While most gastrointestinal stromal tumors are driven by oncogenic mutations in KIT or PDGFRA, 10-15% exhibit functional loss of the succinate dehydrogenase (SDH) complex and genome-wide DNA hypermethylation. Excess meth...While most gastrointestinal stromal tumors are driven by oncogenic mutations in KIT or PDGFRA, 10-15% exhibit functional loss of the succinate dehydrogenase (SDH) complex and genome-wide DNA hypermethylation. Excess methylation in SDH-deficient gastrointestinal stromal tumors disrupts genomic insulators, inducing aberrant expression of oncogenic ligands FGF3, FGF4, and activating an autocrine signaling loop mediated through FGFR1. We conducted a phase 2 trial of pan-fibroblast growth factor receptor inhibitor rogaratinib in patients with sarcoma and report here on the cohort of patients with advanced SDH-deficient GIST. The primary objective was to estimate objective response rate. Secondary objectives were to estimate progression-free survival (PFS) and assess safety and tolerability. Exploratory objectives were to evaluate serial measurements of FGF3 and FGF4 and fibroblast growth factor receptors in serial biopsies, to perform whole-exome sequencing in serial biopsies and to explore rogaratinib exposure with pharmacodynamic effects. Twenty-four patients received rogaratinib and ten experienced partial responses for an objective response rate of 41.7%. Median PFS was 31.0 months (95% confidence interval 20.2-not reached), and 1-year PFS was 77.4% (95% confidence interval 61.7-97.1). Toxicities were manageable and included hyperphosphatemia, fatigue and diarrhea. Elevations in phosphorous were seen across the cohort, consistent with target engagement of FGFR1. Whole-exome and next-generation sequencing revealed alterations in the SDH subunit coding genes (SDHx) as expected. This trial illustrates a successful demonstration of targeted cancer therapy predicated on an epigenetic mechanism of oncogene activation. Clinicaltrials.gov identifier: NCT04595747 .
Ke Y, Jin L, Ong JCL
… +13 more, Thirunavukarasu AJ, Car J, Cheung CY, Tham YC, Ting DSW, Ong MEH, Compton S, Narayan A, Keane PA, Wong TY, Bates DW, Tan P, Liu N
The integration of artificial intelligence (AI) into medical training is accelerating faster than the educational frameworks designed to govern it. This Perspective identifies a risk that has received insufficient attent...The integration of artificial intelligence (AI) into medical training is accelerating faster than the educational frameworks designed to govern it. This Perspective identifies a risk that has received insufficient attention: that trainees who rely on AI during the early formative years of clinical education may fail to develop the foundational reasoning skills that safe, independent practice requires. We refer to this as 'never-skilling', distinguishing it from deskilling in experienced clinicians and from mis-skilling, in which uncritical acceptance of AI errors leads trainees to internalize flawed clinical knowledge as fact. Although direct evidence from medical training is absent, the concern is grounded in established learning theory and supported by early empirical signaling from nonclinical settings. AI is not inherently harmful to learning; its educational impact depends on how and when it is introduced. We propose a three-phase competency-protective framework: establishing AI-independent baseline competency, building critical calibration through structured pedagogy, and integrating AI under supervision in medical training. This is a pedagogy research agenda that requires further empirical investigation to ultimately inform future policy recommendations.
A suboptimal clinical response after metabolic and bariatric surgery (MBS) is common and carries considerable health concerns. Here a double-blinded, randomized (1:1), placebo-controlled trial using semaglutide 2.4 mg we...A suboptimal clinical response after metabolic and bariatric surgery (MBS) is common and carries considerable health concerns. Here a double-blinded, randomized (1:1), placebo-controlled trial using semaglutide 2.4 mg weekly (BARI-STEP) recruited adult participants at least 1 year after gastric bypass or sleeve gastrectomy with a suboptimal clinical response, defined as less than 20% weight loss from surgery. This was an adjunct to lifestyle intervention with a 500-kcal daily energy deficit. The primary outcome was percentage weight loss after 68-week treatment on an intention-to-treat analysis. Seventy participants (mean (s.d.) age = 47.3 (10.3) years, 58 (82.9%) female and 12 (17.1%) male) were randomized to receive 2.4 mg semaglutide (n = 35) or placebo (n = 35). The intention-to-treat sample included 63 participants. Estimated change in mean (s.d.) percentage weight loss from baseline to week 68 was -18.0 (9.2) with semaglutide 2.4 mg (n = 34) versus +0.4 (7.0) with placebo (n = 29). The mean adjusted treatment difference in percentage body weight change for semaglutide 2.4 mg versus placebo was -19.18 (95% confidence interval -23.4 to -14.8; P < 0.001). Adverse events (AEs) were consistent with the known safety and tolerability profile of semaglutide, with no new safety concerns for the post-bariatric population. There were eight serious AEs, one suspected unexpected serious adverse reaction and no treatment-related deaths. BARI-STEP demonstrates that in people with a suboptimal clinical response after MBS, semaglutide results in substantial and clinically significant body weight reduction along with improvement in metabolic parameters and quality of life, compared to placebo. These findings suggest that semaglutide 2.4 mg is a safe and effective treatment option for this patient population. ClinicalTrials.gov: NCT05073835 .
