Citations

There is no therapy that promotes maturation and functionality of a dialysis arteriovenous fistula (AVF). The search for such therapies largely relies on evaluation of vascular responses and putative therapies in experimental AVFs. We studied an AVF in mice with chronic kidney disease (CKD). We demonstrate numerous stressors in the vein of the AVF-CKD group, including pathological shear, mitogenic, inflammatory, and hypoxia-reoxygenation stress. Because stress promotes premature senescence, we examined whether senescence is induced in the vein of the AVF-CKD model. We demonstrate a senescence phenotype in the AVF-CKD model, as indicated by increased expression of p16Ink4a, p21Cip1, and p53 and expected changes for certain senescence-associated microRNAs. RNA-sequencing analysis demonstrated differential expression of ~10,000 genes, including upregulation of proinflammatory and proliferative genes, in the vein of the AVF-CKD group. The vein in the AVF-CKD group exhibited telomere erosion and increased senescence-associated β-galactosidase activity and staining. Senescence was induced in the artery of the AVF-CKD group and in the vein of the AVF without CKD. Finally, given the rapidly rising clinical interest in senolytics, we provide proof of concept of senolytics as a therapeutic approach by demonstrating that senolytics decrease p16Ink4a expression in the AVF-CKD model. This study introduces a novel concept underlying the basis for maturational and functional failure in human dialysis AVFs and identifies a new target for senolytic therapy.

Abstract Background: The utility of alpha-fetoprotein (AFP) for hepatocellular carcinoma (HCC) surveillance is controversial. We aimed to identify factors associated with elevated AFP and define the patients for whom AFP is effective for surveillance. Methods: Data from the NCI Early Detection Research Network phase II HCC biomarker study (233 early-stage HCC and 412 cirrhotic patients) were analyzed. We analyzed 110 early-stage HCC and 362 cirrhotic hepatitis C virus (HCV) patients for external validation. Sensitivity, specificity, and area under the ROC curve (AUC) for HCC were calculated. Results: HCV etiology, non-White race, and serum alanine transaminase (ALT) predicted elevated AFP in cirrhotics. Non-White race and ALT predicted elevated AFP in HCC patients. Higher AUC of AFP for HCC was noted in patients with HBV (0.85) and alcohol (0.84), whereas it was lower in patients with hepatitis C virus (HCV; 0.80) and nonviral/alcohol etiology (0.76). The AUC was higher in HCV patients with serum ALT ≤40 U/L than patients with serum ALT >40 U/L (0.91 vs. 0.75, P < 0.01). At 90% specificity, the sensitivity of AFP increased from 44% to 74% in Whites with HCV and from 50% to 85% in non-Whites with HCV. There was a trend toward higher AUC in HCV patients with serum ALT ≤40 U/L than those with serum ALT >40 U/L (0.79 vs. 0.69, P = 0.10) in the validation cohort. Conclusions: The satisfactory performance of AFP in HCV patients with normal ALT should be further validated. Impact: The AFP may serve as a valuable surveillance test in HCV patients with normal ALT. Cancer Epidemiol Biomarkers Prev; 26(7); 1085–92. ©2017 AACR.

AbstractPleomorphic xanthoastrocytoma (PXA) is a rare localized glioma characterized by frequent BRAF V600E mutation and CDKN2A/B deletion. We explored the association of copy‐number variants (CNVs) with BRAF mutations, tumor grade, and patient survival in a cohort of 41 PXA patients using OncoScan chromosomal microarray. Primary resection specimens were available in 38 cases, including 24 PXA and 14 anaplastic PXA (A‐PXA), 23 BRAF V600E mutant tumors (61%). CNVs were identified in all cases and most frequently involved chromosome 9 with homozygous CDKN2A/B deletion (n = 33, 87%), a higher proportion than previously detected by comparative genomic hybridization (50%–60%) (37). CDKN2A/B deletion was present in similar proportion of PXA (83%), A‐PXA (93%), BRAF V600E (87%), and wild‐type (87%) tumors. Whole chromosome gains/losses were frequent, including gains +7 (n = 15), +2 (n = 11), +5 (n = 10), +21 (n = 10), +20 (n = 9), +12 (n = 8), +15 (n = 8), and losses −22 (n = 11), −14 (n = 7), −13 (n = 5). Losses and copy‐neutral loss of heterozygosity were significantly more common in A‐PXA, involving chromosomes 22 (P = 0.009) and 14 (P = 0.03). Amplification of 8p and 12q was identified in a single tumor. Histologic grade was a robust predictor of overall survival (P = 0.003), while other copy‐number changes, including CDKN2A/B deletion, did not show significant association with survival. Distinct histologic patterns of anaplasia included increased mitotic activity in an otherwise classic PXA or associated with small cell, fibrillary, or epithelioid morphology, with loss of SMARCB1 expression in one case. In 10 cases, matched specimens were compared, including A‐PXA with areas of distinct low‐ and high‐grade morphology (n = 2), matched primary/tumor recurrence (n = 7), or both (n = 1). Copy‐number changes on recurrence/anaplastic transformation were complex and highly variable, from nearly identical profiles to numerous copy‐number changes. Overall, we confirm CDKN2A/B deletion as key a feature of PXA not associated with tumor grade or BRAF mutation, but central to the underlying genetics of PXA.

Hypothalamic hamartomas are rare tumors that typically present in childhood, often with gelastic seizures, precocious puberty, or as a manifestation of Pallister‑Hall syndrome. Neurofibrillary tangles are cytoplasmic aggregates of hyperphosphorylated tau that are best recognized in Alzheimer disease, other tau‐associated neurodegenerative diseases, or as part of aging, but occasionally may be seen in low‐grade neoplasms with a ganglion cell component as gangliocytoma or ganglioglioma. Herein, we report a case of hypothalamic hamartoma with neurofibrillary tangles.

Background: Anti‐muscle specific kinase antibody positive (MuSK Ab) myasthenia gravis (MG) patients are known to have different clinical course compared to anti‐acetylcholine receptor Ab positive MG patients. Therapeutic plasma exchange (TPE) has been reported to be effective; however, little is known of the response and of TPE procedural information. An ASFA Apheresis Registry was developed to analyze those data. Methods: The study collected detailed de‐identified patient data, TPE procedures, and treatment outcome/complications. Collected data was described in aggregate. Results: A total of 15 MuSK Ab MG patients with exacerbation of MG symptoms, 13 females/2 males, median age 44, were investigated. Thirty TPE courses (median 5 procedures/course, total 145 procedures) were evaluated. All TPE procedures were performed with citrate anticoagulation, 1 − 1.25 plasma volume exchange in 100% fluid balance, and 90% of courses used only albumin as replacement. Calcium was added to albumin or given orally as needed. TPE was performed every other day in 55% of courses. Adverse events occurred in 3.4% of procedures. Ten patients (67%) experienced relapses within a median of 7 weeks. Objective symptoms were resolved in more than 75% of courses. Overall subjective improvement rates were 94.1%/93.3% after 3/4 TPE procedures, respectively. Thirty‐one percent of patients responded poorly with minimal recovery. Conclusion: Overall subjective improvement was seen up to 94% of patients after one course of TPE. Some patients were poor‐responders. Five TPE may be adequate for initial course with additional TPE as needed. Based upon this preliminary data, we will modify our future data collection. J. Clin. Apheresis 32:5–11, 2017. © 2016 Wiley Periodicals, Inc.