The Journal of Thoracic and Cardiovascular Surgery

About the journal

Publisher: Mosby
Published: 1959 to the present, United States
Language: English
ISSN: 0022-5223 (print), 1097-685X (electronic)
Continues: Journal of Thoracic Surgery
Its record in the NLM Catalog

2020s

Soluble mesothelin-related peptide as a prognosticator in pleural mesothelioma patients receiving checkpoint immunotherapy. S. Mitra, H.J. Jang, A. Kuncheria, et al. 2025;169(4):1082-1095.e4. PubMed · Publisher · Free full text

Abstract

Background: Immune checkpoint therapy (ICT) has significantly impacted the treatment of malignant pleural mesothelioma (MPM). Despite some promising results from combination therapies, nearly half of MPM patients do not benefit, underscoring the urgent need for reliable predictive biomarkers. This study assesses the prognostic value of serum soluble mesothelin-related peptide (SMRP) and PD-L1 levels in MPM patients receiving ICT.

Methods: We conducted a retrospective analysis of 125 MPM patients treated with ICT by measuring pre-ICT serum levels of SMRP and PD-L1. We also examined the correlation of these serum levels with tumor mRNA expressions of mesothelin and PD-L1. Both univariable and multivariable Cox regression analyses were used to determine independent prognosticators for overall survival (OS). A prospective ICT clinical trial and our historical cohort were included for validation.

Results: Seventy-seven patients (62%) were treated with either anti-PD-(L)1 monotherapy, and the remaining 38% received combination ICT. Higher pre-ICT SMRP levels were observed in epithelioid MPM compared to nonepithelioid MPM. Serum PD-L1 levels did not differ significantly between the different histologic groups. Univariable analysis identified durable clinical benefit, development of immune-related adverse events, and SMRP levels as significantly associated with OS. Multivariable analysis confirmed SMRP as an independent prognostic factor, with lower levels (≤1.35 nmol/L) correlating with improved OS. The association of high SMRP with worse prognosis was validated in the prospective ICT clinical trial cohort and not in our historical cohort treated without ICT.

Conclusions: SMRP is a promising serum biomarker for predicting survival in MPM patients treated with ICT and warrants prospective investigation.

Copyright © 2024 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.
Single-institution experience of 500 pulmonary resections guided by intraoperative molecular imaging. G.T. Kennedy, F.S. Azari, A. Chang, et al. 2023;165(6):1928-1938.e1. PubMed · Publisher · Free full text

Abstract

Objective: Intraoperative molecular imaging (IMI) using tumor-targeted optical contrast agents can improve thoracic cancer resections. There are no large-scale studies to guide surgeons in patient selection or imaging agent choice. Here, we report our institutional experience with IMI for lung and pleural tumor resection in 500 patients over a decade.

Methods: Between December 2011 and November 2021, patients with lung or pleural nodules undergoing resection were preoperatively infused with 1 of 4 optical contrast tracers: EC17, TumorGlow, pafolacianine, or SGM-101. Then, during resection, IMI was used to identify pulmonary nodules, confirm margins, and identify synchronous lesions. We retrospectively reviewed patient demographic data, lesion diagnoses, and IMI tumor-to-background ratios (TBRs).

Results: Five hundred patients underwent resection of 677 lesions. We found that there were 4 types of clinical utility of IMI: detection of positive margins (n = 32, 6.4% of patients), identification of residual disease after resection (n = 37, 7.4%), detection of synchronous cancers not predicted on preoperative imaging (n = 26, 5.2%), and minimally invasive localization of nonpalpable lesions (n = 101 lesions, 14.9%). Pafolacianine was most effective for adenocarcinoma-spectrum malignancies (mean TBR, 2.84), and TumorGlow was most effective for metastatic disease and mesothelioma (TBR, 3.1). False-negative fluorescence was primarily seen in mucinous adenocarcinomas (mean TBR, 1.8), heavy smokers (>30 pack years; TBR, 1.9), and tumors greater than 2.0 cm from the pleural surface (TBR, 1.3).

Conclusions: IMI may be effective in improving resection of lung and pleural tumors. The choice of IMI tracer should vary by the surgical indication and the primary clinical challenge.

Copyright © 2023 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.
Commentary: A return trip to MARS: Less may be more when treating mesothelioma. C.M. Griffin, V.H. van Berkel. 2022;163(6):1948-1949. Editorial · Comment PubMed · Publisher
Commentary: Surgical standardization in mesothelioma trials. V.W. Rusch. 2022;163(6):1949-1950. Editorial · Comment PubMed · Publisher
Acute kidney injury after cytoreductive surgery and hyperthermic intraoperative cisplatin chemotherapy for malignant pleural mesothelioma. T. Hod, K.J. Freedberg, S.S. Motwani, et al. 2021;161(4):1510-1518. PubMed · Publisher

Abstract

Objectives: Cytoreductive surgery with hyperthermic intraoperative chemotherapy with cisplatin has been used successfully to treat malignant pleural mesothelioma, a highly aggressive malignancy that is rapidly fatal in most cases. We hypothesized that the combination of ischemic injury with nephrotoxic injury from cisplatin would result in high rates of acute kidney injury.

Methods: We conducted an observational study in 503 patients to study the risks and outcomes of acute kidney injury after surgical resection of malignant pleural mesothelioma. Eligible subjects underwent extrapleural pneumonectomy or pleurectomy/decortication with or without hyperthermic intraoperative chemotherapy. Acute kidney injury was defined as an increase in creatinine of 26.5 μmol/L or greater within 48 hours of surgery or a 50% or greater increase over 7 days.

Results: Acute kidney injury developed in 243 patients (48.3%). Severe acute kidney injury requiring renal replacement therapy developed in 16 patients (3.2%). Major significant predictors for acute kidney injury included male sex (odds ratio, 2.98; P < .001), intraoperative cisplatin administration (odds ratio, 3.12; P < .001), previous cisplatin exposure (odds ratio, 1.96; P = .02), hypertension (odds ratio, 1.57; P = .02), and longer surgical time (odds ratio, 1.15 per hour; P = .02). Compared with patients without acute kidney injury, those with severe acute kidney injury had longer length of stay (26 vs 13 days) and a 2.71-fold increased risk of death in multivariable-adjusted models.

Conclusions: Acute kidney injury is common after cytoreductive surgery with hyperthermic intraoperative chemotherapy with cisplatin and is associated with poor long-term outcomes. Strategies to prevent postoperative acute kidney injury are needed to improve multimodal treatment of malignant pleural mesothelioma.

Copyright © 2020 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.
Commentary: Acute kidney injury after intrapleural cisplatin: Minimizing collateral damage. M.I. Ebright. 2021;161(4):1522-1523. Editorial · Comment PubMed · Publisher
Commentary: Cisplatin-induced nephrotoxicity following cytoreductive surgery and heated intraoperative chemotherapy for malignant pleural mesothelioma. S.S. Groth, R.T. Ripley. 2021;161(4):1519-1520. Editorial · Comment PubMed · Publisher
Commentary: Winning the battle for local control without losing war for survival against malignant pleural mesothelioma. A. Bribriesco. 2021;161(4):1520-1522. Editorial · Comment PubMed · Publisher
Divided by an ocean of water but united in an ocean of uncertainty: A transatlantic review of mesothelioma surgery guidelines. D.A. Waller, I. Opitz, R. Bueno, et al. 2021;161(6):1922-1925. Editorial PubMed · Publisher
Commentary: A journey of a thousand miles begins with a single step. T.F. Chen-Yoshikawa. 2020;159(5):2092-2093. Editorial · Comment PubMed · Publisher
Commentary: Biphasic malignant mesothelioma-Survival of the fittest. L.M. Felmly, B.C. Gibney. 2020;159(4):1596-1597. Editorial · Comment PubMed · Publisher
Commentary: Filling up my truck from an oil tanker: Can big 'omic' data influence our clinical decisions?. R.T. Ripley. 2020;160(4):1086-1087. Editorial · Comment PubMed · Publisher
Commentary: Focused attention on proactive identification of deep venous thrombosis after pleurectomy/decortication for malignant pleural mesothelioma. S.S. Groth, R.T. Ripley, P.W. Carrott, et al. 2020;160(4):1075-1076. Editorial · Comment PubMed · Publisher
Commentary: Go small or go home. A.W. Kim, U. Ahmad. 2020;160(3):e173-e174. Editorial · Comment PubMed · Publisher
Commentary: Is thoracic cage volume a new parameter for clinical staging in mesothelioma?. M. de Perrot. 2020;159(6):2520-2521. Editorial · Comment PubMed · Publisher
Commentary: Know your enemy-Understanding futility in the battle against malignant pleural mesothelioma. A.E. Giles, B. Kidane. 2020;159(6):2523-2524. Editorial · Comment PubMed · Publisher
Commentary: Local chemotherapy with nanoparticles: A ray of light in the dark?. S. Nakamura, T.F. Chen-Yoshikawa. 2020;160(3):e169-e170. Editorial · Comment PubMed · Publisher
Commentary: Mesothelioma: The Guinness world record holder in thromboembolism. R.B. Cameron. 2020;160(4):1074-1075. Editorial · Comment PubMed · Publisher
Commentary: Not only SMART clinically, but translationally!. H.I. Pass. 2020;159(5):2094-2095. Editorial · Comment PubMed · Publisher
Commentary: One nano-step for murinekind, one giant leap for mesothelioma. J.S. Dutcher, J. D'Cunha. 2020;160(3):e170-e171. Editorial · Comment PubMed · Publisher
Commentary: Picking the winners-Leaning into selection bias. E. Wakeam, B. Kidane. 2020;159(4):1594-1595. Editorial · Comment PubMed · Publisher
Commentary: Surgeon versus mesothelioma in a thoracic cage match. C.D. Hoang. 2020;159(6):2522-2523. Editorial · Comment PubMed · Publisher
Commentary: Tasting individual ingredients of meso soup: Can 'omics bring out the flavor?. H.I. Pass. 2020;160(4):1084-1085. Editorial · Comment PubMed · Publisher
Commentary: To scan or not to scan: No longer the question for mesothelioma patients after pleurectomy. E.A. David, S.M. Atay. 2020;160(4):1076-1077. Editorial · Comment PubMed · Publisher
Mesothelioma in the age of "Omics": Before and after The Cancer Genome Atlas. D.T. Severson, A. De Rienzo, R. Bueno. 2020;160(4):1078-1083.e2. Editorial · Comment PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is a highly fatal cancer of the pleura that has been defeating standard and investigational therapies since its first description. The efficacies of chemotherapy, radiotherapy, and surgical therapy are limited, and we have been writing for decades that improved therapies are needed. MPM is born of inflammation, and approximately 80% of cases are associated with the smoldering tissue inflammatory responses against the carcinogenic fibers of asbestos. Emerging data on the use of programmed cell death protein 1 immune checkpoint inhibitors were initially exciting, but response is less than 20% and these agents are finding their place on the list of approaches with narrow efficacy. Molecular targeted therapies have revolutionized the treatment of other cancers, commonly result in striking antitumor responses, and directly embody precision medicine. For an example, we prescribe drugs for some lung adenocarcinomas that target the secondary mutations that develop as a resistance mechanism to their initial targeted therapy. The discovery of molecular therapeutics for any tumor begins with identification of a target through investigation of the genomic, epigenomic, and transcriptomic drivers of its carcinogenesis. Such an advance could revolutionize the treatment of mesothelioma. A comprehensive dissection of MPM’s molecular structure was recently published by 2 groups, the first from the Brigham and Women’s Hospital and then from The Cancer Genome Atlas. In the Invited Expert Opinion article that follows, a practical account of the molecular underpinnings of MPM is eloquently presented by the Brigham group and will inspire the discovery and translation of novel molecular targets by mesothelioma investigators and practitioners.
Paclitaxel-loaded expansile nanoparticles improve survival following cytoreductive surgery in pleural mesothelioma xenografts. N.Q. Chu, R. Liu, A. Colby, et al. 2020;160(3):e159-e168. PubMed · Publisher · Free full text

Abstract

Objective: Malignant pleural mesothelioma is a lethal malignancy with poor survival and high local recurrence rates despite multimodal therapy with cytoreduction and chemoradiation. We evaluated the antitumor efficacy of a paclitaxel-loaded pH-responsive expansile nanoparticle (PTX-eNP) in 2 clinically relevant murine xenograft models of malignant pleural mesothelioma.

