Citations

355 Background: In this study, we sought to determine the prognostic factors impacting survival of patients with NELM who underwent LT at Mayo Clinic. Methods: We performed a three-site retrospective analysis of patients with unresectable NELM treated with LT from 1990 -2017. Cases were identified from clinical databases at Mayo Clinic. Data on demographics, timing of diagnosis and transplant, extent of liver involvement, and tumor grade, were extracted. Extent of liver involvement was calculated using previously validated standardized volumetry with high defined as > 25% increase in the weight of the extracted liver at the time of the transplant as compared to the standard liver volume. Survival was calculated using the Kaplan–Meier method. Results: We identified 37 patients. Median age at LT was 47 (range 17.0-64.0), male: female (73% vs. 27%, respectively). Primary tumor site was in the pancreas in 51.3% and in the small bowels in 43.2%; 78.4% had NELM at presentation. While primary tumor resection was done at the time of LT in 5 (13.9%) cases, most patients (80.6%) had ˃6-months interval between primary tumor resection and LT surgery. Prior to LT, 25 (74.3%) patients received somatostatin analogues and 18 (61.3%) had liver-directed therapy. Median time from diagnosis to transplant was 33.6 months (0-246). High extent of liver involvement was identified in 12 patients (33.3%). Disease-Free Survival (DFS) at 3, 5, and 10 years was 56.8%, 43.1%, and 22.4% respectively. Overall-survival (OS) at 3, 5, and 10 years was 86.9%, 79.6%, and 52.6% respectively. High extent of liver involvement at the time of transplantation was associated with inferior DFS and OS and patients˃45 years-old at the time of transplantation had worse DFS. Patients whose disease met the OPTN (Organ Procurement and Transplantation Network) criteria for NELM transplantation had significantly better DFS and OS with median 10-year OS of 80.7 % vs. 17%. Conclusions: LT is a reasonable therapeutic option for selected patients with unresectable NELM with 10-year OS of 52.6%. High extent of liver involvement was associated with worse long-term outcomes while meeting OPTN criteria resulted in best outcomes.

Key points Mutations in the caveolae scaffolding protein, caveolin‐3 (Cav3), have been linked to the long QT type 9 inherited arrhythmia syndrome (LQT9) and the cause of underlying action potential duration prolongation is incompletely understood. In the present study, we show that LQT9 Cav3 mutations, F97C and S141R, cause mutation‐specific gain of function effects on Cav1.2‐encoded L‐type Ca2+ channels responsible for ICa,L and also cause loss of function effects on heterologously expressed Kv4.2 and Kv4.3 channels responsible for Ito. A computational model of the human ventricular myocyte action potential suggests that the major ionic current change causing action potential duration prolongation in the presence of Cav3‐F97C is the slowly inactivating ICa,L but, for Cav3‐S141R, both increased ICa,L and increased late Na+ current contribute equally to action potential duration prolongation. Overall, the LQT9 Cav3‐F97C and Cav3‐S141R mutations differentially impact multiple ionic currents, highlighting the complexity of Cav3 regulation of cardiac excitability and suggesting mutation‐specific therapeutic approaches. AbstractMutations in the CAV3 gene encoding caveolin‐3 (Cav3), a scaffolding protein integral to caveolae in cardiomyocytes, have been associated with the congenital long‐QT syndrome (LQT9). Initial studies demonstrated that LQT9‐associated Cav3 mutations, F97C and S141R, increase late sodium current as a potential mechanism to prolong action potential duration (APD) and cause LQT9. Whether these Cav3 LQT9 mutations impact other caveolae related ion channels remains unknown. We used the whole‐cell, patch clamp technique to characterize the effect of Cav3‐F97C and Cav3‐S141R mutations on heterologously expressed Cav1.2+Cavβ2cN4 channels, as well as Kv4.2 and Kv4.3 channels, in HEK 293 cells. Expression of Cav3‐S141R increased ICa,L density without changes in gating properties, whereas expression of Cav3‐F97C reduced Ca2+‐dependent inactivation of ICa,L without changing current density. The Cav3‐F97C mutation reduced current density and altered the kinetics of IKv4.2 and IKv4.3 and also slowed recovery from inactivation. Cav3‐S141R decreased current density and also slowed activation kinetics and recovery from inactivation of IKv4.2 but had no effect on IKv4.3. Using the O'Hara–Rudy computational model of the human ventricular myocyte action potential, the Cav3 mutation‐induced changes in Ito are predicted to have negligible effect on APD, whereas blunted Ca2+‐dependent inactivation of ICa,L by Cav3‐F97C is predicted to be primarily responsible for APD prolongation, although increased ICa,L and late INa by Cav3‐S141R contribute equally to APD prolongation. Thus, LQT9 Cav3‐associated mutations, F97C and S141R, produce mutation‐specific changes in multiple ionic currents leading to different primary causes of APD prolongation, which suggests the use of mutation‐specific therapeutic approaches in the future.

Abstract Perimedullary fistulae of the spinal cord are rare vascular lesions that can present with different clinical patterns: hemorrhage, progressive myelopathy due to arterial steal and/or venous congestion, or symptoms due to compression of neural structures by engorged vessels. Treatment consists of surgical excision, endovascular embolization, or a combination of the two. If complete obliteration of the nidus exposes the patient to undue risk of permanent neurological deficits, incomplete obliteration with reduction of the vascular supply is a reasonable compromise to improve clinical symptomatology. Partial devascularization may also alter the natural history by decreasing the risk of further growth and bleeding. In this video we illustrate the case of a patient with a perimedullary fistula of the conus treated with surgical disconnection of the main fistulous component. Partial devascularization resulted in resolution of MRI signal changes and symptoms with documented good clinical and radiological outcome and progressive regression of the residual nidus over six years of follow-up.

Abstract DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high-density genetic and DNA methylation data in white blood cells from the Framingham Heart Study (N = 1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of P < 7.94 × 10−7. Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely MAPT, HOXB3, ABHD8, ARHGAP27, and SKAP1. We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression. Significance: Identification of novel DNA methylation markers associated with EOC risk suggests that methylation at multiple CpG may affect EOC risk through regulation of gene expression.