TY - JOUR AB - Introduction: An abscopal effect is a clinical observation whereby a local treatment is associated with regression of metastatic cancer at a site distant from the primary location of treatment. Here, we describe the clinical systemic effect induced by regional hyperthermia combined with low-dose chemotherapy and provide immunologic correlates. Case presentation: A 15-year-old patient had been diagnosed with alveolar rhabdomyosarcoma (ARMS). All previous treatment options failed in the patient including haploidentical stem cell transplantation and donor lymphocyte infusion. The patient presented with local and metastatic disease, and upon admission, underwent regional hyperthermia combined with low-dose chemotherapy. Immediately following therapy severe skin reactions were observed. Skin biopsies revealed an intraepithelial lymphocytic infiltration dominated by CD3(+)/CD8(+) T cells with a regular network of dendritic cells. Clinical images compared before and during sequential treatment cycles showed complete metabolic response of the local tumor for more than 10 months of therapy. In addition, metastases completely regressed although they were not direct targets of regional hyperthermia. The systemic effect was associated with enhanced frequency of NK cells and T cells expressing the lectin-like natural-killer group 2 D activating receptor (NKG2D), an increase of the CD56(bright) subset of NK cells, as well as an increase of effector/memory and effector CD8(+) and CD4(+) T cells in the blood while the percentage of CD25(+)FOXP3(+) regulatory T cells declined. Conclusions: Regional hyperthermia combined with low-dose chemotherapy had the potential to create a systemic effect which was associated with activation of NK cells and T cells. AU - Issels, R.D.* AU - Lindner, L.H.* AU - von Bergwelt-Baildon, M.* AU - Lang, P.* AU - Rischpler, C.* AU - Diem, H.* AU - Mosetter, B. AU - Eckl, J.* AU - Schendel, D.J.* AU - Salat, C.* AU - Stötzer, O.* AU - Burdach, S.* AU - von Lüttichau-Teichert, I.* AU - Handgretinger, R.* AU - Neumann, J.* AU - Kirchner, T.* AU - Steiger, K.* AU - Boxberg, M.* AU - Mansmann, U.* AU - Multhoff, G.* AU - Nößner, E. C1 - 57861 C2 - 48152 CY - 2-4 Park Square, Milton Park, Abingdon Or14 4rn, Oxon, England SP - 55-65 TI - Systemic antitumor effect by regional hyperthermia combined with low-dose chemotherapy and immunologic correlates in an adolescent patient with rhabdomyosarcoma - a case report. JO - Int. J. Hyperthermia VL - 37 IS - 1 PB - Taylor & Francis Ltd PY - 2020 SN - 0265-6736 ER - TY - JOUR AB - Bladder cancer, the most common tumour of the urinary tract, ranks fifth among all tumour entities. While local treatment or intravesical instillation of bacillus Calmette–Guerin (BCG) provides a treatment option for non-muscle invasive bladder cancer of low grade, surgery or radio(chemo)therapy (RT) are frequently applied in high grade tumours. It remains a matter of debate whether surgery or RT is superior with respect to clinical outcome and quality of life. Surgical resection of bladder cancer can be limited by acute side effects, whereas, RT, which offers a non-invasive treatment option with organ- and functional conservation, can cause long-term side effects. Bladder toxicity by RT mainly depends on the total irradiation dose, fraction size and tumour volume. Therefore, novel approaches are needed to improve clinical outcome. Local tumour hyperthermia is currently used either as an ablation therapy or in combination with RT to enhance anti-tumour effects. In combination with RT an increase of the temperature in the bladder stimulates the local blood flow and as a result can improve the oxygenation state of the tumour, which in turn enhances radiation-induced DNA damage and drug toxicity. Hyperthermia at high temperatures can also directly kill cells, particularly in tumour areas which are poorly perfused, hypoxic or have a low tissue pH. This review summarises current knowledge relating to the role of hyperthermia in RT to treat bladder cancer, the induction and manifestation of immunological responses induced by hyperthermia, and the utilisation of the stress proteins as tumour-specific targets for tumour detection and monitoring of therapeutic outcome. AU - Multhoff, G. AU - Habl, G.