Methods: Luciferase-transfected MSTO-211H human mesothelioma cells were injected into the thoracic cavity of immunodeficient Nu/J mice. Tumor burden was monitored by bioluminescent imaging. Animals were randomized into 2 models of disease treatment chemotherapy with PTX-eNPs alone delivered locally for early limited disease or cytoreductive surgery plus local PTX-eNP chemotherapy for advanced disease. Within each disease model, anti-tumor efficacy of PTX-eNP was compared against standard formulation paclitaxel and drug-empty nanoparticles. Influence on survival was calculated. Fluorescently labeled PTX-eNPs and immunohistochemistry evaluated in vivo drug localization to tumor.

Results: Intrathoracic injection of MSTO-211H resulted in large tumor deposits distributed within the pleural space of the murine thoracic cavity. Local multidose treatment with PTX-eNPs alone in limited stage disease more than doubled survival compared with drug-empty nanoparticles (P ≤ .0001) and standard formulation paclitaxel (P = .0004). In the model of advanced disease, local multidose treatment with PTX-eNPs following cytoreductive surgery also prolonged survival by 126% and 69.4% compared with drug-empty nanoparticles (P = .0018) and standard formulation paclitaxel (P = .03457), respectively. Immunohistology demonstrated PTX-eNP accumulation within tumor cells in vitro and in vivo.

Conclusions: Local delivery of paclitaxel via eNPs confers prolonged survival in a murine model of malignant pleural mesothelioma as single modality treatment for limited disease and in combination with cytoreductive surgery for advanced disease.

Copyright © 2020 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.
Preoperative prediction of unresectability in malignant pleural mesothelioma. B.M. Burt, H.S. Lee, A.C. Raghuram, et al. 2020;159(6):2512-2520.e1. PubMed · Publisher

Abstract

Objective: Diffuse chest wall invasion (DCWI) is a common finding in patients undergoing intended resection for malignant pleural mesothelioma. We sought to determine the incidence and preoperative predictors of this finding, and to test our anecdotal impression that contraction of the ipsilateral hemithorax is associated with DCWI.

Methods: This was a single-institution retrospective study of 170 patients undergoing intended macroscopic complete resection for malignant pleural mesothelioma from 2014-2018. A novel metric of thoracic cage volume was calculated by preoperative chest computed tomography. Univariable analyses were performed to determine associations of preoperative variables with DCWI.

Results: Macroscopic complete resection was achieved by pleurectomy/decortication in 104 patients (61%) and by extrapleural pneumonectomy in 39 patients (23%). Unresectable disease was discovered at thoracotomy in 27 (16%) of patients; 24 (14%) by DCWI and 3 (2%) by intrathoracic organ invasion. In univariable analysis, decreased ipsilateral thoracic cage volume demonstrated the strongest association with unresectability by DCWI (P = .009) with >5% decrease in thoracic cage volume representing the optimal cutoff (P = .014; area under the curve, 0.67). Other preoperative variables associated with DCWI included preoperative chest pain requiring opioids (P = .028), prior pleurodesis (P = .036), decreased forced vital capacity (P = .023), decreased ipsilateral lung perfusion by ventilation/perfusion lung scan (P = .007), and magnetic resonance imaging findings of chest wall invasion (P = .035).

Conclusions: Preoperative identification of DCWI will avoid unnecessary thoracotomy and accelerate initiation of nonsurgical therapy in malignant pleural mesothelioma. Our data suggest that contraction of thoracic cage volume has merit in predicting malignant pleural mesothelioma unresectability and should be validated in prospective studies.

Copyright © 2019 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.
Prognostic influence of tumor microenvironment after hypofractionated radiation and surgery for mesothelioma. M. de Perrot, L. Wu, M. Cabanero, et al. 2020;159(5):2082-2091.e1. PubMed · Publisher

Abstract

Objective: Cytotoxic CD8+ tumor infiltrating lymphocytes (TILs) can contribute to the benefit of hypofractionated radiation, but programmed cell death pathways (programmed cell death 1 and programmed cell death ligand 1 [PD-1/PD-L1]) may provide a mechanism of tumor immune escape. We therefore reviewed the influence of PD-1/PD-L1 and CD8+ TILs on survival after accelerated hypofractionated hemithoracic radiation followed by extrapleural pneumonectomy for malignant pleural mesothelioma (MPM).

Methods: Sixty-nine consecutive patients undergoing the protocol of Surgery for Mesothelioma after Radiation Therapy (SMART) between November 2008 and February 2016 were analyzed for the presence of PD-L1 on tumor cells, PD-1 on inflammatory cells, and CD8+ TILs. Comparison was made with a cohort of patients undergoing extrapleural pneumonectomy after induction chemotherapy (n = 14) and no induction (n = 2) between March 2005 and October 2008. PD-L1 expression on tumor cells ≥1% was considered positive. CD8+ TILs and PD-1 expression were scored as a percentage of positive cells.

Results: PD-L1 was negative in 75% of MPM after completion of SMART. CD8+ TILs ranged between 0.24% and 8.47% (median 2%). CD8+ TILs ≥2% was associated with significantly better survival in epithelioid MPM (median survival 3.7 years vs 2.3 years in CD8+ TILs <2%; P = .02). PD-L1 positivity was associated with worse survival in biphasic MPM (median survival, 0.4 years vs 1.5 years in biphasic PD-L1 negative tumors; P = .07) after SMART. Multivariate analysis demonstrated that epithelioid MPM, nodal disease, and CD8+ TILs were independent predictors of survival after SMART.

Conclusions: The influence of tumor microenvironment on survival differs between epithelioid and nonepithelioid MPM. CD8+ TILs is an independent factor associated with better survival in epithelioid MPM treated with SMART.

Copyright © 2019 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.
Routine surveillance for diagnosis of venous thromboembolism after pleurectomy for malignant pleural mesothelioma. L.E. De León, C.E. Bravo-Iñiguez, S. Fox, et al. 2020;160(4):1064-1073. PubMed · Publisher · Free full text

Abstract

Objective: The purpose of this study was to determine the incidence of venous thromboembolism and utility of a routine surveillance program in patients undergoing surgery for mesothelioma.

Methods: Patients undergoing pleurectomy from May 2016 to August 2018 were included. A standardized surveillance program to look for venous thromboembolism in this group included noninvasive studies every 7 days postoperatively or earlier if symptomatic. All patients received external pneumatic compression sleeves in addition to prophylactic heparin. If deep vein thrombosis or pulmonary embolus was discovered, heparin drip was initiated until conversion to therapeutic anticoagulation.

Results: A total of 100 patients underwent pleurectomy for mesothelioma. Seven patients were found to have preoperative deep vein thrombosis, and as such only 93 patients were included for analysis. The median age of patients at surgery was 71 years (30-85 years). During the study, 30 patients (32%) developed evidence of thrombosis; 20 patients (22%) developed only deep vein thrombosis without embolism, 3 patients (3%) developed only pulmonary embolism, and 7 patients (7%) developed both deep vein thrombosis and pulmonary embolus. Of the 27 patients who developed deep vein thrombosis, 9 (33%) were asymptomatic at the time of diagnosis, and none of these developed a pulmonary embolus or other bleeding complications. There were 2 (2%) events of major postoperative bleeding related to therapeutic anticoagulation.

Conclusions: The incidence of venous thromboembolism is high (32%) among patients undergoing surveillance after pleurectomy for mesothelioma. Up to 33% of patients with deep vein thrombosis are asymptomatic at the time of diagnosis, and the incidence of complications related to anticoagulation is low. Routine surveillance may be useful to diagnose and treat deep vein thrombosis before it progresses to symptomatic or fatal pulmonary embolus.

Copyright © 2020 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.
Survival results in biphasic malignant pleural mesothelioma patients: A multicentric analysis. F. Lococo, F. Torricelli, L. Lang-Lazdunski, et al. 2020;159(4):1584-1593.e2. PubMed · Publisher

Abstract

Objective: The best strategy of care for biphasic malignant pleural mesothelioma (Biph-MPM) is controversial. In this study, a large dataset of Biph-MPM cases was reviewed to identify prognostic factors and to evaluate the role of a multimodal approach, including cancer-directed surgery.

Methods: A total of 213 patients with Biph-MPM treated at 4 tertiary centers who experienced MPM from January 2009 to December 2016 were selected, and clinical, pathologic, and surgical information was retrieved. A Cox regression model was used to identify predictors of survival, and the Kaplan-Meier method was used to summarize overall survival.

Results: The mean age and the male/female ratio were 68.4 ± 9.5 years and 5:1, respectively. Tumors were assigned to stages I (127, 59.6%), II (3, 1.4%), III (76, 35.4%), and IV (7, 3.3%) according to the Eighth Tumor, Node, Metastasis (TNM) edition. A multimodal treatment including pleurectomy/decortication was performed in 58 patients (27.2%), chemotherapy alone in 99 patients (46.5%), and best supportive care in 56 (26.3%). The median overall survival was 11 months. A univariate analysis revealed that survival was significantly associated with the percentage forced expiratory volume in 1 second (P < .0001), performance status (P = .0002), multimodal treatment including surgery (P < .0001), and TNM stage (P = .011). A multivariable analysis confirmed performance status, percentage forced expiratory volume in 1 second, TNM, and a multimodal approach as independent variables affecting long-term survival.

Conclusions: Despite the overall poor prognosis of biphasic histology, a multimodal approach, including cancer-directed surgery, is associated with improved long-term results in very selected patients with Biph-MPM.

Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.

