Faculty Bibliography

The relative contribution of intrinsic genetic factors and extrinsic environmental ones to cancer aetiology and natural history is a lengthy and debated issue. Gene-environment interactions (G x E) arise when the combined presence of both a germline genetic variant and a known environmental factor modulates the risk of disease more than either one alone. A panel of experts discussed our current understanding of cancer aetiology, known examples of G × E interactions in cancer, and the expanded concept of G × E interactions to include somatic cancer mutations and iatrogenic environmental factors such as anti-cancer treatment. Specific genetic polymorphisms and genetic mutations increase susceptibility to certain carcinogens and may be targeted in the near future for prevention and treatment of cancer patients with novel molecularly based therapies. There was general consensus that a better understanding of the complexity and numerosity of G × E interactions, supported by adequate technological, epidemiological, modelling and statistical resources, will further promote our understanding of cancer and lead to novel preventive and therapeutic approaches.

On March 28th - 29th 2017, the National Cancer Institute (NCI) Thoracic Malignacy Steering Committee (TMSC), the International Association for the Study of Lung Cancer (IASLC) and the Mesothelioma Applied Research Foundation (MARF), convened the NCI-IASLC-MARF Mesothelioma Clinical Trials Planning Meeting in Bethesda, Maryland. The goal of the meeting was to bring together lead academicians, clinicians, scientists and the FDA to focus on the development of clinical trials for patients diagnosed with malignant pleural mesothelioma (MPM). Based on the discovery of new cancer targets impacting the clinical development of novel agents and immunotherapies in malignant mesothelioma, the objective of this meeting was to assemble a consensus on at least 2-3 practice changing multimodality clinical trials to be conducted via NCI's National Clinical Trials Network (NCTN).

PURPOSE/OBJECTIVE:We hypothesized that four criteria could help identify malignant mesotheliomas (MMs) most likely linked to germline mutations of BAP1 or of other genes: family history of MM, BAP1-associated cancers, or multiple malignancies; or age younger than 50 years. PATIENTS AND METHODS/METHODS:Over the course of 7 years, 79 patients with MM met the four criteria; 22 of the 79 (28%) reported possible asbestos exposure. They were screened for germline BAP1 mutations by Sanger sequencing and by targeted next-generation sequencing (tNGS) for germline mutations in 55 additional cancer-linked genes. Deleterious mutations detected by tNGS were validated by Sanger sequencing. RESULTS:Of the 79 patients, 43 (16 probands and 27 relatives) had deleterious germline BAP1 mutations. The median age at diagnosis was 54 years and median survival was 5 years. Among the remaining 36 patients with no BAP1 mutation, median age at diagnosis was 45 years, median survival was 9 years, and 12 had deleterious mutations of additional genes linked to cancer. When compared with patients with MMs in the SEER cohort, median age at diagnosis (72 years), median survival for all MM stages (8 months), and stage I (11 months) were significantly different from the 79 patients with MM in the current study ( P < .0001). CONCLUSION/CONCLUSIONS:We provide criteria that help identify a subset of patients with MM who had significantly improved survival. Most of these patients were not aware of asbestos exposure and carried either pathogenic germline mutations of BAP1 or of additional genes linked to cancer, some of which may have targeted-therapy options. These patients and their relatives are susceptible to development of additional cancers; therefore, genetic counseling and cancer screening should be considered.

Background/UNASSIGNED:Mammalian cells express a single functional heparanase, an endoglycosidase that cleaves heparan sulfate and thereby promotes tumor metastasis, angiogenesis, and inflammation. Malignant mesothelioma is highly aggressive and has a poor prognosis because of the lack of markers for early diagnosis and resistance to conventional therapies. The purpose of this study was to elucidate the mode of action and biological significance of heparanase in mesothelioma and test the efficacy of heparanase inhibitors in the treatment of this malignancy. Methods/UNASSIGNED:The involvement of heparanase in mesothelioma was investigated by applying mouse models of mesothelioma and testing the effect of heparanase gene silencing (n = 18 mice per experiment; two different models) and heparanase inhibitors (ie, PG545, defibrotide; n = 18 per experiment; six different models). Synchronous pleural effusion and plasma samples from patients with mesothelioma (n = 35), other malignancies (12 non-small cell lung cancer, two small cell lung carcinoma, four breast cancer, three gastrointestinal cancers, two lymphomas), and benign effusions (five patients) were collected and analyzed for heparanase content (enzyme-linked immunosorbent assay). Eighty-one mesothelioma biopsies were analyzed by H-Score for the prognostic impact of heparanase using immunohistochemistry. All statistical tests were two-sided. Results/UNASSIGNED:Mesothelioma tumor growth, measured by bioluminescence or tumor weight at termination, was markedly attenuated by heparanase gene silencing (P = .02) and by heparanase inhibitors (PG545 and defibrotide; P < .001 and P = .01, respectively). A marked increase in survival of the mesothelioma-bearing mice (P < .001) was recorded. Heparanase inhibitors were more potent in vivo than conventional chemotherapy. Clinically, heparanase levels in patients' pleural effusions could distinguish between malignant and benign effusions, and a heparanase H-score above 90 was associated with reduced patient survival (hazard ratio = 1.89, 95% confidence interval = 1.09 to 3.27, P = .03). Conclusions/UNASSIGNED:Our results imply that heparanase is clinically relevant in mesothelioma development. Given these preclinical and clinical data, heparanase appears to be an important mediator of mesothelioma, and heparanase inhibitors are worthy of investigation as a new therapeutic modality in mesothelioma clinical trials.

