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Von Hippel Lindau(VHL)syndrome presents with cerebellar and spinal hemangioblastomas, renal cell cancer, neuroendocrine pancreatic tumor, and pheochromocytoma and it is caused by germline mutations in the VHL gene. Pathogenic germline variants in the succinate dehydrogenase A (SDHA) gene are associated with paraganglioma and pheochromocytoma. Here we report co-occurrence of germline pathogenic variants in both VHL and SDHA genes in a patient who presented with pancreatic neuroendocrine tumor. As these genes converge on the pseudo-hypoxia signaling pathway, further studies are warranted to determine the significance of co-occurrence of these variants in relation to tumor penetrance, disease severity, treatment response and clinical outcomes in this selected group of patients. [ABSTRACT FROM AUTHOR]

Objectives: The Ki-67 proliferation index is integral to gastroenteropancreatic neuroendocrine tumor (GEP-NET) assessment. Automated Ki-67 measurement would aid clinical workflows, but adoption has lagged owing to concerns of nonequivalency. We sought to address this concern by comparing 2 digital image analysis (DIA) platforms to manual counting with same-case/different-hotspot and same-hotspot/different-methodology concordance assessment.Methods: We assembled a cohort of GEP-NETs (n = 20) from 16 patients. Two sets of Ki-67 hotspots were manually counted by three observers and by two DIA platforms, QuantCenter and HALO. Concordance between methods and observers was assessed using intraclass correlation coefficient (ICC) measures. For each comparison pair, the number of cases within ±0.2xKi-67 of its comparator was assessed.Results: DIA Ki-67 showed excellent correlation with manual counting, and ICC was excellent in both within-hotspot and case-level assessments. In expert-vs-DIA, DIA-vs-DIA, or expert-vs-expert comparisons, the best-performing was DIA Ki-67 by QuantCenter, which showed 65% cases within ±0.2xKi-67 of manual counting.Conclusions: Ki-67 measurement by DIA is highly correlated with expert-assessed values. However, close concordance by strict criteria (>80% within ±0.2xKi-67) is not seen with DIA-vs-expert or expert-vs-expert comparisons. The results show analytic noninferiority and support widespread adoption of carefully optimized and validated DIA Ki-67. [ABSTRACT FROM AUTHOR]

A membrane-based approach to pulsatile delivery, termed here as Barrier-Mediated Pulsatile Release (BMPR), sequesters each chemical dose into its own stimuli-sensitive reservoir film, each covered by a stimulant barrier membrane to delay triggering for a prescribed period time. These barrier/depot pairs are then stacked sequentially, with the delay time for the next barrier commencing with the stimulation of the previous depot, assuring a controlled period between each pulse. This paper introduces the first generalized BMPR system, using hydrogel depots that can be adapted to a variety of stimulants, coupled with barriers that rely on sacrificial stimulant scavengers to provide controlled delay times spanning orders of magnitude. Poly(methyl methacrylate-co-dimethylamino ethyl methacrylate) hydrogels are used to demonstrate pulsatile release of multiple solutes triggered by buffered citric acid. Zinc oxide nanoparticles loaded in poly(vinyl alcohol) hydrogel barriers delay acid permeation to each depot. Depot thickness, pH, and buffer strength are each shown to affect the stimulant permeation, swelling, and solute diffusion rates from the depots, with different processes becoming rate-limiting under different conditions. The delay time for each barrier varies linearly with ZnO scavenger loading, scavenger center-of-mass, and the square of the barrier thickness, providing multiple pathways for tuning delay time over a wide range. BMPR devices releasing up to 10 pulses are demonstrated, with no inherent limit on the number of pulses possible. [ABSTRACT FROM AUTHOR]