Biomodulatory Treatment of Patients with Castration-Resistant Prostate Cancer: A Phase II Study of Imatinib with Pioglitazone, Etoricoxib, Dexamethasone and Low-Dose Treosulfan.

Therapeutic options for patients with castration-resistant prostate cancer (CRPC) remain limited. In a multicenter, Phase II study, 65 patients with histologically confirmed CRPC received a biomodulatory regimen during the six-month core study. Treatment comprised daily doses of imatinib mesylate, pioglitazone, etoricoxib, treosulfan and dexamethasone. The primary endpoint was prostate-specific antigen (PSA) response. Responders could enter an extension phase until disease progression or intolerable toxicity occurred. Mean PSA was 45.3 ng/mL at baseline, and 77 % of patients had a PSA doubling time <3 months. Of the 61 evaluable patients, 37 patients (60.6 %) responded or had stable disease and 23 of them (37.7 % of 61 patients) were PSA responders. Among the 23 responders mean PSA decreased from 278.9 ± 784.1 ng/mL at baseline to 8.8 ± 11.6 ng/mL at the final visit (week 24). The progression-free survival (PFS) was 467 days in the ITT population. Of the 947 adverse events, 57.6 % were suspected to be drug-related, 13.8 % led to dose adjustment or permanent discontinuation and 40.2 % required concomitant medication. This novel combination approach led to an impressive PSA response rate of 37.7 % in CRPC patients. The good PSA response and PFS rate combined with the manageable toxicity profile suggest an alternative treatment option.

Current status of radiant whole-body hyperthermia at temperatures >41.5 degrees C and practical guidelines for the treatment of adults. The German 'Interdisciplinary Working Group on Hyperthermia'.

The term 'extreme' whole-body hyperthermia (WBH) describes the procedure of raising a patients' body-core temperature to 41.5-42.0 degrees C for 60 min. WBH represents the only hyperthermia technique that enables systemic heat treatment in patients with disseminated malignancies and is, therefore, usually combined with systemic chemotherapy. Up to now, several WBH-approaches have proved to be safe and associated with acceptable toxicity rates when radiant heat devices are employed. Until the late 1990s, the use of radiant WBH was restricted to a few specialized treatment centres worldwide. During the last 5 years, a larger number of WBH-devices were put into operation particularly in Germany. As a result, a novel generation on phase II trials on chemotherapy and adjunctive WBH in patients with various malignancies has been completed. Based on the promising results observed herein, first multi-centric phase III-trials on chemotherapy +/- WBH have been initiated, with a considerable number of patients treated at German institutions. The authors are members of the 'Interdisciplinary Working Group for Hyperthermia' ('Interdisziplinäre Arbeitsgruppe Hyperthermie'), a sub-group of the German Cancer Society. They formulated these guidelines in order to standardize the WBH treatment procedure and supportive measures, to provide some uniformity in the selection of patients to be treated and to define criteria of a successful WBH-treatment. These recommendations may be helpful to ensure the quality of WBH performed at different institutions.

Clonal expansion of Melan A-specific cytotoxic T lymphocytes in a melanoma patient responding to continued immunization with melanoma-associated peptides.

Peptides derived from human tumor antigens have been used in a number of clinical trials to induce specific immune responses against autologous tumors in cancer patients. Although favorable clinical results were observed in single patients, immune responses correlating with tumor regression were either not detected or in case of responses, the T-cell specificity was difficult to demonstrate. In this study, we analyzed antigen-specific T-cell responses induced in the skin and in peripheral blood lymphocytes (PBL) in an HLA-A2-positive melanoma patient. The patient showed major regression of metastatic melanoma under continued immunization with peptides derived from the melanocyte differentiation antigens Melan A/MART-1, tyrosinase and gp100/Pmel17. Based on the identification of different T-cell receptor (TCR) families reactive with Melan A/MART-1, we have demonstrated that i.d. immunization with peptides alone leads to oligoclonal expansion of Melan A/MART-1-specific cytotoxic T lymphocytes (CTL), detectable in local delayed-type hypersensitivity (DTH) reactions and PBL. A monoclonal expansion of a Melan A/MART-1-specific TCR VB 16 CTL was reproducibly observed after in vitro stimulation with Melan A/MART-1 peptides. The same TCR VB 16 CTL clone was detected in skin biopsies taken from vitiligo areas. Our findings provide strong evidence for the effective induction of specific T-cell responses to Melan A/MART-1 by i.d. immunization with peptide alone, which accounts for dermal depigmentation, specific cytotoxicity against Melan A/MART-1-expressing melanoma cells and clinical tumor regression.