Int J Surg. 2008 Aug;6(4):293-7. Epub 2008 May 1.
Morbidity, mortality, mean survival, and the impact of histology on survival after pleurectomy in 64 patients with malignant pleural mesothelioma.
Neragi-Miandoab S, Richards WG, Sugarbaker DJ.
Department of Surgery, Cardiothoracic Surgery, Boston University Medical Center, School of Medicine, One Boston Medical Center Place, Boston MA 02118, USA. sneragi@yahoo.com

AIM: The survival of patients with malignant pleural mesothelioma (MPM) who do not seek treatment ranges from 4 to 12 months. To date, the optimal procedure for resection of malignant pleural mesothelioma is controversial, extrapleural pneumonectomy has been most consistently associated with long-term survival and has provided the most radical cytoreduction; but, unfortunately, not all patients qualify for this invasive surgical approach. METHODS: Between 1992 and 2000, 64 patients underwent pleurectomy as a palliative treatment for MPM. This retrospective study evaluates the operative outcome and the impact of some prognostic factors on patients' survival. Preoperative evaluation included chest X-ray, CT and/or MRI. Diagnosis was made by pleural biopsy via needle, open, or VATS biopsy. The Kaplan-Meier curve and the Log-Rank test were used to analyze the data. RESULTS: The median age of the study group was 65 (with a range of 29-84 years). Thirty-six patients had epithelial histology, and 28 patients had sarcomatoid or mixed type (e.g., epithelial+spindle, epithelial+sarcomatoid). The 30-day mortality rate was 3.1%. The overall survival rate was 43%, 28%, and 10% at 1, 2, and 3 years, respectively. The overall median survival was 9.4 months (ranging from 1.15 to 52.7 months). The overall median survival with epithelial histology (n=36, 56%) was 21.7 months (with a range of 1.4-52.7 months) versus 5.8 months (with a range of 1.15-18.3 months) for the sarcomatoid or mixed type (n=28, 44%), p=0.0001. The morbidity included atrial fibrillation (n=5), wound infection (n=2), prolonged intubation (longer than 24h, n=8), reintubation for respiratory failure (n=2), pulmonary emboli (n=1), UTI (n=16), DVT (n=5), MI (n=4), and postoperative bleeding (n=7). Univariant analysis demonstrated that the only prognostic factors influencing survival in our series was the histologic type. Age, gender, and the affected side of the lung did not affect the median survival. CONCLUSION: Our results show that pleurectomy can be performed as a means of palliation for advanced-stage disease with a low mortality rate and may, in fact, improve survival in patients with epithelial subtype as compared with historical controls in the literature with no surgical intervention.

 Interact Cardiovasc Thorac Surg. 2008 Jul 9. [Epub ahead of print]

Incidence of atrial fibrillation after extrapleural pneumonectomy versus pleurectomy in patients with malignant pleural mesothelioma.
Neragi-Miandoab S, Winer S, Sugarbaker DJ.
New York Medical College, School of Medicine, New York, USA.

Extrapleural pneumonectomy (EPP) and pleurectomy are the surgical procedures for the treatment of pleural mesothelioma. However, EPP increases the risk for postoperative atrial fibrillation (AF) in this patient population, which might be partly explained by increase in right heart stress after EPP. We conducted a retrospective chart review of 130 patients who were treated for malignant pleural mesothelioma with either pleurectomy or EPP between 2001 and 2003 in a single institution. Risk factors for AF were evaluated with logistic regression and the postoperative AF events were evaluated. The absence of a history of cardiac arrhythmia was an inclusion criterion. Seventy patients (excluding the 3 patients with a prior history of AF) underwent EPP and 57 patients underwent pleurectomy. The mean ages were 60+/-11 and 63+/-13, and the male to female ratios were 50/20 and 44/13, respectively. Postoperative AF was observed in 45 patients with 36 (51%) of these cases occurring after EPP and 9 (17%) after pleurectomy (p<0.0001). There were no significant differences between the two treatment groups for gender, age, side of affected lung, preoperative heart rate and history of beta-blocker use, coronary heart disease, and chronic obstructive pulmonary disease. There were significant differences between the two groups for cancer histology (p=0.03) with the EPP group having a larger proportion of epithelial-type histology. Through logistic regression, EPP (OR=7.1, 95% CI: 2.9, 17.8) and age over 65 (OR=2.9, 95% CI: 1.2, 6.8) were found to be risk factors for AF. Abnormal cardiac structure and function were identified as important possible confounder, which could not be adequately evaluated due to missing data. Most of these patients had at least one additional expected risk factor for AF. EPP versus pleurectomy and age over 65 are risk factors for postoperative AF. The increased odds of having AF after EPP could be due to right heart stress caused by pneumonectomy. Increased right heart stress might not be sufficient to cause AF alone, but may be an important risk factor that warrants further investigation. Keywords: Right heart stress; Extrapleural pneumonectomy; Pleurectomy; Atrial fibrillation.

Environ Health Perspect. 2008 Jun;116(6):723-6.

Asbestos burden predicts survival in pleural mesothelioma.

Christensen BC, Godleski JJ, Roelofs CR, Longacker JL, Bueno R, Sugarbaker DJ, Marsit CJ, Nelson HH, Kelsey KT.
Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, USA.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a rapidly fatal asbestos-associated malignancy with a median survival time of <1 year following diagnosis. Treatment strategy is determined in part using known prognostic factors. OBJECTIVE: The aim of this study was to examine the relationship between asbestos exposure and survival outcome in MPM in an effort to advance the understanding of the contribution of asbestos exposure to MPM prognosis. METHODS: We studied incident cases of MPM patients enrolled through the International Mesothelioma Program at Brigham and Women's Hospital in Boston, Massachusetts, using survival follow-up, self-reported asbestos exposure (n=128), and a subset of cases (n=80) with quantitative asbestos fiber burden measures. RESULTS: Consistent with the established literature, we found independent, significant associations between male sex and reduced survival (p<0.04), as well as between nonepithelioid tumor histology and reduced survival (p<0.02). Although self-reported exposure to asbestos was not predictive of survival among our cases, stratifying quantitative asbestos fiber burden [number of asbestos bodies per gram of lung (wet weight)] into groups of low (0-99 asbestos bodies), moderate (100-1,099), and high fiber burden (>1,099), suggested a survival duration association among these groups (p=0.06). After adjusting for covariates in a Cox model, we found that patients with a low asbestos burden had a 3-fold elevated risk of death compared to patients with a moderate fiber burden [95% confidence interval (CI), 0.95-9.5; p=0.06], and patients with a high asbestos burden had a 4.8-fold elevated risk of death (95% CI, 1.5-15.0; p<0.01) versus those with moderate exposure. CONCLUSION: Our data suggest that patient survival is associated with asbestos fiber burden in MPM and is perhaps modified by susceptibility.

Am J Respir Cell Mol Biol. 2008 May 29. [Epub ahead of print]

mTOR Mediates Survival Signals in Malignant Mesothelioma Grown as Tumor Fragment Spheroids.

Wilson SM, Barbone D, Yang TM, Jablons DM, Bueno R, Sugarbaker DJ, Nishimura S, Gordon GJ, Broaddus VC.
University of California San Francisco, Lung Biology Center, San Francisco, CA, United States.

Solid tumors such as mesothelioma exhibit a stubborn resistance to apoptosis that may derive from survival pathways, such as PI3K/Akt/mTOR, that are activated in many tumors including mesothelioma. To address the role of PI3K/Akt/mTOR, we used a novel approach to study mesothelioma ex vivo as tumor fragment spheroids. Freshly resected mesothelioma tissue from 15 different patients was grown in vitro as 1-2 mm diameter fragments, exposed to apoptotic agents for 48 h with or without PI3K/Akt/mTOR inhibitors and doubly stained for cytokeratin and cleaved caspase 3 to identify apoptotic mesothelioma cells. Mesothelioma cells within the tumor spheroids exhibited striking resistance to apoptotic agents such as TRAIL plus gemcitabine that were highly effective against monolayers. In a majority of tumors (67%; 10 of 15), apoptotic resistance could be reduced by more than 50% by rapamycin, an mTOR inhibitor, but not by LY294002, a PI3K inhibitor. Responsiveness to rapamycin correlated with staining for the mTOR target, p-S6K, in the original tumor, but not for p-Akt. As confirmation of the role of mTOR, siRNA knockdown of S6K reproduced the effect of rapamycin in 3 rapamycin-responsive tumors. Finally, in 37 mesotheliomas on tissue microarray, p-S6K correlated only weakly with p-Akt suggesting the existence of Akt-independent regulation of mTOR. We propose that mTOR mediates survival signals in many mesothelioma tumors. Inhibition of mTOR may provide a non-toxic adjunct to therapy directed against malignant mesothelioma, especially in those with high baseline expression of p-S6K.

Magn Reson Imaging Clin N Am. 2008 May;16(2):319-39, x.

MR imaging of benign and malignant pleural disease.

Gill RR, Gerbaudo VH, Jacobson FL, Trotman-Dickenson B, Matsuoka S, Hunsaker A, Sugarbaker DJ, Hatabu H.
Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.

MR imaging serves as a problem-solving tool in the diagnosis of inflammatory and infectious pleural diseases and primary and secondary pleural malignancies. Knowledge of MR imaging appearance of pleural diseases, including pleural effusions and empyema, benign and malignant pleural tumors, and especially mesothelioma, helps guide treatment decisions and surgical planning.

 Cancer Chemother Pharmacol. 2008 Apr;61(4):549-58. Epub 2007 May 24.

Preclinical studies of the proteasome inhibitor bortezomib in malignant pleural mesothelioma.

Gordon GJ, Mani M, Maulik G, Mukhopadhyay L, Yeap BY, Kindler HL, Salgia R, Sugarbaker DJ, Bueno R.
The Thoracic Surgery Oncology Laboratory and the Division of Thoracic Surgery, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St., Boston, MA, 02115, USA. ggordon@partners.org

Malignant pleural mesothelioma (MPM) is a highly lethal neoplasm that is resistant to chemotherapy. Bortezomib is an FDA-approved proteasome inhibitor that is currently under clinical investigation in multiple neoplasms but has not been studied extensively in MPM. In this report, we determine the biological and molecular response of cultured MPM cells to bortezomib alone and in combination with cisplatin or pemetrexed. We used four MPM cell lines (MS589, H28, H2052, JMN), a normal mesothelial cell line (HM3), and a lung cancer cell line (H23) in survival studies utilizing bortezomib, cisplatin, and pemetrexed alone and in combination by administering concurrently or by varying the order of administration. We determined the effect of bortezomib on the cell cycle, apoptosis, and on the expression of cell cycle proteins p21/WAF1 and p27/KIP1 and on apoptosis-related proteins IAP-1, IAP-2, survivin, and XIAP. Bortezomib was highly cytotoxic to MPM cells and induced both G(2)/M and G(1)/S cell cycle arrest. Apoptosis increased in a concentration- and time-dependent manner in 3 of 4 MPM cell lines. Bortezomib stabilized or increased protein levels of p21/WAF1 and IAP-1 and to a lesser degree p27/KIP1, IAP-2, XIAP, and survivin. In combination studies with cisplatin, bortezomib was generally synergistic at high concentrations and antagonistic at low concentrations. Bortezomib increased the cytotoxicity of cisplatin and pemetrexed in a concentration-dependent manner when administered prior to either. Bortezomib may improve outcome in MPM patients alone or in combination with standard chemotherapy but the order of administration is likely to be important. This study justifies further evaluation of bortezomib in MPM.

Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3521-6. Epub 2008 Feb 26.

Transcriptome sequencing of malignant pleural mesothelioma tumors.

