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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

Poly(I:C) enhanced anti-cervical cancer immunities induced by dendritic cells-derived exosomes.
Feb. 2018 | Chen, Shisheng; Lv, Mingfen; Fang, Shan; Ye, Wenxia; Gao, Yu; Xu, Yunsheng
Dendritic cell (DC)-derived exosomes (Dexo) has been confirmed to be able to induce the specific anti-tumor immune response ex vivo and in vivo. Here, the aim of this study was to evaluate the application of the antigen-pulsed Dexo as a new vaccination platform in immunotherapy for cervical cancer. The immunogenic profile of the different Dexo was assessed by the cell proliferation, cytokines secretion and effector functions of CD8 T cells and the splenocytes from Dexo-vaccinated mice. Furthermore, the anti-tumor immunity elicited by Dexo was further compared in cervical cancer-bearing mice. Dexo from DCs loaded with E7 peptide could efficiently induce the cytotoxic activity of CD8 T cells on TC-1 tumor cells ex vivo, the proliferation and IFN-γ excretion of CD8 T cells. Moreover, Dexo vaccine promoted the immune responses of vaccinated mice splenocytes induced by antigen E7 in vitro restimulation. Of note, poly(I:C) was significantly more potent inducer of the antigen-loaded Dexo mediated protective immunity responses for cervical cancer and further evidenced by that Dexo(E7+pIC) markedly inhibited the tumor growth and improved the survival rate of the tumor-bearing mice. We provided evidence that poly(I:C) dramatically increased the potent antitumoral immunity induced by antigen-pulsed Dexo for ameliorating cervical cancer. PMID 29427678

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

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

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

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

Immunotherapy for human papillomavirus-associated disease and cervical cancer: review of clinical and translational research.
Juli 2016 | Lee, Sung Jong; Yang, Andrew; Wu, T C; Hung, Chien Fu
Cervical cancer is the fourth most lethal women's cancer worldwide. Current treatments against cervical cancer include surgery, radiotherapy, chemotherapy, and anti-angiogenic agents. However, despite the various treatments utilized for the treatment of cervical cancer, its disease burden remains a global issue. Persistent infection of human papillomavirus (HPV) has been identified as an essential step of pathogenesis of cervical cancer and many other cancers, and nation-wide HPV screening as well as preventative HPV vaccination program have been introduced globally. However, even though the commercially available prophylactic HPV vaccines, Gardasil (Merck) and Cervarix (GlaxoSmithKline), are effective in blocking the entry of HPV into the epithelium of cervix through generation of HPV-specific neutralizing antibodies, they cannot eliminate the pre-existing HPV infection. For these reason, other immunotherapeutic options against HPV-associated diseases, including therapeutic vaccines, have been continuously explored. Therapeutic HPV vaccines enhance cell-mediated immunity targeting HPV E6 and E7 antigens by modulating primarily dendritic cells and cytotoxic T lymphocyte. Our review will cover various therapeutic vaccines in development for the treatment of HPV-associated lesions and cancers. Furthermore, we will discuss the potential of immune checkpoint inhibitors that have recently been adopted and tested for their treatment efficacy against HPV-induced cervical cancer. PMID 27329199

Natural killer and dendritic cells collaborate in the immune response induced by the vaccine against uterine cervical cancer.
Dez. 2014 | Langers, Inge; Renoux, Virginie; Reschner, Anca; Touzé, Antoine; Coursaget, Pierre; Boniver, Jacques; Koch, Joachim; Delvenne, Philippe; Jacobs, Nathalie
Virus-like particles (VLPs) of human papillomavirus (HPV) are used as a vaccine against HPV-induced cancer, and recently we have shown that these VLPs are able to activate natural killer (NK) cells. Since NK cells collaborate with dendritic cells (DCs) to induce an immune response against viral infections and tumors, we studied the impact of this crosstalk in the context of HPV vaccination. NK cells in the presence of HPV-VLPs enhanced DC-maturation as shown by an upregulation of CD86 and HLA-DR and an increased production of IL-12p70, but not of the immunosuppressive cytokine IL-10. This activation was bidirectional. Indeed, in the presence of HPV-VLPs, DCs further activated NK cells by inducing the upregulation of cell surface activation markers (CD69 and HLA-DR). The function of NK cells was also improved as shown by an increase in IFN-γ secretion and cytotoxic activity against an HPV(+) cell line. This crosstalk between NK cells and DCs needed CD40 interaction and IL-12p70 secretion, whereas NKG2D was not implicated. Our results provide insight into how VLPs interact with innate immune cells and how NK cells and DCs play a role in the immune response induced by this vaccine agent. PMID 25229656

