemic monocyte lymphoma cell U937 line and peripheral blood mononuclear cells (PMBCs) derived from the patient diagnosed with acute myeloid leukemia. Prior to apoptosis experiments, cytotoxicity tests were performed at three types of temperature regimes (40°, 42° and 44°C). We observed a gradual inhibition of cell viability correlating with an increase of temperature and drug concentration in both cell lines. However, there was no significant difference between sham group and groups of leukemic PMBCs treated by high temperature (44°C) and bortezomib. In U937 cells, combined treatment by heat shock and bortezomib led to an increase the number of cells underwent the late apoptosis stage. At the same time, similar treatment of PMBCs resulted in the stimulation of early apoptosis. Our data suggest that combination of bortezomib and hyperthermia enhances apoptosis induction in human cancer white blood cells, indicating a therapeutic potential for blood cancer therapy. PMID 28558940

Combination treatment with transarterial chemoembolization, radiotherapy, and hyperthermia (CERT) for hepatocellular carcinoma with portal vein tumor thrombosis: Final results of a prospective phase II trial.
Mai 2017 | Yu, Jeong Il; Park, Hee Chul; Jung, Sang Hoon; Choi, Changhoon; Shin, Sung Wook; Cho, Sung Ki; Sinn, Dong Hyun; Paik, Yong-Han; Gwak, Geum-Youn; Choi, Moon Seok; Lee, Joon Hyeok; Koh, Kwang Cheol; Yoo, Byung Chul; Sahinbas, Hüseyin; Paik, Seung Woon
This study was designed to evaluate the efficacy and safety of combination transarterial chemoembolization (TACE) followed by radiotherapy (RT) and hyperthermia (CERT) in hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT). PMID 28467966

A short time interval between radiotherapy and hyperthermia reduces in-field recurrence and mortality in women with advanced cervical cancer.
Apr. 2017 | van Leeuwen, Caspar M; Oei, Arlene L; Chin, Kenneth W T K; Crezee, Johannes; Bel, Arjan; Westermann, Anneke M; Buist, Marrije R; Franken, Nicolaas A P; Stalpers, Lukas J A; Kok, H Petra
Combined radiotherapy and hyperthermia is a well-established alternative to chemoradiotherapy for advanced stage cervical cancer patients with a contraindication for chemotherapy. Pre-clinical evidence suggests that the radiosensitizing effect of hyperthermia decreases substantially for time intervals between radiotherapy and hyperthermia as short as 1-2 h, but clinical evidence is limited. The purpose of this study is to determine the effect of the time interval between external beam radiotherapy (EBRT) and same-day hyperthermia on in-field recurrence rate, overall survival and late toxicity in women with advanced stage cervical cancer. PMID 28449703

Temperature measurements in a capacitive system of deep loco-regional hyperthermia.
Apr. 2017 | Sahinbas, H; Rosch, M; Demiray, M
Hyperthermia has been shown to be a medically useful procedure applicable for different indications. For the connection between clinical effects and heat, it is important to understand the actual temperatures achieved in the tissue. There are limited temperature data available when using capacitive hyperthermia devices even though this is worldwide the most widespread method for loco-regional heating. Hence, this study examines temperature measurements using capacitive heating. Bioequivalent phantoms were used for the measurements, which, however, do not consider perfusion in live tissue. In general, the required temperature impact for an effective cancer therapy should need an increase of 0.2°C/min, which has been achieved. In the described tests on the non-perfused dummy, on average, the temperature increases by approximately 2°C in the first 12 min. The temperature difference relative to the starting temperature was 10-12°C within a therapy time of 60 min (rising from the initial room temperature between 20-24°C and 32-34°C). The average deviation with three individual measurements each on different days in a specified localization was 2°C. The minimum temperature difference was 4.2°C, and the maximum value was reached in the liver with 10.5°C. These values were achieved with a moderate energy input of 60-150 watts, with much higher performance outputs still available. These results show that the tested capacitive device is capable of achieving quick temperature increase with a sufficient impact into the depth of a body. PMID 28448752

Reirradiation for locally recurrent breast cancer.
Apr. 2017 | Marta, Gustavo Nader; Hijal, Tarek; de Andrade Carvalho, Heloisa
The aim of this study is to review the current status of reirradiation therapy (Re-RT) for locally recurrent breast cancer. The overall outcome of breast/chest wall Re-RT is difficult to assess because of the wide range of different treatments that a patient may have undergone and the patient's individual features. The local control and complete response rates were reported to be 43-96% and 41-71%, respectively. The combination of Re-RT and hyperthermia seems to be related to improved outcomes. Toxicity rates vary between studies, and Re-RT is generally well tolerated. Re-RT may be considered an option for patients with breast cancer relapse after prior irradiation. Further studies are needed to determine the best irradiation volume and treatment modality for patients with locally recurrent disease. PMID 28395234

Temperature induces significant changes in both glycolytic reserve and mitochondrial spare respiratory capacity in colorectal cancer cell lines.
März 2017 | Mitov, Mihail I; Harris, Jennifer W; Alstott, Michael C; Zaytseva, Yekaterina Y; Evers, B Mark; Butterfield, D Allan
Thermotherapy, as a method of treating cancer, has recently attracted considerable attention from basic and clinical investigators. A number of studies and clinical trials have shown that thermotherapy can be successfully used as a therapeutic approach for various cancers. However, the effects of temperature on cancer bioenergetics have not been studied in detail with a real time, microplate based, label-free detection approach. This study investigates how changes in temperature affect the bioenergetics characteristics (mitochondrial function and glycolysis) of three colorectal cancer (CRC) cell lines utilizing the Seahorse XF96 technology. Experiments were performed at 32°C, 37°C and 42°C using assay medium conditions and equipment settings adjusted to produce equal oxygen and pH levels ubiquitously at the beginning of all experiments. The results suggest that temperature significantly changes multiple components of glycolytic and mitochondrial function of all cell lines tested. Under hypothermia conditions (32°C), the extracellular acidification rates (ECAR) of CRC cells were significantly lower compared to the same basal ECAR levels measured at 37°C. Mitochondrial stress test for SW480 cells at 37°C vs 42°C demonstrated increased proton leak while all other OCR components remained unchanged (similar results were detected also for the patient-derived xenograft cells Pt.93). Interestingly, the FCCP dose response at 37°C vs 42°C show significant shifts in profiles, suggesting that single dose FCCP experiments might not be sufficient to characterize the mitochondrial metabolic potential when comparing groups, conditions or treatments. These findings provide valuable insights for the metabolic and bioenergetic changes of CRC cells under hypo- and hyperthermia conditions that could potentially lead to development of better targeted and personalized strategies for patients undergoing combined thermotherapy with chemotherapy. PMID 28342898

Optimizing non-invasive radiofrequency hyperthermia treatment for improving drug delivery in 4T1 mouse breast cancer model.
März 2017 | Ware, Matthew J; Krzykawska-Serda, Martyna; Chak-Shing Ho, Jason; Newton, Jared; Suki, Sarah; Law, Justin; Nguyen, Lam; Keshishian, Vazrik; Serda, Maciej; Taylor, Kimberly; Curley, Steven A; Corr, Stuart J
Interactions of high-frequency radio waves (RF) with biological tissues are currently being investigated as a therapeutic platform for non-invasive cancer hyperthermia therapy. RF delivers thermal energy into tissues, which increases intra-tumoral drug perfusion and blood-flow. Herein, we describe an optical-based method to optimize the short-term treatment schedules of drug and hyperthermia administration in a 4T1 breast cancer model via RF, with the aim of maximizing drug localization and homogenous distribution within the tumor microenvironment. This method, based on the analysis of fluorescent dyes localized into the tumor, is more time, cost and resource efficient, when compared to current analytical methods for tumor-targeting drug analysis such as HPLC and LC-MS. Alexa-Albumin 647 nm fluorphore was chosen as a surrogate for nab-paclitaxel based on its similar molecular weight and albumin driven pharmacokinetics. We found that RF hyperthermia induced a 30-40% increase in Alexa-Albumin into the tumor micro-environment 24 h after treatment when compared to non-heat treated mice. Additionally, we showed that the RF method of delivering hyperthermia to tumors was more localized and uniform across the tumor mass when compared to other methods of heating. Lastly, we provided insight into some of the factors that influence the delivery of RF hyperthermia to tumors. PMID 28287120

Chemoradiation combined with regional hyperthermia for advanced oesophageal cancer: a systematic review and meta-analysis.
Jan. 2017 | Hu, Y; Li, Z; Mi, D-H; Cao, N; Zu, S-W; Wen, Z-Z; Yu, X-L; Qu, Y
Hyperthermia is an effective treatment modality that augments the anticancer effects of radiotherapy and chemotherapy. Hyperthermia-chemo-radiotherapy (HCRT) is a combination therapy that can strengthen anticancer effects through a synergistic interaction between heat, chemotherapy and radiation. Here, we carried out a systematic review and meta-analysis to evaluate the clinical efficacy and safety of chemoradiation combined with regional hyperthermia (HCRT) for oesophageal carcinoma. PMID 28120520

Targeting therapy-resistant cancer stem cells by hyperthermia.
Jan. 2017 | Oei, A L; Vriend, L E M; Krawczyk, P M; Horsman, M R; Franken, N A P; Crezee, J
Eradication of all malignant cells is the ultimate but challenging goal of anti-cancer treatment; most traditional clinically-available approaches fail because there are cells in a tumour that either escape therapy or become therapy-resistant. A subpopulation of cancer cells, the cancer stem cells (CSCs), is considered to be of particular significance for tumour initiation, progression and metastasis. CSCs are considered in particular to be therapy-resistant and may drive disease recurrence, which positions CSCs in the focus of anti-cancer research, but successful CSC-targeting therapies are limited. Here, we argue that hyperthermia - a therapeutic approach based on local heating of a tumour - is potentially beneficial for targeting CSCs in solid tumours. First, hyperthermia has been described to target cells in hypoxic and nutrient-deprived tumour areas where CSCs reside and ionising radiation and chemotherapy are least effective. Second, hyperthermia can modify factors that are essential for tumour survival and growth, such as the microenvironment, immune responses, vascularisation and oxygen supply. Third, hyperthermia targets multiple DNA repair pathways, which are generally upregulated in CSCs and protect them from DNA-damaging agents. Addition of hyperthermia to the therapeutic armamentarium of oncologists may thus be a promising strategy to eliminate therapy-escaping and -resistant CSCs. PMID 28100096

Regional hyperthermia combined with radiotherapy for esophageal squamous cell carcinoma with supraclavicular lymph node metastasis.
Dez. 2016 | Sheng, Liming; Ji, Yongling; Wu, Qiner; Du, Xianghui
To assess the efficacy and toxicity of Intensity-modulated radiotherapy (IMRT) and hyperthermia for upper and middle thoracic esophageal squamous cell carcinoma (UMT-ESCC) with supraclavicular lymph node metastasis. A total of 50 patients with UMT-ESCC with supraclavicular lymph node metastasis were evaluated in this retrospective study. All patients received IMRT. Hyperthermia was delivered simultaneously with irradiation, in 45 minutes twice a week for 5-6 weeks. Hyperthermia included supraclavicular lymph node metastasis. Forty-four patients (88.0%) received concurrent chemoradiotherapy based on cisplatin regimens. The most common types of hematological toxicities were anemia (62.0%) and leukopenia (60.0%). Most of these events were grade 1-2 and transient. The 3-year progression-free survival (PFS) rate and overall survival (OS) rate were 34.9% and 42.5%, respectively. Cox regression revealed that tumor length and number of supraclavicular lymph node metastasis were two independent predictors of OS (tumor length: HR=3.65, p=0.008; nodal stage: HR=8.07, p=0.019). The IMRT combined with supraclavicular regional hyperthermia has low toxicity and well tolerated with excellent local control in UMT-ESCC with supraclavicular lymph node metastasis. PMID 28029663

Role of CTGF in Sensitivity to Hyperthermia in Ovarian and Uterine Cancers.
Nov. 2016 | Hatakeyama, Hiroto; Wu, Sherry Y; Lyons, Yasmin A; Pradeep, Sunila; Wang, Wanqin; Huang, Qian; Court, Karem A; Liu, Tao; Nie, Song; Rodriguez-Aguayo, Cristian; Shen, Fangrong; Huang, Yan; Hisamatsu, Takeshi; Mitamura, Takashi; Jennings, Nicholas; Shim, Jeajun; Dorniak, Piotr L; Mangala, Lingegowda S; Petrillo, Marco; Petyuk, Vladislav A; Schepmoes, Athena A; Shukla, Anil K; Torres-Lugo, Madeline; Lee, Ju-Seog; Rodland, Karin D; Fagotti, Anna; Lopez-Berestein, Gabriel; Li, Chun; Sood, Anil K
Even though hyperthermia is a promising treatment for cancer, the relationship between specific temperatures and clinical benefits and predictors of sensitivity of cancer to hyperthermia is poorly understood. Ovarian and uterine tumors have diverse hyperthermia sensitivities. Integrative analyses of the specific gene signatures and the differences in response to hyperthermia between hyperthermia-sensitive and -resistant cancer cells identified CTGF as a key regulator of sensitivity. CTGF silencing sensitized resistant cells to hyperthermia. CTGF small interfering RNA (siRNA) treatment also sensitized resistant cancers to localized hyperthermia induced by copper sulfide nanoparticles and near-infrared laser in orthotopic ovarian cancer models. CTGF silencing aggravated energy stress induced by hyperthermia and enhanced apoptosis of hyperthermia-resistant cancers. PMID 27806300

Hyperthermia and radiotherapy with or without chemotherapy in locally advanced cervical cancer: a systematic review with conventional and network meta-analyses.
Sep. 2016 | Datta, Niloy R; Rogers, Susanne; Klingbiel, Dirk; Gómez, Silvia; Puric, Emsad; Bodis, Stephan
A systematic review with conventional and network meta-analyses (NMA) was conducted to examine the outcomes of loco-regional hyperthermia (HT) with radiotherapy (RT) and/or chemotherapy (CT) in locally advanced cervix cancer, IIB-IVA (LACC). PMID 27411568

A multicentre randomised clinical trial of chemoradiotherapy plus hyperthermia versus chemoradiotherapy alone in patients with locally advanced cervical cancer.
Sep. 2016 | Harima, Yoko; Ohguri, Takayuki; Imada, Hajime; Sakurai, Hideyuki; Ohno, Tatsuya; Hiraki, Yoshiyuki; Tuji, Koh; Tanaka, Masahiro; Terashima, Hiromi
To evaluate the effectiveness of whole-pelvic hyperthermia (HT) added to standard chemoradiotherapy (CRT) in locally advanced cervical cancer (CC), by investigating the clinical response and survival of patients treated with cisplatin-based CRT vs. CRT with HT (CRT + HT). PMID 27418208

In vitro comparison of conventional hyperthermia and modulated electro-hyperthermia.
Aug. 2016 | Yang, Kai-Lin; Huang, Cheng-Chung; Chi, Mau-Shin; Chiang, Hsin-Chien; Wang, Yu-Shan; Hsia, Chien-Chung; Andocs, Gabor; Wang, Hsin-Ell; Chi, Kwan-Hwa
Radiofrequency-induced hyperthermia (HT) treatments for cancer include conventional capacitive coupling hyperthermia (cCHT) and modulated electro-hyperthermia (mEHT). In this study, we directly compared these methods with regard to in vitro cytotoxicity and mechanisms of action under isothermal conditions. Hepatoma (HepG2) cells were exposed to HT treatment (42°C for 30 min) using mEHT, cCHT or a water bath. mEHT produced a much higher apoptosis rate (43.1% ± 5.8%) than cCHT (10.0% ± 0.6%), the water bath (8.4% ± 1.7%) or a 37°C control (6.6% ± 1.1%). The apoptosis-inducing effect of mEHT at 42°C was similar to that achieved with a water bath at 46°C. mEHT also increased expression of caspase-3, 8 and 9. All three hyperthermia methods increased intracellular heat shock protein 70 (Hsp70) levels, but only mEHT greatly increased the release of Hsp70 from cells. Calreticulin and E-cadherin levels in the cell membrane also increased after mEHT treatment, but not after cCHT or water bath. These results suggest that mEHT selectively deposits energy on the cell membrane and may be a useful treatment modality that targets cancer cell membranes. PMID 27556507

Comparison of biological effects of modulated electro-hyperthermia and conventional heat treatment in human lymphoma U937 cells.
Aug. 2016 | Andocs, G; Rehman, M U; Zhao, Q-L; Tabuchi, Y; Kanamori, M; Kondo, T
Loco-regional hyperthermia treatment has long history in oncology. Modulated electro-hyperthermia (mEHT, trade name: oncothermia) is an emerging curative treatment method in this field due to its highly selective actions. The impedance-matched, capacitive-coupled modulated radiofrequency (RF) current is selectively focused in the malignant cell membrane of the cancer cells. Our objective is studying the cell-death process and comparing the cellular effects of conventional water-bath hyperthermia treatment to mEHT. The U937 human histiocytic lymphoma cell line was used for the experiments. In the case of conventional hyperthermia treatment, cells were immersed in a thermoregulated water bath, whereas in the case of mEHT, the cells were treated using a special RF generator (LabEHY, Oncotherm) and an applicator. The heating dynamics, the maximum temperature reached (42 °C) and the treatment duration (30 min) were exactly the same in both cases. Cell samples were analysed using different flow cytometric methods as well as microarray gene expression assay and western blot analysis was also used to reveal the molecular basis of the induced effects. Definite difference was observed in the biological response to different heat treatments. At 42 °C, only mEHT induced significant apoptotic cell death. The GeneChip analysis revealed a whole cluster of genes, which are highly up-regulated in case of only RF heating, but not in conventional heating. The Fas, c-Jun N-terminal kinases (JNK) and ERK signalling pathway was the dominant factor to induce apoptotic cell death in mEHT, whereas the cell-protective mechanisms dominated in case of conventional heating. This study has clearly shown that conventional hyperthermia and RF mEHT can result in different biological responses at the same temperature. The reason for the difference is the distinct, non-homogenous energy distribution on the cell membrane, which activates cell death-related signalling pathways in mEHT treatment but not in conventional heat treatment. PMID 27551529

Radiofrequency hyperthermia promotes the therapeutic effects on chemotherapeutic-resistant breast cancer when combined with heat shock protein promoter-controlled HSV-TK gene therapy: Toward imaging-guided interventional gene therapy.
Aug. 2016 | Luo, Jingfeng; Wu, Xiaotian; Zhou, Fei; Zhou, Yurong; Huang, Tongchun; Liu, Fei; Han, Guocan; Chen, Luming; Bai, Weixian; Wu, Xia; Sun, Jihong; Yang, Xiaoming
Gene therapy is a frontier in modern medicine. In the present study, we explored a new technique for the effective treatment of multidrug-resistant (MDR) breast cancer by combining fully the advantages of multidisciplinary fields, including image-guided minimally invasive interventional oncology, radiofrequency technology, and direct intratumoral gene therapy. PMID 27542255

Pilot study of radiofrequency hyperthermia in combination with gefitinib in gefitinib-effective patients with advanced NSCLC.
Juli 2016 | Qin, Yijia; Sun, Yu; Liu, Yongmei; Luo, Yiqiao; Zhu, Jiang
Non-small-cell lung cancer (NSCLC) is the leading cause of death from cancer in China. Gefitinib is effective for patients with positive epidermal growth factor receptor gene mutation; however, acquired drug resistance counteracts the duration response. Hyperthermia is widely clinically applied in the treatment of solid tumors. This pilot study was designed to evaluate the feasibility of the combination of gefitinib and hyperthermia. PMID 27385984

Local hyperthermia in head and neck cancer: mechanism, application and advance.
Juli 2016 | Gao, Shiyu; Zheng, Min; Ren, Xiaohua; Tang, Yaling; Liang, Xinhua
Local hyperthermia (HT), particularly in conjunction with surgery, radiotherapy and chemotherapy was useful for the treatment of human malignant tumors including head and neck cancer. However, at present it suffered from many limitations such as thermal dose control, target treatment regions and discrimination between healthy and cancer cells. Recent developments in nanotechnology have introduced novel and smart therapeutic nanomaterials to local HT of head and neck cancer that basically take advantage of various targeting approaches. The aim of this paper is to give a brief review of the mechanism, methods and clinical applications of local HT in head and neck cancer, mainly focusing on photothermal therapy (PTT) and nanoparticle-based hyperthermia. PMID 27384678

Thermosensitive liposomal cisplatin in combination with local hyperthermia results in tumor growth delay and changes in tumor microenvironment in xenograft models of lung carcinoma.
Juni 2016 | Dou, Yannan Nancy; Dunne, Michael; Huang, Huang; Mckee, Trevor; Chang, Martin C; Jaffray, David A; Allen, Christine
Treatment efficacy of a heat-activated thermosensitive liposome formulation of cisplatin (CDDP), known as HTLC, was determined in xenograft models of non-small-cell lung carcinoma. The short-term impact of local hyperthermia (HT) on tumor morphology, microvessel density and local inflammatory response was also evaluated. The HTLC formulation in combination with local HT resulted in a significant advantage in therapeutic effect in comparison with free drug and a non-thermosensitive liposome formulation of CDDP (i.e. Lipoplatin(TM)) when administered at their maximum tolerated doses. Local HT-induced widespread cell necrosis and a significant reduction in microvessel density in the necrotic regions of tumors. CD11b-expressing innate leukocytes were demonstrated to infiltrate and reside preferentially at the necrotic rim of tumors, likely as a means to phagocytose-damaged tissue. Colocalization of CD11b with a marker of DNA damage (i.e. γH2AX) revealed a small portion of CD11b-expressing leukocytes that were possibly undergoing apoptosis as a result of HT-induced damage and/or the short lifespan of leukocytes. Overall, HT-induced tissue damage (i.e. at 24-h post-treatment) alone did not result in significant improvements in treatment effect, rather, the enhancement in tumor drug availability was correlated with improved therapeutic outcomes. PMID 27310112

Electro-hyperthermia up-regulates tumour suppressor Septin 4 to induce apoptotic cell death in hepatocellular carcinoma.
Juni 2016 | Jeon, Tae-Won; Yang, Heebum; Lee, Chang Geol; Oh, Sang Taek; Seo, Daekwan; Baik, In Hye; Lee, Eun Hye; Yun, Ina; Park, Kyung Ran; Lee, Yun-Han
Modulated electro-hyperthermia (mEHT) has been shown to be effective against various types of human tumours, including hepatocellular carcinoma (HCC). Here we aimed to investigate the molecular mechanism underlying the cytotoxic effects of mEHT to HCC cells. PMID 27269053

Heat Shock Protein-Peptide and HSP-Based Immunotherapies for the Treatment of Cancer.
Mai 2016 | Shevtsov, Maxim; Multhoff, Gabriele
Intracellular residing heat shock proteins (HSPs) with a molecular weight of approximately 70 and 90 kDa function as molecular chaperones that assist folding/unfolding and transport of proteins across membranes and prevent protein aggregation after environmental stress. In contrast to normal cells, tumor cells have higher cytosolic heat shock protein 70 and Hsp90 levels, which contribute to tumor cell propagation, metastasis, and protection against apoptosis. In addition to their intracellular chaperoning functions, extracellular localized and membrane-bound HSPs have been found to play key roles in eliciting antitumor immune responses by acting as carriers for tumor-derived immunogenic peptides, as adjuvants for antigen presentation, or as targets for the innate immune system. The interaction of HSP-peptide complexes or peptide-free HSPs with receptors on antigen-presenting cells promotes the maturation of dendritic cells, results in an upregulation of major histocompatibility complex class I and class II molecules, induces secretion of pro- and anti-inflammatory cytokines, chemokines, and immune modulatory nitric oxides, and thus integrates adaptive and innate immune phenomena. Herein, we aim to recapitulate the history and current status of HSP-based immunotherapies and vaccination strategies in the treatment of cancer. PMID 27199993

In Hyperthermia Increased ERK and WNT Signaling Suppress Colorectal Cancer Cell Growth.
Mai 2016 | Bordonaro, Michael; Shirasawa, Senji; Lazarova, Darina L
Although neoplastic cells exhibit relatively higher sensitivity to hyperthermia than normal cells, hyperthermia has had variable success as an anti-cancer therapy. This variable outcome might be due to the fact that cancer cells themselves have differential degrees of sensitivity to high temperature. We hypothesized that the varying sensitivity of colorectal cancer (CRC) cells to hyperthermia depends upon the differential induction of survival pathways. Screening of such pathways revealed that Extracellular Signal-Regulated Kinase (ERK) signaling is augmented by hyperthermia, and the extent of this modulation correlates with the mutation status of V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS). Through clonal growth assays, apoptotic analyses and transcription reporter assays of CRC cells that differ only in KRAS mutation status we established that mutant KRAS cells are more sensitive to hyperthermia, as they exhibit sustained ERK signaling hyperactivation and increased Wingless/Integrated (WNT)/beta-catenin signaling. We propose that whereas increased levels of WNT and ERK signaling and a positive feedback between the two pathways is a major obstacle in anti-cancer therapy today, under hyperthermia the hyperinduction of the pathways and their positive crosstalk contribute to CRC cell death. Ascertaining the causative association between types of mutations and hyperthermia sensitivity may allow for a mutation profile-guided application of hyperthermia as an anti-cancer therapy. Since KRAS and WNT signaling mutations are prevalent in CRC, our results suggest that hyperthermia-based therapy might benefit a significant number, but not all, CRC patients. PMID 27187477

Hyperthermia: How Can It Be Used?
Mai 2016 | Behrouzkia, Zhaleh; Joveini, Zahra; Keshavarzi, Behnaz; Eyvazzadeh, Nazila; Aghdam, Reza Zohdi
Hyperthermia (HT) is a method used to treat tumors by increasing the temperature of the cells. The treatment can be applied in combination with other verified cancer treatments using several different procedures. We sought to present an overview of the different HT tumor treatment, recent advances in the field, and combinational treatment sequences and outcomes. We used a computer-aided search to identify articles that contained the keywords hyperthermia, cancer treatment, chemotherapy, radiotherapy, nanoparticle, and cisplatin. There are three types of HT treatment, which each need the use of applicators that are in contact with or in the proximity of the patient for the purpose of heating. Heating can be achieved using different types of energy (including microwaves, radio waves, and ultrasound). However, the source of energy will depend on the cancer type and location. The temperature used will also vary. HT is rarely used alone, and can be combined with other cancer treatments. When used in combination with other treatments, improved survival rates have been observed. However, despite in vitro and in vivo studies that support the use of concurrent hypothermia treatments, contradictory results suggest there is a need for more studies to identify other hidden effects of HT. PMID 27168918

Prospective phase II trial of regional hyperthermia and whole liver irradiation for numerous chemorefractory liver metastases from colorectal cancer.
Apr. 2016 | Yu, Jeong Il; Park, Hee Chul; Choi, Doo Ho; Noh, Jae Myoung; Oh, Dongryul; Park, Jun Su; Chang, Ji Hyun; Kim, Seung Tae; Lee, Jeeyun; Park, Se Hoon; Park, Joon Oh; Park, Young Suk; Lim, Ho Yeong; Kang, Won Ki
A prospective phase II trial was conducted to evaluate the effectiveness and toxicity of regional hyperthermia and whole liver irradiation (WLI) for numerous chemorefractory liver metastases from colorectal cancer. PMID 27104165

Improving efficacy of hyperthermia in oncology by exploiting biological mechanisms.
Apr. 2016 | van den Tempel, Nathalie; Horsman, Michael R; Kanaar, Roland
It has long been established that hyperthermia increases the therapeutic benefit of radiation and chemotherapy in cancer treatment. During the last few years there have been substantial technical improvements in the sources used to apply and measure heat, which greatly increases enthusiasm for the clinical use of hyperthermia. These advances are converging with a better understanding of the physiological and molecular effects of hyperthermia. Therefore, we are now at a juncture where the parameters that will influence the efficacy of hyperthermia in cancer treatment can be optimised in a more systematic and rational manner. In addition, the novel insights in hyperthermia's many biological effects on tumour cells will ultimately result in new treatment regimes. For example, the molecular effects of hyperthermia on the essential cellular process of DNA repair suggest novel combination therapies, with DNA damage response targeting drugs that should now be clinically explored. Here, we provide an overview of recent studies on the various macroscopic and microscopic biological effects of hyperthermia. We indicate the significance of these effects on current treatments and suggest how they will help design novel future treatments. PMID 27086587

Effects of hyperthermia as a mitigation strategy in DNA damage-based cancer therapies.
Apr. 2016 | Mantso, Theodora; Goussetis, George; Franco, Rodrigo; Botaitis, Sotiris; Pappa, Aglaia; Panayiotidis, Mihalis
Utilization of thermal therapy (hyperthermia) is defined as the application of exogenous heat induction and represents a concept that is far from new as it goes back to ancient times when heat was used for treating various diseases, including malignancies. Such therapeutic strategy has gained even more popularity (over the last few decades) since various studies have shed light into understanding hyperthermia's underlying molecular mechanism(s) of action. In general, hyperthermia is applied as complementary (adjuvant) means in therapeutic protocols combining chemotherapy and/or irradiation both of which can induce irreversible cellular DNA damage. Furthermore, according to a number of in vitro, in vivo and clinical studies, hyperthermia has been shown to enhance the beneficial effects of DNA targeting therapeutic strategies by interfering with DNA repair response cascades. Therefore, the continuously growing evidence supporting hyperthermia's beneficial role in cancer treatment can also encourage its application as a DNA repair mitigation strategy. In this review article, we aim to provide detailed information on how hyperthermia acts on DNA damage and repair pathways and thus potentially contributing to various adjuvant therapeutic protocols relevant to more efficient cancer treatment strategies. PMID 27025900

Exploiting the Immunogenic Potential of Cancer Cells for Improved Dendritic Cell Vaccines.
Feb. 2016 | Vandenberk, Lien; Belmans, Jochen; Van Woensel, Matthias; Riva, Matteo; Van Gool, Stefaan W
Cancer immunotherapy is currently the hottest topic in the oncology field, owing predominantly to the discovery of immune checkpoint blockers. These promising antibodies and their attractive combinatorial features have initiated the revival of other effective immunotherapies, such as dendritic cell (DC) vaccinations. Although DC-based immunotherapy can induce objective clinical and immunological responses in several tumor types, the immunogenic potential of this monotherapy is still considered suboptimal. Hence, focus should be directed on potentiating its immunogenicity by making step-by-step protocol innovations to obtain next-generation Th1-driving DC vaccines. We review some of the latest developments in the DC vaccination field, with a special emphasis on strategies that are applied to obtain a highly immunogenic tumor cell cargo to load and to activate the DCs. To this end, we discuss the effects of three immunogenic treatment modalities (ultraviolet light, oxidizing treatments, and heat shock) and five potent inducers of immunogenic cell death [radiotherapy, shikonin, high-hydrostatic pressure, oncolytic viruses, and (hypericin-based) photodynamic therapy] on DC biology and their application in DC-based immunotherapy in preclinical as well as clinical settings. PMID 26834740

Eliciting cytotoxic T lymphocytes against human laryngeal cancer-derived antigens: evaluation of dendritic cells pulsed with a heat-treated tumor lysate and other antigen-loading strategies for dendritic-cell-based vaccination.
Jan. 2016 | Wei, Fan-Qin; Sun, Wei; Wong, Thian-Sze; Gao, Wei; Wen, Yi-Hui; Wei, Jia-Wei; Wei, Yi; Wen, Wei-Ping
Dendritic cells (DCs) have been used successfully in clinical pilot studies. However, tumor-specific immunity and clinical responses were only induced in certain cancer patients. It has been well documented that immunotherapy efficacy can be optimized for responses using antigen pulsing. PMID 26795730

Reirradiation and hyperthermia for irresectable locoregional recurrent breast cancer in previously irradiated area: Size matters.
Dez. 2015 | Oldenborg, Sabine; Griesdoorn, Vanessa; van Os, Rob; Kusumanto, Yoka H; Oei, Bing S; Venselaar, Jack L; Zum Vörde Sive Vörding, Paul J; Heymans, Martijn W; Kolff, Merel Willemijn; Rasch, Coen R N; Crezee, Hans; van Tienhoven, Geertjan
Treatment options for irresectable locoregional recurrent breast cancer in previously irradiated area are limited. Hyperthermia, elevating tumor temperature to 40-45°C, sensitizes radio-and-chemotherapy. Four hundred and fourteen patients treated with reirradiation+hyperthermia (reRT+HT) in the AMC(n=301) and the BVI(n=113), from 1982 to 2005 were retrospectively analyzed for treatment response, locoregional control (LC) and prognostic factors for LC and toxicity. PMID 26542015

Local hyperthermia combined with radiotherapy and-/or chemotherapy: Recent advances and promises for the future.
Okt. 2015 | Datta, N R; Ordóñez, S Gómez; Gaipl, U S; Paulides, M M; Crezee, H; Gellermann, J; Marder, D; Puric, E; Bodis, S
Hyperthermia, one of the oldest forms of cancer treatment involves selective heating of tumor tissues to temperatures ranging between 39 and 45°C. Recent developments based on the thermoradiobiological rationale of hyperthermia indicate it to be a potent radio- and chemosensitizer. This has been further corroborated through positive clinical outcomes in various tumor sites using thermoradiotherapy or thermoradiochemotherapy approaches. Moreover, being devoid of any additional significant toxicity, hyperthermia has been safely used with low or moderate doses of reirradiation for retreatment of previously treated and recurrent tumors, resulting in significant tumor regression. Recent in vitro and in vivo studies also indicate a unique immunomodulating prospect of hyperthermia, especially when combined with radiotherapy. In addition, the technological advances over the last decade both in hardware and software have led to potent and even safer loco-regional hyperthermia treatment delivery, thermal treatment planning, thermal dose monitoring through noninvasive thermometry and online adaptive temperature modulation. The review summarizes the outcomes from various clinical studies (both randomized and nonrandomized) where hyperthermia is used as a thermal sensitizer of radiotherapy and-/or chemotherapy in various solid tumors and presents an overview of the progresses in loco-regional hyperthermia. These recent developments, supported by positive clinical outcomes should merit hyperthermia to be incorporated in the therapeutic armamentarium as a safe and an effective addendum to the existing oncological treatment modalities. PMID 26051911

Improving immunological tumor microenvironment using electro-hyperthermia followed by dendritic cell immunotherapy.
Okt. 2015 | Tsang, Yuk-Wah; Huang, Cheng-Chung; Yang, Kai-Lin; Chi, Mau-Shin; Chiang, Hsin-Chien; Wang, Yu-Shan; Andocs, Gabor; Szasz, Andras; Li, Wen-Tyng; Chi, Kwan-Hwa
The treatment of intratumoral dentritic cells (DCs) commonly fails because it cannot evoke immunity in a poor tumor microenvironment (TME). Modulated electro-hyperthermia (mEHT, trade-name: oncothermia) represents a significant technological advancement in the hyperthermia field, allowing the autofocusing of electromagnetic power on a cell membrane to generate massive apoptosis. This approach turns local immunogenic cancer cell death (apoptosis) into a systemic anti-tumor immune response and may be implemented by treatment with intratumoral DCs. PMID 26472466

Electro-hyperthermia inhibits glioma tumorigenicity through the induction of E2F1-mediated apoptosis.
Okt. 2015 | Cha, Jihye; Jeon, Tae-Won; Lee, Chang Geol; Oh, Sang Taek; Yang, Hee-Beom; Choi, Kyung-Ju; Seo, Daekwan; Yun, Ina; Baik, In Hye; Park, Kyung Ran; Park, Young Nyun; Lee, Yun-Han
Modulated electro-hyperthermia (mEHT), also known as oncothermia, shows remarkable treatment efficacies for various types of tumours, including glioma. The aim of the present study was to investigate the molecular mechanism underlying phenotypic changes in oncothermic cancer cells. PMID 26367194

