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Preface xiiiDavid J. Sugarbaker and Michael Y. Chang

Malignant Pleural Mesothelioma: Overview of the North American and European Experience 435Jasleen Kukreja, Michael T. Jaklitsch, Daniel C. Wiener, David J. Sugarbaker, Sjaak Burgers, and Paul Baas

Malignant pleual mesothelioma is an uncommon disease with limited treatment options.Early diagnosis, a standardized staging system, early referral to centers experienced inits treatment, and efforts to develop collaborative multicenter trials are essential toimproving treatment for patients with malignant pleural mesothelioma. Efforts to man-age this malignancy, which is projected to peak in the twenty-first century, constitute animportant international health concern, particularly because the use of asbestos, despitesuccessful regulatory efforts in many parts of the world, continues unabated in others.

Pathology of Mesothelioma 447 Joseph M. Corson

This article describes the progress in the histopathologic separation of mesothelialhyperplasia and fibrosing pleuritis from malignant mesothelioma. Advances in theincorporation of immunohistochemical and histopathologic approaches to the separa-tion of mesothelioma from metastatic adenocarcinoma and to its separation from otherneoplastic mimics are summarized. Attention is directed to recently recognized entities,such as lymphohistiocytic mesothelioma, localized pleural malignant mesothelioma,and primary synovial sarcoma of the pleura.

Genetics of Malignant Pleural Mesothelioma: Molecular Markers and Biologic Targets 461Raphael Bueno and Gavin J. Gordon

Malignant pleural mesothelioma is a highly lethal, asbestos-related thoracic neoplasm.Current knowledge about its pathobiology and genetic expression is limited. Increasedresearch interest combined with emerging genomic technologies will address this insuf-ficiency in the coming years. In this article we briefly summarize the current literatureconcerning mesothelioma etiology and pathobiology and identify ongoing genomics-based research likely to substantially impact its diagnosis and prognosis in the future.Malignant pleural mesothelioma is a poorly understood lethal malignancy. Relatedefforts to identify the molecular markers of mesothelioma are pursued with the aim of

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refining current diagnostic capabilities, predicting prognosis, and designing appropriatetrimodality programs. These new genomic tools also will assist efforts to tailor currentadjuvant and neoadjuvant therapies, optimize their effect, and further research that maylead to new therapeutic options.

Epidemiology, Biologic Behavior, and Natural History of Mesothelioma 469Lambros Zellos and David C. Christiani

Malignant pleural mesothelioma has a well described natural history but poorly definedpathogenesis. It is strongly associated with asbestos exposure. A predominantly locallyinvasive disease, the success of more aggressive life-prolonging therapies has increasedthe potential for the development of distant metastases in survivors. Recently describednew risk factors may increase the incidence of this disease in future generations, under-scoring the need for a more in-depth understanding of its pathobiology. This articlereviews the current body of knowledge about the occurrence, distribution, presentation,and natural history of malignant pleural mesothelioma.

Role of Asbestos in Etiology of Malignant Pleural Mesothelioma 479John J. Godleski

The association of malignant mesothelioma with asbestos exposure has been an acceptedtenet of our understanding of this disease. Asbestos fibers may be genotoxic to mesothelialcells through their distinctive structure and chemistry and through the interactions amongcomplex cellular response mechanisms. Reactive oxygen and nitrogen species play a keyrole. In human disease, the persistence of asbestos fibers in the lung and pleura is a criticalfeature that links exposure to asbestos and the development of malignant mesothelioma.

Evidence of an Important Role for SV40 in Mesothelioma 489Harvey I. Pass, Maurizio Bocchetta, and Michele Carbone

We are only beginning to understand the intricacies of mesothelial carcinogenesis, andevidence is rapidly maturing that the DNA virus, simian virus 40 (SV40), is associatedwith pleural mesothelioma. Once believed to be a product of polymerase chain reaction“contamination,” this virus is currently recognized at the RNA, DNA, and protein levelsnot only to be present in mesothelioma tumors and cell lines but also to have an impacton carcinogenic mechanisms through its tumor antigen. Future studies must concentrateon the relationships between this virus, its products, and asbestos to sort out issues of co-carcinogenicity and to exploit the presence of viral proteins for early detection of andtherapy for this disease.