2010s

A thinner peel to peel: Pleural thickness is prognostic in mesothelioma. S.S. Groth, R.T. Ripley, B.M. Burt. 2019;157(1):414-415. Editorial · Comment PubMed · Publisher
Commentary: Adjuvant intensity-modulated radiation therapy for malignant pleural mesothelioma: Suspension of intention. S.S. Groth, B.M. Burt, R.T. Ripley. 2019;158(3):932-933. Editorial · Comment PubMed · Publisher
Commentary: Return to intended radiation therapy-Criteria for resection?. J. Dux, R. Grosser, P.S. Adusumilli. 2019;158(3):930-931. Editorial · Comment PubMed · Publisher · Free full text
To slay a dragon: Timing of chemotherapy in resectable pleural mesothelioma. B.M. Burt, R.T. Ripley, S.S. Groth. 2019;157(2):767-768. Editorial · Comment PubMed · Publisher
Treatment of malignant pleural mesothelioma with chemotherapy preceding versus after surgical resection. V. Verma, C.A. Ahern, C.G. Berlind, et al. 2019;157(2):758-766.e1. PubMed · Publisher

Abstract

Objectives: There are 2 main treatment paradigms recognized by the National Comprehensive Cancer Network for resectable malignant pleural mesothelioma (MPM): induction chemotherapy followed by resection (IC/R), and up-front resection with postoperative chemotherapy (R/PC). These paradigms are being compared in an accruing randomized phase II trial. In the absence of such completed trials, in this study we evaluated overall survival (OS) and postoperative outcomes of IC/R and R/PC.

Methods: The National Cancer Database was queried for newly diagnosed epithelioid/biphasic MPM. Metastatic, node-positive, and/or cT4 disease was excluded, along with nondefinitive surgery and lack of chemotherapy. Multivariable logistic regression ascertained factors independently associated with induction chemotherapy delivery. Kaplan-Meier analysis was used to evaluate OS between cohorts; multivariable Cox proportional hazards modeling was used to assess factors associated with OS. Survival was also evaluated between propensity-matched populations. Last, postoperative outcomes were assessed between groups.

Results: Overall, 361 patients (182 IC/R, 179 R/PC) were analyzed. Temporal trends revealed that IC/R is decreasing over time. Survival of the IC/R cohort was similar to that of R/PC patients (20.9 vs 21.7 months; P = .500); this persisted after propensity matching (20.8 vs 22.0 months; P = .270). However, patients who underwent IC/R experienced longer postoperative hospitalization (median 7 days vs 6 days; P = .001) and higher 30-day mortality (3.3% vs 0%; P = .020).

Conclusions: To our knowledge, this is the only comparative investigation of the 2 major management paradigms of operable MPM. IC/R regimens are decreasing over time in the United States. Although associated with survival similar to R/PC, IC/R might be associated with worse postoperative outcomes. Careful induction chemotherapy patient selection is thus highly recommended.

Copyright © 2018 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.
Diaphragm and lung-preserving surgery with hyperthermic chemotherapy for malignant pleural mesothelioma: A 10-year experience. M.C. Ambrogi, P. Bertoglio, V. Aprile, et al. 2018;155(4):1857-1866.e2. Comment PubMed · Publisher

Abstract

Background: The best surgical treatment for malignant pleural mesothelioma is still under a debate, but recent evidence points toward a less-invasive approach to reduce morbidity and mortality. We reported our 10-year experience of a limited surgical approach associated with hyperthermic intrathoracic chemotherapy (HITHOC).

Material And Methods: Between 2005 and 2014, patients with epithelioid or biphasic malignant pleural mesothelioma were treated with lung-diaphragm-pericardium-sparing pleurectomy associated with double-drug HITHOC; at least 3 cycles of adjuvant chemotherapy were then administered. The primary outcome examined was the feasibility of the procedure, whereas secondary outcomes were overall survival and disease-free interval.

Results: Among 49 patients, 41 were male. Median age was 68 years (35-76 years). Histology was epithelioid in 43 cases. Pathologic stage I, II, III, and IV occurred in 12, 14, 20, and 3 cases, respectively. No intraoperative complications or postoperative mortality occurred, whereas morbidity rate was 46.9%. Median hospital stay was 8 days (5-45 days). Actuarial median overall survival was 22 months and a 1-, 2-, and 5-year survival accounted for 79.6%, 45.7%, and 9.9%, respectively. Disease-free survival after surgery was 62%, 37.5%, and 18.5% at 1, 2, and 5 years, respectively. Risk factors analysis for overall survival confirmed a significant role for early stages, epithelioid histology, and fibrinogen serum levels.

Conclusions: Cytoreductive surgery associated with HITHOC and adjuvant chemotherapy appears feasible and safe, with no mortality and low morbidity. Preserving lung and diaphragmatic function might warrant an acceptable long-term outcome.

Copyright © 2017 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.
Discussion. 2018;155(6):2732-2733. Comment PubMed · Publisher
Mesothelioma: Live to fight another day. A.S. Wolf, R.M. Flores. 2018;155(4):1855-1856. Editorial PubMed · Publisher

Summary

In this editorial commentary, two thoracic surgeons from the Icahn School of Medicine at Mount Sinai, New York, discussed a retrospective single-center 10-year study by Ambrogi and colleagues. That study reported pleurectomy/decortication (P/D) followed by heated intraoperative chemotherapy (HIOC) for malignant pleural mesothelioma (MPM), leaving the pericardium and diaphragm intact. The commentators listed as strengths the inclusion of a full cohort, comprehensive data, long-term follow-up (median more than 5 years), low mortality and morbidity, and adjuvant therapy for all patients. They identified as weaknesses the small study size, multivariable models that suggested overfitting, and an unusual HIOC protocol. That protocol used a lower cisplatin dose (80 mg/m2) and epirubicin, which had not been investigated in prospective trials of HIOC in MPM. The authors noted growing consensus that lung-preserving surgery is paramount in MPM. Older studies favoring extrapleural pneumonectomy (EPP) had excluded perioperative deaths or evaluated only patients with favorable features. More recent studies showed similar overall survival but lower operative, short-term and one-year mortality with P/D. The authors suggested that less extensive surgery may allow quicker recovery and better tolerance of adjuvant therapy and later treatment. It may also prevent contamination of unaffected cavities: only 2% of Ambrogi's patients recurred in the abdomen, compared with 39% of 169 patients after EPP in another series. They concluded that the study was too small for definitive conclusions but supported the message that in MPM surgery, less is more.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.
Surgery for mesothelioma: Less is more, more or less. S. Milman, T. Ng. 2018;155(4):1867-1868. Editorial · Comment PubMed · Publisher
Therapeutic R2 resection for pleural mesothelioma. D. Nguyen, D.J. Sugarbaker, B.M. Burt. 2018;155(6):2734-2735. Editorial · Comment PubMed · Publisher
Accelerated hemithoracic radiation followed by extrapleural pneumonectomy for malignant pleural mesothelioma. M. de Perrot, R. Feld, N.B. Leighl, et al. 2016;151(2):468-73. PubMed · Publisher

Abstract

Objective: To evaluate a new protocol of accelerated hemithoracic intensity-modulated radiation therapy (IMRT) followed by extrapleural pneumonectomy (EPP) for patients with resectable malignant pleural mesothelioma (MPM).

Methods: A total of 25 Gy of radiation was delivered in 5 daily fractions over 1 week to the entire ipsilateral hemithorax with concomitant boost of 5 Gy to volumes at high risk based on computed tomography and positron emission tomography scan findings. EPP was performed at 6 ± 2 days after the end of radiation therapy. Adjuvant chemotherapy was offered to patients with ypN2 disease.

Results: A total of 62 patients were included between November 2008 and October 2014. One patient died in the hospital 2 months after EPP, for an operative mortality of 1.6%, and 2 died after discharged from the hospital for an overall treatment-related mortality (grade 5 toxicity) of 4.8%. Twenty-four patients (39%) developed grade 3 to 5 (grade 3+) complications. On final pathology, 94% of the patients were stage III or IV, and 52% had ypN2 disease. The median survival for all patients as an intention-to-treat analysis was 36 months. The median overall survival and disease-free survival was 51 and 47 months, respectively, in epithelial subtypes, compared with 10 and 8 months in biphasic subtypes (P = .001). Ipsilateral chest recurrence occurred in 8 patients.

Conclusions: Accelerated hemithoracic IMRT followed by EPP has become our preferred approach for resectable MPM. The results have been encouraging in patients with epithelial subtype.

Copyright © 2016 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.
Adoption of pleurectomy and decortication for malignant mesothelioma leads to similar survival as extrapleural pneumonectomy. H.F. Batirel, M. Metintas, H.B. Caglar, et al. 2016;151(2):478-84. PubMed · Publisher

Abstract

Objective: We changed our surgical approach to malignant pleural mesothelioma (MPM) in August 2011 and adopted pleurectomy and decortication (PD) instead of extrapleural pneumonectomy (EPP). In this study, we analyzed our perioperative and survival results during the 2 periods.

Methods: All patients who underwent surgical intervention for MPM during 2003-2014 were included. Data were retrospectively analyzed from a prospective database. Before August 2011, patients underwent evaluation for EPP and adjuvant chemoradiation (group 1). After August 2011, patients were evaluated for PD and adjuvant chemotherapy and/or radiation (group 2). Demographic characteristics, surgical technique, histology, side, completeness of resection, and types of treatments were recorded. Statistics was performed using Student t test, χ(2) tests, uni- and multivariate regression, and Kaplan-Meier survival analysis.

Results: The same surgical team operated on 130 patients. Median age was 55.7 years (range, 26-80 years) and 76 were men. EPP and extended PD was performed in 72 patients. Ninety-day mortality was 10%. Median survival was 17.8 months with a 5-year survival rate of 14%. Uni- and multivariate analyses showed that epithelioid histology, stage N0, and trimodality treatment were associated with better survival (P = .039, P = .012, and P < .001, respectively). Demographic variables and overall survival (15.6 vs 19.6 months, respectively) were similar between the groups, whereas nonepithelioid histology, use of preoperative chemotherapy, and incomplete resections were more frequent in group 2 (P < .001, P < .001, and P = .006, respectively). Follow-up was shorter in group 2 (22.5 ± 20.6 vs 16.4 ± 10.9 months; P < .001).

Conclusions: Adoption of PD as the main surgical approach is not associated with survival disadvantage in the surgical treatment of MPM.