Hyperthermia induces apoptosis by targeting Survivin in esophageal cancer.
Okt. 2015 | Qin, Sida; Xu, Chongwen; Li, Shuo; Wang, Xifang; Sun, Xin; Wang, Peili; Zhang, Boxiang; Ren, Hong
Hyperthermia is considered the fifth pillar of cancer treatment. It induces cancer cell apoptosis, however, its molecular mechanisms remain unclear. In the present study, the role of Survivin in hyperthermia-induced apoptosis in esophageal cancer was investigated. Different temperatures were used to treat EC109 esophageal cancer cells, and their viability was found to be significantly inhibited with a concomitant increase in apoptosis and necrosis. Necrosis increased in a temperature‑dependent manner, whereas peak apoptosis was reached at 43˚C. The hyperthermia-induced apoptosis was due to the inhibition of Survivin and the activation of caspase-3. Subsequently, overexpression of Survivin inhibited the activation of caspase-3 and hyperthermia-induced apoptosis, however, this inhibition was reversed in the absence of XIAP. Immunoprecipitations showed that Survivin did not directly bind to caspase-3, whereas XIAP interacted with Survivin and caspase-3. Immunohistochemistry was performed to detect the expression of Survivin in esophageal cancer patient samples. A higher expression of Survivin in esophageal cancer tissues compared to normal tissues was observed, and a high expression correlated with poor prognosis. The results indicated that hyperthermia decreases the expression of Survivin, prevents its binding to XIAP, activates caspase-3 and induces apoptosis. Due to its correlation with poor prognosis, Survivin may be a target for hyperthermia in the treatment of esophageal cancer. PMID 26352384

Hyperthermia: an effective strategy to induce apoptosis in cancer cells.
Sep. 2015 | Ahmed, Kanwal; Tabuchi, Yoshiaki; Kondo, Takashi
Heat has been used as a medicinal and healing modality throughout human history. The combination of hyperthermia (HT) with radiation and anticancer agents has been used clinically and has shown positive results to a certain extent. However, the clinical results of HT treatment alone have been only partially satisfactory. Cell death following HT treatment is a function of both temperature and treatment duration. HT induces cancer cell death through apoptosis; the degree of apoptosis and the apoptotic pathway vary in different cancer cell types. HT-induced reactive oxygen species production are responsible for apoptosis in various cell types. However, the underlying mechanism of signal transduction and the genes related to this process still need to be elucidated. In this review, we summarize the molecular mechanism of apoptosis induced by HT, enhancement of heat-induced apoptosis, and the genetic network involved in HT-induced apoptosis. PMID 26354715

Long-term survival of a breast cancer patient with extensive liver metastases upon immune and virotherapy: a case report.
Sep. 2015 | Schirrmacher, Volker; Stücker, Wilfried; Lulei, Maria; Bihari, Akos-Sigmund; Sprenger, Tobias
Liver metastases in breast cancer are associated with a poor prognosis. We report long-term survival of a patient with breast cancer and liver metastases. After operation the patient declined further standard therapy. Instead, she was treated with local hyperthermia, Newcastle disease virus and dendritic cell vaccination at the Immunological and Oncological Center Cologne (IOZK), Germany. A continuous high quality of life was reported and the patient survived more than 66 months after initial diagnosis. No recurrence or further metastases developed under treatment. Following treatment, a long-lasting tumor-reactive memory T-cell responsiveness could be documented. This possibly explains the favorable course of disease. Since this combination of therapies is not restricted to a particular tumor type, further exploration is warranted. PMID 26020523

Hyperthermia-related clinical trials on cancer treatment within the registry.
Sep. 2015 | Cihoric, Nikola; Tsikkinis, Alexandros; van Rhoon, Gerard; Crezee, Hans; Aebersold, Daniel M; Bodis, Stephan; Beck, Marcus; Nadobny, Jacek; Budach, Volker; Wust, Peter; Ghadjar, Pirus
Hyperthermia has been shown to improve the effectiveness of chemotherapy and radiotherapy in the treatment of cancer. This paper summarises all recent clinical trials registered in the registry. PMID 25975276

Hyperthermia Is Now Included in the NCCN Clinical Practice Guidelines for Breast Cancer Recurrences: An Analysis of Existing Data.
Juli 2015 | Kouloulias, Vassilis; Triantopoulou, Sotiria; Uzunoglou, Nikolaos; Pistevou-Gompaki, Kyriaki; Barich, Alfred; Zygogianni, Anna; Kyrgias, George; Kardamakis, Dimitris; Pectasidis, Dimitris; Kouvaris, John; ,
Hyperthermia has been included in the 2013 National Comprehensive Cancer Network (NCCN) guidelines as an option for the treatment of breast recurrences. The purpose of this article is to demonstrate the important role of hyperthermia as a therapeutic modality by presenting clinical trials on this subject carried out in the last decades. PMID 26195939

Concomitant trimodality therapy of re-irradiation, chemotherapy and regional hyperthermia for a pretreated inoperable sarcoma recurrence.
Juli 2015 | LI, Minglun; Andrä, Claudia; Niyazi, Maximilian; Issels, Rolf D; Abdel-Rahman, Sultan; Oskan, Feras; Manapov, Farkhad
We hereby present a case of pre-treated unresectable sarcoma recurrence of the trunk which showed an excellent response to concomitant tri-modal therapy, consisting of re-irradiation, chemotherapy and regional hyperthermia even with a strong compromised re-irradiation dose. No significant toxicity of the combined therapy and fast achievement of the pain and neurological symptoms relief are reported. The case shows that concurrent tri-modality treatment can be considered as a therapeutic option for the management of pre-treated unresectable recurrence even in there-irradiation setting. PMID 25838253

Hyperthermia and radiation therapy for locally advanced or recurrent breast cancer.
Juni 2015 | Refaat, Tamer; Sachdev, Sean; Sathiaseelan, Vythialinga; Helenowski, Irene; Abdelmoneim, Salah; Pierce, Margaret C; Woloschak, Gayle; Small, William; Mittal, Bharat; Kiel, Krystyna D
This study aims to report the outcome and toxicity of combined hyperthermia (HT) and radiation therapy (RT) in treatment of locally advanced or loco-regionally recurrent breast cancer. PMID 25900383

Hyperthermia combined with 5-fluorouracil promoted apoptosis and enhanced thermotolerance in human gastric cancer cell line SGC-7901.
Juni 2015 | Liu, Tao; Ye, Yan-Wei; Zhu, A-Li; Yang, Zhen; Fu, Yang; Wei, Chong-Qing; Liu, Qi; Zhao, Chun-Lin; Wang, Guo-Jun; Zhang, Xie-Fu
This study was designed to investigate the proliferation inhibition and apoptosis-promoting effect under hyperthermia and chemotherapy treatment, at cellular level. Human gastric cancer cell line SGC-7901 was cultivated with 5-fluorouracil at different temperatures. Cell proliferation and apoptosis were determined, and expression of Bcl-2 and HSP70 was measured at different treatments. Cell survival rates and inhibition rates in chemotherapy group, thermotherapy group, and thermo-chemotherapy group were drastically lower than the control group (P<0.05). For tumor cells in the thermo-chemotherapy group, survival rates and inhibition rates at three different temperatures were all significantly lower than those in chemotherapy group and thermotherapy group (P<0.05). 5-Fluorouracil induced apoptosis of SGC-7901 cells with a strong temperature dependence, which increased gradually with increase in temperature. At 37°C and 43°C there were significant differences between the thermotherapy group and chemotherapy group and between the thermo-chemotherapy group and thermotherapy group (P<0.01). The expression of Bcl-2 was downregulated and HSP70 was upregulated, with increase in temperature in all groups. Cell apoptosis was not significant at 46°C (P>0.05), which was probably due to thermotolerance caused by HSP70 accumulation. These results suggested that hyperthermia combined with 5-fluorouracil had a synergistic effect in promoting apoptosis and enhancing thermotolerance in gastric cancer cell line SGC-7901. PMID 26064061

Local control rate after the combination of re-irradiation and hyperthermia for irresectable recurrent breast cancer: Results in 248 patients.
Mai 2015 | Linthorst, Marianne; Baaijens, Margreet; Wiggenraad, Ruud; Creutzberg, Carien; Ghidey, Wendimagegn; van Rhoon, Gerard C; van der Zee, Jacoba
Randomized studies have shown that adding hyperthermia (HT) to re-irradiation (re-RT) improves treatment outcome for patients with breast cancer recurrences. We evaluated the efficacy and side effects in patients treated with re-RT and HT for irresectable locoregional breast cancer recurrences. PMID 26002305

Hyperthermia Sensitizes Glioma Stem-like Cells to Radiation by Inhibiting AKT Signaling.
Apr. 2015 | Man, Jianghong; Shoemake, Jocelyn D; Ma, Tuopu; Rizzo, Anthony E; Godley, Andrew R; Wu, Qiulian; Mohammadi, Alireza M; Bao, Shideng; Rich, Jeremy N; Yu, Jennifer S
Glioma stem-like cells (GSC) are a subpopulation of cells in tumors that are believed to mediate self-renewal and relapse in glioblastoma (GBM), the most deadly form of primary brain cancer. In radiation oncology, hyperthermia is known to radiosensitize cells, and it is reemerging as a treatment option for patients with GBM. In this study, we investigated the mechanisms of hyperthermic radiosensitization in GSCs by a phospho-kinase array that revealed the survival kinase AKT as a critical sensitization determinant. GSCs treated with radiation alone exhibited increased AKT activation, but the addition of hyperthermia before radiotherapy reduced AKT activation and impaired GSC proliferation. Introduction of constitutively active AKT in GSCs compromised hyperthermic radiosensitization. Pharmacologic inhibition of PI3K further enhanced the radiosensitizing effects of hyperthermia. In a preclinical orthotopic transplant model of human GBM, thermoradiotherapy reduced pS6 levels, delayed tumor growth, and extended animal survival. Together, our results offer a preclinical proof-of-concept for further evaluation of combined hyperthermia and radiation for GBM treatment. PMID 25712125

Hyperthermia combined with chemotherapy for patients with residual or recurrent oesophageal cancer after definitive chemoradiotherapy.
Apr. 2015 | Nishimura, Sho; Saeki, Hiroshi; Nakanoko, Tomonori; Kasagi, Yuta; Tsuda, Yasuo; Zaitsu, Yoko; Ando, Koji; Nakashima, Yuichiro; Imamura, Y U; Ohgaki, Kippei; Oki, Eiji; Ohga, Saiji; Nakamura, Katsumasa; Morita, Masaru; Maehara, Yoshihiko
Definitive chemoradiotherapy (dCRT) is frequently administered in oesophageal cancer. We carried out hyperthermochemotherapy (HCT) for residual or recurrent cases after dCRT for oesophageal cancer. The aim of this study was to elucidate the usefulness of salvage HCT for these patients. PMID 25862892

PET response criteria in solid tumors predicts progression-free survival and time to local or distant progression after chemotherapy with regional hyperthermia for soft-tissue sarcoma.
Apr. 2015 | Fendler, Wolfgang P; Lehmann, Mona; Todica, Andrei; Herrmann, Ken; Knösel, Thomas; Angele, Martin K; Dürr, Hans Roland; Rauch, Josefine; Bartenstein, Peter; Cyran, Clemens C; Hacker, Marcus; Lindner, Lars H
We evaluated the prognostic accuracy of established PET and CT response criteria in patients with soft-tissue sarcoma (STS) after combined chemotherapy plus regional hyperthermia (RHT). PMID 25722445

Hyperthermia restores apoptosis induced by death receptors through aggregation-induced c-FLIP cytosolic depletion.
Feb. 2015 | Morlé, A; Garrido, C; Micheau, O
TRAIL is involved in immune tumor surveillance and is considered a promising anti-cancer agent owing to its limited side effects on healthy cells. However, some cancer cells display resistance, or become resistant to TRAIL-induced cell death. Hyperthermia can enhance sensitivity to TRAIL-induced cell death in various resistant cancer cell lines, including lung, breast, colon or prostate carcinomas. Mild heat shock treatment has been proposed to restore Fas ligand or TRAIL-induced apoptosis through c-FLIP degradation or the mitochondrial pathway. We demonstrate here that neither the mitochondria nor c-FLIP degradation are required for TRAIL-induced cell death restoration during hyperthermia. Our data provide evidence that insolubilization of c-FLIP, alone, is sufficient to enhance apoptosis induced by death receptors. Hyperthermia induced c-FLIP depletion from the cytosolic fraction, without apparent degradation, thereby preventing c-FLIP recruitment to the TRAIL DISC and allowing efficient caspase-8 cleavage and apoptosis. Hyperthermia-induced c-FLIP depletion was independent of c-FLIP DED2 FL chain assembly motif or ubiquitination-mediated c-FLIP degradation, as assessed using c-FLIP point mutants on lysine 167 and 195 or threonine 166, a phosphorylation site known to regulate ubiquitination of c-FLIP. Rather, c-FLIP depletion was associated with aggregation, because addition of glycerol not only prevented the loss of c-FLIP from the cytosol but also enabled c-FLIP recruitment within the TRAIL DISC, thus inhibiting TRAIL-induced apoptosis during hyperthermia. Altogether our results demonstrate that c-FLIP is a thermosensitive protein whose targeting by hyperthermia allows restoration of apoptosis induced by TNF ligands, including TRAIL. Our findings suggest that combining TRAIL agonists with whole-body or localized hyperthermia may be an interesting approach in cancer therapy. PMID 25675293

Overexpression of heat shock protein 27 (HSP27) increases gemcitabine sensitivity in pancreatic cancer cells through S-phase arrest and apoptosis.
Jan. 2015 | Guo, Yang; Ziesch, Andreas; Hocke, Sandra; Kampmann, Eric; Ochs, Stephanie; De Toni, Enrico N; Göke, Burkhard; Gallmeier, Eike
We previously established a role for HSP27 as a predictive marker for therapeutic response towards gemcitabine in pancreatic cancer. Here, we investigate the underlying mechanisms of HSP27-mediated gemcitabine sensitivity. Utilizing a pancreatic cancer cell model with stable HSP27 overexpression, cell cycle arrest and apoptosis induction were analysed by flow cytometry, nuclear staining, immunoblotting and mitochondrial staining. Drug sensitivity studies were performed by proliferation assays. Hyperthermia was simulated using mild heat shock at 41.8°C. Upon gemcitabine treatment, HSP27-overexpressing cells displayed an early S-phase arrest subsequently followed by a strongly increased sub-G1 fraction. Apoptosis was characterized by PARP-, CASPASE 3-, CASPASE 8-, CASPASE 9- and BIM- activation along with a mitochondrial membrane potential loss. It was reversible through chemical caspase inhibition. Importantly, gemcitabine sensitivity and PARP cleavage were also elicited by heat shock-induced HSP27 overexpression, although to a smaller extent, in a panel of pancreatic cancer cell lines. Finally, HSP27-overexpressing pancreatic cancer cells displayed an increased sensitivity also towards death receptor-targeting agents, suggesting another pro-apoptotic role of HSP27 along the extrinsic apoptosis pathway. Taken together, in contrast to the well-established anti-apoptotic properties of HSP27 in cancer, our study reveals novel pro-apoptotic functions of HSP27-mediated through both the intrinsic and the extrinsic apoptotic pathways-at least in pancreatic cancer cells. HSP27 could represent a predictive marker of therapeutic response towards specific drug classes in pancreatic cancer and provides a novel molecular rationale for current clinical trials applying the combination of gemcitabine with regional hyperthermia in pancreatic cancer patients. PMID 25331547

Hyperthermia, radiation and chemotherapy: the role of heat in multidisciplinary cancer care.
Dez. 2014 | Hurwitz, Mark; Stauffer, Paul
The compelling biologic basis for combining hyperthermia with modern cancer therapies including radiation and chemotherapy was first appreciated nearly half a century ago. Hyperthermia complements radiation as conditions contributing to radio-resistance generally enhance sensitivity to heat and sensitizing effects occur through increased perfusion/tumor oxygenation and alteration of cellular death pathways. Chemosensitization with hyperthermia is dependent on the particular mechanism of effect for each agent with synergistic effects noted for several commonly used agents. Clinically, randomized trials have demonstrated benefit including survival with the addition of hyperthermia to radiation or chemotherapy in treatment of a wide range of malignancies. Improvements in treatment delivery techniques, streamlined logistics, and greater understanding of the relationship of thermal dosimetry to treatment outcomes continue to facilitate wider clinical implementation. Evolving applications include thermal enhancement of immunotherapy, targeted drug delivery and application of principals of thermal biology towards integration of thermal ablation into multimodality oncologic care. PMID 25499632

Thermotolerance induced at a mild temperature of 40°C alleviates heat shock-induced ER stress and apoptosis in HeLa cells.
Dez. 2014 | Bettaieb, Ahmed; Averill-Bates, Diana A
Hyperthermia (39-45°C) has emerged as an alternate prospect for cancer therapy in combination with radiation and chemotherapy. Despite promising progress in the clinic, molecular mechanisms involved in hyperthermia-induced cell death are not clear. Hyperthermia causes protein denaturation/aggregation, which results in cell death by apoptosis and/or necrosis. Hyperthermia also induces thermotolerance, which renders cells resistant to subsequent exposure to lethal heat shock. This study investigates the role of both lethal (42-43°C) and mild (40°C) hyperthermia in regulating ER stress and ER stress-induced apoptosis in HeLa cells. The ability of mild thermotolerance induced at 40°C to alleviate either or both of these processes is also determined. Hyperthermia (42-43°C) induced ER stress, revealed by phosphorylation of PERK, eIF2α and IRE1α, cleavage of ATF6 and increased expression of BiP and sXBP1. Real-time PCR revealed that mRNA levels of ATF6, ATF4, BiP, sXBP1 and CHOP increased in cells exposed to hyperthermia. Moreover, hyperthermia caused disruption of calcium homeostasis and activated the calpain-calpastatin proteolytic system and ER resident caspase 4. Pre-exposure to mild hyperthermia (40°C) alleviated the induction of cytotoxicity and ER stress by hyperthermia (42-43°C) and protected cells against ER stress-induced apoptosis. ShRNA-mediated depletion of Hsp72 abrogated protective effects of mild thermotolerance (40°C) against heat-shock induced ER stress and sensitized cells to ER stress-mediated apoptosis. Our findings show that Hsp72 contributes to the protective effects of mild hyperthermia (40°C) against hyperthermia-induced ER stress and apoptosis. PMID 25260982

Local tumour hyperthermia as immunotherapy for metastatic cancer.
Nov. 2014 | Toraya-Brown, Seiko; Fiering, Steven
Abstract Local tumour hyperthermia for cancer treatment is currently used either for ablation purposes as an alternative to surgery or less frequently, in combination with chemotherapy and/or radiation therapy to enhance the effects of those traditional therapies. As it has become apparent that activating the immune system is crucial to successfully treat metastatic cancer, the potential of boosting anti-tumour immunity by heating tumours has become a growing area of cancer research. After reviewing the history of hyperthermia therapy for cancer and introducing methods for inducing local hyperthermia, this review describes different mechanisms by which heating tumours can elicit anti-tumour immune responses, including tumour cell damage, tumour surface molecule changes, heat shock proteins, exosomes, direct effects on immune cells, and changes in the tumour vasculature. We then go over in vivo studies that provide promising results showing that local hyperthermia therapy indeed activates various systemic anti-tumour immune responses that slow growth of untreated tumours. Finally, future research questions that will help bring the use of local hyperthermia as systemic immunotherapy closer to clinical application are discussed. PMID 25430985

Inhibition of cell proliferation by mild hyperthermia at 43˚C with Paris Saponin I in the lung adenocarcinoma cell line PC-9.
Nov. 2014 | Zhao, Pengjun; Jiang, Hao; Su, Dan; Feng, Jianguo; Ma, Shenglin; Zhu, Xinhai
Rhizoma paridis is widely used for cancer therapy due to its potential involvement in the suppression of tumor growth. However, at present there is no clear explanation for the mechanism underlying the inhibitory effects of Rhizoma paridis combined with hyperthermia on tumor growth. The aim of the present study was to evaluate the effects of Paris saponin I (PSI) combined with hyperthermia on a variety of non-small cell lung cancer (NSCLC) cell lines. An MTT assay was used to determine the levels of growth inhibition. The cell cycle was analyzed using flow cytometry and cell apoptosis was analyzed with Annexin V/propidium iodide staining and the Hoechst assay. The morphology of cells during apoptosis was determined using a transmission electron microscope. The expression levels of B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax) and caspase-3 proteins were detected using western blotting. The inhibition rates significantly increased with PSI in combination with hyperthermia at 43˚C. PSI with hyperthermia at 43˚C caused G2/M phase arrest and significantly induced apoptosis. The expression level of Bcl-2 decreased, while Bax expression increased following treatment with PSI with hyperthermia at 43˚C. In addition, the protein expression of caspase-3 was significantly enhanced. PSI combined with hyperthermia is a potent antitumor treatment through the inhibition of proliferation of NSCLC cells and may be developed as a new antitumor therapy. PSI combined with hyperthermia significantly induced apoptosis through a multi regulatory process involving G2/M arrest and regulation of Bax, Bcl-2 and caspase-3 expression, resulting in cell death and tumor inhibition. PMID 25322761

Long-term remission of prostate cancer with extensive bone metastases upon immuno- and virotherapy: A case report.
Nov. 2014 | Schirrmacher, Volker; Bihari, Akos-Sigmund; Stücker, Wilfried; Sprenger, Tobias
The present study reports the case of a patient with hormone-refractory metastatic prostate cancer who had failed standard therapy, but then achieved complete remission following combined treatment with local hyperthermia (LHT), Newcastle disease virus and dendritic cell (DC) vaccination, which was an unusual combination. In August 2005, the patient underwent a radical prostatectomy. Despite standard treatment, the patient developed progressive bone metastases and stopped conventional therapy in June 2007. Starting in October 2007, the patient was treated with LHT, oncolytic virotherapy and DC vaccination. Prostate-specific antigen (PSA)-levels, with the highest level of 233.8 ng/ml in January 2008, decreased to 0.8 ng/ml in late February 2008. In March 2008, a reduction in bone metastases could be detected by positron emission tomography/computed tomography. Since then, the PSA levels have remained low and the patient is doing well. The treatment induced a long-lasting antitumor memory T-cell response. This possibly explains the long-term effectiveness of this novel experimental combined treatment approach. PMID 25364402

Modulated electro-hyperthermia enhances dendritic cell therapy through an abscopal effect in mice.
Okt. 2014 | Qin, Wei; Akutsu, Yasunori; Andocs, Gabor; Suganami, Akiko; Hu, Xin; Yusup, Gulbostan; Komatsu-Akimoto, Aki; Hoshino, Isamu; Hanari, Naoyuki; Mori, Mikito; Isozaki, Yuka; Akanuma, Naoki; Tamura, Yutaka; Matsubara, Hisahiro
The aim of this study was to assess whether modulated electro-hyperthermia (mEHT) can induce an abscopal effect and thereby enhance the antitumor effects of immunotherapy. We used an intratumoral dendritic cell (DC) injection and mEHT to treat C3H/He mice inoculated with squamous cell carcinoma SCCVII cells in the left leg, and we assessed the whole body antitumor effects. Tumors were examined every two or three days in order to assess growth inhibition. The tumor-draining lymph nodes were removed to enable flow cytometric analysis of CD3+ and CD8+ cells, whereas immunohistochemistry was used to assess CD8, S100 and Foxp3 expression in the tumors. Additionally, GP96 expression in the tumors from the different treatment groups was measured. In the control group, the mean tumor volume was larger than that in other groups. These results indicated that the combination therapy of an intratumoral DC injection and mEHT evoked systemic antitumor activity. A larger number of CD3+ and CD8+ cells were detected by flow cytometric analysis in the DC plus mEHT treatment group. Tumor tissue immunostaining showed that CD8 and S100 were more strongly expressed in the DC plus mEHT treatment group, although Foxp3 expression was much higher in the control group. The GP96 gene expression level in the mEHT group was significantly different from the expression level in the control group. An abscopal effect may be induced by mEHT, and the effect of immunotherapy with DCs was strongly enhanced by the overexpression of GP96. GP96 is thought to be one of the molecules explaining the abscopal effect. Direct intratumoral administration of DCs and mEHT may be a feasible future treatment strategy. PMID 25242303

[The effect of immunotherapy and hyperthermia on patients with advanced or recurrent cancer - analyses by cancer type and recurrence form].
Okt. 2014 | Takeda, Tsutomu; Nakamura, Kana; Sato, Mitsuyuki; Takeda, Takashi; Tomimaru, Yoshihito; Takeda, Hiroko
We treated 1,939 patients with advanced or recurrent cancer using hyperthermia and or immunotherapy between July 2005 and November 2013. Standard therapy showed no effect or was refused by these patients. There were 309(15.9%)patients who experienced a clinical benefit(complete response[CR], partial response[PR], and long-term stable disease[SD], >6 months), including 52 CR cases. The effective rate of immunotherapy increased from 9.9%to 19.1%using hyperthermia. The effective rate for patients with hyperthermia-alone was 3.6%, and skin and regional lymph node metastases disappeared. Immunotherapy alone was effective for liver or lung metastases. Combined hyperthermia and immunotherapy had a beneficial effect on multiple metastases observed in important plural solid organs. Ovarian cancer had the highest effective rate (25.0%), followed by prostate cancer. PMID 25335711

Noninvasive radiofrequency treatment effect on mitochondria in pancreatic cancer cells.
Okt. 2014 | Curley, Steven A; Palalon, Flavio; Lu, Xiaolin; Koshkina, Nadezhda V
The development of novel therapeutic approaches for cancer therapy is important, especially for tumors that have poor response or develop resistance to standard chemotherapy and radiation. We discovered that noninvasive radiofrequency (RF) fields can affect cancer cells but not normal cells, inhibit progression of tumors in mice, and enhance the anticancer effects of chemotherapy. However, it remains unclear what physiological and molecular mechanisms this treatment induces inside cells. Here, we studied the effect of RF treatment on mitochondria in human pancreatic cancer cells. PMID 24986120

Hyperthermia induces apoptosis through endoplasmic reticulum and reactive oxygen species in human osteosarcoma cells.
Okt. 2014 | Hou, Chun-Han; Lin, Feng-Ling; Hou, Sheng-Mon; Liu, Ju-Fang
Osteosarcoma (OS) is a relatively rare form of cancer, but OS is the most commonly diagnosed bone cancer in children and adolescents. Chemotherapy has side effects and induces drug resistance in OS. Since an effective adjuvant therapy was insufficient for treating OS, researching novel and adequate remedies is critical. Hyperthermia can induce cell death in various cancer cells, and thus, in this study, we investigated the anticancer method of hyperthermia in human OS (U-2 OS) cells. Treatment at 43 °C for 60 min induced apoptosis in human OS cell lines, but not in primary bone cells. Furthermore, hyperthermia was associated with increases of intracellular reactive oxygen species (ROS) and caspase-3 activation in U-2 OS cells. Mitochondrial dysfunction was followed by the release of cytochrome c from the mitochondria, and was accompanied by decreased anti-apoptotic Bcl-2 and Bcl-xL, and increased pro-apoptotic proteins Bak and Bax. Hyperthermia triggered endoplasmic reticulum (ER) stress, which was characterized by changes in cytosolic calcium levels, as well as increased calpain expression and activity. In addition, cells treated with calcium chelator (BAPTA-AM) blocked hyperthermia-induced cell apoptosis in U-2 OS cells. In conclusion, hyperthermia induced cell apoptosis substantially via the ROS, ER stress, mitochondria, and caspase pathways. Thus, hyperthermia may be a novel anticancer method for treating OS. PMID 25268613

Sorafenib and locoregional deep electro-hyperthermia in advanced hepatocellular carcinoma: A phase II study.
Sep. 2014 | Gadaleta-Caldarola, Gennaro; Infusino, Stefania; Galise, Ida; Ranieri, Girolamo; Vinciarelli, Gianluca; Fazio, Vito; Divella, Rosa; Daniele, Antonella; Filippelli, Gianfranco; Gadaleta, Cosmo Damiano
The standard treatment for advanced hepatocellular carcinoma (HCC) is sorafenib, a multikinase inhibitor of tumor cell proliferation and angiogenesis. Hyperthermia inhibits angiogenesis and promotes apoptosis. Potential synergic antiangiogenic and proapoptotic effects represent the rationale for combining sorafenib with electro-hyperthermia (EHY) in HCC. A total of 21 patients (median age, 64 years; range, 55-73 years) with advanced HCC were enrolled in the current study between February 2009 and September 2010. EHY was achieved by arranging capacitive electrodes with a deep hypothermia radiofrequency field of 13.56 Mhz at 80 W for 60 min, three times per week for six weeks, followed by two weeks without treatment, in combination with sorafenib at a dose of 800 mg every other day. According to the modified Response Evaluation Criteria in Solid Tumors criteria, 50% achieved stable disease, 5% achieved partial response and 45% achieved progressive disease. No complete response was observed. The progression-free survival (PFS) rate at six months was 38%, while the median PFS and overall survival times were 5.2 [95% confidence interval (CI), 4.2-6.2) and 10.4 (95% CI, 10-11) months, respectively. The overall incidence of treatment-related adverse events was 80%, predominantly of grade 1 or 2. Grade 3 toxicity included fatigue, diarrhea, hand-foot skin reaction and hypertension. In the present study, the sorafenib plus EHY combination was feasible and well tolerated, and no major complications were observed. The initial findings indicated that this combination offers a promising option for advanced HCC. PMID 25202410

The effects of non-invasive radiofrequency treatment and hyperthermia on malignant and nonmalignant cells.
Sep. 2014 | Curley, Steven A; Palalon, Flavio; Sanders, Kelly E; Koshkina, Nadezhda V
Exposure of biological subjects to electromagnetic fields with a high frequency is associated with temperature elevation. In our recent studies, we reported that non-invasive radiofrequency (RF) treatment at 13.56 MHz with the field ranging from 1 KeV to 20 KeV/m2 inhibits tumor progression in animals with abdominal tumor xenografts and enhances the anticancer effect of chemotherapy. The RF treatment was followed by temperature elevation in tumors to approximately 46 °C during 10 min of exposure. In contrast, the temperature of normal tissues remained within a normal range at approximately 37 °C. Whether all biological effects of RF treatment are limited to its hyperthermic property remains unclear. Here, we compared how RF and hyperthermia (HT) treatments change the proliferation rate, oxygen consumption and autophagy in malignant and nonmalignant cells. PMID 25192147

DNA fragmentation and caspase-independent programmed cell death by modulated electrohyperthermia.
Aug. 2014 | Meggyeshazi, N; Andocs, G; Balogh, L; Balla, P; Kiszner, G; Teleki, I; Jeney, A; Krenacs, T
The electric field and the concomitant heat (electrohyperthermia) can synergistically induce cell death in tumor tissue, due to elevated glycolysis, ion concentration, and permittivity in malignant compared with nonmalignant tissues. Here we studied the mechanism and time course of tumor destruction caused by electrohyperthermia. PMID 24562547

Two phase I dose-escalation/pharmacokinetics studies of low temperature liposomal doxorubicin (LTLD) and mild local hyperthermia in heavily pretreated patients with local regionally recurrent breast cancer.
Aug. 2014 | Zagar, Timothy M; Vujaskovic, Zeljko; Formenti, Silvia; Rugo, Hope; Muggia, Franco; O'Connor, Brigid; Myerson, Robert; Stauffer, Paul; Hsu, I-Chow; Diederich, Chris; Straube, William; Boss, Mary-Keara; Boico, Alina; Craciunescu, Oana; Maccarini, Paolo; Needham, David; Borys, Nicholas; Blackwell, Kimberly L; Dewhirst, Mark W
Unresectable chest wall recurrences of breast cancer (CWR) in heavily pretreated patients are especially difficult to treat. We hypothesised that thermally enhanced drug delivery using low temperature liposomal doxorubicin (LTLD), given with mild local hyperthermia (MLHT), will be safe and effective in this population. PMID 25144817

Hyperthermia inhibits recombination repair of gemcitabine-stalled replication forks.
Aug. 2014 | Raoof, Mustafa; Zhu, Cihui; Cisneros, Brandon T; Liu, Heping; Corr, Stuart J; Wilson, Lon J; Curley, Steven A
Gemcitabine is a potent nucleoside analogue against solid tumors, but development of drug resistance is a substantial problem. Removal of gemcitabine incorporated into DNA by repair mechanisms may contribute to resistance in chemo-refractory solid tumors. Human hepatocellular carcinoma (HCC) is usually very chemoresistant to gemcitabine. PMID 25128695

The inhibitory effect of heat treatment against epithelial-mesenchymal transition (EMT) in human pancreatic adenocarcinoma cell lines.
Aug. 2014 | Kimura-Tsuchiya, Reiko; Ishikawa, Takeshi; Kokura, Satoshi; Mizushima, Katsura; Adachi, Satoko; Okajima, Manabu; Matsuyama, Tatsuzo; Okayama, Tetsuya; Sakamoto, Naoyuki; Katada, Kazuhiro; Kamada, Kazuhiro; Uchiyama, Kazuhiko; Handa, Osamu; Takagi, Tomohisa; Yagi, Nobuaki; Naito, Yuji; Itoh, Yoshito
Epithelial-mesenchymal transition (EMT) plays a crucial role in cancer metastasis. In this study, we evaluated the effect of heat treatment on tumor growth factor-β1 (TGF-β1)-induced EMT in pancreatic cancer cells and tried to ascertain the mechanism related to any observed effects. Human pancreatic cancer cell lines (BxPC-3, PANC-1 and MIAPaCa-2) were stimulated by TGF-β1, and evaluated for morphological changes using immunofluorescence and EMT-related factors (i.e., E-cadherin, Vimentin, Snail or ZEB-1) using RT-PCR. To examine the effect of heat on EMT, the cancer cells were heat-treated at 43°C for 1 h then stimulated with TGF-β1. We then evaluated whether or not heat treatment changed the expression of EMT-related factors and cell migration and also whether Smad activation was inhibited in TGF-β signaling. After being treated with TGF-β1, pancreatic cancer cells resulted in EMT and cell migration was enhanced. Heat treatment inhibited TGF-β1-induced changes in morphology, inhibited the expression of EMT-related factors, and attenuated TGF-β1-induced migration in pancreatic cancer cells. Additionally, we observed that heat treatment blocked TGF-β1-induced phosphorylation of Smad2 in PANC-1 cells. Our results suggest that heat treatment can suppress TGF-β1-induced EMT and opens the possibility of a new therapeutic use of hyperthermia as a potential treatment for cancer metastasis. PMID 25120280

Identification of pancreatic cancer-associated tumor antigen from HSP-enriched tumor lysate-pulsed human dendritic cells.
Juni 2014 | Kim, Han-Soo; Kang, Dukjin; Moon, Myeong Hee; Kim, Hyung Jik
Vaccine strategies utilizing dendritic cells (DCs) to elicit anti-tumor immunity are the subject of intense research. Although we have shown that DCs pulsed with heat-treated tumor lysate (HTL) induced more potent anti-tumor immunity than DCs pulsed with conventional tumor lysate (TL), the underlying molecular mechanism is unclear. In order to explore the molecular basis of this approach and to identify potential antigenic peptides from pancreatic cancer, we analyzed and compared the major histocompatibility complex (MHC) ligands derived from TL- and HTL-pulsed dendritic cells by mass spectrophotometry. PMID 24954332