Sugarbaker DJ, Richards WG, Gordon GJ, Dong L, De Rienzo A, Maulik G, Glickman JN, Chirieac LR, Hartman ML, Taillon BE, Du L, Bouffard P, Kingsmore SF, Miller NA, Farmer AD, Jensen RV, Gullans SR, Bueno R.
International Mesothelioma Program, Division of Thoracic Surgery, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.

Cancers arise by the gradual accumulation of mutations in multiple genes. We now use shotgun pyrosequencing to characterize RNA mutations and expression levels unique to malignant pleural mesotheliomas (MPMs) and not present in control tissues. On average, 266 Mb of cDNA were sequenced from each of four MPMs, from a control pulmonary adenocarcinoma (ADCA), and from normal lung tissue. Previously observed differences in MPM RNA expression levels were confirmed. Point mutations were identified by using criteria that require the presence of the mutation in at least four reads and in both cDNA strands and the absence of the mutation from sequence databases, normal adjacent tissues, and other controls. In the four MPMs, 15 nonsynonymous mutations were discovered: 7 were point mutations, 3 were deletions, 4 were exclusively expressed as a consequence of imputed epigenetic silencing, and 1 was putatively expressed as a consequence of RNA editing. Notably, each MPM had a different mutation profile, and no mutated gene was previously implicated in MPM. Of the seven point mutations, three were observed in at least one tumor from 49 other MPM patients. The mutations were in genes that could be causally related to cancer and included XRCC6, PDZK1IP1, ACTR1A, and AVEN.

Carcinogenesis. 2008 Feb 28. [Epub ahead of print]

Asbestos exposure predicts cell cycle control gene promoter methylation in pleural mesothelioma.

Christensen BC, Godleski JJ, Marsit CJ, Houseman EA, Lopez-Fagundo CY, Longacker JL, Bueno R, Sugarbaker DJ, Nelson HH, Kelsey KT.
Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts 02115.

Malignant pleural mesothelioma (MPM) is a rapidly fatal tumor with increasing incidence world-wide responsible for many thousands of deaths annually. Although there is a clear link between exposure to asbestos and mesothelioma, and asbestos is known to be both clastogenic and cytotoxic to mesothelial cells, the mechanisms of causation of MPM remain largely unknown. However, there is a rapidly emerging literature that describes inactivation of a diverse array of tumor suppressor genes (TSG) via promoter DNA CpG methylation in MPM, although the etiology of these alterations remains unclear. We studied the relationships among promoter methylation silencing, asbestos exposure, patient demographics, and tumor histology using a directed approach; examining six cell cycle control pathway TSGs in an incident case series of 70 MPMs. Promoter hypermethylation of APC, CCND2, CDKN2A, CDKN2B, HPPBP1, and RASSF1 were assessed. We observed significantly higher lung asbestos body burden if any of these cell cycle genes were methylated (p<0.02), and there was a significant trend of increasing asbestos body counts as the number of methylated cell cycle pathway genes increased from 0, to 1, to >1, (p<0.005). This trend of increasing asbestos body count and increasing number of methylated cell cycle pathway genes remained significant (p<0.05) after controlling for age, gender, and tumor histology. These data suggest a novel tumorigenic mechanism of action of asbestos, and may contribute to the understanding of precisely how asbestos exposure influences the etiology and clinical course of malignant mesothelioma.

Eur J Radiol. 2007 Dec;64(3):356-66. Epub 2007 Oct 22.

Morphologic and functional imaging of malignant pleural mesothelioma.

Yamamuro M, Gerbaudo VH, Gill RR, Jacobson FL, Sugarbaker DJ, Hatabu H.
Department of Radiology and Surgery, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.

Malignant pleural mesothelioma (MPM) is an aggressive tumor that arises from the pleura and frequently extends to adjacent structures. MPM cells produce and respond to many angiogenic factors, such as vascular endothelial growth factor (VEGF). VEGF expression in MPM is correlated with microvascular density, which is associated with poor survival. CT has been widely used as the primary imaging modality for the clinical evaluation of MPM. Major findings include nodular pleural thickening, unilateral pleural effusion, and tumor invasion of adjacent structures. CT tends to underestimate early chest wall invasion and peritoneal involvement and has well-known limitations in the evaluation of lymph node metastases. Perfusion CT can evaluate the microvasculature of tumors, while its disadvantages, such as high radiation exposure or side effects from iodinated contrast, limit its use in both research and clinical settings. MRI can provide additional information to CT. Because of its excellent contrast resolution, MRI is superior to CT, both in the differentiation of malignant from benign pleural disease, and in the assessment of chest wall and diaphragmatic involvement. Perfusion MRI is the most promising technique for the assessment of the tumor microvasculature. In MPM, therapeutic effects of chemotherapy can be monitored with perfusion MRI. It has been shown that FDG-PET is useful for the differentiation of benign from malignant lesions, for staging and monitoring metabolic response to therapy against MPM, and that it has prognostic value. An initial report on PET/CT imaging of MPM has shown increased accuracy of overall staging, improving the assessment of tumor resectability. PET/CT seems to be superior to other imaging modalities in detecting more extensive disease involvement, and identifying unsuspected occult distant metastases.

Int J Radiat Oncol Biol Phys. 2007 Aug 1;68(5):1366-74.

Influence of radiotherapy technique and dose on patterns of failure for mesothelioma patients after extrapleural pneumonectomy.

Allen AM, Den R, Wong JS, Zurakowski D, Soto R, Jänne PA, Zellos L, Bueno R, Sugarbaker DJ, Baldini EH.

Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. aallen@lroc.harvard.edu

PURPOSE: Extrapleural pneumonectomy (EPP) is an effective treatment of malignant pleural mesothelioma. We compared the outcomes after moderate-dose hemithoracic radiotherapy (MDRT) and high-dose hemithoracic RT (HDRT) after EPP for malignant pleural mesothelioma. METHODS AND MATERIALS: Between July 1994 and April 2004, 39 patients underwent EPP and adjuvant RT at Dana-Farber Cancer Institute/Brigham and Women's Hospital. Between 1994 and 2002, MDRT, including 30 Gy to the hemithorax, 40 Gy to the mediastinum, and boosts to positive margins or nodes to 54 Gy, was given, generally with concurrent chemotherapy. In 2003, HDRT to 54 Gy with a matched photon/electron technique was given, with sequential chemotherapy. RESULTS: A total of 39 patients underwent RT after EPP. The median age was 59 years (range, 44-77). The histologic type was epithelial in 25 patients (64%) and mixed or sarcomatoid in 14 patients (36%). Of the 39 patients, 24 underwent MDRT and 15 (39%) HDRT. The median follow-up was 23 months (range, 6-71). The median overall survival was 19 months (95% confidence interval, 14-24). The median time to distant failure (DF) and local failure (LF) was 20 months (95% confidence interval, 14-26) and 26 months (95% confidence interval, 16-36), respectively. On univariate and multivariate analyses, only a mixed histologic type was predictive of inferior DF (p <0.006) and overall survival (p <0.004). The RT technique was not predictive of LF, DF, or overall survival. The LF rate was 50% (12 of 24) after MDRT and 27% (4 of 15) after HDRT (p = NS). Four patients who had undergone HDRT were alive and without evidence of disease at the last follow-up. CONCLUSIONS: High-dose hemithoracic RT appears to limit in-field LF compared with MDRT. However, DF remains a significant challenge, with one-half of our patients experiencing DF.

 J Pathol. 2007 Mar;211(4):439-46

Inhibitor of apoptosis proteins are regulated by tumour necrosis factor-alpha in malignant pleural mesothelioma.

Gordon GJ, Mani M, Mukhopadhyay L, Dong L, Yeap BY, Sugarbaker DJ, Bueno R.

The Thoracic Surgery Oncology Laboratory and the Division of Thoracic Surgery, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St, Boston, MA 02115, USA. ggordon@partners.org

Inhibitor of apoptosis proteins (IAPs) are overexpressed by most neoplasms and promote tumour cell survival after a wide variety of apoptotic stimuli elicited via intrinsic (ie mitochondrial) and extrinsic (ie death receptor) pathways. It has previously been reported that one of these proteins, IAP-1(MIHC/cIAP2), is overexpressed in malignant pleural mesothelioma (MPM) and is responsible for a large degree of the resistance of cultured MPM cells to cisplatin. Subsequent analysis in a larger number of human tumours revealed that additional IAPs (eg IAP-2/MIHB/cIAP1, livin/ML-IAP/KIAP, survivin, and XIAP/MIHA/hILP) are also overexpressed in MPM and, with the exception of IAP-2, have expression patterns that correlate with prognosis. In the present study, potential regulatory mechanisms of IAP genes in MPM were investigated and it was found that tumour necrosis factor-alpha (TNF-alpha) can increase mRNA and protein levels of IAP-1, IAP-2, and XIAP, but not livin or survivin in MPM cell lines (n=4). It was also found that IAP gene expression levels are increased concomitantly with translocation to the nucleus of the TNF-responsive transcription factor NF-kappaB. Co-incubation of MPM cells with TNF-alpha and pyrrolidine dithiocarbamate (PDTC), an NF-kappaB inhibitor, prevented TNF-mediated up-regulation of IAP gene expression levels. In survival studies, TNF-alpha was not toxic to MPM cells at any concentration examined. However, MPM cells exposed to TNF-alpha were twice as resistant to cisplatin in dose response survival assays compared with unstimulated controls and were found to have a significantly greater fraction of surviving cells at multiple cisplatin concentrations (p<0.0087). Finally, it was found that levels of circulating TNF-alpha were statistically significantly (p=0.031) (median 312.5 pg/ml) higher in MPM patients (n=6) prior to surgical tumour debulking compared with those after surgery (median 0 pg/ml). These results when combined with previous observations by our laboratory and others strongly suggest that IAPs act synergistically with TNF family members to promote survival of MPM tumour cells after exposure to cisplatin and possibly other chemotherapeutic drugs. Copyright (c) 2007 Pathological Society of Great Britain and Ireland.

J Pathol. 2007 Mar;211(4):447-54.

Expression patterns of inhibitor of apoptosis proteins in malignant pleural mesothelioma.

Gordon GJ, Mani M, Mukhopadhyay L, Dong L, Edenfield HR, Glickman JN, Yeap BY, Sugarbaker DJ, Bueno R.

The Thoracic Surgery Oncology Laboratory and the Division of Thoracic Surgery, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St, Boston, MA 02115, USA. ggordon@partners.org

Inhibitor of apoptosis proteins (IAPs) comprise a family of structurally similar proteins, five of which are widely studied in the context of cancer: IAP-1/MIHC/cIAP2, IAP-2/MIHB/cIAP1, livin/ML-IAP/KIAP, survivin, and XIAP/MIHA/hILP. IAPs are overexpressed by most neoplasms, promote tumour cell survival after a wide variety of apoptotic stimuli, and frequently have gene and/or protein expression patterns associated with a relatively poor prognosis. However, many IAPs are also expressed by normal tissues, can facilitate apoptotic cell death, and have expression patterns associated with a relatively favourable prognosis in some cases. The result is that the precise role(s) of IAPs in human tumours is not exactly known. It has been previously reported that IAP-1 is overexpressed in malignant pleural mesothelioma (MPM) and is responsible for a large degree of the resistance of cultured MPM cells to cisplatin. Given the high homology of IAP family members, it is likely that other IAPs will be important in MPM. In the present study, the gene and protein expression patterns of IAP-1, IAP-2, survivin, livin, and XIAP have been determined in MPM cell lines (n=9) and a large number of MPM tumours using high-density oligonucleotide microarrays (n=40) and an MPM tissue array (n=66). Human tumours were linked to clinical data and it was found that IAP-1 and survivin mRNA expression patterns were associated with a relatively shorter patient survival, while those of XIAP and livin were associated with a relatively longer patient survival. Abundant protein for all IAPs was also detected in MPM tumours, where they were expressed primarily in the cytoplasm. Only IAP-1 and livin protein was expressed in the nucleus of MPM tumours. These results provide the rationale for additional study of this gene family in MPM and cancer in general. Copyright (c) 2007 Pathological Society of Great Britain and Ireland.