In vitro and in vivo evaluations of human papillomavirus type 16 (HPV16)-derived peptide-loaded dendritic cells (DCs) with a CpG oligodeoxynucleotide (CpG-ODN) adjuvant as tumor vaccines for immunotherapy of cervical cancer.
Jan. 2014 | Wang, Hua Li; Xu, Hui; Lu, Wei Hua; Zhu, Lin; Yu, Yun Hai; Hong, Fan Zhen
To evaluate the immunotherapeutic potentials for human dendritic cells (DCs) loaded with different HPV16-associated antigens, including HPV16E7 (E) protein, HPV16E7 polypeptide (P), as well as CpG-oligodeoxynucleotide (ODN) 2006 as a promising immune adjuvant for vaccination against cervical carcinoma. PMID 23912529

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

[Study on the specific immunity induced by dendritic cell vaccine loading allogenic microvascular endothelial cell bEnd.3 antigen against U14 cervical cancer cell in mice].
März 2011 | Zhao, Jun; Lu, Jing; Liu, Ya-qin; Yang, Hong-yan; Huang, You-tian; Zhao, Ji-min; Li, Shan; Zhai, Jing-ming; Zhao, Ming-yao; Zhang, Xi; Dong, Zi-ming
To explore the specific cellular and humoral immunity induced by dendritic cells (DC) vaccine loading allogenic microvascular endothelial cell bEnd.3 antigen against U14 cervical cancer cell of mice. PMID 21429436

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

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

Radiotherapy and hyperthermia for treatment of primary locally advanced cervix cancer: results in 378 patients.
Dez. 2008 | Franckena, Martine; Lutgens, Ludy C; Koper, Peter C; Kleynen, Catharina E; van der Steen-Banasik, Elsbieta M; Jobsen, Jan J; Leer, Jan Willem; Creutzberg, Carien L; Dielwart, Michel F; van Norden, Yvette; Canters, Richard A M; van Rhoon, Gerard C; van der Zee, Jacoba
To report response rate, pelvic tumor control, survival, and late toxicity after treatment with combined radiotherapy and hyperthermia (RHT) for patients with locally advanced cervical carcinoma (LACC) and compare the results with other published series. PMID 18990505

Long-term improvement in treatment outcome after radiotherapy and hyperthermia in locoregionally advanced cervix cancer: an update of the Dutch Deep Hyperthermia Trial.
März 2008 | Franckena, Martine; Stalpers, Lukas J A; Koper, Peter C M; Wiggenraad, Ruud G J; Hoogenraad, Wim J; van Dijk, Jan D P; Wárlám-Rodenhuis, Carla C; Jobsen, Jan J; van Rhoon, Gerard C; van der Zee, Jacoba
The local failure rate in patients with locoregionally advanced cervical cancer is 41-72% after radiotherapy (RT) alone, whereas local control is a prerequisite for cure. The Dutch Deep Hyperthermia Trial showed that combining RT with hyperthermia (HT) improved 3-year local control rates of 41-61%, as we reported earlier. In this study, we evaluate long-term results of the Dutch Deep Hyperthermia Trial after 12 years of follow-up. PMID 17881144

