Citations

Abstract Context von Hippel-Lindau (VHL) disease, comprising renal cancer, hemangioblastoma, and/or pheochromocytoma (PHEO), is caused by missense or truncating variants of the VHL tumor-suppressor gene, which is involved in degradation of hypoxia-inducible factors (HIFs). However, the role of synonymous VHL variants in the disease is unclear. Objective We evaluated a synonymous VHL variant in patients with familial PHEO or VHL disease without a detectable pathogenic VHL mutation. Design We performed genetic and transcriptional analyses of leukocytes and/or tumors from affected and unaffected individuals and evaluated VHL splicing in existing cancer databases. Results We identified a synonymous VHL variant (c.414A>G, p.Pro138Pro) as the driver event in five independent individuals/families with PHEOs or VHL syndrome. This variant promotes exon 2 skipping and hence, abolishes expression of the full-length VHL transcript. Exon 2 spans the HIF-binding domain required for HIF degradation by VHL. Accordingly, PHEOs carrying this variant display HIF hyperactivation typical of VHL loss. Moreover, other exon 2 VHL variants from the The Cancer Genome Atlas pan-cancer datasets are biased toward expression of a VHL transcript that excludes this exon, supporting a broader impact of this spliced variant. Conclusion A recurrent synonymous VHL variant (c.414A>G, p.Pro138Pro) confers susceptibility to PHEO and VHL disease through splice disruption, leading to VHL dysfunction. This finding indicates that certain synonymous VHL variants may be clinically relevant and should be considered in genetic testing and surveillance settings. The observation that other coding VHL variants can exclude exon 2 suggests that dysregulated splicing may be an underappreciated mechanism in VHL-mediated tumorigenesis.

Background Chronic rhinosinusitis (CRS) and allergic rhinitis (AR) may be associated with an increased risk of subsequent diagnosis of nasopharyngeal carcinoma (NPC) or paranasal sinus cancer (PSC) in elderly Americans. The clinical utility of this association remains uncertain. Objective To compare early computed tomography (CT) or nasal endoscopy (NE) with late diagnostic studies for the diagnosis of NPC or PSC in elderly Americans with CRS or AR. Methods The Surveillance, Epidemiology, and End Results (SEER)-Medicare database was queried from 2003 to 2011 and included 150 088 Medicare beneficiaries. Patients with a diagnosis of CRS or AR were examined for either NE or CT performed within 6 months of the exposure diagnosis. The risk of a cancer diagnosis was determined between the early and the late diagnostic groups. Results The relative risk of early cancer diagnosis with NE was 1.98 (95% confidence interval [CI], 1.60–2.43). The number needed to detect (NND) a case of cancer with NE was 503 (95% CI, 387–718). The relative risk of an early cancer diagnosis using CT was 3.40 (95% CI, 2.85–4.06) and NND was 221 (95% CI, 194–255). The stage of NPC or PSC for the late diagnostic group was not different from those with early NE ( P = .458) or CT ( P = .497). Overall survival was not different between diagnostic groups for NE ( P = .789) or CT ( P = .425). Conclusions Early NE or CT is associated with a higher likelihood of cancer diagnosis in elderly individuals with a diagnosis of CRS or AR. The clinical utility of this association is limited due to the low prevalence of these malignancies and lack of difference in disease stage and overall survival between diagnostic groups.

Introduction: Frailty and decreased physical performance are associated with poor outcomes after kidney transplant. Less is known about their relationship with pretransplant outcomes. The aim of this study was to characterize associations between frailty and physical performance with death on the kidney transplant waiting list. Design: Since December 2014, high-risk kidney transplant candidates at our center (age > 59, diabetic and/or history of >3 years dialysis) have undergone frailty and physical performance testing using Fried Criteria and the Short Physical Performance Battery. Results: Between December 2014 and November 2016, 272 high-risk candidates underwent testing and were approved for transplant. Both frailty and physical performance score were significantly associated with death on the waiting list (hazard ratio [HR]: 6.7, confidence interval [CI]: 1.5-30.1; P = .01; HR: 0.8 per 1-point increase, CI: 0.7-1.0; P = .02, respectively). The relationship between frailty, physical performance score, and death on the waiting list appeared to be independent of age, diabetes, or duration of dialysis. Discussion: Frailty and decreased physical performance appear to be independently associated with increased mortality on the kidney transplant waiting list. Further studies are needed to determine whether improving frailty and physical performance prior to transplant can decrease waiting list mortality.