* AU - Combs, S.E. C1 - 48436 C2 - 41156 CY - Abingdon SP - 455-463 TI - Rationale of hyperthermia for radio(chemo)therapy and immune responses in patients with bladder cancer: Biological concepts, clinical data, interdisciplinary treatment decisions and biological tumour imaging. JO - Int. J. Hyperthermia VL - 32 IS - 4 PB - Taylor & Francis Ltd PY - 2016 SN - 0265-6736 ER - TY - JOUR AB - Purpose: 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 degrees +/- to 42 degrees C. Therefore G plus Cis with regional hyperthermia (RHT) might be beneficial for patients with G-refractory APC. Patients and methods: We retrospectively analysed 23 patients with advanced (n = 2) or metastatic (n = 21) pancreatic cancer with relapse after G mono first-line chemotherapy (n = 23). Patients had received G (day 1, 1000 mg/m(2)) and Cis (day 2 and 4, 25 mg/m(2)) in combination with RHT (day 2 and 4, 1 h) biweekly for 4 months. We analysed feasibility, toxicity, time to second progression (TTP2), overall survival (OS) and clinical response. Results: Between October 1999 and August 2008 23 patients were treated. Haematological toxicity was low with no grade 4 event. Hyperthermia-associated toxicity consisted of discomfort because of bolus pressure (3%), power-related pain (7%) or position-related pain (17%). Median TTP1 was 5.9 months (95% confidence interval (CI): 2.6-9.2), median TTP2 was 4.3 months (95%CI: 1.2-7.4) and OS 12.9 months (95%CI: 9.9-15.9). The disease control rate in 16 patients with available CT scans was 50%. Conclusion: We show first clinical data of G plus Cis with RHT being clinically active in G-pretreated APC with low toxicity. A prospective controlled phase II second-line clinical trial (EudraCT:2005-003855-11) and a randomised phase III adjuvant clinical trial offering this treatment (HEAT; EudraCT: 2008-004802-14) are currently open for recruitment. AU - Tschöp-Lechner, K.E.* AU - Milani, V.* AU - Berger, F.* AU - Dieterle, N.* AU - Abdel-Rahman, S.* AU - Salat, C.* AU - Issels, R.D. C1 - 22663 C2 - 30927 SP - 8-16 TI - Gemcitabine and cisplatin combined with regional hyperthermia as second-line treatment in patients with gemcitabine-refractory advanced pancreatic cancer. JO - Int. J. Hyperthermia VL - 29 IS - 1 PB - Informa Healthcare PY - 2013 SN - 0265-6736 ER - TY - JOUR AB - Purpose: Adding hyperthermia to chemotherapy improved the clinical outcome of patients with high risk soft tissue sarcoma. Further improvement might be possible if combined with vaccination strategies. As no sarcoma-associated antigens are known, the ecto AU - Tschöp-Lechner, K. AU - Drexler, I. AU - Hammer, D. AU - Neumann, D. AU - Pohla, H. AU - Sutter, G.* AU - Nößner, E. AU - Issels, R.D. C1 - 8000 C2 - 29990 SP - 33-42 TI - Modified vaccinia virus Ankara delivers a robust surrogate marker for immune monitoring to sarcoma cells even if cells are being exposed to chemotherapy and heat treatment. JO - Int. J. Hyperthermia VL - 28 IS - 1 PB - Informa Healthcare PY - 2012 SN - 0265-6736 ER - TY - JOUR AB - Much information can be gained by investigating the consequences of hyperthermia on individual cell populations in vitro, however the precise effects of such a therapeutic modality in vivo depend on the tumour microenvironment and the cellular composition therein. Although the direct cytotoxic effects of hyperthermia on tumour tissue can lead to an immediate reduction in tumour volume, long-term benefits to local and distal tumour recurrence will very much depend on the induction of