Current status of oncothermia therapy for lung cancer.
Apr. 2014 | Szasz, Andras
Lung cancer is one of the most common malignant tumors, and it has the highest death rate. Oncothermia is a feasible and successful treatment for lung cancer. Results show a remarkable survival benefit for patients, with a good quality of life. The treatment has no, or in some cases mild, side-effects and could decrease the adverse effects of the complementary treatment. Applying oncothermia together with other treatment methods could increase the effects and result in better performance. A comparison of studies demonstrates a good correspondence in the data, which strengthens the reliability of the studies, and clearly shows the feasibility of the application of oncothermia to treating all kinds of pulmonary malignancies including non-small-cell and small-cell primary tumors, and all of the metastatic diseases of the pulmonary system. PMID 24782955

Temperature matters! And why it should matter to tumor immunologists.
Apr. 2014 | Repasky, Elizabeth A; Evans, Sharon S; Dewhirst, Mark W
A major goal of cancer immunology is to stimulate the generation of long-lasting, tumor antigen-specific immune responses that recognize and destroy tumor cells. This article discusses advances in thermal medicine with the potential to improve cancer immunotherapy. Accumulating evidence indicates that survival benefits are accorded to individuals who achieve an increase in body temperature (i.e. fever) following infection. Furthermore, accumulating evidence indicates that physiological responses to hyperthermia impact the tumor microenvironment through temperature-sensitive check-points that regulate tumor vascular perfusion, lymphocyte trafficking, inflammatory cytokine expression, tumor metabolism, and innate and adaptive immune function. Nevertheless, the influence of thermal stimuli on the immune system, particularly the antitum or immune response, remains incompletely understood. In fact, temperature is still rarely considered as a critical variable in experimental immunology. We suggest that more attention should be directed to the role of temperature in the regulation of the immune response and that thermal therapy should be tested in conjunction with immunotherapy as a multi-functional adjuvant that modulates the dynamics of the tumor microenvironment. PMID 24490177

Fighting fire with fire: the revival of thermotherapy for gliomas.
Feb. 2014 | Lee Titsworth, William; Murad, Greg J A; Hoh, Brian L; Rahman, Maryam
In 1891, an orthopedic surgeon in New York noted the disappearance of an inoperable sarcoma in a patient after a febrile illness. This observation resulted in experiments assessing the utility of heat therapy or thermotherapy for the treatment of cancer. While it initially fell from favor, thermotherapy has recently made a resurgence, sparking investigations into its anticancer properties. This therapy is especially attractive for glioblastoma multiforme (GBM) which is difficult to target due to the blood-brain barrier and recalcitrant to treatment. Here we briefly review the history of thermotherapy and then more methodically present the current literature as it relates to central nervous system malignancies. Recent developments show that heat is preferentially cytotoxic to tumor cells and induces cellular pathways which result in apoptotic and non-apoptotic death. Techniques to induce hyperthermia include regional hyperthermia by water bath, focused ultrasound, radiofrequency microwaves, laser-induced interstitial thermotherapy, and magnetic energy. The recent revival of these therapeutic approaches and their preliminary outcomes in the treatment of GBM is reviewed. From bacterial toxins to infusion of magnetic nanoparticles, hyperthermia has the potential to be an effective and easy-to-execute adjuvant therapy for GBM. Hyperthermia for GBM is a promising therapy as part of a growing armamentarium for malignant glioma treatment. PMID 24510985

[The effect of immunotherapy and hyperthermia on patients with advanced or recurrent breast cancer].
Jan. 2014 | Takeda, Tsutomu; Takeda, Takashi; Etani, Mio; Kobayashi, Shogo; Takeda, Hiroko
We treated 172 patients with advanced or recurrent breast cancer using hyperthermia or immunotherapy between July 2005 and September 2012. In these patients, standard therapy showed no results, or it was refused. Clinical benefit( complete response [CR], partial response[PR], and long stable disease [SD] for more than 6 months) was observed in 30 patients( 17.4%), including CR in 5 patients. The effective rate of immunotherapy increased from 7.7% to 26.0% using hyperthermia. The effective rate of hyperthermia was only 5.1%. The standard therapy had not been altered in 23 of the 30 patients in whom clinical benefit was observed. Thus, immunotherapy or hyperthermia had benefited these 23 patients. Of the 23 effectively treated patients, skin or regional lymph node metastases disappeared in 3 patients treated with hyperthermia alone, and lung metastases disappeared and carcinomatous pleuritis improved in 1 patient treated with immunotherapy alone. In the remaining 19 effectively treated patients, multiple metastases were observed in important solid organs such as the liver, lung, bone, and brain. Combined hyperthermia and immunotherapy was used to treat these 19 patients to good effect. PMID 24393860

[Immunotherapy and hyperthermia for the treatment of patients with advanced or recurrent colorectal cancer].
Jan. 2014 | Takeda, Tsutomu; Akita, Hirofumi; Takeda, Takashi; Nakamura, Kana; Kobayashi, Shogo; Takeda, Hiroko
We treated 226 patients with advanced or recurrent colorectal cancer using hyperthermia or immunotherapy between July 2005 and September 2012. Clinical benefit (complete response [CR], partial response [PR], and long stable disease [SD] for more than 6 months) was observed in 30 patients (13.3%), including CR in 5 patients. The effective rate of immunotherapy increased from 14.3% to 16.1% using hyperthermia. The effective rate of hyperthermia was 3.9%. Of the 30 effectively treated patients, liver metastases disappeared in 2 patients treated with hyperthermia alone, and lung metastases disappeared in 2 patients treated with immunotherapy alone. In the remaining 26 effectively treated patients, multiple metastases were observed in solid organs. Both hyperthermia and immunotherapy were administered and were found to be effective in the treatment of patients with advanced or recurrent colorectal cancer. PMID 24393863

Re-irradiation and hyperthermia after surgery for recurrent breast cancer.
Dez. 2013 | Linthorst, Marianne; van Geel, Albert N; Baaijens, Margreet; Ameziane, Ali; Ghidey, Wendim; van Rhoon, Gerard C; van der Zee, Jacoba
Evaluation of efficacy and side effects of combined re-irradiation and hyperthermia electively or for subclinical disease in the management of locoregional recurrent breast cancer. PMID 23742962

Phase II study of concomitant chemoradiotherapy with local hyperthermia and metronidazole for locally advanced fixed rectal cancer.
Sep. 2013 | Barsukov, Yu A; Gordeyev, S S; Tkachev, S I; Fedyanin, M Yu; Perevoshikov, A G
Locally advanced fixed T4 rectal cancer has a poor prognosis and no standard treatment strategy. The aim of this study was to investigate the safety and efficacy of neoadjuvant chemoradiotherapy using hypofractionated radiotherapy combined with local hyperthermia, capecitabine, oxaliplatin and metronidazole. PMID 23668626

Heat-shock proteins as dendritic cell-targeting vaccines--getting warmer.
Juli 2013 | McNulty, Shaun; Colaco, Camilo A; Blandford, Lucy E; Bailey, Christopher R; Baschieri, Selene; Todryk, Stephen
Heat-shock proteins (hsp) provide a natural link between innate and adaptive immune responses by combining the ideal properties of antigen carriage (chaperoning), targeting and activation of antigen-presenting cells (APC), including dendritic cells (DC). Targeting is achieved through binding of hsp to distinct cell surface receptors and is followed by antigen internalization, processing and presentation. An improved understanding of the interaction of hsp with DC has driven the development of numerous hsp-containing vaccines, designed to deliver antigens directly to DC. Studies in mice have shown that for cancers, such vaccines generate impressive immune responses and protection from tumour challenge. However, translation to human use, as for many experimental immunotherapies, has been slow partly because of the need to perform trials in patients with advanced cancers, where demonstration of efficacy is challenging. Recently, the properties of hsp have been used for development of prophylactic vaccines against infectious diseases including tuberculosis and meningitis. These hsp-based vaccines, in the form of pathogen-derived hsp-antigen complexes, or recombinant hsp combined with selected antigens in vitro, offer an innovative approach against challenging diseases where broad antigen coverage is critical. PMID 23551234

Identification of common gene networks responsive to mild hyperthermia in human cancer cells.
Mai 2013 | Kariya, Ayako; Tabuchi, Yoshiaki; Yunoki, Tatsuya; Kondo, Takashi
Hyperthermia (HT) has been used as a possible treatment modality for various types of malignant tumors. Due to its pleiotropic effects, its combined use with radiotherapy and/or chemotherapy has proven to be beneficial. However, the molecular mechanisms underling the cellular responses to heat stress remain unclear. Therefore, the aim of this study was to identify common gene expression patterns responsive to mild HT (MHT) in human cancer cells. HeLa human cervical squamous cell carcinoma (SCC) and HSC-3 human oral SCC cells were exposed to MHT at 41˚C for 30 min, followed by culture at 37˚C for 0-24 h. MHT did not affect cell viability or the cell cycle. GeneChip microarray analysis clearly revealed that many probe sets were differentially expressed by a factor of ≥1.5 in both cell lines following exposure to MHT. Of the many differentially expressed probe sets, 114 genes were found to be commonly upregulated in both HeLa and HSC‑3 cells, and two significant gene networks were obtained from the commonly upregulated genes. Gene network A included several heat shock proteins, as well as BCL2-associated athanogene 3 (BAG3), and was found to be mainly associated with the biological functions of cellular function and maintenance. Gene network B included several anti-cell death genes, such as early growth response 1 (EGR1) and endothelin 1 (EDN1) and was found to be associated with the biological functions of cell death and survival. Real‑time quantitative polymerase chain reaction demonstrated that the gene expression patterns of the 12 genes selected were consistent with the microarray data in four cancer cell lines. These findings may provide further insight into the detailed molecular mechanisms of the MHT response in cancer cells. PMID 23632739

Hyperthermia versus Oncothermia: Cellular Effects in Complementary Cancer Therapy.
Mai 2013 | Hegyi, Gabriella; Szigeti, Gyula P; Szász, András
Hyperthermia means overheating of the living object completely or partly. Hyperthermia, the procedure of raising the temperature of a part of or the whole body above normal for a defined period of time, is applied alone or as an adjunctive with various established cancer treatment modalities such as radiotherapy and chemotherapy. However, hyperthermia is not generally accepted as conventional therapy. The problem is its controversial performance. The controversy is originated from the complications of the deep heating and the focusing of the heat effect. The idea of oncothermia solves the selective deep action on nearly cellular resolution. We would like to demonstrate the force and perspectives of oncothermia, as a highly specialized hyperthermia in clinical oncology. Our aim is to prove the ability of oncothermia to be a candidate to become a widely accepted modality of the standard cancer care. We would like to show the proofs and the challenges of the hyperthermia and oncothermia applications to provide the presently available data and summarize the knowledge in the topic. Like many early stage therapies, oncothermia lacks adequate treatment experience and long-range, comprehensive statistics that can help us optimize its use for all indications. PMID 23662149

Short-term hyperthermia promotes the sensitivity of MCF-7 human breast cancer cells to paclitaxel.
März 2013 | Lin, Yan; Liu, Zhihui; Li, Yongqiang; Liao, Xiaoli; Liao, Sina; Cen, Shaofang; Yang, Ling; Wei, Jiazhang; Hu, Xiaohua
As a physical adjuvant approach in the treatment of solid tumors, regional hyperthermia plays a synergistic role in enhancing the efficacy of simultaneous chemotherapy. Paclitaxel (PTX) is an anti-mitotic taxane drug that is widely used in chemotherapy for the treatment of various human malignancies such as lung, ovarian, breast, and head and neck cancers. Since the possibility that hyperthermia can enhance the anti-tumor effects of PTX has not yet been investigated, the present study was designed to evaluate the effects of short-term hyperthermia on PTX-induced antitumor activity in the human breast cancer line MCF-7. It was found that short-term hyperthermia promoted PTX-induced suppression of cell proliferation. The IC for PTX was reduced from 18.2±1.0 to 15.0±0.45 nM (p<0.05). The level of PTX-induced cell apoptosis was increased from 8.5±1.2 to 16.4±2.4% (p<0.05) and from 15.2±1.4 to 34.9±2.8% (p<0.05), at the end of the first and second hyperthermia cycles, respectively; both the activity and expression of caspase-7 were enhanced. In addition, PTX-induced cell cycle arrest in the G2/M phase was further promoted by short-term hyperthermia, from 9.3±0.7 to 12.5±0.9% (p<0.05). In contrast, short-term hyperthermia affected neither tumor cell migration nor invasion in the presence or absence of PTX. The presented data thus suggest that short-term hyperthermia may serve as a feasible approach in the promotion of breast cancer cell sensitivity to PTX. PMID 23229357

Radiotherapy in conjunction with superficial and intracavitary hyperthermia for the treatment of solid tumors: survival and thermal parameters.
Jan. 2013 | Triantopoulou, S; Efstathopoulos, E; Platoni, K; Uzunoglou, N; Kelekis, N; Kouloulias, V
Hyperthermia is an effective modality for the treatment of cancer, which is mainly used in conjunction with radiotherapy as this combined treatment offers a better clinical outcome. There are many ways that hyperthermia can be applied and depends on the kind of tumor of the patients. The great advantage of this method is that it is tolerable for the majority of patients without severe toxicity. Many clinical trials have been realized in order to prove that hyperthermia in addition to radiotherapy offers an advantage in the survival and local control of patients in comparison to radiotherapy alone. Many studies have also investigated if exists any correlation between the thermal parameters of hyperthermia and the clinical outcome. This is a review of these studies and it concerns superficial hyperthermia for superficial tumors-melanoma, head and neck, breast cancer-and intracavitary hyperthermia for rectal cancer, esophageal cancer and prostate carcinoma. PMID 23180345

Successful treatment of solitary bone metastasis of non-small cell lung cancer with bevacizumab and hyperthermia.
Jan. 2013 | Rubovszky, Gábor; Nagy, Tünde; Gődény, Mária; Szász, András; Láng, István
Non-small cell lung cancer (NSCLC) represents 85 % of all malignant lung cancers. In metastatic disease the principle goal of palliative therapy is to prolong survival with least toxicity and best patients' quality of life. Bevacizumab (BEV) has been approved as first line treatment in combination with platinum based chemotherapy and maintenance therapy in NSCLC. BEV can be added safely to several chemotherapeutic agents, however there is no data on coadministration with thermotherapy. Even in localized disease no robust evidence exists about the beneficial effect of loco-regional thermotherapy on overall survival, but it might be used successfully in symptom palliation. In this article a successful co-administration of BEV and hyperthermia is reported in a patient with monolocalized bone metastasis from previously operated NSCLC. This case suggests that electrohyperthermia can probably be incorporated in palliative therapy added not only to radiotherapy or chemotherapy but also to anti-angiogenic BEV treatment. PMID 22752712

Gemcitabine and cisplatin combined with regional hyperthermia as second-line treatment in patients with gemcitabine-refractory advanced pancreatic cancer.
Jan. 2013 | Tschoep-Lechner, Katharina Elisabeth; Milani, Valeria; Berger, Frank; Dieterle, Nelli; Abdel-Rahman, Sultan; Salat, Christoph; Issels, Rolf-Dieter
There is no standard second-line therapy for patients with advanced pancreatic cancer (APC) after gemcitabine (G) failure. Cisplatin (Cis)-based chemotherapy has shown activity in APC. It is proven that cytotoxicity of G and Cis is enhanced by heat exposure at 40° to 42°C. Therefore G plus Cis with regional hyperthermia (RHT) might be beneficial for patients with G-refractory APC. PMID 23245336

[Immunotherapy with hyperthermia for advanced or recurrent breast cancer patients in whom standard therapy showed no effect or was refused].
Dez. 2012 | Takeda, Tsutomu; Takeda, Takashi; Kobayashi, Shogo; Takeda, Hiroko
We treated 168 advanced or recurrent breast cancer patients with hyperthermia or immunotherapy (2005/7-2011/12). In these cases, standard therapy showed no effect or was refused. Clinical benefit( complete response: CR, partial response, and long stable disease) was observed in 26 cases; CR occurred in 4 cases. The effective rate of immunotherapy increased from 9.1% to 23.9% using hyperthermia. Both hyperthermia and immunotherapy needed to be used together to be effective in 20 cases with distant metastases to solid organs. PMID 23267880

Heat shock proteins (HSPs) based anti-cancer vaccines.
Dez. 2012 | Ciocca, D R; Cayado-Gutierrez, N; Maccioni, M; Cuello-Carrion, F D
The importance of HSPs themselves in antigen presentation and cross-presentation remains controversial. Most studies agree that as part of their molecular chaperone function, HSPs can bind and present tumor associated antigens to professional antigen presenting cells through MHC class I and class II molecules, leading to the activation of anti-tumor CD8+ and CD4+ T cells. The regulation of the innate and adaptive immune responses by HSPs is still a matter of intense research. HSPs are seen as important anticancer vaccine adjuvants. They are used through different delivery systems: HSPs/antibodies, peptide/protein-HSP complexes, tumor antigen/HSP gene fusion, viral peptides/HSP complexes or gene fusion, viral proteins/bacterial HSP fusion. In preclinical models different administration routes, subcutaneous, intradermal, intramuscular or even peroral (under special conditions) can be used, and the animal toxicities are non-significant. The HSP-based vaccines can induce specific and non-specific cellular immune responses all of which are important to induce tumor rejection. In addition, the antibodies generated after vaccination are emerging as important protagonist in the antitumoral response. This response is significantly enhanced when the suppressive tumor microenvironment and the immune suppressing effector cells are blocked. Several clinical studies have been carried out and are ongoing, immunizing cancer patients with autologous tumor derived HSP-peptide complexes (HSPPCs). The most promising results have been observed in patients with melanoma and renal clear cell cancer without advanced disease. There are clinical trials with HSP-based anticancer vaccines other than with HSPPCs (including patients with non-Hodgkin lymphoma, high-grade transitional cell carcinoma of the bladder, high-grade cervical dysplasia, etc). PMID 22804241

Hyperthermia induces cytoskeletal alterations and mitotic catastrophe in p53-deficient H1299 lung cancer cells.
Nov. 2012 | Pawlik, Andrzej; Nowak, Jakub Marcin; Grzanka, Dariusz; Gackowska, Lidia; Michalkiewicz, Jacek; Grzanka, Alina
Hyperthermia is used in cancer therapy, however much remains to be discovered regarding its mechanisms of action at the cellular level. In this study, the effects of hyperthermia on cell death, survival, morphology and the cytoskeleton were investigated in a non-small cell lung cancer cell line, H1299. Despite the fact that this cell line is widely used in research, it has not yet been tested for heat shock sensitivity. Cells were given a 30-min heat shock at 43.5°C and 45°C and left to recover at 37°C for 24 and 48 h. 24 h after heat shock treatment, we monitored changes in the organization of the cytoskeleton using immunofluorescence microscopy. The number of actin stress fibers was significantly reduced, microtubules formed a looser meshwork, a portion of the cells possessed multipolar mitotic spindles, whereas vimentin filaments collapsed into perinuclear complexes. 48 h following heat stress, most of the cells showed recovery of the cytoskeleton, however we observed a considerable number of giant cells that were multinucleated or contained one enlarged nucleus. The data obtained by MTT assay showed a dose-dependent decrease of cell viability, while flow cytometric analysis revealed an increase in the number of cells with externalized phosphatidylserine. The results suggest that one of the modes of heat-induced cell death in H1299 cells is mitotic catastrophe, which probably ends in apoptosis. PMID 22483983

Pathological complete response and sphincter-sparing surgery after neoadjuvant radiochemotherapy with regional hyperthermia for locally advanced rectal cancer compared with radiochemotherapy alone.
Nov. 2012 | Schroeder, Christopher; Gani, Cihan; Lamprecht, Ulf; von Weyhern, Claus Hann; Weinmann, Martin; Bamberg, Michael; Berger, Bernhard
To evaluate the influence of regional hyperthermia on rates of complete pathological response (pCR) and sphincter-sparing surgery in the context of an up-to-date radiochemotherapy protocol for locally advanced rectal cancer. PMID 23006132

Effect of preoperative fever-range whole-body hyperthermia on immunological markers in patients undergoing colorectal cancer surgery.
Okt. 2012 | Sulyok, I; Fleischmann, E; Stift, A; Roth, G; Lebherz-Eichinger, D; Kasper, D; Spittler, A; Kimberger, O
Previous studies have demonstrated beneficial immunological effects of fever-range whole-body hyperthermia (FR-WBH) as an adjunct to non-surgical cancer therapy. We conducted a study of preoperative FR-WBH in patients undergoing colorectal cancer surgery to evaluate perioperative, hyperthermia-induced immunomodulation. PMID 22855633

Phase II trial of combined regional hyperthermia and gemcitabine for locally advanced or metastatic pancreatic cancer.
Okt. 2012 | Ishikawa, Takeshi; Kokura, Satoshi; Sakamoto, Naoyuki; Ando, Takashi; Imamoto, Eiko; Hattori, Takeshi; Oyamada, Hirokazu; Yoshinami, Naomi; Sakamoto, Masafumi; Kitagawa, Kazutomo; Okumura, Yoko; Yoshida, Naohisa; Kamada, Kazuhiro; Katada, Kazuhiro; Uchiyama, Kazuhiko; Handa, Osamu; Takagi, Tomohisa; Yasuda, Hiroaki; Sakagami, Junichi; Konishi, Hideyuki; Yagi, Nobuaki; Naito, Yuji; Yoshikawa, Toshikazu
Despite advances in cancer therapy, treating pancreatic cancer remains one of the major challenges in the field of medical oncology. We conducted this phase II study to evaluate the efficacy and safety of regional hyperthermia combined with gemcitabine for the treatment of unresectable advanced pancreatic cancer. PMID 22838644

Old and new facts about hyperthermia-induced modulations of the immune system.
Aug. 2012 | Frey, Benjamin; Weiss, Eva-Maria; Rubner, Yvonne; Wunderlich, Roland; Ott, Oliver J; Sauer, Rolf; Fietkau, Rainer; Gaipl, Udo S
Hyperthermia (HT) is a potent sensitiser for radiotherapy (RT) and chemotherapy (CT) and has been proven to modulate directly or indirectly cells of the innate and adaptive immune system. We will focus in this article on how anti-tumour immunity can be induced by HT. In contrast to some in vitro assays, in vivo examinations showed that natural killer cells and phagocytes like granulocytes are directly activated against the tumour by HT. Since heat also activates dendritic cells (DCs), HT should be combined with further death stimuli (RT, CT or immune therapy) to allocate tumour antigen, derived from, for example, necrotic tumour cells, for uptake by DCs. We will outline that induction of immunogenic tumour cells and direct tumour cell killing by HT in combination with other therapies contributes to immune activation against the tumour. Studies will be presented showing that non-beneficial effects of HT on immune cells are mostly timely restricted. A special focus is set on immune activation mediated by extracellular present heat shock proteins (HSPs) carrying tumour antigens and further danger signals released by dying tumour cells. Local HT treatment in addition to further stress stimuli exerts abscopal effects and might be considered as in situ tumour vaccination. An increased natural killer (NK) cell activity, lymphocyte infiltration and HSP-mediated induction of immunogenic tumour cells have been observed in patients. Treatments with the addition of HT therefore can be considered as a personalised cancer treatment approach by specifically activating the immune system against the individual unique tumour. PMID 22690925

Heat shock protein 27 as a prognostic and predictive biomarker in pancreatic ductal adenocarcinoma.
Juli 2012 | Schäfer, Claus; Seeliger, Hendrik; Bader, Dominik C; Assmann, Gerald; Buchner, Denise; Guo, Yang; Ziesch, Andreas; Palagyi, Andreas; Ochs, Stephanie; Laubender, Rüdiger P; Jung, Andreas; De Toni, Enrico N; Kirchner, Thomas; Göke, Burkhard; Bruns, Christiane; Gallmeier, Eike
A role of heat shock protein 27 (HSP27) as a potential biomarker has been reported in various tumour entities, but comprehensive studies in pancreatic cancer are lacking. Applying tissue microarray (TMA) analysis, we correlated HSP27 protein expression status with clinicopathologic parameters in pancreatic ductal adenocarcinoma specimens from 86 patients. Complementary, we established HSP27 overexpression and RNA-interference models to assess the impact of HSP27 on chemo- and radiosensitivity directly in pancreatic cancer cells. In the TMA study, HSP27 expression was found in 49% of tumour samples. Applying univariate analyses, a significant correlation was found between HSP27 expression and survival. In the multivariate Cox-regression model, HSP27 expression emerged as an independent prognostic factor. HSP27 expression also correlated inversely with nuclear p53 accumulation, indicating either protein interactions between HSP27 and p53 or TP53 mutation-dependent HSP27-regulation in pancreatic cancer. In the sensitivity studies, HSP27 overexpression rendered HSP27 low-expressing PL5 pancreatic cancer cells more susceptible towards treatment with gemcitabine. Vice versa, HSP27 protein depletion in HSP27 high-expressing AsPC-1 cells caused increased gemcitabine resistance. Importantly, HSP27 expression was inducible in pancreatic cancer cell lines as well as primary cells. Taken together, our study suggests a role for HSP27 as a prognostic and predictive marker in pancreatic cancer. Assessment of HSP27 expression could thus facilitate the identification of specific patient subpopulations that might benefit from individualized treatment options. Additional studies need to clarify whether modulation of HSP27 expression could represent an attractive concept to support the incorporation of hyperthermia in clinical treatment protocols for pancreatic cancer. PMID 22004109

Successful treatment of advanced ovarian cancer with thermochemotherapy and adjuvant immune therapy.
Juni 2012 | Kleef, R; Kekic, S; Ludwig, N
We report on a 4-year progression-free survival of a 54-year-old female first diagnosed in December 2007 with advanced bilateral ovarian cancer FIGO IIIc, disseminated peritoneal carcinosis and malignant diaphragm invasion. Treatment started in January 2008 with 6 cycles of Taxol 175 mg/m(2)/carboplatin AUC 5 in 3-week intervals. Twenty-four hours following each chemotherapy session, fever-range long-duration whole-body hyperthermia (WBH) was performed at the temperature plateau of 40°C body core temperature for 6 h. Three months after completion of chemotherapy, 4 more long-duration WBH procedures were performed in monthly intervals. Importantly, long-duration WBH was paralleled with intradermal vaccination of autologous dendritic cells. No other treatment was given to the patient. Four years following the first diagnosis, the patient is still in complete remission with no evidence of disease. PMID 22679425

Re-irradiation plus regional hyperthermia for recurrent non-small cell lung cancer: a potential modality for inducing long-term survival in selected patients.
Juni 2012 | Ohguri, Takayuki; Imada, Hajime; Yahara, Katsuya; Moon, Seung Dae; Yamaguchi, Shinsaku; Yatera, Kazuhiro; Mukae, Hiroshi; Hanagiri, Takeshi; Tanaka, Fumihiro; Korogi, Yukunori
The purpose of this study was to assess the toxicity and efficacy of re-irradiation plus regional hyperthermia for recurrent NSCLC and to identify the predictors of long-term survival. PMID 22445656

Hyperthermia-enhanced TRAIL- and mapatumumab-induced apoptotic death is mediated through mitochondria in human colon cancer cells.
Apr. 2012 | Song, Xinxin; Kim, Han-Cheon; Kim, Seog-Young; Basse, Per; Park, Bae-Hang; Lee, Byeong-Chel; Lee, Yong J
Colorectal cancer is the third leading cause of cancer-related mortality in the world; death usually results from uncontrolled metastatic disease. Previously, we developed a novel strategy of TNF-related apoptosis-inducing ligand (Apo2L/TRAIL) in combination with hyperthermia to treat hepatic colorectal metastases. However, previous studies suggest a potential hepatocyte cytotoxicity with TRAIL. Unlike TRAIL, anti-human TRAIL receptor antibody induces apoptosis without hepatocyte toxicity. In this study, we evaluated the anti-tumor efficacy of humanized anti-death receptor 4 (DR4) antibody mapatumumab (Mapa) by comparing it with TRAIL in combination with hyperthermia. TRAIL, which binds to both DR4 and death receptor 5 (DR5), was approximately tenfold more effective than Mapa in inducing apoptosis. However, hyperthermia enhances apoptosis induced by either agent. We observed that the synergistic effect was mediated through elevation of reactive oxygen species, c-Jun N-terminal kinase activation, Bax oligomerization, and translocalization to the mitochondria, loss of mitochondrial membrane potential, release of cytochrome c to cytosol, activation of caspases, and increase in poly(ADP-ribose) polymerase cleavage. We believe that the successful outcome of this study will support the application of Mapa in combination with hyperthermia to colorectal hepatic metastases. PMID 22174016

Sodium arsenite ± hyperthermia sensitizes p53-expressing human ovarian cancer cells to cisplatin by modulating platinum-DNA damage responses.
Apr. 2012 | Muenyi, Clarisse S; Pinhas, Allan R; Fan, Teresa W; Brock, Guy N; Helm, C William; States, J Christopher
Epithelial ovarian cancer (EOC) is the leading cause of gynecological cancer death in the United States. Cisplatin is a DNA damaging agent initially effective against EOC but limited by resistance. P53 plays a critical role in cellular response to DNA damage and has been implicated in EOC response to platinum chemotherapy. In this study, we examined the role of p53 status in EOC response to a novel combination of cisplatin, sodium arsenite, and hyperthermia. Human EOC cells were treated with cisplatin ± 20μM sodium arsenite at 37°C or 39°C for 1 h. Sodium arsenite ± hyperthermia sensitized wild-type p53-expressing (A2780, A2780/CP70, OVCA 420, OVCA 429, and OVCA 433) EOC cells to cisplatin. Hyperthermia sensitized p53-null SKOV-3 and p53-mutant (OVCA 432 and OVCAR-3) cells to cisplatin. P53 small interfering RNA (siRNA) transfection abrogated sodium arsenite sensitization effect. XPC, a critical DNA damage recognition protein in global genome repair pathway, was induced by cisplatin only in wild-type p53-expressing cells. Cotreatment with sodium arsenite ± hyperthermia attenuated cisplatin-induced XPC in wild-type p53-expressing cells. XPC siRNA transfection sensitized wild-type p53-expressing cells to cisplatin, suggesting that sodium arsenite ± hyperthermia attenuation of XPC is a mechanism by which wild-type p53-expressing cells are sensitized to cisplatin. Hyperthermia ± sodium arsenite enhanced cellular and DNA accumulation of platinum in wild-type p53-expressing cells. Only hyperthermia enhanced platinum accumulation in p53-null cells. In conclusion, sodium arsenite ± hyperthermia sensitizes wild-type p53-expressing EOC cells to cisplatin by suppressing DNA repair protein XPC and increasing cellular and DNA platinum accumulation. PMID 22331493

Effector CD8+ T cell IFN-γ production and cytotoxicity are enhanced by mild hyperthermia.
Jan. 2012 | Mace, Thomas A; Zhong, Lingwen; Kokolus, Kathleen M; Repasky, Elizabeth A
Clinical trials combining hyperthermia with radiation and/or chemotherapy for cancer treatment have resulted in improved overall survival and control of local recurrences. The contribution of thermally enhanced anti-immune function in these effects is of considerable interest, but not understood; studies on the fundamental effects of elevated temperature on immune effector cells are needed. The goal of this study is to investigate the potential of mild hyperthermia to impact tumour antigen-specific (Ag) effector CD8+ T cell functions. PMID 22235780

Reirradiation and hyperthermia for radiation-associated sarcoma.
Jan. 2012 | de Jong, Marianne A A; Oldenborg, Sabine; Bing Oei, S; Griesdoorn, Vanessa; Kolff, M Willemijn; Koning, Caro C E; van Tienhoven, Geertjan
The objective of this study was to evaluate the role of reirradiation and hyperthermia in the treatment of radiation-associated sarcoma (RAS) in the thoracic region, which is an increasing, yet extremely rare condition with a poor prognosis. PMID 21713762

Inhibition of checkpoint kinase 1 abrogates G2/M checkpoint activation and promotes apoptosis under heat stress.
Jan. 2012 | Furusawa, Yukihiro; Iizumi, Takashi; Fujiwara, Yoshisada; Zhao, Qing-Li; Tabuchi, Yoshiaki; Nomura, Takaharu; Kondo, Takashi
Hyperthermia induced by heat stress (HS) inhibits the proliferation of cancer cells and induces their apoptosis. However, the mechanism underlying HS-induced apoptosis remains elusive. Here, we demonstrated a novel evidence that checkpoint kinase 1 (Chk1) plays crucial roles in the apoptosis and regulation of cell cycle progression in cells under HS. In human leukemia Jurkat cells, interestingly, the ataxia telangiectasia and Rad-3 related (ATR)-Chk1 pathway was preferentially activated rather than the ataxia telangiectasia mutated (ATM)-checkpoint kinase 2 (Chk2) pathway under HS. The selective inhibitors of ATR or Chk1 abrogated HS-induced apoptosis in human leukemia Jurkat cells whereas the inhibition of ATM or Chk2 caused only marginal effects. Inhibition of ATR and Chk1 also abrogated G2/M checkpoint activation by HS in Jurkat cells. The effects of small interfering RNA targeting Chk1 were similar to those of the selective inhibitor of Chk1. In addition, the efficiencies of Chk1 inhibition on G2/M checkpoint abrogation and apoptosis induction were confirmed in the adherent cancer cell lines HeLa, HSC3, and PC3, suggesting that the targeting of Chk1 can be effective in solid tumors cells. In conclusion, these findings indicate a novel molecular basis of G2/M checkpoint activation and apoptosis in cells exposed to HS. PMID 22080164

Tumor response and negative distal resection margins of rectal cancer after hyperthermochemoradiation therapy.
Nov. 2011 | Tsutsumi, Soichi; Tabe, Yuichi; Fujii, Takaaki; Yamaguchi, Satoru; Suto, Toshinaga; Yajima, Reina; Morita, Hiroki; Kato, Toshihide; Shioya, Mariko; Saito, Jun-Ichi; Asao, Takayuki; Nakano, Takashi; Kuwano, Hiroyuki
The safety of regional hyperthermia has been tested in locally advanced rectal cancer. The aim of this study was to assess the effects of shorter distal margins on local control and survival in rectal cancer patients who were treated with preoperative hyperthermochemoradiation therapy (HCRT) and underwent rectal resection by using the total mesorectal excision (TME) method. PMID 22110227

Radiation combined with hyperthermia induces HSP70-dependent maturation of dendritic cells and release of pro-inflammatory cytokines by dendritic cells and macrophages.
Nov. 2011 | Schildkopf, Petra; Frey, Benjamin; Ott, Oliver J; Rubner, Yvonne; Multhoff, Gabriele; Sauer, Rolf; Fietkau, Rainer; Gaipl, Udo S
Hyperthermia (HT) treatment of cancer patients was revived over the last years and has been proven to be beneficiary for many cancer entities when applied temperature controlled in multimodal treatments. We examined whether a combination of ionizing irradiation (X-ray) and HT (41.5°C; 1 h) can induce the release of heat shock protein (HSP) 70 by tumor cells and thereby lead to the activation of dendritic cells and macrophages. PMID 21704416

