van der Most RG, Currie AJ, Mahendran S, Prosser A, Darabi A, Robinson BW, Nowak AK, Lake RA.

National Centre for Asbestos Related Diseases, School of Medicine and Pharmacology, University of Western Australia, Perth, Australia. robbertvdm@gmail.com

Abstract

Tumor cell death potentially engages with the immune system. However, the efficacy of anti-tumor chemotherapy may be limited by tumor-driven immunosuppression, e.g., through CD25+ regulatory T cells. We addressed this question in a mouse model of mesothelioma by depleting or reconstituting CD25+ regulatory T cells in combination with two different chemotherapeutic drugs. We found that the efficacy of cyclophosphamide to eradicate established tumors, which has been linked to regulatory T cell depletion, was negated by adoptive transfer of CD25+ regulatory T cells. Analysis of post-chemotherapy regulatory T cell populations revealed that cyclophosphamide depleted cycling (Ki-67(hi)) T cells, including foxp3+ regulatory CD4+ T cells. Ki-67(hi) CD4+ T cells expressed increased levels of two markers, TNFR2 and ICOS, that have been associated with a maximally suppressive phenotype according to recently published studies. This suggest that cyclophosphamide depletes a population of maximally suppressive regulatory T cells, which may explain its superior anti-tumor efficacy in our model. Our data suggest that regulatory T cell depletion could be used to improve the efficacy of anti-cancer chemotherapy regimens. Indeed, we observed that the drug gemcitabine, which does not deplete cycling regulatory T cells, eradicates established tumors in mice only when CD25+ CD4+ T cells are concurrently depleted. Cyclophosphamide could be used to achieve regulatory T cell depletion in combination with chemotherapy.

Keywords: Tumor immunity – Regulatory CD4+ T cells – Chemotherapy – Mesothelioma – Gemcitabine – Cyclophosphamide

Barata F, Cortesao N, Marques A, Figueiredo A.

Servico Pneumologia Centro Hospitalar de Coimbra.

Abstract

Rational and objective: During the last few years a variety of new chemotherapy agents have been used (mostly in combination) in the treatment of malignant pleural mesothelioma (MPM). Combination therapy with platinum was the mainstay therapy for late stages. Recently, combination cisplatinum/pemetrexed was approved as standard first-line treatment for MPM. The aim of this study is to review results obtained with chemotherapy in MPM. Material and methods: We treated 16 patients in a 7-year period. From 1997 to 1999 we used a combination regimen of cisplatinum + epirubicin + cyclophosphamide (6 patients). From 2000 to 2004 we used gemcitabine + carboplatinum (8 patients) or gemcitabine + cisplatinum (2 patients).

Results: Polichemotherapy was administered to 16 patients (15 men, 1 woman) with mean age of 61.4 (44-76) years. Thirteen patients had an initial PS=0/1; ten patients had professional contact with products presumably containing asbestos; histology results identified epithelial-type in 14 patients and mixed-type in 2; all patients were in stages III or IV; diagnosis was made by VATS in 14 patients, blind pleural biopsy in 1 patient and guided transthoracic biopsy in 1 patient. Thirteen patients had palliative radiotherapy over the area submitted to specimen collection. We obtained partial responses in 4 patients (25%), stability in 6 (37.5%) and progression in 6 (37.5%). Mean number of chemotherapy sessions was 4.5. To date (September, 2005) 15 patients have died. Mean length to progression was 6.4 months (2-14) and survival 13.8 months (4-29). We observed 7 cases of neutropenia (grades 3 and 4), 2 of which were febrile neutropenia with hospital admission.

Reflection: Our results regarding this rare pathology were similar to those found in the literature. It would be interesting to collect national data from all units that treat or have treated MPM; a clinical study comparing the actual chemotherapy regimen to one of those used previously would be another interesting approach to this pathology.

F B, N C, A M, A F.

Servico Pneumologia Centro Hospitalar de Coimbra.

Abstract

Rational and objective: During the last few years a variety of new chemotherapy agents have been used (mostly in combination) in the treatment of malignant pleural mesothelioma (MPM). Combination therapy with platinum was the mainstay therapy for late stages. Recently, combination cisplatinum/pemetrexed was approved as standard first-line treatment for MPM. The aim of this study is to review results obtained with chemotherapy in MPM.