Copyright © 2016 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.
Discussion. D. Rice, D. Sugarbaker, R. Flores, et al. 2016;151(2):473-5. Comment PubMed · Publisher
Pleurectomy decortication for mesothelioma: The procedure of choice when possible. R.M. Flores. 2016;151(2):310-2. Editorial PubMed · Publisher

Summary

In this editorial, a thoracic surgeon at the Icahn School of Medicine at Mount Sinai, New York, addressed which operation offers more benefit to patients with mesothelioma: extrapleural pneumonectomy (EPP) or pleurectomy decortication (PD). He set aside the question of surgery versus medical therapy. The author described how his view had changed since his training in the mid 1990s, when he favoured EPP. He argued that neither operation achieves a true R0 resection. He also argued that the data supporting EPP came mainly from biased retrospective studies of highly selected patients, and that survival in these studies tended to worsen as more patients were added. He judged the MARS trial (24 patients in the EPP arm and 26 in the nonsurgical arm, with 18% operative mortality) too underpowered to show that EPP harms patients. In his view, it showed only that such a randomized trial is not feasible. He proposed a 5-year survival of 15% in patients without surgical resection as the minimum standard for comparing treatments. He cited a study of 663 patients (385 EPP, 278 PD) in which EPP was associated with worse survival (hazard ratio 1.4) after controlling for histologic type, stage, multimodality treatment and sex. He concluded that PD preserves more lung, has lower morbidity and mortality, and gives similar or better survival. He was not ready to abandon EPP completely.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.
SMART or simply bold?. V.W. Rusch, A. Rimner, P.S. Adusumilli. 2016;151(2):476-7. Editorial · Comment PubMed · Publisher

Summary

This editorial commentary discussed a study by de Perrot and colleagues at the University of Toronto, published in the same issue, which reported expanded phase II experience with the Surgery for Mesothelioma After Radiation Therapy (SMART) regimen for malignant pleural mesothelioma (MPM). In that regimen, intensity-modulated radiation therapy with a high dose per fraction was given before extrapleural pneumonectomy (EPP). This shortened radiation from about 6 weeks to 5 days. The commentators noted that all 62 patients completed the planned treatment. Operative mortality was 1.6%, overall treatment-related mortality was 4.8%, there were no bronchial stump leaks, and only 4 resections were incomplete (R2). Median overall survival was 36 months on an intention-to-treat basis and 51 months for patients with epithelioid histologic type. The authors described several challenges: careful patient selection, the difficulty of predicting resectability with current staging, the need for EPP shortly after radiation to avoid life-threatening radiation pneumonitis, and the need for high-volume expert centers. They suggested that EPP may still have a role in selected patients with epithelioid tumors and no nodal metastases. They also raised the possibility that preoperative radiation affects immune response and thereby survival. They concluded that the results should be corroborated at a few other expert centers. In their view, studies of radiation and immune response would likely be more productive than a randomized trial of uncertain feasibility.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.
The mesothelioma surgery shift. R.M. Flores. 2016;151(2):485-6. Editorial · Comment PubMed · Publisher

Summary

In this editorial commentary, the author discussed the shift in surgery for malignant pleural mesothelioma from extrapleural pneumonectomy (EPP) to pleurectomy and decortication (PD), responding to a study by Batirel and colleagues in the same issue. He noted that a large multicenter comparison had not shown great survival differences between the two procedures, and that the MARS group had begun a trial comparing PD with nonsurgical treatment. He questioned whether macroscopic complete resection (MCR), which he described as essentially an R1 resection, should be the sole primary goal of surgery. He observed that MCR was championed mainly on the basis of a highly selected study of patients with epithelioid disease who underwent EPP, with a median survival of 18 months. He highlighted two findings from the Batirel study. R1 (MCR) resection fell from 65% to 41% with the shift to PD, and 87% of EPP patients versus 59% of PD patients had epithelioid histology. Yet no survival difference favoring EPP was observed. He suggested that the adverse effects of pneumonectomy may offset the benefits of cytoreduction. These include higher operative and longer-term mortality and quicker death after recurrence. He proposed a risk-benefit equation and concluded that current data favor PD, that a randomized trial was not necessary to answer the question, and that surgeons should remove as much tumor as possible without sacrificing the lung.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.
What is the best approach for surgery of malignant pleural mesothelioma? It is to put our efforts into obtaining trustworthy evidence for practice. T. Treasure. 2016;151(2):307-9. Editorial PubMed · Publisher

Abstract

It is accepted that however radical and expertly done, surgery cannot eradicate mesothelioma and therefore cannot realistically be expected to cure the disease other than in a vanishingly few atypical cases. This is implicit in the adoption of ‘‘macroscopic complete resection’’ as the surgical objective. Because of the nature of the disease and the multiplicity of treatment protocols, defining the direction and magnitude of a survival difference cannot be determined from personal experience, follow-up studies or other methods lacking rigorous control data. Several randomized trials including surgery have been and are being carried out, so ‘‘can’t be done’’ is not a defensible position. Independently run multicenter trials are needed.

PubMed has no abstract for this study. This is the authors' abstract, copied from the article.
Closing the stable door before the horse leaves. V. Acton. 2015;149(5):1467. Letter · Comment PubMed · Publisher
Discussion. 2015;149(6):1546-7. Comment PubMed · Publisher
Fibrinogen concentrate as first-line therapy in children undergoing cardiac surgery: Promising perspectives. D. Faraoni. 2015;149(5):1466-7. Letter · Comment PubMed · Publisher
Fifteen years in the evaluation of extrapleural pneumonectomy: Lessons to be learned. T. Treasure, F. Macbeth. 2015;149(5):1382-3. Editorial · Comment PubMed · Publisher

Summary

This editorial commentary, written in response to a related article in the same issue, reviewed 15 years of evaluating extrapleural pneumonectomy (EPP) for mesothelioma. The related study reported patterns of recurrence among 169 (38%) of 447 patients recorded as having had EPP in the Brigham and Women's Hospital (BWH) International Mesothelioma Program registry from 2001 to 2010. The remaining 62%, treated first with chemotherapy, were excluded. Median survival was 15 months for the EPP-first patients. The authors recalled a 1999 BWH report of 19 months median survival after trimodal therapy with EPP. They distinguished efficacy from effectiveness. They noted that EPP combined with intensity-modulated radiotherapy was associated with 10 months median survival, and EPP with heated intra-operative chemotherapy with 13 months. They argued that the appropriate comparator was not patients fit only for supportive care, who had 7 months median survival. They also argued that patient selection and immortal time bias confound such analyses. In the randomized MARS trial, patients assessed as suitable for EPP but assigned not to have it had a median survival of 19.5 months. The authors noted that the BWH study did not report quality of life. They cited evidence that EPP has a high complication rate and, in nonrandomized comparisons, gave poorer quality of life and shorter survival than lung-sparing surgery. They concluded that more multicenter randomized trials and independent analysis of all data were needed.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.
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. L. Frischknecht, M. Meerang, A. Soltermann, et al. 2015;149(6):1539-46.e1. PubMed · Publisher

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.

Copyright © 2015 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.
Into another dimension: Assessing novel therapeutics in a more lifelike microenvironment. M.B. Antonoff. 2015;149(5):1426-7. Editorial · Comment PubMed · Publisher
Paclitaxel-loaded expansile nanoparticles enhance chemotherapeutic drug delivery in mesothelioma 3-dimensional multicellular spheroids. H. Lei, S.C. Hofferberth, R. Liu, et al. 2015;149(5):1417-24; discussion 1424-25.e1. PubMed · Publisher

Abstract

Objectives: Intraperitoneal administration of paclitaxel-loaded expansile nanoparticles (Pax-eNPs) significantly improves survival in an in vivo model of malignant mesothelioma compared with conventional drug delivery with the clinically utilized Cremophor EL/ethanol (C/E) excipient. However, in vitro monolayer cell culture experiments do not replicate this superior efficacy, suggesting Pax-eNPs utilize a unique mechanism of drug delivery. Using a mesothelioma spheroid model, we characterized the mechanisms of enhanced tumor cytotoxicity leveraged by Pax-eNPs.

Methods: Human malignant mesothelioma (MSTO-211H) spheroids were co-incubated for 24 hours with Oregon Green-conjugated paclitaxel dissolved in C/E or loaded into eNPs. Oregon Green-paclitaxel uptake was measured as Oregon Green intensity via confocal microscopy and kinetics of tumor cytotoxicity were assessed via propidium iodide staining. Pharmacologic endocytotic inhibitors were used to elucidate mechanisms of eNP uptake into spheroids.

Results: Increased drug penetration and a 38-fold higher intraspheroidal drug concentration were observed 24 hours after MSTO-211H spheroids were treated with Oregon Green-conjugated paclitaxel loaded into eNPs compared with Oregon Green-conjugated paclitaxel dissolved in C/E (P < .01). Macropinocytosis was the dominant endocytotic pathway of eNP uptake. Spheroids were more susceptible to paclitaxel when delivered via eNP, exhibiting more than twice the propidium iodine intensity compared with an equivalent paclitaxel-C/E dose.

Conclusions: Compared with monolayer cell culture, the in vitro 3-D tumor spheroid model better reflects the superior in vivo efficacy of Pax-eNPs. Persistent tumor penetration and prolonged intratumoral release are unique mechanisms of Pax-eNP cytotoxicity. 3-D spheroid models are valuable tools for investigating cytotoxic mechanisms and nanoparticle-tumor interactions, particularly given the costs and limitations of in vivo animal studies.

Copyright © 2015 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.
Pleurectomy/decortication, hyperthermic pleural lavage with povidone-iodine, prophylactic radiotherapy, and systemic chemotherapy in patients with malignant pleural mesothelioma: a 10-year experience. L. Lang-Lazdunski, A. Bille, S. Papa, et al. 2015;149(2):558-65; discussion 565-6. PubMed · Publisher

Abstract

Objectives: We evaluated the long-term results of pleurectomy/decortication (P/D), hyperthermic pleural lavage with povidone-iodine, prophylactic chest wall radiotherapy (21 Gy), and systemic chemotherapy in patients with malignant pleural mesothelioma.

Methods: A cohort of patients having surgery between January 2004 and December 2013 were retrospectively studied. All patients received prophylactic radiotherapy postoperatively and all were supposed to receive systemic chemotherapy, either preoperatively or as adjuvant therapy. Patients were reviewed at 30 days, then followed up 6-monthly. (18)F-FDG-PET-CT was used routinely to diagnose disease recurrence. Second-line therapies were administered when appropriate. Survival and prognostic factors were analyzed by the Kaplan-Meier method, log-rank test, and Cox regression analysis.

Results: One hundred two patients had P/D followed by prophylactic radiotherapy and were referred for adjuvant chemotherapy. Median age at operation was 64 years. Eighty-one patients (79.4%) were male; 57 patients (55.9%) had complete macroscopic resection. Thirty-day mortality was nil and 30 patients (29.4%) experienced postoperative complications. Seventy-three patients had epithelioid mesothelioma (71.5%). Sixty-eight patients (66.6%) had N0 disease. Ninety-six patients (94.1%) received the planned 4 to 6 chemotherapy cycles. At last follow-up, 49 patients were alive. Univariate analysis showed no significant difference when sex, age >70 years, nodal status, or prior chemotherapy were considered. The overall median survival was 32 months and 5-year survival rate was 23.1%. Median survival and 5-year survival rates were 35.0 months and 30.7% for epithelioid mesothelioma and 15 months and 7% for nonepithelioid mesothelioma, respectively (P = .0001). Median survival was 45.0 months for R0-R1 resection versus 17.4 months for R2 resection (P = .0001).

Conclusions: P/D, hyperthermic pleural lavage with povidone-iodine, prophylactic chest wall radiotherapy, and systemic chemotherapy is a safe and well-tolerated multimodality therapy.