Differentiation of CD8+ T cells into effector cells is enhanced by physiological range hyperthermia.
Nov. 2011 | Mace, Thomas A; Zhong, Lingwen; Kilpatrick, Casey; Zynda, Evan; Lee, Chen-Ting; Capitano, Maegan; Minderman, Hans; Repasky, Elizabeth A
In this study, we asked whether exposure to different physiologically relevant temperatures (33°C, 37°C, and 39.5°C) could affect subsequent antigen-specific, activation-related events of naive CD8(+) T cells. We observed that temporary exposure of CD62L(hi)CD44(lo) Pmel-1 CD8(+) cells to 39.5°C prior to their antigen-dependent activation with gp100(25-33) peptide-pulsed C57BL/6 splenocytes resulted in a greater percentage of cells, which eventually differentiated into CD62L(lo)CD44(hi) effector cells compared with cells incubated at 33°C and 37°C. However, the proliferation rate of naive CD8(+) T cells was not affected by mild heating. While exploring these effects further, we observed that mild heating of CD8(+) T cells resulted in the reversible clustering of GM1(+) CD-microdomains in the plasma membrane. This could be attributable to a decrease in line tension in the plasma membrane, as we also observed an increase in membrane fluidity at higher temperatures. Importantly, this same clustering phenomenon was observed in CD8(+) T cells isolated from spleen, LNs, and peripheral blood following mild whole-body heating of mice. Further, we observed that mild heating also resulted in the clustering of TCRβ and the CD8 coreceptor but not CD71R. Finally, we observed an enhanced rate of antigen-specific conjugate formation with APCs following mild heating, which could account for the difference in the extent of differentiation. Overall, these novel findings may help us to further understand the impact of physiologically relevant temperature shifts on the regulation of antigen-specific CD8(+) T cell activation and the subsequent generation of effector cells. PMID 21873456

Regional hyperthermia combined with chemoradiotherapy in primary or recurrent locally advanced pancreatic cancer : an open-label comparative cohort trial.
Okt. 2011 | Maluta, Sergio; Schaffer, Moshe; Pioli, Fabio; Dall'oglio, Stefano; Pasetto, Stefano; Schaffer, Pamela M; Weber, Bernard; Giri, Maria Grazia
To evaluate the therapeutic effect of delivering regional hyperthermia (HT) plus chemoradiotherapy (CRT) in patients suffering from locally advanced unresectable pancreatic cancer (LAPC). PMID 21932025

Synergistic effect of hyperthermia and neferine on reverse multidrug resistance in adriamycin-resistant SGC7901/ADM gastric cancer cells.
Aug. 2011 | Huang, Chenghui; Li, Yaping; Cao, Peiguo; Xie, Zhaoxia; Qin, Zhiqiang
Multidrug resistance (MDR) plays a major obstacle to successful gastric cancer chemotherapy. The purpose of this study was to investigate the MDR reversal effect and mechanisms of hyperthermia in combination with neferine (Nef) in adriamycin (ADM) resistant human SGC7901/ADM gastric cancer cells. The MDR cells were heated at 42°C and 45°C for 30 min alone or combined with 10 μg/mL Nef. The cytotoxic effect of ADM was evaluated by MTT assay. Cellular plasma membrane lipid fluidity was detected by fluorescence polarization technique. Intracellular accumulation of ADM was monitored with high performance liquid chromatography. Mdr-1 mRNA, P-glycoprotein (P-gp), γH2AX expression and γH2AX foci formation were determined by real-time PCR, Western blot and immunocytochemical staining respectively. It was found that different heating methods induced different cytotoxic effects. Water submerged hyperthermia had the strongest cytotoxicity of ADM and Nef combined with hyperthermia had a synergistic cytotoxicity of ADM in the MDR cells. The water submerged hyperthermia increased the cell membrane fluidity. Both water submerged hyperthermia and Nef increased the intracellular accumulation of ADM. The water submerged hyperthermia and Nef down-regulated the expression of mdr-1 mRNA and P-gp. The water submerged hyperthermia could damage DNA and increase the γH2AX expression of SGC7901/ADM cells. The higher temperature was, the worse effect was. Our results show that combined treatment of hyperthermia with Nef can synergistically reverse MDR in human SGC7901/ADM gastric cancer cells. PMID 21823010

Inhibition of B16 murine melanoma metastasis and enhancement of immunity by fever-range whole body hyperthermia.
Apr. 2011 | Jia, Dewei; Rao, Wei; Wang, Chao; Jin, Chao; Wang, Suqiong; Chen, Dongwei; Zhang, Minghui; Guo, Junwei; Chang, Zhijie; Liu, Jing
Whole body hyperthermia (WBH) has been regarded as a promising alternative therapy to cure late stage cancer with metastasis. As the final biological and therapeutic effects are dependent on the specific protocol, the potential of using a microwave-based WBH approach for metastasis inhibition is established and its typical results are discussed. PMID 21501029

Effect of hyperthermia on invasion ability and TGF-β1 expression of breast carcinoma MCF-7 cells.
Apr. 2011 | Xie, Xiaoxue; Shao, Xunfan; Gao, Fuping; Jin, Hekun; Zhou, Jumei; Du, Lehui; Zhang, Yingying; Ouyang, Weiwei; Wang, Xiaowen; Zhao, Lingyun; Zhang, Xiaodong; Tang, Jintian
The present study aimed to investigate heating-induced alterations of breast cancer cell invasion abilities and the potential mechanisms associated with TGF-β1 expression. MCF-7 cells were heated at 43, 45, 47 and 37 °C for 30 min. In vitro cell invasion ability was evaluated by matrigel invasion assay. The activity of matrix metalloproteinase (MMP)-2/9 was investigated by gelatin zymographic assays. Expression of vascular endothelial growth factor (VEGF) and transforming growth factor-β1 (TGF-β1) was investigated by immunocytochemistry and RT-PCR. Apoptosis was analysed by flow-cytometry. The invasive potential of MCF-7 cells was reduced by heating, and MMP-2/9 secretion and enzymatic activity were suppressed. Furthermore, VEGF and TGF-β1 mRNA and proteins were suppressed by hyperthermia. These results suggest that down-regulation of the expression of TGF-β1, EGF and MMPs by hyperthermia probably accounts for the inhibition of the invasive abilities of MCF-7 cells. PMID 21455587

Heat-shock induction of tumor-derived danger signals mediates rapid monocyte differentiation into clinically effective dendritic cells.
Apr. 2011 | Aguilera, Raquel; Saffie, Carlos; Tittarelli, Andrés; González, Fermín E; Ramírez, Marcos; Reyes, Diego; Pereda, Cristián; Hevia, Daniel; García, Tamara; Salazar, Lorena; Ferreira, Arturo; Hermoso, Marcela; Mendoza-Naranjo, Ariadna; Ferrada, Carlos; Garrido, Paola; López, Mercedes N; Salazar-Onfray, Flavio
This study characterizes, biologically and clinically, a novel type of dendritic cells (DC) produced in the short term and called tumor antigen-presenting cells (TAPCells). In particular, we identified factors present in a lysate derived from heat-shocked allogeneic melanoma cells (TRIMEL) that are associated with TAPCells' enhanced capability to induce CD8(+) T-cell responses in vitro and in vaccinated melanoma patients. PMID 21292818

Effect of hyperthermia on the apoptosis and proliferation of CaSki cells.
Apr. 2011 | Zhou, Jumei; Wang, Xiaowen; Du, Lehui; Zhao, Linyun; Lei, Fenglin; Ouyang, Weiwei; Zhang, Yingying; Liao, Yuping; Tang, Jintian
Hyperthermia is a promising treatment for human cervical cancer. However, little is known about whether and under what conditions heat treatment exerts tumor inhibition effects on cervical cancer, and the molecular mechanisms behind these cellular responses have yet to be elucidated. We employed the human cervical cancer cell line CaSki as a cellular model and examined the effect of cell apoptosis and proliferation under gradient thermal conditions (43, 45 and 47˚C for 40 min). Heat treatment was found to induce CaSki cell apoptosis and necrosis. Cell cycle analysis showed that cells were arrested in S phase upon the application of hyperthermia, and MTT analysis revealed that cell viability was also reduced. Of the thermal conditions, 45˚C exhibited the best induction of apoptosis, while 47˚C induced direct fierce necrosis. This was further demonstrated by examining the expression level of several key apoptosis-related genes: caspase-3, Smac and Survivin. During apoptosis, caspase-3 and Smac levels were up-regulated, whereas anti-apoptotic Survivin was down-regulated, enhancing programmed cell death. Our results reveal that heating at ≥45˚C induced cell apoptosis and necrosis, and inhibited cell proliferation at both the cellular and molecular levels. These findings support the use of hyperthermia in a clinical setting for the treatment of human cervical cancer. PMID 21461584

The role of hyperthermia in the battle against cancer.
März 2011 | Palazzi, Mario; Maluta, Sergio; Dall'Oglio, Stefano; Romano, Mario
Hyperthermia, the heating of tumors to 41.5-43 degrees C, could be today considered the fourth pillar of the treatment of cancer. Employed for 20 years in Europe, the U.S.A. and Asia, hyperthermia, used in addition to radiotherapy, chemotherapy and surgery, increases both local control and overall survival, restores the chance of the surgery for inoperable tumors and allows a new low-dosage treatment of relapsed cancers previously treated with high radiotherapy dosage without increasing toxicity. PMID 21388050

Intracavity hyperthermia in nasopharyngeal cancer: a phase III clinical study.
Feb. 2011 | Hua, Yonghong; Ma, Shenglin; Fu, Zhenfu; Hu, Qiaoying; Wang, Lei; Piao, Yongfeng
To compare the local tumour control, survival, and acute mucous toxicity of nasopharyngeal cancer (NPC) patients treated with conventional radiotherapy (RT) combined with intracavity hyperthermia versus conventional RT alone. PMID 20858104

Hyperthermia enhances the effect of β-lapachone to cause γH2AX formations and cell death in human osteosarcoma cells.
Jan. 2011 | Hori, Takeshi; Kondo, Takashi; Lee, Hyemi; Song, Chang W; Park, Heon Joo
The anti-cancer effect of β-lapachone (β-lap) is positively related to the cellular activity of NAD(P)H:quinone oxidoreductase (NQO1). Heat shock has been reported to elevate cellular NQO1. The effect of heating on the NQO1 expression in human osteosarcoma cells (HOS) and the response of the cells to the combined treatment with β-lap and hyperthermia was investigated. PMID 21070139

KNK437, a benzylidene lactam compound, sensitises prostate cancer cells to the apoptotic effect of hyperthermia.
Jan. 2011 | Sahin, Emel; Sahin, Mehmet; Sanlioğlu, Ahter Dilsad; Gümüslü, Saadet
Hyperthermia is known to serve as a powerful tool in the treatment of prostate cancer which is commonly diagnosed in men. Quercetin and KNK437, Hsp70 inhibitors, play an important role in blocking thermotolerance in some cancer cells. In the present study we investigated the effects of KNK437 and quercetin on the acquisition of thermotolerance and heat-induced apoptosis. Also, it was examined whether the possible mechanism triggering apoptotic pathway included caspase-3 activation in prostate cancer cells. For this purpose, PC-3 and LNCaP cells were treated with hyperthermia following pretreatment with or without KNK437 or quercetin. Thermotolerance was investigated by colony formation assay in these cells, while Hsp70 mRNA levels were measured by real time RT-PCR. Sandwich ELISA was used for detection of Hsp70 protein levels. Apoptosis was detected by flow cytometric annexin V binding assay and by western blot analysis of procaspase-3 and cleaved poly (ADP-ribose) polymerase levels. In our study, KNK437 and quercetin inhibited thermotolerance in a dose-dependent manner in PC-3 cells. KNK437 and quercetin decreased heat-induced accumulation of Hsp70 mRNA and protein in PC-3 and LNCaP cells. KNK437 and quercetin pretreatment enhanced the apoptotic effect of hyperthermia in both cells. We found that KNK437 was more effective than quercetin in inducing apoptotic cell death, activation of caspase-3, and cleavage of PARP in prostate cancer cells. We suggest that KNK437 is a useful agent for enhancing the efficiency of hyperthermic therapy which has less toxic side-effects in prostate cancer. PMID 21204621

Hyperthermia combined with radiation for the treatment of locally advanced prostate cancer: long-term results from Dana-Farber Cancer Institute study 94-153.
Jan. 2011 | Hurwitz, Mark D; Hansen, Jorgen L; Prokopios-Davos, Savina; Manola, Judith; Wang, Qian; Bornstein, Bruce A; Hynynen, Kullervo; Kaplan, Irving D
The authors present long-term results from a phase 2 study that assessed the efficacy of transrectal ultrasound hyperthermia plus radiation with or without androgen suppression for the treatment of locally advanced prostate cancer. PMID 20886629

[Multidisciplinary therapy for 984 cancer patients--hyperthermic immunotherapy].
Jan. 2011 | Takeda, Tsutomu; Miyazawa, Kenki; Takeda, Takashi; Takeda, Hiroko; Takeda, Yutaka
We treated 984 advanced or recurrent cancer patients with hyperthermia or immunotherapy (2005/7-2009/12). We have 137 clinical benefit cases (CR, PR and long SD) including 22 complete response (CR) cases. Effective rates of immunotherapy increased from 9.8% to 17.8% using hyperthermia. In the cases of ovarian cancer, head and neck cancer, lung cancer, prostatic cancer, gastric cancer, thyroid cancer and breast cancer, all confirmed high effective rates with hyperthermic immunotherapy. PMID 21224535

Hyperthermia as a treatment for bladder cancer.
Dez. 2010 | Rampersaud, Edward N; Vujaskovic, Zeljko; Inman, Brant A
Modern cancer care is characterized by a focus on organ-sparing multi-modal treatments. In the case of non-muscle-invasive bladder cancer this is particularly true; treatment is focused on reducing the frequency of low-risk recurrences and preventing high-risk progression. Deep regional hyperthermia is an oncologic therapeutic modality that can help achieve these two goals. The combination of hyperthermia with chemotherapy and radiotherapy has improved patient outcomes in several tumor types. In this review, we highlight the biology of therapeutic fever-range hyperthermia, discuss how hyperthermia is administered and dosed, demonstrate how heat can be added to other treatment regimens, and summarize the data supporting the role of hyperthermia in the management of bladder cancer. PMID 21141697

Palliation of recurrent myxofibrosarcoma with radiotherapy and hyperthermia.
Dez. 2010 | Ichinohe, K; Kobayakawa, M
Soft tissue sarcomas are rare biologically and histologically heterogeneous neoplasms that may arise throughout the body. The preferred treatment is total resection with a sufficient margin. Radiotherapy with or without chemotherapy offers another treatment option, but its effectiveness is limited. Hyperthermia, a treatment method that heats tumour tissue by exposing the target tissues to conductive heat sources or non-ionising radiation, is known to enhance the effect of radiotherapy. We report a case of an elderly man with a second recurrent myxofibrosarcoma in the left groin, who responded well to radiotherapy in combination with hyperthermia. This combination treatment was effective in maintaining the patient's quality of life during his remaining years. PMID 21140105

Durable palliation of breast cancer chest wall recurrence with radiation therapy, hyperthermia, and chemotherapy.
Nov. 2010 | Zagar, Timothy M; Higgins, Kristin A; Miles, Edward F; Vujaskovic, Zeljko; Dewhirst, Mark W; Clough, Robert W; Prosnitz, Leonard R; Jones, Ellen L
Chest wall recurrences of breast cancer are a therapeutic challenge and durable local control is difficult to achieve. Our objective was to determine the local progression free survival (LPFS) and toxicity of thermochemoradiotherapy (ThChRT) for chest wall recurrence. PMID 21074876

NADPH oxidase-mediated reactive oxygen species production activates hypoxia-inducible factor-1 (HIF-1) via the ERK pathway after hyperthermia treatment.
Nov. 2010 | Moon, Eui Jung; Sonveaux, Pierre; Porporato, Paolo E; Danhier, Pierre; Gallez, Bernard; Batinic-Haberle, Ines; Nien, Yu-Chih; Schroeder, Thies; Dewhirst, Mark W
Hyperthermia (HT) is a strong adjuvant treatment with radiotherapy and chemotherapy because it causes tumor reoxygenation. However, the detailed molecular mechanisms of how HT enhances tumor oxygenation have not been elucidated. Here we report that 1 h of HT activates hypoxia-inducible factor-1 (HIF-1) in tumors and its downstream targets, vascular endothelial growth factor (VEGF) and pyruvate dehydrogenase kinase 1 (PDK1). Consistent with HIF-1 activation and up-regulation of its downstream genes, HT also enhances tumor perfusion/vascularization and decreases oxygen consumption. As a result, tumor hypoxia is reduced after HT, suggesting that these physiological changes contribute to HT-induced tumor reoxygenation. Because HIF-1 is a potent regulator of tumor vascularization and metabolism, our findings suggest that HIF-1 plays a role in HT-induced tumor reoxygenation by transactivating its downstream targets. We demonstrate that NADPH oxidase-mediated reactive oxygen species production, as a mechanism, up-regulates HIF-1 after HT. Furthermore, we determine that this pathway is initiated by increased transcription of NADPH oxidase-1 through the ERK pathway. In conclusion, this study determines that, although HIF-1 is a good therapeutic target, the timing of its inhibition needs to be optimized to achieve the most beneficial outcome when it is combined with other treatments of HT, radiation, and chemotherapy. PMID 21059928

Combination of ionising irradiation and hyperthermia activates programmed apoptotic and necrotic cell death pathways in human colorectal carcinoma cells.
Nov. 2010 | Mantel, Frederick; Frey, Benjamin; Haslinger, Stefan; Schildkopf, Petra; Sieber, Renate; Ott, Oliver J; Lödermann, Barbara; Rödel, Franz; Sauer, Rolf; Fietkau, Rainer; Gaipl, Udo S
The malignancy of tumor cells can be attenuated by interfering with cell death pathways. Since hyperthermia (HT) is a very potent radiosensitizer, the influence of HT (41.5 °C for 1 hour) alone and in combination with ionising irradiation (X-ray; 5 Gy or 10 Gy) on the form of cell death as well as on the expression of proteins known to be major components in tumor cells' apoptotic and necrotic pathways were examined in colorectal tumor cells. PMID 21069267

Measurement and mathematical modeling of thermally induced injury and heat shock protein expression kinetics in normal and cancerous prostate cells.
Nov. 2010 | Rylander, Marissa Nichole; Feng, Yusheng; Zimmermann, Kristen; Diller, Kenneth R
Hyperthermia can induce heat shock protein (HSP) expression in tumours, which will cause enhanced tumour viability and increased resistance to additional thermal, chemotherapy, and radiation treatments. The study objective was to determine the relationship of hyperthermia protocols with HSP expression kinetics and cell death and develop corresponding computational predictive models of normal and cancerous prostate cell response. PMID 20858083

Biological rationales and clinical applications of temperature controlled hyperthermia--implications for multimodal cancer treatments.
Sep. 2010 | Schildkopf, P; Ott, O J; Frey, B; Wadepohl, M; Sauer, R; Fietkau, R; Gaipl, U S
Hyperthermia (HT)--heating the tumor in the range of 40.0- 44.0 °C--combined with radiation (RT) and/or chemotherapy (CT) is a well proven treatment for malignant tumors. The improvement of the techniques for monitoring and adapting of the desired temperatures even in deep seated tumors has led to a renaissance of, now quality-controlled, HT in multimodal tumor therapy approaches. Randomized clinical trials have shown improved disease-free survival and local tumor control without an increase in toxicity for the combined treatment. In this review, we will focus on biological rationales of HT comprising direct cytotoxicity, systemic effects, chemosensitization, radiosensitization, and immune modulation. The latter is a prerequisite for the control of recurrent tumors and micrometastases. Immunogenic tumor cell death forms induced by HT will be introduced. Modulations of the cytotoxic properties of chemotherapeutic agents by HT as well as synergistic effects of HT with RT will be presented in the context of the main aims of anti-tumor therapy. Furthermore, modern techniques for thermal mapping like magnet resonance imaging will be outlined. The effectiveness of HT will be demonstrated by reviewing recent clinical trials applying HT in addition to CT and/or RT. We conclude that hyperthermia is a very potent radio- as well as chemosensitizer, which fosters the induction of immunogenic dead tumor cells leading to local and in special cases also to systemic tumor control. PMID 20629627

Hyperthermia combined with radiation therapy for superficial breast cancer and chest wall recurrence: a review of the randomised data.
Sep. 2010 | Zagar, Timothy M; Oleson, James R; Vujaskovic, Zeljko; Dewhirst, Mark W; Craciunescu, Oana I; Blackwell, Kimberly L; Prosnitz, Leonard R; Jones, Ellen L
Hyperthermia has long been used in combination with radiation for the treatment of superficial malignancies, in part due to its radiosensitising capabilities. Patients who suffer superficial recurrences of breast cancer, be it in their chest wall following mastectomy, or in their breast after breast conservation, typically have poor clinical outcomes. They often develop distant metastatic disease, but one must not overlook the problems associated with an uncontrolled local failure. Morbidity is enormous, and can significantly impair quality of life. There is no accepted standard of care in treating superficial recurrences of breast cancer, particularly in patients that have previously been irradiated. There is a substantial literature regarding the combined use of hyperthermia and radiotherapy for these superficial recurrences. Most of it is retrospective in nature, but there are several larger phase III randomised trials that show an improved rate of clinical complete response in patients treated with both modalities. In this review article, we will highlight the important prospective data that has been published regarding the combined use of hyperthermia and radiation. PMID 20849256

Hyperthermia potentiates oncolytic herpes viral killing of pancreatic cancer through a heat shock protein pathway.
Juli 2010 | Eisenberg, David P; Carpenter, Susanne G; Adusumilli, Prasad S; Chan, Mei-Ki; Hendershott, Karen J; Yu, Zhenkun; Fong, Yuman
Oncolytic herpes simplex virus-1 (HSV-1) is designed to specifically infect, replicate in, and lyse cancer cells. This study investigates a novel therapeutic regimen, combining the effects of NV1066 (a recombinant HSV-1) and hyperthermia in the treatment of pancreatic cancer. PMID 20633729

Transcranial electro-hyperthermia combined with alkylating chemotherapy in patients with relapsed high-grade gliomas: phase I clinical results.
Juni 2010 | Wismeth, Caecilia; Dudel, Christine; Pascher, Christina; Ramm, Paul; Pietsch, Torsten; Hirschmann, Birgit; Reinert, Christiane; Proescholdt, Martin; Rümmele, Petra; Schuierer, Gerhard; Bogdahn, Ulrich; Hau, Peter
Non-invasive loco-regional electro-hyperthermia (EHT) plus alkylating chemotherapy is occasionally used as salvage treatment in the relapse of patients with high-grade gliomas. Experimental data and retrospective studies suggest potential effects. However, no prospective clinical results are available. We performed a single-center prospective non-controlled single-arm Phase I trial. Main inclusion criteria were recurrent high-grade glioma WHO Grade III or IV, age 18-70, and Karnofsky performance score > or = 70. Primary endpoints were dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) with the combined regimen. Groups of 3 or 4 patients were treated 2-5 times a week in a dose-escalation scheme with EHT. Alkylating chemotherapy (ACNU, nimustin) was administered at a dose of 90 mg/m(2) on day 1 of 42 days for up to six cycles or until tumor progression (PD) or DLT occurred. Fifteen patients with high-grade gliomas were included. Relevant toxicities were local pain and increased focal neurological signs or intracranial pressure. No DLT occurred. In some patients, the administration of mannitol during EHT or long-term use of corticosteroids was necessary to resolve symptoms. Although some patients showed responses in their primarily treated sites, the pattern of response was not well defined. EHT plus alkylating chemotherapy is tolerable in patients with relapse of high-grade gliomas. Episodes of intracranial pressure were, at least, possibly attributed to EHT but did not cause DLTs. A Phase II trial targeting treatment effects is warranted on the basis of the results raised in this trial. PMID 20033471

Neo-adjuvant chemotherapy alone or with regional hyperthermia for localised high-risk soft-tissue sarcoma: a randomised phase 3 multicentre study.
Juni 2010 | Issels, Rolf D; Lindner, Lars H; Verweij, Jaap; Wust, Peter; Reichardt, Peter; Schem, Baard-Christian; Abdel-Rahman, Sultan; Daugaard, Soeren; Salat, Christoph; Wendtner, Clemens-Martin; Vujaskovic, Zeljko; Wessalowski, Rüdiger; Jauch, Karl-Walter; Dürr, Hans Roland; Ploner, Ferdinand; Baur-Melnyk, Andrea; Mansmann, Ulrich; Hiddemann, Wolfgang; Blay, Jean-Yves; Hohenberger, Peter; , ; ,
The optimum treatment for high-risk soft-tissue sarcoma (STS) in adults is unclear. Regional hyperthermia concentrates the action of chemotherapy within the heated tumour region. Phase 2 studies have shown that chemotherapy with regional hyperthermia improves local control compared with chemotherapy alone. We designed a parallel-group randomised controlled trial to assess the safety and efficacy of regional hyperthermia with chemotherapy. PMID 20434400

Combined use of hyperthermia and radiation therapy for treating locally advanced cervix carcinoma.
März 2010 | Lutgens, Ludy; van der Zee, Jacoba; Pijls-Johannesma, Madelon; De Haas-Kock, Danielle Fm; Buijsen, Jeroen; Mastrigt, Ghislaine Apg van; Lammering, Guido; De Ruysscher, Dirk K M; Lambin, Philippe
Hyperthermia is a type of cancer treatment in which body tissue is exposed to high temperatures to damage and kill cancer cells. It was introduced into clinical oncology practice several decades ago. Positive clinical results, mostly obtained in single institutions, resulted in clinical implementation albeit in a limited number of cancer centres worldwide. Because large scale randomised clinical trials (RCTs) are lacking, firm conclusions cannot be drawn regarding its definitive role as an adjunct to radiotherapy in the treatment of locally advanced cervix carcinoma (LACC). PMID 20238344

Fine-tuning immune surveillance by fever-range thermal stress.
März 2010 | Fisher, Daniel T; Vardam, Trupti D; Muhitch, Jason B; Evans, Sharon S
An effectively orchestrated immune response to infection and disease depends on efficient trafficking of lymphocytes across vascular beds at distinct tissue sites. Local inflammation and systemic fever increase immune surveillance to immune-relevant sites throughout the body. During the initiation phase of inflammation, this tightly regulated process improves leukocyte trafficking to the secondary lymphoid organs where they undergo activation and expansion in response to cognate antigen. In the resolution phase following the clearance of the invading pathogen, lymphocyte entry is rapidly returned to baseline conditions. Specialized blood vessels termed high endothelial venules (HEVs) have emerged as critical 'hotspots' controlling the rate of lymphocyte entry into lymphoid organs during both phases of inflammation. In this review, we will examine the remarkably tight regulation of lymphocyte trafficking across HEVs conferred by inflammatory cues associated with the thermal element of fever. These studies have revealed a novel role for interleukin-6 (IL-6) trans-signaling in eliciting systemic effects on lymphocyte trafficking patterns to fine-tune immune surveillance. PMID 19760057

Diverse immune mechanisms may contribute to the survival benefit seen in cancer patients receiving hyperthermia.
März 2010 | Peer, Adrienne J; Grimm, Melissa J; Zynda, Evan R; Repasky, Elizabeth A
There is increasing documentation of significant survival benefits achieved in cancer patients treated with hyperthermia in combination with radiation and/or chemotherapy. Most evidence collected regarding the mechanisms by which hyperthermia positively influences tumor control has centered on in vitro data showing the ability of heat shock temperatures (usually above 42 degrees C) to result in radio- or chemosensitization. However, these high temperatures are difficult to achieve in vivo, and new thermometry data in patients reveal that much of the tumor and surrounding region is only heated to 40-41 degrees C or less as a result of vascular drainage from the target zone of the heated tumor. Thus, there is now a growing appreciation of a role for mild hyperthermia in the stimulation of various arms of the immune system in contributing to long term protection from tumor growth. Indeed, a review of recent literature suggests the existence of an array of thermally sensitive functions which may exist naturally to help the organism to establish a new "set point" of immune responsiveness during fever. This review summarizes recent literature identifying complex effects of temperature on immune cells and potential cellular mechanisms by which increased temperature may enhance immune surveillance. PMID 19756410

Enhanced T-cell activation by immature dendritic cells loaded with HSP70-expressing heat-killed melanoma cells.
Feb. 2010 | Knudsen, Susanne; Schardt, Anke; Buhl, Timo; Boeckmann, Lars; Schön, Michael P; Neumann, Christine; Haenssle, Holger A
Vaccination protocols that utilize dendritic cells (DCs) to elicit therapeutic immunity against tumors are the subject of intense research. Given that the capacity of DCs to cross-present antigens is physiologically low, there is considerable interest to develop strategies that enhance that pathway. In order to best exploit the enhanced cross-presentation of antigens bound to heat shock protein 70 (HSP70), we analysed melanoma cell preparations for their HSP70 expression. Western blotting revealed strong upregulation of HSP70 after heat-killing in contrast to UV-B irradiation. When the uptake of heat-killed necrotic cells by DCs at various levels of maturation was assessed, 61 +/- 7% of immature DCs (iDCs) internalized fluorescence-labelled necrotic material. Apoptotic material from UV-B-irradiated cells was internalized by only 48 +/- 5% of iDCs. Maturation-inducing cytokines did not affect the uptake when added simultaneously with the tumor cell preparations. Loading DCs with heat-necrotic or apoptotic melanoma cells slightly reduced CD83 expression while leaving CD208 (DC-LAMP) expression unchanged. As determined by IFN-gamma-detecting enzyme-linked-immunospot assays, iDCs loaded with heat-killed melanoma cells activated autologous T cells most effectively when used without any further maturation, whereas DCs loaded with apoptotic material required maturation. In conclusion, HSP70-expressing melanoma cells could be generated by heat-killing. Loading iDCs with heat-killed melanoma cells resulted in a superior priming of autologous T cells in vitro. PMID 19758341

Regional abdominal hyperthermia combined with systemic chemotherapy for the treatment of patients with ovarian cancer relapse: Results of a pilot study.
Feb. 2010 | Fotopoulou, Christina; Cho, Chie Hee; Kraetschell, Robert; Gellermann, Johanna; Wust, Peter; Lichtenegger, Werner; Sehouli, Jalid
Due to the poor prognosis of patients with ovarian cancer relapse (OCR), newer strategies are warranted to improve the therapeutic index. We performed a prospective phase I/II-study of regional abdominal hyperthermia (RHT) combined with systemic chemotherapy in OCR patients in order to evaluate outcome, efficacy and tolerance. PMID 20146566

Heat shock proteins and immunity: application of hyperthermia for immunomodulation.
Dez. 2009 | Torigoe, Toshihiko; Tamura, Yasuaki; Sato, Noriyuki
Heat shock proteins (HSPs) play an important role as 'endogenous danger signals' in the immune surveillance system. Extracellular HSPs released from damaged cells can stimulate professional antigen-presenting cells, followed by cytokine release and expression of cell surface molecules. In addition to such activity stimulating innate immunity, extracellular HSPs can promote the cross-presentation of HSP-bound peptide antigens to MHC class I molecules in dendritic cells, leading to efficient induction of antigen-specific cytotoxic T-lymphocytes. The roles of HSPs stimulating both innate immunity and adaptive immunity can explain at least in part the molecular mechanism by which thermal stress bolsters the host immune system. In the present review, we present novel aspects of the roles of HSPs in immunity and discuss the therapeutic application of hyperthermia for immunomodulation. PMID 20021222

Abrogation of local cancer recurrence after radiofrequency ablation by dendritic cell-based hyperthermic tumor vaccine.
Nov. 2009 | Liu, Qiong; Zhai, Bo; Yang, Wen; Yu, Le-Xing; Dong, Wei; He, Ya-Qin; Chen, Lei; Tang, Liang; Lin, Yan; Huang, Dan-Dan; Wu, Hong-Ping; Wu, Meng-Chao; Yan, He-Xin; Wang, Hong-Yang
Local recurrence is a therapeutic challenge for radiofrequency ablation (RFA) in treatment of small solid focal malignancies. Here we show that RFA induced heat shock proteins (HSPs) expression and high mobility group box-1 (HMGB1) translocation in xenografted melanoma, which might create a proinflammatory microenvironment that favors tumor antigen presentation and activation of the effector T cells. On this basis, we investigate whether a prime-boost strategy combining a prime with heat-shocked tumor cell lysate-pulsed dendritic cell (HT-DC) followed by an in situ boost with radiofrequency thermal ablation can prevent local tumor recurrence. The combination treatment with HT-DC and RFA showed potent antitumor effects, with >or=90% of tumor recurrence abrogated following RFA treatment. By contrast, prevaccination with unheated tumor lysate-pulsed DC had little effect on tumor relapse. Analysis of the underlying mechanism revealed that splenocytes from mice treated with HT-DC plus RFA contained significantly more tumor-specific, IFN-gamma-secreting T cells compared with control groups. Moreover, adoptive transfer of splenocytes from successfully treated tumor-free mice protected naive animals from tumor recurrence following RFA, and this was mediated mainly by CD8(+) T cells. Therefore, the optimal priming for the DC vaccination before RFA is important for boosting antigen-specific T cell responses and prevention of cancer recurrence. PMID 19773743

Heat shock proteins in glioblastomas.
Nov. 2009 | Yang, Isaac; Fang, Shanna; Parsa, Andrew T
Glioblastoma multiforme is the most common primary central nervous system tumor. The prognosis for these malignant brain tumors is poor, with a median survival of 14 months and a 5-year survival rate below 2%. Development of novel treatments is essential to improving survival and quality of life for these patients. Endogenous heat shock proteins have been implicated in mediation of both adaptive and innate immunity, and there is a rising interest in the use of this safe and multifaceted heat shock protein vaccine therapy as a promising treatment for human cancers, including glioblastoma multiforme. PMID 19944971

Heat-shock protein vaccines as active immunotherapy against human gliomas.
Nov. 2009 | Yang, Isaac; Han, Seunggu; Parsa, Andrew T
Modern advances in cancer immunotherapy have led to the development of active immunotherapy that utilizes tumor-associated antigens to induce a specific immune response against the tumor. Current methods of immunotherapy implementation are based on the principle that tumor-associated antigens are capable of being processed by antigen-presenting cells and inducing an activated cytotoxic T-lymphocyte-specific immune response that targets the tumor cells. Antigen internalization and processing by antigen-presenting cells, such as dendritic cells, or macrophages results in their surface association with MHC class I molecules, which can be recognized by an antigen-specific cytotoxic T-lymphocyte adaptive immune response. With the aim of augmenting current immunotherapeutic modalities, much effort has been directed towards enhancing antigen-presenting cell activation and optimizing the processing of tumor-associated antigens and major histocompatibility molecules. The goal of these immunotherapy modifications is to ultimately improve the adaptive specific immune response in killing of tumor cells while sparing normal tissues. Immunotherapy has been actively studied and applied in glioblastomas. Preclinical animal models have shown the feasibility of an active immunotherapy approach through the utilization of tumor vaccines, and recently several clinical studies have also been initiated. Recently, endogenous heat-shock proteins have been implicated in the mediation of both the adaptive and innate immune responses. They are now being investigated as a potential modality and adjuvant to immunotherapy, and they represent a promising novel treatment for human glioblastomas. PMID 19895242

Quadrimodal treatment of high-risk T1 and T2 bladder cancer: transurethral tumor resection followed by concurrent radiochemotherapy and regional deep hyperthermia.
Nov. 2009 | Wittlinger, Michael; Rödel, Claus M; Weiss, Christian; Krause, Steffen F; Kühn, Reinhard; Fietkau, Rainer; Sauer, Rolf; Ott, Oliver J
To assess the safety and effectiveness of treating high-risk T1 and T2 bladder cancer with transurethral resection (TUR-BT) followed by radiochemotherapy (RCT) combined with regional deep hyperthermia (RHT). PMID 19837472

Oncothermia treatment of cancer: from the laboratory to clinic.
Okt. 2009 | Andocs, G; Szasz, O; Szasz, A
Oncothermia is a long-time applied method (since 1989) in oncology. Its clinical results excellently show its advantages, however the details of its mechanism are under investigation even today. The method is based on a self-selective process of energy concentration and targets the membrane of the malignant cell, using the temperature gradient and the beta-dispersion of the membrane proteins. To prove the theory we show the experimental evidences in vitro experiments where we showed the definite difference between the conventional heating and the oncothermia at the same temperature. In the next step, we studied some xenograft nude-mice models, verifying the temperature-dependent and non temperature dependent factors. In addition, the synergic effect with some chemotherapies were studied, having more efficacy of the oncothermia with drugs than the conventional heating. These experiments show the definite advantages of the oncothermia compared to its classical counterpart, acting on the same temperature. We have also proved the beneficial effect of oncothermia treatment in the veterinary practice Oncothermia is applied in numerous clinics and hospitals, and we would like to show some characteristic case-reports and also the clinical benefit on the survival time elongation of liver-, pancreas-, brain-, and lung-tumor-lesions. PMID 19811397

