Oncogenic Signaling Pathways in The Cancer Genome Atlas.

Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFß signaling, p53 and ß-catenin/Wnt. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these pathways, and 57% percent of tumors had at least one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy.

Characterization of Infants with Idiopathic Transient and Persistent T Cell Lymphopenia Identified by Newborn Screening-a Single-Center Experience in New York State.

PURPOSE: Newborn screening (NBS) quantifies T cell receptor excision circles (TREC) and identifies infants with T cell lymphopenia (TCL). This study elucidates the demographics, laboratory characteristics, genetics, and clinical outcomes following live viral vaccine administration of term infants with transient or persistent idiopathic TCL. METHODS: A single-center retrospective analysis was performed from September 2010 through June 2018. Laboratory variables were compared with Mann-Whitney tests. Correlations between initial TREC levels and T cell counts were determined by Spearman tests. RESULTS: Twenty-two transient and 21 persistent TCL infants were identified. Males comprised 68% of the transient and 52% of the persistent TCL cohorts. Whites comprised 23% of the transient and 29% of the persistent cohorts. Median initial TREC levels did not differ (66 vs. 60 TRECs/µL of blood, P = 0.58). The transient cohort had higher median initial CD3+ (2135 vs. 1169 cells/µL, P < 0.001), CD4+ (1460 vs. 866 cells/µL, P < 0.001), and CD8+ (538 vs. 277 cells/µL, P < 0.001) counts. The median age of resolution for the transient cohort was 38 days. Genetic testing revealed 2 genes of interest which warrant further study and several variants of uncertain significance in immunology-related genes in the persistent cohort. 19 transient and 14 persistent subjects received the initial rotavirus and/or MMRV immunization. No adverse reactions to live viral vaccines were reported in either cohort. CONCLUSION: Transient and persistent TCL infants differ by demographic, laboratory, and clinical characteristics. Select transient and persistent TCL patients may safely receive live attenuated viral vaccines, but larger confirmatory studies are needed.

Regional isolation in the right atrium with disruption of intra-atrial conduction after catheter ablation of atrial tachycardia.

BACKGROUND: Ablation of atrial tachycardia (AT) that occurs after cardiac surgery or prior ablation often requires complex lesion sets. In combination with the pre-existing atrial scar, these lesion sets may result in inadvertent intra-atrial conduction block. This study reports the phenomenon of incidental isolation of right atrial (RA) regions that occurs secondary to AT ablation, which in some cases results in profound bradycardia due to sinus exit block. METHODS AND RESULTS: Intracardiac electrograms were examined in consecutive patients who underwent AT ablation in the RA. Cases of localized isolation of the RA were defined as areas that developed electrical dissociation during ablation. Of 132 patients having ablation in both the RA free wall and the cavotricuspid isthmus (CTI), 10 (7.6%) developed unintentional isolation of the lateral RA. Five of these patients had prior mitral valve surgery, comprising 12.2% of all 41 patients with mitral surgery who underwent ablation in the CTI and the RA free wall. All patients with regional isolation had a pre-existing scar in the lateral wall of the RA. In six patients, isolation of the lateral RA resulted in profound bradycardia due to exit block from the peri-sinus node myocardium. CONCLUSIONS: Complex ablation lesions in patients with prior valve surgery, prior ablation, or atrial myopathy may result in unintended localized conduction block in the RA. In some cases, isolation of the lateral RA can result in complete sinus exit block with profound bradycardia requiring pacemaker implantation.

The Left Atrial Appendage Ostium: Hotspots for Localized Re-Entry.

