Citations

The NCCN Guidelines for Head and Neck Cancers address tumors arising in the oral cavity (including mucosal lip), pharynx, larynx, and paranasal sinuses, as well as occult primary cancer, salivary gland cancer, and mucosal melanoma (MM). The specific site of disease, stage, and pathologic findings guide treatment (eg, the appropriate surgical procedure, radiation targets, dose and fractionation of radiation, indications for systemic therapy). The NCCN Head and Neck Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel’s most recent recommendations regarding management of nasopharynx cancer and ongoing research in this area.

INTRODUCTION: Barrett esophagus (BE) is the strongest known risk factor for developing esophageal adenocarcinoma (EAC), the second-most lethal cancer in the United States. Esopredict is a novel validated methylation-based biomarker assay that provides precise quantification of neoplastic progression risk in BE patients. Inherit challenges, including tissue heterogeneity, sampling error, interobserver variability, and inconsistent adherence to surveillance biopsy guidelines, may affect the predictive value results of Esopredict obtained at different anatomic locations or different sampling time points. METHODS: To investigate the spatiotemporal performance of Esopredict across multiple spatiotemporal sampling points, we profiled 220 biopsies obtained from 58 BE patients, including 11 patients with overlapping spatial and temporal biopsies. We focused on spatial profiling (i.e., multiple biopsies obtained at several anatomic locations during a single endoscopy) and temporal profiling (i.e., biopsies obtained from multiple endoscopies performed at different time points). Each patient had an initial histologic diagnosis of nondysplastic Barrett esophagus, indefinite for dysplasia, or low-grade dysplasia. Final follow-up (endpoint) biopsies showed either high-grade dysplasia or EAC (progressors), or nondysplastic Barrett esophagus, indefinite for dysplasia, or low-grade dysplasia (nonprogressors). Biopsies were analyzed with Esopredict to compute a progression risk score, which quantified the likelihood of future progression to high-grade dysplasia or EAC within 5 years. RESULTS: In 52 spatially profiled patients, Esopredict demonstrated a sensitivity of 81% (17/21 progressor patients), based on the highest-scoring biopsy from each patient; sensitivity increased to 100% (12/12) when end point biopsies occurred within 5 years of the index (initial) biopsy. In 28 temporally profiled patients, sensitivity was 100% (8/8 patients), based on the biopsy performed at the time point closest to the end point biopsy. DISCUSSION: Esopredict showed high predictive performance in multiple spatiotemporal samples in BE patients. These data further support the use of Esopredict as a robust test to distinguish high-risk BE patients, who may benefit from endoscopic eradication therapy or increased surveillance frequency, from low-risk patients, who may be candidates for less frequent surveillance and noninterventional observation.

Abstract The aging process is universal, and it is characterized by a progressive deterioration and decrease in physiological function leading to decline on the organismal level. Nevertheless, a number of genetic and nongenetic interventions have been described, which successfully extend healthspan and lifespan in different species. Furthermore, a number of clinical trials have been evaluating the feasibility of different interventions to promote human health. The goal of the annual Biological Sciences Section of the Gerontological Society of America meeting was to share current knowledge of different topics in aging research and provide a vision of the future of aging research. The meeting gathered international experts in diverse areas of aging research including basic biology, demography, and clinical and translational studies. Specific topics included metabolism, inflammaging, epigenetic clocks, frailty, senescence, neuroscience, stem cells, reproductive aging, inter-organelle crosstalk, comparative transcriptomics of longevity, circadian clock, metabolomics, and biodemography.

Purpose To establish consensus statements via a modified Delphi process about ethics, transparency, regulation, and best practices for the use of orthobiologics in clinical practice for musculoskeletal pathology. Methods A consensus process on the regulation of orthobiologics at the provider level was conducted using a modified Delphi technique. Twenty orthopaedic surgeons, sports medicine physicians, or basic scientists participated. Each participant was a Biologic Association member organization representative and asked to participate because of their active interest in the field of orthobiologics. Levels of consensus were delineated according to the number of votes for each statement: no consensus, <80%; consensus, 80% to 89%; strong consensus, 90% to 99%; unanimous, 100%. Results The 26 consensus statements on orthobiologics resulted in 14 achieving unanimous consensus, 8 achieving strong consensus, 3 achieving consensus, and 1 did not achieve consensus. Overall, 85% of the statements reached either a unanimous or strong consensus. Of the statements regarding communication and transparency, 9 reached unanimous consensus, including information to convey and helpful tools to describe current orthobiologics, persistent misinformation, use of the word “stem cells,” “off‐label” use, and problems with the present regulatory environment. Five statements discussing the regulation of novel orthobiologics achieved unanimous consensus. These statements highlighted research regulation, safety, and suggested improvements to regulatory issues. The statement that did not achieve any consensus was on the regulatory processes that should be in place by an institution providing novel orthobiologic treatments. No statement reached a unanimous agreement on cost or ethical considerations. Conclusions This study successfully identified key consensus statements emphasizing the importance of ethics, transparency, and regulation in the use of orthobiologics, with 85% of statements reaching unanimous or strong consensus. These findings underscore the need for standardized communication, improved regulatory frameworks, and enhanced safety measures while highlighting persistent challenges in addressing cost and ethical considerations. Level of Evidence Level V, expert opinion.

