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Mesothelioma: HELP
Articles by Dr. Rolf Stahel
Based on 46 articles published since 2008
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Between 2008 and 2019, R. Stahel wrote the following 46 articles about Mesothelioma.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Guideline [Guidelines of the European Respiratory Society and the European Society of Thoracic Surgeons for the management of malignant pleural mesothelioma]. 2010

Scherpereel, A / Astoul, P / Baas, P / Berghmans, T / Clayson, H / de Vuyst, P / Dienemann, H / Galateau-Salle, F / Hennequin, C / Hillerdal, G / Le Pe'choux, C / Mutti, L / Pairon, J-C / Stahel, R / van Houtte, P / van Meerbeeck, J / Waller, D / Weder, W / Anonymous220676 / Anonymous230676. ·Dept of Pulmonary and Thoracic Oncology,Hospital Calmette CHRU of Lille 59037 Lille Cedex, France. a-scherpereel@chru-lille.fr ·Zhongguo Fei Ai Za Zhi · Pubmed #20976998.

ABSTRACT: -- No abstract --

2 Guideline Malignant pleural mesothelioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. 2010

Stahel, R A / Weder, W / Lievens, Y / Felip, E / Anonymous2920663. ·Clinic and Policlinic of Oncology, University Hospital of Zürich, Switzerland. ·Ann Oncol · Pubmed #20555061.

ABSTRACT: -- No abstract --

3 Guideline Guidelines of the European Respiratory Society and the European Society of Thoracic Surgeons for the management of malignant pleural mesothelioma. 2010

Scherpereel, A / Astoul, P / Baas, P / Berghmans, T / Clayson, H / de Vuyst, P / Dienemann, H / Galateau-Salle, F / Hennequin, C / Hillerdal, G / Le Péchoux, C / Mutti, L / Pairon, J-C / Stahel, R / van Houtte, P / van Meerbeeck, J / Waller, D / Weder, W / Anonymous1990637. ·Dept of Pulmonary and Thoracic Oncology, Hôpital Calmette, CHRU of Lille, 59037 Lille Cedex, France. a-scherpereel@chru-lille.fr ·Eur Respir J · Pubmed #19717482.

ABSTRACT: Malignant pleural mesothelioma (MPM) is a rare tumour but with increasing incidence and a poor prognosis. In 2008, the European Respiratory Society/European Society of Thoracic Surgeons Task Force brought together experts to propose practical and up-to-dated guidelines on the management of MPM. To obtain an earlier and reliable diagnosis of MPM, the experts recommend performing thoracoscopy, except in cases of pre-operative contraindication or pleural symphysis. The standard staining procedures are insufficient in approximately 10% of cases. Therefore, we propose using specific immunohistochemistry markers on pleural biopsies. In the absence of a uniform, robust and validated staging system, we advice use of the most recent TNM based classification, and propose a three step pre-treatment assessment. Patient's performance status and histological subtype are currently the only prognostic factors of clinical importance in the management of MPM. Other potential parameters should be recorded at baseline and reported in clinical trials. MPM exhibits a high resistance to chemotherapy and only a few patients are candidates for radical surgery. New therapies and strategies have been reviewed. Because of limited data on the best combination treatment, we emphasise that patients who are considered candidates for a multimodal approach should be included in a prospective trial at a specialised centre.

4 Guideline Malignant pleural mesothelioma: ESMO clinical recommendations for diagnosis, treatment and follow-up. 2008

Stahel, R A / Weder, W / Felip, E / Anonymous3530598. ·Clinic and Policlinic of Oncology, University Hospital of Zürich, Switzerland. ·Ann Oncol · Pubmed #18456764.

ABSTRACT: -- No abstract --

5 Review A New Prognostic Score Supporting Treatment Allocation for Multimodality Therapy for Malignant Pleural Mesothelioma: A Review of 12 Years' Experience. 2015

Opitz, Isabelle / Friess, Martina / Kestenholz, Peter / Schneiter, Didier / Frauenfelder, Thomas / Nguyen-Kim, Thi Dan Linh / Seifert, Burkhardt / Hoda, Mir Alireza / Klepetko, Walter / Stahel, Rolf A / Weder, Walter. ·*Division of Thoracic Surgery, †Department of Diagnostic Radiology, University Hospital Zurich, Zurich, Switzerland; ‡Department of Biostatistics, Epidemiology, Biostatistics and Prevention Unit, University Zurich, Zurich, Switzerland; §Division of Thoracic Surgery, Medical University Vienna, Vienna, Austria; and ‖Laboratory of Molecular Oncology, University Hospital Zurich, Zurich, Switzerland. ·J Thorac Oncol · Pubmed #26317916.

ABSTRACT: INTRODUCTION: Treatment of malignant pleural mesothelioma (MPM) remains a clinical challenge. The aim of this study was to identify selection factors for allocation of MPM patients to multimodal therapy based on survival data from 12 years of experience. METHODS: Eligible patients had MPM of all histological subtypes with clinical stage T1-3 N0-2 M0. Induction chemotherapy consisted of cisplatin/gemcitabine (cis/gem) or cisplatin/pemetrexed (cis/pem), followed by extrapleural pneumonectomy (EPP). Multivariate analysis was performed to assess independent prognosticators for overall survival (OS). A Multimodality Prognostic Score was developed based on clinical variables available before surgery. RESULTS: From May 1999 to August 2011, 186 MPM patients were intended to be treated with induction chemotherapy followed by EPP. Hematologic toxicity was significantly less frequent after cis/pem compared to cis/gem, but there was no difference in response or OS between the regimens. One hundred and twenty-eight patients underwent EPP with a 30-day mortality of 4.7%. Fifty-two percent of the patients received adjuvant radiotherapy. The median OS of patients undergoing EPP was significantly longer with 22 months (95% confidence interval: 20-24) when compared to 11 months (9-12) for patients treated without EPP. A prognostic score was defined considering tumor volume, histology, C-reactive protein level, and response to chemotherapy that identified patient groups not benefitting from multimodality treatment which was confirmed in an independent cohort. CONCLUSION: Patients receiving induction chemotherapy followed by EPP for MPM of all histological subtypes and irrespective of nodal status showed a median survival of 22 months. A prognostic score is proposed to help patient allocation for surgery after validation in an independent cohort.

6 Review Searching for targets for the systemic therapy of mesothelioma. 2015

Stahel, R A / Weder, W / Felley-Bosco, E / Petrausch, U / Curioni-Fontecedro, A / Schmitt-Opitz, I / Peters, S. ·Department of Oncology, University Hospital, Zürich rolf.stahel@usz.ch. · Department of Thoracic Surgery, University Hospital, Zürich. · Department of Oncology, University Hospital, Zürich. · Department of Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. ·Ann Oncol · Pubmed #25722383.