immunity and the capacity of effector cells to traffic to tumours and elicit their cytotoxic functions. The immunological sequelae to hyperthermia are even more important in those instances when large tumour volumes preclude the delivery of appropriate thermal damage. The development of protective anti-tumour immunity requires a plethora of interactions and responses, the vast majority of which can be influenced by temperatures that are consistent with fever-like temperatures (39 degrees -40 degrees C), as well as hyperthermia treatment (<41 degrees C). This article reviews current knowledge relating to the effects of hyperthermia treatment on aspects of the induction and manifestation of immunological responses that are most pertinent to the development and maintenance of protective anti-tumour immunity. AU - Muthana, M.* AU - Multhoff, G. AU - Pockley, A.G.* C1 - 1684 C2 - 27189 SP - 247-255 TI - Tumour infiltrating host cells and their significance for hyperthermia. JO - Int. J. Hyperthermia VL - 26 IS - 3 PB - Informa Healthcare USA, Inc. PY - 2010 SN - 0265-6736 ER - TY - JOUR AB - PURPOSE: We report data from phase II trials examining the efficacy of multimodality treatment with neoadjuvant chemotherapy, hyperthermia, surgery, radiation and postoperative thermochemotherapy in adult patients with high-risk sarcomas of the extremities. PATIENTS AND METHODS: From 1991 to 2001 47 patients with high risk soft tissue sarcoma of the extremities were prospectively treated in two clinical trials with a treatment plan of four cycles of etoposide, ifosfamide and doxorubicin combined with regional hyperthermia followed by surgery, radiation and adjuvant chemotherapy. RESULTS: Objective response rate assessable in 39 patients was 21% (one complete and seven partial responses). A favourable histological response (>75% tumour necrosis) was observed in 34% of the 35 evaluable patients who had surgical resection. Median overall survival (OS) was 105 months. The five-year probability of local failure-free survival (LFFS), distant disease-free survival (DDFS), event-free survival (EFS) and OS were 48%, 55%, 35% and 57%, respectively. There were no significant differences between responders and non-responders of minimum temperatures (Tmin) and time-averaged temperatures achieved in 50% (T(50)) and 90% (T(90)) at all measured tumour sites. Response to this neoadjuvant regimen predicted for prolonged LFFS (p = 0.0123), but not for OS (p = 0.2). Limb preservation was achieved in 37 patients (79%) and did not result in inferior DDFS (52% versus 50%) or OS (61% versus 50%) at five years (p = 0.8) in comparison to patients who underwent amputation. CONCLUSION: Response to combined modality treatment with RHT and neoadjuvant chemotherapy was predictive for an improved LFFS and led to limb preservation in 79% of patients with extremity sarcomas. AU - Schlemmer, M.* AU - Wendtner, C.M.* AU - Lindner, L.* AU - Abdel-Rahman, S.* AU - Hiddemann, W.* AU - Issels, R.D. C1 - 979 C2 - 27345 SP - 127-135 TI - Thermochemotherapy in patients with extremity high-risk soft tissue sarcomas (HR-STS). JO - Int. J. Hyperthermia VL - 26 IS - 2 PB - Informa UK Ltd. PY - 2010 SN - 0265-6736 ER - TY - JOUR AB - The proteasome inhibitor bortezomib exhibits antitumor activity in many malignancies including mantle cell lymphoma (MCL). Unfortunately, many patients fail to respond to treatment or become refractory. Hyperthermia is an effective chemosensitizer that in combination with some chemotherapeutic agents has shown clinical activity in phase II and III studies. The aim of this study was to use MCL cell lines to investigate the potential benefit of combining clinically relevant doses of bortezomib with two different thermal doses (41.8 degrees C/120 min and 44 degrees C/30 min) that mimic the heterogeneity of the temperature distributions achieved within tumors during hyperthermia. Treated