Copyright © 2015 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.
Povidone iodine: the new solution for mesothelioma?. V.W. Rusch. 2015;149(2):567-8. Editorial · Comment PubMed · Publisher
The mesothelioma enigma. R.M. Flores. 2015;149(6):1548-9. Editorial · Comment PubMed · Publisher

Summary

In this editorial commentary, the author discussed a study by Frischknecht and colleagues, published in the same issue. That study assessed whether ERCC1 and RRM1 levels, measured in pretreatment tissue biopsies, predicted outcome in patients with mesothelioma who underwent induction chemotherapy followed by extrapleural pneumonectomy (EPP). It found that high ERCC1 expression was associated with a worse prognosis and high RRM1 with a better one, and these findings were statistically significant by univariate analyses. The author noted that median survivals of 21 months for epithelioid and 12 months for mixed and sarcomatoid histology, reported for patients as far back as 1939, were similar to results today. He identified several weaknesses in the study. The multivariate model omitted histology, age, gender and nodal status. Freedom from recurrence was a suboptimal end point because radiologic assessment of mesothelioma is unreliable. The analysis also focused on patients who survived the treatment selection process, ignoring the intent-to-treat principle. He concluded that the prognostic role of the two markers was not clinically relevant at this time and that predictive ability had not been demonstrated. He also argued that induction chemotherapy followed by EPP is not standard treatment. He cited a meta-analysis in which median survivals after EPP and pleurectomy decortication were similar but operative mortality appeared 3-fold higher with EPP, and suggested reserving EPP as a last resort or eliminating it.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.
Updated patterns of failure after multimodality therapy for malignant pleural mesothelioma. E.H. Baldini, W.G. Richards, R.R. Gill, et al. 2015;149(5):1374-81. PubMed · Publisher · Free full text

Abstract

Objective: We have previously described patterns of failure after extrapleural pneumonectomy and multimodality therapy for malignant pleural mesothelioma and sought to update our results with a larger cohort of recent patients.

Methods: A total of 169 patients underwent extrapleural pneumonectomy without preoperative chemotherapy between 2001 and 2010. Data for treatment, recurrence, and survival were determined from medical records. A thoracic radiologist reviewed postoperative computed tomography or positron emission tomography computed tomography scans to determine sites of recurrence. Time to recurrence was estimated by the Kaplan-Meier method. Rates were compared using the Fisher exact test.

Results: The median age of patients was 62 years. Histology on final pathology was epithelial for 104 patients (62%) and nonepithelial for 65 patients (38%). A total of 132 patients (78%) received heated intraoperative chemotherapy; 77 patients (45%) received adjuvant chemotherapy, and 71 patients (42%) received adjuvant radiation therapy. Most chemotherapy regimens included platinum or pemetrexed. Median radiation therapy dose was 54 Gy. Among 158 evaluable patients, a recurrence developed in 118 (75%). Median follow-up was 83 months, median time to recurrence was 13.1 months, and median survival was 15 months. Sites of first recurrence were in the ipsilateral hemithorax or mediastinum for 54% of patients, in the abdomen for 39% of patients, in the contralateral hemithorax for 28% of patients, and in other distant sites for 5% of patients. Some patients had simultaneous recurrences in multiple sites.

Conclusions: The most common site of recurrence after extrapleural pneumonectomy and planned multimodality therapy remains the ipsilateral hemithorax (including mediastinum), and true distant failure (other than the abdomen or contralateral hemithorax) remains unusual. The distribution of recurrences is strikingly similar to our prior report.

Copyright © 2015 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.
Discussion. 2014;147(1):516. Comment PubMed · Publisher
Malignant pleural mesothelioma and the Society of Thoracic Surgeons Database: an analysis of surgical morbidity and mortality. B.M. Burt, R.B. Cameron, N.M. Mollberg, et al. 2014;148(1):30-5. PubMed · Publisher

Abstract

Background: To date, reported surgical morbidity and mortality for pleurectomy/decortication and extrapleural pneumonectomy performed for malignant pleural mesothelioma primarily represent the experience of a few specialized centers. For comparison, we examined early outcomes of pleurectomy/decortication and extrapleural pneumonectomy from a broader group of centers/surgeons participating in the Society of Thoracic Surgeons-General Thoracic Database.

Methods: All patients in the Society of Thoracic Surgeons-General Thoracic Database (version 2.081, representing 2009-2011) who underwent pleurectomy/decortication or extrapleural pneumonectomy for malignant pleural mesothelioma were identified. Patient characteristics, morbidity, mortality, center volume, and procedure were examined using univariable and multivariable analyses.

Results: A total of 225 patients underwent pleurectomy/decortication (n = 130) or extrapleural pneumonectomy (n = 95) for malignant pleural mesothelioma at 48 centers. Higher volumes of procedures (≥5/y) were performed at 3 pleurectomy/decortication and 2 extrapleural pneumonectomy centers. Patient characteristics were statistically equivalent between pleurectomy/decortication and extrapleural pneumonectomy groups, except those undergoing extrapleural pneumonectomy were younger (63.2 ± 7.8 years vs 68.3 ± 9.5 years; P < .001) and more likely to have received preoperative chemotherapy (30.1% vs 17.8%; P = .036). Major morbidity was greater after extrapleural pneumonectomy, including acute respiratory distress syndrome (8.4% vs 0.8%; P = .005), reintubation (14.7% vs 2.3%; P = .001), unexpected reoperation (9.5% vs 1.5%; P = .01), and sepsis (4.2% vs 0%; P = .03), as was mortality (10.5% vs 3.1%; P = .03). Multivariate analyses revealed that extrapleural pneumonectomy was an independent predictor of major morbidity or mortality (odds ratio, 6.51; P = .001). Compared with high-volume centers, increased acute respiratory distress syndrome was seen in low-volume centers performing extrapleural pneumonectomy (0% vs 12.5%; P = .05).

Conclusions: Extrapleural pneumonectomy is associated with greater morbidity and mortality compared with pleurectomy/decortication when performed by participating surgeons of the Society of Thoracic Surgeons-General Thoracic Database. Effects of center volume require further study.

Copyright © 2014 The American Association for Thoracic Surgery. All rights reserved.
Pleurodesis to prevent mesothelioma. V. Acton. 2014;147(3):1111. Letter · Comment PubMed · Publisher
Preventing pleural mesothelioma in patients with recognizable asbestos-related pleural plaques. V. Acton. 2014;148(4):1763. Letter · Comment PubMed · Publisher
Reply to the editor. W.T. Vigneswaran. 2014;148(4):1763-4. Letter · Comment PubMed · Publisher
Targeting of the Hedgehog signal transduction pathway suppresses survival of malignant pleural mesothelioma cells in vitro. M. You, J. Varona-Santos, S. Singh, et al. 2014;147(1):508-16. PubMed · Publisher

Abstract

Objective: The present study sought to determine whether the Hedgehog (Hh) pathway is active and regulates the cell growth of cultured malignant pleural mesothelioma (MPM) cells and to evaluate the efficacy of pathway blockade using smoothened (SMO) antagonists (SMO inhibitor GDC-0449 or the antifungal drug itraconazole [ITRA]) or Gli inhibitors (GANT61 or the antileukemia drug arsenic trioxide [ATO]) in suppressing MPM viability.

Methods: Selective knockdown of SMO to inhibit Hh signaling was achieved by small interfering RNA in 3 representative MPM cells. The growth inhibitory effect of GDC-0449, ITRA, GANT61, and ATO was evaluated in 8 MPM lines, with cell viability quantified using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cell death was determined by annexinV/propidium iodide staining and flow cytometry.

Results: SMO small interfering RNA mediated a two- to more than fivefold reduction of SMO and Gli1 gene expression as determined by real-time quantitative reverse-transcriptase polymerase chain reaction, indicating significant Hh pathway blockade. This was associated with significantly reduced cell viability (34% ± 7% to 61% ± 14% of nontarget small interfering RNA controls; P = .0024 to P = .043). Treating MPM cells with Hh inhibitors resulted in a 1.5- to 4-fold reduction of Gli1 expression. These 4 Hh antagonists strongly suppressed MPM cell viability. More importantly, ITRA, ATO, GANT61 induced significant apoptosis in the representative MPM cells.

Conclusions: Hh signaling is active in MPM and regulates cell viability. ATO and ITRA were as effective as the prototypic SMO inhibitor GDC-0449 and the Gli inhibitor GANT61 in suppressing Hh signaling in MPM cells. Pharmaceutical agents Food and Drug Administration-approved for other indications but recently found to have anti-Hh activity, such as ATO or ITRA, could be repurposed to treat MPM.

Copyright © 2014 The American Association for Thoracic Surgery. All rights reserved.
Clinical indications and results after chest wall resection for recurrent mesothelioma. B.M. Burt, S.O. Ali, M.C. DaSilva, et al. 2013;146(6):1373-9; discussion 1379-80. PubMed · Publisher

Abstract

Objective: The ipsilateral hemithorax is the most common site of recurrence after surgical resection for malignant pleural mesothelioma. Salvage treatment has generally been ineffective. We reviewed the outcomes after resection of isolated ipsilateral chest recurrence after cytoreductive surgery in patients with malignant pleural mesothelioma.

Methods: Patients with malignant pleural mesothelioma who underwent initial surgical resection at our institution from 1988 to 2011 and were subsequently treated for localized recurrence with an additional chest resection were identified and their data retrospectively reviewed.

Results: A total of 1142 patients underwent either extrapleural pneumonectomy (n = 794) or pleurectomy/decortication (n = 348). Of the patients who returned for follow-up, 47 (4.1%) had chest wall recurrence amenable to resection. The location of recurrence was predominantly incisional (49%) and/or costophrenic (38%). The median time to recurrence after either extrapleural pneumonectomy or pleurectomy/decortication was 16.1 months (range, 2.7-58.2). No 30-day mortality was found for chest wall resection, and the median length of stay in the hospital was 3 days (range, 0-12). The median overall survival duration after chest wall resection correlated positively with the time to recurrence (epithelial: median, 8.9, 17.2, and 35.8 months for a time to recurrence of <12, 12 to <24, and ≥24 months, respectively; biphasic: median, 2.7 and 15.9 months for a time to recurrence of <10 and ≥10 months, respectively).

Conclusions: Chest wall resection is a safe and effective therapeutic option in the management of localized chest wall recurrence of malignant pleural mesothelioma. The time to recurrence appears to be predictive of the expected survival benefit in both epithelial and biphasic malignant pleural mesothelioma.

Copyright © 2013. Published by Mosby, Inc.
Hyperthermic intraoperative pleural cisplatin chemotherapy extends interval to recurrence and survival among low-risk patients with malignant pleural mesothelioma undergoing surgical macroscopic complete resection. D.J. Sugarbaker, R.R. Gill, B.Y. Yeap, et al. 2013;145(4):955-963. PubMed · Publisher

Abstract

Objective: Local recurrence limits long-term survival in patients with malignant pleural mesothelioma. We investigated whether hyperthermic intraoperative cisplatin chemotherapy lavage affects the interval to recurrence and overall survival among patients with favorable prognostic factors.

Methods: Using a preoperative risk assessment algorithm we had previously developed and validated, we retrospectively identified a cohort of patients treated with cytoreductive surgery from 2001 to 2009. The patients had epithelial histologic findings on biopsy and were characterized as having a low risk of early recurrence and death (ie, tumor volume ≤ 500 cm(3) and were either men with a hemoglobin level of ≥ 13 g/dL or were women). Those patients who had received hyperthermic intraoperative cisplatin chemotherapy were compared with a comparison group of those who had not. Fisher's exact test was used to determine the balance of prognostic factors. The Kaplan-Meier method and log-rank tests were used to estimate and compare the interval to recurrence and overall survival. Cox proportional hazards regression was used for multivariate analysis.