ABSTRACT: Malignant mesothelioma is an incurable disease associated with asbestos exposure arising in the pleural cavity and less frequently in the peritoneal cavity. Platinum-based combination chemotherapy with pemetrexed is the established standard of care. Multimodality approaches including surgery and radiotherapy are being investigated. Increasing knowledge about the molecular characteristics of mesothelioma had led to the identification of novel potential targets for systemic therapy. Current evidence suggests pathways activated in response to merlin deficiency, including Pi3K/mTOR and the focal adhesion kinase, as well as immunotherapeutic approaches to be most promising. This review elaborates on the rationale behind targeted approaches that have been and are undergoing exploration in mesothelioma and summarizes available clinical results and ongoing efforts to improve the systemic therapy of mesothelioma.

7 Review Multimodality strategies in malignant pleural mesothelioma. 2009

Weder, Walter / Opitz, Isabelle / Stahel, Rolf. ·Division of Thoracic Surgery, University Hospital Zurich, Zürich, Switzerland. walter.weder@chi.usz.ch ·Semin Thorac Cardiovasc Surg · Pubmed #19822290.

ABSTRACT: Over the last decade, several improvements have been made in the diagnosis and treatment of malignant pleural mesothelioma, including better understanding of tumor biology, availability of more potent chemotherapeutic drugs, improved surgical management, and optimized multidisciplinary therapy. Radical tumor resection by means of extrapleural pneumonectomy (EPP) is now feasible with acceptable morbidity and mortality, even after neoadjuvant chemotherapy, if performed in specialized centers. To date, the best survival data have been reported after multimodality treatment strategies that include surgical resection. In this article, we discuss several strategies that involve EPP or pleurectomy/decortication in combination with various adjuvant and neoadjuvant therapies.

8 Review Improving the outcome in malignant pleural mesothelioma: nonaggressive or aggressive approach? 2009

Stahel, Rolf A / Weder, Walter. ·Clinic and Policlinic of Oncology and Thoracic Surgery, University Hospital, Zürich CH 8091, Switzerland. rolf.stahel@usz.ch ·Curr Opin Oncol · Pubmed #19532013.

ABSTRACT: PURPOSE OF REVIEW: The treatment of malignant pleural mesothelioma continues to be a clinical challenge. The question, however, is no longer whether to provide active treatment or not, but how aggressive the treatment should be in view of the limited life expectancy of patients with this disease. RECENT FINDINGS: With platin and pemetrexed-based combination chemotherapy having become the preferred systemic therapy, the major questions now evolve around the identification of a suitable second line therapy and the quest for innovative new approaches. Surgical interventions from pleurectomy and decortication to extrapleural pneumonectomy have increasingly come of use in specialized centres. With neoadjuvant chemotherapy and extrapleural pneumonectomy median survival times of almost 2 years have been reported. Studies on high-dose hemithoracic radiotherapy after extrapleural pneumonectomy suggested a beneficial effect on local recurrence. However, both extrapleural pneumonectomy and high-dose hemithoracic radiotherapy are associated with potential treatment-related mortality and morbidity and cannot yet be recommended outside specialized centres. SUMMARY: More than ever, the diagnosis and treatment of patients with malignant pleural mesothelioma mandate a multidisciplinary approach.

9 Review Malignant pleural mesothelioma: ESMO clinical recommendations for diagnosis, treatment and follow-up. 2009

Stahel, R A / Weder, W / Felip, E / Anonymous2980629. ·Clinic and Policlinic of Oncology, University Hospital of Zürich, Zürich, Switzerland. ·Ann Oncol · Pubmed #19454470.

ABSTRACT: -- No abstract --

10 Review Malignant pleural mesothelioma. 2009

Stahel, Rolf A / Felley-Bosco, Emanuela / Opitz, Isabelle / Weder, Walter. ·Laboratory of Molecular Oncology, Clinic and Policlinic of Oncology, University Hosptial, CH-8091 Zürich, Switzerland. rolf.stahel@usz.ch ·Future Oncol · Pubmed #19374545.

ABSTRACT: Malignant pleural mesothelioma continues to be a challenge. The diagnosis and treatment of patients with malignant pleural mesothelioma requires a multidisciplinary approach. The diagnosis is best made by thoracoscopic biopsy and the aid of immunohistochemistry. Molecular studies identified inactivation of the neurofibromatosis-2 gene and INK4alpha/ARF to be key events in tumorigenesis. Based on the results of a Phase III trial, the combination of cisplatin with pemetrexed has become the preferred choice for chemotherapy, although there is suggestive evidence for the activity of other platin combinations based on Phase II studies. The optimal second-line chemotherapy remains to be defined. Surgical interventions ranging from pleurectomy/decortication to extrapleural pneumonectomy are increasingly offered in specialized centers, and the results of multimodality approaches with neoadjuvant or adjuvant chemotherapy and extrapleural pneumonectomy are encouraging. Ongoing investigations are defining the role of postoperative radiotherapy and the clinical activity of tyrosine kinase inhibitors targeting VEGFR2, histone deacetylase inhibitors and proteosome inhibitors.

11 Clinical Trial Neoadjuvant chemotherapy and extrapleural pneumonectomy of malignant pleural mesothelioma with or without hemithoracic radiotherapy (SAKK 17/04): a randomised, international, multicentre phase 2 trial. 2015

Stahel, Rolf A / Riesterer, Oliver / Xyrafas, Alexandros / Opitz, Isabelle / Beyeler, Michael / Ochsenbein, Adrian / Früh, Martin / Cathomas, Richard / Nackaerts, Kristiaan / Peters, Solange / Mamot, Christoph / Zippelius, Alfred / Mordasini, Carlo / Caspar, Clemens B / Eckhardt, Katrin / Schmid, Ralph A / Aebersold, Daniel M / Gautschi, Oliver / Nagel, Wolfgang / Töpfer, Michael / Krayenbuehl, Jerome / Ribi, Karin / Ciernik, Ilja / Weder, Walter. ·Laboratory for Molecular Biology, University Hospital of Zurich, Zurich, Switzerland. Electronic address: rolf.stahel@usz.ch. · Radiation-Oncology, University Hospital of Zurich, Zurich, Switzerland. · Biostatistics, SAKK Coordination Centre, Bern, Switzerland. · Thoracic Surgery, University Hospital of Zurich, Zurich, Switzerland. · Clinical Project Management, SAKK Coordination Centre, Bern, Switzerland. · Medical Oncology, University Hospital of Bern-Inselspital, Bern, Switzerland. · Medical Oncology, Cantonal Hospital of St Gallen, St Gallen, Switzerland. · Medical Oncology, Cantonal Hospital of Graubunden, Chur, Switzerland. · Respiratory Diseases/Respiratory Oncology Unit, KU Leuven-University of Leuven, University Hospitals, Leuven, Belgium. · Medical Oncology, University Hospital of Vaud-CHUV, Lausanne, Switzerland. · Medical Oncology, Cantonal Hospital of Aarau, Aarau, Switzerland. · Medical Oncology, University Hospital of Basel, Basel, Switzerland. · Medical Oncology, Tiefenau Hospital, Bern, Switzerland. · Medical Oncology, Cantonal Hospital of Baden, Baden, Switzerland. · Division of General Thoracic Surgery, University Hospital of Bern-Inselspital, Bern, Switzerland. · Radiation-Oncology, University Hospital of Bern-Inselspital, Bern, Switzerland. · Thoracic Surgery, Cantonal Hospital of St Gallen, St Gallen, Switzerland. · Radiation-Oncology, Cantonal Hospital of St Gallen, St Gallen, Switzerland. · Quality of Life Office, International Breast Cancer Study Group-IBCSG, Bern, Switzerland. · Radio-Oncology, Klinikum Dessau, Dessau-Rosslau, Germany. ·Lancet Oncol · Pubmed #26538423.

