SummaryBackgroundThe effects of extra-pleural pneumonectomy (EPP) on survival and quality of life in patients with malignant pleural mesothelioma have, to our knowledge, not been assessed in a randomised trial. We aimed to assess the clinical outcomes of patients who were randomly assigned to EPP or no EPP in the context of trimodal therapy in the Mesothelioma and Radical Surgery (MARS) feasibility study.MethodsMARS was a multicentre randomised controlled trial in 12 UK hospitals. Patients aged 18 years or older who had pathologically confirmed mesothelioma and were deemed fit enough to undergo trimodal therapy were included. In a prerandomisation registration phase, all patients underwent induction platinum-based chemotherapy followed by clinical review. After further consent, patients were randomly assigned (1:1) to EPP followed by postoperative hemithorax irradiation or to no EPP. Randomisation was done centrally with computer-generated permuted blocks stratified by surgical centre. The main endpoints were feasibility of randomly assigning 50 patients in 1 year (results detailed in another report), proportion randomised who received treatment, proportion eligible (registered) who proceeded to randomisation, perioperative mortality, and quality of life. Patients and investigators were not masked to treatment allocation. This is the principal report of the MARS study; all patients have been recruited. Analyses were by intention to treat. This trial is registered, number ISRCTN95583524.FindingsBetween Oct 1, 2005, and Nov 3, 2008, 112 patients were registered and 50 were subsequently randomly assigned: 24 to EPP and 26 to no EPP. The main reasons for not proceeding to randomisation were disease progression (33 patients), inoperability (five patients), and patient choice (19 patients). EPP was completed satisfactorily in 16 of 24 patients assigned to EPP; in five patients EPP was not started and in three patients it was abandoned. Two patients in the EPP group died within 30 days and a further patient died without leaving hospital. One patient in the no EPP group died perioperatively after receiving EPP off trial in a non-MARS centre. The hazard ratio [HR] for overall survival between the EPP and no EPP groups was 1·90 (95% CI 0·92–3·93; exact p=0·082), and after adjustment for sex, histological subtype, stage, and age at randomisation the HR was 2·75 (1·21–6·26; p=0·016). Median survival was 14·4 months (5·3–18·7) for the EPP group and 19·5 months (13·4 to time not yet reached) for the no EPP group. Of the 49 randomly assigned patients who consented to quality of life assessment (EPP n=23; no EPP n=26), 12 patients in the EPP group and 19 in the no EPP group completed the quality of life questionnaires. Although median quality of life scores were lower in the EPP group than the no EPP group, no significant differences between groups were reported in the quality of life analyses. There were ten serious adverse events reported in the EPP group and two in the no EPP group.InterpretationIn view of the high morbidity ...

Masaoka stages III-IV, incomplete resection and non-thymoma histology showed a significant impact in increasing recurrence and in worsening survival. The administration of adjuvant therapy after complete resection is associated with improved survival.

Introduction: Molecular and immunologic breakthroughs are transforming the management of thoracic cancer, although advances have not been as marked for malignant pleural mesothelioma where pathologic diagnosis has been essentially limited to three histologic subtypes.Conclusions: These multidisciplinary recommendations for pathology classification and application will allow more informative pathologic reporting and potential risk stratification, to support clinical practice, research investigation and clinical trials.