Preliminary results of M-VAC chemotherapy combined with mild hyperthermia, a new therapeutic strategy for advanced or metastatic transitional cell carcinoma of the urothelium.
Aug. 2009 | Yamada, Yoshiaki; Itoh, Youko; Aoki, Shigeyuki; Nakamura, Kogenta; Taki, Tomohiro; Naruse, Katsuya; Tobiume, Motoi; Zennami, Kenji; Katsuda, Remi; Kato, Yoshiharu; Watanabe, Masahito; Nishikawa, Genya; Minami, Miwako; Nakahira, Mariko; Ukai, Sayaka; Sawada, Masaki; Kitamura, Akiko; Honda, Nobuaki
We evaluated the efficacy and safety of M-VAC chemotherapy combined with mild hyperthermia, a new therapeutic strategy for advanced metastatic transitional cell carcinoma of the urothelium. PMID 19277660

Hyperthermia dose-effect relationship in 420 patients with cervical cancer treated with combined radiotherapy and hyperthermia.
Juli 2009 | Franckena, Martine; Fatehi, Daryoush; de Bruijne, Maarten; Canters, Richard A M; van Norden, Yvette; Mens, Jan Willem; van Rhoon, Gerard C; van der Zee, Jacoba
Adding hyperthermia to standard radiotherapy (RT+HT) improves treatment outcome for patients with locally advanced cervical cancer (LACC). We investigated the effect of hyperthermia dose on treatment outcome for patients with LACC treated with RT+HT. We collected treatment and outcome data of 420 patients with LACC treated with hyperthermia at our institute from 1990 to 2005. Univariate and multivariate analyses were performed on response rate, local control, disease-specific survival and toxicity for these patients to search for a thermal dose response relationship. Besides commonly identified prognostic factors in LACC like tumour stage, performance status, radiotherapy dose and tumour size, thermal parameters involving both temperature and duration of heating emerged as significant predictors of the various end-points. The more commonly used CEM43T90 (cumulative equivalent minutes of T90 above 43 degrees C) was less influential than TRISE (based on the average T50 increase and the duration of heating, normalised to the scheduled duration of treatment). CEM43T90 and TRISE measured intraluminally correlate significantly and independently with tumour control and survival. These findings stimulate further technological development and improvement of deep hyperthermia, as they strongly suggest that it might be worthwhile to increase the thermal dose for LACC, either by treatment optimisation or by prolonging the treatment time. These results also confirm the beneficial effects from hyperthermia as demonstrated in our earlier randomised trial, and justify applying radiotherapy and hyperthermia as treatment of choice for patients with advanced cervical cancer. PMID 19361982

Hyperthermia as an immunotherapy strategy for cancer.
Juni 2009 | Skitzki, Joseph J; Repasky, Elizabeth A; Evans, Sharon S
The use of hyperthermia as an adjunct to cancer immunotherapy is supported by an increasing number of research data. Both preclinical and clinical data results have demonstrated improved antitumor immune responses with the addition of mild hyperthermia. The molecular mechanisms responsible for the improved immune reactivity observed in the presence of hyperthermia include the generation of Hsps, the activation of antigen-presenting cells and changes in lymphocyte trafficking. Understanding these hyperthermia-induced processes can serve as the foundation for analyzing current clinical trials, as well as designing future trials in cancer immunotherapy. PMID 19513944

Nitric oxide-mediated inhibition of NFkappaB regulates hyperthermia-induced apoptosis.
März 2009 | Aravindan, Natarajan; Mohan, Sumathy; Herman, Terence S; Natarajan, Mohan
Ascertaining the upstream regulatory mechanisms of hyperthermia-induced apoptosis is important to understand the role of hyperthermia in combined modality cancer therapy. Accordingly, we investigated whether (i) hyperthermia-induced apoptosis is mediated through the nitric oxide (NO) signaling pathway and (ii) inhibition of post-translational modification of IkappaBalpha and down regulation of NFkappaB-DNA binding activity is an intermediate step in NO-dependent apoptosis in MCF-7 breast cancer cells. For hyperthermia treatment, the cells were exposed to 43 degrees C. Intracellular NO levels measured by the fluorescent intensity of DAF-2A and iNOS expression by immunobloting revealed an increased level of iNOS dependent NO production after 43 degrees C. Apoptosis measured by Annexin V expression and cell survival by clonogenic assay showed a 20% increase in apoptosis after 43 degrees C treatments. EMSA analysis showed a dose-dependent inhibition of NFkappaB-DNA binding activity. The hyperthermia-mediated inhibition of NFkappaB was persistent even after 48 h. Inhibition of NO by L-NAME rescued the NFkappaB-DNA binding activity and inhibits heat-induced apoptosis. Similarly, over-expression of NFkappaB by transient transfection inhibits heat-induced apoptosis. These results demonstrate that apoptosis upon hyperthermia exposure of MCF-7 cells is regulated by NO-mediated suppression of NFkappaB. PMID 19204936

Use of the concept of equivalent biologically effective dose (BED) to quantify the contribution of hyperthermia to local tumor control in radiohyperthermia cervical cancer trials, and comparison with radiochemotherapy results.
März 2009 | Plataniotis, George A; Dale, Roger G
To express the magnitude of contribution of hyperthermia to local tumor control in radiohyperthermia (RT/HT) cervical cancer trials, in terms of the radiation-equivalent biologically effective dose (BED) and to explore the potential of the combined modalities in the treatment of this neoplasm. PMID 19306750

Regulation of heat-induced apoptosis by Mcl-1 degradation and its inhibition by Hsp70.
März 2009 | Stankiewicz, A R; Livingstone, A M; Mohseni, N; Mosser, D D
Cellular stress eliminates irreversibly damaged cells by initiating the intrinsic death pathway. Cell stress is sensed by pro- and antiapoptotic members of the Bcl-2 protein family, which regulate the release of apoptogenic factors, such as cytochrome c, from mitochondria. Exposure of cells to hyperthermia results in the activation of the proapoptotic Bcl-2 family protein Bax, which plays an essential role in cytochrome c release. Heat directly affects Bax activity in vitro; however, antiapoptotic Bcl-2 family proteins, such as Bcl-xL, can suppress this activation, suggesting that a second heat-sensitive step must be breached before apoptosis ensues in cells exposed to hyperthermia. Here we show that heat shock causes the loss of Mcl-1 protein. Depletion of Noxa by short hairpin RNA protected cells from hyperthermia by preventing Mcl-1 degradation. Heat shock caused the dissociation of Noxa from Mcl-1, which allowed binding of the BH3-containing ubiquitin ligase Mule followed by Mcl-1 ubiquitination and degradation. Overexpression of Hsp70, which prevents heat-induced Bax activation, stabilized Mcl-1 protein levels in heat-shocked cells. This resulted from reduced Mule binding and ubiquitination as well as enhanced Mcl-1 expression compared with cells without Hsp70. Our results demonstrate that loss of Mcl-1 is a critical heat-sensitive step leading to Bax activation that is controlled by Hsp70. PMID 19148187

The effect of mild whole-body hyperthermia on systemic levels of TNF-alpha, IL-1beta, and IL-6 in patients with ankylosing spondylitis.
Feb. 2009 | Tarner, Ingo H; Müller-Ladner, Ulf; Uhlemann, Christine; Lange, Uwe
Serial mild whole-body hyperthermia is a widely used balneotherapy modality for clinically inactive ankylosing spondylitis (AS) in rehabilitative medicine. Thus far, the mechanisms of its favorable influence on the symptoms of AS are not completely understood. We therefore analyzed the effect of mild whole-body hyperthermia on the systemic levels of pivotal proinflammatory cytokines. Twelve male subjects with AS and 12 healthy control subjects received nine cycles of whole-body hyperthermia (target body core temperature, 38.5 degrees C; duration, 50 min). Serum samples were taken at the beginning of the last cycle and at 1, 6, and 24 h for measurement of tumor necrosis factor alpha, interleukin 1beta and interleukin 6. Significant differences of cytokine levels were found between both groups. In AS patients, hyperthermia caused a significant reduction of all cytokines by 40-50%. Thus, serial mild whole-body hyperthermia in AS results in heat-induced changes of the proinflammatory cytokine network. PMID 19089489

Strong synergy of heat and modulated electromagnetic field in tumor cell killing.
Feb. 2009 | Andocs, Gabor; Renner, Helmut; Balogh, Lajos; Fonyad, Laszlo; Jakab, Csaba; Szasz, Andras
Hyperthermia is an emerging complementary method in radiooncology. Despite many positive studies and comprehensive reviews, the method is not widely accepted as a combination to radiotherapy. Modulated electrohyperthermia (mEHT; capacitive, electric field modulated, 13.56 MHz) has been used in clinical practice for almost 2 decades in Germany, Austria and Hungary. This in vivo study in nude mice xenograft tumors compares mEHT with "classic" radiative hyperthermia (radHT). PMID 19240999

Hyperthermia as an adjunctive treatment for soft-tissue sarcoma.
Feb. 2009 | Pennacchioli, Elisabetta; Fiore, Marco; Gronchi, Alessandro
The treatment for high-risk soft-tissue sarcomas (STSs) in adults remains a challenge for the multidisciplinary approach. Despite aggressive local treatment, high-risk STSs have a tendency for hematogenous spread, which is related, for each histologically distinct sarcoma, to risk factors, such as pathologic grade, size and location. The multimodality approach focuses on the combination of radiochemotherapy in a neoadjuvant or adjuvant setting, surgery being considered the mainstay of local treatment. Therefore, current clinical research aims include preoperative treatment to control systemic microscopic disease and to downsize the primary tumor mass. Within the past 20 years, the application of hyperthermia has been integrated in multimodal treatment strategies in several forms of advanced malignant tumors, as well as in STSs. Hyperthermia is of clinical interest in the temperature range of 40-43 degrees C. Higher temperatures of 44-46 degrees C are not clinically realistic. The rationale for the combination of cytotoxic drugs with regional hyperthermia in the treatment of STS is based upon experimental and clinical evidence that heat increases the killing of tumor cells by direct thermal toxicity and enhances the efficacy of some drugs, such as alkylating agents and platinum analogs. Moreover, recent results show that hyperthermia may be able to modulate the immune system by inducing the expression of heat-shock proteins. The approach of multimodality treatment in STS has used regional hyperthermia with systemic chemotherapy within a preoperative and postoperative strategy. The synergistic effect of hyperthermia with chemotherapy is also used in locoregional treatments, such as isolated limb perfusion and intraperitoneal chemotherapy. PMID 19192958

Whole-body hyperthermia (WBH) in combination with carboplatin in patients with recurrent ovarian cancer - a phase II study.
Jan. 2009 | Atmaca, Akin; Al-Batran, Salah-Eddin; Neumann, Antje; Kolassa, Yvonne; Jäger, Dirk; Knuth, Alexander; Jäger, Elke
Despite considerable progress in the front-line treatment in patient with advanced ovarian cancer, the outcome of patients with recurrent or refractory disease is still poor. Based on promising results of a pilot study, we initiated a phase II study with WBH and carboplatin in pretreated patients with advanced ovarian cancer to investigate the toxicity and efficacy of WBH in combination with carboplatin. PMID 19059635

Hyperthermia-treated mesenchymal stem cells exert antitumor effects on human carcinoma cell line.
Jan. 2009 | Cho, Jung Ah; Park, Ho; Kim, Hee Kyung; Lim, Eun Hye; Seo, Sang Won; Choi, Joong Sub; Lee, Kyo Won
Mesenchymal stem cells (MSCs) possess the potential for differentiation into multilineages. MSCs have been reported to play a role as precursors for tumor stroma in providing a favorable environment for tumor progression. Hyperthermia destroys cancer cells by raising the temperature of tumor-loaded tissue to 40 degrees C to 43 degrees C and causes indirect sensitizing effects when combined with chemo- and/or radiotherapy. However, how hyperthermia affects the tumor-supportive stroma is unknown. Here, the authors investigated the effects of hyperthermia-treated MSCs, from different sources, on the human ovarian cancer cell line SK-OV-3. PMID 19109817

TIMP-1-GPI in combination with hyperthermic treatment of melanoma increases sensitivity to FAS-mediated apoptosis.
Jan. 2009 | Djafarzadeh, Roghieh; Milani, Valeria; Rieth, Nicole; von Luettichau, Irene; Skrablin, Petra S; Hofstetter, Monika; Noessner, Elfriede; Nelson, Peter J
Resistance to apoptosis is a prominent feature of malignant melanoma. Hyperthermic therapy can be an effective adjuvant treatment for some tumors including melanoma. We developed a fusion protein based on the tissue inhibitor of matrix metalloproteinase-1 linked to a glycosylphosphatidylinositol anchor (TIMP-1-GPI). The TIMP-1-GPI-fusion protein shows unique properties. Exogenous administration of TIMP-1-GPI can result in transient morphological changes to treated cells including modulation of proliferation and decreased resistance to apoptosis. The effect of TIMP-1-GPI on the biology of melanoma in the context of a defined hyperthermic dose was evaluated in vitro. Clonogenic assays were used to measure cell survival. Gelatinase zymography determined secretion of MMP-2 and MMP-9. Monoclonal antibody against FAS/CD95 was applied to induce apoptosis. The expression of pro- and anti-apoptotic proteins and the secretion of immunoregulatory cytokines were then evaluated using Western blot and ELISA. TIMP-1-GPI combined with a sub-lethal hyperthermic treatment (41.8 degrees C for 2 h) suppressed tumor cell growth capacity as measured by clonogenic assay. The co-treatment also significantly suppressed tumor cell proliferation, enhanced FAS receptor surface expression increased tumor cell susceptibility to FAS-mediated killing. The increased sensitivity to FAS-induced apoptosis was linked to alterations in the apoptotic mediators Bcl-2, Bax, Bcl-XL and Apaf-1. The agent works in concert with sub-lethal hyperthermic treatment to render melanoma cells sensitive to FAS killing. The targeted delivery of TIMP-1-GPI to tumor environments in the context of regional hyperthermic therapy could be optimized through the use of thermosensitive liposomes. PMID 18618109

Fever-range whole-body thermal therapy combined with cisplatin, gemcitabine, and daily interferon-alpha: a description of a phase I-II protocol.
Dez. 2008 | Bull, Joan M C; Scott, Glenna L; Strebel, Frederick R; Nagle, Verne L; Oliver, Dwight; Redwine, Michael; Rowe, R Wanda; Ahn, Chul W; Koch, Steven M
The purpose of the Phase I component of this study was to find the maximally tolerated dose (MTD) of cisplatin administered within a regimen of fever-range whole body thermal therapy (FR-WB-TT), cisplatin, gemcitabine, and low-dose interferon-alpha (IFN-alpha). The Phase II component aimed to assess which cancer diagnoses responded to the regimen, the response rate, and response duration. PMID 18608594

Regional hyperthermia of the abdomen in conjunction with chemotherapy for peritoneal carcinomatosis: evaluation of two annular-phased-array applicators.
Aug. 2008 | Cho, C H; Wust, P; Hildebrandt, B; Issels, R D; Sehouli, J; Kerner, T; Deja, M; Budach, V; Gellermann, J
Peritoneal carcinomatosis is a stage of gynecological and gastrointestinal malignancies with poor prognosis. Options for enhancing the effect of standard chemotherapy, such as aggressive surgery and intraperitoneal chemotherapy, have limitations. In this phase I/II study, we evaluated regional hyperthermia of the pelvis and abdomen using the annular-phased-array technique as an adjunct to chemotherapy. PMID 18608591

A two-state cell damage model under hyperthermic conditions: theory and in vitro experiments.
Juli 2008 | Feng, Yusheng; Tinsley Oden, J; Rylander, Marissa Nichole
The ultimate goal of cancer treatment utilizing thermotherapy is to eradicate tumors and minimize damage to surrounding host tissues. To achieve this goal, it is important to develop an accurate cell damage model to characterize the population of cell death under various thermal conditions. The traditional Arrhenius model is often used to characterize the damaged cell population under the assumption that the rate of cell damage is proportional to exp(-EaRT), where Ea is the activation energy, R is the universal gas constant, and T is the absolute temperature. However, this model is unable to capture transition phenomena over the entire hyperthermia and ablation temperature range, particularly during the initial stage of heating. Inspired by classical statistical thermodynamic principles, we propose a general two-state model to characterize the entire cell population with two distinct and measurable subpopulations of cells, in which each cell is in one of the two microstates, viable (live) and damaged (dead), respectively. The resulting cell viability can be expressed as C(tau,T)=exp(-Phi(tau,T)kT)(1+exp(-Phi(tau,T)kT)), where k is a constant. The in vitro cell viability experiments revealed that the function Phi(tau,T) can be defined as a function that is linear in exposure time tau when the temperature T is fixed, and linear as well in terms of the reciprocal of temperature T when the variable tau is held as constant. To determine parameters in the function Phi(tau,T), we use in vitro cell viability data from the experiments conducted with human prostate cancerous (PC3) and normal (RWPE-1) cells exposed to thermotherapeutic protocols to correlate with the proposed cell damage model. Very good agreement between experimental data and the derived damage model is obtained. In addition, the new two-state model has the advantage that is less sensitive and more robust due to its well behaved model parameters. PMID 18601458

Immunological response in the mouse melanoma model after local hyperthermia.
Juli 2008 | Kubes, J; Svoboda, J; Rosina, J; Starec, M; Fiserová, A
Our study was aimed to characterize the phenotype and functional endpoints of local microwave hyperthermia (LHT, 42 degrees C) on tumor infiltrating and spleen leukocytes. The effectiveness of LHT applied into the tumor of B16F10 melanoma-bearing C57/BL6 mice was compared with anesthetized and non-treated animals. Subpopulations of leukocytes were analyzed using the flow cytometry, and the cytotoxic activity of splenocytes against syngeneic B16F10 melanoma and NK-sensitive YAC-1 tumor cell lines was evaluated in (51)Cr-release assay. Similarly, the in vitro modification of the heat treatment was performed using healthy and melanoma-bearing splenocytes. We found a 40 % increase of activated monocytes (CD11b+CD69+) infiltration into the tumor microenvironment. In the spleen of experimental animals, the numbers of cytotoxic T lymphocytes (CTLs-CD3+CD8+) and NK cell (CD49b+NK1.1+) raised by 22 % and 14 %, respectively, while the NK1.1+ monocytes decreases by 37 %. This was accompanied by an enhancement of cytotoxic effector function against B16F10 and YAC-1 targets in both in vivo and in vitro conditions. These results demonstrate that LHT induces better killing of syngeneic melanoma targets. Furthermore, LHT evokes the homing of activated monocytes into the tumor microenvironment and increases the counts of NK cells and CTL in the spleen. PMID 17552874

Therapeutic vaccination with dendritic cells pulsed with tumor-derived Hsp70 and a COX-2 inhibitor induces protective immunity against B16 melanoma.
Juni 2008 | Toomey, Deirdre; Conroy, Helen; Jarnicki, Andrew G; Higgins, Sarah C; Sutton, Caroline; Mills, Kingston H G
Prophylactic immunization of mice with autologous tumor-derived heat shock proteins (Hsp) generates effective anti-tumor immunity. However, this approach is ineffective when used therapeutically, partly due to the immunosuppressive effects of the growing tumor. Here we sought to overcome this problem by therapeutic vaccination with dendritic cells (DC) pulsed with Hsp70 and a COX-2 inhibitor. We found that Hsp70 induces IL-6 and IL-10 production and suppressed expression of CD40 on DC. Incubation of DC with tumor-conditioned medium attenuated Hsp70-induced expression of CD80 and induced expression of COX-2. Inhibition of COX-2 partially reversed the stimulatory effect of Hsp70 on DC IL-6 and IL-10 production and enhanced expression of CD80 and MHC classes I and II. Therapeutic administration of DC pulsed in vitro with Hsp70 in the presence of a COX-2 inhibitor significantly reduced progression of B16 tumors in mice and significantly enhanced survival. This was associated with a reduction in the frequency of IL-10-producing CD4(+) T cells and enhancement of IFN-gamma-producing CD8(+) T cells. Our findings provide a novel immunotherapeutic approach against cancer based on attenuation of COX-2-mediated immunosuppression using in vitro modulated DC. PMID 18479787

Regional hyperthermia in high-risk soft tissue sarcomas.
Juni 2008 | Issels, Rolf D
On the basis of the definition of high-risk soft tissue sarcomas and prognostic factors, the most recent developments of preoperative treatment strategies with special emphasis on regional hyperthermia combined chemotherapy are reviewed. PMID 18525341

Hyperthermia induces endoplasmic reticulum-mediated apoptosis in melanoma and non-melanoma skin cancer cells.
März 2008 | Shellman, Yiqun G; Howe, William R; Miller, Leslie A; Goldstein, Nathaniel B; Pacheco, Theresa R; Mahajan, Roop L; LaRue, Susan M; Norris, David A
Hyperthermia has been revived as a promising approach for cancer treatment. To understand the underlying mechanisms of hyperthermic killing of cancer cells, we examined the cytotoxic effects of hyperthermia on various skin cancer cell lines using cell viability, morphological analyses, and caspase activation assays. Hyperthermia induced cytotoxicity in a time- and temperature-dependent manner. At middle dose/time combinations, heat-induced apoptosis, whereas at higher doses, necrosis was the mechanism of cell death. To investigate the mechanisms of hyperthermia-induced apoptosis, we examined the activation of extrinsic (Caspase 8) and intrinsic (Caspase 9) apoptotic pathways. Hyperthermia did not activate Caspases 8 or 9, but did activate Caspase 3/7, suggesting a non-conventional apoptotic pathway. Last, analysis of Grp78 expression and Caspase 12 or 4 activation indicated that hyperthermia induced endoplasmic reticulum-mediated apoptosis. Thus, hyperthermia induced apoptosis in two types of skin cancer cells through endoplasmic reticulum-mediated apoptosis and not through the classical intrinsic or extrinsic apoptosis pathways. Hyperthermia may be a promising treatment for basal cell carcinoma and melanoma, bypassing the antiapoptotic defenses concentrated in the intrinsic and extrinsic apoptosis pathways. These results also raise the possibility that heat may be combined with other approaches for induction of apoptosis to achieve synergistic killing of skin cancers. PMID 17989736

The importance of schedule in whole body thermochemotherapy.
Feb. 2008 | Bull, J M C; Strebel, F R; Jenkins, G N; Deng, W; Rowe, R W
To determine an effective triple-agent schedule combining fever-range whole body thermal therapy (FR-WB-TT) with cisplatin and gemcitabine by optimizing the timing of drug with heat, and drug with drug. PMID 18283593

Experimental evidence for the efficacy of combined therapy of CPT-11 and hyperthermia for squamous cell carcinoma of the esophagus.
Feb. 2008 | Nozoe, Tadahiro; Yasuda, Mitsuhiro; Honda, Masayuki; Imutsuka, Sadaaki; Korenaga, Daisuke
The aim of the current study was to show an anti-tumor effect for esophageal squamous carcinoma cells derived from a combination of hyperthermia and CPT-11, which would ultimately lead to the clinical usage of this therapeutic modality for patients with squamous cell carcinoma of the esophagus. PMID 18265646

Targeted regulation of a lymphocyte-endothelial-interleukin-6 axis by thermal stress.
Jan. 2008 | Evans, Sharon S; Fisher, Daniel T; Skitzki, Joseph J; Chen, Qing
Immune protection from microbial invaders or malignant progression is dependent on the ability of lymphocytes to efficiently traffic across morphologically and biochemically distinct vascular sites throughout the body. Lymphocyte trafficking to target tissues is orchestrated by adhesion molecules and chemokines that stabilize dynamic interactions between circulating lymphocytes and endothelial cells lining blood vessels. While the molecular mechanisms that regulate the efficient migration of lymphocytes across specialized high endothelial venules (HEVs) in secondary lymphoid organs have been extensively characterized, there is a paucity of information available regarding the mechanisms that dictate the rate of lymphocyte entry into tumor tissues. This article summarizes recent evidence that inflammatory cues associated with fever-range thermal stress promote lymphocyte extravasation across HEVs of lymphoid organs through a highly regulated lymphocyte-endothelial-interleukin-6 (IL-6) biological axis. The potential for using thermally-based strategies to improve lymphocyte delivery to the tumor microenvironment during T cell-based immunotherapy will also be discussed. PMID 18214770

Dissecting the role of hyperthermia in natural killer cell mediated anti-tumor responses.
Jan. 2008 | Dayanc, Baris E; Beachy, Sarah H; Ostberg, Julie R; Repasky, Elizabeth A
The effects of hyperthermia on natural killer (NK) cell cytotoxicity against tumor cell targets are not yet fully understood. A more complete understanding of these effects could be important for maximizing the clinical benefits obtained by using hyperthermia for cancer therapy. Here, we summarize results in the literature regarding the effects of elevated temperatures on NK cells and our own recent data on the effects of fever-range temperatures. At treatment temperatures above 40 degrees C, (which is above the physiological body temperatures normally achieved during fever or exercise), both enhancing and inhibitory effects on cytotoxic activity of NK cells against tumor cells have been reported. Our own results have shown that fever-range thermal stress (using a temperature of 39.5 degrees C) enhances human NK cell cytotoxicity against tumor target cells. This effect requires function of the NKG2D receptor of NK cells, and is maximal when both NK and tumor cell targets are heated. Reported heat sensitive cellular targets affected by hyperthermia on tumor cells include heat shock proteins, MICA and MHC Class I. In NK cells, plasma membrane reorganization may occur after mild heat stress. We conclude this review by listing several unresolved questions that should be addressed for a more complete understanding of the molecular mechanisms which underlie the effects of thermal stress on the function of NK cells. Altogether, the available data indicate a strong potential for heat-induced enhancement of NK cell activity in mediating, at least in part, the improved clinical responses seen when hyperthermia is used in combination with other therapies. PMID 18214768

Antitumor effect of whole body hyperthermia with alpha-galactosylceramide in a subcutaneous tumor model of colon cancer.
Nov. 2007 | Hattori, Takeshi; Kokura, Satoshi; Okuda, Toshimitsu; Okayama, Tetsuya; Takagi, Tomohisa; Handa, Osamu; Naito, Yuji; Yoshida, Norimasa; Yoshikawa, Toshikazu
Whole body hyperthermia (WBH) has been used clinically as an adjunct to radio- and chemotherapy in patients with various cancers. Recently, it has been reported that an activation of the immune system has recently been reported as a possible contributor to the therapeutic effects of WBH. Conversely, the glycolipid alpha-galactosylceramide (alpha-GalCer) is recognized by natural killer (NK) T cells together with the monomorphic MHC-like antigen, CD1d, in mice and humans. This study investigated the antitumor effects of WBH combined with alpha-GalCer in a mouse subcutaneous tumor model of colon cancer. PMID 18038289

Hyperthermia today: electric energy, a new opportunity in cancer treatment.
Nov. 2007 | Fiorentini, Giammaria; Szasz, Andras
Hyperthermia is an ancient, but nowadays rapidly developing treatment method in tumor-therapy. Its new paradigm applied in the electro-hyperthermia (oncothermia), which provides energy by means of electric-field and produces non-equilibrium thermal situation in the tissue. The temperature gradients formed in stationary conditions, destroy the membrane of the malignant cells and selectively eliminate the cancer tissue. The characteristic control parameter is the absorbed energy-dose, which is partly used to make the distortions, partly to increase the temperature of the target. This type of technique could be applied for some tumor sites, including brain, soft tissues, liver and abdominal masses, pancreatic cancer, head and neck tumors as well. PMID 17998673

Regression of intestinal adenomas by vaccination with heat shock protein 105-pulsed bone marrow-derived dendritic cells in Apc(Min/+) mice.
Okt. 2007 | Yokomine, Kazunori; Nakatsura, Tetsuya; Senju, Satoru; Nakagata, Naomi; Minohara, Motozumi; Kira, Jun-Ichi; Motomura, Yutaka; Kubo, Tatsuko; Sasaki, Yutaka; Nishimura, Yasuharu
Heat shock protein (HSP) 105 is overexpressed in various cancers, but is expressed at low levels in many normal tissues, except for the testis. A vaccination with HSP105-pulsed bone marrow-derived dendritic cells (BM-DC) induced antitumor immunity without causing an autoimmune reaction in a mouse model. Because Apc(Min/+) mice develop multiple adenomas throughout the intestinal tract by 4 months of age, the mice provide a clinically relevant model of human intestinal tumor. In the present study, we investigated the efficacy of the HSP105-pulsed BM-DC vaccine on tumor regression in the Apc(Min/+) mouse. Western blot and immunohistochemical analyses revealed that the tumors of the Apc(Min/+) mice endogenously overexpressed HSP105. Immunization of the Apc(Min/+) mice with a HSP105-pulsed BM-DC vaccine at 6, 8, and 10 weeks of age significantly reduced the number of small-intestinal polyps accompanied by infiltration of both CD4(+) and CD8(+) T cells in the tumors. Cell depletion experiments proved that both CD4(+) and CD8(+) T cells play a critical role in the activation of antitumor immunity induced by these vaccinations. These findings indicate that the HSP105-pulsed BM-DC vaccine can provide potent immunotherapy for tumors that appear spontaneously as a result of the inactivation of a tumor suppressor gene, such as in the Apc(Min/+) mouse model. PMID 17892515

Fever-range whole body hyperthermia increases the number of perfused tumor blood vessels and therapeutic efficacy of liposomally encapsulated doxorubicin.
Okt. 2007 | Xu, Yan; Choi, Jason; Hylander, Bonnie; Sen, Arindam; Evans, Sharon S; Kraybill, William G; Repasky, Elizabeth A
Two major questions were addressed: (1) Can fever-range whole body hyperthermia (FR-WBH) affect the number of perfused tumor blood vessels? (2) Can pre-treatment with FR-WBH improve accumulation or anti-tumor efficacy of doxorubicin or DOXIL (liposomal doxorubicin)? PMID 17952765

Reversing adriamycin resistance of human breast cancer cells by hyperthermia combined with Interferon alpha and Verapamil.
Aug. 2007 | Zhang, L; Yang, Y; Wei, X Y; Shi, Y R; Liu, H Y; Niu, R F; Hao, X S
One of the major obstacles related to chemotherapy is resistance against anticancer drugs, including Adriamycin (ADM). The purpose of the present work is to investigate the reversal effects on ADM resistance by hyperthermia (42.5 degrees C) combined with two reversal agents (Interferon alpha and Verapamil) in MCF-7/ADR (ADM-resistant MCF-7 breast cancer cell line), and its relevant molecular mechanism of action. The cell survival rate and ADM IC50 of different experiment groups were measured by MTT test. The quantitative expression of MDR1 gene in cells was detected by Real-time PCR, and the expression of P-glycoprotein (P-gp) on the cells surface and the intracellular ADM accumulation was detected by flow cytometry (FCM). The ADM IC50 of the MCF-7/ADR cells decreased 830-fold after combined with Interferon alpha (IFN-alpha) and Verapamil (VRP). Although there was no distinction in the mRNA expression of MDR1, the P-gp on the MCF-7/ADR cell membrane was significantly reduced and the cellular ADM uptake increased markedly as compared to pretreatment. Our results suggeste that hyperthermia induces a considerably reversal activity against ADM resistance synergizing other reversal agents (IFN-alpha and VRP). The reversal mechanism needs further study. However, these features of hyperthermia may be exploited in clinical cancer chemotherapy. PMID 17725099

Laboratory and clinical basis for hyperthermia as a component of intracavitary chemotherapy.
Aug. 2007 | Sugarbaker, P H
Intraoperative chemotherapy with heat has been identified as a treatment option for patients with cancer spread to peritoneal surfaces. This treatment modality is viewed as a supplement to several other treatments for this group of patients including cytoreductive surgery, systemic chemotherapy, early postoperative intraperitoneal chemotherapy, and long-term bidirectional chemotherapy. The pharmacologic basis for using heat to supplement chemotherapy effects are related to the increased penetration of chemotherapy into tumor with hyperthermia, the delayed clearance of chemotherapy from the peritoneal cavity after direct instillation, and an increased cytotoxicity that has been documented with selected chemotherapy agents. Data to support the use of perioperative hyperthermic intraperitoneal chemotherapy with mucinous appendiceal carcinomatosis comes from a large number of single institution phase II studies. Also, peritoneal and pleural mesothelioma are benefited. In colon cancer carcinomatosis, large phase II multi-institutional trials and a single phase III trial documented an increased median survival of these patients from approximately 1 year to over 2 years. Prophylaxis against peritoneal carcinomatosis in gastric cancer has been demonstrated in phase III trials. In ovarian cancer the rationale for this treatment remains large but its current application is limited. Much work needs to be done to identify a proper clinical perspective on hyperthermia used with chemotherapy in patients with peritoneal surface malignancy. PMID 17701534

Localized hyperthermia combined with intratumoral dendritic cells induces systemic antitumor immunity.
Aug. 2007 | Mukhopadhaya, Arunika; Mendecki, Joseph; Dong, Xinyuan; Liu, Laibin; Kalnicki, Shalom; Garg, Madhur; Alfieri, Alan; Guha, Chandan
Prostate adenocarcinoma, treated with localized tumor hyperthermia (LTH), can potentially serve as a source of tumor antigen, where dying apoptotic/necrotic cells release tumor peptides slowly over time. In addition, LTH-treated cells can release heat shock proteins that can chaperone antigenic peptides to antigen-presenting cells, such as dendritic cells. We attempted to discern whether sequential LTH and intratumoral dendritic cell and/or systemic granulocyte macrophage colony-stimulating factor (GM-CSF) would activate antitumor immune response in a syngeneic murine model of prostate cancer (RM-1). Palpable RM-1 tumors, grown in the distal appendage of C57BL/6 male mice, were subjected to LTH (43.7 degrees C for 1 h) x 2, separated by 5 days. Following the second LTH treatment, animals received either PBS or dendritic cells (2 x 10(6)) intratumorally (every 3 days for three injections). Separate cohorts also received i.v. injection of recombinant adenovirus-expressing murine GM-CSF (AdGMCSF), 1 day after LTH. Control animals received AdenoLacZ or AdenoGFP. Intratumoral dendritic cell injection induced tumor-specific T-helper cell activity (IFNgamma ELISPOTS) and CTL activity, which was further augmented by AdGMCSF, indicating amplification of tumor-specific TH1 immunity. The combination of LTH, AdGMCSF, and intratumoral dendritic cell injection resulted in significant tumor growth delays when compared with animal cohorts that received LTH alone. These results support an in situ autovaccination strategy where systemic administration of GM-CSF and/or intratumoral injection of autologous dendritic cells, when combined with LTH, could be an effective treatment for local and systemic recurrence of prostate cancer. PMID 17699785

Conformal radiotherapy plus local hyperthermia in patients affected by locally advanced high risk prostate cancer: preliminary results of a prospective phase II study.
Aug. 2007 | Maluta, S; Dall'Oglio, S; Romano, M; Marciai, N; Pioli, F; Giri, M G; Benecchi, P L; Comunale, L; Porcaro, A B
Hyperthermia has been used in several trials to treat pelvic cancers without excessive toxicity and with positive results. The aim of this study was to evaluate feasibility and results in terms of biochemical recurrence-free, disease-free survival, overall survival, and treatment toxicity profile of hyperthermia combined with radiotherapy in locally advanced high risk prostate cancer. PMID 17701536