ABSTRACT: BACKGROUND: Postoperative hemithoracic radiotherapy has been used to treat malignant pleural mesothelioma, but it has not been assessed in a randomised trial. We assessed high-dose hemithoracic radiotherapy after neoadjuvant chemotherapy and extrapleural pneumonectomy in patients with malignant pleural mesothelioma. METHODS: We did this phase 2 trial in two parts at 14 hospitals in Switzerland, Belgium, and Germany. We enrolled patients with pathologically confirmed malignant pleural mesothelioma; resectable TNM stages T1-3 N0-2, M0; WHO performance status 0-1; age 18-70 years. In part 1, patients were given three cycles of neoadjuvant chemotherapy (cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 given every 3 weeks) and extrapleural pneumonectomy; the primary endpoint was complete macroscopic resection (R0-1). In part 2, participants with complete macroscopic resection were randomly assigned (1:1) to receive high-dose radiotherapy or not. The target volume for radiotherapy encompassed the entire hemithorax, the thoracotomy channel, and mediastinal nodal stations if affected by the disease or violated surgically. A boost was given to areas at high risk for locoregional relapse. The allocation was stratified by centre, histology (sarcomatoid vs epithelioid or mixed), mediastinal lymph node involvement (N0-1 vs N2), and T stage (T1-2 vs T3). The primary endpoint of part 1 was the proportion of patients achieving complete macroscopic resection (R0 and R1). The primary endpoint in part 2 was locoregional relapse-free survival, analysed by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00334594. FINDINGS: We enrolled patients between Dec 7, 2005, and Oct 17, 2012. Overall, we analysed 151 patients receiving neoadjuvant chemotherapy, of whom 113 (75%) had extrapleural pneumonectomy. Median follow-up was 54·2 months (IQR 32-66). 52 (34%) of 151 patients achieved an objective response. The most common grade 3 or 4 toxic effects were neutropenia (21 [14%] of 151 patients), anaemia (11 [7%]), and nausea or vomiting (eight [5%]). 113 patients had extrapleural pneumonectomy, with complete macroscopic resection achieved in 96 (64%) of 151 patients. We enrolled 54 patients in part 2; 27 in each group. The main reasons for exclusion were patient refusal (n=20) and ineligibility (n=10). 25 of 27 patients completed radiotherapy. Median total radiotherapy dose was 55·9 Gy (IQR 46·8-56·0). Median locoregional relapse-free survival from surgery, was 7·6 months (95% CI 4·5-10·7) in the no radiotherapy group and 9·4 months (6·5-11·9) in the radiotherapy group. The most common grade 3 or higher toxic effects related to radiotherapy were nausea or vomiting (three [11%] of 27 patients), oesophagitis (two [7%]), and pneumonitis (two [7%]). One patient died of pneumonitis. We recorded no toxic effects data for the control group. INTERPRETATION: Our findings do not support the routine use of hemithoracic radiotherapy for malignant pleural mesothelioma after neoadjuvant chemotherapy and extrapleural pneumonectomy. FUNDING: Swiss Group for Clinical Cancer Research, Swiss State Secretariat for Education, Research and Innovation, Eli Lilly.

12 Clinical Trial Re-directed T cells for the treatment of fibroblast activation protein (FAP)-positive malignant pleural mesothelioma (FAPME-1). 2012

Petrausch, Ulf / Schuberth, Petra C / Hagedorn, Christian / Soltermann, Alex / Tomaszek, Sandra / Stahel, Rolf / Weder, Walter / Renner, Christoph. ·Department of Immunology, University Hospital Zurich, Rämistr, 100, 8091, Zürich, Switzerland. ulf.petrausch@usz.ch ·BMC Cancer · Pubmed #23259649.

ABSTRACT: BACKGROUND: Asbestos is the main cause of MPM in industrialized countries. Even since asbestos is banned in most developed countries, the peak wave of MPM incidence is anticipated for the next years due to the long latency of asbestos induced MPM. MPM patients not eligible for surgical procedures like decortication or pleuro-pneumectomie have a median survival of 12 months with palliative chemotherapy. Therefore, new therapeutic approaches are of crucial need in this clinical situation. METHODS/DESIGN: This is a phase I trial for patients with malignant pleural mesothelioma with pleural effusion testing the safety of a fixed single dose of 1x106 adoptively transferred FAP-specific re-directed T cells given directly in the pleural effusion. Lymphocytes will be taken 21 days before transfer from peripheral blood. CD8 positive T cells will be isolated and re-programmed by retroviral transfer of a chimeric antigen receptor recognizing FAP which serves as target structure in MPM. At day 0 of the protocol, re-directed T cells will be injected in the pleural effusion and patients will be monitored for 48h under intermediate care conditions. AE, SAE, SADR and SUSAR will be monitored for 35 days and evaluated by an independent safety board to define any dose limiting toxicity (DLT). No further patient can be treated before the previous patient passed day 14 after T cell transfer. The protocol will be judged as save when no DLT occurred in the first 3 patients, or 1 DLT in 6 patients. Secondary objectives are feasibility and immune monitoring. DISCUSSION: Adoptive T cell transfer is a new and rapidly expanding branch of immunotherapies focusing on cancer treatment. Recently, objective responses could be observed in patients with chronic lymphatic leukemia treated with adoptively transferred CD19-specific re-directed T cells. The choice of the target antigen determines the possible on-target off-tissue toxicity of such approaches. There are reports of severe toxicity in patients who received T cells intravenously due to unexpected expression of the target antigen (on-target) in other tissues than the tumor (off-tissue). To minimize the risk of on-target off-tissue toxicity and to maximize the on-target anti-tumor effect we propose a clinical protocol with loco-regional administration of re-directed T cells. FAP-specific T cells will be directly injected in the pleural effusion of patients with MPM. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01722149).

13 Clinical Trial Malignant peritoneal mesothelioma-Results from the International Expanded Access Program using pemetrexed alone or in combination with a platinum agent. 2009

Carteni, G / Manegold, C / Garcia, G Martin / Siena, S / Zielinski, C C / Amadori, D / Liu, Y / Blatter, J / Visseren-Grul, C / Stahel, R. ·Cardarelli Hospital, Medical Oncology, Via Cardarelli 9, 80100 Naples, Italy. giacomo.carteni@ospedalecardarelli.it ·Lung Cancer · Pubmed #19042053.

