舍列赫医学中心

In 2024, a comprehensive framework for the screening, diagnosis, and management of metabolic dysfunction–associated steatotic liver disease (MASLD) was incorporated in the EASL-EASD-EASO clinical practice guidelines. However, physicians often face barriers applying these recommendations in routine clinical care, especially in the Southeastern Europe, Middle East, and Africa (SEEMEA) region. As a multidisciplinary group of physicians involved in MASLD and metabolic dysfunction-associated steatohepatitis (MASH) management, our objective is to provide a practice-oriented roadmap including practical and educational considerations beyond the hepatology field that could improve patient care and support implementation of clinical guidance within the SEEMEA region. This work is informed by a narrative review and expert input obtained through structured discussions, to examine the status quo and identify key gaps in the MASLD/MASH management, unravelling the patient journey from screening and diagnosis to treatment and follow-up. Furthermore, we advise on priorities on screening triggers and, considering the limited availability of vibration-controlled transient elastography (VCTE), discuss alternative approaches to achieve accurate and timely diagnosis. Finally, following the approval of resmetirom and semaglutide 2.4 mg for MASH treatment, we review the evolving pharmacotherapy landscape and propose a “blueprint” for a specialised MASLD clinic, suggesting mandatory and optional facilities for optimised care.

BACKGROUND:Methotrexate-based chemoradiotherapy is effective in primary central nervous system lymphoma (PCNSL) but carries a risk of severe neurotoxicity. In a single-arm study, a regimen with methotrexate, procarbazine, vincristine, and cytarabine was combined with rituximab (R-MPV-A) and substantially reduced doses of whole-brain radiotherapy (LD-WBRT), resulting in excellent progression-free survival (PFS) and overall survival (OS). Because R-MPV-A had never been tested without radiation, we sought to evaluate the efficacy of R-MPV-A with and without LD-WBRT, as well as determining if such low radiotherapy doses influenced disease control and/or neurotoxicity. METHODS:Patients were randomized to receive R-MPV-A alone (Chemo arm) or combined with LD-WBRT (ChemoRT arm), given at 2,340 cGy (180cGy X13). Primary endpoint was intent-to-treat (ITT) PFS. A sample size of 89 would provide 80% power to detect a hazard ratio (HR) of 0.63 (one-sided alpha = 0.15). RESULTS:Ninety-one patients were randomized, with 44 analyzed in the ChemoRT and 46 in the Chemo arm. Median age was 66 and 59.5, respectively. R-MPV-A was well tolerated, achieving a complete response rate of 92.3% (ChemoRT) and 76.3% (Chemo). After median follow-up of 4.6 years, median PFS was not reached (ChemoRT) vs 2.1 years (Chemo), HR = 0.47 (P = .007; 95% CI, 0.26-0.87). The 2-year PFS was 78.7% vs 54%, respectively. Differences in OS did not reach statistical significance (HR = 0.71; P = .33). Neuropsychological evaluation showed no differences in cognitive outcomes, with several tests favoring ChemoRT. CONCLUSIONS:R-MPV-A is a highly efficacious and safe regimen with or without LD-WBRT. LD-WBRT contributes to disease control and increases PFS in PCNSL.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by core behavioral symptoms. We previously showed that nitric oxide (NO) plays a key role in ASD. However, the precise molecular mechanism through which NO acts via its posttranslational modification, S-nitrosylation (SNO), in ASD remains largely unknown. Emerging evidence, including our previous studies, suggests that the mechanistic target of the rapamycin (mTOR) signaling pathway plays a critical role in ASD pathophysiology. Our SNO-proteome systems biology analysis showed the enrichment of the mTOR pathway. In this study, we deciphered a novel mechanism of the cross talk between NO and mTOR pathway using two well-established mouse models as well as clinical samples of children with ASD. To assess changes in the SNO-proteome, we used the SNOTRAP method, revealing increased S-nitrosylation of tuberous sclerosis complex 2 (TSC2) in Shank3Δ4–22 and Cntnap2(-/-) mutant mice. We proved that this modification led to the loss of TSC2 protein via ubiquitination, resulting in dysregulated mTOR signaling in both excitatory and inhibitory neurons. Pharmacological inhibition of neuronal nitric oxide synthase (nNOS) successfully prevented TSC2 S-nitrosylation, mTOR overactivation, and altered protein translation in ASD models, highlighting NO’s role in modulating mTOR function. To further validate the role of TSC2 S-nitrosylation in ASD, we generated a cysteine-to-serine mutation (C203S) in TSC2 to prevent its S-nitrosylation. Intracranial injection of the mutant TSC2 (C203S) in Shank3Δ4–22 mice in the prefrontal cortex prevented ASD-like behaviors, confirming the pathogenic role of NO-mediated TSC2 modification. Critically, analysis of clinical samples from children with ASD, including those with SHANK3 mutations and idiopathic ASD, revealed reduced TSC2 levels and increased mTOR signaling activity, further validating our findings. Collectively, this study uncovers a novel molecular mechanism by which S-nitrosylation disrupts TSC2 function, leading to aberrant mTOR signaling and ASD-like phenotypes. By revealing a unique SNO-TSC2-mTOR axis, our work deciphers the novel nitric oxide-mediated mTOR activation and opens new avenues for targeted therapeutic strategies in ASD, including those carrying SHANK3 mutations.