Results: The cohort criteria identified 103 patients: 72 who received hyperthermic intraoperative cisplatin chemotherapy and 31 who did not. The groups were balanced for prognostic factors, except for the use of neoadjuvant chemotherapy (more common in the comparison group). The hyperthermic intraoperative cisplatin chemotherapy group exhibited a significantly longer interval to recurrence (27.1 vs 12.8 months) and overall survival (35.3 vs 22.8 months) than the comparison group. The improved interval to recurrence and overall survival for the hyperthermic intraoperative cisplatin chemotherapy group were particularly evident among the subgroups of patients who had not received hemithoracic radiotherapy and who had pathologic stage N1 or N2 lymph node metastases.

Conclusions: A favorable outcome and minimal incremental morbidity support the incorporation of hyperthermic intraoperative cisplatin chemotherapy into multimodality treatment strategies for patients with low-risk epithelial malignant pleural mesothelioma.

Copyright © 2013. Published by Mosby, Inc.
Intraoperative hyperthermic chemotherapy perfusion for malignant pleural mesothelioma: an in vitro evaluation. R.B. Cameron, D. Hou. 2013;145(2):496-504. PubMed · Publisher

Abstract

Objectives: Hyperthermic chemotherapy perfusion has been used in the treatment of both pleural and peritoneal mesothelioma without an extensive basic science foundation. Clinical data are limited with no prospective randomized trials to support the use of this potentially toxic therapy. We sought to generate basic scientific support for this clinical practice and to define the optimal conditions for use in future clinical trials.

Methods: Growth of a variety of in vitro established cell lines, including a hyperthermia-sensitive Chinese hamster ovary (CHO)-K1 cell line, a normal lung fibroblast line (MRC-5), a lung cancer line (A549), and 3 human mesothelioma cell lines (NCI-H28, NCI-H2052, and MSTO-211H), was assessed using a novel tetrazolium compound (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt [MTS]) and an electron coupling reagent (phenazine methosulfate), which measures the absorbance at 490 nm of a formazan product reduced from MTS by living cells (MTS metabolic assay), or a standard dilution clonogenic assay, which enumerates colony-forming units of more than 50 cells. Each cell line was plated into flasks and then exposed to varying combinations of chemotherapy agents and hyperthermia (37°C-45°C). The cells then were harvested and assessed in either assay. The role of chemotherapeutic agents currently most commonly used in clinical practice, including cisplatin, gemcitabine, and pemetrexed, was assessed with and without simultaneous heat exposure.

Results: Conditions initially were explored using hyperthermia alone in CHO-K1, A549, and NCI-H28 cell lines using temperatures of 37°C, 42°C, and 45°C for 20, 40, and 60 minutes, respectively. This showed a reproducible dose-response curve in CHO-K1 cells with increasing temperature producing lower survival to only 1.5% of the control at 45°C for 60 minutes (P < .01). The A549 cells also showed a response but only at the highest temperature, and the NCI-H28 cells showed a more modest reduction to 65% at 45°C for 60 minutes (P < .01). When the 2 assays were directly compared, the MTS assay failed to detect differences between groups and therefore was discontinued from the remainder of these experiments. Next, hyperthermia was limited to the physiologic limit of 42°C, and the addition of chemotherapy was assessed. Doses were chosen on the basis of prior pharmacokinetic data from studies showing a maximum tissue/blood level of 200 ng/mL for cisplatin pleural instillation and were thought to more accurately reflect actual tumor levels. Cisplatin alone modestly reduced the clonogenic potential to 26%, 16.4%, and 13.6% at 42°C, respectively, for 60 minutes (P < .01); however, this was only a further reduction of 29.6%, 33.8%, and 34.2%, respectively, from the cisplatin alone control. Therefore, most of the reduction was attributable to chemotherapy and not hyperthermia. With combinations of cisplatin/gemcitabine and cisplatin/pemetrexed, the effect was larger, with reduction to 9.6%, 0%, and 0%, respectively (P < .01) (incremental reduction of 16.5%, 0%, and 0%, respectively, due to hyperthermia). Cisplatin/pemetrexed produced essentially identical results.

Conclusions: Intrapleural chemotherapy seems to be most effective when using 2 drug combinations. All mesothelioma cell lines showed no particular sensitivity to heat. The use of hyperthermia alone or with chemotherapy produces at best only a modest effect and does not necessarily support its current clinical use.

Copyright © 2013 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.
Outcome and prognostic factors of pleural mesothelioma after surgical diagnosis and/or pleurodesis. M. Baud, S. Strano, A. Dechartres, et al. 2013;145(5):1305-11. PubMed · Publisher

Abstract

Objective: The objective of this study was to evaluate long-term survival and prognostic factors in patients with malignant pleural mesothelioma.

Methods: All consecutive patients referred for surgical diagnosis and/or pleurodesis for malignant pleural mesothelioma between 2000 and 2010 were studied. The following parameters were prospectively recorded: age, sex, tobacco consumption, asbestos exposure, type and duration of symptoms, American Society of Anesthesiologists (ASA) score, body mass index, preoperative C-reactive protein levels, white blood cells and platelet count, pachypleuritis on chest radiograph, type of diagnostic surgical procedure, histologic type, modality of pleurodesis, and chemotherapy. Survival was assessed on March 1, 2011.

Results: A total of 170 patients were included. For the entire population, median survival was 12 months (95% confidence interval [CI], 10-15). Two-, 5-, and 7-year overall survival was 26% (95% CI, 19-35), 11% (95% CI, 6-21), and 5% (95% CI, 9-22), respectively. Asbestos exposure, age, ASA class III versus ASA classes I and II, nonepithelioid histology, C-reactive protein levels >3 mg/L, and white cell count >12,000/mm(3) influenced outcome in univariate analysis. Multivariate analysis showed that nonepithelioid histology (hazard ratio [HR], 2.76; 95% CI, 1.50-5.08); age (HR, 1.05; 95% CI, 1.01-1.08); C-reactive protein levels between 4 and 50 mg/L, and >51 (HR, 2.28; 95% CI, 1.18-4.42; and HR, 2.69; CI, 1.29-5.60, respectively); and leukocytosis >12,000/mm(3) (HR, 2.28; 95% CI, 1.22-4.25) were independent worse survival predictors.

Conclusions: Median survival in an unselected population of patients with malignant pleural mesothelioma treated nonsurgically is 12 months. Nonepithelioid histology, older age, abnormal C-reactive protein levels, and leukocytosis are independent predictors of worse survival.

Copyright © 2013 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.
Reply to the editor. M. Baud, P. Forgez, D. Damotte, et al. 2013;146(4):990-1. Letter · Comment PubMed · Publisher
The dog didn't bark. V. Acton. 2013;146(4):990. Letter · Comment PubMed · Publisher
The role of surgical cytoreduction in the treatment of malignant pleural mesothelioma: meeting summary of the International Mesothelioma Interest Group Congress, September 11-14, 2012, Boston, Mass. V. Rusch, E.H. Baldini, R. Bueno, et al. 2013;145(4):909-910. PubMed · Publisher

Summary

This article summarized discussions at the International Mesothelioma Interest Group (IMIG) Congress, held September 11-14, 2012, in Boston, on the role of surgical cytoreduction, extrapleural pneumonectomy (EPP) or extended pleurectomy/decortication (P/D), in treating malignant pleural mesothelioma (MPM). More than 500 participants from the involved specialties took part. The authors described shortcomings of the Mesothelioma and Radical Surgery (MARS) I feasibility trial. Its survival analysis used fewer than 10% of the required sample size. Protocol compliance was poor: 6 of 26 no-EPP patients had off-protocol surgery, and only 16 of 24 EPP-group patients underwent EPP. EPP-associated morbidity (69%) and mortality (19%) were higher than in the literature. The authors concluded that no conclusions about the efficacy of EPP could be drawn from MARS I. Presentations at the meeting reaffirmed that recurrence is primarily local. Six institutional series from the US, Europe and Japan reported median survival of 25 to 37 months for patients with epithelial disease and negative extrapleural lymph nodes, with operative mortality of 0% to 2%. A preliminary IASLC staging analysis showed 19-month median survival among 1359 patients undergoing resection, and a median of 40 months after EPP for early-stage disease. Attendees agreed on several points. Surgery aiming at macroscopic complete resection should be part of multimodality therapy, with the type chosen on clinical factors and surgical judgment. Patients should be evaluated in a multidisciplinary setting, with clinical staging and histologic subtyping done before therapy.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.
Detection of integrin-linked kinase in the serum of patients with malignant pleural mesothelioma. S.B. Watzka, F. Posch, H.I. Pass, et al. 2011;142(2):384-9. PubMed · Publisher

Abstract

Objective: Integrin-linked kinase, which is relevant to neoplastic transformation, is highly expressed in malignant pleural mesothelioma. Recently, detection of integrin-linked kinase in serum of patients with ovarian cancer has been reported. This study asks whether integrin-linked kinase can also be detected in serum of patients with malignant pleural mesothelioma and whether serum level has diagnostic or prognostic relevance for that disease.

Methods: A sandwich enzyme-linked immunosorbent assay was designed to detect integrin-linked kinase and applied to serum samples from 46 patients with malignant pleural mesothelioma, 98 patients with other malignant chest disease, and 23 patients with benign chest disease. Integrin-linked kinase serum concentration and clinical data were correlated statistically.

Results: Median serum integrin-linked kinase concentration was significantly higher in malignant pleural mesothelioma (8.89 ng/mL) than in other malignant chest disease (0.66 ng/mL) or benign chest disease (0.78 ng/mL, P < .001). There was no relevant correlation of serum integrin-linked kinase with cell lysis parameters (R(2) < 0.1). Serum integrin-linked kinase concentration greater than 2.48 ng/mL had diagnostic sensitivity of 80%, specificity of 95%, positive predictive value of 85.7%, negative predictive value of 92.7%, and overall accuracy of 91% for distinction between malignant pleural mesothelioma and other diseases. Serum integrin-linked kinase concentration in malignant pleural mesothelioma was independent of histologic subtype or asbestos exposure. There was no statistically significant impact of serum integrin-linked kinase concentration on prognosis.

Conclusions: Integrin-linked kinase can be detected in serum of patients with malignant pleural mesothelioma and may be a diagnostic marker for the disease.

Copyright © 2011 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.
No matter how complex the problem, there is always a simple solution--which is wrong!. V. Acton. 2011;142(2):477. Letter PubMed · Publisher
Combined treatment with cisplatin and sirolimus to enhance cell death in human mesothelioma. M.L. Hartman, J.M. Esposito, B.Y. Yeap, et al. 2010;139(5):1233-40. PubMed · Publisher

Abstract

Objective: Although platinum-based chemotherapy is widely used in malignant pleural mesothelioma, its modest therapeutic effect warrants identification of enhancing agents. As with many cancers, the phosphatidylinositol 3-kinase/Akt pathway is often activated in malignant pleural mesothelioma and has been implicated in the tumor's aggressiveness. Sirolimus is a well-established inhibitor of the mammalian target of rapamycin. We sought to determine whether combination treatment with sirolimus and cisplatin would enhance cell death in malignant pleural mesothelioma.