ABSTRACT: AIM: Peritoneal mesothelioma (PM) has rarely been studied. The Expanded Access Program (EAP) provided access to 109 patients with PM. METHODS: This was a nonrandomized, open-label study conducted in chemo-naïve or previously treated patients with PM not amenable to curative surgery. Patients received pemetrexed (PEM) 500 mg/m2 alone or with cisplatin (CIS) 75 mg/m2 or carboplatin (CARBO) AUC 5 every 21 days, supplemented with standard vitamin B(12), folate, and dexamethasone. RESULTS: Response rates (95% CI) for PEM, PEM/CIS, and PEM/CARBO were 12.5% (3.5, 29.0), 20.0% (7.7, 38.6), and 24.1% (10.3, 43.5), respectively. Median survival for PEM was 10.3 months. One-year survival rates for PEM/CIS and PEM were 57.4% (95% CI: 10.3, 100) and 41.5% (95% CI: 4.6, 78.4), respectively, and were not available for PEM/CARBO. Anemia was the most common serious adverse event (6.4%). Neutropenia (34.6%) was the most frequent CTC grade 3 or 4 toxicity reported. CONCLUDING STATEMENT: PEM with or without a platinum agent was both active and well tolerated in patients with peritoneal mesothelioma.

14 Clinical Trial Pemetrexed plus cisplatin or pemetrexed plus carboplatin for chemonaïve patients with malignant pleural mesothelioma: results of the International Expanded Access Program. 2008

Santoro, Armando / O'Brien, Mary E / Stahel, Rolf A / Nackaerts, Kristiaan / Baas, Paul / Karthaus, Meinolf / Eberhardt, Wilfried / Paz-Ares, Luis / Sundstrom, Stein / Liu, Yushan / Ripoche, Veronique / Blatter, Johannes / Visseren-Grul, Carla M / Manegold, Christian. ·Istituto Clinico Humanitas, Rozzano, Italy. armando.santoro@humanitas.it ·J Thorac Oncol · Pubmed #18594322.

ABSTRACT: INTRODUCTION: Previously published results from a randomized phase III study of pemetrexed plus cisplatin in patients with malignant pleural mesothelioma (MPM) demonstrated a significant survival benefit and higher response rate compared with cisplatin. Although pemetrexed was under review by regulatory agencies, an International Expanded Access Program (EAP) provided more than 3000 mesothelioma patients with access to single-agent pemetrexed or pemetrexed in combination with cisplatin or carboplatin in 13 countries. This manuscript reports the safety and efficacy data from the nonrandomized open-label study in chemonaïve patients receiving pemetrexed plus platinum under the EAP. METHODS: Patients with histologically confirmed MPM, not amenable to curative surgery, received pemetrexed 500 mg/m in combination with either cisplatin 75 mg/m or carboplatin AUC 5, once every 21 days with standard premedication. Efficacy data were recorded at the end of study participation. RESULTS: A total of 1704 chemonaïve patients received pemetrexed plus cisplatin (n = 843) or pemetrexed plus carboplatin (n = 861) and were evaluated for safety. The efficacy evaluable population consisted of 745 patients in the pemetrexed plus cisplatin group and 752 patients in the pemetrexed plus carboplatin group for whom physician-reported tumor response was available. The pemetrexed plus cisplatin group demonstrated a response rate of 26.3% compared with 21.7% for the pemetrexed plus carboplatin group, with similar 1-year survival rates (63.1% versus 64.0%) and median time to progressive disease (7 months versus 6.9 months). The most common grade 3/4 hematologic toxicity was neutropenia in 23.9% of the pemetrexed plus cisplatin group and 36.1% of the pemetrexed plus carboplatin group. CONCLUSION: This large EAP confirmed the activity of pemetrexed plus cisplatin and pemetrexed plus carboplatin in chemonaïve patients with MPM, demonstrating clinically similar time to progressive disease and 1-year survival rates.

15 Clinical Trial Individual versus standard quality of life assessment in a phase II clinical trial in mesothelioma patients: feasibility and responsiveness to clinical changes. 2008

Ribi, Karin / Bernhard, Jürg / Schuller, Jan C / Weder, Walter / Bodis, Stephan / Jörger, Markus / Betticher, Daniel / Schmid, Ralph A / Stupp, Roger / Ris, Hans-Beat / Stahel, Rolf A / Anonymous5150597. ·Swiss Group for Clinical Cancer Research SAKK Coordinating Center, Bern, Switzerland. karin.ribi@sakk.ch ·Lung Cancer · Pubmed #18433927.

ABSTRACT: BACKGROUND: In patients with malignant pleural mesothelioma undergoing a multimodality therapy, treatment toxicity may outweigh the benefit of progression-free survival. The subjective experience across different treatment phases is an important clinical outcome. This study compares a standard with an individual quality of life (QoL) measure used in a multi-center phase II trial. PATIENTS AND METHODS: Sixty-one patients with stage I-III technically operable pleural mesothelioma were treated with preoperative chemotherapy, followed by pleuropneumonectomy and subsequent radiotherapy. QoL was assessed at baseline, at day 1 of cycle 3, and 1, 3 and 6 months post-surgery by using the Rotterdam Symptom Checklist (RSCL) and the Schedule for the Evaluation of Quality of Life-Direct Weighting (SEIQoL-DW), a measure that is based on five individually nominated and weighted QoL-domains. RESULTS: Completion rates were 98% (RSCL) and 92% (SEIQoL) at baseline and 98%/89% at cycle 3, respectively. Of the operated patients (N=45) RSCL and SEIQoL were available from 86%/72%, 93%/74%, and 94%/76% at months 1, 3, and 6 post-surgery. Average assessment time for the SEIQoL was 24min compared to 8min needed for the RSCL. Median changes from baseline indicate that both RSCL QoL overall score and SEIQoL index remained stable during chemotherapy with a clinically significant deterioration (change>or=8 points) 1 month after surgery (median change of -66 and -14 for RSCL and SEIQoL, respectively). RSCL QoL overall scores improved thereafter, but remained beneath baseline level until 6 months after surgery. SEIQoL scores improved to baseline-level at month 3 after surgery, but worsened again at month 6. RSCL QoL overall score and SEIQoL index were moderately correlated at baseline (r=.30; pThe SEIQoL assessment seems to be feasible within a phase II clinical trial, but may require more effort from staff. More distinctive QoL changes in accordance with clinical changes were measured with the RSCL. Our findings suggest that the two measures are not interchangeable: the RSCL is to favor when mainly information related to the course of disease- and treatment is of interest.