To compare the outcomes of two different multimodality regimens involving neoadjuvant chemotherapy, extrapleural pneumonectomy (EPP) and adjuvant radiotherapy versus pleurectomy/decortication (P/D), hyperthermic pleural lavage with povidone-iodine, and adjuvant chemotherapy in patients with malignant pleural mesothelioma. Methods: Nonrandomized prospective study of patients treated by multimodality therapy and operated on between January 2004 and June 2011. Second-line treatments were administered when appropriate. Survival and prognostic factors were analyzed by the Kaplan Meier method, log rank test, and Cox regression analysis. Results: Twenty-five consecutive patients received neoadjuvant chemotherapy, 22 underwent EPP, and 17 received adjuvant radiotherapy. over the same period, 54 consecutive patients underwent P/D and hyperthermic pleural lavage and received prophylactic radiotherapy and adjuvant chemotherapy. The 30-day mortality rate was 4.5% in the EPP group and nil in the P/D group. Fifteen patients (68%) in the EPP group and 15 (27.7%) in the P/D group experienced complications. There were no differences between the EPP and P/D groups for age, sex, histology, pathologic stage, and nodal status. Trimodality therapy was completed by 68% of the patients in the EPP group and 100% in the P/D group. Survival was significantly better in the P/D group: median survival was 23 months versus 12.8 months, 2-year survival was 49% versus 18.2 %, and 5-year survival was 30.1% versus 9%, respectively (p = 0.004). At multivariate analysis, epithelioid histology, P/D, and completeness of resection were independent prognostic factors. Conclusions: In our experience, P/D, hyperthermic pleural lavage with povidone-iodine, and adjuvant chemotherapy were superior to neoadjuvant chemotherapy, EPP, and adjuvant radiotherapy.

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Cell death from spinal cord injury is mediated in part by apoptotic mechanisms involving downstream caspases (e.g., caspase-3). Upstream mechanisms may involve other caspases such as procaspase-8, a 55 kDa apical caspase, which we found constitutively expressed within spinal cord neurons along with Fas. As early as 1.5 hr after transient ischemia, activated caspase-8 (p18) and caspase-8 mRNA appeared within neurons in intermediate gray matter and in medial ventral horn. We also detected evidence for an increase in death receptor complex by co-immunoprecipitation using Fas and anti-procaspase-8 after ischemia. At early time points, Fas and p18 were co-expressed within individual neurons, as were activated caspase-8 and caspase-3. Moreover, we detected p18 in cells before procaspase-3 cleavage product (p20), suggesting sequential activation. The appearance of cytosolic cytochrome c and gelsolin cleavage after ischemia was consistent with mitochondrial release and caspase-3 activation, respectively. Numerous terminal deoxynucleotidyl transferase-mediated DNA nick end-labelingpositive neurons contained p18 or p20 (65 and 80%, respectively), thereby supporting the idea that cells undergoing cell death contain both processed caspases. Our data are consistent with the idea that transient spinal cord ischemia induces the formation of a death-inducing signaling complex, which may participate in caspase-8 activation and sequential caspase-3 cleavage. Death receptors as well as downstream caspases may be useful therapeutic targets for limiting the death of cells in spinal cord. Key words: caspase-8; caspase-3; spinal cord ischemia; Fas; DISC; cell deathSpinal cord injury after trauma or cerebral ischemia is a major cause of morbidity and mortality (Kouchoukos, 1991;Von Oppel et al., 1994;Cheshire et al., 1996). Many injured cells die by a necrotic mechanism characterized by disruption of nuclear and cell membranes and disintegration of cytoplasmic organelles (Garcia et al., 1995). Some cells die by a mechanism resembling apoptosis, as evidenced by caspase activation (Hara et al., 1997;Endres et al., 1998;Namura et al., 1998;Springer et al., 1999).Caspases are important mediators of ischemic cell death. Procaspase-8 [Fas-associated death domain protein (FADD)-like interleukin-1␤ converting enzyme or MORT1-associated CED-3 homolog] is a 55 kDa initiator caspase (Boldin et al., 1996;Fernandes-Alnemri et al., 1996;Muzio et al., 1996). Procaspase-8 can process itself after ligation of the Fas-tumor necrosis factor family of death receptors (Kischkel et al., 1995;Los et al., 1995;Medema et al., 1997). Fas, a 45 kDa membrane receptor, forms a death-inducing signaling complex (DISC) with an adaptor protein, FADD, and procaspase-8 (Nagata and Goldstein, 1995; Nagata, 1997). Active caspase-8 initiates downstream cleavage of caspase-3 by direct or mitochondrial-dependent mechanisms via BH3 interacting death domain agonist cleavage, leading to apoptosis (Kuwana et al., 1998;Stennicke et al., 1998). In addition, activated caspase-3 may...

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