Abstract MCAM (CD146) is a cell surface adhesion molecule that has been reported to promote cancer development, progression and metastasis and is considered as a potential tumor biomarker and therapeutic target. However, inconsistent reports exist, and its clinical value is yet to be confirmed. Here we took advantage of several large genomic data collections (Genotype-Tissue Expression, The Cancer Genome Atlas and Cancer Cell Line Encyclopedia) and comprehensively analyzed MCAM expression in thousands of normal and cancer samples and cell lines along with their clinical phenotypes and drug response information. Our results show that MCAM is very highly expressed in large vessel tissues while majority of tissues have low or minimal expression. Its expression is dramatically increased in a few tumors but significantly decreased in most other tumors relative to their pairing normal tissues. Increased MCAM expression is associated with a higher tumor stage and worse patient survival for some less common tumors but not for major ones. Higher MCAM expression in primary tumors may be complicated by tumor-associated or normal stromal blood vessels yet its significance may differ from the one from cancer cells. MCAM expression is weakly associated with the response to a few small molecular drugs and the association with targeted anti-BRAF agents suggests its involvement in that pathway which warrants further investigation.

Alpha‐1 antitrypsin deficiency (AATD) liver disease is characterized by marked heterogeneity in presentation and progression, despite a common underlying gene mutation, strongly suggesting the involvement of other genetic and/or epigenetic modifiers. Variation in clinical phenotype has added to the challenge of detection, diagnosis, and testing of new therapies in patients with AATD. We examined the contribution of DNA methylation (5‐methylcytosine [5mC]) to AATD liver disease heterogeneity because 5mC responds to environmental and genetic cues and its deregulation is a major driver of liver disease. Using liver biopsies from adults with early‐stage AATD and the ZZ genotype, genome‐wide 5mC patterns were interrogated. We compared DNA methylation among patients with early AATD, and among patients with normal liver, cirrhosis, and hepatocellular carcinoma derived from multiple etiologic exposures, and linked patient clinical/demographic features. Global analysis revealed significant genomic hypomethylation in AATD liver–impacting genes related to liver cancer, cell cycle, and fibrosis, as well as key regulatory molecules influencing growth, migration, and immune function. Further analysis indicated that 5mC changes are localized, with hypermethylation occurring within a background of genome‐wide 5mC loss and with patients with AATD manifesting distinct epigenetic landscapes despite their mutational homogeneity. By integrating clinical data with 5mC landscapes, we observed that CpGs differentially methylated among patients with AATD disease are linked to hallmark clinical features of AATD (e.g., hepatocyte degeneration and polymer accumulation) and further reveal links to well‐known sex‐specific effects of liver disease progression. Conclusion: Our data reveal molecular epigenetic signatures within this mutationally homogeneous group that point to ways to stratify patients for liver disease risk.

AbstractBackgroundAn association is suggested between gastroesophageal reflux disease (GERD) or laryngopharyngeal reflux (LPR) and malignancy of the larynx in elderly patients in the United States. Early detection with flexible fiberoptic laryngoscopy (FFL) or CT remains poorly defined.MethodsThe Surveillance, Epidemiology, and End Results (SEER)‐Medicare linked database was queried from 2003 to 2011.A case‐cohort design evaluated patients aged 66 and older with a diagnosis of GERD and/or LPR for the occurrence of FFL or CT within 6 months of the exposure diagnosis.ResultsOf a total 156 426 Medicare beneficiaries, the relative risk of early cancer diagnosis with FFL was 14.61(95% confidence interval [CI], 13.59‐15.70), corresponding to a number needed to detect (NND) a case of cancer of 13(95% CI, 13‐14). The relative risk of an early cancer diagnosis with CT was 31.83 (95% CI, 29.57‐34.26), with a NND of 5 (95% CI, 5‐5).ConclusionsEarly FFL and CT are associated with a higher likelihood of laryngeal cancer diagnosis in elderly individuals with a diagnosis of reflux. Screening trials are necessary to establish this relationship.

Abstract Posterior pilon fractures involve the medial malleolus (MM). Our purpose was to define the characteristics of posterior pilon fractures, and propose a classification system based on fracture morphology and type of management. The records of patients with posterior pilon fractures treated from 2011 to 2015 were retrospectively reviewed. The injury mechanism, fracture morphology, surgical approach, and follow-up results were reviewed and analyzed. This study was approved by the Institutional Review Board of PLA Army General Hospital. Thirty-six patients, 18 males and 18 females (mean age: 48.9 years) were included in the study. Four characteristics were used to define posterior pilon fractures. A simple posterolateral approach or a combined posterolateral and posteromedial approach was used for reduction and fixation in all patients. The mean follow-up time was 28.2 months, and at the end of follow-up, the mean American Orthopedic Foot and Ankle Society Score (AOFAS) was 82.5 points (range: 35–100 points). Based on injury mechanism and fracture morphology, we classified posterior pilon fractures into 3 types that suggest the optimal surgical approach: type I, a single complete fracture fragment; type II, a posterior malleolus fracture with 2 subtypes; type III, a posterior malleolus fracture associated with complete MM fracture with 2 subtypes. The proposed classification system based on injury mechanism and fracture morphology can guide the surgical approach to maximize outcomes.