 Int J Radiat Oncol Biol Phys. 2006 Jul 1;65(3):640-5.

Fatal pneumonitis associated with intensity-modulated radiation therapy for mesothelioma.

Allen AM, Czerminska M, Jänne PA, Sugarbaker DJ, Bueno R, Harris JR, Court L, Baldini EH.

Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA, USA. aallen@lroc.harvard.edu

PURPOSE: To describe the initial experience at Dana-Farber Cancer Institute/Brigham and Women's Hospital with intensity-modulated radiation therapy (IMRT) as adjuvant therapy after extrapleural pneumonectomy (EPP) and adjuvant chemotherapy. METHODS AND MATERIALS: The medical records of patients treated with IMRT after EPP and adjuvant chemotherapy were retrospectively reviewed. IMRT was given to a dose of 54 Gy to the clinical target volume in 1.8 Gy daily fractions. Treatment was delivered with a dynamic multileaf collimator using a sliding window technique. Eleven of 13 patients received heated intraoperative cisplatin chemotherapy (225 mg/m(2)). Two patients received neoadjuvant intravenous cisplatin/pemetrexed, and 10 patients received adjuvant cisplatin/pemetrexed chemotherapy after EPP but before radiation therapy. All patients received at least 2 cycles of intravenous chemotherapy. The contralateral lung was limited to a V20 (volume of lung receiving 20 Gy or more) of 20% and a mean lung dose (MLD) of 15 Gy. All patients underwent fluorodeoxyglucose positron emission tomography (FDG-PET) for staging, and any FDG-avid areas in the hemithorax were given a simultaneous boost of radiotherapy to 60 Gy. Statistical comparisons were done using two-sided t test. RESULTS: Thirteen patients were treated with IMRT from December 2004 to September 2005. Six patients developed fatal pneumonitis after treatment. The median time from completion of IMRT to the onset of radiation pneumonitis was 30 days (range 5-57 days). Thirty percent of patients (4 of 13) developed acute Grade 3 nausea and vomiting. One patient developed acute Grade 3 thrombocytopenia. The median V20, MLD, and V5 (volume of lung receiving 5 Gy or more) for the patients who developed pneumonitis was 17.6% (range, 15.3-22.3%), 15.2 Gy (range, 13.3-17 Gy), and 98.6% (range, 81-100%), respectively, as compared with 10.9% (range, 5.5-24.7%) (p = 0.08), 12.9 Gy (range, 8.7-16.9 Gy) (p = 0.07), and 90% (range, 66-98.3%) (p = 0.20), respectively, for the patients who did not develop pneumonitis. CONCLUSIONS: Intensity-modulated RT treatment for mesothelioma after EPP and adjuvant chemotherapy resulted in a high rate of fatal pneumonitis when standard dose parameters were used. We therefore recommend caution in the utilization of this technique. Our data suggest that with IMRT, metrics such as V5 and MLD should be considered in addition to V20 to determine tolerance levels in future patients.

PMID: 16751058 [PubMed - indexed for MEDLINE]

 J Clin Oncol. 2006 Apr 1;24(10):1561-7.

Phase I to II study of pleurectomy/decortication and intraoperative intracavitary hyperthermic cisplatin lavage for mesothelioma.

Richards WG, Zellos L, Bueno R, Jaklitsch MT, Jänne PA, Chirieac LR, Yeap BY, Dekkers RJ, Hartigan PM, Capalbo L, Sugarbaker DJ.

Brigham and Women's Hospital, Boston, MA 02115, USA.

PURPOSE: To evaluate morbidity, mortality, maximum-tolerated dose (MTD), and outcome of intraoperative intracavitary hyperthermic cisplatin lavage in patients undergoing pleurectomy for malignant pleural mesothelioma (MPM). PATIENTS AND METHODS: Sixty-one patients were prospectively registered. Forty-four resectable patients with MPM underwent pleurectomy, followed by a 1-hour lavage of the resection cavity with dose-escalated cisplatin (50, 100, 150, 175, 200, 225, and 250 mg/m2) at 42 degrees C and then intravenous sodium thiosulfate (16 g/m2 over 6 hours). Survival estimates were compared using the log-rank test and proportional hazards regression. RESULTS: Median age was 71 years (range, 50 to 82 years). Twenty-four patients had epithelial tumors, and 20 had sarcomatous or mixed histology. Postoperative mortality was 11% (five of 44 patients). Dose-limiting renal toxicity occurred at 250 mg/m2, establishing the MTD at 225 mg/m2. Other morbidity included atrial fibrillation (14 of 44 patients, 32%) and deep venous thrombosis (four of 44 patients, 9%). Median survival time of all registered patients was 9 months, and the median survival time of resected patients was 13 months. Survival estimates differed significantly for resectable patients exposed to low doses (50 to 150 mg/m2; n = 9; median, 6 months) versus high doses (175 to 250 mg/m2; n = 35; median, 18 months) of hyperthermic cisplatin (P = .0019); recurrence-free interval also differed significantly (4 v 9 months, respectively; P < .0001). Low dose level (relative risk = 3.418) and nonepithelial histology (relative risk = 2.336) were independent risk factors for poor survival. Twenty patients with epithelial tumors who underwent high-dose cisplatin lavage had a 26-month median survival time. CONCLUSION: Pleurectomy and high-dose intraoperative intracavitary hyperthermic cisplatin lavage is feasible in this patient population with restricted surgical options. An apparent dose-related survival benefit warrants further study.

J Thorac Oncol. 2006 Feb;1(2):175-6.

Macroscopic complete resection: the goal of primary surgery in multimodality therapy for pleural mesothelioma.

Sugarbaker DJ.

Department of Surgery, Division of Thoracic Surgery, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. dsugarbaker@partners.org

 Cancer Res. 2006 Jan 1;66(1):352-61.

Functional analysis of c-Met/hepatocyte growth factor pathway in malignant pleural mesothelioma.

Jagadeeswaran R, Ma PC, Seiwert TY, Jagadeeswaran S, Zumba O, Nallasura V, Ahmed S, Filiberti R, Paganuzzi M, Puntoni R, Kratzke RA, Gordon GJ, Sugarbaker DJ, Bueno R, Janamanchi V, Bindokas VP, Kindler HL, Salgia R.

Section of Hematology/Oncology, Department of Medicine, University of Chicago Cancer Research Center, University of Chicago Medical Center, Pritzker School of Medicine, Chicago, Illinois 60637, USA.

c-Met receptor tyrosine kinase (RTK) has not been extensively studied in malignant pleural mesothelioma (MPM). In this study, c-Met was overexpressed and activated in most of the mesothelioma cell lines tested. Expression in MPM tissues by immunohistochemistry was increased (82%) in MPM in general compared with normal. c-Met was internalized with its ligand hepatocyte growth factor (HGF) in H28 MPM cells, with robust expression of c-Met. Serum circulating HGF was twice as high in mesothelioma patients as in healthy controls. There was a differential growth response and activation of AKT and extracellular signal-regulated kinase 1/2 in response to HGF for the various cell lines. Dose-dependent inhibition (IC50 < 2.5 micromol/L) of cell growth in mesothelioma cell lines, but not in H2052, H2452, and nonmalignant MeT-5A (IC50 > 10 micromol/L), was observed with the small-molecule c-Met inhibitor SU11274. Furthermore, migration of H28 cells was blocked with both SU11274 and c-Met small interfering RNA. Abrogation of HGF-induced c-Met and downstream signaling was seen in mesothelioma cells. Of the 43 MPM tissues and 7 cell lines, we have identified mutations within the semaphorin domain (N375S, M431V, and N454I), the juxtamembrane domain (T1010I and G1085X), and an alternative spliced product with deletion of the exon 10 of c-Met in some of the samples. Interestingly, we observed that the cell lines H513 and H2596 harboring the T1010I mutation exhibited the most dramatic reduction of cell growth with SU11274 when compared with wild-type H28 and nonmalignant MeT-5A cells. Ultimately, c-Met would be an important target for therapy against MPM.

Clin Cancer Res. 2005 Jun 15;11(12):4406-14.

Validation of genomics-based prognostic tests in malignant pleural mesothelioma.

Gordon GJ, Rockwell GN, Godfrey PA, Jensen RV, Glickman JN, Yeap BY, Richards WG, Sugarbaker DJ, Bueno R.

Thoracic Surgery Oncology Laboratory and Division of Thoracic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. ggordon@partners.org

PURPOSE: Malignant pleural mesothelioma (MPM) is a highly lethal neoplasm with limited pretreatment prognostication strategies. In this report, we examine the accuracy of a previously proposed prognostic test in an independent cohort of MPM patients. This test uses simple ratios of gene expression levels to provide a novel prognostication scheme. EXPERIMENTAL DESIGN: Gene expression data using high-density oligonucleotide microarrays (approximately 22,000 genes) were obtained for a new cohort of human MPM tumors from patients undergoing similar treatments (n = 39). The relative expression levels for specific genes were also determined using real-time quantitative reverse transcription-PCR. We also used a subset of these tumors associated with widely divergent patient survival (n = 23) as a training set to identify new treatment-specific candidate prognostic molecular markers and gene ratio-based prognostic tests. The predictive nature of these newly discovered markers and gene ratio-based prognostic tests were then examined in an independent group of tumors (n = 52) using microarray data and quantitative reverse transcription-PCR. RESULTS: Previously described MPM prognostic genes and gene ratio-based prognostic tests predicted clinical outcome in 39 independent MPM tumor specimens in a statistically significant manner. Newly discovered treatment-specific prognostic genes and gene ratio-based prognostic tests were highly accurate and statistically significant when examined in an independent group of 52 tumors from patients undergoing similar treatment. CONCLUSIONS: The data support the use of gene ratios in translating gene expression data into easily reproducible, statistically validated clinical tests for the prediction of outcome in MPM.

 Am J Pathol. 2005 Jun;166(6):1827-40.

Identification of novel candidate oncogenes and tumor suppressors in malignant pleural mesothelioma using large-scale transcriptional profiling.

Gordon GJ, Rockwell GN, Jensen RV, Rheinwald JG, Glickman JN, Aronson JP, Pottorf BJ, Nitz MD, Richards WG, Sugarbaker DJ, Bueno R.

Thoracic Surgery Oncology Laboratory, Division of Thoracic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. ggordon@partners.org

Malignant pleural mesothelioma (MPM) is a highly lethal, poorly understood neoplasm that is typically associated with asbestos exposure. We performed transcriptional profiling using high-density oligonucleotide microarrays containing approximately 22,000 genes to elucidate potential molecular and pathobiological pathways in MPM using discarded human MPM tumor specimens (n = 40), normal lung specimens (n = 4), normal pleura specimens (n = 5), and MPM and SV40-immortalized mesothelial cell lines (n = 5). In global expression analysis using unsupervised clustering techniques, we found two potential subclasses of mesothelioma that correlated loosely with tumor histology. We also identified sets of genes with expression levels that distinguish between multiple tumor subclasses, normal and tumor tissues, and tumors with different morphologies. Microarray gene expression data were confirmed using quantitative reverse transcriptase-polymerase chain reaction and protein analysis for three novel candidate oncogenes (NME2, CRI1, and PDGFC) and one candidate tumor suppressor (GSN). Finally, we used bioinformatics tools (ie, software) to create and explore complex physiological pathways. Combined, all of these data may advance our understanding of mesothelioma tumorigenesis, pathobiology, or both.

N Engl J Med. 2005 May 5;352(18):1929-30.

Cardiac sarcoma 14 years after treatment for pleural mesothelioma.