16 Article Propensity matched comparison of extrapleural pneumonectomy and pleurectomy/decortication for mesothelioma patients. 2017

Kostron, Arthur / Friess, Martina / Inci, Ilhan / Hillinger, Sven / Schneiter, Didier / Gelpke, Hans / Stahel, Rolf / Seifert, Burkhardt / Weder, Walter / Opitz, Isabelle. ·Division of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland. · Department of Oncology, University Hospital Zurich, Zurich, Switzerland. · Institute of Epidemiology, Biostatistics and Prevention, University of Zurich, Zurich, Switzerland. ·Interact Cardiovasc Thorac Surg · Pubmed #28453802.

ABSTRACT: OBJECTIVES: The objective of this retrospective study was to assess perioperative outcomes, overall survival and freedom from recurrence after induction chemotherapy followed by extrapleural pneumonectomy (EPP) or pleurectomy/decortication (P/D) in patients with mesothelioma in a propensity score matched analysis. METHODS: Between September 1999 and August 2015, 167 patients received multimodality treatment (platinum-based chemotherapy followed by EPP [ n =  141] or P/D [ n =  26]). We performed 2:1 propensity score matching for gender, laterality, epithelioid histological subtype and International Mesothelioma Interest Group (iMig) stage (52 EPP and 26 P/D). RESULTS: Postoperative major morbidity (48% vs 58%, P =  0.5) was similar in both groups; however, the complication profile and severity were different and favoured P/D; the 90-day mortality (8% vs 0%, P =  0.3) rate was lower in P/D although not statistically significant. Prolonged air leak (≥10 days) occurred in 15 patients (58%) undergoing P/D. The intensive care unit stay was significantly longer after EPP ( P =  0.001). Freedom from recurrence was similar for both groups (EPP: median 15 months, 95% confidence interval [CI]: 10-21; P/D: 13 months, 95% CI: 11-17) ( P =  0.2). Overall survival was significantly longer for patients undergoing P/D (median 32 months, 95% CI: 29-35) compared to EPP (23 months, 95% CI: 21-25) ( P =  0.031), but in the P/D group many cases were censored (73%) and the follow-up time was relatively short. CONCLUSIONS: P/D and EPP seem to have similar rates of major morbidity, although the profile of complications is different and more severe after EPP. Freedom from recurrence is comparable in both groups whereas improved overall survival needs to be confirmed in a large patient group with longer follow-up.

17 Article A Novel BRCA1-Associated Protein-1 Isoform Affects Response of Mesothelioma Cells to Drugs Impairing BRCA1-Mediated DNA Repair. 2017

Parrotta, Rossella / Okonska, Agata / Ronner, Manuel / Weder, Walter / Stahel, Rolf / Penengo, Lorenza / Felley-Bosco, Emanuela. ·Laboratory of Molecular Oncology, Division of Thoracic Surgery, University Hospital Zürich, Zürich, Switzerland. · Division of Thoracic Surgery, University Hospital Zürich, Zürich, Switzerland. · Cancer Center Zürich, University Hospital Zürich, Zürich, Switzerland. · Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland. · Laboratory of Molecular Oncology, Division of Thoracic Surgery, University Hospital Zürich, Zürich, Switzerland. Electronic address: emanuela.felley-bosco@usz.ch. ·J Thorac Oncol · Pubmed #28389374.

ABSTRACT: INTRODUCTION: BRCA1 associated protein1 (BAP1) is a tumor suppressor involved in multiple cellular processes such as transcriptional regulation, chromatin modification by deubiquitinating histone 2A, and DNA repair. BAP1 mutations are frequent in malignant pleural mesothelioma (MPM). Our aim was to functionally characterize a newly identified isoform of BAP1 and investigate the effects of its expression on drug sensitivity in MPM. METHODS: Expression of BAP1 isoforms was detected by quantitative polymerase chain reaction in MPM and normal mesothelium cell lines and tumor and nontumor samples. Histone H2A ubiquitination levels were analyzed by Western blot after acidic extraction of core histones. Subcellular localization of BAP1 isoforms was examined by immunofluorescence. MPM cell survival in response to poly(adenosine diphosphate-ribose) polymerase (PARP) and dual phosphoinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) inhibitors was analyzed by in vitro assays. RESULTS: We have identified a novel alternative splice isoform of BAP1 (BAP1Δ) that misses part of the catalytic domain. Cells transfected with BAP1Δ showed reduced deubiquitinating activity compared with full-length BAP1. The expression of BAP1Δ transcript is more abundant in nontumor than in tumor samples. MPM cell lines expressing more than 20% of BAP1Δ are more sensitive to olaparib (a PARP1 inhibitor) cytotoxicity, and this sensitivity is enhanced when olaparib treatment is combined with GDC0980 (a dual PI3K-mTOR inhibitor), which induces downregulation of BRCA1. CONCLUSIONS: These observations suggest that BAP1Δ does regulate DNA damage response and influences drug sensitivity. It might therefore be relevant to investigate whether patients with high expression of BAP1Δ may be responsive to PARP/PI3K-mTOR inhibitors.

18 Article Low Merlin expression and high Survivin labeling index are indicators for poor prognosis in patients with malignant pleural mesothelioma. 2016

Meerang, Mayura / Bérard, Karima / Friess, Martina / Bitanihirwe, Byron K Y / Soltermann, Alex / Vrugt, Bart / Felley-Bosco, Emanuela / Bueno, Raphael / Richards, William G / Seifert, Burkhardt / Stahel, Rolf / Weder, Walter / Opitz, Isabelle. ·Division of Thoracic Surgery, University Hospital Zürich, Zürich 8091, Switzerland. · Institute of Surgical Pathology, University Hospital Zürich, Zürich 8091, Switzerland. · Laboratory of Molecular Oncology, University Hospital Zürich, Zürich 8091, Switzerland. · Thoracic Surgery, Harvard Medical School, Brigham and Women's Hospital, Boston, MA 02115, USA. · Department of Biostatistics, Epidemiology, Biostatistics, and Prevention Institute (EBPI), University of Zürich, Zürich 8001, Switzerland. · Division of Thoracic Surgery, University Hospital Zürich, Zürich 8091, Switzerland. Electronic address: isabelle.schmitt-opitz@usz.ch. ·Mol Oncol · Pubmed #27378628.