BackgroundOsimertinib has been approved as a treatment option for epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC). However, despite the identification of common mutations, there are still no additional pathological factors that can be used to predict treatment response and improvement in survival.MethodsThis retrospective study utilized data from a multi-center registry of NSCLC patients with EGFR mutations who were treated with first-line osimertinib therapy between March 2017 and December 2024. The variant allele frequency (VAF) was evaluated as a potential predictive factor for overall survival (OS).ResultsFor the cohort of 147 patients who met eligibility requirements, the mean OS was 25.5 months (95% CI 20.28–30.75) and progression-free survival (PFS) was 21.4 months (95% CI 17.38–25.37). The mean OS was 19.7 months (95% CI 14.21–25.10) for VAF <30% and 31.4 months (95% CI 23.15–39.56) for VAF ≥30%. The mean PFS was 18.2 months (95% CI 12.94–23.46) for VAF <30% and 25.0 months (95% CI 19.14–30.94) for VAF ≥30%. In the subgroup of EGFR ex 19del the mean OS was 21.1 months (95% CI 11.04–31.25) for VAF <30% and 36.6 months (95% CI 25.61–47.50) for VAF ≥30% and for the subgroup with EGFR ex21 L858R the mean OS was 18.7 months (95% CI 12.36–25.00) for VAF <30% and 25.5 months (95% CI 13.78–37.22) for VAF ≥30%.ConclusionOur study demonstrated that the VAF is a significant factor in predicting OS and PFS in EGFR mutant patients treated with osimertinib. Patients with a VAF ≥30% showed significantly improved OS and PFS compared to those with a VAF <30%. Specifically, the mean OS was longer for patients with higher VAF in both the overall cohort and in subgroups with EGFR exon 19 deletions and exon 21 L858R mutations. These findings suggest that VAF could serve as a valuable predictive biomarker for treatment outcomes in EGFR-mutated NSCLC patients, highlighting its potential role in personalizing treatment strategies.

Background:Frailty is regarded as a key predictor of adverse surgical outcomes. The 5-item modified frailty index (mFI-5) offers a simplified version of the validated 11-item risk stratification tool. Despite its use across surgical fields, its utility in plastic and reconstructive surgery remains underexplored. The purpose of this study was to evaluate and quantify the predictive value of frailty, as measured by the mFI-5 on postoperative outcomes in adult patients undergoing plastic and reconstructive surgery. Methods:PubMed, Embase, Web of Science, and Cochrane Library were systematically queried for studies comparing adverse events in frail (mFI-5 ≥ 2) versus nonfrail patients undergoing plastic and reconstructive surgery. Two independent reviewers performed study selection, data extraction, and risk of bias assessment using the risk of bias in non-randomized studies-of interventions tool, with evidence quality evaluated using the grading of recommendations, assessment, development and evaluation approach. Outcomes included surgical, medical, and any complications, readmission, reoperation, and mortality. Subgroup analyses were conducted by subject of study, database source, and study sample size. Results:Twenty-nine studies encompassing 302,641 patients were included. Frailty was significantly associated with increased odds of complications, readmission, reoperation, and mortality. Subgroup analyses by procedure type, database, and sample size consistently confirmed elevated risk across all outcomes, with varying degrees of statistical significance. Conclusions:Frailty, as measured by the mFI-5, is associated with an increased risk of postoperative complications, hospital readmission, reoperation, and mortality in plastic and reconstructive surgery patients. These findings support the integration of the index in clinical practice and preoperative patient evaluation and decision-making.