Human papillomavirus type 16 and 18 E7-pulsed dendritic cell vaccination of stage IB or IIA cervical cancer patients: a phase I escalating-dose trial.
Jan. 2008 | Santin, Alessandro D; Bellone, Stefania; Palmieri, Michela; Zanolini, Alessandro; Ravaggi, Antonella; Siegel, Eric R; Roman, Juan J; Pecorelli, Sergio; Cannon, Martin J
The safety and immunogenicity of the human papillomavirus type 16 (HPV16) or HPV18 (HPV16/18) E7 antigen-pulsed mature dendritic cell (DC) vaccination were evaluated for patients with stage IB or IIA cervical cancer. Escalating doses of autologous DC (5, 10, and 15 x 10(6) cells for injection) were pulsed with recombinant HPV16/18 E7 antigens and keyhole limpet hemocyanin (KLH; an immunological tracer molecule) and delivered in five subcutaneous injections at 21-day intervals to 10 cervical cancer patients with no evidence of disease after they underwent radical surgery. Safety, toxicity, delayed-type hypersensitivity (DTH) reaction, and induction of serological and cellular immunity against HPV16/18 E7 and KLH were monitored. DC vaccination was well tolerated, and no significant toxicities were recorded. All patients developed CD4(+) T-cell and antibody responses to DC vaccination, as detected by enzyme-linked immunosorbent spot (ELISpot) and enzyme-linked immunosorbent assays (ELISA), respectively, and 8 out of 10 patients demonstrated levels of E7-specific CD8(+) T-cell counts, detected by ELISpot during or immediately after immunization, that were increased compared to prevaccination baseline levels. The vaccine dose did not predict the magnitude of the antibody or T-cell response or the time to detection of HPV16/18 E7-specific immunity. DTH responses to intradermal injections of HPV E7 antigen and KLH were detected for all patients after vaccination. We conclude that HPV E7-loaded DC vaccination is safe and immunogenic for stage IB or IIA cervical cancer patients. Phase II E7-pulsed DC-based vaccination trials with cervical cancer patients harboring a limited tumor burden, or who are at significant risk of tumor recurrence, are warranted. PMID 18057249

RF-power and temperature data analysis of 444 patients with primary cervical cancer: deep hyperthermia using the Sigma-60 applicator is reproducible.
Dez. 2007 | Fatehi, Daryoush; van der Zee, Jacoba; de Bruijne, Maarten; Franckena, Martine; van Rhoon, Gerard C
Treatment reproducibility is important to guarantee reproducible treatment-outcome, a low-complication rate and efficient treatment procedures. This study evaluated the performance of loco-regional deep hyperthermia with four BSD-2000 configurations during 1990-2005 using the direct available parameters, i.e., temperature and power. Primary cervical cancer patients (n = 444) were all treated within the Sigma-60. Patients were grouped in three weight-groups: <61 kg, 61-70 kg, >70 kg. Different temperature and power indices were extensively analyzed per BSD configuration, per weight-group, and over the time-period. No substantial variations were found for temperature/power indices over the four BSD configurations or for the temperature doses in similar weight-groups. The 'bare' power indices were increased with weight; however, the derivative power-related (W/kg, W/cm(2)) and temperature indices decreased. Large variations were found in the power-related parameters during 1991-1996 (1st time-period), whereas they were much smaller during 1997-2005 (2nd time-period). The most relevant change noted was the adaptation of the treatment strategy with respect to power modulation. The average frequency of switched-off was 3.4 and 8.9 times/treatment session for the 1st and 2nd time-period, respectively, while the average duration of each switched-off time was 78.2 vs. 38.3 s. The yearly average of vagina T(50) was in the range of 39.3-40.2 degrees C (1st time-period) and 40.0-40.5 degrees C (2nd time-period). In 40% of the patients, a positive correlation was found between normalized net integrated power per pelvic area and vagina T(50). Good reproducible heating is achieved with the BSD-2000 Sigma-60 irrespective of the regular technological upgrades of the system and variation of trained staff-members. PMID 18097850