ABSTRACT: INTRODUCTION: Alterations of the tumor suppressor Neurofibromatosis type II (NF2) have been reported in about 40% of Malignant pleural mesothelioma (MPM) patients. NF2 (Merlin) deficiency leads to alterations of the Hippo pathway; resulting in activation of the oncogenic Yes Associated Protein-1 (YAP1). Our aim was to investigate the association between these alterations and clinical outcomes. MATERIAL AND METHODS: Tissue microarrays composed of MPM tumors derived from 2 independent MPM cohorts were employed for this study. Immunohistochemical expression of Merlin, YAP1 and its target genes, Survivin and connective tissue growth factor (CTGF) were assessed in nuclear and cytoplasmic fractions. Cohort 1 was comprised of 145 patients intended to be treated with chemotherapy (CTX) followed by extrapleural pneumonectomy (EPP), thus both pre- and post-CTX tissues were available. Cohort 2 was comprised of 59 patients treated with EPP followed by intraoperative hyperthermic cisplatin and/or adjuvant CTX and/or radiotherapy. Marker expression was quantified by means of labeling index (%) for nuclear Survivin and by H-score for the other markers. The dichotomized marker expression was tested for the association with overall survival (OS) and freedom from recurrence (FFR). RESULTS: Kaplan-Meier survival curves revealed a significant association between low cytoplasmic Merlin expression in pre-induction CTX tissues of cohort 1 with shorter FFR (p = 0.02) and OS (p = 0.03). The same tendency was observed in the chemotherapy naïve tissues obtained during EPP of cohort 2. Low nuclear Merlin expression in post-CTX tissues (available from cohort 1 only) was associated with shorter FFR (p = 0.04) and OS (p = 0.05). High nuclear Survivin labeling indices in both pre- and post-CTX tissues of cohort 1 was associated with shorter FFR (p = 0.02). In cohort 2, this was associated with both FFR and OS (p = 0.046 and p = 0.002, respectively). In multivariate analysis, low expression of cytoplasmic Merlin remained an independent prognosticator for shorter FFR of cohort 1 [hazard ratio (HR) = 0.5, 95% confidence interval (CI) = 0.3-0.9, p = 0.001] and OS [HR = 0.5, 95% CI = 0.3-1, p = 0.04]. High Survivin labeling index was an independent prognostic factor for shorter FFR in patients from cohort 1 [HR = 3.4, 95% CI = 1.7-6.8, p = 0.006] and shorter OS in patients from cohort 2 [HR = 2.35, 95% CI = 1.27-4.33, p = 0.006]. CONCLUSIONS: Our findings uncover the significance of Merlin protein expression and Survivin labeling index as prognosticators for poor clinical outcome in two independent MPM cohorts. If confirmed, these markers may be used to identify subgroups of patients benefitting from additional treatment.

19 Article Diagnostic accuracy of sequential co-registered PET+MR in comparison to PET/CT in local thoracic staging of malignant pleural mesothelioma. 2016

Martini, Katharina / Meier, Andreas / Opitz, Isabelle / Weder, Walter / Veit-Haibach, Patrick / Stahel, Rolf A / Frauenfelder, Thomas. ·Institute of Diagnostic and Interventional Radiology, University Hospital Zurich, University of Zurich, Switzerland. Electronic address: Katharina.Martini@usz.ch. · Institute of Diagnostic and Interventional Radiology, University Hospital Zurich, University of Zurich, Switzerland. Electronic address: Andreas.Meier@usz.ch. · Division of Thoracic Surgery, University Hospital Zurich,University of Zurich, Switzerland. Electronic address: Isabelle.Schmitt-Opitz@usz.ch. · Division of Thoracic Surgery, University Hospital Zurich,University of Zurich, Switzerland. Electronic address: Walter.Weder@usz.ch. · Institute of Diagnostic and Interventional Radiology, University Hospital Zurich, University of Zurich, Switzerland; Clinic of Nuclear Medicine, University Hospital Zurich,University of Zurich, Switzerland. Electronic address: Patrick.Veit-Haibach@usz.ch. · Department of Oncology, University Hospital Zurich,University of Zurich, Switzerland. Electronic address: Rolf.Stahel@usz.ch. · Institute of Diagnostic and Interventional Radiology, University Hospital Zurich, University of Zurich, Switzerland. Electronic address: Thomas.Frauenfelder@usz.ch. ·Lung Cancer · Pubmed #26973205.

ABSTRACT: PURPOSE: To investigate the diagnostic accuracy of sequential co-registered PET+MR (PET+MR) for local staging of malignant pleural mesothelioma (MPM) compared to PET/CT. MATERIAL AND METHODS: In a prospective clinical trial 34 consecutive patients (median age 66 years; range 40-79 years; 1 female, 33 male) with known MPM, who underwent PET/CT and PET+MR exams for either staging or re-staging/follow-up were evaluated. Imaging was conducted using a tri-modality PET/CT-MR set-up (Discovery PET/CT 690, 3T Discovery MR 750w, both GE Healthcare, Waukesha, WI, USA). In 26 cases histopathology served as standard of reference. Two independent readers evaluated images for T and N stage, confidence level (sure to unsure; 1-3) and subjective overall image quality (very good to non-diagnostic; 1-4). Inter-observer agreement of T and N stages (Cohen's kappa) and interclass correlation coefficient (ICC) between PET/CT vs. PET+MR was calculated. RESULTS: Inter observer agreement for evaluation of T and N Stage in PET/CT images was excellent (k=0.844 and k=0.824, respectively), whereas PET+MR imaging showed substantial agreement in T and N stage (k=0.729 and k=0.691, respectively). The ICC of PET/CT vs. PET+MR for evaluation of both, T and N Stage, was excellent (ICC=0.951 and ICC=0.93, respectively). Diagnostic confidence was scored significantly higher in PET+MR compared to PET/CT (mean score=1.66 and 1.93, respectively; p=0.004). Image quality was diagnostic for all image series. Comparing pT and pN stage vs cT and cN stage (n=26 cases), both imaging modalities showed excellent agreement for T stage (ICCPET+MR=0.888 vs. ICCPET/CT=0.853, respectively) and substantial to moderate agreement for N stage (ICCPET+MR=0.683 vs. ICC=0.595PET/CT, respectively). CONCLUSION: Our findings suggest that diagnostic accuracy of PET+MR is comparable to PET/CT for local staging of MPM, whereas radiologists felt significantly more confident staging PET+MR compared to PET/CT images (p=0003), using dedicated sequences.

20 Article Identification of cis- and trans-acting elements regulating calretinin expression in mesothelioma cells. 2016

Kresoja-Rakic, Jelena / Kapaklikaya, Esra / Ziltener, Gabriela / Dalcher, Damian / Santoro, Raffaella / Christensen, Brock C / Johnson, Kevin C / Schwaller, Beat / Weder, Walter / Stahel, Rolf A / Felley-Bosco, Emanuela. ·Laboratory of Molecular Oncology, Clinic of Oncology, University Hospital Zürich, Zürich, Switzerland. · Institute of Veterinary Biochemistry and Molecular Biology, University of Zürich, Zürich, Switzerland. · Departments of Epidemiology, Pharmacology and Toxicology and Community and Family Medicine, Geisel School of Medicine at Dartmouth, Hanover, NH, USA. · Anatomy, Department of Medicine, University of Fribourg, Fribourg, Switzerland. · Division of Thoracic Surgery, University Hospital Zürich, Zürich, Switzerland. ·Oncotarget · Pubmed #26848772.

