Citations

Abstract Purpose: Pulmonary carcinoid tumors account for up to 5% of all lung malignancies in adults, comprise 30% of all carcinoid malignancies, and are defined histologically as typical carcinoid (TC) and atypical carcinoid (AC) tumors. The role of specific genomic alterations in the pathogenesis of pulmonary carcinoid tumors remains poorly understood. We sought to identify genomic alterations and pathways that are deregulated in these tumors to find novel therapeutic targets for pulmonary carcinoid tumors. Experimental Design: We performed integrated genomic analysis of carcinoid tumors comprising whole genome and exome sequencing, mRNA expression profiling and SNP genotyping of specimens from normal lung, TC and AC, and small cell lung carcinoma (SCLC) to fully represent the lung neuroendocrine tumor spectrum. Results: Analysis of sequencing data found recurrent mutations in cancer genes including ATP1A2, CNNM1, MACF1, RAB38, NF1, RAD51C, TAF1L, EPHB2, POLR3B, and AGFG1. The mutated genes are involved in biological processes including cellular metabolism, cell division cycle, cell death, apoptosis, and immune regulation. The top most significantly mutated genes were TMEM41B, DEFB127, WDYHV1, and TBPL1. Pathway analysis of significantly mutated and cancer driver genes implicated MAPK/ERK and amyloid beta precursor protein (APP) pathways whereas analysis of CNV and gene expression data suggested deregulation of the NF-κB and MAPK/ERK pathways. The mutation signature was predominantly C>T and T>C transitions with a minor contribution of T>G transversions. Conclusions: This study identified mutated genes affecting cancer relevant pathways and biological processes that could provide opportunities for developing targeted therapies for pulmonary carcinoid tumors. Clin Cancer Res; 24(7); 1691–704. ©2018 AACR.

AbstractBackgroundCalciphylaxis is a devastating multifactorial disorder of the subcutaneous fat that is known to be associated with hypercoagulability. Recent literature has proposed subclassifying patients with calciphylaxis as having warfarin‐associated or warfarin‐unassociated disease.AimWe aimed to determine whether patients with warfarin‐associated calciphylaxis differ clinically from patients with warfarin‐unassociated calciphylaxis.Materials and methodsWe performed a subgroup analysis of patients with nonuremic calciphylaxis from a previously studied cohort and compared clinical and outcomes features of patients who were taking warfarin at the time of disease onset to those of patients who were not.ResultsNineteen patients with nonuremic calciphylaxis were identified, including 10 (53%) who had been on warfarin at the time of disease onset and 9 (47%) who had not. Of all clinical and outcomes parameters tested, no significant differences were detected between the two groups.Discussion and ConclusionsThough this study is limited by its retrospective nature and the relatively small number of patients studied, available data do not support subclassifying patients with nonuremic calciphylaxis as having warfarin‐associated or warfarin‐unassociated disease. Rather, the body of literature would suggest that identification and correction of underlying disorders of hypercoagulability should be prioritized.

AbstractBackgroundClinical diagnostic criteria for PD rely on rest tremor, bradykinesia, and rigidity. These features are non‐specific and neuropathological confirmation remains the gold standard for diagnosis. This study presents data on clinical certainty ratings in autopsy‐proven PD.MethodsSubjects were assessed annually by a movement disorders specialist and assigned to a clinical certainty group for PD based on multiple clinical features before autopsy. The three groups considered for analysis are as follows: Group I 0–49% certainty, Group II 50‐89% certainty, and Group III 90–100% certainty. All subjects were autopsied and had a standardized neuropathological assessment.Results275 subjects were assigned a PD certainty at their last visit before death. Group I had 80 subjects, Group II 56 subjects, and Group III 139 subjects. The clinical features recorded in Group I, II, and III, were as follows: rest tremor, bradykinesia, rigidity, postural instability, asymmetric onset, persistent asymmetry, current response to dopaminergic treatment, motor fluctuations, and dyskinesia. Rigidity, postural instability, asymmetric onset, current response to dopaminergic treatment, motor fluctuation, and dyskinesia were more likely to be present in the group which was rated with higher certainty. The final diagnosis of PD was confirmed by neuropathological assessment in 85% of the patients in Group III as compared to 30% in Group II and 5% in Group I.ConclusionsHigh certainty (90–100%) had strong positive predictive value (85%) for autopsy‐proven PD as compared to either lower certainty groups (0–49% and 50–89%) which had lower predictive value (5% and 30% respectively).

AbstractBackgroundThis study presents oncologic outcomes after transoral robotic surgery (TORS) ± adjuvant therapy for oropharyngeal squamous cell carcinoma (SCC).MethodsThree hundred fourteen patients undergoing TORS ± adjuvant therapy for oropharyngeal SCC from May 1, 2007, to May 31, 2015, are analyzed.ResultsMedian follow‐up was 3.3 years (interquartile range [IQR] 1.8‐5.3 years; range 1 day to 9.3 years). Estimated locoregional recurrence‐free survival, distant metastasis‐free survival (DMFS), overall survival (OS), and cancer‐specific survival (CSS) rates (95% confidence interval [CI] number still at risk) at 5 years after surgery were 92% (88‐95; 92), 90% (86‐94; 92), 86% (82‐92; 98), and 94% (91‐97; 98), respectively. Negative margins were achieved in 98% of cases. The adult comorbidity evaluation (ACE)‐27 comorbidity index, human papillomavirus (HPV) status, pathologic N classification, and number of attempts to clear margins were associated with death due to cancer (P = .003, P = .002, P = .030, and P = .002, respectively).ConclusionThe need to take ≥2 margins to achieve resection portends an increased risk of locoregional recurrence and death due to disease in oropharyngeal SCC.

SNF'ing out antitumor immunity Immune checkpoint inhibitors induce durable tumor regressions in some, but not all, cancer patients. Understanding the mechanisms that determine tumor sensitivity to these drugs could potentially expand the number of patients who benefit (see the Perspective by Ghorani and Quezada). Pan et al. discovered that tumor cells in which a specific SWI/SNF chromatin remodeling complex had been experimentally inactivated were more sensitive to T cell–mediated killing. The cells were more responsive to interferon-γ, leading to increased secretion of cytokines that promote antitumor immunity. Miao et al. examined the genomic features of tumors from patients with metastatic renal cell carcinoma who had been treated with immune checkpoint inhibitors. Tumors harboring inactivating mutations in PBRM1 , which encodes a subunit of the same SWI/SNF complex, were more likely to respond to the drugs. Science , this issue p. 770 , p. 801 ; see also p. 745