Immunological role of dendritic cells in cervical cancer.
Aug. 2007 | Manickam, Alagar; Sivanandham, Muthukumaran; Tourkova, Irina L
Cervical cancer is the second most frequent gynecological malignancy in the world. Human papillomavirus (HPV) infection is the primary etiologic agent of cervical cancer. However, HPV alone is not sufficient for tumor progression. The clinical manifestation of HPV infection depends also on the host's immune status. Both innate and adaptive immunity play a role in controlling HPV infection. In untransformed HPV-infected keratinocytes, the innate immunity is induced to eliminate the invading HPV pathogen through sensitization to HPV-related proteins by epithelial-residing Langerhans cells (LCs), macrophages, and other immune cells. Once the HPV infection escapes from initial patrolling by innate immunity, cellular immunity becomes in charge of killing the HPV-infected keratinocytes of the uterine cervix through systemic immune response developing by dendritic cells (DCs) in the regional lymphoid organs or through local immune response developing by LCs in the cervix. Thereby, DC/LC plays a critical role in eliciting innate and adaptive cellular immune responses against HPV infection. HPV-associated cervical malignancies might be prevented or treated by induction of the appropriate virus-specific immune responses in patients. Encouraging results from experimental vaccination systems in animal models have led to several prophylactic and therapeutic vaccine clinical trials. PMID 17713002

Weekly systemic cisplatin plus locoregional hyperthermia: an effective treatment for patients with recurrent cervical carcinoma in a previously irradiated area.
Aug. 2007 | Franckena, Martine; De Wit, Ronald; Ansink, Anca C; Notenboom, Annelise; Canters, Richard A M; Fatehi, Daryoush; Van Rhoon, Gerard C; Van Der Zee, Jacoba
Patients with recurrent cervical carcinoma within a previously irradiated area respond poorly to chemotherapy. We have treated these patients with simultaneous cisplatin and hyperthermia (CDDP + HT) and investigated response, toxicity, palliative effect and survival. PMID 17701535

Therapeutic dendritic cell vaccination with Ag coupled to cholera toxin in combination with intratumoural CpG injection leads to complete tumour eradication in mice bearing HPV 16 expressing tumours.
Juli 2007 | Chandy, Annie George; Nurkkala, Merja; Josefsson, Agnetha; Eriksson, Kristina
We have evaluated whether cholera toxin (CT) can enhance the efficiency of therapeutic dendritic cell (DC) vaccination in mice bearing a human papilloma virus (HPV) 16 antigen (Ag) expressing tumour. Mice were therefore injected with the TC-1 cancer cell line expressing E6 and E7, which are the major oncogenic proteins produced in HPV-induced cervical cancer, and they were then vaccinated with Ag pulsed DCs. While vaccination with E7 pulsed DCs had no impact on tumour growth, DCs pulsed with CT conjugated E7 (CT-E7) significantly reduced tumour size. However, this treatment was only able to eradicate the tumour in 11% of the affected animals. For complete tumour eradication, combinational therapy with CT-E7 pulsed DCs and local treatment of the tumour with CpG oligodeoxynucleotides (CpG) was required. Combinational therapy was associated with increased expression of MHC I and MHC II and increased levels of chemokine production in the tumour. These results suggest that combined treatment with CT-Ag pulsed DCs and local CpG administration offers an efficient strategy to eradicate an already existing HPV-E7 expressing tumour in mice. PMID 17629599

On verification of hyperthermia treatment planning for cervical carcinoma patients.
Mai 2007 | van Haaren, P M A; Kok, H P; van den Berg, C A T; Zum Vörde Sive Vörding, P J; Oldenborg, S; Stalpers, L J A; Schilthuis, M S; de Leeuw, A A C; Crezee, J
The aim of this study was to verify hyperthermia treatment planning calculations by means of measurements performed during hyperthermia treatments. The calculated specific absorption rate (SAR(calc)) was compared with clinically measured SAR values, during 11 treatments in seven cervical carcinoma patients. PMID 17523022