Neragi-Miandoab S, Gangadharan SP, Sugarbaker DJ.

 AJR Am J Roentgenol. 2005 Feb;184(2):381-90.

Radiofrequency ablation of thoracic lesions: part 2, initial clinical experience--technical and multidisciplinary considerations in 30 patients.

VanSonnenberg E, Shankar S, Morrison PR, Nair RT, Silverman SG, Jaklitsch MT, Liu F, Cheung L, Tuncali K, Skarin AT, Sugarbaker DJ.

Department of Radiology, Brigham and Women's Hospital, Boston, MA 02115, USA. ericvansonnenberg@yahoo.com

OBJECTIVE: The purpose of our study was to report our initial experience with patients who underwent percutaneous imaging-guided radiofrequency ablation of thoracic lesions, and to emphasize technical and multidisciplinary issues and adjunctive procedures specific to thoracic tumor ablation. MATERIALS AND METHODS: Our cohort consisted of 30 patients with a spectrum of primary (n=18) and secondary (n=11) lung tumors, mesothelioma (n=1), and five secondarily eroded, painful ribs who underwent ablation of 36 total lesions (one patient had two ablations). Patients either were nonsurgical candidates because of medical comorbidities or extent of disease, or had exhausted chemotherapy and radiation therapy options, or had refused surgery or undergone unsuccessful surgery. Patients were treated with radiofrequency ablation after agreement among oncologists, thoracic surgeons, and interventional radiologists. An array-style electrode under impedance control was used to treat 29 thoracic tumors and the adjacent rib metastases (n=5). A cool-tip radiofrequency probe was used for two patients. CT guidance and general anesthetic were used for all but one patient. Sonographic guidance and IV conscious sedation were used in one patient. Pain (n=11) and tumor cure or control (n=19) were the primary indications for the procedures. Adjunctive procedures to the radiofrequency ablations included the creation of saline or water windows (n=3); establishment of transosseous and transchondral routes (n=4); use of intercostal and paravertebral nerve blocks (n=15); and use of an intraprocedural catheter (n=1), needle (n=1), or sheath (n=3) for treatment of pneumothoraces. Follow-up was from 2 to 26 months. RESULTS: All ablations were technically successful. No periprocedural mortality occurred. Necrosis of tumor was greater than 90% in 26 of 30 lesions based on short-term follow-up imaging (CT, PET, MRI). In the 11 patients who underwent ablation for pain, relief was complete in four and partial in the other seven. One patient developed a local skin burn, four patients had self-limited hemoptysis up to 4 days after ablation, one had transient atrial fibrillation, one developed hoarseness, and two patients were transiently reintubated after extubation. Eight pneumothoraces developed; one patient underwent placement of a chest tube. Four patients died within 1 year of ablation from extrathoracic spread of tumor. CONCLUSION: Radiofrequency ablation for a variety of thoracic tumors can be performed safely and with a high degree of efficacy for pain control and tumor killing. The effect of ablation can be assessed with CT, MRI, or PET. Various technical issues differentiate thoracic tumor ablation from standard abdominal ablations. Numerous other thoracic interventional radiology procedures are beneficial to assist the radiofrequency ablation. A multidisciplinary approach offers valuable expertise for patient care.

Ann Thorac Surg. 2004 Nov;78(5):1774-6.

Pleural biopsy: a reliable method for determining the diagnosis but not subtype in mesothelioma.

Bueno R, Reblando J, Glickman J, Jaklitsch MT, Lukanich JM, Sugarbaker DJ.

Division of Thoracic Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA. rbueno@partners.org

BACKGROUND: Survival after tri-modality therapy with extrapleural pneumonectomy (EPP) and postoperative chemoradiotherapy is longer for patients with epithelial MPM versus mixed or sarcomatoid subtypes, leading some to decline aggressive therapy for patients with nonepithelial histology. However, pathologic diagnosis of malignant pleural mesothelioma (MPM) and subclassification into one of the three histologic subtypes (epithelial, mixed, sarcomatoid) can be challenging. Pleural biopsy has been proposed as the diagnostic gold standard. We investigated the accuracy of open pleural biopsy for diagnosis and subtype identification in MPM. METHODS: Patients with suspected MPM routinely undergo open pleural biopsy to establish diagnosis. Those diagnosed definitively by pleural biopsy or cytology are offered pleurectomy or EPP dependent on stage and cardiorespiratory status. We reviewed medical records for all patients undergoing EPP at our institution, comparing tissue and subtype diagnosis at initial diagnostic biopsy versus definitive resection. RESULTS: Between 1988 and 2000, 305 of 332 consecutive patients undergoing EPP had MPM. One patient diagnosed with MPM at pleural biopsy was misclassified. Subtype analysis at pleural biopsy proved correct in 80% (226/282). Most patients (174/192) with epithelial subtype at final diagnosis were diagnosed correctly at pleural biopsy. However, 44% (45/103) with pathologic diagnosis of nonepithelial subtype at resection were initially misdiagnosed with the epithelial subtype. The sensitivity of pleural biopsy for epithelial MPM was 97% with a specificity of 56%. CONCLUSIONS: Open pleural biopsy is accurate and should be considered the gold standard diagnostic method for MPM. It is less sensitive for determining histologic subclass, particularly with nonepithelial subtypes.

Thorac Surg Clin. 2004 Nov;14(4):549-56.

Innovative therapies: intraoperative intracavitary chemotherapy.

Chang MY, Sugarbaker DJ.

Division of Thoracic Surgery, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.

Both phase I studies demonstrated that high-dose cisplatin can be delivered safely with acceptable complication rates. The maximum tolerated doses of 225 mg/m2 and 250 mg/m2 cisplatin, respectively, are higher than any other published report of intrapleural cisplatin. The intrapleural cisplatin doses reported in other trials have been 80 mg/m2, 100 mg/m2, and 200 mg/m2. Despite the use of high-dose intraoperative chemotherapy, the group of 50 patients who underwent EPP experienced mortality and morbidity comparable to the contemporaneous group of 41 patients who did not participate in the protocol, except for increased rates of deep venous thrombosis and diaphragmatic patch failure. The 44 patients who underwent P/D experienced a slightly higher mortality rate and creatinine toxicity rate than the first phase I trial. Given the demographics of this patient cohort (higher age, lower FEV1, and inability to withstand pneumonectomy because of limited cardiopulmonary reserve), however, the mortality and morbidity rates seem acceptable. The pharmacologic data from both studies support our hypothesis that high regional doses of cisplatin can be delivered with less systemic absorption than can be achieved with intravenous administration (data not shown). With the maximum tolerated dose of intracavitary cisplatin and safety of intraoperative administration after surgical resection firmly established by these phase I trials, we are prepared to implement phase II and III studies of EPP and P/D with intraoperative cisplatin lavage. We aim to monitor tumor recurrence and patient survival prospectively and compare these results with historic controls. We also intend to document prospectively the morbidity and mortality of the treatment protocols. Finally, we plan to evaluate the pharmacokinetics of cisplatin by measuring tissue and perfusate levels of active and inactive cisplatin. By approaching the problem of local recurrence after resection of MPM in a careful and methodical manner, we hope to decrease or delay the rate of recurrence and potentially improve longterm survival in patients with this lethal disease.

Thorac Surg Clin. 2004 Nov;14(4):523-30.

Extrapleural pneumonectomy for diffuse malignant pleural mesothelioma: techniques and complications.

Chang MY, Sugarbaker DJ.

Division of Thoracic Surgery, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.

Innovative therapeutic agents and strategies are being investigated to improve survival with this lethal disease. New chemotherapy agents, including gemcitabine (Eli Lilly and Company; Indianapolis, Indiana) and pemtrexed (Eli Lilly and Company) show promise against mesothelioma. Kaiser has reported using novel therapies, such as cytokines and suicide gene therapy, to target mesothelioma. Pass et al , Moskal et al , Schouwink et al , and Friedberg et al have applied photodynamic therapy to the hemithorax after surgical resection. Because recurrence of mesothelioma after surgical resections tends be locoregional rather than distant , strategies to improve local control may be beneficial. Several groups, including our Brigham and Women's Hospital Thoracic Surgery Division and Dana Farber Thoracic Oncology Program, are investigating intraoperative intracavitary lavage of hyperthermic chemotherapy immediately after EP (discussed elsewhere in this issue). Although mesothelioma remains a difficult disease to treat, the techniques of surgical resection for mesothelioma have improved dramatically. Currently, EPP can be performed with acceptable morbidity and mortality at experienced centers.

 Thorac Surg Clin. 2004 Nov;14(4):435-45.

Malignant pleural mesothelioma: overview of the North American and European experience.

Kukreja J, Jaklitsch MT, Wiener DC, Sugarbaker DJ, Burgers S, Baas P.

Division of Thoracic Surgery, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.

MPM is an uncommon disease with limited treatment options. Early diagnosis, a standardized staging system, early referral to centers experienced in MPM, and efforts to develop collaborative multicenter trials are essential to improving treatment for patients with MPM. Efforts to manage this malignancy, which is projected to peak in the twenty-first century, constitute an important international health concern, particularly because the use of asbestos, despite successful regulatory efforts in many parts of the world, continues unabated in others.

J Thorac Cardiovasc Surg. 2004 Jul;128(1):138-46.

Prevention, early detection, and management of complications after 328 consecutive extrapleural pneumonectomies.

Sugarbaker DJ, Jaklitsch MT, Bueno R, Richards W, Lukanich J, Mentzer SJ, Colson Y, Linden P, Chang M, Capalbo L, Oldread E, Neragi-Miandoab S, Swanson SJ, Zellos LS.

Division of Thoracic Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA. dsugarbaker@partners.org

OBJECTIVE: Extrapleural pneumonectomy for therapy of mesothelioma has been associated with significant perioperative mortality and morbidity. Postoperative complications of this procedure require a unique management approach. We developed treatment algorithms for most of the common complications of extrapleural pneumonectomy resulting in reduced mortality and hospital stay. Complications after extrapleural pneumonectomy were further analyzed to elucidate means of prevention, early detection, and treatment. METHODS: A total of 496 patients undergoing extrapleural pneumonectomy were reviewed for mortality rates, with a subset of 328 consecutive patients between 1980 and 2000 who were examined for detailed morbidity data by using a prospective clinical database. RESULTS: Median age was 58 years (range, 28-77 years), with a 10-day (range, 4-101 days) median length of stay. One hundred ninety-eight (60.4%) of 328 patients experienced minor and major complications, and 11 of 328 patients died, for an overall mortality rate of 3.4%. Complications included the following: atrial fibrillation (145 [44.2%]), prolonged intubation (26 [7.9%]), vocal cord paralysis (22 [6.7%]), deep vein thrombosis (21 [6.4%]), technical complications (patch dehiscence, hemorrhage, or both; 20 [6.1%]), tamponade (12 [3.6%]), acute respiratory distress syndrome (12 [3.6%]), cardiac arrest (10 [3%]), constrictive physiology (9 [2.7%]), aspiration (9 [2.7%]), renal failure (9 [2.7%]), empyema (8 [2.4%]), tracheostomy (6 [1.8%]), myocardial infarction (5 [1.5%]), pulmonary embolus (5 [1.5%]), and bronchopleural fistula (2 [0.6%]). Clinical data demonstrated the following: (1) prophylaxis for atrial fibrillation is recommended; (2) early ambulation, aspiration precautions, endoscopic assessment of the vocal cords, and avoidance of fluid overload are crucial; (3) perioperative diagnosis and aggressive management of deep vein thrombosis are important; (4) immediate reoperation and open cardiac massage are essential for relief of cardiac herniation and tamponade from cardiac patch dysfunction; (5) diaphragmatic patch dehiscence, hemorrhage, or both require immediate reoperation; (6) early signs of infection might indicate bronchopleural fistula or empyema and should be treated with thoracoscopic or open drainage and staged removal of patch material; and (7) excessive perioperative mediastinal shift is treated with a catheter placed intraoperatively. CONCLUSION: Complications after extrapleural pneumonectomy require a unique approach to management, and mortality can be minimized by early detection and aggressive treatment.

