Citations

Abstract Background Diffuse Midline Glioma (DMG) with the H3K27M mutation is a lethal childhood brain cancer, with patients rarely surviving 2 years from diagnosis. Methods We conducted a multi-site Phase 1 trial of the imipridone ONC201 for children with H3K27M-mutant glioma (NCT03416530). Patients enrolled on Arm D of the trial (n = 24) underwent serial lumbar puncture for cell-free tumor DNA (cf-tDNA) analysis and patients on all arms at the University of Michigan underwent serial plasma collection. We performed digital droplet polymerase chain reaction (ddPCR) analysis of cf-tDNA samples and compared variant allele fraction (VAF) to radiographic change (maximal 2D tumor area on MRI). Results Change in H3.3K27M VAF over time (“VAF delta”) correlated with prolonged PFS in both CSF and plasma samples. Nonrecurrent patients that had a decrease in CSF VAF displayed a longer progression free survival (P = .0042). Decrease in plasma VAF displayed a similar trend (P = .085). VAF “spikes” (increase of at least 25%) preceded tumor progression in 8/16 cases (50%) in plasma and 5/11 cases (45.4%) in CSF. In individual cases, early reduction in H3K27M VAF predicted long-term clinical response (>1 year) to ONC201, and did not increase in cases of later-defined pseudo-progression. Conclusion Our work demonstrates the feasibility and potential utility of serial cf-tDNA in both plasma and CSF of DMG patients to supplement radiographic monitoring. Patterns of change in H3K27M VAF over time demonstrate clinical utility in terms of predicting progression and sustained response and possible differentiation of pseudo-progression and pseudo-response.

Abstract Aim To evaluate whether short‐term treatment with a selective 11β‐Hydroxysteroid dehydrogenase‐1 (11β‐HSD1) inhibitor, AZD4017, would block hepatic cortisol production and thereby decrease hepatic fat in patients with nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH), with or without type 2 diabetes (T2D). Materials and Methods This was a randomized, double‐blind, placebo‐controlled, phase 2 study conducted at two sites. Key inclusion criteria were the presence of NAFLD or NASH on magnetic resonance imaging (MRI) or recent biopsy positive for NASH. Enrolled patients were randomly assigned (1:1) to AZD4017 or placebo for 12 weeks. Primary outcomes were between‐group differences in mean change from baseline to week 12 in liver fat fraction (LFF) and conversion of 13 C cortisone to 13 C cortisol in the liver. Results A total of 93 patients were randomized; 85 patients completed treatment. The mean (standard deviation [SD]) change in LFF was −0.667 (5.246) and 0.139 (4.323) in the AZD4017 and placebo groups ( P = 0.441). For patients with NASH and T2D, the mean (SD) change in LFF was significantly improved in the AZD4017 versus the placebo group (−1.087 [5.374] vs. 1.675 [3.318]; P = 0.033). Conversion of 13 C cortisone to 13 C cortisol was blocked in all patients in the AZD4017 group. There were no significant between‐group differences (AZD4017 vs. placebo) in changes in fibrosis, weight, levels of liver enzymes or lipids, or insulin sensitivity. Conclusion Although the study did not meet one of the primary outcomes, AZD4017 blocked the conversion of 13 C cortisone to 13 C cortisol in the liver in all patients who received the drug. In patients with NASH and T2D, AZD4017 improved liver steatosis versus placebo.

Objective Breast cancer (BC) is the most common form of cancer among Asian females. Mutations in the BRCA1/ BRCA2 genes are often observed in BC cases and largely increase the lifetime risk of having BC. Because of the paucity of high-quality data on the molecular spectrum of BRCA mutations in South Asian populations, we aimed to explore these mutations among South Asian countries. Methods A systematic literature search was performed for the BRCA1 and BRCA2 gene mutation spectrum using electronic databases such as PubMed, EMBASE, and Google Scholar. Twenty studies were selected based on specific inclusion and exclusion criteria. Results The 185delAG (c.68_69del) mutation in exon 2 of BRCA1 was the most common recurrent mutation and founder mutation found. Various intronic variants, variants of unknown significance, large genomic rearrangements, and polymorphisms were also described in some studies. Conclusions The South Asian population has a wide variety of genetic mutations of BRCA1 and BRCA2 that differ according to countries and ethnicities. A stronger knowledge of various population-specific mutations in these cancer susceptibility genes can help provide efficient strategies for genetic testing.

Although most patients with hepatitis E virus (HEV) infection are asymptomatic or have mild symptoms, its infection is generally underdiagnosed and overlooked. In immunocompromised patients, HEV infection can lead to acute liver failure and death. However, the clinical evidence of HEV infection in hematopoietic stem cell transplant (HSCT) recipients is scarce; thus, we conducted this systematic review and meta-analysis to assess the prevalence of HEV infection in this population. We searched MEDLINE, EMBASE, and the Cochrane Library databases from inception through October 2020 to identify studies that reported the prevalence of HEV infection among HSCT recipients. HEV infections were confirmed by HEV-IgG/IgM or HEV-RNA assay. A total of 1977 patients from nine studies with a follow-up time up to 40 months were included in the final analysis. The pooled prevalence of positive HEV-RNA was 3.0% (95% CI 2.3% to 4.0%). The pooled prevalence of positive HEV-IgG was 10.3% (95% CI 4.5% to 21.8%). The pooled prevalence of de novo HEV infection was 2.9% (95% CI 1.8% to 4.5%). Age and male gender were not associated with HEV-RNA or HEV-IgG positivity in the meta-regression analysis. In conclusion, the prevalence of HEV-IgG in HSCT recipients was about 10%, while the prevalence of HEV-RNA was only 3%. However, further studies that focus on the clinical outcomes in this population are warranted.

Background: Fecal microbiota transplantation (FMT) is a safe and effective therapy for recurrent Clostridioides difficile infection (CDI). Data on FMT for CDI in patients with underlying inflammatory bowel disease (IBD) are emerging but conflicting. We performed a systematic review and meta-analysis to describe the efficacy and safety of FMT for CDI in IBD and its impact on IBD outcomes. Methods: A systematic search of multiple databases including Embase, Scopus, and Web of Science was performed. Our primary analysis focused on pooled rate of CDI resolution after single and multiple FMTs in IBD patients. Additional analyses included rates of IBD-associated outcomes (flare, surgery, symptom improvement) after FMT. The random-effects model was used to calculate pooled rates. Results: Among 457 adult patients, 363 had CDI resolution after first FMT with a pooled cure rate of 78% [95% confidence interval (CI): 73%-83%; I 2=39%]. Overall pooled rate cure rate with single and multiple FMTs was 88% (95% CI: 81%-94%; I 2=73%). The pooled rate of an IBD flare after FMT was 26.8% (95% CI: 22.5%-31.6%; I 2=9%) and of colectomy was 7.3% (95% CI: 4.7%-10.5%; I 2=56%). Among 141 pediatric patients, 106 had CDI resolution after first FMT with pooled cure rate of 78% (95% CI: 58%-93%; I 2=59%). Overall pooled cure rate with single and multiple FMTs was 77% (95% CI: 50%-96%; I 2=63%). The pooled rate of an IBD flare after FMT was 10.8% (95% CI: 5.7%-18.5% I 2=43%), and of colectomy was 10.3% (95% CI: 2.1%-30.2% I 2=23%). Conclusions: FMT appears to be a highly effective therapy for preventing recurrent CDI in patients with IBD. Patients who fail a single FMT may benefit from multiple FMTs.