Methods: Human malignant pleural mesothelioma cell lines were incubated with sirolimus or cisplatin alone or in combination and assayed for cell viability. To characterize phosphorylation status after treatment, Akt and downstream proteins of mammalian target of rapamycin pathway, p70 S6 kinase and 4E-BP1, were analyzed by Western blot. Effect of combination treatment was also analyzed with extreme drug resistance assay in 12 human malignant pleural mesothelioma tumors with varying resistance to cisplatin.

Results: Individual malignant pleural mesothelioma cell lines exhibited a range of sensitivities to each drug without correlation with subtype. Sirolimus and cisplatin significantly (P = .029) increased cell death versus either drug alone in 4 cell lines. Combined treatment caused dephosphorylation of Akt, 4E-BP1, and p70 S6 kinase. Cell proliferation was significantly decreased in tumors subjected to sirolimus and cisplatin versus cisplatin or sirolimus alone.

Conclusions: Sirolimus appears to enhance the cytotoxicity of cisplatin in malignant pleural mesothelioma cell lines through the mammalian target of rapamycin pathway. These results provide a basis for the clinical evaluation of combined sirolimus and cisplatin chemotherapy in malignant pleural mesothelioma.

2010. Published by Mosby, Inc.
Prevalence of in vitro chemotherapeutic drug resistance in primary malignant pleural mesothelioma: result in a cohort of 203 resection specimens. A.A. Mujoomdar, T.R. Tilleman, W.G. Richards, et al. 2010;140(2):352-5. PubMed · Publisher

Abstract

Objective: Optimizing the multimodality treatment of malignant pleural mesothelioma depends on many factors including an adequate chemotherapeutic response. Currently, chemotherapy regimens for patients with mesothelioma are empirically selected. In vitro chemotherapy resistance in human mesothelioma has not been reported. Our goal was to determine the prevalence of drug resistance in a large sample of malignant pleural mesothelioma using a commercially available assay.

Methods: Tumors specimens (n = 203) were cultured for analysis of chemoresistance using the extreme drug resistance assay. Evaluable results were obtained in 168 (168/203 = 83%) specimens. Each specimen was tested with 3 drugs: cisplatin, gemcitabine, and vinorelbine. Drug resistance was characterized as low, intermediate, or extreme. Median age was 64 years (30-85 years). Forty-four (26%) patients received neoadjuvant chemotherapy before sampling and testing. The distribution of histopathologic cell types was epithelial (103; 61%), mixed (57; 34%), and sarcomatoid (8; 5%).

Results: A significant proportion of tumors had extreme/intermediate drug resistance to cisplatin (27%), gemcitabine (31%), or vinorelbine (59%). Nineteen tumors (11%) had extreme/intermediate resistance to all 3 drugs. Resistance (extreme/intermediate) to cisplatin was more prevalent in epithelial tumors than in nonepithelial (33% vs 18%; P = .0394). No significant differences in chemoresistance were found in tumors of patients who had received neoadjuvant chemotherapy compared with those who had not.

Conclusions: The feasibility of performing off-site in vitro drug resistance assays on resected malignant mesothelioma specimens is reported. A significant proportion of mesothelioma tumors exhibited extreme/intermediate resistance to cisplatin, gemcitabine, or vinorelbine.

2000s

Extrapleural pneumonectomy for malignant pleural mesothelioma: outcomes of treatment and prognostic factors. T.D. Yan, M. Boyer, M.M. Tin, et al. 2009;138(3):619-24. PubMed · Publisher

Abstract

Objective: This study aimed to evaluate the perioperative and long-term outcomes associated with extrapleural pneumonectomy for patients with malignant pleural mesothelioma.

Methods: From October 1994 to April 2008, 70 patients were selected for extrapleural pneumonectomy. Univariate analysis was performed using the Kaplan-Meier method and compared using the log-rank test. Multivariate analysis with entering and removing limits of P less than .10 and P greater than .05, respectively, was used. The prognostic factors included age, gender, side of disease, asbestos exposure, histology, positron emission tomography, date of surgery, neoadjuvant chemotherapy, completeness of cytoreduction, lymph node involvement, perioperative morbidity, adjuvant radiotherapy, and pemetrexed-based chemotherapy.

Results: The mean age of patients was 55 years (standard deviation = 10). Fifty-eight patients had epithelial tumors. Six patients received neoadjuvant chemotherapy, 28 patients received adjuvant radiotherapy, and 16 patients received postoperative pemetrexed-based chemotherapy. Forty-four patients had no lymph node involvement. The perioperative morbidity and mortality were 37% and 5.7%, respectively. Complications included hemothorax (n = 7), atrial fibrillation (n = 6), empyema (n = 4), bronchopulmonary fistula (n = 3), right-sided heart failure (n = 2), pneumonia (n = 1), constrictive pericarditis (n = 1), acute pulmonary edema (n = 1), small bowel herniation (n = 1), and disseminated intravascular coagulopathy (n = 1). The median survival was 20 months, with a 3-year survival of 30%. Asbestos exposure, negative lymph node involvement, and receipt of adjuvant radiation or postoperative pemetrexed-based chemotherapy were associated with improved survival on both univariate and multivariate analyses.

Conclusion: The present study supports the use of extrapleural pneumonectomy-based multimodal therapy in carefully selected patients with malignant pleural mesothelioma.
Antisense therapy for malignant mesothelioma with oligonucleotides targeting the bcl-xl gene product. W.R. Smythe, I. Mohuiddin, M. Ozveran, et al. 2002;123(6):1191-8. PubMed · Publisher

Abstract

Objective: Malignant pleural mesothelioma is resistant to conventional therapies and to apoptosis. The bcl-2 family genes are major determinants of apoptotic homeostasis. Malignant pleural mesothelioma lines and tumors rarely express the antiapoptotic Bcl-2 protein but routinely express the antiapoptotic protein Bcl-xl and the proapoptotic proteins Bax and Bak. We have previously shown pharmacologic inhibition of bcl-xl expression in malignant pleural mesothelioma can lead to apoptosis, so we sought to determine whether antisense oligonucleotides directed at bcl-xl messenger RNA would engender apoptosis, possibly through a "forced imbalance" of bcl-2 family proteins.

Methods: Malignant pleural mesothelioma lines REN (epithelial) and I-45 (sarcomatous) were exposed to modified bcl-xl antissense oligonecleotides directed near the messenger RNA initiation sequence with and without a liposomal delivery system. Untreated cells and bcl-xl sense oligonucleotides were controls. Cell viability was measured by colorimetric assay, and apoptosis was evaluated with Hoechst staining and sub-G(1) fluorescence-activated cell sorter analysis.

Results: Bcl-xl protein expression after antisense oligonucleotides was downwardly regulated in both cell lines relative to sense oligonucleotides (>65%). Significant cellular killing in both the I-45 and REN cell lines was achieved with antisense oligonucleotides (compared with sense oligonucleotides) without (P =.003 and.006, respectively) and with (P =.006 and.0005, respectively) liposomal delivery. Hoechst staining and sub-G(1) fluorescence-activated cell sorter analysis demonstrated apoptosis to be the mechanism of cellular death. Use of a liposomal delivery system increased therapeutic effect and allowed lower doses of antisense oligonucleotides.

Conclusion: Antisense oligonucleotides directed at the bcl-xl gene product engender apoptosis in mesothelioma cell lines. The therapeutic potential of inhibiting expression of this protein in mesothelioma should be evaluated.
Despite some expression of folate receptor alpha in human mesothelioma cells, internalization of methotrexate is predominantly carrier mediated. N.Z. Khokhar, A.F. Lam, V.W. Rusch, et al. 2002;123(5):862-8. PubMed · Publisher

Abstract

Objective: As a response to a published report documenting some expression of folate receptor alpha in human mesothelioma, studies were carried out examining the role of this receptor versus that of the reduced folate carrier in the internalization of folate analogs in this neoplasm.

Methods: Influx measurements of tritiated methotrexate were carried out in 4 mesothelioma cell lines, and 2 additional cell lines were used as comparators. Relative gene-expression analysis for the carrier and receptor gene was done by using real-time reverse transcriptase-polymerase chain reaction in the above-mentioned cell lines and mesothelioma tumor tissues obtained from patients.

Results: Internalization of tritiated methotrexate in mesothelioma cell lines grown at physiologic folate levels was carrier mediated rather than receptor mediated. Influx of this model permeant by these cells exhibited characteristics of carrier-mediated membrane transport and was only minimally reduced by the addition of 5 micromol/L folic acid, a concentration of this natural folate that would have completely inhibited influx by the folate receptor. Gene-expression analysis revealed prominent expression of the folate receptor in some but not all mesothelioma cell lines, and in only one case was expression of this receptor gene greater than expression of the reduced folate carrier gene. Similar analysis of human mesothelioma tumor tissue showed that, with few exceptions, receptor gene expression was substantially less than that for the carrier gene.

Conclusion: In view of the ongoing reduced folate carrier-mediated internalization that occurs in mesothelioma cells, these results would seem to argue against a role for the folate receptor in the internalization and cellular pharmacokinetics of methotrexate and other classic folate analogs in this neoplasm. Identifying the mediated route for internalization of these agents in tumor cells is a prerequisite for improving their structural design.
Extensive epidural cufflike growth of malignant pleural mesothelioma causing spinal cord compression. J.M. Gijtenbeek, H.I. Brouwer, R.H. Boerman, et al. 2002;124(1):200-2. Case report PubMed · Publisher

Summary

The authors described 4 patients with pleural malignant mesothelioma whose tumor grew from a paravertebral mass through the intervertebral foramina into the spinal epidural space, causing signs of spinal cord compression. The patients were seen at Dutch neurology, radiotherapy and neuro-oncology departments. The neurologic complication developed 4 months, and 2, 6 and 7 years, after diagnosis. Patient 1, a 56-year-old woman exposed to asbestos through her husband's working clothes, had been treated for pleural effusion for 7 years. Mesothelioma was found on psoas muscle biopsy, and epidural tumor later extended through the foramen magnum into the skull. Patient 2, a 46-year-old man diagnosed 6 years earlier, had an epidural cuff from T10 to L3 that later reached the foramen magnum despite radiotherapy. Patient 3, a 41-year-old woman, developed cervical cord compression 2 years after diagnosis, and later a cufflike epidural tumor from C2 to the sacrum. Patient 4, a 53-year-old man, had cord compression at T10 four months after diagnosis. All received radiotherapy, with temporary improvement in some, and all died of respiratory failure. Autopsy in 2 cases confirmed widespread cufflike epidural extension. The authors concluded that radicular pain should alert clinicians to possible epidural tumor in patients with known or suspected mesothelioma, and that radiotherapy should be started immediately to preserve neurologic function.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.
Synovial sarcoma of the pleura: a clinical and pathologic study of three cases. A.S. Colwell, J. D'Cunha, S.O. Vargas, et al. 2002;124(4):828-32. Case report PubMed · Publisher