Thorax. 2003 Dec;58(12):1077-82.

Metabolic significance of the pattern, intensity and kinetics of 18F-FDG uptake in malignant pleural mesothelioma.

Gerbaudo VH, Britz-Cunningham S, Sugarbaker DJ, Treves ST.

Division of Nuclear Medicine, Department of Radiology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. vgerbaudo@bics.bwh.harvard.edu

BACKGROUND: Malignant pleural mesothelioma is an aggressive neoplasm with a highly variable course. This pilot study evaluated the significance of the pattern, intensity and kinetics of 18F-FDG uptake in mesothelioma in the context of histopathology and surgical staging. METHODS: Sixteen consecutive patients with pleural disease on CT scan underwent 18F-FDG imaging. Imaging was performed with a dual detector gamma camera operating in coincidence mode. Semiquantitative image analysis was performed by obtaining lesion-to-background ratios (18F-FDG uptake index) and calculating the increment of 18F-FDG lesion uptake over time (malignant metabolic potential index (MMPi)). RESULTS: Twelve patients had histologically proven malignant mesotheliomas (10 epithelial, two sarcomatoid). Thirty two lesions were positive for tumour. Patterns of uptake matched the extent of pleural and parenchymal involvement observed on CT scanning and surgery. Mean (SD) 18F-FDG uptake index for malignant lesions was 3.99 (1.92), range 1.5-9.46. Extrathoracic spread and metastases had higher 18F-FDG uptake indices (5.17 (2)) than primary (3.42 (1.52)) or nodal lesions (2.99 (1)). No correlation was found between histological grade and stage. The intensity of lesion uptake had poor correlation with histological grade but good correlation with surgical stage. 18F-FDG lesion uptake increased over time at a higher rate in patients with more advanced disease. The MMPi was a better predictor of disease aggressiveness than the histological grade. CONCLUSIONS: This pilot study suggests that the pattern, intensity, and kinetics of 18F-FDG uptake in mesothelioma are good indicators of tumour aggressiveness and are superior to the histological grade in this regard.

J Natl Cancer Inst. 2003 Apr 16;95(8):598-605.

Using gene expression ratios to predict outcome among patients with mesothelioma.

Gordon GJ, Jensen RV, Hsiao LL, Gullans SR, Blumenstock JE, Richards WG, Jaklitsch MT, Sugarbaker DJ, Bueno R.

Division of Thoracic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

BACKGROUND: We have recently demonstrated that simple ratios of the expression levels of selected genes in tumor samples can be used to distinguish among types of thoracic malignancies. We examined whether this technique could predict treatment-related outcome for patients with mesothelioma. METHODS: We used gene expression profiling data previously collected from 17 mesothelioma patients with different overall survival times to define two outcome-related groups of patients and to train an expression ratio-based outcome predictor model. A Student's t test was used to identify genes among the two outcome groups that had statistically significant, inversely correlated expression levels; those genes were used to form prognostic expression ratios. We used a combination of several highly accurate expression ratios and cross-validation techniques to assess the internal consistency of this predictor model, quantitative reverse transcription-polymerase chain reaction of tumor RNA to confirm the microarray data, and Kaplan-Meier survival analysis to validate the model among an independent set of 29 mesothelioma tumors. All statistical tests were two-sided. RESULTS: We developed an expression ratio-based test capable of identifying 100% (17/17) of the samples used to train the model. This test remained highly accurate (88%, 15/17) after cross-validation. A four-gene expression ratio test statistically significantly (P =.0035) predicted treatment-related patient outcome in mesothelioma independent of the histologic subtype of the tumor. CONCLUSIONS: Gene expression ratio-based analysis accurately predicts treatment-related outcome in mesothelioma samples. This technique could impact the clinical treatment of mesothelioma by allowing the preoperative identification of patients with widely divergent prognoses.

Chest. 2002 Dec;122(6):2256-9.

Cardiac decortication (epicardiectomy) for occult constrictive cardiac physiology after left extrapleural pneumonectomy.

Byrne JG, Karavas AN, Colson YL, Bueno R, Richards WG, Sugarbaker DJ, Goldhaber SZ.

Cardiac Surgery, Brigham and Women's Hospital, 75 Francis Street, Boston, MA, USA. jbyrne@partners.org

Constrictive cardiac physiology typically does not occur in the absence of parietal pericardium. However, we report eight patients who, after left extrapleural pneumonectomy and removal of the parietal pericardium for malignancy, presented with dyspnea, jugular venous distension, and peripheral or generalized edema unresponsive to diuretics. Cardiac decortication (epicardiectomy) was performed whereby a thickened peel encasing the heart was surgically excised, resulting in vigorous contraction and expansion of the heart. In one patient, decortication occurred early after pneumonectomy and was incomplete. Acute signs of inflammation were present, and recurrence necessitated repeat decortication. When patients present with dyspnea, hepatojugular reflux, and peripheral edema refractory to diuretics, constrictive cardiac physiology should be considered in the differential diagnosis, even in the absence of parietal pericardium.

 Cancer Res. 2002 Sep 1;62(17):4963-7.

Translation of microarray data into clinically relevant cancer diagnostic tests using gene expression ratios in lung cancer and mesothelioma.

Gordon GJ, Jensen RV, Hsiao LL, Gullans SR, Blumenstock JE, Ramaswamy S, Richards WG, Sugarbaker DJ, Bueno R.

Division of Thoracic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

The pathological distinction between malignant pleural mesothelioma (MPM)and adenocarcinoma (ADCA) of the lung can be cumbersome using established methods. We propose that a simple technique, based on the expression levels of a small number of genes, can be useful in the early and accurate diagnosis of MPM and lung cancer. This method is designed to accurately distinguish between genetically disparate tissues using gene expression ratios and rationally chosen thresholds. Here we have tested the fidelity of ratio-based diagnosis in differentiating between MPM and lung cancer in 181 tissue samples (31 MPM and 150 ADCA). A training set of 32 samples (16 MPM and 16 ADCA) was used to identify pairs of genes with highly significant, inversely correlated expression levels to form a total of 15 diagnostic ratios using expression profiling data. Any single ratio of the 15 examined was at least 90% accurate in predicting diagnosis for the remaining 149 samples (e.g., test set). We then examined (in the test set) the accuracy of multiple ratios combined to form a simple diagnostic tool. Using two and three expression ratios, we found that the differential diagnoses of MPM and lung ADCA were 95% and 99% accurate, respectively. We propose that using gene expression ratios is an accurate and inexpensive technique with direct clinical applicability for distinguishing between MPM and lung cancer. Furthermore, we provide evidence suggesting that this technique can be equally accurate in other clinical scenarios.

 J Nucl Med. 2002 Sep;43(9):1144-9.

Assessment of malignant pleural mesothelioma with (18)F-FDG dual-head gamma-camera coincidence imaging: comparison with histopathology.

Gerbaudo VH, Sugarbaker DJ, Britz-Cunningham S, Di Carli MF, Mauceri C, Treves ST.

Division of Nuclear Medicine, Department of Radiology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. vgerbaudo@bics.bwh.harvard.edu

Malignant pleural mesothelioma is an aggressive primary neoplasm for which early detection and accurate staging are known diagnostic challenges. The role of (18)F-FDG dual-head gamma-camera coincidence imaging ((18)F-FDG-CI) is yet to be defined. The purpose of this study was to evaluate the usefulness of (18)F-FDG-CI in the assessment of malignant pleural mesothelioma using histopathology as the gold standard. METHODS: Fifteen consecutive patients with CT scan evidence of pleural thickening, fluid, plaques, or calcification underwent (18)F-FDG imaging 1.5 h after the intravenous administration of 370 MBq (18)F-FDG. Imaging was performed with a dual-head gamma camera equipped with 2.54-cm-thick NaI crystals operating in coincidence mode. Using an iterative algorithm, whole-body images were reconstructed as transaxial, sagittal, and coronal images. No attenuation correction was applied. The results of (18)F-FDG-CI scans were compared with CT and with histopathologic diagnosis. RESULTS: Eleven of 15 patients had histologically proven malignant mesotheliomas (10 epithelial, 1 sarcomatoid). All 11 primary tumors were detected by (18)F-FDG, and absence of disease was confirmed in the 4 patients who were disease free. Thirty-four lesions were biopsied; among these, 29 were found to be positive for tumor. (18)F-FDG was true-positive in 28 lesions, true-negative in 4, false-negative in 1 (0.5 cm in diameter), and false-positive in 1 (inflammatory pleuritis). The smallest lesion detected was 0.8 cm. For biopsied lesions, overall sensitivity, specificity, and accuracy for (18)F-FDG-CI were 97%, 80%, and 94% respectively, compared with 83%, 80%, and 82% for CT. Twenty-one of 29 positive lesions involved the pleura, lung parenchyma, or chest wall and were all (18)F-FDG avid. In the mediastinum, (18)F-FDG-CI detected 7 of 8 biopsy-positive lesions (88%), whereas CT was positive in 6 of 8 lesions (75%). (18)F-FDG identified extrathoracic metastases in 5 patients, excluding them from surgical therapy. CONCLUSION: These preliminary results suggest that (18)F-FDG-CI appears to be an accurate method to diagnose and to define the extent of disease in patients with diffuse malignant pleural mesothelioma.

Curr Oncol Rep. 2002 Jul;4(4):354-60.

Current surgical management of malignant pleural mesothelioma.

Zellos L, Sugarbaker DJ.

Division of Thoracic Surgery, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.

Malignant pleural mesothelioma is a rare and very aggressive malignancy with an increasing incidence. Single-modality therapy has failed to improve median survival. Current surgical therapies include palliative and cytoreductive procedures. The rarity of the disease, the lack of randomized surgical studies, and the lack of a universally accepted and validated staging system make it difficult to reach consensus and establish stage-specific protocols. However, with strict criteria, subsets of patients can be identified who can benefit from aggressive cytoreductive surgical approaches, such as extrapleural pneumonectomy, and adjuvant chemoradiation protocols. Our experience with this type of protocol in carefully selected patients has resulted in increased median survival. The lack of cure in any of the published protocols demonstrates the need for new therapies and approaches for this disease.

Oncology (Williston Park). 2002 Jul;16(7):907-13; discussion 916-7, 919-20, 925.

Diffuse malignant mesothelioma of the pleural space and its management.

Zellos LS, Sugarbaker DJ.

Division of Thoracic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

Diffuse malignant pleural mesothelioma is a rare and aggressive malignancy of the pleura that is usually caused by exposure to asbestos. Between 2,000 and 3,000 new cases are expected to be diagnosed annually in the United States. Difficulties in diagnosis, staging, and treatment set this disease apartfrom other malignancies. The variable clinical presentation and problems in establishing a definite histopathologic diagnosis result in significant delays in treatment. Three histologic subtypes of the disease are described in this review: epithelial, sarcomatous, and mixed histologies. The Butchart, International Mesothelioma Interest Group, and Brigham staging systems are the most commonly used staging systems. The disease's natural history involves aggressive local growth, invasion of vital mediastinal structures, and death within 4 to 12 months without treatment. Single-modality therapy of any kind has failed to substantially alter this natural history. Aggressive, multimodality regimens that include surgery, radiation, and chemotherapy have resulted in improved survival in properly selected patients. However, innovative therapies are still needed to prolong survival in patients with early and advanced disease.

Carcinogenesis. 2002 Jun;23(6):1017-24.

Inhibitor of apoptosis protein-1 promotes tumor cell survival in mesothelioma.