Radiochemotherapy combined with regional pelvic hyperthermia induces high response and resectability rates in patients with nonresectable cervical cancer > or =FIGO IIB "bulky".
Dez. 2006 | Sreenivasa, Geetha; Hildebrandt, Bert; Kümmel, Sherko; Jungnickel, Kirsten; Cho, Chie Hee; Tilly, Wolfgang; Böhmer, Dirk; Budach, Volker; Felix, Roland; Wust, Peter
To evaluate preoperative radiochemotherapy combined with regional pelvic hyperthermia in patients with nonresectable cervical cancer >/= International Federation of Gynecology and Obstetrics (FIGO) IIB "bulky" in a Phase II study. PMID 16979843

Sensitive detection of human papillomavirus type 16 E7-specific T cells by ELISPOT after multiple in vitro stimulations of CD8+ T cells with peptide-pulsed autologous dendritic cells.
Nov. 2006 | Cools, Nathalie; Ponsaerts, Peter; Lenjou, Marc; Nijs, Griet; Van Bockstaele, Dirk R; Van Tendeloo, Viggo F I; Berneman, Zwi N
Cervical cancer is the second most common gynecological cancer amongst women world-wide. Despite optimized protocols, standard treatments still face several disadvantages. Therefore, research aims at the development of immune-based strategies using tumor antigen-loaded dendritic cells for the induction of cellular anti-tumor immunity. PMID 17067378

[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

Targeting the heat shock factor 1 by RNA interference: a potent tool to enhance hyperthermochemotherapy efficacy in cervical cancer.
Aug. 2006 | Rossi, Antonio; Ciafrè, Stefania; Balsamo, Mirna; Pierimarchi, Pasquale; Santoro, M Gabriella
Carcinoma of the uterine cervix is one of the highest causes of mortality in female cancer patients worldwide, and improved treatment options for this type of malignancy are highly needed. Local hyperthermia has been successfully used in combination with systemic administration of cisplatin-based chemotherapy in phase I/II clinical studies. Heat-induced expression of cytoprotective and antiapoptotic heat shock proteins (HSP) is a known complication of hyperthermia, resulting in thermotolerance and chemoresistance and hindering the efficacy of the combination therapy. Heat shock transcription factor 1 (HSF1) is the master regulator of heat-induced HSP expression. In the present report, we used small interfering RNA (siRNA) to silence HSF1 and to examine the effect of HSF1 loss of function on the response to hyperthermia and cisplatin-based chemotherapy in HeLa cervical carcinoma. We have identified the 322-nucleotide to 340-nucleotide HSF1 sequence as an ideal target for siRNA-mediated HSF1 silencing, have created a pSUPER-HSF1 vector able to potently suppress the HSF1 gene, and have generated for the first time human cancer cell lines with stable loss of HSF1 function. We report that, although it surprisingly does not affect cancer cell sensitivity to cisplatin or elevated temperatures up to 43 degrees C when administered separately, loss of HSF1 function causes a dramatic increase in sensitivity to hyperthermochemotherapy, leading to massive (>95%) apoptosis of cancer cells. These findings indicate that disruption of HSF1-induced cytoprotection during hyperthermochemotherapy may represent a powerful strategy to selectively amplify the damage in cancer cells and identify HSF1 as a promising therapeutic target in cervical carcinoma. PMID 16885369

Temperature data analysis for 22 patients with advanced cervical carcinoma treated in Rotterdam using radiotherapy, hyperthermia and chemotherapy: a reference point is needed.
Juni 2006 | Fatehi, D; van der Zee, J; van der Wal, E; Van Wieringen, W N; Van Rhoon, G C
The growing interest and participation in multi-institutional trials involving deep hyperthermia treatment is an important step towards the further consolidation of hyperthermia as an oncological treatment modality. However, the differences in the clinical procedures of hyperthermia application also raises questions as how to compare the reported temperatures data obtained by the different institutes. In this study our recent developed approach, RHyThM (Rotterdam Hyperthermia Thermal Modulator), has been used for thermal data analysis to investigate the temperature dynamics behaviour of a series of deep hyperthermia treatments. PMID 16754355