Counterpoint: Hyperthermia with radiation therapy for chest wall recurrences.
Apr. 2007 | McCormick, Beryl
The 2007 National Comprehensive Cancer Network Breast Cancer Clinical Practice Guidelines in Oncology include a consideration for hyperthermia (HT) and radiation for women with recurrent locoregional advanced breast cancers after first-line surgery or radiation failed. Although HT in this setting has been used for several decades, recent reports are few. This article reviews the data from several recent studies, selected because they included at least 100 patients. Unresolved issues of radiation dose, optimal temperature and timing of HT, and quality assurance problems with thermometry are apparent from these studies. Although clearly an effective treatment option in this clinical scenario, more research on HT and radiation is needed before this treatment combination can be considered standard care. PMID 17439763

Point: Hyperthermia with radiation for chest wall recurrences.
Apr. 2007 | Jones, Ellen L; Marks, Lawrence B; Prosnitz, Leonard R
Treatment of a locoregional recurrence of breast cancer after mastectomy remains a clinically challenging problem. Often these patients have undergone prior radiotherapy and chemotherapy. Therapeutic options usually include resection or additional radiation; however, the long-term control rates are often suboptimal with these approaches. Data from several randomized trials suggest that the addition of hyperthermia to radiation can increase the response rate for such local recurrences. Therefore, in settings where the available therapies are unlikely to yield local control (e.g., local/ regional recurrence after prior radiation), a reasonable option to consider is radiation with hyperthermia as a radiation sensitizer. This article reviews the rationale and supporting literature for this recommendation. PMID 17439762

Intratumoral injection of dendritic cells in combination with local hyperthermia induces systemic antitumor effect in patients with advanced melanoma.
Apr. 2007 | Guo, Jun; Zhu, Jun; Sheng, Xinan; Wang, Xiaopei; Qu, Li; Han, Yan; Liu, Yuexiang; Zhang, Hui; Huo, Ling; Zhang, Shuhui; Lin, Baohe; Yang, Zhi
Dendritic cells (DC) are potent antigen-presenting cells that can present tumor antigens chaperoned by heat shock proteins (HSPs), while local hyperthermia (LHT) can increase the expression of HSPs. In this study, we determine if intratumoral injection of immature DC after LHT (LHT+IT-DC) induces systemic antitumor immunity in patients with advanced melanoma, and investigate the potential immunological mechanisms involved in the treatments. Patients were randomly assigned to intratumoral administration of autologous immature DC triweekly, with (LHT+IT-DC, arm A, n = 9) or without (IT-DC, arm B, n = 9) LHT. Our results showed that there were no grade 3/4 toxicities. The time to progress (TTP) of arm A was 5 months, significantly longer than that in arm B (2 months, p < 0.05). However, the overall survival time had no statistical difference (13 months vs. 6 months, p > 0.05) between the 2 groups. Our ELISPOT assay showed a significantly increased melanoma-specific IFN-gamma production in arm A, suggesting that LHT+IT-DC was more effective in the induction of cytotoxic T lymphocytes (CTL) than IT-DC alone. Furthermore, we detected an increased HSPs expression 4 hr after the first LHT, an enhanced Th1/Th2 chemokines production 24 hr after the first LHT+IT-DC treatment, a promoted migration of DC to afferent lymph nodes, and a decreased infiltration of regulatory T cells (CD4(+)CD25(+)) and an increased infiltration of active CTL (CD8(+)CD28(+)) 48 hr after the third DC injection in arm A patients. Therefore, LHT+IT-DC can induce effective specific antitumor immunity and facilitate a Th1-polarized immune response in patients with advanced melanoma. PMID 17294445

Enhanced T-cell immunity induced by dendritic cells with phagocytosis of heat shock protein 70 gene-transfected tumor cells in early phase of apoptosis.
März 2007 | Chan, T; Chen, Z; Hao, S; Xu, S; Yuan, J; Saxena, A; Qureshi, M; Zheng, C; Xiang, J
The dual role of heat shock protein 70 (HSP70), as antigenic peptide chaperone and danger signal, makes it especially important in dendritic cell (DC)-based vaccination. In this study, we investigated the impacts of apoptotic transgenic MCA/HSP tumor cells expressing HSP70 on DC maturation, T-cell stimulation and vaccine efficacy. We found that DCs with phagocytosis of MCA/HSP in early phase of apoptosis expressed more pMHC I complexes, stimulated stronger cytotoxic T lymphocyte (CTL) responses (40% specific killing at an E:T cell ratio of 50) and induced immune protection in 90% of mice against MCA tumor cell challenge, compared with 25% specific CTL killing activity and 60% immune protection seen in mice immunized with DC with phagocytosis of MCA/HSP in late phase of apoptosis (P<0.05). Similar results were confirmed in another EG7 tumor model also expressing HSP70. Taken together, our data demonstrate that HSP70 on apoptotic tumor cells stimulate DC maturation, and DC with phagocytosis of apoptotic tumor cells expressing HSP70 in early phase of apoptosis more efficiently induced tumor-specific CTL responses and immunity than DCs with phagocytosis of apoptotic tumor cells in late phase of apoptosis. These results may have an important impact in designing DC-based antitumor vaccines. PMID 17235354

[Malignant peritoneal mesothelioma. Our experienced with triple combined therapy: cytoreduction, intraperitoneal perioperative chemotherapy and hyperthermia].
Feb. 2007 | Gómez Portilla, Alberto; Cendoya, Ignacio; Muriel, Jesús; Olabarria, Ignacio; Guede, Nera; Moraza, Nuria; Fernández, Elena; Martínez de Lecea, Concepción; Magrach, Luis; Martín, Ernesto; Romero, Erika; Aguado, Iker; Valdovinos, Mercedes; Larrabide, Iñaki
Malignant peritoneal mesothelioma is the most common primary neoplasm of the serous peritoneum. Most patients die of the complications of local disease confined to the peritoneal cavity, while nodal or distant dissemination is extremely rare. Prognosis with traditional therapeutic options is dismal, with a median survival of between 4 and 12 months from diagnosis. The application of a new combined therapy with cytoreductive surgery, intraperitoneal perioperative chemotherapy and heated intraperitoneal intraoperative chemotherapy, followed by early postoperative intraperitoneal chemotherapy is currently providing good results, in some instances even allowing curative intent. We present a series of patients treated with this triple combined therapy. PMID 17306123

Fever-range thermal stress promotes lymphocyte trafficking across high endothelial venules via an interleukin 6 trans-signaling mechanism.
Jan. 2007 | Chen, Qing; Fisher, Daniel T; Clancy, Kristen A; Gauguet, Jean-Marc M; Wang, Wan-Chao; Unger, Emily; Rose-John, Stefan; von Andrian, Ulrich H; Baumann, Heinz; Evans, Sharon S
Fever is an evolutionarily conserved response during acute inflammation, although its physiological benefit is poorly understood. Here we show thermal stress in the range of fever temperatures increased the intravascular display of two 'gatekeeper' homing molecules, intercellular adhesion molecule 1 (ICAM-1) and CCL21 chemokine, exclusively in high endothelial venules (HEVs) that are chief portals for the entry of blood-borne lymphocytes into lymphoid organs. Enhanced endothelial expression of ICAM-1 and CCL21 was linked to increased lymphocyte trafficking across HEVs. A bifurcation in the mechanisms controlling HEV adhesion was demonstrated by evidence that the thermal induction of ICAM-1 but not of CCL21 involved an interleukin 6 trans-signaling pathway. Our findings identify the 'HEV axis' as a thermally sensitive alert system that heightens immune surveillance during inflammation by amplifying lymphocyte trafficking to lymphoid organs. PMID 17086187

The role of hyperthermia in combined treatment in the management of soft tissue sarcoma.
Jan. 2007 | Issels, Rolf D; Schlemmer, Marcus; Lindner, Lars H
For high-risk soft tissue sarcomas (HR-STS) of adults, new treatment strategies are needed to improve outcome with regard to local control and overall survival. Systemic chemotherapy has been integrated either after (adjuvant) or before (neoadjuvant) optimal local treatment by surgery and radiotherapy in HR-STS. This short overview summarizes the results of the combination with regional hyperthermia as a new treatment strategy to open a new therapeutic window. PMID 17254531

Hyperthermia and immunity. A brief overview.
Jan. 2007 | Baronzio, Gianfranco; Gramaglia, Alberto; Fiorentini, Gianmaria
After many years, hyperthermia (HT) is experiencing a new resurgence as seen by the positive results of many randomized trials all over the world. Tumour immunity similarly is suggested as the fourth modality of therapy for metastatic tumours from renal carcinoma and melanoma. An overwhelming amount of data from animal models and human patients indicate that whole body and locoregional hyperthermia exerts many biological and therapeutic effects on immune competent cells and cytokines. Among these effects, hyperthermia has recently been demonstrated to enhance the antigen presentation and consequently the activity of dendritic cells. This improvement is obtained through several mechanisms: a) increased lymphocyte recruitment and trafficking into the tumour area; b) increased immunogenicity of heat treated tumour cells; and c) increased production of the heat-shock proteins and costimulatory molecules. The effects and mechanisms of HT on immunity, lymphocyte recruitment and dendritic cell stimulation by heat shock proteins are reviewed here. Moreover the use of HT as an innate immunity booster in association with biological response modifiers is suggested. PMID 17203747

A phase II clinical study on relapsed malignant gliomas treated with electro-hyperthermia.
Jan. 2007 | Fiorentini, Giammaria; Giovanis, Petros; Rossi, Susanna; Dentico, Patrizia; Paola, Raffaele; Turrisi, Gina; Bernardeschi, Paolo
The purpose of this study was to evaluate the activity and toxicity of electro-hyperthermia (ET) on relapsed malignant glioma patients. Twelve patients with histologically diagnosed malignant glioma entered the study. Eight patients had glioblastoma multiforme, two had anaplastic astrocytoma grade III and two had anaplastic oligodendroglioma. All patients were pre-treated with temozolamide-based chemotherapy and radiotherapy. Hyperthermia with short radiofrequency waves of 13.56 MHz was applied using a capacitive coupling technique keeping the skin surface at 20 degrees C. The applied power ranged between 40-150 Watts and the calculated average equivalent temperature in the tumours was above 40 degrees C for more than 90% of the treatment duration. One complete remission and 2 partial remission were achieved, with a response rate of 25%. The median duration of response was 10 months (range 4-32). The median survival of the entire patient population was 9 months, with 25% survival rate at 1 year. ET appears to have some effectiveness in adults with relapsed malignant glioma. PMID 17203754

Combined use of dendritic cells enhances specific antileukemia immunity by leukemia cell-derived heat shock protein 70 in a mouse model with minimal residual leukemia cells.
Dez. 2006 | Iuchi, Yasuyuki; Torimoto, Yoshihiro; Sato, Kazuya; Tamura, Yasuaki; Jimbo, Junko; Inamura, Junki; Shindo, Motohiro; Ikuta, Katsuya; Ohnishi, Kouhei; Kohgo, Yutaka
We have reported that immunotherapy using leukemia cell-derived heat shock proteins (HSPs) is effective against minimal residual disease (MRD) after syngeneic stem cell transplantation (SCT) in mice. However, leukemia patients after SCT are usually immunocompromised and immunologically tolerant to leukemia cells. We investigated whether the use of dendritic cells (DCs) in combination with HSP70 enhances cytotoxicity against B-cell leukemia cell line A20 in mice after syngeneic SCT. All unimmunized mice died of leukemia early after A20 cell inoculation, whereas mice immunized with HSP70 or HSP70-pulsed DCs survived significantly longer. Although only 60% of the HSP70-immunized mice survived, all mice immunized with HSP70-pulsed DCs survived without MRD. In addition, the cytotoxicities against A20 cells for splenocytes from mice immunized with HSP70-pulsed DCs were significantly higher than those of HSP70-immunized mice, and the cytotoxicities against A20 cells were significantly blocked by anti-CD8 antibody and by major histocompatibility complex class I antibody, but not by anti-CD4 antibody. Moreover, abnormalities were detected in neither the biochemical data nor the histopathologic findings. These findings indicate that the combined use of DCs and leukemia cell-derived HSP70 enhances the antileukemia effect by inducing the specific cytotoxicities of CD8+ cytotoxic T-cells, thereby eradicating MRD effectively and safely, even in an immunocompromised state after syngeneic SCT. This approach may thus be useful for further application of HSP in leukemia patients after autologous SCT. PMID 17189229

Gene expression in enhanced apoptosis of human lymphoma U937 cells treated with the combination of different free radical generators and hyperthermia.
Dez. 2006 | Wada, Shigehito; Tabuchi, Yoshiaki; Kondo, Takashi; Cui, Zheng-Guo; Zhao, Qing-Li; Takasaki, Ichiro; Salunga, Thucydides L; Ogawa, Ryohei; Arai, Toshiyuki; Makino, Keisuke; Furuta, Isao
The effects of various free radicals derived from 6-formylpterin (6-FP), alpha-phenyl-tert-butyl nitrone (PBN) and 2,2'-azobis (2-amidinopropane) dihydrochloride (AAPH) combined with hyperthermia, on gene expression in similarly enhanced apoptosis of human lymphoma U937 cells were investigated using cDNA microarrays containing approximately 16,600 genes and computational gene expression analysis tools. When the cells were treated for 10 min at 44 degrees C (15% apoptosis level), 39 up-regulated and 3 down-regulated genes were identified. In the up-regulated genes, apoptosis- and unfolded protein response-associated genes were contained. The combined treatment with heat and either chemical enhanced apoptosis level (approximately 30%) and showed a chemical-specific gene expression pattern. Furthermore, the expression levels of selected genes were confirmed by a real-time quantitative PCR. The present results will provide a basis for further understanding the molecular mechanisms in enhancement of heat-induced apoptosis by different intracellular oxidative stress. PMID 17164180

Hyperthermia combined with intra-thoracic chemotherapy and radiotherapy for malignant pleural mesothelioma.
Nov. 2006 | Xia, Hongqiang; Karasawa, Katsuyuki; Hanyu, Nahoko; Chang, Ta-Chen; Okamoto, Masahiko; Kiguchi, Yurie; Kawakami, Mutsumi; Itazawa, Tomoko
Prognosis for patients with malignant pleural mesothelioma (MPM) remains poor and such patients require intensive treatment. Few studies have examined hyperthermia for MPM. The present study investigated the feasibility of hyperthermia combined with weekly chemo-radiotherapy for patients with MPM and estimated the efficacy of this regimen. PMID 17079218

[Clinical impact of locoregional hyperthermia in gynecological oncology].
Sep. 2006 | Bischoff, J; Lindner, L H; Issels, R D; Costa, S
In the last decade progress in gynecological oncology has been achieved mainly by new cytotoxic drugs and advances in radiation technology. For example, the use of taxanes in the primary therapy of ovarian cancers and of combined radio-chemotherapy in cervical cancer has led to significant prolongations of survival. However, in case of relapse most gynaecological malignancies are associated with very poor prognosis. Efficacy of local and systemic therapy can be increased by combining radiotherapy and/or chemotherapy with locoregional hyperthermia (LRH). Increasing the temperature of the target tissue up to 41-43 degrees C leads to local hyperaemia and the tumor tissue becomes more responsive to cytotoxic interventions. In several prospective randomized studies the combination between LRH and radiotherapy was superior to radiotherapy alone in terms of local control (e. g. chest wall recurrence in breast cancer) and has led to longer overall survival in advanced cervical cancer. Platinum derivatives and other cytotoxic drugs have shown synergistic effects with LRH and the combination of both has elicited high response rates in recurrent cervical cancer. In phase-II-clinical trials the newly developed liposomal anthracyclines demonstrated synergistic effects with LRH in patients with refractory ovarian cancer. Our own experience has shown that adding LRH to radio- and/or chemotherapy is well tolerated by the patients. Despite of the fact, that the available data are still preliminary, the inclusion of LRH into multimodal cancer therapy concepts appears to be very promising. Well-designed comparative studies are still needed to evaluate the role of hyperthermia as an adjunct to conventional cancer therapy. PMID 17001560

Noninvasive magnetic resonance thermography of soft tissue sarcomas during regional hyperthermia: correlation with response and direct thermometry.
Sep. 2006 | Gellermann, Johanna; Hildebrandt, Bert; Issels, Rolf; Ganter, Hildegard; Wlodarczyk, Waldemar; Budach, Volker; Felix, Roland; Tunn, Per-Ulf; Reichardt, Peter; Wust, Peter
The objective of this study was to evaluate noninvasive magnetic resonance (MR) thermography for the monitoring of regional hyperthermia (RHT) in patients with soft tissue sarcomas of the lower extremities and pelvis. PMID 16902986

Analysis of cell proliferation and cell death during in situ hyperthermic treatment of neoplastic cells: a case report of human non-Hodgkin lymphoma.
Juli 2006 | Barni, S; Pontiggia, E; Bertone, V; Pontiggia, P; Mathé, G
In this study we observed the effects in vivo of hyperthermic treatment on the cell kinetics (cell proliferation/cell death) in one case of human non-Hodgkin lymphoma, by analyzing the following morpho-cytochemical parameters: Acridine Orange fluorochromasia, mitotic index, proliferating cell nuclear antigen (PCNA) expression, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) labeling, and ultrastructure morphology. After two hyperthermic exposures there was a significant reduction of cell growth rate (e.g. mitotic and PCNA positive cells) and an increase in cell loss by death. The cell death occurred by the typical apoptotic cascade, namely DNA fragmentation, chromatin hypercondensation and margination, karyorrhexis, ribonucleoproteins segregation and cytoplasm cleavage; in addition some necrotic cells were found. The data indicates that the hyperthermic treatments limit the cell proliferation (e.g. arrest and/or deceleration of the cell cycle) by facilitating the trigger of programmed cell death. It was concluded that thermal injury can be considered an effective inducer of antiproliferative and apoptogenic associated effects on the growth of this kind of neoplasia. PMID 16757146

High-risk soft tissue sarcoma: clinical trial and hyperthermia combined chemotherapy.
Juni 2006 | Issels, Rolf D
For high-risk soft tissue sarcomas (HR-STS) of adults, new treatment strategies are needed to improve outcome with regard to local control and overall survival. Systemic chemotherapy has been integrated either after (adjuvant) or before (neoadjuvant) optimal local treatment by surgery and radiotherapy in HR-STS. This short overview summarizes the results of the combination with regional hyperthermia as a new treatment strategy to open a new therapeutic window. PMID 16754344

Immunization with heat shock protein 105-pulsed dendritic cells leads to tumor rejection in mice.
März 2006 | Yokomine, Kazunori; Nakatsura, Tetsuya; Minohara, Motozumi; Kira, Jun-ichi; Kubo, Tatsuko; Sasaki, Yutaka; Nishimura, Yasuharu
Recently, we reported that heat shock protein 105 (HSP105) DNA vaccination induced anti-tumor immunity. In this study, we set up a preclinical study to investigate the usefulness of dendritic cells (DCs) pulsed with mouse HSP105 as a whole protein for cancer immunotherapy in vivo. The recombinant HSP105 did not induce DC maturation, and the mice vaccinated with HSP105-pulsed BM-DCs were markedly prevented from the growth of subcutaneous tumors, accompanied with a massive infiltration of both CD4+ T cells and CD8+ T cells into the tumors. In depletion experiments, we proved that both CD4+ T cells and CD8+ T cells play a crucial role in anti-tumor immunity. Both CD4+ T cells and CD8+ T cells specific to HSP105 were induced by stimulation with HSP105-pulsed DCs. As a result, vaccination of mice with BM-DCs pulsed with HSP105 itself could elicit a stronger tumor rejection in comparison to DNA vaccination. PMID 16540092

Recent advances in heat shock protein-based cancer vaccines.
Feb. 2006 | Wang, Hao-Hao; Mao, Chen-Yu; Teng, Li-Song; Cao, Jiang
Active immunotherapy has been successful in preventing many infectious diseases, and is being explored for its anti-tumor use. Purified antigens, peptides, gene-based systems and antigens contained in whole cells or cell lysates are used in specific active immunotherapy for cancer, known as cancer vaccines. Cancer vaccines do not directly kill tumor cells, but prime a specific humoral and/or cellular immune response against the tumor. Up to date, many kinds of cancer vaccines have been tested in the world and have shown their own advantages. Heat shock protein (HSP)-based cancer vaccine is one of the outstanding representatives. In this paper, we review recent advances in HSP-based cancer vaccines. PMID 16481277

Hyperthermia enhances CTL cross-priming.
Feb. 2006 | Shi, Hongzhen; Cao, Tinghua; Connolly, John E; Monnet, Laurence; Bennett, Lynda; Chapel, Sylvie; Bagnis, Claude; Mannoni, Patrice; Davoust, Jean; Palucka, A Karolina; Banchereau, Jacques
Dendritic cells (DCs) loaded with killed allogeneic melanoma cells can cross-prime naive CD8(+) T cells to differentiate into melanoma-specific CTLs in 3-wk cultures. In this study we show that DCs loaded with killed melanoma cells that were heated to 42 degrees C before killing are more efficient in cross-priming of naive CD8(+) T cells than DCs loaded with unheated killed melanoma cells. The enhanced cross-priming was demonstrated by several parameters: 1) induction of naive CD8(+) T cell differentiation in 2-wk cultures, 2) enhanced killing of melanoma peptide-pulsed T2 cells, 3) enhanced killing of HLA-A*0201(+) melanoma cells in a standard 4-h chromium release assay, and 4) enhanced capacity to prevent tumor growth in vitro in a tumor regression assay. Two mechanisms might explain the hyperthermia-induced enhanced cross-priming. First, heat-treated melanoma cells expressed increased levels of 70-kDa heat shock protein (HSP70), and enhanced cross-priming could be reproduced by overexpression of HSP70 in melanoma cells transduced with HSP70 encoding lentiviral vector. Second, hyperthermia resulted in the increased transcription of several tumor Ag-associated Ags, including MAGE-B3, -B4, -A8, and -A10. Thus, heat treatment of tumor cells permits enhanced cross-priming, possibly via up-regulation of both HSPs and tumor Ag expression. PMID 16455969

Thermal regulation of lymphocyte trafficking: hot spots of the immune response.
Dez. 2005 | Chen, Qing; Evans, Sharon S
Lymphocytes use extensive vascular networks to traffic to various destinations in the body, including lymphoid organs and extra-lymphoid tissues. This discussion will focus on the emerging evidence that thermal stress regulates the traffic signals that direct the exit of lymphocytes from the vascular freeway. This issue is particularly relevant to T cell-based cancer immunotherapy where delivery of immune effector lymphocytes to neoplastic lesions depends on their extravasation across tumour micro-vessels. Although tumours are frequently highly vascularized by vessels that are competent to support blood flow, the tumour micro-environment has been characterized as non-permissive to lymphocyte extravasation. This may lead to a scenario where limited leukocyte infiltration at tumour sites correlates with a poor prognosis. These observations support the thesis that adjuvant strategies that promote trafficking of tumour-reactive cytolytic leukocytes to tumour sites have the potential to improve the efficacy of immune-based cancer therapy. PMID 16338855

Dynamic control of lymphocyte trafficking by fever-range thermal stress.
Nov. 2005 | Chen, Qing; Fisher, Daniel T; Kucinska, Sylvia A; Wang, Wan-Chao; Evans, Sharon S
Migration of blood-borne lymphocytes into tissues involves a tightly orchestrated sequence of adhesion events. Adhesion molecules and chemokine receptors on the surface of circulating lymphocytes initiate contact with specialized endothelial cells under hemodynamic shear prior to extravasation across the vascular barrier into tissues. Lymphocyte-endothelial adhesion occurs preferentially in high endothelial venules (HEV) of peripheral lymphoid organs. The continuous recirculation of naïve and central memory lymphocytes across lymph node and Peyer's patch HEV underlies immune surveillance and immune homeostasis. Lymphocyte-endothelial interactions are markedly enhanced in HEV-like vessels of extralymphoid organs during physiological responses associated with acute and chronic inflammation. Similar adhesive mechanisms must be invoked for efficient trafficking of immune effector cells to tumor sites in order for the immune system to have an impact on tumor progression. Here we discuss recent evidence for the role of fever-range thermal stress in promoting lymphocyte-endothelial adhesion and trafficking across HEV in peripheral lymphoid organs. Findings are also presented that support the hypothesis that lymphocyte-endothelial interactions are limited within tumor microenvironments. Further understanding of the molecular mechanisms that dynamically promote lymphocyte trafficking in HEV may provide the basis for novel approaches to improve recruitment of immune effector cells to tumor sites. PMID 16044255

Emerging evidence indicates that physiologically relevant thermal stress regulates dendritic cell function.
Nov. 2005 | Ostberg, Julie R; Repasky, Elizabeth A
Elevations in temperature that are associated with inflammation or fever have been linked to improved survival from infections, enhanced immunological functions, and increased control of tumor growth. Over the past few years, several groups have begun to explore the possible linkage among these observations and have tested the hypothesis that various immune cells are especially sensitive to thermal stimulation. However, relatively little is known regarding the effects of thermal stimulation on antigen presenting cells (APCs), such as dendritic cells (DCs). Very recently, several groups have begun to examine the ability of thermal stimuli to regulate the function of these cells which are known to play a pivotal role in the efficacy of vaccines and other immunotherapies. In this review, we summarize what has been discovered about the role of mild thermal stress in regulating various Dendritic cell (DC) activities. Excitingly, it appears that mild elevations of temperature have the potential to enhance antigen uptake, activation associated migration, maturation, cytokine expression and T cell stimulatory activity of DCs. While these studies reveal that the timing, temperature and duration of heating is important, they also set the stage for essential questions that now need to be investigated regarding the molecular mechanisms by which elevated temperatures regulate DC function. With this information, we may soon be able to maximize the strategic use of thermal therapy as an adjuvant, i.e., combining its use with cancer immunotherapies such as vaccines, which depend upon the function of DCs. Several possible strategies and timepoints involving the clinical application of hyperthermia in combination with immunotherapy are presented. PMID 15864585

Chaperone-rich cell lysates, immune activation and tumor vaccination.
Nov. 2005 | Zeng, Yi; Graner, Michael W; Katsanis, Emmanuel
We have utilized a free-solution-isoelectric focusing technique (FS-IEF) to obtain chaperone-rich cell lysates (CRCL) fractions from clarified tumor homogenates. The FS-IEF technique for enriching multiple chaperones from tumor lysate is relatively easy and rapid, yielding sufficient immunogenic material for clinical use. We have shown that tumor-derived CRCL carry antigenic peptides. Dendritic cells (DCs) uptake CRCL and cross-present the chaperoned peptides to T cells. Tumor-derived CRCL induce protective immune responses against a diverse range of murine tumor types in different genetic backgrounds. When compared to purified heat shock protein 70 (HSP70), single antigenic peptide or unfractionated lysate, CRCL have superior ability to activate/mature DCs and are able to induce potent, long lasting and tumor specific T-cell-mediated immunity. While CRCL vaccines were effective as stand-alone therapies, the enhanced immunogenicity arising from CRCL-pulsed DC as a vaccine indicates that CRCL could be the antigen source of choice for DC-based anti-cancer immunotherapies. The nature of CRCL's enhanced immunogenicity may lie in the broader antigenic peptide repertoire as well as the superior immune activation capacity of CRCL. Exongenous CRCL also supply danger signals in the context of apoptotic tumor cells and enhance the immunogenicity of apoptotic tumor cells, leading to tumor-specific T cell dependent long-term immunity. Moreover, CRCL based vaccines can be effectively combined with chemotherapy to treat cancer. Our findings indicate that CRCL have prominent adjuvant effects and are effective sources of tumor antigens for pulsing DCs. Tumor-derived CRCL are promising anti-cancer vaccines that warrant clinical research and development. PMID 15887013

Efficacy of superficial and deep regional hyperthermia combined with systemic chemotherapy and radiotherapy in metastatic melanoma.
Nov. 2005 | Richtig, E; Hoff, M; Rehak, P; Kapp, K; Hofmann-Wellenhof, R; Zalaudek, I; Poschauko, J; Uggowitzer, M; Kohek, P; Smolle, J
Response rates of cutaneous-subcutaneous or lymph node metastases of melanoma to systemic chemotherapy are rather low. We report our clinical experience with superficial and deep regional hyperthermia in combination with radiotherapy and/or chemotherapy with carboplatin. PMID 16296154

Hyperthermia combined with radiation in treatment of locally advanced prostate cancer is associated with a favourable toxicity profile.
Nov. 2005 | Hurwitz, Mark D; Kaplan, Irving D; Hansen, Jorgen L; Prokopios-Davos, Savina; Topulos, George P; Wishnow, Kenneth; Manola, Judith; Bornstein, Bruce A; Hynynen, Kullervo
Hyperthermia is used to treat several pelvic tumours. An important step in establishing a broader role for hyperthermia in treatment of prostate cancer is verification of an acceptable toxicity profile. In this report, short- and long-term toxicity profiles of a completed phase II trial of transrectal ultrasound hyperthermia combined with radiation in treatment of locally advanced prostate cancer are presented. PMID 16278168

Comparison of the anti-tumor effects of various whole-body hyperthermia protocols: correlation with HSP 70 expression and composition of splenic lymphocytes.
Sep. 2005 | Zhang, Honghai; Wang, Weirong; Zhang, Shuhong; Huang, Weida
Whole-body hyperthermia (WBH) has been used as an adjunct approach to radio-/ chemotherapy for tumor therapy for many years. However, the molecular mechanism underlying the enhancement of tumor control is not clearly understood. It has been hypothesized that WBH might activate immune system by inducing the expression of heat shock proteins (HSPs), which are thought to facilitate the presentation of tumor-specific antigens. In the present work, we examined the effects of various thermal doses of WBH on tumor growth delay and HSP70 levels in tumors on C57BL/6 mice, as well as on splenic lymphocyte subpopulations. The maximal WBH effect (about 40% decrease in tumor weight) was achieved by a 2-hour WBH treatment everyday at 40.0 degrees C. By using this treatment schedule, the populations of CD3+/CD4+ T cells and CD3+/CD8+ T cells increased by 4 and 3 times, respectively, at the end of WBH treatment period. When the length of day-by-day WBH treatment was longer than 2 hours or the frequency of WBH treatment was lower than once a day, the effect of tumor growth delay and the population of CD3+ T lymphocyte in spleen increase were discounted. On the other hand, the HSP70 levels in tumor nodules rose continuously as the WBH treating time increased, but the populations of NK cells in spleen did not change significantly. The results suggest that an increased CD3+ T lymphocyte population is closely related to the anti-tumor effect of WBH, which might be a useful marker for effectiveness of hyperthermia. However, neither the levels of HSP70 nor the NK cell populations in spleen appear to correlate to tumor control. PMID 16136780

The anti-tumor effect of interleukin-12 is enhanced by mild (fever-range) thermal therapy.
Sep. 2005 | Pritchard, M T; Wolf, S F; Kraybill, W F; Repasky, Elizabeth A
The cytokine interleukin 12 (IL-12) has resulted in notable anti-tumor activity in animal models and in patients and as a result there is considerable interest in learning how to maximize its therapeutic potential while at the same time reducing its known toxic side effects. Strategies which could maintain its effectiveness while permitting reduced dosage could be especially valuable. In this study we used BALB/c mice bearing CT26 tumors as a model for testing whether combining murine IL-12 with a mild (fever range) whole body hyperthermia protocol could result in such a strategy. Our data revealed that 100 ng of IL-12/mouse/day used in combination with FR-WBH was as effective as one in which 300 ng of IL-12/mouse/day was used alone. Importantly, the mice receiving the combination treatment exhibited fewer treatment related toxicities compared to those that received high dose IL-12 alone. Initiation of the IL-12 treatment immediately after FR-WBH induced the greatest anti-tumor effect. This effect does not appear to depend on differences in IL-12-induced IFN-gamma, but may involve production of nitric oxide (NO), since treatment of mice with a NOS inhibitor, NG-monomethyl-L-arginine (L-NMA), abolishes the additive anti-tumor effect of the combination treatment. Collectively, these data suggest that modification of physiological parameters in the host by mild fever-like thermal stimuli may be an effective and feasible adjuvant for cytokine-based immunotherapeutic strategies. PMID 16136786

Impact of fever-range thermal stress on lymphocyte-endothelial adhesion and lymphocyte trafficking.
Sep. 2005 | Appenheimer, Michelle M; Chen, Qing; Girard, Rachael A; Wang, Wan-Chao; Evans, Sharon S
The evolutionarily conserved febrile response has been associated with improved survival during infection in endothermic and ectothermic species although its protective mechanism of action is not fully understood. Temperatures within the range of physiologic fever influence multiple parameters of the immune response including lymphocyte proliferation and cytotoxic activity, neutrophil and dendritic cell migration, and production or bioactivity of proinflammatory cytokines. This review focuses on the emerging role of fever-range thermal stress in promoting lymphocyte trafficking to secondary lymphoid organs that are major sites for launching effective immune responses during infection or inflammation. Specific emphasis will be on the molecular basis of thermal control of lymphocyte-endothelial adhesion, a critical checkpoint controlling lymphocyte extravasation, as well as the contribution of interleukin-6 (IL-6) trans-signaling to thermal activities. New results are presented indicating that thermal stimulation of lymphocyte homing potential is evident in evolutionarily distant endothermic vertebrate species. These observations support the view that the evolutionarily conserved febrile response contributes to immune protection and host survival by amplifying lymphocyte access to peripheral lymphoid organs. PMID 16136783

An important role for granulocytes in the thermal regulation of colon tumor growth.
Sep. 2005 | Ostberg, Julie R; Ertel, Bradley R; Lanphere, Julie A
Several lines of research show that cells of the immune response are sensitive to thermal variations in their microenvironment, such as that which occurs during inflammation and fever; these data have led to the hypothesis that strategic applications of heat could assist in controlling tumor growth in animal models. The innate immune response is known to play a critical role in the development of effective anti-tumor immunity and granulocytes such as polymorphonuclear neutrophils (PMNs), as key mediators of inflammation, have been suggested to have the potential to initiate immune response cascades against tumors. Thus, we hypothesized that PMNs may play a crucial role in mediating the anti-tumor effects of a mild, fever-range whole-body hyperthermia (FR-WBH) protocol, where core body temperatures are raised to 39.5-40 degrees C for 8 hrs. Indeed, in BALB/c mice bearing the colon tumor CT26, the anti-tumor effect of WBH correlates with increased granulocytic infiltrate at the tumor site as determined using immunohistochemical analysis for Gr-1+ cells. In both BALB/c mice bearing CT26 and SCID mice bearing human colon tumors, PMN depletion in vivo using anti-Gr-1 ascites ablated the anti-tumor effect of mild WBH. Because mild thermal stress is also found to enhance the respiratory burst of granulocytes, these data collectively suggest that the thermal stimulation of granulocytes may help to prevent tumor establishment. Overall, these results may have implications for the design of thermal therapy protocols in cancer immunotherapy. PMID 16136781