Gordon GJ, Appasani K, Parcells JP, Mukhopadhyay NK, Jaklitsch MT, Richards WG, Sugarbaker DJ, Bueno R.

Division of Thoracic Surgery, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.

Malignant pleural mesothelioma (MPM) is a highly lethal pleural neoplasm that is often resistant to chemotherapeutic drugs, including cisplatin, and for which little is known regarding carcinogenic pathways. We used differential display to compare gene expression patterns in mesothelioma, normal pleura and normal lung, in order to better understand MPM pathobiology, and to search for genes that may facilitate drug resistance in this cancer. The human inhibitor of apoptosis protein-1 gene (IAP-1/MIHC/cIAP2) was discovered to be highly expressed in MPM. We confirmed overexpression of IAP-1 mRNA and protein in 39 additional human MPM tumor specimens and 3/5 (60%) MPM cell lines by multiple methods, including real time quantitative reverse transcription-PCR and western blot analysis. Using an antisense targeting approach, we found that attenuation of IAP-1 mRNA levels decreases baseline cell viability and increases the sensitivity of MPM cell lines to cisplatin by nearly 20-fold. Reduced IAP-1 gene expression also results in a concordant increase of the pro-apoptotic cleavage product of caspase 9 and a reduction in the number of viable tumor cells. Our observations strongly suggest that IAP-1 is at least partly responsible for promoting carcinogenesis and mediating resistance to cisplatin in many MPM tumors and that further study of this apoptotic pathway is warranted.

Oncol Rep. 2002 May-Jun;9(3):631-4.

Detection and quantification of SV40 large T-antigen DNA in mesothelioma tissues and cell lines.

Gordon GJ, Chen CJ, Jaklitsch MT, Richards WG, Sugarbaker DJ, Bueno R.

Division of Thoracic Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA.

SV40 viral DNA sequences, particularly large T-antigen (T-ag) DNA, have been reported in malignant pleural mesothelioma (MPM) and suggested to play a role in the tumorigenesis of this cancer. These results remain somewhat controversial owing to variability among a number of laboratories in reported SV40 DNA and protein detection in MPM tissues. This could be explained in part if SV40 DNA is present in relatively low abundance in many MPM tissues determined to contain viral sequences and is therefore difficult to detect. To this end, we investigated the efficacy of real time quantitative PCR in detecting low copy number SV40 DNA sequences, then we quantified SV40 copy number in MPM tissues and cell lines at our institution. Quantitative PCR demonstrated consistent precision and accuracy in detecting SV40 DNA sequences over a large logarithmic range of viral copy number. In addition, SV40 sequences were found in 2/35 tissues and 3/7 cell lines in relatively low abundance. We conclude that SV40 is not a contributing factor in the pathobiology of the majority of MPM tumors from patients at our institution.

Semin Oncol. 2002 Feb;29(1):41-50.

Multimodality treatment of diffuse malignant pleural mesothelioma.

Zellos LS, Sugarbaker DJ.

Department of Surgery, Division of Thoracic Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA.

Diffuse malignant pleural mesothelioma (DMPM) is a challenging disease in all of its aspects, from presentation and diagnosis to staging and treatment. Single-modality therapy was the initial approach to this disease. It generally has not been effective in changing the natural history of DMPM. As a result, multimodality regimens involving surgery with radiation, chemotherapy, or immunotherapy delivered regionally or systemically have been evaluated. Randomized controlled studies comparing various strategies are lacking and, thus, the debate continues regarding the effectiveness of different treatment approaches. Copyright 2002 by W.B. Saunders Company.

World J Surg. 2001 Feb;25(2):210-7.

Treatment of malignant mesothelioma.

Jaklitsch MT, Grondin SC, Sugarbaker DJ.

Department of Surgery, Division of Thoracic Surgery, Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA.

Malignant pleural mesothelioma (MPM) is a rare tumor that predominantly afflicts men over 50 years of age. Nearly 3000 MPMs are reported annually in the United States with the incidence expected to rise into the new millenium. Over the past 40 years, MPM has been unequivocally linked to asbestos exposure worldwide. Recently, however, a new theory on the carcinogenesis of this tumor has been proposed with the isolation of a simian virus (SV 40)-like gene sequence in mesothelioma tumor cells. The clinical presentation of MPM is variable, although most patients typically present with dyspnea, chest pain, or pleural effusion. Obtaining a diagnosis of MPM has been greatly assisted by video-assisted surgery and the use of immunohistochemistry and electron microscopic techniques, which help distinguish MPM from other tumor pathologies such as adenocarcinoma. Computed tomography and magnetic resonance imaging have been also useful for determining tumor burden and resectability. Traditionally, strategies for the treatment of MPM have included supportive care, surgery, radiotherapy, and chemotherapy. Survival with supportive care alone ranges between 4 and 12 months. Single-modality therapy using traditional approaches (surgery, radiotherapy, chemotherapy) alone has failed to improve patient survival significantly. Recently, results using a multimodality approach have been favorable. In particular, cytoreductive surgery (pleuropneumonectomy) followed by sequential chemotherapy and radiotherapy have demonstrated improved survival, especially for patients with epithelial histology, negative resection margins, and no metastases to extrapleural lymph nodes. Innovative therapies such as the use of photodynamic, targeted cytokines and gene therapy are currently being investigated for management of MPM.

Cancer Treat Res. 2001;105:327-73.

Malignant pleural mesothelioma.

Ho L, Sugarbaker DJ, Skarin AT.

M.D. Anderson Cancer Center, Houston, TX 77030, USA.

Malignant pleural mesothelioma remains a difficult tumor to treat, much less cure. Currently, the best chance for long-term survival lies with early diagnosis and aggressive surgical extirpation, but given the typically long delay between the onset of symptoms and diagnosis, this is only possible with a high index of suspicion and an aggressive diagnosis workup. Early referral to a tertiary center experienced in the treatment of MPM may be important for several reasons: (1) decreased risk of tumor spread along multiple thoracenesis/biopsy tracts, (2) the availability of specialized pathologic assays for definitive diagnosis, (3) the availability of critical staging modalities (aggressive mediastinoscopy +/- thoracoscopy, MRI scans performed according to specific mesothelioma protocols, and perhaps PET scans), (4) surgical experience with pleurectomy/decortication and/or extrapleural pneumonectomy, that may decrease morbidity and mortality, and (5) the availability of novel adjuvant protocols. Single-modality therapy is unlikely to result in long-term survival. Aggressive surgery is required for optimal debulking, and extrapleural pneumonectomy may offer better local control compared with pleurectomy/ecortication. Delivery of optimal radiation schedules, which may involve large fractions as well as large total doses, is limited by the presence of nearby dose-limiting structures. Current chemotherapy is severely lacking in producing objective responses and improved survival although gemcitabine and IL-2 may be active agents to be combined with radiation and/or other agents. Hyperthermia, photodynamic therapy, intracavitary therapy, and gene therapy are all relatively new techniques under active investigation that should be supported by enrollment in on-going protocols. Predictably, many of these techniques provide greater benefit when used in the setting of adjuvant protocols or minimal residual disease, emphasizing the importance of multimodality therapy.

Ann Thorac Surg. 2000 Jul;70(1):306.

Malignant mesothelioma of the pleural space.

Flores RM, Sugarbaker DJ.

Division of Thoracic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. rflores@bics.bwh.harvard.edu

 Chest. 1999 Dec;116(6 Suppl):450S-454S.

Pleuropneumonectomy in the treatment of malignant pleural mesothelioma.

Grondin SC, Sugarbaker DJ.

Division of Thoracic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

STUDY OBJECTIVES: Malignant pleural mesothelioma (MPM) is predominantly a local/regional disease that results in a survival time that ranges from 4 to 12 months without treatment. Single-modality therapy using surgery, chemotherapy, or radiotherapy alone is largely ineffective. The objective of the study was presentation of the use of pleuropneumonectomy in a multimodality treatment setting and the results. DESIGN: Didactic presentation. SETTING: Academic tertiary-care hospital. PATIENTS: One hundred eighty-three patients who underwent multimodality therapy. INTERVENTIONS: Of all the single-modality treatment approaches, pleuropneumonectomy has been associated most consistently with long-term disease-free survival and has provided the greatest amount of tumor cytoreduction. The technique of pleuropneumonectomy traditionally has been linked with high perioperative mortality and morbidity when compared with that of other cytoreductive techniques such as pleurectomy/decortication. Recently, improvements in operative mortality (< 5%) have been reported, largely due to improvements in patient selection and perioperative management. Multimodality therapy, including chemotherapy, radiotherapy, and extrapleural pneumonectomy, was used to treat patients. RESULTS: Outcomes were presented for 183 patients with MPM who underwent multimodality therapy. CONCLUSIONS: With the development of multimodality therapy, pleuropneumonectomy followed by sequential chemotherapy and radiotherapy has demonstrated a significant survival benefit, especially for patients who have epithelial tumor histology, tumor-free resection margins, and tumor-free extrapleural node status.

Oncology (Williston Park). 1999 Jul;13(7):919-26; discussion 926, 931-2.

Malignant mesothelioma of the pleural space.

Grondin SC, Sugarbaker DJ.

Division of Thoracic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Malignant pleural mesothelioma is an aggressive tumor associated with exposure to asbestos. Although this disease is rare, with an annual incidence in the United States of 2,000 to 3,000 cases, a steady rise in cases has been reported. Malignant pleural mesothelioma has a variable clinical presentation and may be difficult to diagnose. Pathologically, the disease is subdivided into three microscopic subtypes: epithelial, sarcomatous, and mixed histologies. Although there is no widely accepted staging system for mesothelioma, the Butchart, TNM, and Brigham staging systems have been used most commonly. Diffuse malignant pleural mesothelioma is resistant to standard modes of therapy and, if untreated, results in death 4 to 12 months from the time of diagnosis. For selected patients, an aggressive approach combining radical surgery with chemotherapy and radiotherapy has demonstrated a long-term survival advantage. New and innovative therapeutic modalities are presently being investigated in an attempt to provide viable alternatives for patients with early and advanced disease.

Thorac Cardiovasc Surg. 1999 Jan;117(1):54-63; discussion 63-5.

Resection margins, extrapleural nodal status, and cell type determine postoperative long-term survival in trimodality therapy of malignant pleural mesothelioma: results in 183 patients.

Sugarbaker DJ, Flores RM, Jaklitsch MT, Richards WG, Strauss GM, Corson JM, DeCamp MM Jr, Swanson SJ, Bueno R, Lukanich JM, Baldini EH, Mentzer SJ.

Division of Thoracic Surgery and the Department of Pathology, Brigham and Women's Hospital, Boston, Mass 02115, USA.

OBJECTIVES: Our aim was to identify prognostic variables for long-term postoperative survival in trimodality management of malignant pleural mesothelioma. METHODS: From 1980 to 1997, 183 patients underwent extrapleural pneumonectomy followed by adjuvant chemotherapy and radiotherapy. RESULTS: Forty-three women and 140 men (age range 31-76 years) had a median follow-up of 13 months. The perioperative mortality rate was 3.8% (7 deaths) and the morbidity, 50%. Survival in the 176 remaining patients was 38% at 2 years and 15% at 5 years (median 19 months). Univariate analysis identified 3 prognostic variables associated with improved survival: epithelial cell type (52% 2-year survival, 21% 5-year survival, 26-month median survival; P =.0001), negative resection margins (44% at 2 years, 25% at 5 years, median 23 months; P =.02), and extrapleural nodes without metastases (42% at 2 years, 17% at 5 years, median 21 months; P =.004). Using the Cox proportional hazards, the relative risk of death was calculated for nonepithelial cell type (OR 3.0, CI 2.0-4.5; P <.0001), positive resection margins (OR 1.7, CI 1.2-2.6; P =.0082), and metastatic extrapleural nodes (OR 2.0, CI 1.3-3.2; P =.0026). Thirty-one patients with 3 positive variables had the best survival (68% 2-year survival, 46% 5-year survival, median 51 months; P =.013). A previously published staging system using these variables stratified survival (P <.05). CONCLUSIONS: (1) Multimodality therapy including extrapleural pneumonectomy is feasible in selected patients with malignant pleural mesotheliomas, (2) pre-resectional evaluation of extrapleural nodes may select patients for radical therapy, (3) microscopic resection margins affect long-term survival, highlighting the need for further investigation of locoregional control, and (4) patients with epithelial, margin-negative, extrapleural node-negative resection had extended survival.