Causality of Mesothelioma: SV40 Question 497Keerti V. Shah

The reported link between SV40 and mesothelioma is questionable. The most recentstudies do not confirm the previous reports of SV40 sequences in mesothelioma tissues,and one study raises the possibility that contamination with common laboratory plas-mids may account for some of the previous data. Individuals exposed to SV40 in contaminated vaccines have not been shown to be at increased risk for mesothelioma.With SV40 and mesothelioma, the data on viral sequences in tumors are inconsistent anddisputed, and serologic evidence does not support any association. The epidemiologicdata do not show that documented exposures to SV40 increase the risk of mesothelioma.It seems unlikely that infection with SV40 contributes to the development of humanmesothelioma or of any other human cancer.

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Preoperative Assessment and Therapeutic Options for Patients withMalignant Pleural Mesothelioma 505Subroto Paul, Siyamek Neragi-Miandoab, and Michael T. Jaklitsch

Prompt medical evaluation and aggressive treatment can lead to prolonged survival orsuccessful palliation of symptoms for patients with malignant pleural mesothelioma, butthe window for implementing treatment is short. Clinical recognition of the cancer isconfounded by numerous factors, including long latency between exposure to asbestosand expression of the disease, nonspecific nature of the presenting symptoms, rarity ofthe disease, a lack of experience in clinical diagnosis, and rapidly deteriorating clinicalcourse after diagnosis. Heightened clinical suspicion and proper patient selectionthrough accurate staging and pathologic identification are paramount to defining anddelivering therapy for this rare, lethal cancer.

Pleurectomy and Decortication for Malignant Mesothelioma 517Scott W. Cowan and Taine T. Pechet

Therapeutic options for the treatment of malignant pleural mesothelioma includechemotherapy, radiotherapy, and surgery. The principal surgical options are pleurectomyand decortication or extrapleural pneumonectomy. These cytoreductive procedures aregenerally used in conjunction with other treatment modalities. Pleurectomy and decor-tication originally were pursued to achieve pleural apposition, but they have had limitedsuccess in eradication of tumor and long-term cure. Novel treatment options includepleurectomy and decortication combined with phototherapy, immune modulating factors,and gene therapy. Although these options hold promise, the optimal treatment strategy formalignant pleural mesothelioma remains to be determined.

Extrapleural Pneumonectomy for Diffuse Malignant Pleural Mesothelioma: Techniques and Complications 523Michael Y. Chang and David J. Sugarbaker

The surgical arm of trimodality therapy for malignant pleural mesothelioma includestwo principal procedures used for cytoreduction, namely, extrapleural pneumonectomyand pleurectomy and decortication. The more radical of the two procedures, extrapleuralpneumonectony, can be performed with acceptable morbidity and mortality at experiencedcenters. This article provides a detailed description of the operation followed by a dis-cussion of the clinical results and complications observed during our 12-year experienceat the Brigham and Women’s Hospital Thoracic Surgery Division and Dana FarberThoracic Oncology Program.

Multimodality Therapy in Mesothelioma: Role of Chemotherapy 531Nicholas J. Vogelzang

The search for chemotherapeutic agents to treat patients with malignant pleuralmesothelioma has been extensive. Survivors have been cured with radical surgical extir-pation often followed by radiation and chemotherapy. For patients with resectable disease, multimodality therapy is becoming the standard of care. Chemotherapy alonehas been studied extensively, but its role as neoadjuvant therapy to radical surgery is lesswell defined. Promising new doublet regimens combine an antimetabolite (pemetrexed,gemcitabine or raltitrexed) and a platinating agent (cisplatin, carboplatin or oxaliplatin).Treatment with combined pemetrexed and cisplatin has exhibited improved survivalover cisplatin alone. Phase II studies demonstrate neoadjuvant chemotherapy to be safeand apparently effective. Further phase II investigation of pemetrexed plus cisplatin forpatients with resectable T1-3 N0-2 mesothelioma is under way. Results demonstrating a

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measurable pathologic complete response rate and median survival exceeding 20 to 24 months would spur future phase III trials comparing surgery plus radiation to surgeryplus radiation plus chemotherapy.