Cervical cancer: radiotherapy and hyperthermia.
Juni 2006 | van der Zee, Jacoba; van Rhoon, Gerard C
For many years, the standard treatment of advanced cervical cancer has been radiotherapy (RT), including brachytherapy. The achievement of locoregional tumour control is essential for cure. Results of RT in early stages are reasonably satisfactory, but locoregional failure rates for stage IIIb and IVa are high. In several randomized trials, the addition of hyperthermia (HT) to RT has been investigated. PMID 16754343

HPV16/18 E7-pulsed dendritic cell vaccination in cervical cancer patients with recurrent disease refractory to standard treatment modalities.
Feb. 2006 | Santin, Alessandro D; Bellone, Stefania; Palmieri, Michela; Ravaggi, Antonella; Romani, Chiara; Tassi, Renata; Roman, Juan J; Burnett, Alexander; Pecorelli, Sergio; Cannon, Martin J
To evaluate the potential of human papillomavirus (HPV) type 16 and 18 E7 antigen-loaded autologous dendritic cells (DC) as a therapeutic cellular vaccine in a case series of cervical cancer patients harboring recurrent/metastatic disease refractory to standard treatment modalities. PMID 16249018

Therapeutic vaccines for cervical cancer: dendritic cell-based immunotherapy.
Okt. 2005 | Santin, Alessandro D; Bellone, Stefania; Roman, Juan J; Burnett, Alexander; Cannon, Martin J; Pecorelli, Sergio
Human papillomavirus (HPV) infection represents the most important risk factor for the development of cervical dysplasia and cervical cancer. Several lines of evidence suggest that cell-mediated immune responses are important in controlling both HPV infections and HPV-associated neoplasia. Since HPV E6 and E7 oncoproteins are expressed in these lesions and are necessary for the maintenance of the malignant phenotype, these proteins might be potential tumor-specific target antigens for immunotherapy of cervical cancer. The gold standard treatment for locally advanced cervical cancer is primary radiation therapy combined with chemotherapy. A potential drawback of this potentially curative treatment is a profound and long lasting negative effect on the immune system. Treatment-induced immunosuppression combined with tumor-induced subversion of the immune system may therefore impose severe limitations on the efficacy of conventional vaccination strategies in late stage cervical cancer patients. The recognition of dendritic cells (DC) as powerful antigen-presenting cells capable of inducing primary T cell responses in vitro and in vivo, has recently generated widespread interest in DC-based immunotherapy of several human malignancies. Here, we review various therapeutic HPV vaccines being developed and implemented in human clinical trials, with a particular emphasis on the use of autologous DC pulsed with full-length HPV 16 or 18 E7 oncoproteins as a novel strategy to induce HPV E7-specific and tumor-specific T cell responses in cervical cancer patients following conventional treatment. PMID 16248803

Human papillomavirus L1L2-E7 virus-like particles partially mature human dendritic cells and elicit E7-specific T-helper responses from patients with cervical intraepithelial neoplasia or cervical cancer in vitro.
Aug. 2005 | Warrino, Dominic E; Olson, Walter C; Scarrow, Meera I; D'Ambrosio-Brennan, Lori J; Guido, Richard S; Da Silva, Diane M; Kast, W Martin; Storkus, Walter J
We evaluated the ability of autologous dendritic cells (DC) pulsed with recombinant human papillomavirus 16 L1L2-E7 virus-like particles (VLPs) to stimulate E7-specific CD4+ T-cell responses from normal donors and patients with cervical intraepithelial neoplasia lesions or cervical carcinoma in vitro. Exposure to VLPs partially matured DCs, as evidenced by upregulated expression of costimulatory and major histocompatibility complex molecules and the reduced capacity of treated DCs to process exogenous antigens. However, VLP treatment failed to promote strong expression of the CD83 or CCR7 markers or to modulate interleukin-12p70 secretion, indicators of terminal DC maturation. Notably, both normal donor- and patient-derived DCs behaved similarly after exposure to VLPs. A single round of in vitro stimulation of CD4+ T cells with DCs exposed to L1L2-E7 VLPs promoted specific anti-E7 responses in the majority of donors. In particular, DCs exposed to VLPs effectively stimulated type 1 biased E7-specific CD4+ T-cell responses in patients with premalignant cervical intraepithelial neoplasia I-III lesions, but type 2 or Treg biased responses in patients with cervical cancer. Given the high rate of CD4+ T-cell responses (14 [93%] of 15 patients) against DC-L1L2-E7 VLP stimulation, this vaccine modality could serve as a foundation for developing a general treatment option for patients with human papillomavirus 16-associated malignancies. PMID 16112023