Chest. 1998 Jan;113(1 Suppl):61S-65S.

Multimodality management of malignant pleural mesothelioma.

Sugarbaker DJ, Norberto JJ.

Division of Thoracic Surgery, Brigham and Women's Hospital, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA 02115, USA.

In this article, we explain the current trimodality approach used to treat malignant pleural mesothelioma. Our current approach employs extrapleural pneumonectomy as the cytoreductive procedure followed by combination chemoradiotherapy. Trimodality therapy was performed at the Dana-Farber Cancer Institute/Brigham and Women's Hospital Thoracic Oncology Program. From 1980 to 1995, we prospectively followed up a series of 120 patients with confirmed malignant pleural mesothelioma who underwent trimodality therapy. Two- and 5-year survival rates for the entire cohort were 45% and 22%, respectively. Survival rates were 65% and 27%, respectively, at 2 and 5 years for patients with epithelial histology. Patients with sarcomatous or mixed histology had the poorest prognosis, with 2- and 5-year survival rates of 20% and 0%, respectively. For patients with epithelial tumors and negative nodes, survival at 2 and 5 years was 74% and 39%, respectively. Extrapleural pneumonectomy in the context of trimodality therapy is a potential surgical option for a selected group of patients with malignant pleural mesothelioma.

Chest. 1997 Oct;112(4 Suppl):272S-275S.

Multimodality therapy for malignant pleural mesothelioma.

Sugarbaker DJ, Garcia JP.

Thoracic Oncology Program, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.

Mesothelioma is a rare disease for which neither single modality nor bimodality therapy improves survival. For this reason, from 1980 to 1995, we used trimodality therapy in an attempt to improve survival in selected patients at Brigham and Women's Hospital and Dana-Farber Cancer Institute. One hundred twenty patients underwent trimodality treatment involving extrapleural pneumonectomy followed by combination chemoradiotherapy. Twenty-seven women and 93 men (mean age, 56 years) were evaluable for response and treatment-related morbidity. The operative mortality rate was 5%, and 22% of patients experienced major morbidity. Cell type and nodal status were significant prognostic variables. The respective 2- and 5-year survival rates were 45% and 22% overall, 70% and 37% for patients with epithelial cell type, 20% and 0% for patients with sarcomatous or mixed-histologic-type tumors, and 74% and 39% for patients who were node-negative with epithelial histologic type. Positive resection margins impacted survival only in the case of full-thickness, transdiaphragmatic invasion. A revised staging system stratified survival with median intervals of 22, 17, and 11 months for stages I, II, and III disease, respectively (p=0.04). Thus, extrapleural pneumonectomy with adjuvant therapy is appropriate and effective treatment for patients with stage I disease according to the revised staging system.

Semin Thorac Cardiovasc Surg. 1997 Oct;9(4):373-82.

Extrapleural pneumonectomy in the setting of multimodality therapy for diffuse malignant pleural mesothelioma.

Sugarbaker DJ, Norberto JJ, Swanson SJ.

Brigham and Women's Hospital, and the Dana-Farber Cancer Institute, Department of Surgery, Harvard Medical School, Boston, MA 02115, USA.

Diffuse malignant pleural mesothelioma, a rare disease, is characterized by an aggressive local behavior and scant response to therapy. The first series using single modality therapy showed failure in terms of survival and local control. More recently, multimodality therapy has been used against this disease with better results, but still with more room for substantial improvement. The current multimodality series reported are isolated, single-institutional experiences with different treatment schemes, using different staging systems, most of which have not been validated. There is an enormous need for multiinstitutional prospective trials to evaluate the current treatment schemes in light of the steady increase in the incidence of this lethal tumor. The trimodality therapy used at the Brigham and Women's Hospital for selected patients is described.

Semin Thorac Cardiovasc Surg. 1997 Oct;9(4):356-60.

Surgical staging and work-up of patients with diffuse malignant pleural mesothelioma.

Sugarbaker DJ, Norberto JJ, Swanson SJ.

Division of Thoracic Surgery, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, USA.

The current modalities used to treat diffuse malignant pleural mesothelioma (DMPM) have not been evaluated in the setting of prospective, multi-institutional randomized trials for two reasons: DMPM is a rare disease, and there is a lack of a widely accepted and standarized staging system. Several staging systems have been proposed in an effort to categorize patients with DMPM into homogeneous groups. These efforts have been hampered by a lack of correlation between staging and survival. In our institutional experience, the Brigham staging system has been able to stratify patients with similar survival. This is an institutional experience that needs validation in a multi-institutional setting and, furthermore, in a trial based on stage-specific adjuvant therapies.

PMID: 9352952 [PubMed - indexed for MEDLINE]

Semin Thorac Cardiovasc Surg. 1997 Oct;9(4):345-6.

Diffuse malignant pleural mesothelioma: introduction.

Sugarbaker DJ.

Cancer Control. 1997 Jul;4(4):326-334.

Current Therapy for Mesothelioma.

Sugarbaker DJ, Norberto JJ, Bueno R.

Division of Thoracic Surgery, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.

BACKGROUND: Diffuse malignant pleural mesotheliomas (DMPMs) are highly lethal tumors that are becoming more common. Standard management approaches have provided limited effectiveness. METHODS: The literature on management has been revised, and the authors present their data on outcomes for 120 patients treated with an aggressive trimodality approach. RESULTS: An aggressive trimodality approach including extrapleural pneumonectomy followed by chemoradiation produces low mortality and acceptable morbidity. The five-year survival rate in patients with epithelial histology and negative nodes approaches 40%. CONCLUSIONS: Nodal status and histologic subtype are major predictors for survival in patients with early DMPM. A uniformly accepted staging system would allow comparison of treatment approaches from various institutions. More effective management interventions are required.

Am J Clin Pathol. 1997 Feb;107(2):206-10.

Effusion cytology after extrapleural pneumonectomy for treatment of malignant mesothelioma.

Renshaw AA, Nappi D, Swanson S, Sugarbaker DJ.

Department of Pathology, Brigham and Women's Hospital, Boston MA 02115, USA.

Extrapleural pneumonectomy to treat malignant mesothelioma may offer a significant survival advantage for selected patients. The role of effusion cytology in these patients has not been previously examined. To evaluate this, cytology, pathology, and medical records of 26 cases in 21 patients who underwent extrapleural pneumonectomy because of malignant mesothelioma were reviewed. Positive cytologic results were noted on average 13 months later than negative results. Recurrence was most common in the peritoneum, followed by the ipsilateral thorax and contralateral thorax. Five of 11 true-negative results were secondary to infection; cytologic analysis revealed neutrophils in each case. Four of 5 false-negative cases were from the ipsilateral thorax, and no mesothelial cells were found. When these 4 cases are excluded, the sensitivity of cytologic examination in this setting was 91%, and specificity was 100%. Effusion cytology in patients after extrapleural pneumonectomy is an effective means of diagnosing recurrent malignant mesothelioma.

Ann Thorac Surg. 1997 Feb;63(2):334-8.

Patterns of failure after trimodality therapy for malignant pleural mesothelioma.

Baldini EH, Recht A, Strauss GM, DeCamp MM Jr, Swanson SJ, Liptay MJ, Mentzer SJ, Sugarbaker DJ.

Joint Center for Radiation Therapy, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

BACKGROUND: Malignant pleural mesothelioma is uncommon, and presently, no standard treatment of this disease exists. The objective of our analysis was to study the patterns of failure for malignant pleural mesothelioma after trimodality treatment consisting of extrapleural pneumonectomy, chemotherapy, and radiation therapy. METHODS: Between 1987 and 1993, 49 patients with malignant pleural mesothelioma underwent extrapleural pneumonectomy. There were two perioperative deaths, and 1 patient died 5 weeks after extrapleural pneumonectomy. Thirty-five of the surviving patients received adjuvant chemotherapy (32/35 received cyclophosphamide, doxorubicin, and cisplatin) followed by hemithorax radiation therapy. Ten patients received chemotherapy but no radiation therapy, and 1 patient received no adjuvant therapy. Median follow-up time for the 23 living patients from the date of operation was 18 months. RESULTS: Of the 46 evaluable patients, 25 had recurrence (54%), with a median time to first failure of 19 months (range, 5 to 51 months). The sites of first recurrence were local in 35% of patients, abdominal in 26%, the contralateral thorax in 17%, and other distant sites in 8%. (Some patients had recurrence in multiple sites simultaneously.) CONCLUSIONS: The most common site of failure after trimodality therapy was the ipsilateral hemithorax. Isolated distant failures were uncommon. Future strategies should investigate methods of enhancing local tumor control.

Adv Surg. 1997;31:253-71.

Extrapleural pneumonectomy for malignant mesothelioma.

Sugarbaker DJ, Richards WG, Garcia JP.

Division of Thoracic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Chest. 1997 Jan;111(1):106-9.

The role of cytologic evaluation of pleural fluid in the diagnosis of malignant mesothelioma.

Renshaw AA, Dean BR, Antman KH, Sugarbaker DJ, Cibas ES.

Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.

STUDY OBJECTIVE: Treatment of malignant mesothelioma (MM) at an early stage results in increased survival. Cytologic examination of pleural effusions is one of the first diagnostic techniques attempted in these patients. The objective of this study was to define the role of cytologic examination of pleural fluid in facilitating early diagnosis. DESIGN: The medical records and cytologic slides of patients with pleural MM were reviewed. SETTING: Medical records were reviewed from two institutions: a large general hospital and a cancer hospital. PATIENTS: Twenty-nine patients ranging in age from 32 to 81 years (mean, 59 years) met the study criteria. INTERVENTIONS: All patients had at least one cytologic pleural fluid examination. MEASUREMENTS AND RESULTS: The median time from initial symptoms to the diagnosis of MM was 8 weeks for all patients. For patients with a positive or suspicious cytologic result, the median was 4 weeks, and in those with a negative cytologic result, it was 12 weeks. The overall sensitivity of cytologic examination for the diagnosis of MM was 32%. Cytogenetic analysis of pleural fluid had a sensitivity of 56%, and was positive in 1 case in which results of cytologic examination were negative. Patients in whom the time from presentation to diagnosis was greater than 1 year all had negative cytologic results followed by long periods without further workup, despite a history of exposure to asbestos. CONCLUSIONS: A positive or suspicious cytologic result was associated with a decreased median time to diagnosis. Unfortunately, the sensitivity of cytologic examination for a diagnosis of MM was only 32%. Until better diagnostic techniques are developed, we recommend immediate pleural biopsy in patients in whom MM is suspected and cytologic evaluation of pleural fluid gives negative results.

Ann Surg. 1996 Sep;224(3):288-94; discussion 294-6.

Extrapleural pneumonectomy in the multimodality therapy of malignant pleural mesothelioma. Results in 120 consecutive patients.

Sugarbaker DJ, Garcia JP, Richards WG, Harpole DH Jr, Healy-Baldini E, DeCamp MM Jr, Mentzer SJ, Liptay MJ, Strauss GM, Swanson SJ.