Pathogenic B cell activation underlies many autoimmune diseases (AIDs), and their depletion is an attractive therapeutic approach. Chimeric antigen receptor (CAR)-expressing cells-initially developed and successfully use...Pathogenic B cell activation underlies many autoimmune diseases (AIDs), and their depletion is an attractive therapeutic approach. Chimeric antigen receptor (CAR)-expressing cells-initially developed and successfully used to treat certain cancers-are increasingly being developed to selectively deplete B cells and 'reset' the immune system in AIDs. In this Review, we survey this fast-developing field, providing insights on the current unmet needs in the treatment of AIDs and how CAR T cells could address these needs. In particular, we explore the concept of deep B cell depletion, discuss the currently available technologies and review the key targets (CD19 and B cell maturation antigen) relevant for the treatment of AIDs. We summarize current evidence on the efficacy, safety, risks and limitations of autologous and allogeneic CAR T cells in this setting. Finally, we discuss the future outlook-from a technological and clinical standpoint-for development of engineered CAR-expressing cell therapies for AIDs.
Wang H, Dong X, Xiao F
… +26 more, Li G, Lu Y, Qiao M, Wu B, Ni Q, Yan K, Li Q, Yin Z, Yang L, Chen D, Chen L, Kang W, Wei Q, Tao L, Cheng G, Wang L, Li K, Shen C, Wang S, Xu X, Yang M, Liu F, Li H, Zhang K, Zhou W, International Consortium in Digital Twins in Healthcare and Medicine
Next-generation sequencing technologies have been widely applied in diagnosing genetic disorders in pediatric patients. However, the cancer predisposition and tumor characteristics in individuals who have germline pathog...Next-generation sequencing technologies have been widely applied in diagnosing genetic disorders in pediatric patients. However, the cancer predisposition and tumor characteristics in individuals who have germline pathogenic variants remain unclear. We analyzed exome sequencing data from 75,602 pediatric patients referred for genetic testing between January 2016 and January 2025, tracking cancer as a secondary finding. The most common reasons for genetic testing were symptoms related to the nervous system, metabolic disorders and immune dysfunction. Among 110,692 variants of 139 tumor susceptibility genes, we identified 501 (456 single-nucleotide variants, 45 copy number variations, 0.45%) pathogenic or likely pathogenic (P/LP) and 3,848 (3,650 single-nucleotide variants, 198 copy number variations, 3.5%) variants of uncertain significance leaning toward likely pathogenic variants. Of 411 patients with tumors (203 with preexisting tumors and 208 with new tumors diagnosed during follow-up), 134 (32.6%) harbored causative germline P/LP variants in genes such as NF1 (13.1%), TSC2 (5.8%), RB1 (4.6%) and WT1 (3.2%). Critically, prospective follow-up of 64,187 patients without initial tumors revealed a significantly higher incidence of malignant tumors in those carrying P/LP variants (3.23 per 1,000 person-years) compared with those with variants of uncertain significance leaning toward likely pathogenic or other variants (0.236 and 0.272 per 1,000 person-years, respectively). These findings underscore the importance of proactive genetic counseling and surveillance for pediatric patients with pathogenic germline variants.
Since the inception of the World Health Organization (WHO) Extended Programme on Immunization in 1974, vaccines have saved the lives of approximately 150 million children, and they continue to save 2-5 million lives each...Since the inception of the World Health Organization (WHO) Extended Programme on Immunization in 1974, vaccines have saved the lives of approximately 150 million children, and they continue to save 2-5 million lives each year, according to WHO estimates. The consensus around the benefit and funding of childhood vaccination in low- and middle-income countries has unraveled, and the hard-won gains of the past quarter century are at risk. At the same time, in some high-income countries, vaccine hesitancy-sometimes enabled by government policy pronouncements-has led to reductions in vaccination, resulting in outbreaks of measles in countries that had eliminated this disease. Despite these setbacks, advances in vaccine platform technologies, new immunogens, and new and expanding target populations have the potential to extend the direct and indirect effects of vaccination across the life course. In this Perspective, we discuss how each of these advances could shape the future vaccine landscape. We also highlight cross-cutting issues, including those related to equity, manufacturing, funding and vaccine hesitancy, which make successful implementation more complex.