First results of triple-modality treatment combining radiotherapy, chemotherapy, and hyperthermia for the treatment of patients with stage IIB, III, and IVA cervical carcinoma.
Aug. 2005 | Westermann, Anneke M; Jones, Ellen L; Schem, Baard-Christian; van der Steen-Banasik, Elzbieta M; Koper, Peter; Mella, Olav; Uitterhoeve, Apollonia L J; de Wit, Ronald; van der Velden, Jacobus; Burger, Curt; van der Wilt, Clasina L; Dahl, Olav; Prosnitz, Leonard R; van der Zee, Jacoba
Patients with advanced cervical carcinoma are treated routinely with radiotherapy and cisplatin-containing chemotherapy. It has been shown that hyperthermia can improve the results of both radiotherapy and cisplatin. In the current study, the feasibility and efficacy of the combination of all three modalities was studied in previously untreated patients with cervical carcinoma. PMID 15968685

Phase II study of carboplatin and whole body hyperthermia (WBH) in recurrent and metastatic cervical cancer.
Dez. 2004 | Richel, O; Zum Vörde Sive Vörding, P J; Rietbroek, R; Van der Velden, J; Van Dijk, J D P; Schilthuis, M S; Westermann, A M
Hyperthermia enhances carboplatin cytotoxicity preclinically, and clinical studies have shown radiant heat Whole Body Hyperthermia (WBH) to be safe. In this study, the efficacy and toxicity of the combination of 41.8 degrees C WBH and carboplatin in recurrent and/or metastatic cervical cancer were explored. PMID 15581981

Dendritic cell-based vaccines in breast and gynaecologic cancer.
Dez. 2003 | Hernando, Juan José; Park, Tjoung-Won; Kuhn, Walther C
Major advances in understanding the functional interactions between tumour cells and the host immune system, in particular the generation and regulation of T cell immunity, have revived interest in cancer vaccination strategies. A crucial step for mounting an anti-tumour response is the capture, processing and presentation of tumour antigens (TA) to cognate T cells by professional antigen-presenting cells (APC), followed by their activation and clonal proliferation. Dendritic cells (DC) are potent APC with the unique ability to stimulate primary immune responses. Animal models have demonstrated that TA-charged DC can activate specific cytotoxic T cells (CTL) and even regression of established tumours in cancer-bearing hosts. These findings, as well as the elaboration of methods for generating large numbers of DC ex vivo, have provided a compelling rationale for using DC as potent adjuvants to deliver TA to the immune system in order to trigger or amplify an inadequate response. The capacity of TA-pulsed DC to induce significant CTL immunity translating into occasional therapeutic benefit has been documented in several clinical settings including B cell lymphoma, myeloma, melanoma, prostate, colon, ovarian and renal cell carcinoma. In this review, we summarize key biological functions of DC and focus on recent DC-based vaccination trials of breast, ovarian and cervical cancer. PMID 14666641

Dendritic cell-based tumor vaccine for cervical cancer II: results of a clinical pilot study in 15 individual patients.
Sep. 2003 | Ferrara, Alfonso; Nonn, Marion; Sehr, Peter; Schreckenberger, Carola; Pawlita, Michael; Dürst, Matthias; Schneider, Achim; Kaufmann, Andreas M
Human papillomavirus (HPV) type 16 and 18 are the most prevalent genotypes in cervical cancer. The viral oncoproteins E6 and E7 are considered to be tumor-specific targets for immunotherapy. HPV E7 antigen-loaded autologous dendritic cells (DC) were evaluated as cellular tumor vaccine in a case series of cervical cancer patients. PMID 12898233

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