External Beam Radiation Therapy for the Treatment of Pleural Mesothelioma 543Elizabeth H. Baldini

The treatment of pleural mesothelioma presents a significant challenge to the radiationoncologist. The main problem is the exquisite radiation sensitivity of the surroundingnormal structures, which include the lung (if still present), heart and stomach (for left-sided tumors), liver (for right-sided tumors), contralateral lung, spinal cord, and ipsi-lateral kidney. This article reviews the details of radiation techniques used in the case of an intact lung or after extrapleural pneumonectomy. None of the techniques presentedare ideal, but the complex high-dose techniques used after extrapleural pneumonectomyare associated with good local control rates and acceptable toxicity.

Innovative Therapies: Intraoperative Intracavitary Chemotherapy 549Michael Y. Chang and David J. Sugarbaker

Microscopic tumor involvement at the surgical margin after cytoreductive surgery formalignant pleural mesothelioma plays a significant role in tumor recurrence and survival. Several adjuvant modalities aimed at improving locoregional control to decreaseor delay the rate of recurrence currently are being investigated, including hyperthermicintracavitary chemotherapy. Recently concluded phase I studies have defined the maxi-mum therapeutic dose and established the safety of hyperthermic intracavitary chemo-therapy with cisplatin lavage after extrapleural pneumonectomy and pleurectomy anddecortication, paving the way for future phase II and III clinical trials.

Innovative Therapies: Photodynamic Therapy 557Evelio Rodriguez, Paul Baas, and Joseph S. Friedberg

The number of cases of malignant pleural mesothelioma diagnosed each year is increas-ing and is expected to peak around 2010. There is no current standard of care for thetreatment of pleural mesothelioma. Only a few trials combining surgery with adjuvanttherapies in selected patients have demonstrated any significant impact on the expectedcourse of the disease. Newer diagnostic and treatment techniques are needed to improvesurvival in patients with malignant pleural mesothelioma. This article focuses on the useof photodynamic diagnosis and photodynamic therapy in the management of malignantpleural mesothelioma.

Patterns of Failure Following Surgical Resection for MalignantPleural Mesothelioma 567Pasi A. Jänne and Elizabeth H. Baldini

The treatment of malignant pleural mesothelioma can involve surgical resection, adju-vant chemotherapy, and radiation. These treatment modalities have not been evaluatedin randomized clinical trials, and their therapeutic contribution remains to be deter-mined. An analysis of patterns of failure from these therapeutic studies may aid in thedesign and development of future therapeutic strategies. This article reviews the patterns of failure in patients with malignant pleural mesothelioma treated with surgeryor chemotherapy or radiation.

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Anesthetic Strategies for Patients Undergoing Extrapleural Pneumonectomy 575Philip M. Hartigan and Ju-Mei Ng

Anesthetic management of patients with extrapleural pneumonectomy may contributeto risk reduction, and it differs from management of patients with standard pneumonec-tomy in several respects. Hemodynamic and intravascular fluid management is compli-cated by the significantly greater blood loss and impairments of venous return imposedby weighty tumors and the blunt dissection process. There are greater risks of cata-strophic (central) bleeding, dysrhythmias, cardiac herniation, and electrocardiographicchanges. Restrictive forces increase the likelihood of dependent lung atelectasis duringsingle-lung ventilation. Preoperative assessment of cardiopulmonary reserve remains animprecise process. Awareness of these risks and limitations enables the anesthesiologistto understand, anticipate, and potentially preempt many intraoperative problems.

Pain Management Strategies for Patients Undergoing Extrapleural Pneumonectomy 585Ju-Mei Ng and Philip M. Hartigan

Aggressive management of acute postoperative pain after extrapleural pneumonectomyis essential to achieve extubation, limit perioperative pulmonary and cardiac complications,accelerate recovery, and prevent or alleviate chronic pain. Thoracic epidural analgesiausing a synergistic combination of local anesthetics and narcotics is the most widelyused, evidence-supported technique. Advantages and limitations of this and alternativeor adjunctive analgesic regimens are discussed briefly.

Cumulative Index 2004 593

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