Targeting vaccinia to solid tumors with local hyperthermia.
Mai 2005 | Chang, Eugene; Chalikonda, Sricharan; Friedl, Josef; Xu, Hui; Phan, Giao Q; Marincola, Francesco M; Alexander, H Richard; Bartlett, David L
We have previously demonstrated that mutant vaccinia viruses target tumors in vivo after systemic delivery, and they have potential as vectors for tumor-directed gene therapy. We hypothesized that hyperthermia may augment vaccinia delivery to tumors after systemic injection, as hyperthermia increases the permeability of the endothelial vasculature to nanoparticles. In our in vitro experiments, we have shown that hyperthermia does not alter tumor cells' susceptibility to the intrinsic cytopathogenicity of the vaccinia virus compared with normothermic controls. Hyperthermia also does not change the viral infectivity or the level of viral marker gene expression when compared with normothermia. In an in vitro model of endothelial cell monolayer permeability, we have demonstrated that hyperthermia increases the permeability of the monolayer to vaccinia virus and that this phenomenon is completely reversible. In vivo we have demonstrated that the tumors that were treated with systemic vaccinia under conditions of hyperthermia (41.5 degrees C for 30 min) had significantly higher levels of vaccinia marker gene activity (>100-fold) than those treated under normothermic conditions (p < 0.05) and that this effect was specific to tumor. We also demonstrated that mice with 1 cm subcutaneous tumors treated with a systemically delivered, conditionally replicating vaccinia under conditions of hyperthermia had complete tumor regression in 50% and significantly improved antitumor response, compared with normothermic viral-treated controls (mean tumor volume of 110 mm(3) vs 3169 mm(3), 13 days after treatment) and compared with hyperthermic, nonvirally treated control animals (p < 0.0001). Regional hyperthermia improves vaccinia targeting to tumors, and thereby enhances the antitumor response. PMID 15871675

Randomized trial of hyperthermia and radiation for superficial tumors.
Apr. 2005 | Jones, Ellen L; Oleson, James R; Prosnitz, Leonard R; Samulski, Thaddeus V; Vujaskovic, Zeljko; Yu, Daohai; Sanders, Linda L; Dewhirst, Mark W
Randomized clinical trials have demonstrated hyperthermia (HT) enhances radiation response. These trials, however, generally lacked rigorous thermal dose prescription and administration. We report the final results of a prospective randomized trial of superficial tumors (

A thermometry system for quality assurance and documentation of whole body hyperthermia procedures.
März 2005 | Hjertaker, B T; Frøystein, T; Schem, B C
Since December 2001, the Department of Oncology and Medical Physics, Haukeland University Hospital, Norway has been conducting whole body hyperthermia (WBH) studies, treating patients with either ovarian carcinoma or non-Hodgkin lymphomas. Accurate and reliable thermometry instrumentation is important in all types of hyperthermia procedures, particularly in WBH, where the target patient body temperature is 41.8 degrees C. Reliable documentation of side-effects in clinical studies is also dependent on precise temperature monitoring, since in this temperature range even small, but systematic, inaccuracies (0.1-0.2 degrees C) in the temperature monitoring is expected to affect the amount of side effects. Readily available heating and temperature data from previous treatment sessions of the same patient is also valuable for precise temperature control in future treatment sessions. The WBH thermometry system implemented at Haukeland University Hospital is described. It is based on commercially available components, including standard medical thermistor probes, and includes a temperature calibration and verification facility. The thermometry system is accurate, reliable, easy to use, comfortable for the patient and relatively inexpensive. By implementing the Steinhart-Hart polynomial fit to standard medical thermistor probe data, it is shown that the WBH treatment thermometers used can measure the patient body temperatures with a short- and long-term accuracy of +/- 0.01 degrees C. PMID 15764350

Effects of febrile temperature on adenoviral infection and replication: implications for viral therapy of cancer.
Dez. 2004 | Thorne, Stephen H; Brooks, Gabriel; Lee, Yeun-Ling; Au, Tina; Eng, Lawrence F; Reid, Tony
We previously conducted a phase I/II study using arterial infusions of ONYX-015 (dl1520), a replication-selective adenoviral vector, with E1b deleted, for patients with metastatic colorectal cancer. No dose-limiting toxicities occurred, but >90% of the patients experienced fever. The effects of temperature on the replication of dl1520 in normal and transformed cells had not been studied. Therefore, replication and cell viability assays were performed with a panel of nontransformed and transformed cell lines cultured at 37 and 39.5 degrees C and treated with adenovirus type 5 (Ad5) or dl1520. Ad5-mediated cytolytic effects were inhibited and production of infectious particles decreased by >1,000-fold in the nontransformed cells at 39.5 degrees C. Seven of nine of the tumor cell lines retained significant cell-killing effects when treated with Ad5 at 39.5 degrees C. When dl1520 was used, no cytolytic effects were observed at 39.5 degrees C in the nontransformed cell lines; however, cytolytic effects occurred in six of nine tumor cell lines at 39.5 degrees C. Notably, a subset of the tumor cell lines demonstrated increased dl1520-mediated cytolytic effect and replication at 39.5 degrees C. Suppression of Ad5 and dl1520 replication at 39.5 degrees C was not related to p53 status or HSP70 expression. Also, at 39.5 degrees C, E1a expression was inhibited in nontransformed cells but was still abundant in the transformed cells, indicating that a novel early block in viral replication occurred in the nontransformed cells. Fever may therefore augment the therapeutic index of oncolytic viruses by inhibiting replication in normal cells while permitting or enhancing viral replication in some tumor cells. PMID 15596850

Therapeutic cancer vaccines: using unique antigens.
Okt. 2004 | Lewis, Jonathan J
A decade ago, it seemed rational that our rapidly increasing knowledge of the molecular identities of tumor antigens and a deeper understanding of basic immunology would point the way to an effective therapeutic cancer vaccine. Significant progress has been made, but we do not yet have a cancer vaccine that can reliably and consistently induce tumor destruction or improve patient survival. Random mutations in cancer cells generate unique antigens in each individual, and this may be important in terms of generating a therapeutic immune response. Autologous heat shock protein-peptide complexes produced from each patient's tumor is a logical personalized approach that may obviate the need to identify the unique antigens contained in the individual vaccine. Heat shock proteins elicit adaptive and innate immune responses and have been tested in a variety of animal models and different human cancers. Activity has been seen in several animal studies. Early-phase human studies have also suggested some activity in certain cancers. Large, randomized phase 3 studies are ongoing, and these will effectively answer the question of efficacy regarding this approach to therapeutic vaccination. There are sufficient data to support the notion that cancer vaccines can induce anti-tumor immune responses in humans with cancer. How best to translate this increase in immune responsiveness to consistently and reproducibly induce objective cancer regression or increased survival remains unclear at this time. PMID 15297620

A feasibility study in oesophageal carcinoma using deep loco-regional hyperthermia combined with concurrent chemotherapy followed by surgery.
Sep. 2004 | Albregts, M; Hulshof, M C C M; Zum Vörde Sive Vörding, P J; van Lanschot, J J B; Richel, D J; Crezee, H; Fockens, P; van Dijk, J D P; González González, D
This phase I-II study investigated the feasibility of external deep loco-regional hyperthermia in localized primarily operable carcinoma of the thoracic oesophagus and gastro-oesophageal junction. Toxicity when combining neo-adjuvant hyperthermia with concurrent chemotherapy (CDDP and etoposide) was evaluated. Hyperthermia was given with a four antenna array, operating at 70 MHz arranged around the thorax. Temperatures were monitored rectally, intra-oesophageal at tumour level and intramuscular near the spine. In four steps, a thermal dose escalation was performed from 15-60 min of heating to 41 degrees C with two patients in each step. The combined treatment courses were repeated every 3 weeks for a maximum of four courses. From January 1999-February 2002, 31 patients were included. Pre-treatment tumour stage mainly consisted of T3N1 (stage III) tumours, with a mean length of 6 cm. The maximum tumour temperature failed to reach at least 41 degrees C in five patients during the test session of hyperthermia alone. Combined hyperthermia and chemotherapy was given 55 times in 26 patients. The amplitude was set at a ratio between top:bottom:left:right = 1:3:3:3, with a power range of 800-1000 W. Thermal data showed that is was technically feasible to heat the oesophagus; the median results were T(90) = 39.3 degrees C, T(50) = 40 degrees C, T(10) = 40.7 degrees C and a median T(max) = 41.9 degrees C. In more distally located tumours higher temperatures were reached. In one patient, a transient grade 2 sensory neuropathy was seen. Further toxicity was mainly of haematological origin. Blisters or fat necrosis were not observed. Twenty-two patients underwent oesophageal-cardia resection with gastric tube reconstruction. There was no report of complications in the post-operative phase, which could be contributed to either the prior chemotherapy or the hyperthermia. PMID 15370820

Thermal enhancement of oxaliplatin-induced inhibition of cell proliferation and cell cycle progression in human carcinoma cell lines.
Juni 2004 | Atallah, D; Marsaud, V; Radanyi, C; Kornprobst, M; Rouzier, R; Elias, D; Renoir, J-M
Hyperthermia is used to treat intraperitoneal colorectal carcinomatosis. In this setting, the molecular effects of oxaliplatin and hyperthermia, in combination and alone, were deciphered in ovarian and colon cancer cells. The combined antiproliferative effects of hyperthermia and oxaliplatin (Eloxatine) on human IGROV-1 ovarian carcinoma, Caco-2 and HT-29 colon carcinoma cell lines were investigated by cell viability test, cell cycle analysis and modulation of expression of cell cycle-related proteins. Oxaliplatin inhibited growth of all cell lines in a dose-dependent manner. The efficacy of the drug was markedly enhanced by concurrent exposure to mild heat shock (1 h, 42 degree C). In IGROV-1 cells, a low concentration (15 microg/ml) of oxaliplatin in combination with hyperthermia induced a transient G2/M arrest. In both colon carcinoma cell lines, a G1/S arrest with a reduction of the G0/G1 population occurred. In IGROV-1 and Caco-2 cells, growth arrest was accompanied by apoptosis as suggested by the appearance of sub-G1 population. Time-course changes of cell cycle regulatory proteins levels revealed accumulation of cyclins A and B as well as of cdc2 and cdk2 upon exposure of IGROV-1 cells to hyperthermia and oxaliplatin. In this cell line, p53 appeared to be implicated in both G2/M arrest and apoptosis. G1/S arrest of HT-29 cells was linked to up-regulation of cyclin E and p27(Kip1) and accumulation of the hypophosphorylated form of pRB, whereas in Caco-2 cells only the hyperphosphorylated form was detected as well as a down-regulation of the proto-oncogene c-myc. Taken together, the results of these in vitro studies suggest that hyperthermia and oxaliplatin might elicit antiproliferative effects by modulating the expression of cell cycle regulatory proteins through different signalling pathways. PMID 15204521

Whole-body hyperthermia in combination with platinum-containing drugs in patients with recurrent ovarian cancer.
Apr. 2004 | Douwes, Friedrich; BogoviC, Juri; Douwes, Ortrun; Migeod, Friedrich; Grote, Christoph
Patients with advanced ovarian cancer have an enormous risk of relapse after primary therapy, and the prognosis for these patients remains bleak. Primary and acquired resistance of tumor cells to antineoplastic drugs is a major cause of the limited effectiveness of chemotherapy. The effect of whole-body hyperthermia (WBH) combined with platinum-containing chemotherapy in the treatment of recurrent ovarian cancer was examined in this study. PMID 15108039

[Evaluation of the therapeutic benefit of 41.8 degrees C whole body hyperthermia plus ifosfamide, carboplatin and etoposide (ICE) for patients with malignant pleural mesothelioma using the Modified Brunner-Score (MBS)].
Apr. 2004 | Bruns, I; Kohlmann, Th; Wiedemann, G J; Bakhshandeh, A
We performed a phase-II-study combining 41.8 degrees C whole body hyperthermia with ICE chemotherapy, i. e., ifosfamide (5 g/m (2) on day 1), carboplatin (300 mg/m (2) on day 1) and etoposide (150 mg/m (2) on days 2 and 3), administered every 4 weeks, to assess the treatment benefit for patients with malignant pleural mesothelioma. To date this is mainly done by measurement of response rates and overall survival, as it can be widely found in the literature. In fewer cases there is also a quality of life assessment. Here we describe an instrument well-capable for a more comprehensive statement on the therapeutic benefit by linking several study end points including quality of life assessment, the Modified Brunner-Score (MBS). PMID 15098157

Tumor-derived heat shock protein 70-pulsed dendritic cells elicit tumor-specific cytotoxic T lymphocytes (CTLs) and tumor immunity.
März 2004 | Ueda, Gosei; Tamura, Yasuaki; Hirai, Itaru; Kamiguchi, Kenjirou; Ichimiya, Shingo; Torigoe, Toshihiko; Hiratsuka, Hiroyoshi; Sunakawa, Hajime; Sato, Noriyuki
Vaccination with autologous tumor-derived heat shock proteins (Hsp), such as Hsp70, Hsp90 and gp96, has been demonstrated to elicit specific immune responses against the tumor from which the Hsps were isolated. The effect of Hsp immunization is wholly dependent on the presence of functional antigen-presenting cells (APCs) in the immunized host, and Hsp receptors on APCs have recently been identified. Here we show that bone marrow-derived dendritic cells (DCs) are able to internalize HSP-peptide complex and that peptides are re-presented by DCs via the major histocompatibility complex (MHC) class I presentation pathway. In addition, immunization with tumor-derived HSP-pulsed DCs induces strong cytotoxic T cell (CTL) responses against multiple antigenic peptides in a transporter-associated antigen processing (TAP)-dependent manner. The results of the present study provide strong evidence of an efficient cross-priming activity of Hsp70, which could be exploited in the development of new and more effective immunotherapeutic strategies for cancer patients. PMID 15016325

An approach for cure: PEI-chemotherapy and regional deep hyperthermia in children and adolescents with unresectable malignant tumors.
Dez. 2003 | Wessalowski, R; Schneider, D T; Mils, O; Hannen, M; Calaminus, G; Engelbrecht, V; Pape, H; Willers, R; Engert, J; Harms, D; Göbel, U
Elevated temperatures of 40 - 44 degrees C increase the actions of various anticancer drugs including N-lost derivatives, cytotoxic antibiotics and platinum analoga. In clinical usage thermochemotherapy (TCH) should facilitate surgical resection and ameliorate local tumor control. PMID 14677093

Ifosfamide with regional hyperthermia in soft-tissue sarcomas.
Okt. 2003 | Schlemmer, M; Wendtner, C M; Issels, R D
For high-risk soft tissue sarcomas (HR-STS) of adults, new treatment strategies are needed to improve outcome with regard to local control and overall survival. Therefore, systemic chemotherapy has been integrated either after (adjuvant) or before (neoadjuvant) optimal local treatment by surgery and radiotherapy in HR-STS. The combination with regional hyperthermia as a new treatment strategy seems to open a new therapeutic window. PMID 14586154

Thermal regulation of dendritic cell activation and migration from skin explants.
Aug. 2003 | Ostberg, J R; Kabingu, E; Repasky, E A
Dendritic cells (DCs) in the skin rapidly take up antigen and migrate out of the skin to draining lymph nodes for antigen presentation. As a result, these cells play an important role in generating specific immune responses against infectious agents that enter the skin and against antigens delivered as vaccines. Previous efforts revealed that fever-like elevations in body temperature enhance antigen-dependent immune responses initiated at the site of the skin and stimulate the migration of epidermal DCs to draining lymph nodes. Collectively, these data have led to the hypothesis that the activation of epidermal DCs is sensitive to physiological thermal stimuli. In this study, ear skin explants derived from BALB/c mice were either maintained at 37 degrees C or incubated at 40 degrees C for the first 6.5 h before being placed at 37 degrees C. This heating protocol altered the density and morphology of the epidermal DCs in a manner suggestive of an increased kinetics of activation-associated DC migration. Flow cytometric analysis of the emigrated cells also indicated that mild heating enhanced the migration kinetics of DCs and increased the DC expression of MHC class II and the activation marker CD86. Importantly, these migrated cells displayed higher stimulatory capacity in a mixed lymphocyte reaction compared to those of controls. Overall, these results suggest that mild thermal stimuli can enhance DC activation and function and that strategic applications of heat could enhance the potency of vaccines consisting of relatively weak antigens, such as cancer vaccines. PMID 12944167

Fever-like temperature induces maturation of dendritic cells through induction of hsp90.
Aug. 2003 | Basu, Sreyashi; Srivastava, Pramod K
Fever is a phylogenetically conserved biological phenomenon and a common consequence of infection. Here, we examine in vitro and in vivo the effect of febrile temperature on dendritic cells (DC), a key antigen-presenting cell in the immune system. Elevated temperatures are observed to cause immature DC to mature, specifically through elevation of intracellular levels of hsp90. Surprisingly, even brief exposure to elevated temperatures has a powerful effect on the immunostimulatory capacity of DC. These results bear on the mechanisms of the salutary effects of fever as well as of behavioral elevations of temperature such as saunas and warm blankets. PMID 12917257

Doxorubicin activity is enhanced by hyperthermia in a model of ex vivo vascular perfusion of human colon carcinoma.
Juni 2003 | Pilati, Pierluigi; Mocellin, Simone; Rossi, Carlo R; Scalerta, Romano; Alaggio, Rita; Giacomelli, Luciano; Geroni, Cristina; Nitti, Donato; Lise, Mario
There is little information on the pharmacokinetics and pharmacodynamics of doxorubicin (DXR) administered during locoregional treatments of colon carcinoma under hyperthermic conditions. The aim of this study was to evaluate distribution and activity of DXR in healthy tissue and tumor tissues under hyperthermic conditions by using an experimental model of ex vivo isolated vascular perfusion of human colon segments bearing primary carcinoma. The influence of topoisomerase-II alpha (TPI2 alpha) expression on the anti-cancer activity of DXR combined with heat was evaluated as well. Twenty seven colon segments surgically resected for primary carcinoma were perfused ex vivo under physiological conditions (group A, n = 7), with DXR (group B, n = 6), under hyperthermic conditions (group C, n = 6), and with the combination DXR-hyperthermia (group D, n = 8). Samples of perfusate and tissues (normal and pathologic) were collected during 90 minutes of perfusion. Doxorubicin concentration in perfusate and tissues was assessed with high-performance liquid chromatography. Protein expression of TPI2 alpha, the main molecular target of DXR, was measured by image analysis in normal mucosa and tumor samples. Drug uptake was increased by heat equally in healthy and diseased tissue. Under hyperthermic conditions, DXR activity was significantly higher in pathologic mucosa than in normal mucosa. Furthermore, the activity of DXR combined with heat correlated with baseline TPI2 alpha levels in tumor tissue. From these findings, it appears that heat sensitizes tumor cells-but not normal mucosa-to DXR activity. Furthermore, protein levels of TPI2 alpha in pretreatment samples could predict tumor sensitivity to DXR. PMID 12734680

Heat shock factor 1-independent activation of dendritic cells by heat shock: implication for the uncoupling of heat-mediated immunoregulation from the heat shock response.
Juni 2003 | Zheng, Hong; Benjamin, Ivor J; Basu, Sreyashi; Li, Zihai
The induction of heat shock proteins by heat shock is classically defined as the heat shock response, which is involved in cytoprotection, inflammation and immune responses. Whereas the cytoprotective properties of heat shock have been well characterized, the immunomodulating roles of the heat shock response on the immune system are just emerging. In particular, it is not known whether immunomodulating functions of heat are mediated by the heat shock response. We addressed this question genetically, using a murine model that is unable to mount the heat shock response because of deletion of a major transcriptional factor, heat shock factor 1 (Hsf1). We focused on the roles of heat shock on modulating the functions of dendritic cells (DC) because of their important roles in both innate and adaptive immunity. We found that heat shock matures CD11c(+) DC both in vitro and in vivo, phenotypically and functionally, in the absence of any exogenous inflammatory stimuli. Furthermore, heat-shock-mediated DC maturation is independent of Hsf1, as Hsf1(-/-) DC can be matured by heat shock equally well as wild-type DC. Our novel findings demonstrate that heat shock, one of the most primitive biological responses, can modulate the immune response without the requirement for the transcriptional induction/repression of target genes mediated by Hsf1. PMID 12778494

A Systemic Hyperthermia Oncologic Working Group trial. Ifosfamide, carboplatin, and etoposide combined with 41.8 degrees C whole-body hyperthermia for metastatic soft tissue sarcoma.
Mai 2003 | Westermann, A M; Wiedemann, G J; Jager, E; Jager, D; Katschinski, D M; Knuth, A; Vörde Sive Vörding, P Z; Van Dijk, J D P; Finet, J; Neumann, A; Longo, W; Bakhshandeh, A; Tiggelaar, C L; Gillis, W; Bailey, H; Peters, S O; Robins, H I; ,
Based on earlier clinical and preclinical studies, we conducted a phase II trial in metastatic sarcoma patients of the combination of 41.8 degrees C (x60 min) radiant heat (Aquatherm) whole-body hyperthermia (WBH) with 'ICE' chemotherapy. The ICE regimen consists of ifosfamide (5 g/m(2)), carboplatin (300 mg/m(2)) and etoposide (100 mg/m(2)), concurrent with WBH, with etoposide also on days 2 and 3 post-WBH. PMID 12759526

The effect of whole-body hyperthermia combined with 'metronomic' chemotherapy on rat mammary adenocarcinoma metastases.
März 2003 | Sumiyoshi, K; Strebel, F R; Rowe, R W; Bull, J M C
Many women diagnosed with invasive breast cancer have undetected occult metastases at the time of their primary tumour diagnosis. The development and growth of these micro-metastases relies heavily on angiogenesis. Therefore, administering an angiogenesis-blocking treatment from the time of diagnosis could reduce the incidence of metastasis and, ultimately, increase patient survival. It is hypothesized that an antiangiogenesis strategy combining fever-range whole-body hyperthermia (FR-WBH) and metronomic chemotherapy could inhibit the development of metastatic disease with minimal toxicity. To test this theory, a low, daily dose of the topoisomerase-I inhibitor irinotecan hydrochloride (CPT-11) was administered over a prolonged period of time to rats bearing the highly metastatic MTLn3 mammary adenocarcinoma primary tumour surgically excised on day 12 after implantation. The metronomic CPT-11 was combined with long-duration, low-temperature, fever-range whole body hyperthermia (FR-WBH). This systemic hyperthermia enhances chemotherapy-induced cytotoxicity as well as immunological activity. Both the group treated with FR-WBH alone and the combined FR-WBH + CPT-11 group had delayed onset and reduced incidence of axillary lymph node metastases compared to control (p < 0.05). Combination therapy of FR-WBH + CPT-11 resulted in a significantly greater inhibition of axillary lymph node metastasis volume compared to both control and CPT-11 alone (p < 0.02) at day 16. Interestingly, none of the therapies significantly affected inguinal lymph node metastases. Lung metastases were decreased by 36% at the time of death in rats treated with FR-WBH + CPT-11, by 25% in the CPT-11 alone group and by 14% in the FR-WBH alone group. Rats treated with FR-WBH, + CPT-11 survived significantly longer (35%) than control animals (p < 0.04). Neither significant body weight loss nor gastrointestinal toxicity was observed in any group. These data suggest that, after excision of the primary tumour, FR-WBH and metronomic CPT-11 can be safely combined to reduce distant lymph node and lung metastases and, thus, to increase survival. PMID 12623634

Ifosfamide, carboplatin and etoposide combined with 41.8 degrees C whole body hyperthermia for malignant pleural mesothelioma.
Feb. 2003 | Bakhshandeh, A; Bruns, I; Traynor, A; Robins, H I; Eberhardt, K; Demedts, A; Kaukel, E; Koschel, G; Gatzemeier, U; Kohlmann, Th; Dalhoff, K; Ehlers, E M; Gruber, Y; Zumschlinge, R; Hegewisch-Becker, S; Peters, S O; Wiedemann, G J
We performed a phase II study combining 41.8 degrees C whole body hyperthermia with ICE chemotherapy, i.e. ifosfamide (5 g/m(2)), carboplatin (300 mg/m(2)) and etoposide (150 mg/m(2) on days 2 and 3), administered every 4 weeks, for patients with malignant pleural mesothelioma. Of 27 chemonäive, non-metastatic patients enrolled, 25 patients were evaluable for response. Overall response rate was 20% (five partial remissions; 95% CI 8.9-39.1%). Median survival time from the start of treatment for all patients was 76.6 weeks (95% CI 65.4-87.8 weeks). Progression free survival for all patients measured 29.6 weeks (95% CI 24.4-34.7 weeks). One year overall survival was 68% and 2 year overall survival was 20%. Major treatment toxicities included grade 3/4 neutropenia and thrombocytopenia in 74 and 33% of treatment cycles, respectively. One patient died due to sepsis. These promising results are consistent with continued clinical investigation; a phase III clinical trial with whole body hyperthermia as the independent variable has been initiated. PMID 12609573

Cancer immunotherapy: stress proteins and hyperthermia.
Feb. 2003 | Manjili, M H; Wang, X Y; Park, J; Macdonald, I J; Li, Y; Van Schie, R C A A; Subjeck, J R
Heat shock proteins (hsps) can induce anti-cancer immune responses by targeting associated tumour antigens to the immune system. Hsps are not merely carriers of antigen but can also induce maturation of dendritic cells (DCs), resulting in a more efficient antigen presentation. However, improvement of hsp-based vaccines is still desirable if one is to realize their full therapeutic potential. Since the immune system consists of different elements functioning together in a highly integrated way, a combination therapy utilizing important immunomodulators together with hsp-based vaccination may improve therapeutic response. Hyperthermia has been shown to have important stimulatory effects on several cellular and organismal endpoints related to the immune system. This review highlights advantages and disadvantages of various ways of using stress proteins in cancer immunotherapy. It also overviews the interaction of hyperthermia with heat shock protein therapy and the related effects on the host's immune response. PMID 12537751

Stimulation of Th1-polarizing cytokines, C-C chemokines, maturation of dendritic cells, and adjuvant function by the peptide binding fragment of heat shock protein 70.
Aug. 2002 | Wang, Yufei; Kelly, Charles G; Singh, Mahavir; McGowan, Edward G; Carrara, Anne-Sophie; Bergmeier, Lesley A; Lehner, Thomas
The peptide binding C-terminal portion of heat shock protein (HSP)70 (aa 359-610) stimulates human monocytes to produce IL-12, TNF-alpha, NO, and C-C chemokines. The N-terminal, ATPase portion (HSP70(1-358)) failed to stimulate any of these cytokines or chemokines. Both native and the truncated HSP70(359-610) stimulation of chemokine production is mediated by the CD40 costimulatory molecule. Maturation of dendritic cells was induced by stimulation with native HSP70, was not seen with the N-terminal HSP70(1-358), but was enhanced with HSP70(359-610), as demonstrated by up-regulation of CD83, CCR7, CD86, CD80, and HLA class II. In vivo studies in macaques showed that immunization with HSP70(359-610) enhances the production of IL-12 and RANTES. Immunization with peptide-bound HSP70(359-610) in mice induced higher serum IgG2a and IgG3 Abs than the native HSP70-bound peptide. This study suggests that the C-terminal, peptide-binding portion of HSP70 is responsible for stimulating Th1-polarizing cytokines, C-C chemokines, and an adjuvant function. PMID 12193710

Heating the patient: a promising approach?
Aug. 2002 | van der Zee, J
There is a clear rationale for using hyperthermia in cancer treatment. Treatment at temperatures between 40 and 44 degrees C is cytotoxic for cells in an environment with a low pO(2) and low pH, conditions that are found specifically within tumour tissue, due to insufficient blood perfusion. Under such conditions radiotherapy is less effective, and systemically applied cytotoxic agents will reach such areas in lower concentrations than in well perfused areas. Therefore, the addition of hyperthermia to radiotherapy or chemotherapy will result in at least an additive effect. Furthermore, the effects of both radiotherapy and many drugs are enhanced at an increased temperature. Hyperthermia can be applied by several methods: local hyperthermia by external or internal energy sources, regional hyperthermia by perfusion of organs or limbs, or by irrigation of body cavities, and whole body hyperthermia. The use of hyperthermia alone has resulted in complete overall response rates of 13%. The clinical value of hyperthermia in addition to other treatment modalities has been shown in randomised trials. Significant improvement in clinical outcome has been demonstrated for tumours of the head and neck, breast, brain, bladder, cervix, rectum, lung, oesophagus, vulva and vagina, and also for melanoma. Additional hyperthermia resulted in remarkably higher (complete) response rates, accompanied by improved local tumour control rates, better palliative effects and/or better overall survival rates. Generally, when combined with radiotherapy, no increase in radiation toxicity could be demonstrated. Whether toxicity from chemotherapy is enhanced depends on sequence of the two modalities, and on which tissues are heated. Toxicity from hyperthermia cannot always be avoided, but is usually of limited clinical relevance. Recent developments include improvements in heating techniques and thermometry, development of hyperthermia treatment planning models, studies on heat shock proteins and an effect on anti-cancer immune responses, drug targeting to tumours, bone marrow purging, combination with drugs targeting tumour vasculature, and the role of hyperthermia in gene therapy. The clinical results achieved to date have confirmed the expectations raised by results from experimental studies. These findings justify using hyperthermia as part of standard treatment in tumour sites for which its efficacy has been proven and, furthermore, to initiate new studies with other tumours. Hyperthermia is certainly a promising approach and deserves more attention than it has received until now. PMID 12181239

Whole-body hyperthermia: a review of theory, design and application.
Juli 2002 | Vertree, Roger A; Leeth, Angela; Girouard, Mark; Roach, John D; Zwischenberger, Joseph B
The intentional induction of elevated body temperature to treat malignant lesions has its origins in the 18th century. The mechanism of heat-induced cell death is not clear; however, heat induces a variety of cellular changes. For heat to exert a therapeutic effect, pathogens (bacteria, viruses, or neoplastic tissues) need to be susceptible within temperature ranges that do not exert deleterious effects on normal tissues. Hyperthermia has been used successfully to treat isolated neoplastic lesions of the head and neck, regional tumors such as melanoma of the limb, and is under investigation as either an adjunct to, or therapy for, locally disseminated and systemic diseases. The clinical utility of perfusion hyperthermia has evolved into three approaches - isolated organ or limb, tumorous invasion of a cavity, and systemic or metastatic spread. When whole-body hyperthermic treatment has been tried, it has been induced in the patient by submersion in hot wax or liquid, wrapping in plastic, encasement in a high-flow water perfusion suit, or by extracorporeal perfusion. Our group has developed an extracorporeal method, veno-venous perfusion-induced systemic hyperthermia, that was used first to safely heat swine homogenously to an average body temperature of 43 degrees C for 2 h. More recently, a Phase I clinical trial has been completed in which all patients were safely heated to 42 or 42.5 degrees C for 2 h and survived the 30-day study period. We have been sufficiently encouraged by these results and are continuing to develop this technology. PMID 12139385

A phase I study of fever-range whole body hyperthermia (FR-WBH) in patients with advanced solid tumours: correlation with mouse models.
Mai 2002 | Kraybill, W G; Olenki, T; Evans, S S; Ostberg, J R; O'Leary, K A; Gibbs, J F; Repasky, E A
Various studies in animal tumour models have revealed the potential of fever-range whole body hyperthermia (FR-WBH) to be used in cancer therapy. To determine the safety of FR-WBH treatment in the clinic, patients with advanced solid tumours were heated in the outpatient setting to 39-39.5 degrees C for 3 or 6h, or 39.5-40 degrees C for 6h using the Heckel-HT 2000 apparatus. These WBH treatments were well tolerated, with no significant adverse events related to cardiac, hepatic, renal or pulmonary systems. In the majority of patients, flow cytometric analysis of peripheral blood leukocyte populations indicated that there were transient decreases in the number of circulating T lymphocytes and a concomitant decrease in the number of L-selectin positive lymphocytes in the peripheral blood. These findings closely mimic the affects seen previously in pre-clinical murine studies in which this same fever-like treatment was shown to inhibit tumour growth. These studies have established the safety of this treatment and will allow for future clinical trials where application of FR-WBH treatment can be combined with other anti-cancer therapies, including immunotherapy and chemotherapy. PMID 12028640

Enhancement of hyperthermia-induced apoptosis by local anesthetics on human histiocytic lymphoma U937 cells.
Mai 2002 | Arai, Yoko; Kondo, Takashi; Tanabe, Kiyoshi; Zhao, Qing-Li; Li, Fu-Jun; Ogawa, Ryohei; Li, Min; Kasuya, Minoru
The combined effects of hyperthermia at 44 degrees C and local anesthetics on apoptosis in human histiocytic lymphoma U937 cells were investigated. When the cells were exposed to hyperthermia for l0 min marginal DNA fragmentation and nuclear fragmentation were observed. In the presence of amide-type local anesthetics further enhancement was found depending on concentration. The order of the concentration required for maximum induction was the reverse order of the lipophilicity (prilocaine > lidocaine > bupivacaine). Western blotting revealed that in hyperthermia there was initial release of Ca(2+) from the intracellular store site as indicated by increased expression of the type 1 inositol-1,4,5-trisphosphate receptor. However, the combination with lidocaine did not induce any further enhancement. Lidocaine enhanced the decrease in ATP content and the increase in intracellular Ca(2+) concentration in individual cells induced by hyperthermia. In addition, superoxide formation, decrease in the mitochondrial membrane potential, and activation of intracellular caspase-3 were found in the cells treated with hyperthermia and lidocaine. All of these were suppressed in part in the presence of the intracellular Ca(2+) ion chelator BAPTA-AM (bis-(O-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl). The present results indicate that local anesthetics at optimal concentrations enhance hyperthermia-induced apoptosis via Ca(2+)- and mitochondria-dependent pathways. Initial release of Ca(2+) from intracellular store sites caused by hyperthermia and followed by the subsequent increase in the intracellular Ca(2+) concentration and the additional activation of the mitochondrial caspase-dependent pathway (partly regulated by intracellular Ca(2+) concentration) plays a crucial role in the enhancement of apoptosis induced by the combination of hyperthermia and lidocaine. PMID 11861640

Hyperthermia for rectal cancer.
Jan. 2002 | Ohno, Shinji; Sumiyoshi, Yasushi; Mori, Masaki; Sugimachi, Keizo
In order to improve the clinical results of rectal cancer, hyperthermia has been prescribed in combination with chemotherapy and radiotherapy. The techniques of hyperthermia and their clinical applications to rectal cancer were reviewed. PMID 11821798

Effect of hyperthermia on AKR lymphoma variants differing in degree of malignancy.
Dez. 2001 | Sharabi, Y; Klorin, G; Leibovici, J
The effect of hyperthermic treatment on AKR lymphoma cells of varying malignancy was investigated. Tumor cells were pretreated at 37 or 43 degrees C and then injected to mice. The effect on the highly malignant variant, TAU-38, was compared to that on the low-malignancy variant, TAU-39, following both subcutaneous (s.c.) and intravenous (i.v.) inoculation. Hyperthermia showed no effect on the TAU-39 variant following s.c. inoculation on the primary tumors or mice survival, but the TAU-38 variant exhibited a significant delay of tumor appearance following treatment, namely, decreased tumor size and increased life span. Following i.v. inoculation, in both variants, hyperthermia caused a significant decrease in metastatic spread and an increased life span. We conclude that hyperthermia, in addition to exerting a greater effect on the high-malignancy variant, acts at the late phases of metastasis. Hyperthermia might therefore have a place in the management of cancer in its advanced disseminated phase. PMID 11768032

Heat shock and heat shock protein 70i enhance the oncolytic effect of replicative adenovirus.
Dez. 2001 | Haviv, Y S; Blackwell, J L; Li, H; Wang, M; Lei, X; Curiel, D T
Replication-competent viruses are currently being evaluated for their cancer cell-killing properties. These vectors are designed to induce tumor regression after selective viral propagation within the tumor. However, replication-competent viruses have not resulted heretofore in complete tumor eradication in the clinical setting. Recently, heat shock has been reported to partially alleviate replication restriction on an avian adenovirus (Ad) in a human lung cancer cell line. Therefore, we hypothesized that heat shock and overexpression of heat shock protein (hsp) would support the oncolytic effect of a replication-competent human Ad. To this end, we tested the oncolytic and burst kinetics of a replication-competent Ad after exposure to heat shock or to inducible hsp 70 overexpression by a replication-deficient Ad (Adhsp 70i). Heat-shock resulted in augmentation of Ad burst and oncolysis while decreasing total intracellular Ad DNA. Overexpression of hsp 70i also enhanced Ad-mediated oncolysis but did not decrease intracellular Ad DNA levels. We conclude that heat shock and Adhsp 70i enhance the Ad cell-killing potential via distinct mechanisms. A potential therapeutic implication would be the use of local hyperthermia to augment oncolysis by increasing the burst of replication-competent Ad. The role of hsp in Ad-mediated oncolysis should be additionally explored. PMID 11731408