OBJECTIVES: The goal of this study was to characterize the location and electrophysiological properties of left atrial appendage (LAA) atrial tachycardia (AT). BACKGROUND: The LAA has been reported to be a source of AT and atrial fibrillation (AF) triggers. METHODS: This study retrospectively reviewed ATs mapped to the LAA. Activation and entrainment mapping were used to determine the mechanism and localize each AT circuit/origin. RESULTS: From 2014 to 2018, a total of 45 patients (mean age 65 ± 10 years; 69% male) had 51 LAA ATs: 43 (84%) after AF ablation and 8 de novo (no prior AF). Overall, 50 (98%) were due to localized re-entry/micro-re-entry, whereas only 1 was a focal triggered AT. All 50 micro-re-entrant LAA ATs were mapped to the anterior base (70%) or LAA ridge (30%), and all were successfully treated with focal ablation; no case required LAA isolation. After successful ablation of the initial AT at the LAA base, 23 (62%) of 37 patients with AF also had inducible macro-re-entrant peri-mitral flutter, but none had AF triggers from inside the LAA. CONCLUSIONS: LAA ATs are almost always micro-re-entrant in mechanism and originate from either the anterior base or LAA ridge. AT originating from inside the LAA body is very rare. The anterior and ridge aspects of the LAA-left atrium junction seem to be arrhythmogenic hotspots prone to localized re-entry. These ATs are treatable with focal ablation without LAA isolation but are frequently associated with macro-re-entrant peri-mitral flutter.

Regulation of human sphingomyelin synthase 1 translation through its 5'-untranslated region.

Bcr-abl1 oncogene causes a shift in the transcription start site of the SMS1 gene (SGMS1) encoding the sphingomyelin (SM) synthesizing enzyme, sphingomyelin synthase 1 (SMS1). This results in an mRNA with a significantly shorter 5'-UTR, called 7-SGMS1, which is translated more efficiently than another transcript (IIb-SGMS1) with a longer 5'UTR in Bcr-abl1-positive cells. Here, we determine the effects of these alternative 5'UTRs on SMS1 translation and investigate the key features underlying such regulation. First, the presence of the longer IIb 5'UTR is sufficient to greatly impair translation of a reporter gene. Deletion of the upstream open reading frame (-164 nt) or of the predicted stem-loops in the 5'UTR of IIb-SGMS1 has minimal effects on SGMS1 translation. Conversely, deletion of nucleotides -310 to -132 enhanced transcription of IIb-SGMS1 to reach that of 7-SGMS1. We thus suggest that regulatory features within nucleotides -310 and -132 modulate IIb-SGMS1 translation efficiency.

Clinical and Molecular Predictors of Response to Immune Checkpoint Inhibitors in Patients with Advanced Esophagogastric Cancer.

PURPOSE: Immune checkpoint inhibitors (ICI) are effective in only a minority of patients with esophagogastric cancer (EGC). Here, we aimed to identify predictors of durable clinical benefit to ICI in EGC. EXPERIMENTAL DESIGN: Patients with advanced EGC treated with ICIs at Memorial Sloan Kettering Cancer Center (New York, NY) were identified. Clinicopathologic variables were assessed. In patients profiled by MSK-IMPACT-targeted sequencing, outcomes were correlated with tumor genomic features. RESULTS: One-hundred sixty-one patients were treated with ICIs (110 with anti-PD-1/PD-L1 antibodies and 51 with anti-CTLA-4 and PD-1/PD-L1 antibodies). The median progression-free survival (PFS) and overall survival (OS) were 1.7 and 4.9 months, respectively. Greater number of disease sites (≥3), liver metastases, treatment with ≥3 prior therapies and ECOG performance status ≥2 were associated with poorer PFS and OS. Patients treated with combination ICI and those with PD-L1-positive tumors had improved outcomes. There was no difference in outcomes between patients treated with antibiotics during or in the 2 months preceding ICI treatment versus those who were not. Occurrence of irAEs was associated with improved OS. In genomically profiled tumors (n = 89), survival was associated with increasing tumor mutation burden (TMB). However, in multivariable analyses and when microsatellite unstable (MSI) patients were excluded, a significant association was no longer observed. CONCLUSIONS: In patients with advanced EGC, heavily pretreated patients, those with high-volume disease and/or poor PS were less likely to benefit from ICI. irAEs were associated with improved OS. TMB correlated with improved survival, but this association was not observed when MSI-high patients were excluded.