Bevacizumab in combination with carboplatin and paclitaxel improved overall response and time to progression in patients with advanced or recurrent non-small-cell lung cancer. Patients with nonsquamous cell histology appear to be a subpopulation with improved outcome and acceptable safety risks.

Mesothelioma affects mostly older individuals who have been occupationally exposed to asbestos. The global mesothelioma incidence and mortality rates are unknown, because data are not available from developing countries that continue to use large amounts of asbestos. The incidence rate of mesothelioma has decreased in Australia, the United States, and Western Europe, where the use of asbestos was banned or strictly regulated in the 1970s and 1980s, demonstrating the value of these preventive measures. However, in these same countries, the overall number of deaths from mesothelioma has not decreased as the size of the population and the percentage of old people have increased. Moreover, hotspots of mesothelioma may occur when carcinogenic fibers that are present in the environment are disturbed as rural areas are being developed. Novel immunohistochemical and molecular markers have improved the accuracy of diagnosis; however, about 14% (high-resource countries) to 50% (developing countries) of mesothelioma diagnoses are incorrect, resulting in inadequate treatment and complicating epidemiological studies. The discovery that germline BRCA1-asssociated protein 1 (BAP1) mutations cause mesothelioma and other cancers (BAP1 cancer syndrome) elucidated some of the key pathogenic mechanisms, and treatments targeting these molecular mechanisms and/or modulating the immune response are being tested. The role of surgery in pleural mesothelioma is controversial as it is difficult to predict who will benefit from aggressive management, even when local therapies are added to existing or novel systemic treatments. Treatment outcomes are improving, however, for peritoneal mesothelioma. Multidisciplinary international collaboration will be necessary to improve prevention, early detection, and treatment. CA Cancer J Clin 2019;69:402-429.

Study objective-To demonstrate the efficacy, safety, and appropriate mode of instillation of talc for sclerosis in treatment of malignant pleural effusions (MPEs).Design-A prospective, randomized trial was designed to compare thoracoscopy with talc insufflation (TTI) to thoracostomy and talc slurry (TS) for patients with documented MPE.Measurements-The primary end point was 30-day freedom from radiographic MPE recurrence among surviving patients whose lungs initially re-expanded > 90%. Morbidity, mortality, and quality of life were also assessed.Results-Of 501 patients registered, those eligible were randomized to TTI (n = 242) or TS (n = 240). Patient demographics and primary malignancies were similar between study arms. Overall, there was no difference between study arms in the percentage of patients with successful 30-day outcomes (TTI, 78%; TS, 71%). However, the subgroup of patients with primary lung or breast cancer had higher success with TTI than with TS (82% vs 67%). Common morbidity included fever, dyspnea, and pain. Treatment-related mortality occurred in nine TTI patients and seven TS patients. Respiratory complications were more common following TTI than TS (14% vs 6%).Correspondence to: Carolyn Dresler, MD, MPA, Head, Tobacco Unit, International Agency for Research on Cancer, Lyon, France; Carolyn_dresler@ksg03.harvard.edu. HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptRespiratory failure was observed in 4% of TS patients and 8% of TTI patients, accounting for five toxic deaths and six toxic deaths, respectively. Quality-of-life measurement demonstrated less fatigue with TTI than TS. Patient ratings of comfort and safety were also higher for TTI, but there were no differences on perceived value or convenience of the procedures. Since that time, a significant number of single institution reports have been published, primarily using thorascopically insufflated talc. However, a growing number of authors have advocated talc slurry via a percutaneously placed chest tube as a simpler and equally effective method for control of MPE with minimal short-term morbidity. However, several reports 10,11 of serious respiratory complications with talc have also been published. Conclusions-BothThe objectives of the current trial Cooperative Groups Cancer and Leukemia Group B (CALGB) 9334 compare tube thoracostomy with talc slurry (TS) to surgical thoracoscopy with talc insufflation (TTI), and assesses their efficacy at 30 days, in addition to the safety and associated quality of life in a randomized multicenter trial. Portions of this work have been presented in abstract form. 12 Materials and MethodsThis was an intergroup cooperative trial led by the CALGB and monitored semiannually by its Data and Safety Monitoring Board, with participation by the Radiation Therapy Oncology Group, the Eastern Cooperative Oncology Group (ECOG), and the North Central Cooperative Oncology Group, encompassing both private and teaching hospitals. Credentialing of participating surgeon...

Summary Lung cancer, the leading cause of cancer mortality, exhibits heterogeneity that enables adaptability, limits therapeutic success, and remains incompletely understood. Single-cell RNA sequencing (scRNA-seq) of metastatic lung cancer was performed using 49 clinical biopsies obtained from 30 patients before and during targeted therapy. Over 20,000 cancer and tumor microenvironment (TME) single-cell profiles exposed a rich and dynamic tumor ecosystem. scRNA-seq of cancer cells illuminated targetable oncogenes beyond those detected clinically. Cancer cells surviving therapy as residual disease (RD) expressed an alveolar-regenerative cell signature suggesting a therapy-induced primitive cell-state transition, whereas those present at on-therapy progressive disease (PD) upregulated kynurenine, plasminogen, and gap-junction pathways. Active T-lymphocytes and decreased macrophages were present at RD and immunosuppressive cell states characterized PD. Biological features revealed by scRNA-seq were biomarkers of clinical outcomes in independent cohorts. This study highlights how therapy-induced adaptation of the multi-cellular ecosystem of metastatic cancer shapes clinical outcomes.