Effect of whole body hyperthermia on radiation therapy of transplanted fibrosarcoma in Swiss mice.
Okt. 2001 | Zaidi, A K; Patil, M S; Bhatt, M B; Bagewadikar, R S; Subramanian, M; Rajan, R; Kaklij, G S; Singh, B B
The exposure of normal mice to whole body hyperthermia (1 h WBH at 39 or 40 degrees C), 20 or 48 h prior to total body irradiation (TBI) with lethal doses of gamma-rays affords significant protection as assessed by survival. The radioprotective effect of WBH, as observed in normal mice, diminished in tumour bearing mice depending upon the size of tumour. Treatment of tumour bearing mice with mild WBH, 20 h prior to local irrradiation (LIR), did not protect the transplanted tumour against radiotherapy with a single dose of 20 Gy or fractionated dose (in five fractions) of 7.5 Gy on alternate days. In fact, mild WBH treatment enhanced the tumour regression and increased the mean survival time after fractionated dose therapy. However, the prior mild WBH was found to be ineffective in protecting normal tissue, as assessed by skin contraction after local irradiation (50 Gy). This indicates that mild WBH treatment given 20 h prior to local radiotherapy enhances fibrosarcoma tumour regression but cannot protect skin (normal tissue) against local irradiation. It appears that radioprotection of animals by WBH may be the consequence of its radioprotective effect on haemopoietic tissues mediated through certain cytokines. Perhaps WBH may not have a radioprotective effect on other tissues, as evident from skin contraction studies. PMID 11587080

Neoadjuvant chemotherapy combined with regional hyperthermia (RHT) for locally advanced primary or recurrent high-risk adult soft-tissue sarcomas (STS) of adults: long-term results of a phase II study.
Aug. 2001 | Issels, R D; Abdel-Rahman, S; Wendtner, C; Falk, M H; Kurze, V; Sauer, H; Aydemir, U; Hiddemann, W
In this phase II study, activity and safety of neoadjuvant regional hyperthermia (RHT) combined with chemotherapy was investigated in 59 patients with primary advanced or recurrent high-risk soft-tissue sarcoma (STS). Patients received four EIA cycles consisting of etoposide, ifosfamide and doxorubicin combined with RHT followed by surgical resection and adjuvant treatment. The overall objective response (OR) rate was 17%, with one complete (2%) and eight partial (15%) responses. In addition, 13 minor responses (25%) were seen. At time of surgery, complete necrosis (pCR) occurred in 6 patients and >75% necrosis (favourable histological response (FHR)) in 12 patients. At the completion of protocol treatment, 36 patients were rendered disease-free which was significantly associated with the initial radiographic and/or pathological tumour response (P=0.004). Treatment-related toxicity was acceptable overall. At a medium follow-up of 82 months, local treatment failure occurred in 33 patients, median overall survival (OS) was 52 months, and the 5-year survival rate was 49% (95% confidence interval (CI): 36-61%). OS which did not differ for extremity versus non-extremity STS (P=0.21) was better for patients responding to EIA combined with RHT (P<0.01). PMID 11527684

[Addition of hyperthermia. Heat potentiates cancer therapy].
Juli 2001 | Hegewisch-Becker, S; Hossfeld, D K
It has been unequivocally demonstrated that hyperthermia (40-44 degrees C) has an potentiating effect on radiotherapy and chemotherapy. Technical improvements have facilitated the application of both local and whole-body hyperthermia, and have thus made this form of treatment available to large numbers of patients. Randomized phase III studies performed in patients with breast cancer, malignant melanoma and cervical cancer have convincingly confirmed the increased efficacy of the combination of radiotherapy with local or regional hyperthermia in comparison with radiotherapy alone. The effectiveness of other procedures such as the combination of radio- and chemotherapy with regional hyperthermia, regional thermochemotherapy and whole-body hyperthermia has so far been investigated mainly in phase II studies focusing on head and neck cancer, cervical and ovarian cancer, sarcoma, malignant germ cell tumors, and rectal carcinoma. However, the actual place of hyperthermia as a permanent element in a multimodal therapeutic concept has yet to be shown in prospective phase III studies. PMID 11468993

The role of heat shock protein (hsp70) in dendritic cell maturation: hsp70 induces the maturation of immature dendritic cells but reduces DC differentiation from monocyte precursors.
Juli 2001 | Kuppner, M C; Gastpar, R; Gelwer, S; Nössner, E; Ochmann, O; Scharner, A; Issels, R D
Members of the heat shock protein (hsp70) family are either constitutively expressed (hsc70) or can be induced by hyperthermic stress (hsp70). Recombinant hsp70 (rhsp70) stimulates cytokine production from monocytes and enhances NK cell proliferation and cytotoxicity. Here we demonstrate that rhsp70 binds to immature dendritic cells (DC) derived from monocyte precursors and induces their maturation as evidenced by an increase in CD40, CD86 and CD83 expression. Immature DC stimulated to mature with rhsp70 show an enhanced ability to present tyrosinase peptide to specific CTL. Mature DC did not bind rhsp70, suggesting a down-regulation in the expression of its receptor. When rhsp70 was added to monocyte precursors at the same time as GM-CSF and IL-4 it reduced the differentiation of monocytes into DC as shown by a decrease in the level of CD40, CD83, CD86 and HLA-DR expression and an increase in CD14 expression. The constitutively expressed hsc70 had neither a stimulatory effect on the maturation of immature DC nor did it reduce the differentiation of monocytes into DC. These findings demonstrate the specific ability of rhsp70 to induce the maturation of immature DC. Therefore rhsp70 may be useful for its adjuvant like properties in DC based immunotherapy of certain tumors. PMID 11465118

Posttreatment histology and microcirculation status of osteogenic sarcoma after a neoadjuvant chemo- and radiotherapy in combination with local electromagnetic hyperthermia.
Juli 2001 | Bogovic, J; Douwes, F; Muravjov, G; Istomin, J
Many biological attributes of tumors (including regional blood flow and microcirculation) can deteriorate the homogeneity of heat distribution and temperature elevation during hyperthermia. We analyzed the connection between the microcirculation status of osteogenic sarcomas and the posttreatment histology after neoadjuvant chemotherapy, irradiation and local hyperthermia. PMID 11441282

Enhancement of the therapeutic outcome of radio-immunotherapy by combination with whole-body mild hyperthermia.
Juli 2001 | Saga, T; Sakahara, H; Nakamoto, Y; Sato, N; Ishimori, T; Mamede, M; Kobayashi, H; Masunaga, S; Sasai, K; Kuroki, M; Konishi, J
To enhance the effect of radio-immunotherapy for solid cancers, whole-body mild hyperthermia was added, and its effects on the pharmacokinetics of radiolabelled antibody, outcome of radio-immunotherapy, and radiosensitivity of the tumour were investigated. Nude mice bearing human colon cancer xenografts were heated to 40 degrees C for 3 or 6 h. After heating, mice received intravenous (i.v.) injections of [131I]-labelled anti-carcinoembryonic antigen (CEA) monoclonal antibody. Although 6-h heating did not alter the biodistribution of the radiolabelled antibody, and alone did not show any therapeutic effect on tumour growth, when combined with radio-immunotherapy, the therapeutic effect on tumour growth was significantly enhanced. Three-hour heating also significantly enhanced the effect of radio-immunotherapy. Colony formation assay showed that the radiosensitivity of the tumour was significantly enhanced after heating, which was achieved by a reduction of the hypoxic fraction of the tumour. In conclusion, the addition of whole-body mild hyperthermia significantly enhanced the therapeutic effect of radio-immunotherapy by increasing the radiosensitivity of the tumour. PMID 11435076

The heat shock protein gp96 induces maturation of dendritic cells and down-regulation of its receptor.
Sep. 2000 | Singh-Jasuja, H; Scherer, H U; Hilf, N; Arnold-Schild, D; Rammensee, H G; Toes, R E; Schild, H
Peptides associated with the heat shock protein gp96 induce a specific T cell response against cells from which gp96 is isolated. Recently, we have shown that gp96 binds to a yet unknown receptor present on dendritic cells (DC) and that receptor-mediated uptake is required for cross-presentation of gp96-associated peptides by DC. We now describe that gp96 mediates maturation of DC as determined by up-regulation of MHC class II and CD86 molecules, secretion of the cytokines IL-12 and TNF-alpha and enhanced T cell stimulatory capacity. Heat-denatured gp96 is not able to induce DC maturation and cytokine secretion. Furthermore, we show that mature DC are no longer able to bind gp96 molecules. Hence, the gp96 receptor is down-regulated on mature DC, suggesting that this receptor behaves similar to other receptors involved in antigen uptake like the scavenger receptor CD36, the mannose receptor or the integrins alpha(v)beta(3) and alpha(v)beta(5). Together, our findings provide an additional explanation for the remarkable immunogenicity of gp96 as a cross-priming antigen carrier and direct activator of DC. PMID 10940912

Receptor-mediated uptake of antigen/heat shock protein complexes results in major histocompatibility complex class I antigen presentation via two distinct processing pathways.
Aug. 2000 | Castellino, F; Boucher, P E; Eichelberg, K; Mayhew, M; Rothman, J E; Houghton, A N; Germain, R N
Heat shock proteins (HSPs) derived from tumors or virally infected cells can stimulate antigen-specific CD8(+) T cell responses in vitro and in vivo. Although this antigenicity is known to arise from HSP-associated peptides presented to the immune system by major histocompatibility complex (MHC) class I molecules, the cell biology underlying this presentation process remains poorly understood. Here we show that HSP 70 binds to the surface of antigen presenting cells by a mechanism with the characteristics of a saturable receptor system. After this membrane interaction, processing and MHC class I presentation of the HSP-associated antigen can occur via either a cytosolic (transporter associated with antigen processing [TAP] and proteasome-dependent) or an endosomal (TAP and proteasome-independent) route, with the preferred pathway determined by the sequence context of the optimal antigenic peptide within the HSP-associated material. These findings not only characterize two highly efficient, specific pathways leading to the conversion of HSP-associated antigens into ligands for CD8(+) T cells, they also imply the existence of a mechanism for receptor-facilitated transmembrane transport of HSP or HSP-associated ligands from the plasma membrane or lumen of endosomes into the cytosol. PMID 10839810

HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine.
Juni 2000 | Asea, A; Kraeft, S K; Kurt-Jones, E A; Stevenson, M A; Chen, L B; Finberg, R W; Koo, G C; Calderwood, S K
Here, we demonstrate a previously unknown function for the 70-kDa heat-shock protein (HSP70) as a cytokine. HSP70 bound with high affinity to the plasma membrane, elicited a rapid intracellular calcium flux, activated nuclear factor (NF)-kappaB and upregulated the expression of pro-inflammatory cytokines tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6 in human monocytes. Furthermore, two different signal transduction pathways were activated by exogenous HSP70: one dependent on CD14 and intracellular calcium, which resulted in increased IL-1beta, IL-6 and TNF-alpha; and the other independent of CD14 but dependent on intracellular calcium, which resulted in an increase in TNF-alpha but not IL-1beta or IL-6. These findings indicate that CD14 is a co-receptor for HSP70-mediated signaling in human monocytes and are indicative of an previously unrecognized function for HSP70 as an extracellular protein with regulatory effects on human monocytes, having a dual role as chaperone and cytokine. PMID 10742151

Comparison of radiotherapy alone with radiotherapy plus hyperthermia in locally advanced pelvic tumours: a prospective, randomised, multicentre trial. Dutch Deep Hyperthermia Group.
Mai 2000 | van der Zee, J; González González, D; van Rhoon, G C; van Dijk, J D; van Putten, W L; Hart, A A
Local-control rates after radiotherapy for locally advanced tumours of the bladder, cervix, and rectum are disappointing. We investigated the effect of adding hyperthermia to standard radiotherapy. PMID 10791373

Temperature-dependent changes in physiologic parameters of spontaneous canine soft tissue sarcomas after combined radiotherapy and hyperthermia treatment.
Feb. 2000 | Vujaskovic, Z; Poulson, J M; Gaskin, A A; Thrall, D E; Page, R L; Charles, H C; MacFall, J R; Brizel, D M; Meyer, R E; Prescott, D M; Samulski, T V; Dewhirst, M W
The objectives of this study were to evaluate effects of hyperthermia on tumor oxygenation, extracellular pH (pHe), and blood flow in 13 dogs with spontaneous soft tissue sarcomas prior to and after local hyperthermia. PMID 10656391

Deep hyperthermia with radiofrequencies in patients with liver metastases from colorectal cancer.
Jan. 2000 | Hager, E D; Dziambor, H; Höhmann, D; Gallenbeck, D; Stephan, M; Popa, C
Patients at advanced stage of colorectal cancer with liver metastases have been treated with deep hyperthermia alone or in combination with chemotherapy (5-FU + FA + MMC). Hyperthermia was achieved by arrangements of capacitive electrodes with a radiofrequency field of 13.56 MHz (RF-DHT). This prospective open single-arm clinical study with 80 patients suffering from liver metastases from colorectal cancer gives some first hints, that deep RF-hyperthermia alone may have a substantial beneficial effect on overall survival time of patients with liver metastases from colorectal cancer. Long lasting no-change, partial and even some complete remissions could be observed. The overall median survival time from progression of metastases or relapse was 24.5 months and survival rates at 1, 2 or 3 years from first diagnosis of metastases or progression were twice as high as expected from patients treated with chemotherapy. The combination of hyperthermia with delayed chemotherapy did not change overall survival time. These encouraging results deserve to be confirmed in randomized clinical studies. PMID 10629627

Tumour cell kinetics as predictors of response in canine lymphoma treated with chemotherapy alone or combined with whole body hyperthermia.
Jan. 2000 | Larue, S M; Fox, M H; Ogilvie, G K; Page, R L; Getzy, D M; Thrall, D E; Johnson, J L; Dewhirst, M W; Gillette, E L
Kinetic parameters including potential doubling time (Tpot), duration of S phase (Ts), labelling index (LI), and DNA index (DI) were obtained from 42 dogs with previously untreated lymphoma. Standard flow cytometric techniques using BrdUrd were employed. All dogs were treated with L-asparaginase and remission was induced in 26 dogs, which were then randomized to receive chemotherapy only (doxorubicin [DOX] alone or with lonidamine) or chemotherapy plus whole body hyperthermia (WBH). Dogs were treated every 3 weeks for up to five treatments and evaluated every 3 weeks for evidence of tumour recurrence. Within this subset of animals there was no difference in outcome based on treatment group. Median values for Tpot, Ts and LI were 3.4 days, 7.23 h and 12.49%, respectively. Dogs that had tumours with LI > or = 20% had a shorter time until recurrence than dogs with tumours characterized by LI < 20%. In dogs treated only with chemotherapy, dogs bearing tumours with longer than median Tpot and Ts values and lower than median LI had significantly longer remission duration than dogs with more rapidly proliferating tumours. Dogs treated only with chemotherapy, which had longer than median Tpot and Ts values and lower than median LI, had significantly longer remission duration than all other dogs in the study. The mechanisms in which kinetics are associated with response to chemotherapy are not clear and vary depending on tumour type and treatment regimen. More work is needed to understand factors involved in cell killing during in vivo hyperthermia. PMID 10598945

Characterization of mild whole-body hyperthermia protocols using human breast, ovarian, and colon tumors grown in severe combined immunodeficient mice.
Juli 1999 | Repasky, E A; Tims, E; Pritchard, M; Burd, R
We have shown that one treatment of fever-like whole body hyperthermia (WBH) on mice bearing human breast tumors results in a tumor growth delay. Our goal was to repeat this study in mice bearing human ovarian or colon tumors. We further evaluated this WBH protocol by performing multiple and interrupted WBH treatments. PMID 10231015

For the clinical application of thermochemotherapy given at mild temperatures.
Juni 1999 | Urano, M; Kuroda, M; Nishimura, Y
It has been demonstrated in vitro and in vivo that hyperthermia can enhance the cytotoxicity of some chemotherapeutic agents. This paper summarizes the authors' own laboratory studies on the effect of chemotherapeutic agents given at elevated temperatures, experimental results obtained using animal tumour systems in other laboratories, and clinical trials of thermochemotherapy reported in literature. The in vivo studies have demonstrated that the thermal enhancement of cytotoxicity of many chemotherapeutic agents is maximized at mild temperatures such as at 40.5-43 degrees C. Comparison of in vitro and in vivo results using five agents show that the in vivo thermal enhancement increases with an increase in the activation energy obtained in the temperature range between 40.5 and 43.0 degrees C. A summary of experimental results obtained by various investigators indicates a potentially wide variation in the thermal enhancement of a given agent among the different types of tumours and suggests potential agents useful at moderately elevated temperatures. In vivo studies on nine different agents indicate that the drug(s) of choice at physiological temperatures may not be the drug(s) of choice at elevated temperatures. It is also shown that drug concentration in the target must be high for sufficient thermal enhancement. Clinical trials of thermochemotherapy have employed various heating methods, including local heating, hyerthermic perfusion and whole body hyperthermia. Extensive trials have been made in the treatment of melanoma and soft tissue sarcoma in the extremity. Hyperthermic isolated perfusion with chemotherapeutic(s) provides much higher drug concentration than a systemic drug administration in the target(s), resulting in a high tumour response rate and an increased survival of the patients. It is of interest that the most successful agent used in the treatment of both melanomas and sarcomas is melphalan and is the drug of choice at moderately elevated temperatures among the nine agents tested in the in vivo studies. Current results using the tumour necrosis factor with melphalan are impressive. In several institutes, techniques have been developed to uniformly heat the localized tumour, but studies are needed to find an agent effective at elevated temperatures to each type of tumours and to establish the methods for obtaining a sufficient drug concentration in the target tissue. PMID 10323618

Cutting edge: receptor-mediated endocytosis of heat shock proteins by professional antigen-presenting cells.
Mai 1999 | Arnold-Schild, D; Hanau, D; Spehner, D; Schmid, C; Rammensee, H G; de la Salle, H; Schild, H
Immunization with heat shock proteins (HSPs) induces Ag-specific CTL responses. The specificity of the immune response is based on peptides associated with HSPs. To investigate how exogenous HSP/peptide complexes gain access to the MHC class I-restricted Ag presentation pathway, we incubated the monocytic cell line P388D1 and the dendritic cell line D2SC/1 with gold-labeled HSPs gp96 and HSC70. We show that HSPs bind specifically to the surface of these APCs and are internalized spontaneously by receptor-mediated endocytosis, demonstrating the existence of specific receptors for HSPs on these cells. In addition, we observe colocalization of internalized HSPs and surface MHC class I molecules in early and late endosomal structures. These findings provide possible explanations for the immunogenicity of HSP/peptide complexes and for the transfer of HSP-associated peptides onto MHC class I molecules. PMID 10201889

A pilot study of melphalan, tumor necrosis factor-alpha and 41.8 degrees C whole-body hyperthermia.
Apr. 1999 | Robins, H I; Katschinski, D M; Longo, W; Grosen, E; Wilding, G; Gillis, W; Kraemer, C; Tiggelaar, C L; Rushing, D; Stewart, J A; Spriggs, D; Love, R; Arzoomanian, R Z; Feierabend, C; Alberti, D; Morgan, K; Simon, K; d'Oleire, F
To evaluate the feasibilitv of sequencing (based on preclinical modeling) tumor necrosis factor-a (TNF) at two dose levels with melphalan (L-PAM) and 41.8 C whole-body hyperthermia (WBH) for 60 min. PMID 10100597

[Hyperthermia in combination with chemotherapy in gynecological cancers].
Apr. 1999 | Rietbroek, R C; Schilthuis, M S; van der Zee, J; González González, D
Hyperthermia in combination with chemotherapy has a strong biological rationale based on thermal enhancement of cytotoxicity and partial circumvention of resistance. Weekly locoregional hyperthermia in combination with cisplatin is an effective treatment (response rate: 52%) for patients with a recurrence of a previously irradiated carcinoma of the uterine cervix. A comparative trial versus cisplatin alone was recently started. Hyperthermic intraperitoneal chemotherapy is aimed at situations after optimal cytoreductive surgery in patients with carcinomatous peritonitis. The warmth enhances the penetration of the oncolytic agent. Whole-body hyperthermia using the Aquatherm apparatus in combination with chemotherapy is feasible: results in patients with metastatic sarcomas are promising. Trials with whole-body hyperthermia are in progress in patients with platinum refractory ovarian cancer and in patients with a metastatic carcinoma of the uterine cervix. PMID 10086110

[Current methods of radiation therapy in patients with prostatic cancer: subtotal body radiation, local hyperthermia].
März 1999 | Granov, A M; Vinogradov, V M; Metelev, V V; Kozlov, A A; Shkol'nik, M I; Lisitsyn, I Iu; Karelin, M I
The paper deals with the preliminary data of treatment of patients with prostatic cancer by using unconventional methods of radiation therapy (RT), such as subtotal radiation of the body (STRB) and thermoradiation treatment (TRT). Out of 72 patients receiving RT, 16 and 8 had STRB and TRT, respectively. Systemic and local drug therapies were made to prevent radiation reactions and injuries. In all cases, STRB and TRT showed a significant objective and subjective effect. To evaluate the long-term results of treatment needs further studies. PMID 9987941

Systemic hyperthermia and ICE chemotherapy for sarcoma patients: rationale and clinical status.
Okt. 1997 | Wiedemann, G J; Robins, H I; Katschinski, D M; Mentzel, M; D'Oleire, F; Kutz, M; Wagner, T
Preclinical studies are consistent with the concept that 41.8 degrees C whole body hyperthermia (WBH) can enhance the therapeutic index of specific chemotherapeutic agents. These laboratory investigations resulted in 2 phase I clinical studies, which also support this hypothesis. These trials were extended to 2 sequential phase II investigations of WBH plus ifosfamide, carboplatin and etoposide (ICE) for refractory sarcoma patients. The first study (involving 12 patients) using extra-corporeal WBH was prematurely closed to adopt a less toxic WBH technology, i.e., the radiant heat Aquatherm. To date, 12 patients have been accrued to the Aquatherm trial. Projections regarding reduced morbidity were correct. The response rate for ICE/WBH is currently 63%. The review to follow will summarize the results of these trials, as well as the laboratory and clinical data which serve to explicate the dramatic clinical results observed to date. PMID 9329558

Radiotherapy with or without hyperthermia in the treatment of superficial localized breast cancer: results from five randomized controlled trials. International Collaborative Hyperthermia Group.
Aug. 1996 | Vernon, C C; Hand, J W; Field, S B; Machin, D; Whaley, J B; van der Zee, J; van Putten, W L; van Rhoon, G C; van Dijk, J D; González González, D; Liu, F F; Goodman, P; Sherar, M
Claims for the value of hyperthermia as an adjunct to radiotherapy in the treatment of cancer have mostly been based on small Phase I or II trials. To test the benefit of this form of treatment, randomized Phase III trials were needed. PMID 8690639

Hyperthermia as an adjuvant to radiation therapy of recurrent or metastatic malignant melanoma. A multicentre randomized trial by the European Society for Hyperthermic Oncology.
Aug. 1996 | Overgaard, J; Gonzalez Gonzalez, D; Hulshof, M C; Arcangeli, G; Dahl, O; Mella, O; Bentzen, S M
The ESHO protocol 3-85 is a multicentre randomized trial investigating the value of hyperthermia as an adjuvant to radiotherapy in treatment of malignant melanoma. A total of 134 metastatic of recurrent malignant melanoma lesions in 70 patients were randomized to receive radiotherapy alone (3 fractions in 8 days) or each fraction followed by hyperthermia (aimed for 43 degrees C for 60 min). Radiation was given with high voltage photons or electrons. Tumours were stratified according to institution and size (above or below 4 cm) and randomly assigned to a total radiation dose of either 24 or 27 Gy to be given with or without hyperthermia. The endpoint was persistent complete response in the treated area. A number of 128 tumours in 68 patients were evaluable, with an observation time between 3 and 72 months. Sixty-five tumours were randomized to radiation alone and 63 to radiation + heat. Sixty received 24 Gy and 68 tumours received 27 Gy, respectively. Size was < or = 4 cm in 81 and > 4 cm in 47 tumours. Overall the 2-year actuarial local tumour control was 37%. Univariate analysis showed prognostic influence of hyperthermia (rad alone 28% versus rad + heat 46%, p = 0.008) and radiation dose (24 Gy 25% versus 27 Gy 56%, p = 0.02), but not of tumour size (small 42% versus large 29%, p = 0.21). A Cox multivariate regression analysis showed the most important prognostic parameters to be: hyperthermia (odds ratio: 1.73 (1.07-2.78), p = 0.02), tumour size (odds ratio: 0.91 (0.85-0.99), p = 0.05) and radiation dose (odds ratio: 1.17 (1.01-1.36), p = 0.05). Analysis of the heating quality showed a significant relationship between the extent of heating and local tumour response. Addition of heat did not significantly increase the acute or late radiation reactions. The overall 5-year survival rate of the patients was 19%, but 38% in patients if all known disease was controlled, compared to 8% in the patients with persistent active disease. PMID 8676005

Feasibility, toxicity, and preliminary results of weekly loco-regional hyperthermia and cisplatin in patients with previously irradiated recurrent cervical carcinoma or locally advanced bladder cancer.
Apr. 1996 | Rietbroek, R C; Bakker, P J; Schilthuis, M S; Postma, A J; Zum Vörde Sive Vording, P J; Gonzalèz Gonzalèz, D; Kurth, K H; Bakker, A J; Veenhof, C H
The biological rationale for combining locoregional hyperthermia (HT) with cisplatin (CDDP) is the potentiating effect of HT on CDDP uptake and cytotoxicity. Feasibility, toxicity, and preliminary results of a clinical trial of weekly loco-regional HT in combination with cisplatin are described in this article. PMID 8598366

Phase I/II trial of preoperative thermoradiotherapy in the treatment of urinary bladder cancer.
Mai 1994 | Masunaga, S I; Hiraoka, M; Akuta, K; Nishimura, Y; Nagata, Y; Jo, S; Takahashi, M; Abe, M; Terachi, T; Oishi, K
Between April 1984 and September 1988, preoperative radiotherapy or thermoradiotherapy was administered to 49 patients with bladder cancer (T1-4N0M0; UICC classification, 1987). Twenty-one patients were preoperatively treated by radiotherapy alone, with 4 Gy per fraction and three fractions per week to a total dose of 24 Gy (TDF = 53, group 1). The other 28 patients were treated by the same radiotherapy regimen in combination with hyperthermia (group 2). Regional hyperthermia was administered for 35-60 min immediately after irradiation (two sessions per week to a total of four sessions) using an 8 MHz RF capacitive heating device. Group 2 was divided into group 2 (high), in which the average intravesical temperature (T(av)) was > 41.5 degrees C, which was the mean value, and group 2 (low) with a T(av) < 41 x 5 degrees C. Group 2 (high) showed a significantly higher incidence of down-staging and tumour degeneration than both group 1 and group 2 (low). In addition, the local recurrence rate was lower and survival time was longer in group 2 than in group 1, although not significantly so. In particular, the patients with T3-4 or grade 3 bladder cancer in group 2 had a longer average survival than those in group 1, although the difference was not significant. The toxicity associated with hyperthermia was pain during treatment, and complications were not serious. PMID 8144986

Feasibility and toxicity of transrectal ultrasound hyperthermia in the treatment of locally advanced adenocarcinoma of the prostate.
Juni 1993 | Fosmire, H; Hynynen, K; Drach, G W; Stea, B; Swift, P; Cassady, J R
This Phase I trial tests the ability of a new hyperthermia device, the transrectal ultrasound probe, to heat the prostate gland, and evaluates the toxicity of transrectal ultrasound hyperthermia (TRUSH) given with concurrent standard external beam irradiation in the treatment of locally-advanced adenocarcinoma of the prostate. PMID 8491683

Treatment of malignant gliomas with interstitial irradiation and hyperthermia.
Dez. 1992 | Stea, B; Kittelson, J; Cassady, J R; Hamilton, A; Guthkelch, N; Lulu, B; Obbens, E; Rossman, K; Shapiro, W; Shetter, A
A Phase I study of interstitial thermoradiotherapy for high-grade supratentorial gliomas has been completed. The objective of this trial was to test the feasibility and toxicity of hyperthermia induced by ferromagnetic implants in the treatment of intracranial tumors. The patient population consisted of 16 males and 12 females, with a median age of 44 years and a median Karnofsky score of 90. Nine patients had anaplastic astrocytoma while 19 had glioblastoma multiforme. Twenty two patients were treated at the time of their initial diagnosis with a course of external beam radiotherapy (median dose 48.4 Gy) followed by an interstitial implant with Ir-192 (median dose 32.7 Gy). Six patients with recurrent tumors received only an interstitial implant (median dose 40 Gy). Median implant volume for all patients was 55.8 cc and median number of treatment catheters implanted per tumor was eighteen. A 60-minute hyperthermia treatment was given through these catheters just before and right after completion of brachytherapy. Time-averaged temperatures of all treatments were computed for sensors located within the core of (> 5 mm from edge of implant), and at the periphery of the implant (outer 5 mm). The percentage of sensors achieving an average temperature > 42 degrees C was 61% and 35%, respectively. Hyperthermia was generally well tolerated; however, there have been 11 minor toxicities, which resolved with conservative management, and one episode of massive edema resulting in the death of a patient. In addition, there were three major complications associated with the surgical implantation of the catheters. Preliminary survival analysis shows that 16 of the 28 patients have died, with a median survival of 20.6 months from diagnosis. We conclude that interstitial hyperthermia of brain tumors with ferromagnetic implants is feasible and carries significant but acceptable morbidity given the extremely poor prognosis of this patient population. PMID 1429088

[Radiofrequency hyperthermia in malignant brain tumors: clinical trials].
Juli 1988 | Tanaka, R
Local hyperthermia using 13.56-MHz radiofrequency (RF) capacitive heating was evaluated in 19 patients with malignant brain tumor. Intraoperative heating was performed in 4 patients. RF applicators were placed on the cerebral convexity and medial surface with the tumor between them. RF power was controlled so as to maintain the brain temperature below 40 degrees C. Under these conditions, the highest temperature of each tumor varied from 44 to 52 degrees C. After heating alone for about 60 min, 3 tumors showed regression on CT scan. Extracranial heating was performed in 15 patients with cerebral glioblastoma. RF applicators were placed on the scalp and applied to diametrically opposite sides of the tumor after bilateral craniectomy not smaller than the size of the applicator. The heating was performed for about 60 min at each session and repeated twice a week for a total of 4 to 10 times in combination with radiation and ACNU-chemotherapy. The brain temperatures were maintained below 42 degrees C. The highest temperatures of the tumor varied from 42 to 46 degrees C. Seven of 13 evaluable tumors on CT scan showed regression after the treatment. Low-density lesions appeared transiently in the brains of 2 patients, located in the RF field. In conclusion, RF capacitive heating can be applied to human malignant cerebral tumors. PMID 3289497

[Local hyperthermia of malignant brain tumors].
Aug. 1987 | Heppner, F; Schuy, S; Ascher, P W; Holzer, P; Wiesspeiner, G
In glioblastoma multiforme and high-grade astrocytomas the following procedure has been implemented to try and prevent recurrence: after extirpation of the tumour its bed is lined with metal powder and the patient's head is exposed to a high-frequency magnetic field every 4 weeks. As a result the temperature is raised by induction to +45 degrees C at the boundary between metal and brain tissue. This ought to be sufficient to prevent tumour recurrence. Varied results were achieved using this technique in 103 patients. PMID 3039746

Combination radiofrequency hyperthermia and chemotherapy (BCNU) for brain malignancy. Animal experience and two case reports.
Okt. 1984 | Silberman, A W; Morgan, D F; Storm, F K; Rand, R W; Benz, M; Drury, B; Morton, D L
Patients with high-grade primary and metastatic brain malignancies have a median survival time of 3-8 months, regardless of therapy. Because MagnetrodeTM hyperthermia provides safe, deep internal heating without normal-tissue injury, we studied its effects first on the brain and surrounding tissues of rabbits. The normal rabbit brain (n = 26) could be heated to potentially tumoricidal temperatures (42-43 degrees C) without apparent histopathologic or clinical damage to the brain, skull, external eye, subcutaneous tissue or skin. Intracranial pressure did not rise significantly. Using transplanted VX-2 carcinoma, we showed both the safety and potential efficacy of thermochemotherapy (IV BCNU: 14 mg/kg) in the presence of a solid brain tumor. The average maximum brain temperature achieved was 43.06 degrees C. Mean survival from the time of tumor implantation in the treated group (n = 16) was 18.56 days, compared to 9.3 days for untreated controls (n = 30) (p less than .0001). Two patients have been treated with localized brain hyperthermia combined with intravenous BCNU (80 mg/m2) for a total of eight treatments. Maximum normal brain temperature achieved was 40.0 degrees C in Patient #1 and 41.5 degrees C in Patient #2. A tumor temperature of 42.9 degrees C was achieved in Patient #2. Intracranial pressure remained within the upper limits of normal. Swan-Ganz monitoring in Patient #1 revealed a stable cardiac index and mean pulmonary artery pressure with mild fluctuations in the CVP, PAD, and PCW. No increase in chemotherapy toxicity was observed and no normal tissue injury occurred in either patient. We conclude that non-invasive localized radiofrequency hyperthermia to the brain is feasible and can be performed safely in the presence of a solid brain tumor. PMID 6470758

[Effect of whole-body artificial hyperthermia on the immunity function in cancer patients].
Juli 1984 | Dzhaginian, A I; Balliuzek, F V
The changes in immunologic indexes were studied in 90 cancer patients treated with artificial whole body hyperthermia and hyperglycemia. The changes of the indexes under study showed a double-phase curve after a hyperthermic session--the phase of "heat shock aftermath" involving a short-term decline in certain immunologic indexes was followed by a general improvement of immunologic vigor of cancer patients. Different components of cancer patient immunologic system reacted differently to whole body hyperthermia. PMID 6730415

Doxorubicin, cyclophosphamide, and whole body hyperthermia for treatment of advanced soft tissue sarcoma.
Juli 1984 | Gerad, H; van Echo, D A; Whitacre, M; Ashman, M; Helrich, M; Foy, J; Ostrow, S; Wiernik, P H; Aisner, J
Eleven patients with advanced soft tissue sarcoma were treated with whole body hyperthermia (41.8 degrees C-43.0 degrees C) for 2 hours, doxorubicin (45 mg/m2) at the beginning of peak temperature and cyclophosphamide (1000 mg/m2) 6 hours after doxorubicin. Warming was accomplished with a nylon and vinyl mesh water perfused suit and heating blankets under barbiturate anesthesia. Thirty-five thermochemotherapy treatments were administered after an initial baseline euthermic course. There were two complete and two partial responses including three of three liposarcomas and one of two leiomyosarcomas, and there were two disease stabilizations . Morbidity included anasarca, nausea and vomiting, diarrhea, myalgias, mild surface burns, perioral herpes simplex, reversible neuropathy, hypotension, and cardiac arrythmias . Hyperglycemia and hypophosphatemia were found during heating, and normalized at 24 hours. Liver enzyme elevations occurred 24 hours after heating and normalized within 1 week. A uniform platelet decrease (mean, 107,000/microliter) was found at 24 hours. Thermochemotherapy was found to be a feasible approach for selected patients with advanced soft tissue sarcoma for the subset of liposarcomas and leiomyosarcomas. PMID 6722720