ABSTRACT: Calretinin (CALB2) is a diagnostic marker for epithelioid mesothelioma. It is also a prognostic marker since patients with tumors expressing high calretinin levels have better overall survival. Silencing of calretinin decreases viability of epithelioid mesothelioma cells. Our aim was to elucidate mechanisms regulating calretinin expression in mesothelioma. Analysis of calretinin transcript and protein suggested a control at the mRNA level. Treatment with 5-aza-2'-deoxycytidine and analysis of TCGA data indicated that promoter methylation is not likely to be involved. Therefore, we investigated CALB2 promoter by analyzing ~1kb of genomic sequence surrounding the transcription start site (TSS) + 1 using promoter reporter assay. Deletion analysis of CALB2 proximal promoter showed that sequence spanning the -161/+80bp region sustained transcriptional activity. Site-directed analysis identified important cis-regulatory elements within this -161/+80bp CALB2 promoter. EMSA and ChIP assays confirmed binding of NRF-1 and E2F2 to the CALB2 promoter and siRNA knockdown of NRF-1 led to decreased expression of calretinin. Cell synchronization experiment showed that calretinin expression was cell cycle regulated with a peak of expression at G1/S phase. This study provides the first insight in the regulation of CALB2 expression in mesothelioma cells.

21 Article Antagonizing the Hedgehog Pathway with Vismodegib Impairs Malignant Pleural Mesothelioma Growth In Vivo by Affecting Stroma. 2016

Meerang, Mayura / Bérard, Karima / Felley-Bosco, Emanuela / Lauk, Olivia / Vrugt, Bart / Boss, Andreas / Kenkel, David / Broggini-Tenzer, Angela / Stahel, Rolf A / Arni, Stephan / Weder, Walter / Opitz, Isabelle. ·Division of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland. · Laboratory of Molecular Oncology, University Hospital Zurich, Zurich, Switzerland. · Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland. · Institute of Diagnostic and Interventional Radiology, University Hospital Zurich, Zurich, Switzerland. · Laboratory for Molecular Radiobiology, Radiation Oncology, University Hospital Zurich, Zurich, Switzerland. · Clinic for Oncology, University Hospital Zurich, Zurich, Switzerland. · Division of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland. isabelle.schmitt-opitz@usz.ch. ·Mol Cancer Ther · Pubmed #26839306.

ABSTRACT: An autocrine-driven upregulation of the Hedgehog (Hh) signaling pathway has been described in malignant pleural mesothelioma (MPM), in which the ligand, desert Hh (DHH), was produced from tumor cells. However, our investigation revealed that the Hh pathway is activated in both tumor and stroma of MPM tumor specimens and an orthotopic immunocompetent rat MPM model. This was demonstrated by positive immunohistochemical staining of Glioma-associated oncogene 1 (GLI1) and Patched1 (PTCH1) in both tumor and stromal fractions. DHH was predominantly expressed in the tumor fractions. To further investigate the role of the Hh pathway in MPM stroma, we antagonized Hh signaling in the rat model of MPM using a Hh antagonist, vismodegib, (100 mg/kg orally). Daily treatment with vismodegib efficiently downregulated Hh target genes Gli1, Hedgehog Interacting Protein (Hhip), and Ptch1, and caused a significant reduction of tumor volume and tumor growth delay. Immunohistochemical analyses revealed that vismodegib treatment primarily downregulated GLI1 and HHIP in the stromal compartment along with a reduced expression of previously described fibroblast Hh-responsive genes such as Fibronectin (Fn1) and Vegfa Primary cells isolated from the rat model cultured in 3% O2 continued to express Dhh but did not respond to vismodegib in vitro However, culture supernatant from these cells stimulated Gli1, Ptch1, and Fn1 expression in mouse embryonic fibroblasts, which was suppressed by vismodegib. Our study provides new evidence regarding the role of Hh signaling in MPM stroma in the maintenance of tumor growth, emphasizing Hh signaling as a treatment target for MPM. Mol Cancer Ther; 15(5); 1095-105. ©2016 AACR.

22 Article Relapse pattern and second-line treatment following multimodality treatment for malignant pleural mesothelioma. 2016

Kostron, Arthur / Friess, Martina / Crameri, Ornella / Inci, Ilhan / Schneiter, Didier / Hillinger, Sven / Stahel, Rolf / Weder, Walter / Opitz, Isabelle. ·Division of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland. · Department of Oncology, University Hospital Zurich, Zurich, Switzerland. · Division of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland isabelle.schmitt-opitz@usz.ch. ·Eur J Cardiothorac Surg · Pubmed #26590183.

ABSTRACT: OBJECTIVES: To analyse the relapse pattern and influence of second-line treatment after recurrence of malignant pleural mesothelioma (MPM) in patients who had previously undergone multimodality treatment. METHODS: Between September 1999 and December 2013, 136 patients underwent macroscopic complete resection (MCR) by extrapleural pneumonectomy after induction chemotherapy for MPM. We analysed 106 patients who presented with recurrent disease until October 2014. Data were retrieved from our mesothelioma database, with additional information regarding precise localization gathered by reviewing the imaging and medical records. RESULTS: The overall recurrence rate was 78% (106/136 patients). The median freedom from recurrence was 9 months after surgery [95% confidence interval (95% CI) 7-10]. Local recurrence only was observed in 33 patients (31%), distant metastases only in 27 patients (26%) and simultaneous distant and local recurrence in 46 patients (43%). Local recurrence was observed significantly less frequently in patients having received adjuvant radiotherapy (19 vs 47%, P = 0.003), but there was no significant impact on overall survival (OS) [radiation: 22 months (95% CI 19-24); no-radiation: 23 months (95% CI 18-27), P = 0.6]. The median OS was 22 months (95% CI 21-24), median post-recurrence survival (PRS) was 7 months (95% CI 5-9) and patients with local recurrence only survived significantly longer (12 months, 95% CI 8-16) compared with patients with distant recurrence only (5 months, 95% CI 2-8) or distant plus local relapse (6 months, 95% CI 3-9; P = 0.04). A total of 78 patients received a second-line therapy after tumour recurrence: chemotherapy (n = 48), local radiotherapy (n = 9), surgery (n = 10) or a combination thereof (n = 11). Patients undergoing second-line treatment survived significantly longer compared with patients not receiving therapy (P < 0.0005). The median PRS after surgery was significantly longer than that of patients receiving chemo-, radio- or chemo-radiotherapy (P = 0.04). CONCLUSIONS: Local recurrence of MPM remains the most frequent type of relapse even after multimodality treatment including MCR. In the present cohort, active treatment seems beneficial to the patient since surgical excision of local tumour relapse has good long-term outcome in selected patients. Thus, second-line treatment may prolong PRS; however, these results need to be confirmed in a prospective manner.

23 Article Expression of the Stem Cell Factor Nestin in Malignant Pleural Mesothelioma Is Associated with Poor Prognosis. 2015

Thies, Svenja / Friess, Martina / Frischknecht, Lukas / Korol, Dimitri / Felley-Bosco, Emanuela / Stahel, Rolf / Vrugt, Bart / Weder, Walter / Opitz, Isabelle / Soltermann, Alex. ·Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland. · Division of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland. · Cancer Registry, University Hospital Zurich, Zurich, Switzerland. · Clinic of Oncology, University Hospital Zurich, Zurich, Switzerland. ·PLoS One · Pubmed #26421614.