tumor cells were assessed for proliferation using the WST-1 assay and for apoptosis by annexin V staining, while heat shock protein (HSP) levels were determined following western blot analysis. Our results demonstrated that MCL cell lines that are sensitive to bortezomib are also thermosensitive and have low basal expression of hsp27, whereas the bortezomib-resistant MCL cell line strongly expresses hsp27 and is thermoresistant. Interestingly, pre-treatment of MCL cell lines with heat at the two different thermal doses, and the transient elevation of hsp27 and hsp70, do not impair their primary sensitivity to bortezomib. Finally, we show that the concurrent treatment of heat and bortezomib results in additive killing in MCL cell lines. In conclusion, these results suggest that the application of bortezomib, under thermal conditions, in mantle cell lymphoma cells may be beneficial and warrants further investigation. AU - Milani, V. AU - Lorenz, M. AU - Weinkauf, M. AU - Rieken, M. AU - Pastore, A. AU - Dreyling, M. AU - Issels, R.D. C1 - 1343 C2 - 26289 SP - 262-272 TI - Combination of hyperthermia and bortezomib results in additive killing in mantle cell lymphoma cells. JO - Int. J. Hyperthermia VL - 25 IS - 4 PB - Informa Healthcare PY - 2009 SN - 0265-6736 ER - TY - JOUR AB - Intracellular heat shock proteins (HSP) function as molecular chaperones, they support folding and transport mechanisms of other proteins under physiological conditions and following physical or chemical stress. More recently, extracellular localized HSP have been found to play key roles in the induction of a cellular immune response. Either they act as carrier molecules for immunogenic peptides that are presented on Antigen Presenting Cells (APC) to cytotoxic T-cells or they themselves act as activatory molecules for the innate immune system. Binding of uncomplexed HSP to HSP-receptors on APC has been found to induce the secretion of inflammatory cytokines. Furthermore, an unusual tumor-selective membrane-localization of non-conserved regions of the 72 000 Da HSP (Hsp70) has been found to act as a recognition structure for natural killer (NK) cells. In this review the interaction of NK cells with Hsp70 or peptides derived thereof will be eluciated in more detail. AU - Multhoff, G. C1 - 2261 C2 - 26201 SP - 169-175 TI - Activation of natural killer cells by heat shock protein 70. JO - Int. J. Hyperthermia VL - 25 IS - 3 PB - Informa Healthcare PY - 2009 SN - 0265-6736 ER - TY - JOUR AB - Purpose: To compare the radiological criteria RECIST, WHO, and tumor volume for evaluation of tumor response in patients with soft tissue sarcomas (STS) showing either good or poor pathohistological response to neoadjuvant chemotherapy combined with regional hyperthermia, and to examine the dependence of the findings on the applied thermal dose. Materials and methods: 19 patients with pathohistological complete response (no vital tumor cells, group 1) and 27 with pathohistological no response (< 25% necrosis, group 2) were selected from our previous clinical trials. The change in tumor size before and after therapy was determined. Intratumoral temperature (T-90) and thermal dose (CEM 43 degrees C T-90) were calculated for 13 patients. Results: In the first group, 6 partial response (PR) and 13 stable disease (SD) according to RECIST, 7 PR and 12 SD according to WHO, 7 PR and 12 SD according to volumetric criteria were evaluated. In the second group, the results were 10 PR and 17 SD (RECIST), 9 PR and 18 SD (WHO), 8 PR and 19 SD (volume). The concordance of these criteria was 73.7% in group 1 and 74% in group 2. PR and SD were equally distributed in both groups (p>0.421). Thermal parameters were not different between the groups (p>0.327). Conclusions: SD or PR in radiological response assessment does not correlate with the pathohistological response after neoadjuvant thermochemotherapy. RECIST, WHO and volumetric criteria for response evaluation in STS are in substantial agreement. For irregularly shaped lesions, volumetric criteria seem to be more appropriate. AU - Stahl, R.