We describe here the existence of a heregulin-HER3 autocrine loop, and the contribution of heregulin-dependent, HER2-mediated HER3 activation to gefitinib insensitivity in non-small cell lung cancer (NSCLC). ADAM17 protein, a major ErbB ligand sheddase, is upregulated in NSCLC and is required not only for heregulin-dependent HER3 signaling, but also for EGFR ligand-dependent signaling in NSCLC cell lines. A selective ADAM inhibitor, INCB3619, prevents the processing and activation of multiple ErbB ligands, including heregulin. In addition, INCB3619 inhibits gefitinib-resistant HER3 signaling and enhances gefitinib inhibition of EGFR signaling in NSCLC. These results show that ADAM inhibition affects multiple ErbB pathways in NSCLC and thus offers an excellent opportunity for pharmacological intervention, either alone or in combination with other drugs.

No abstract

Summary Background The frequent recurrence of early-stage non-small-cell lung cancer (NSCLC) is generally attributable to metastatic disease undetected at complete resection. Management of such patients depends on prognostic staging to identify the individuals most likely to have occult disease. We aimed to develop and validate a practical, reliable assay that improves risk stratification compared with conventional staging. Methods A 14-gene expression assay that uses quantitative PCR, runs on formalin-fixed paraffin-embedded tissue samples, and differentiates patients with heterogeneous statistical prognoses was developed in a cohort of 361 patients with non-squamous NSCLC resected at the University of California, San Francisco. The assay was then independently validated by the Kaiser Permanente Division of Research in a masked cohort of 433 patients with stage I non-squamous NSCLC resected at Kaiser Permanente Northern California hospitals, and on a cohort of 1006 patients with stage I–III non-squamous NSCLC resected in several leading Chinese cancer centres that are part of the China Clinical Trials Consortium (CCTC). Findings Kaplan-Meier analysis of the Kaiser validation cohort showed 5 year overall survival of 71·4% (95% CI 60·5–80·0) in low-risk, 58·3% (48·9–66·6) in intermediate-risk, and 49·2% (42·2–55·8) in high-risk patients (ptrend=0·0003). Similar analysis of the CCTC cohort indicated 5 year overall survivals of 74·1% (66·0–80·6) in low-risk, 57·4% (48·3–65·5) in intermediate-risk, and 44·6% (40·2–48·9) in high-risk patients (ptrend<0·0001). Multivariate analysis in both cohorts indicated that no standard clinical risk factors could account for, or provide, the prognostic information derived from tumour gene expression. The assay improved prognostic accuracy beyond National Comprehensive Cancer Network criteria for stage I high-risk tumours (p<0·0001), and differentiated low-risk, intermediate-risk, and high-risk patients within all disease stages. Interpretation Our practical, quantitative-PCR-based assay reliably identified patients with early-stage non-squamous NSCLC at high risk for mortality after surgical resection. Funding UCSF Thoracic Oncology Laboratory and Pinpoint Genomics.

Nasopharyngeal carcinoma (NPC) is a head and neck cancer rare throughout most of the world but common in certain geographic areas, such as southern Asia. While environmental factors and genetic susceptibility play important roles in NPC pathogenesis, the Epstein-Barr virus in particular has been implicated in the molecular abnormalities leading to NPC. There is upregulation of cellular proliferation pathways such as the Akt pathway, mitogen-activated protein kinases, and the Wnt pathway. Cell adhesion is compromised due to abnormal E-cadherin and β-catenin function. Aberrations in cell cycle are due to dysregulation of factors such as p16, cyclin D1, and cyclin E. Anti-apoptotic mechanisms are also upregulated. There are multiple abnormalities unique to NPC that are potential targets for novel treatments. Keywordsnasopharyngeal carcinoma (NPC); Epstein; Barr virus (EBV); LMP1; tumorigenesis; review Nasopharyngeal carcinoma (NPC) is a squamous cell carcinoma that usually develops around the ostium of the Eustachian tube in the lateral wall of the nasopharynx. 1 Though rare among whites, NPC is particularly common in the southern Chinese population of Guangdong, Inuits of Alaska, and native Greenlanders. 2,3 Chinese emigrants continue to have a high incidence of the disease, but the rate of NPC among ethnic Chinese born in North America is considerably lower than those born in China. 4 This epidemiologic evidence implies that both environmental factors and genetic susceptibility play roles in the development of NPC. The environmental factors may include exposure to nitrosamines in salted and pickled foods. 5 Certain human leukocyte antigen subtypes have been associated with NPC, as they have various genetic polymorphisms. 6 The World Health Organization classifies NPC based on histology. 7 Type 1, keratinizing squamous carcinoma, is characterized by well-differentiated cells that produce keratin. Type 2, nonkeratinizing squamous carcinoma, varies in cell differentiation but does not produce keratin. Type 3 is also nonkeratinizing, but is less differentiated, with highly variable cell types (clear cell, spindle cell, anaplastic). Types 2 and 3 NPC are Epstein-Barr virus (EBV) Correspondence to: D. M. Jablons, jablonsd@surgery.ucsf.edu. Standard treatment for NPC is radiotherapy, but concurrent adjuvant chemotherapy improves survival rates. 10 As with other cancers, the prognosis of NPC depends upon tumor size, lymph node involvement, and distant metastasis (TMN staging). 11 But NPC, in contrast to other head and neck malignancies, is highly sensitive to radiation and chemotherapy. 12,13 High survival rates are reported for stage 1 and 2 diseases, but the prognosis for metastatic disease remains poor even with combined radiation and chemotherapy treatment, with disease relapse rates as high as 82%. 14,15 Unfortunately, the majority of NPC is diagnosed at an advanced stage because of non-specific presenting symptoms (cervical nodal enlargement, headache, nasal and aural dysfunction), delay in seeking treat...