ABSTRACT: BACKGROUND: The epithelioid and sarcomatoid histologic variants of malignant pleural mesothelioma (MPM) can be considered as E- and M-parts of the epithelial-mesenchymal transition (EMT) axis; the biphasic being an intermediate. EMT is associated with an increase of stem cell (SC) traits. We correlated the neural crest SC marker nestin and the EMT marker periostin with histology, type of neo-adjuvant chemotherapy (CT) and overall survival (OS) of MPM patients. PATIENTS AND METHODS: Tumor tissues of a historic cohort 1 (320 patients) and an intended induction chemotherapy followed by extrapleural pneumonectomy (EPP) cohort 2 (145 patients) were immunohistochemically H-scored (intensity of immunoreactivity multiplied by frequency of stained cells). Paired chemo-naïve biopsies and -treated surgical specimens were available for 105/145 patients. CT included platinum/gemcitabine (Pla/Gem) or platinum/pemetrexed (Pla/Pem). RESULTS: Expression of any cytosolic nestin progressively increased from epithelioid to biphasic to sarcomatoid MPM in cohort 1, whereas the diagnostic markers calretinin and podoplanin decreased. In cohort 2, Pla/Pem CT increased the expression level of nestin in comparison to Pla/Gem, whereas the opposite was found for periostin. In Pla/Pem treated patients, nestin was higher in biphasic MPM compared to epithelioid. In addition to non-epithelioid histology, any expression of nestin in chemo-naïve biopsies (median overall survival: 22 vs. 17 months) and chemo-treated surgical specimens (18 vs. 12 months) as well as high periostin in biopsies (23 vs. 15 months) were associated with poor prognosis. In the multivariate survival analysis, any nestin expression in chemo-naïve biopsies proved to be an independent prognosticator against histology. In both pre- and post-CT situations, the combination of nestin or periostin expression with non-epithelioid histology was particularly/ dismal (all p-values <0.05). CONCLUSIONS: The SC marker nestin and the EMT marker periostin allow for further prognostic stratification among histologic variants of MPM. Their expression level is influenced by neo-adjuvant chemotherapy.

24 Article Inhibition of autophagy sensitizes malignant pleural mesothelioma cells to dual PI3K/mTOR inhibitors. 2015

Echeverry, N / Ziltener, G / Barbone, D / Weder, W / Stahel, R A / Broaddus, V C / Felley-Bosco, E. ·Laboratory of Molecular Oncology, Clinic of Oncology, University Hospital of Zürich, Häldeliweg 4, Zürich 8044, Switzerland. · Department of Medicine, Division of Pulmonary, San Francisco General Hospital, University of California San Francisco, San Francisco, CA 94110, USA. · Division of Thoracic Surgery, University Hospital Zürich, Zürich, Switzerland. ·Cell Death Dis · Pubmed #25950487.

ABSTRACT: Malignant pleural mesothelioma (MPM) originates in most of the cases from chronic inflammation of the mesothelium due to exposure to asbestos fibers. Given the limited effect of chemotherapy, a big effort is being made to find new treatment options. The PI3K/mTOR pathway was reported to be upregulated in MPM. We tested the cell growth inhibition properties of two dual PI3K/mTOR inhibitors NVP-BEZ235 and GDC-0980 on 19 MPM cell lines. We could identify resistant and sensitive lines; however, there was no correlation to the downregulation of PI3K/mTOR activity markers. As a result of mTOR inhibition, both drugs efficiently induced long-term autophagy but not cell death. Autophagy blockade by chloroquine in combination with the dual PI3K/mTOR inhibitors significantly induced caspase-independent cell death involving RIP1 in the sensitive cell line SPC212. Cell death in the resistant cell line Mero-82 was less pronounced, and it was not induced via RIP1-dependent mechanism, suggesting the involvement of RIP1 downstream effectors. Cell death induction was confirmed in 3D systems. Based on these results, we identify autophagy as one of the main mechanisms of cell death resistance against dual PI3K/mTOR inhibitors in MPM. As PI3K/mTOR inhibitors are under investigation in clinical trials, these results may help interpreting their outcome and suggest ways for intervention.

25 Article Importance of excision repair cross-complementation group 1 and ribonucleotide reductase M1 as prognostic biomarkers in malignant pleural mesothelioma treated with platinum-based induction chemotherapy followed by surgery. 2015

Frischknecht, Lukas / Meerang, Mayura / Soltermann, Alex / Stahel, Rolf / Moch, Holger / Seifert, Burkhardt / Weder, Walter / Opitz, Isabelle. ·Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland. · Division of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland. · Laboratory of Molecular Oncology, University Hospital Zurich, Zurich, Switzerland. · Division of Biostatistics, ISPM, University Zurich, Zurich, Switzerland. · Division of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland. Electronic address: isabelle.schmitt-opitz@usz.ch. ·J Thorac Cardiovasc Surg · Pubmed #25840756.

ABSTRACT: OBJECTIVES: Survival and response to platinum-based induction chemotherapy are heterogeneous among patients with malignant pleural mesothelioma. The aim of the present study was to assess the prognostic role of DNA repair markers, such as excision repair cross-complementation group 1 and ribonucleotide reductase M1, in multimodally treated patients with malignant pleural mesothelioma. METHODS: Tumor tissue of a malignant pleural mesothelioma cohort (n = 107) treated with platinum/gemcitabine (n = 46) or platinum/pemetrexed (n = 61) induction chemotherapy followed by extrapleural pneumonectomy was assembled on a tissue microarray. Immunohistochemical expression of excision repair cross-complementation group 1 (nuclear) and ribonucleotide reductase M1 (nuclear and cytoplasmic) was assessed for its prognostic impact (association with overall survival or freedom from recurrence). RESULTS: Patients with high nuclear ribonucleotide reductase M1 expression before chemotherapy showed significantly longer freedom from recurrence (P = .03). When specifically analyzed in the subgroup of patients receiving platinum/gemcitabine followed by extrapleural pneumonectomy, high nuclear ribonucleotide reductase M1 was associated with prolonged freedom from recurrence (P = .03) and overall survival (P = .02). Low excision repair cross-complementation group 1 expression in prechemotherapy tumor tissues was associated with significantly longer freedom from recurrence (P = .04). Nuclear ribonucleotide reductase M1 and excision repair cross-complementation group 1 were independent prognosticators of freedom from recurrence in addition to pT stage in multivariate analysis. CONCLUSIONS: In the present study, nuclear ribonucleotide reductase M1 and excision repair cross-complementation group 1 expression were identified as independent prognosticators for freedom from recurrence of malignant pleural mesothelioma in patients undergoing induction chemotherapy followed by extrapleural pneumonectomy.

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