* AU - Wang, T.* AU - Lindner, L.H. AU - Abdel-Rahman, S. AU - Santl, M. AU - Reiser, M.F.* AU - Issels, R.D. C1 - 2058 C2 - 26408 CY - London SP - 289-298 TI - Comparison of radiological and pathohistological response to neoadjuvant chemotherapy combined with regional hyperthermia (RHT) and study of response dependence on the applied thermal parameters in patients with soft tissue sarcomas (STS). JO - Int. J. Hyperthermia VL - 25 IS - 4 PB - Informa Healthcare PY - 2009 SN - 0265-6736 ER - TY - JOUR AB - The goal of immune-based tumor therapies is the activation of immune cells reactive against a broad spectrum of tumor-expressed antigens. Vaccines based on chaperone proteins appear promising as these proteins naturally exist as complexes with various protein fragments including those derived from tumor-associated antigens. Multi-chaperone systems are expected to have highest polyvalency as different chaperones can carry distinct sets of antigenic fragments. A free-solution isoelectric focusing (FS-IEF) technique was established to generate chaperone-rich cell lysates (CRCL). Results from murine systems support the contention that CRCL induce superior anti-tumor responses than single chaperone vaccines. We established an in vitro model for human melanoma to evaluate the capacity of CRCL to transfer endogenously expressed tumor antigens to the cross-presentation pathway of dendritic cells (DC) for antigen-specific T cell stimulation. CRCL prepared from human melanoma lines contained the four major chaperone proteins Hsp/Hsc70, Hsp90, Grp94/gp96 and calreticulin. The chaperones within the melanoma cell-derived CRCL were functionally active in that they enhanced cross-presentation of exogenous peptides mixed into the CRCL preparation. Superior activity was observed for Hsp70-rich CRCL obtained from heat-stressed melanoma cells. Despite the presence of active chaperones, melanoma cell-derived CRCL failed to transfer endogenously expressed melanoma-associated antigens to DC for cross-presentation and cytotoxic T cell (CTL) recognition, even after increasing intracellular protein levels of tumor antigen or chaperones. These findings reveal limitations of the CRCL approach regarding cross-presentation of endogenously expressed melanoma-associated antigens. Yet, CRCL may be utilized as vehicles to enhance the delivery of exogenous antigens for DC-mediated cross-presentation and T cell stimulation. AU - Bleifuss, E. AU - Bendz, H. AU - Sirch, B.* AU - Thompson, S.* AU - Brandl, A. AU - Milani, V.* AU - Graner, M.W.* AU - Drexler, I. AU - Kuppner, M.* AU - Katsanis, E.* AU - Nößner, E. AU - Issels, R.D. C1 - 1809 C2 - 25934 SP - 623-637 TI - Differential capacity of chaperone-rich lysates in cross-presenting human endogenous and exogenous melanoma differentiation antigens. JO - Int. J. Hyperthermia VL - 24 IS - 8 PB - Informa Healthcare PY - 2008 SN - 0265-6736 ER - TY - JOUR AB - 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. METHODS: Forty-five patients with peritoneal carcinomatosis (with or without liver metastases) in colorectal cancer (CRC) (n = 16), ovarian cancer (OC) (n = 17), or gastric/pancreatic/biliary cancer (n = 12) underwent standard chemotherapy and regional hyperthermia. Most CRC patients received second-line chemotherapy. All OC patients were platinum resistant. Regional hyperthermia was applied using a SIGMA-60 applicator (OC), a SIGMA-Eye/MR applicator (CRC), or various ring applicators (gastric/pancreatic/biliary cancer). RESULTS: Abdominal regional hyperthermia was well tolerated, with acceptable acute discomfort and no long-term morbidity. The SIGMA-Eye/MR applicator achieved higher systemic temperatures (associated with higher systemic stress) and