Abstract

Synovial sarcomas are rare soft tissue malignancies that most commonly affect the extremities in the vicinity of large joints. These malignancies typically occur in adolescents and young adults between the ages of 15 and 40 years.(1,2) Historically they are believed to originate from primitive pluripotent mesenchyme capable of synovial differentiation. This belief is consistent with the malignancy's origin from sites devoid of normal synovium, such as the pleural cavity. A variety of pleural cavity sarcomas have been described, including liposarcoma,(3) chondrosarcoma,(4) osteosarcoma,(5) and malignant schwannoma.(6) Pleural synovial sarcoma, however, is a much rarer entity. In fact, pleural synovial sarcoma was first described only 6 years ago(7) and has not yet been reported in the surgical literature. Because of its rarity, pleural synovial sarcoma is often mistaken for the histologically similar malignant mesothelioma, the most common of the pleural neoplasms. This is a critical distinction, because synovial sarcoma may be extremely aggressive. Studies in the last 10 years have shown it to be extremely sensitive to ifosfamide-based chemotherapy, and survival of patients with synovial sarcoma has recently increased with chemotherapy, with 5-year survivals now as high as 57%.(8-10) In this report, we describe 3 cases of synovial sarcoma of the pleura. Clinical findings are correlated with pathologic features, including immunohistochemical stains and fluorescence in situ hybridization (FISH) for the identification of the diagnostic chromosomal translocation, t(X;18)(p11.2;q11.2). This delineation of the clinical and pathologic aspects of this rare, newly recognized tumor should increase awareness among the surgical community.
Sarcomatous mesothelioma in the left ventricle: a rare entity. M. Jianyang, Z. Xiuhui, Y. Hongsheng, et al. 2001;122(2):394-5. Case report PubMed · Publisher
The alpha folate receptor is highly activated in malignant pleural mesothelioma. R. Bueno, K. Appasani, H. Mercer, et al. 2001;121(2):225-33. PubMed · Publisher

Abstract

Objective: To determine whether the folate receptor gene is overexpressed in malignant pleural mesothelioma.

Methods: Differential display analysis was performed with fresh frozen RNA obtained from normal lung, pleura, and mesothelioma. Sixty differentially expressed genes were identified and characterized. One gene that was over-expressed in mesothelioma versus normal tissue was the human alpha folate receptor. In situ hybridization with antisense probes designed on the basis of the sequence of the folate receptor was performed with frozen sections from 61 patients (33 epithelial and 28 mixed or sarcomatoid tumors) with malignant pleural mesothelioma. The controls included normal pleura, normal lung, other cancers, and sense controls for all of the tumors. Northern analysis with a folate receptor probe and immunohistochemical analysis with anti-alpha folate receptor antibodies were also performed.

Results: Forty-four (72%) of the 61 mesothelioma tumors were found to have between 2-fold and 4-fold higher mRNA expression of the folate receptor when compared with the control tissues. The histologic type of the tumor did not affect the rate of folate receptor activation. Northern analysis and immunohistochemical experiments confirmed these findings.

Conclusions: A majority of mesothelioma tumors examined overexpress the alpha folate receptor protein when compared with normal adjacent tissues. This finding may help explain the observations that antifolate drugs have activity in the treatment of mesothelioma. It also encourages further study of folate receptor-related treatment strategies in this malignancy.
Positron emission tomography with f18-fluorodeoxyglucose in the staging and preoperative evaluation of malignant pleural mesothelioma. D.B. Schneider, C. Clary-Macy, S. Challa, et al. 2000;120(1):128-33. PubMed · Publisher

Abstract

Objectives: The purpose of this study was to evaluate the utility of positron emission tomography with F18-fluorodeoxyglucose in the preoperative evaluation and staging of malignant mesothelioma in patients who were candidates for aggressive combined modality therapy.

Methods: Eighteen consecutive patients with biopsy-proven malignant mesothelioma underwent positron emission tomographic scanning. The results of positron emission tomographic imaging were compared with results obtained by computed tomography, mediastinoscopy, thoracoscopy, and pathologic examination of surgical specimens. All patients fasted and received an average of 14.5 +/- 2.7 mCi of F18-fluorodeoxyglucose for positron emission tomographic scanning. Attenuation-corrected whole-body and regional emission images of the chest and upper abdomen were acquired and formatted into transaxial, coronal, and sagittal images.

Results: All primary malignant mesotheliomas accumulated F18-fluorodeoxyglucose, and the mean standardized uptake value was 7. 6 (range, 3.33-14.85; n = 9). There were no false-negative results of positron emission tomography. Identification of occult extrathoracic metastases by positron emission tomography was the basis for excluding two patients from surgical therapy. There were two false-positive results of positron emission tomography: increased F18-fluorodeoxyglucose uptake in the contralateral chest that was negative by thoracoscopic biopsy (n = 1) and increased abdominal F18-fluorodeoxyglucose uptake after partial colectomy for diverticular disease (n = 1).

Conclusions: Positron emission tomography can identify malignant pleural mesothelioma and appears to be a useful noninvasive staging modality for patients being considered for aggressive combined modality therapy.

1990s

Human mesotheliomas contain the simian virus-40 regulatory region and large tumor antigen DNA sequences. H.I. Pass, J.S. Donington, P. Wu, et al. 1998;116(5):854-9. PubMed · Publisher

Abstract

Background: A cohort (20%) of patients with mesothelioma will not have an exposure to asbestos. Recently, a DNA tumor virus (simian virus 40) has been shown to cause hamster mesotheliomas; we previously described simian virus 40-like DNA amino terminus sequences in 29 of 48 mesotheliomas. We analyzed an additional 42 mesotheliomas to determine (1) whether our initial observations were durable and (2) the extent to which the simian virus 40 genome is present in mesotheliomas.

Methods: Genomic DNA was extracted from snap frozen mesothelioma tumor samples and from the simian virus 40-induced hamster mesothelioma tumor H9A. Polymerase chain reaction primers were used to amplify various simian virus 40 large T-antigen regions including a 105-base pair amino terminus fragment, a 281-base pair carboxyl terminus fragment, and a 310-base pair fragment of the enhancer promoter region. Endonuclease digestions and Southern blotting were used to verify the expected product.

Results: Thirty of the 42 (71%) samples amplified T-antigen amino sequences, and specificity was verified by Southern hybridization. Sixteen of 42 samples (38%) amplified the appropriate size fragment for the carboxyl terminus, and digestion with BsaB1 matched that of H9A. Twenty-two of 42 samples (52%) amplified simian virus 40 regulatory sequences and Fok1 digestion matched that of the hamster control tumor. Sequence analysis (4 patients) revealed 100% homology with the regulatory region of simian virus 40 strain 776.

Conclusions: These data suggest an association between the simian virus 40 virus and human mesothelioma that could be exploited for diagnostic/therapeutic options including early detection and potential vaccination strategies.
The importance of surgical staging in the treatment of malignant pleural mesothelioma. V.W. Rusch, E. Venkatraman. 1996;111(4):815-25; discussion 825-6. PubMed · Publisher

Abstract

Objectives: Progress in the therapy of malignant pleural mesothelioma is limited by the lack of an adequate staging system and controversy about prognostic factors. This surgical series was analyzed to determine whether a new TNM staging system proposed by the International Mesothelioma Interest Group and certain prognostic factors could stratify patients in future clinical trials.

Methods: Thoracotomy was performed if computed tomographic scans showed resectable tumor confined to one hemithorax. Pleurectomy/decortication was done if visceral pleural tumor was minimal, and extrapleural pneumonectomy was done for more locally advanced disease. Complete resection was defined as no gross residual tumor. Adjuvant therapy was given as required by serial clinical trials. Patients had computed tomographic scans every 3 months until death. Prognostic factors were examined by log-rank and Cox regression analyses.

Results: From October 1983 to July 1994, a total of 131 thoracotomies were performed, resulting in 101 resections, 72 of which were complete. Extrapleural pneumonectomy was done in 50 patients and pleurectomy/decortication in 51. The ratio of men to women was 108:23. Median age was 63 years (range 32 to 80 years). Operative mortality was five of 131 patients (3.8%), three of 50 in the group having extrapleural pneumonectomy (6%). Ninety-five of the 131 tumors were epithelial. Fifty-one of 89 patients (57%) having node dissections had diseased nodes, 45 (50%) N2. By univariate analysis, type of resection, T and N status, stage, histologic type, and adjuvant therapy, but no gender or age, significantly affected survival. Type of resection, stage, and histologic type were significant in a multivariate analysis. Local recurrence occurred mainly after pleurectomy/decortication, and distant metastases developed after extrapleural pneumonectomy.

Conclusions: (1) N2 nodal disease is more frequent than previously reported; (2) the prognostic importance of histologic type is confirmed; (3) both T and N status influence outcome, and the International Mesothelioma Interest Group staging system successfully identifies patients whose prognosis is poor; (4) despite more locally advanced disease in most patients with extrapleural pneumonectomy, that approach provided better local control than pleurectomy/decortication but failed to improve survival because of distant metastatic disease. Contrary to past practice, future clinical trials should stratify for histologic type, must control for TNM stage, and must consider the impact of type of surgical resection on the pattern of relapse.
Differential sensitivity of thoracic malignant tumors to adenovirus-mediated drug sensitization gene therapy. W.R. Smythe, H.C. Hwang, A.A. Elshami, et al. 1995;109(4):626-30; discussion 630-1. PubMed · Publisher

Abstract

Malignant mesothelioma may prove to be an attractive candidate for somatic gene therapy with replication-deficient recombinant adenovirus transfer of a toxic, or drug sensitization gene. Transfer of the herpes simplex thymidine kinase type I gene (HSVtk), followed by exposure to the acyclic nucleoside drug ganciclovir, has been shown to be an effective tumor cell killing system. To study generalized applicability, we tested a number of thoracic malignant cell lines for their sensitivity to gancyclovir after infection with an adenoviral vector containing the HSVtk gene (Ad.RSVtk). Using the concentration of gancyclovir required to kill 50% of the cells (IC50) as a measure of sensitivity, we detected variable sensitivity among cell lines, with mesothelioma most sensitive (IC50 = 0.075 to 2.8 mumol/L gancyclovir), and non-small-cell carcinoma lines having an intermediate sensitivity (IC50 = 1.5 to 100 mumol/L). In contrast, an ovarian carcinoma line was extremely resistant (IC50 > 2000 mumol/L). To study the possible mechanisms for these differences, we studied cell lines with regard to their ability to be infected with an adenoviral vector containing a marker gene (Ad.CMVlacZ) and expression of the vitronectin receptor alpha v (an integrin cell adhesion molecule shown to be required for adenovirus internalization after initial binding). We found that the degree of lacZ transduction correlated with HSVtk sensitivity, whereas vitronectin receptor expression did not, suggesting that differences in initial viral binding ability, rather than internalization, may explain the sensitivity differences seen in vitro.
Successful operation for solitary fibrous tumor of the epicardium. D. Segawa, H. Yoshizu, Y. Haga, et al. 1995;109(6):1246-8. Case report PubMed · Publisher

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