Thoracic Oncology Program, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

OBJECTIVE: The authors examine the feasibility and efficacy of trimodality therapy in the treatment of malignant pleural mesothelioma and identify prognostic factors. BACKGROUND: Mesothelioma is a rare, uniformly fatal disease that has increased in incidence in recent decades. Single and bimodality therapies do not improve survival. METHODS: From 1980 to 1995, 120 patients underwent treatment for pathologically confirmed malignant mesothelioma at Brigham and Women's Hospital and Dana-Farber Cancer Institute (Boston, MA). Initial patient evaluation was performed by a multimodality team. Patients meeting selection criteria and with resectable disease identified by computed tomography scan or magnetic resonance imaging underwent extrapleural pneumonectomy followed by combination chemotherapy and radiotherapy. RESULTS: The cohort included 27 women and 93 men with a mean age of 56 years. Operative mortality rate was 5.0%, with a major morbidity rate of 22%. Overall survival rates were 45% at 2 years and 22% at 5 years. Two and 5-year survival rates were 65% and 27%, respectively, for patients with epithelial cell type, and 20% and 0%, respectively, for patients with sarcomatous or mixed histology tumors. Nodal involvement was a significant negative prognostic factor. Patients who were node negative with epithelial histology had 2- and 5-year survival rates of 74% and 39%, respectively. Involvement of margins at time of resection did not affect survival, except in the case of full-thickness, transdiaphragmatic invasion. Classification on the basis of a revised staging system stratified median survivals, which were 22, 17, and 11 months for stages I, II, and III, respectively (p = 0.04). CONCLUSIONS: Extrapleural pneumonectomy with adjuvant therapy is appropriate treatment for selected patients with malignant mesothelioma selected using a revised staging system.

Ann Thorac Surg. 1996 Mar;61(3):977-82.

Prospective analysis of pneumonectomy: risk factors for major morbidity and cardiac dysrhythmias.

Harpole DH, Liptay MJ, DeCamp MM Jr, Mentzer SJ, Swanson SJ, Sugarbaker DJ.

Division of Thoracic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston 02115, USA.

BACKGROUND: Data were acquired prospectively on 136 consecutive patients undergoing pneumonectomy for cancer from 1988 to 1993, to define factors that increase the risk of major morbidity and postoperative cardiac dysrhythmias. METHODS: There were 81 patients (60%) with non-small cell lung cancer (standard pneumonectomy) and 55 patients (40%) with malignant pleural mesothelioma (extrapleural pneumonectomy). RESULTS: Four perioperative deaths occurred (3%) with no identifiable associated risk factors. Twenty-three patients (17%) had a major complication with an increase in the median length of stay from 7 to 11 days (p < 0.01). Age greater than 65 years, right-sided procedures, and dysrhythmias were associated with an increased risk of a major complication (p < 0.05). Thirty-two patients (24%) had supraventricular dysrhythmias, which occurred on postoperative days 1 to 2 (n = 8), 3 to 4 (n = 13), 5 to 6 (n = 6), and 7 to 12 (n = 5). The median length of stay increased from 8 to 11 days with dysrhythmias (p < 0.05). Factors associated with an increased risk of dysrhythmias included age greater than 65 years, intrapericardial or extrapleural pneumonectomy, right-sided procedure, and any major complication. CONCLUSIONS: Pneumonectomy can be performed safely in selected patients with cancer. Supraventricular dysrhythmia was the most common complication noted with a peak incidence at 3 to 4 days after resection.

 Oncogene. 1995 Aug 3;11(3):511-5.

Codeletion of p15 and p16 in primary malignant mesothelioma.

Xio S, Li D, Vijg J, Sugarbaker DJ, Corson JM, Fletcher JA.

Department of Pathology, Children's Hospital, Boston, Massachusetts USA.

The p15 and p16 CDK4 inhibitor genes map within the chromosome band 9p21 region deleted frequently in malignant mesothelioma and other cancers. p16 has been implicated recently as a potential target of 9p21 deletions in mesothelioma, but the role of this gene is uncertain because deletions have been detected more often in established cell lines than in primary tumor specimens. We determined p15 and p16 copy number by fluorescence in situ hybridization with a P1 contig in 50 primary mesotheliomas. Codeletion of p15 and p16 was found in 72% of mesotheliomas, including all cases with spindle-cell components (n = 21) and total deletion of p15 and p16 was found in several mesotheliomas that lacked cytogenetic deletion of the chromosome 9 short arm. Point mutations were not found, however, in exon 2 of retained p15 and p16 alleles from seven mesotheliomas. These findings demonstrate that p15, p16 and/or a closely neighboring gene, are the targets of frequent chromosome 9p deletion in primary malignant mesothelioma.

Chest. 1995 Jun;107(6 Suppl):345S-350S.

Mesothelioma and radical multimodality therapy: who benefits?

Sugarbaker DJ, Jaklitsch MT, Liptay MJ.

Division of Thoracic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

The incidence of malignant pleural mesothelioma is increasing. Untreated, patients with this disease experience a rapid and horrendous clinical decline. Surgery plays a role in the diagnosis, staging, and treatment of this malignancy. Surgery, chemotherapy, and radiotherapy alone have been unable to achieve major improvements in survival for most patients. More recent phase II trials suggest that surgery, at one time a purely palliative approach, may have a potentially curative role when used in combination with chemotherapy and radiotherapy.

J Clin Oncol. 1993 Jun;11(6):1172-8.

Node status has prognostic significance in the multimodality therapy of diffuse, malignant mesothelioma.

Sugarbaker DJ, Strauss GM, Lynch TJ, Richards W, Mentzer SJ, Lee TH, Corson JM, Antman KH.

Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115.

PURPOSE: We studied a multimodality approach using extrapleural pneumonectomy, chemotherapy, and radiotherapy in patients with malignant pleural mesothelioma. PATIENTS AND METHODS: From 1980 to 1992, 52 selected patients, underwent treatment. Median age was 53 years (range, 33 to 69). Initial patient evaluation was performed by a multimodality team. Pathologic diagnosis was reviewed and confirmed before therapy. Patients with no medical contraindication and potentially resectable mesothelioma on computed tomography (CT) (magnetic resonance imaging [MRI] when it became available) received extrapleural pneumonectomy, cyclophosphamide, doxorubicin, and cisplatin (CAP) chemotherapy, and radiotherapy. RESULTS: Perioperative morbidity and mortality rates were 17% and 5.8%, respectively. The overall median survival duration is 16 months (range, 1 month to 8 years). The 32 patients with epithelial histologic variant had 1-, 2-, and 3-year survival rates of 77%, 50%, and 42%, respectively. Patients with mixed and sarcomatous cell disease had 1- and 2-year survival rates of 45% and 7.5%; no patient lived longer than 25 months (P < .01). At resection, positive regional mediastinal lymph nodes were found in 13. Positive lymph nodes were associated with poorer survival than were negative nodes (P < .01). Patients with epithelial variant and negative mediastinal lymph nodes had a survival rate of 45% at 5 years. CONCLUSION: Multimodality therapy including extrapleural pneumonectomy has acceptable morbidity and mortality for selected patients. Prolonged survival occurred in patients with epithelial histologic variant and negative mediastinal lymph nodes. These data provide a rationale for a revised staging system for malignant pleural mesothelioma; furthermore, they permit stratification of patients into groups likely to benefit from aggressive multimodality treatment.

Chest. 1993 Apr;103(4 Suppl):377S-381S.

Extrapleural pneumonectomy in the setting of a multimodality approach to malignant mesothelioma.

Sugarbaker DJ, Mentzer SJ, DeCamp M, Lynch TJ Jr, Strauss GM.

Harvard Medical School, Brigham and Women's Hospital, Boston 02115.

The use of extrapleural pneumonectomy in a multimodality treatment setting for malignant pleural mesothelioma is described, presenting first the right-sided approach and then the left-sided. This technique used in a multimodality approach with CAP chemotherapy (cyclophosphamide 600 mg/m2, doxorubicin 60 mg/m2, cisplatin 75 mg/m2) 5 cycles at 3-week intervals, and radiotherapy (55 Gy radiation to sites of previous bulky disease or residual disease) to treat 44 patients with malignant pleural mesothelioma resulted in improved operative mortality and decreased length of hospital stay.

AJR Am J Roentgenol. 1992 Nov;159(5):961-6.

Malignant pleural mesothelioma: value of CT and MR imaging in predicting resectability.

Patz EF Jr, Shaffer K, Piwnica-Worms DR, Jochelson M, Sarin M, Sugarbaker DJ, Pugatch RD.

Department of Radiology, Brigham and Women's Hospital, Boston, MA 02115.

OBJECTIVE. Our objective was to determine if CT or MR imaging findings could be used to accurately predict resectability in patients with biopsy-proved malignant pleural mesotheliomas. SUBJECTS AND METHODS. CT and MR findings in 41 consecutive patients with malignant mesotheliomas who were referred to the thoracic surgery clinic for extrapleural pneumonectomy were studied by thoracic radiologists before surgery. Review of radiologic studies focused on local invasion of three separate regions: the diaphragm, chest wall, and mediastinum. Results of all imaging examinations were carefully correlated with intraoperative, gross, and microscopic pathologic findings. RESULTS. After radiologic and clinical evaluation, 34 patients (83%) had thoracotomy; 24 of these had tumors that were resectable. The sensitivity was high (> 90%) for both CT and MR in each region. Specificity, however, was low, probably because of the small number of patients with unresectable tumors. CONCLUSION. CT and MR provided similar information on resectability in most cases. Sensitivity was high for both procedures. Because CT is more widely available and used, we suggest it as the initial study when determining resectability. In difficult cases, important complementary anatomic information can be derived from MR images obtained before surgical intervention.

 Ann Thorac Surg. 1992 Nov;54(5):941-6.

Extrapleural pneumonectomy in the treatment of malignant pleural mesothelioma.

Sugarbaker DJ, Mentzer SJ, Strauss G.

Division of Thoracic Surgery, Brigham and Women's Hospital, Boston, MA 02115.

A technique for extrapleural pneumonectomy in diffuse, malignant, pleural mesothelioma is described. The technique used in a protocol at Brigham and Women's Hospital has resulted in improved operative mortality figures and length of hospital stay. The right-sided procedure is presented followed by differences in technique required by the left-sided approach.

J Thorac Cardiovasc Surg. 1991 Jul;102(1):10-4; discussion 14-5.

Extrapleural pneumonectomy, chemotherapy, and radiotherapy in the treatment of diffuse malignant pleural mesothelioma.

Sugarbaker DJ, Heher EC, Lee TH, Couper G, Mentzer S, Corson JM, Collins JJ Jr, Shemin R, Pugatch R, Weissman L, et al.

Division of Thoracic Surgery, Brigham & Women's Hospital, Boston, MA 02115.

Malignant pleural mesothelioma has been considered a uniformly fatal disease associated with a median survival of 4 to 18 months. Extrapleural pneumonectomy alone has proved disappointing in the treatment of this disease, as have chemotherapy and radiotherapy. From 1980 to 1990, 31 patients with pleural mesothelioma underwent multimodality therapy that included extrapleural pneumonectomy with resection of the pericardium and diaphragm. The age of the patients was 53.4 +/- 8.6 years; 26 were male. All patients had the pathologic diagnosis reviewed before treatment. At thoracotomy six patients had residual (unresectable) gross disease, and in 23 there was histologic evidence of disease at the resection margin. The perioperative morbidity and mortality rates were 19% and 6%, respectively. The mean length of hospital stay for the 29 patients who survived the operation was 10.9 +/- 3.5 days. Postoperatively 26 patients received cyclophosphamide, doxorubicin, and cis-platinum chemotherapy with or without radiotherapy. The survival rates were 70% at 1 year and 48% at 2 years. Trends toward improved survival in the patients with complete resections approached but did not reach statistical significance. These data suggest that this multimodality protocol can be administered with acceptable morbidity and mortality. Prospective trials are justified to further clarify the role of this approach.