ABSTRACT Genes involved in the regulation of chromatin structure are frequently disrupted in cancer, contributing to an aberrant transcriptome and phenotypic plasticity. Yet, therapeutics targeting mutant forms of chromatin-modifying enzymes have yielded only modest clinical utility, underscoring the difficulty of targeting the epigenomic underpinnings of aberrant gene regulatory networks. Here, we sought to identify novel epigenetic vulnerabilities in diffuse large B-cell lymphoma (DLBCL). Through phenotypic screens and biochemical analysis, we demonstrated that inhibition of the H3K9 demethylases KDM4A and KDM4C elicits potent, subtype-agnostic cytotoxicity by antagonizing transcriptional networks associated with B-cell identity and epigenetically rewiring heterochromatin. KDM4 demethylases associated with the KRAB zinc finger ZNF587, and their enzymatic inhibition led to DNA replication stress and DNA damage-induced cGAS-STING activation. Broad surveys of transcriptional data from patients also revealed KDM4 family dysregulation in several other cancer types. To explore this potential therapeutic avenue, we performed high-throughput small molecule screens with H3K9me3 nucleosome substrates and identified novel KDM4 demethylase inhibitors. AI-guided protein-ligand binding predictions suggested diverse modes of action for various small molecule hits. Our findings underscore the relevance of targeting fundamental transcriptional and epigenetic mechanisms for anti-cancer therapy. HIGHLIGHTS Phenotypic screens identified JIB-04 as a potent anti-cancer agent for multiple subtypes of diffuse large B-cell lymphoma JIB-04 binds and inhibits KDM4 demethylases resulting in epigenomic rewiring of heterochromatin KDM4 demethylases cooperate with KRAB zinc fingers to limit DNA replication stress, and KDM4 inhibition instigates DNA-damage and cGAS-STING activation in several human cancers High-throughput small molecule screens with semi-synthetic nucleosome substrates and AI-guided molecular docking simulations identify novel KDM4 inhibitors

Abstract We present a comprehensive global analysis of genetic variants associated with autosomal-dominant Alzheimer’s disease (ADAD). A total of 550 variants in the APP, PSEN1 and PSEN2 genes were identified, of which 279 were classified as pathogenic or likely pathogenic based on American College of Medical Genetics and Genomics and the Association for Molecular Pathology criteria, utilizing data from the Dominantly Inherited Alzheimer Network (DIAN), literature and public databases. Symptomatic age at onset (AAO) data were estimated for 227 of these variants, allowing detailed characterization of their frequency, pathogenicity and AAO. Importantly, 226 variants met eligibility criteria for inclusion in disease-modifying clinical trials. Furthermore, we demonstrated the predictive value of mean variant AAO and parental AAO in predicting symptomatic AAO, validated against converters who became symptomatic during follow-up in the DIAN Observational Study. This dataset provides critical insights into the global landscape of ADAD and reveals the genetic and AAO heterogeneity of ADAD variants while refining variant trial eligibility criteria.

Key Points Loss-of-function ALG8 and ALG9 variants were enriched in polycystic kidney/liver groups and International Classification of Diseases–coded cystic individuals in population cohorts. The ALG8 and ALG9 kidney phenotypes were usually mild to moderate, and lower eGFR or kidney failure was rare. ALG8 pathogenic variants sometimes resulted in severe polycystic liver disease. Background Autosomal dominant polycystic kidney disease (ADPKD) is a common, inherited nephropathy often resulting in kidney failure. It is genetically heterogeneous; along with the major genes, PKD1 and PKD2 , at least eight others have been suggested. ALG8 pathogenic variants have been associated with autosomal dominant polycystic liver disease and implicated in ADPKD, while ALG9 has been suggested as an ADPKD gene, but details of the phenotypes and penetrance are unclear. Methods We screened >3900 families with cystic kidneys and/or livers using global approaches to detect ALG8 or ALG9 pathogenic variants. In addition, population cohorts with sequence data (Genomics England 100K Genomics Project, UK Biobank, and Mayo Clinic Biobank [MCBB]) were screened for ALG8 / ALG9 pathogenic variants. Results Multicenter screening of individuals with polycystic kidney and/or liver disease identified 51 (1.3%) ALG8 (7 multiplex) and 23 (0.6%) ALG9 (5 multiplex) families—frequencies that were approximately 10× and approximately 24× greater than nonpolycystic kidney disease controls. Analysis of individuals with polycystic kidney disease phenotypes in 100K Genomics Project, UK Biobank, and MCBB identified nine ALG8 (0.39%) and nine ALG9 (0.39%) families, an enriched frequency over controls. Two individuals had PKD1 and ALG8 pathogenic changes. Eighty-nine percent of individuals with ALG8 mutations with imaging in the entire MCBB had kidney cysts (50%, >10 cysts), with greater median kidney and liver cyst numbers than controls. For ALG9, 78% had kidney cysts (27%, >10 cysts). Individuals with ALG8 mutations typically had mild cystic kidneys with limited enlargement. Liver cysts were common (71%), with enlarged livers (>2L) found in 11 of 62 patients, although surgical intervention was rare. The ALG9 kidney phenotype was also of mild cystic kidneys, but enlarged livers were rare; for both genes, CKD or kidney failure were rare. Conclusions ALG8 and ALG9 are defined as cystic kidney/liver genes but with limited penetrance for lower eGFR.