Comparative Molecular Analysis of Gastrointestinal Adenocarcinomas

We analyzed 921 adenocarcinomas of the esophagus, stomach, colon, and rectum to examine shared and distinguishing molecular characteristics of gastrointestinal tract adenocarcinomas (GIACs). Hypermutated tumors were distinct regardless of cancer type and comprised those enriched for insertions/deletions, representing microsatellite instability cases with epigenetic silencing of MLH1 in the context of CpG island methylator phenotype, plus tumors with elevated single-nucleotide variants associated with mutations in POLE. Tumors with chromosomal instability were diverse, with gastroesophageal adenocarcinomas harboring fragmented genomes associated with genomic doubling and distinct mutational signatures. We identified a group of tumors in the colon and rectum lacking hypermutation and aneuploidy termed genome stable and enriched in DNA hypermethylation and mutations in KRAS, SOX9, and PCBP1. Liu et al. analyze 921 gastrointestinal (GI) tract adenocarcinomas and find that hypermutated tumors are enriched for insertions/deletions, upper GI tumors with chromosomal instability harbor fragmented genomes, and a group of genome-stable colorectal tumors are enriched in mutations in SOX9 and PCBP1

The initial results of using brolucizumab (Beovu®), an angiogenesis inhibitor, for choroidal neovascularization in patients with age-related macular degeneration

N.S. Zhayvoronok1, O.V. Kolenko1–3, L.P. Danilova1,2, E.L. Sorokin1,3 1Khabarovsk Branch of the S. Fedorov Eye Microsurgery Federal State Institution, Khabarovsk, Russian Federation 2Institute of Advanced Training of Healthcare Specialists, Khabarovsk, Russian Federation 3Far Eastern State Medical University, Khabarovsk, Russian Federation Aim: to assess the clinical efficacy of brolucizumab for choroidal neovascularization (CNV) in patients with age-related macular degeneration (AMD). Patients and Methods: clinical assessment of the efficacy of brolucizumab was performed in 25 patients (25 eyes) with neovascular AMD. The dynamic monitoring included optical coherence tomography to assess the localization and area of the neovascular complex, as well as the density and thickness of the new blood vessels (OCT-angiography). Three injections of brolucizumab (in a dose of 6 mg/0.05 mL) were performed once a month. The follow-up period was 4 months. Results: the mean age of patients was 68±5 years. After the first injection of brolucizumab, there was a statistically significant decrease in the mean values of central retinal thickness (CRT) and macular volume (MV) vs the baseline values. By month 4, a statistically significant increase in the best corrected visual acuity (BCVA) vs. that at the baseline was achieved: from 0.3 (0.2; 0.45) to 0.6 (0.4; 0.6) (p&lt;0,001). In all patients after three injections the minimal values of CRT were reported: they decreased from 298 (284; 302) to 268 (263; 270) µm. Also, MV reduced from 10.4 (9.5; 10.7) to 8.8 (8.7; 9.3) mm3 (p&lt;0,001). After one month in 22 of 25 patients and after three intravitreal injections of brolucizumab in 3 patients an adhesion of the neuro- and pigment epithelium was recorded with the complete resorption of the subretinal fluid, and the subretinal fluid was not found. Subjectively, all patients noted an improvement in the quality and contrast sensitivity of central vision after treatment. Conclusions: after each injection of brolucizumab, there was a statistically significant progressive reduction in macular parameters, CRT and MV, coupled with an increase in mean BCVA values. Keywords: vascular endothelial growth factor, anti-VEGF, brolucizumab, age-related macular degeneration, neovascular age-related macular degeneration, wet age-related macular degeneration, treatment efficacy. For citation: Zhayvoronok N.S., Kolenko O.V., Danilova L.P., Sorokin E.L. The initial results of using brolucizumab (Beovu®), an angiogenesis inhibitor, for choroidal neovascularization in patients with age-related macular degeneration. Russian Journal of Clinical Ophthalmology. 2022;22(4):228–233 (in Russ.). DOI: 10.32364/2311-7729-2022-22-4-228-233. </p

Comparative Molecular Analysis of Gastrointestinal Adenocarcinomas

We analyzed 921 adenocarcinomas of the esophagus, stomach, colon, and rectum to examine shared and distinguishing molecular characteristics of gastrointestinal tract adenocarcinomas (GIACs). Hypermutated tumors were distinct regardless of cancer type and comprised those enriched for insertions/deletions, representing microsatellite instability cases with epigenetic silencing of MLH1 in the context of CpG island methylator phenotype, plus tumors with elevated single-nucleotide variants associated with mutations in POLE. Tumors with chromosomal instability were diverse, with gastroesophageal adenocarcinomas harboring fragmented genomes associated with genomic doubling and distinct mutational signatures. We identified a group of tumors in the colon and rectum lacking hypermutation and aneuploidy termed genome stable and enriched in DNA hypermethylation and mutations in KRAS, SOX9, and PCBP1. Liu et al. analyze 921 gastrointestinal (GI) tract adenocarcinomas and find that hypermutated tumors are enriched for insertions/deletions, upper GI tumors with chromosomal instability harbor fragmented genomes, and a group of genome-stable colorectal tumors are enriched in mutations in SOX9 and PCBP1

The Immune Landscape of Cancer

We performed an extensive immunogenomic analysis of more than 10,000 tumors comprising 33 diverse cancer types by utilizing data compiled by TCGA. Across cancer types, we identified six immune subtypes\u2014wound healing, IFN-\u3b3 dominant, inflammatory, lymphocyte depleted, immunologically quiet, and TGF-\u3b2 dominant\u2014characterized by differences in macrophage or lymphocyte signatures, Th1:Th2 cell ratio, extent of intratumoral heterogeneity, aneuploidy, extent of neoantigen load, overall cell proliferation, expression of immunomodulatory genes, and prognosis. Specific driver mutations correlated with lower (CTNNB1, NRAS, or IDH1) or higher (BRAF, TP53, or CASP8) leukocyte levels across all cancers. Multiple control modalities of the intracellular and extracellular networks (transcription, microRNAs, copy number, and epigenetic processes) were involved in tumor-immune cell interactions, both across and within immune subtypes. Our immunogenomics pipeline to characterize these heterogeneous tumors and the resulting data are intended to serve as a resource for future targeted studies to further advance the field. Thorsson et al. present immunogenomics analyses of more than 10,000 tumors, identifying six immune subtypes that encompass multiple cancer types and are hypothesized to define immune response patterns impacting prognosis. This work provides a resource for understanding tumor-immune interactions, with implications for identifying ways to advance research on immunotherapy