Importance/UNASSIGNED:Stereotactic body radiation therapy (SBRT) has become a standard treatment for patients with medically inoperable early-stage lung cancer. However, its effectiveness in patients medically suitable for surgery is unclear. Objective/UNASSIGNED:To evaluate whether noninvasive SBRT delivered on an outpatient basis can safely eradicate lung cancer and cure selected patients with operable lung cancer, obviating the need for surgical resection. Design, Setting, and Participants/UNASSIGNED:Single-arm phase 2 NRG Oncology Radiation Therapy Oncology Group 0618 study enrolled patients from December 2007 to May 2010 with median follow-up of 48.1 months (range, 15.4-73.7 months). The setting was a multicenter North American academic and community practice cancer center consortium. Patients had operable biopsy-proven peripheral T1 to T2, N0, M0 non-small cell tumors no more than 5 cm in diameter, forced expiratory volume in 1 second (FEV1) and diffusing capacity greater than 35% predicted, arterial oxygen tension greater than 60 mm Hg, arterial carbon dioxide tension less than 50 mm Hg, and no severe medical problems. The data analysis was performed in October 2014. Interventions/UNASSIGNED:The SBRT prescription dose was 54 Gy delivered in 3 18-Gy fractions over 1.5 to 2.0 weeks. Main Outcomes and Measures/UNASSIGNED:Primary end point was primary tumor control, with survival, adverse events, and the incidence and outcome of surgical salvage as secondary end points. Results/UNASSIGNED:Of 33 patients accrued, 26 were evaluable (23 T1 and 3 T2 tumors; 15 [58%] male; median age, 72.5 [range, 54-88] years). Median FEV1 and diffusing capacity of the lung for carbon monoxide at enrollment were 72.5% (range, 38%-136%) and 68% (range, 22%-96%) of predicted, respectively. Only 1 patient had a primary tumor recurrence. Involved lobe failure, the other component defining local failure, did not occur in any patient, so the estimated 4-year primary tumor control and local control rate were both 96% (95% CI, 83%-100%). As per protocol guidelines, the single patient with local recurrence underwent salvage lobectomy 1.2 years after SBRT, complicated by a grade 4 cardiac arrhythmia. The 4-year estimates of disease-free and overall survival were 57% (95% CI, 36%-74%) and 56% (95% CI, 35%-73%), respectively. Median overall survival was 55.2 months (95% CI, 37.7 months to not reached). Protocol-specified treatment-related grade 3, 4, and 5 adverse events were reported in 2 (8%; 95% CI, 0.1%-25%), 0, and 0 patients, respectively. Conclusions and Relevance/UNASSIGNED:As given, SBRT appears to be associated with a high rate of primary tumor control, low treatment-related morbidity, and infrequent need for surgical salvage in patients with operable early-stage lung cancer. Trial Registration/UNASSIGNED:ClinicalTrials.gov Identifier: NCT00551369.

Shoulder tip pain may occur after thoracic surgical procedures. The pain is caused by diaphragmatic irritation and is referred to the shoulder. Shoulder tip pain is often resistant to treatment with conventional analgesics. The sphenopalatine ganglion block has been described to manage many painful conditions. We report here the first use of this block to treat shoulder tip pain in 2 thoracic surgical patients. In both patients, the block produced rapid and sustained relief of the shoulder tip pain. We suggest that sphenopalatine ganglion block be considered to treat postoperative shoulder tip pain after thoracic surgical procedures.

OBJECTIVES: Despite previous retrospective reports that the number of lymph nodes resected at curative intent surgery for lung cancer correlates with overall survival (OS), no consensus exists regarding the minimal nor optimal number of lymph nodes to resect at curative lung cancer surgery. METHODS: We studied subjects in the Surveillance Epidemiology and End Results Database (SEER) diagnosed with non-small cell lung cancer between 2000 and 2011 who underwent either lobectomy or pneumonectomy and had pathologic negative nodal evaluation. We excluded patients with sublobar resection and/or no lymph node evaluation. We examined associations between number of lymph nodes evaluated and OS/lung cancer-specific survival by multivariable Cox regression; and predictors of evaluation of more lymph nodes. RESULTS: Among the 33,463 patients in our sample, a median of 7 lymph nodes were evaluated. We found that lung cancer-specific survival and OS improved with increasing lymph node evaluation up to 16 to 18 lymph nodes (hazard ratio, 0.77 [95% confidence interval, 0.70-0.85] and 0.78 [95% confidence interval, 0.72-0.86], respectively). There was little additional improvement in outcomes with evaluation of >16 to 18 lymph nodes. Blacks, Hispanics, females, and patients from distinct geographical regions were less likely to have 16 or more lymph nodes evaluated. CONCLUSIONS: There was a consistently increasing survival benefit associated with a more extensive lymph node evaluation at lung cancer resection, up to 16 to 18 lymph nodes removed. The median number of nodes evaluated was, however, only 7, suggesting that setting a goal of >/=16 examined lymph nodes may lead to improved survival outcomes, and reduce disparities in care.