more effective heating of the upper abdomen; the SIGMA-60 applicator achieved higher temperatures (and power densities) in the pelvis. Three-year overall survival was encouraging for patients with CRC (22%) and OC (29%) but not gastric/pancreatic/biliary cancer. For the SIGMA-60 applicator (patients with OC), higher measured temperatures at the vaginal stump correlated with better outcome. CONCLUSIONS. The SIGMA-60 and SIGMA-Eye/MR applicators are feasible for abdominal heating and have low toxicity. The SIGMA-60 applicator is specifically suitable for malignancies with high pelvic burden; the SIGMA-Eye/MR applicator better heats the upper abdomen, including the liver. Further randomized investigations are warranted. AU - Cho, C.H.* AU - Wust, P.* AU - Hildebrandt, B.* AU - Issels, R.D. AU - Sehouli, J.* AU - Kerner, T.* AU - Deja, M.* AU - Budach, V.* AU - Gellermann, J.* C1 - 795 C2 - 25615 SP - 399-408 TI - Regional hyperthermia of the abdomen in conjunction with chemotherapy for peritoneal carcinomatosis: Evaluation of two annular-phased-array applicators. JO - Int. J. Hyperthermia VL - 24 IS - 5 PB - Taylor & Francis PY - 2008 SN - 0265-6736 ER - TY - JOUR AU - Issels, R.D. C1 - 789 C2 - 23588 SP - 235-239 TI - High-risk soft tissue sarcoma: Clinical trial and hyperthermia combined chemotherapy. JO - Int. J. Hyperthermia VL - 22 PY - 2006 SN - 0265-6736 ER - TY - JOUR AU - Lindner, L.H. AU - Reinl, H.M.* AU - Schlemmer, M.* AU - Stahl, R.* AU - Peller, M.* C1 - 3703 C2 - 23217 SP - 575-588 TI - Paramagnetic thermosensitive liposomes for MR-thermometry. JO - Int. J. Hyperthermia VL - 21 PY - 2005 SN - 0265-6736 ER - TY - JOUR AU - Fiegl, M.* AU - Schlemmer, M. AU - Wendtner, C.-M.* AU - Abdel-Rahman, S.* AU - Fahn, W.* AU - Issels, R.D. C1 - 4282 C2 - 22205 SP - 661-670 TI - Ifosfamide, carboplatin and etoposide (ICE) as second-line regimen alone and in combination with regional hyperthermia is active in chemo-pre-treated advanced soft tissue sarcoma of adults. JO - Int. J. Hyperthermia VL - 20 PY - 2004 SN - 0265-6736 ER - TY - JOUR AU - Baur, A.* AU - Stäbler, A.* AU - Wendtner, C.M.* AU - Arbogast, S.* AU - Rahman, S.A.* AU - Santl, M.* AU - Issels, R.D. AU - Reiser, M.* C1 - 22340 C2 - 21199 SP - 391-401 TI - MR-imaging changes of musculoskeletal soft-tissue sarcomas associated with neoadjuvant chemotherapy and hyperthermia. JO - Int. J. Hyperthermia VL - 19 PY - 2003 SN - 0265-6736 ER - TY - JOUR AU - Milani, V. AU - Nößner, E. AU - Ghose, S. AU - Kuppner, M. AU - Ahrens, B. AU - Scharner, A. AU - Gastpar, R.* AU - Issels, R.D. C1 - 10130 C2 - 21203 SP - 563-575 TI - Heat shock protein 70 : role in antigen presentation and immune stimulation. JO - Int. J. Hyperthermia VL - 18 PY - 2002 SN - 0265-6736 ER - TY - JOUR AB - Heat sensitization to cisplatin was studied in drug-sensitive Chinese hamster fibroblast (CH) and inherently drug-resistant hamster kidney (HaK) cells. Under normothermic conditions the slopes of the survival curves differed by a factor of 3.6, while the cellular uptake was higher in CH cells by a factor of 3. When heat and drug treatment were given simultaneously, both effects were increased in CH and HaK cells: thermal enhancement factors at 43°C were 5.5 (CH) and 2.9 (HaK) for cytotoxic drug action and 3.9 and 2.2 for the increase in cellular drug content. Increase in cell sensitization was also obtained if the cells were heat pretreated (42.5-44°C for various times) followed by drug exposure at 37°C. It is concluded that thermal enhancement depends on the efficiency of cisplatin cytotoxicity, which in turn correlates with cellular drug uptake in both the sensitive and resistant cell line. AU - Eichholtz-Wirth, H. AU - Hietel, B. C1 - 33827 C2 - 36403 SP - 47-55 TI - Heat sensitization to cisplatin in two cell lines with different drug sensitivities. JO - Int. J. Hyperthermia VL - 6 IS - 1 PY - 1990 SN - 0265-6736 ER -