Material and methods: We treated 16 patients in a 7-year period. From 1997 to 1999 we used a combination regimen of cisplatinum + epirubicin + cyclophosphamide (6 patients). From 2000 to 2004 we used gemcitabine + carboplatinum (8 patients) or gemcitabine + cisplatinum (2 patients).

Results: Polichemotherapy was administered to 16 patients (15 men, 1 woman) with mean age of 61.4 (44-76) years. Thirteen patients had an initial PS=0/1; ten patients had professional contact with products presumably containing asbestos; histology results identified epithelial-type in 14 patients and mixed-type in 2; all patients were in stages III or IV; diagnosis was made by VATS in 14 patients, blind pleural biopsy in 1 patient and guided transthoracic biopsy in 1 patient. Thirteen patients had palliative radiotherapy over the area submitted to specimen collection. We obtained partial responses in 4 patients (25%), stability in 6 (37.5%) and progression in 6 (37.5%). Mean number of chemotherapy sessions was 4.5. To date (September, 2005) 15 patients have died. Mean length to progression was 6.4 months (2-14) and survival 13.8 months (4-29). We observed 7 cases of neutropenia (grades 3 and 4), 2 of which were febrile neutropenia with hospital admission.

Reflection: Our results regarding this rare pathology were similar to those found in the literature. It would be interesting to collect national data from all units that treat or have treated MPM; a clinical study comparing the actual chemotherapy regimen to one of those used previously would be another interesting approach to this pathology.

Stathopoulos J, Antoniou D, Stathopoulos GP, Rigatos SK, Dimitroulis J, Koutandos J, Michalopoulou P, Athanasiades A, Veslemes M.

SOLCA Study Group and First Department of Medical Oncology, Errikos Dunant Hospital, Athens, Greece. dr-gps@ath.forthnet.gr

Abstract

Background: Our purpose was to evaluate the survival of patients with pleural and intraperitoneal malignant mesothelioma and, particularly, to estimate the efficacy of chemotherapy as well as radiotherapy and surgery. A review of the literature with respect to these parameters is included.

Patients and Methods: Thirty-five patients with malignant mesothelioma (28 with pleural and 7 with intraperitoneal) were enrolled. Twenty-eight patients underwent chemotherapy, 7/35 radiation and 9/35 surgery (2 with pleural and 7 with abdominal disease). Combination chemotherapy included cisplatin-gemcitabine, cisplatin (or carboplatin) with premetrexed and doxorubicin-cyclophosphamide.

Results: In 2/28 patients with pleural mesothelioma the tumor was excised and in 7 with intraperitoneal disease, surgical therapy was palliative and there was survival prolongation. Radiotherapy was only palliative. Chemotherapy produced a very low response: 2/28 (7.14%) patients achieved a partial response. The median survival was 17 months, 4-year survival, 24.4% and 5-year survival, 12.12%. No serious toxicity was observed.

Conclusion: Malignant mesothelioma of the pleura and intraperitoneum is a slow-growing disease which is indicated by the long survival, despite the failure of chemotherapy, radiation therapy and surgery.

Riehemann K, Schmitt O, Ehlers EM.

Institut fur Anatomie, Universitat zu Lubeck, Ratzeburger Allee 160, 23538, Lubeck, Germany. riehemannk@web.de

Abstract

The human malignant pleural mesothelioma is related to the use of asbestos in the majority of cases. Though the use of asbestos has been prohibited since the 1990s, the incidence of pleural mesothelioma is still increasing because of a latency period of at least 20 years. This study investigated the benefit of single therapy with cyclophosphamide or hyperthermia or the combination of both on cells of a human pleural mesothelioma cell line, xenotransplanted subcutaneously in the paw of mice. A CONTROL group received the same volume of physiological saline. The oxygenation of tumours was measured, tumour growth was followed over 3 weeks, immunohistochemical studies and a light and electron microscopic evaluation were performed. Chemotherapy or hyperthermia alone was only temporarily effective. The greatest benefit was achieved using combined thermochemotherapy consisting of cyclophosphamide plus hyperthermia: 50% of this group had partial remissions, and 67% responded to this therapy. After 3 weeks tumours grew again. Superior effects could be achieved by performing additional cycles of chemotherapy or adding another drug or radiation for instance. This study shows promising results in the treatment of malignant pleural mesothelioma.