Ori Wald

Genomic Analysis of Thymic Epithelial Tumors Identifies Novel Subtypes Associated with Distinct Clinical Features.

Purpose: To reconcile the heterogeneity of thymic epithelial tumors (TET) and gain deeper understanding of the molecular determinants of TETs, we set out to establish a clinically relevant molecular classification system for these tumors. Experimental Design: Molecular subgrouping of TETs was performed in 120 patients from The Cancer Genome Atlas using a multidimensional approach incorporating analyses of DNA mutations, mRNA expression, and somatic copy number alterations (SCNA), and validated in two independent cohorts. Results: Four distinct molecular subtypes of TETs were identified. The most commonly identified gene mutation was a missense mutation in General Transcription Factor II-I (GTF2I group), which was present in 38% of patients. The next group was identified by unsupervised mRNA clustering of GTF2I wild-type tumors and represented TETs enriched in expression of genes associated with T-cell signaling (TS group; 33%). The remaining two groups were distinguished by their degree of chromosomal stability (CS group; 8%) or instability (CIN group; 21%) based upon SCNA analyses. Disease-free survival and overall survival were favorable in the GTF2I group and unfavorable in the CIN group. These molecular subgroups were associated with TET histology and clinical features including disease-free survival. Finally, we demonstrate high expression of PD1 mRNA and correlation of PD1 and CD8A in the TS subgroup. Conclusions: Molecular subtyping of TETs is associated with disease-free and overall survival. Classification of TETs by a molecular framework could aid in the refinement of staging and in the discovery and development of rational treatment options for patients with TETs. Clin Cancer Res; 23(16); 4855–64. ©2017 AACR.

Matrix metalloproteinase 12 promotes tumor propagation in the lung

Objective: Past studies are inconsistent with regard to the role of matrix metalloproteinase 12 in lung tumorigenesis. This is due, in part, to differential tumorigenesis based on tumor‐derived versus immune‐derived matrix metalloproteinase 12 expression. Our study aims to thoroughly dissect the role of matrix metalloproteinase 12 in lung tumorigenesis. Methods: We tested matrix metalloproteinase 12 expression and the association with prognosis using a tissue array and a published non–small cell lung cancer gene expression database. In addition, we characterized the contribution of matrix metalloproteinase 12 to tumor propagation in the lung using a series of in vitro and in vivo studies. Results: Tumor cells of a diverse set of human lung cancers stained positive for matrix metalloproteinase 12, and high matrix metalloproteinase 12 mRNA levels in the tumor were associated with reduced survival. The lung microenvironment stimulated endogenous production of matrix metalloproteinase 12 in lung cancer cells (human 460 lung cancer cell line, Lewis lung carcinoma). In vitro, matrix metalloproteinase 12 knockout Lewis lung carcinoma and Lewis lung carcinoma cells had the same proliferation rate, but Lewis lung carcinoma showed increased invasiveness. In vivo, deficiency of matrix metalloproteinase 12 in Lewis lung carcinoma cells, but not in the host, reduced tumor growth and invasiveness. Conclusions: We suggest that tumor cell–derived matrix metalloproteinase 12 promotes tumor propagation in the lung and that in the context of pulmonary malignancies matrix metalloproteinase 12 should further be tested as a potential novel therapeutic target.

New Concepts in the Treatment of Malignant Pleural Mesothelioma

Malignant pleural mesothelioma (MPM) is a highly aggressive and generally incurable cancer. Current anti-MPM chemotherapy-based treatments are only marginally effective, and long-term survival remains an unmet goal. Nonetheless, in selected cases, personalized surgery-based multimodality treatments (MMT) have been shown to significantly extend survival. The design of MMT and selection of patients are challenging, and optimal results require accurate presurgical diagnosis, staging, and risk stratification. Further, meticulous surgical techniques and advanced radiation protocols must be applied. We review key principles and evolving concepts in the care of MPM patients with a focus on the expanding role of MMT in MPM.

Pneumonectomy for Non–Small Cell Lung Cancer

Lung cancer is the leading cause of cancer deaths and its incidence continues to increase. Emerging therapies as part of a multimodal approach are making more patients eligible for surgical resection. As more surgeons are treating locally advanced non-small cell lung cancer they find themselves recommending pneumonectomy as the surgical component of the multidisciplinary plan. Performing a pneumonectomy is technically demanding and is associated with many potential perioperative comorbidities. With the proper preparation, experience, and attention to perioperative care, pneumonectomy can be carried out safely with excellent outcomes and a good quality of life.

Perspective on malignant pleural mesothelioma diagnosis and treatment.

Malignant pleural mesothelioma (MPM) is an aggressive solid malignancy with dismal prognosis. The majority of newly diagnosed MPM patients present with advanced (IMIG/UICC stage IV) disease and are therefore treated with chemotherapy and supportive measures. The median survival of this group of patients ranges from 12 months with chemotherapy to 7 months with supportive care (1,2). Nonetheless, for a selected group of patients that present with a locally advanced disease (IMIG/UICC stage I–III), a personally tailored multimodality therapeutic (MMT) protocol comprising of cyto-reductive surgery and chemotherapy with or without radio-therapy may be the best therapeutic option. Although MMT is also associated with high rates of morbidity and mortality, it remains the sole option to significantly extend the survival of patients that physically and clinically qualify for this aggressive treatment strategy (3-8) .

Malignant pleural mesothelioma: key determinants in tailoring the right treatment for the right patient

Malignant pleural mesothelioma (MPM) is an aggressive solid malignancy with a dismal prognosis. Data from the International Association for the Study of Lung Cancer (IASLC) mesothelioma staging project, which is based on the records of both operable and non-operable MPM patients, indicates a median overall survival of 21, 19, 14 and 10 months for MPM patients with stage I, II, III and IV disease, respectively (1). Unfortunately, at diagnosis, the majority of MPM patients present with extensive disease and impaired functional status.

Commentary on: “uniportal video-assisted thoracoscopic surgery: safety, efficacy and learning curve during the first 250 cases in Quebec, Canada”

The past two decades have seen video-assisted thoracoscopic surgery (VATS) become the preferred approach for the treatment of early stage lung cancer (1,2) (NCCN, ACCP). Traditionally performed through 2–4 small incisions, thoracoscopic resection by a single 3–4 cm incision, or uniportal VATS resections, gaining traction at many centers around the globe. The adoption of anatomic resection by a uniportal thoracoscopic approach is still in a relatively early, phase with champions and critics on both teams (3,4). Proponents of uniportal VATS lobectomy advocate that this approach is associated with decreased pain, paresthesias, and morbidity, when compared to a multiportal thoracoscopic approach, resulting in expedited recovery. Opponents of the uniportal approach intimate concerns of patient safety and a steep learning curve as a result of the technical requirements of having all instrumentation share the same incision, in addition to unresolved questions of oncologic adequacy.

Role of thoracoscopy, mediastinoscopy and laparoscopy in the diagnosis and staging of malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is an aggressive malignancy with dismal prognosis. Unfortunately, chemotherapy only marginally extends patient survival and palliative care often remains the sole therapeutic option. Nonetheless, for a selected group of patients that present with an early disease stage and an epithelioid histology, a personally tailored multimodality therapeutic (MMT) protocol comprising of cyto-reductive surgery and chemotherapy with or without radiation therapy may significantly prolong survival. Accurately selecting patients for this aggressive therapeutic approach is challenging and is based in part on optimal pre-surgical staging. Here we discuss the role of thoracoscopy, mediastinoscopy and laparoscopy in the diagnosis and staging of MPM patients prior to definite surgical resection.