Citations

ABSTRACT Background Coeliac disease is due to an acquired, lifelong gluten‐specific immune response resulting in a gluten‐dependent chronic immune‐mediated enteropathy associated with gastrointestinal and extraintestinal morbidity. Strictly avoiding dietary gluten is the only available management but has never been subjected to rigorous efficacy assessment now required for a pharmaceutical agent. Gluten‐free diet (GFD) is partially and inconsistently effective, but it places a high burden on patients, families, the food industry, and regulators and is defined inconsistently around the world, highlighting the need for effective and convenient adjunctive pharmacological therapies. Aims To summarize key patient, scientific, and regulatory considerations for coeliac disease drug development based on a multi‐stakeholder meeting focused on accelerating clinical trials. Methods A pre‐competitive meeting convened by the Beyond Celiac Coalition (May 2024) included patients with coeliac disease, academic experts, pharmaceutical industry representatives, and participants from the US Food and Drug Administration. Moderated panel addressed patient priorities, symptom and histologic endpoints, biopsy and histology methods, gluten challenge design, clinical trial duration, and regulatory expectations. Themes were synthesized qualitatively with focus on trial design implications and unresolved questions. Results Participants described high symptom burden and psychosocial impact despite gluten‐free diet adherence underscoring unmet therapeutic need in coeliac disease. Regulatory perspectives emphasized the need for clinically meaningful improvement and evidence of intestinal benefit, framed as symptom and histology co‐primary endpoints in clinical trials. These expectations were discussed as most applicable to trial populations with both clinically meaningful symptoms and active histologic injury at baseline; for other phenotypes, it was emphasized that endpoint strategy, the role of gluten exposure, and trial duration should be tailored case by case to the population and mechanism of action. Practical challenges identified included endpoint selection and definition, discordance between symptoms and histology, selecting fit‐for‐purpose symptom measures; standardizing biopsy acquisition and central histology reads to address patchiness and variability, pre‐specifying definitions of meaningful histologic change given ongoing uncertainty about healing, and trial feasibility. Controlled gluten exposure was discussed as a tool to improve interpretability of efficacy outcomes, with careful consideration of dose, duration, patient burden and safety. Discussion addressed the ideal length of the double‐blind period, including a shorter 24‐week double‐blind study with an open‐label extension versus a 52‐week double‐blind design. Trial duration should balance scientific rigour, patient retention, and the need for longer‐term safety and durability data, with flexibility to tailor the approach to context. Conclusions Progress in coeliac disease drug development will require patient‐centred, scientifically robust but feasible trial designs with appropriate endpoints, justified use of gluten exposure, consideration of improved biomarkers to reduce patient burden and early regulatory engagement. Continued multi‐stakeholder collaboration, including dedicated consideration of paediatric drug development, is essential to advance effective therapies.

Abstract Introduction Ovarian cancer (OvCa) remains the most lethal gynecologic malignancy, with older women experiencing the poorest outcomes. Aging profoundly remodels the ovarian tumor immune microenvironment (TME), promoting regulatory T cell (Treg) mediated immune evasion; however, the underlying metabolic mechanisms remain unclear. Methods Using young (3-month) and aged (22-month) female mice injected intraperitoneally with ID8p53⁻/⁻ OvCa cells, we investigated how age associated metabolic reprogramming influences tumor immunity Results Aged OvCa bearing mice exhibited accelerated tumor progression, reduced survival (median 54 vs. 72 days), decreased CD4+ and CD8+ T cells, and an expanded Treg population. Metabolomic profiling revealed increased succinate accumulation in ascites, tumor tissue, and serum of aged mice and elderly OvCa patients. Exogenous succinate enhanced CCR4+FOXP3+ Treg frequency and upregulated IL-10 and TGF-β secretion. Elevated levels of CCL22, a CCR4 ligand, were also detected in ascites from aged mice and patients, suggesting a chemokine-driven reinforcement of Treg recruitment. PBMCs from aged patients displayed an OXPHOS-reprogrammed CCR4+FOXP3+ Treg subset with heightened suppressive capacity, markedly inhibiting CD4+ and CD8+ effector cytotoxicity. Treatment with AA6, an α-ketoglutarate dehydrogenase inhibitor that blocks succinate synthesis, reduced CCR4+FOXP3+ Treg accumulation, restored effector T-cell function, and significantly prolonged survival in aged OvCa-bearing mice. Conclusion Together, these findings reveal a novel succinate—CCR4 metabolic—chemokine axis that drives Treg mediated immunosuppression in aged OvCa. Targeting this pathway offers a promising strategy to restore anti-tumor immunity and overcome age-related immunotherapy resistance in ovarian cancer. Funding Source N/A Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

ABSTRACT Background Multiple meta‐analyzes suggest that acne improvement with isotretinoin leads to improved mental health outcomes in adults, though isotretinoin‐related psychiatric data, including for suicidality, are limited for adolescents. Methods PubMed, MEDLINE, EmBase, PsychINFO, and the Cochrane Library databases were searched for papers published between 1982 and September 2024 that reported suicidality following isotretinoin treatment for acne vulgaris in adolescents aged 18 or younger. Results A total of 24 full text articles were reviewed. Despite numerous case reports describing suicidal ideation, suicide attempts, and completed suicides were rare. Databases suggest that adolescents taking isotretinoin are the group with the most suicide attempts, but epidemiological studies including matched controls suggest this could be a function of the number of prescriptions in this population. Observational, cohort, and case‐time‐control studies did not consistently report an increased risk of suicidality with isotretinoin. When compared with those prescribed antibiotics, isotretinoin‐prescribed adolescents had no increase in suicidality during treatment but had a higher prevalence of suicidal behavior in the year after treatment. If patients prescribed isotretinoin developed suicidal ideation, it was more likely to develop early in or following completion of treatment. Conclusion There exists a conventionally held belief in the association between isotretinoin use and suicidal ideation for adolescent patients, but this narrative review does not indicate a consistent relationship.

Abstract Background Breast cancer is etiologically heterogeneous, but which risk factors differ in their associations across tumor subtypes remains unclear. We conducted a large, pooled analysis to evaluate independent, dose-response associations between breast cancer risk factors and quantitative tumor features. Methods Analyses of 15,731 invasive breast cancers from 24 studies evaluated associations (p-trend) between reproductive and hormonal factors, body mass index (BMI), alcohol, smoking, and family history in relation to quantitative immunohistochemistry measures on tissue microarrays (ER, PR, HER2, KI67, TP53) and tumor grade. Analyses in a subset of 10 population-based studies estimated subtype-specific odds ratios (ORs) comparing cases to controls. A Bayesian False Discovery Probability (BFDP) <0.2 was used to identify associations with strong statistical evidence. Results Nulliparity and later age at menopause were associated with higher ER-positivity (p-trend=0.021 and 0.001, respectively), with corresponding OR[ER+] (95% CI) = 1.49 (1.16-1.90) for nulliparous vs. parous and 1.07 (1.03-1.11) per 5 years. Current combined menopausal hormone therapy (MHT) use was associated with lower grade (p-trend<0.001), with OR [grade1] = 3.37 (2.69-4.21) for current vs. never users. Higher BMI was associated with lower ER-positivity and higher grade in premenopausal women (p-trend<0.001 and <0.001), with OR[ER+] = 0.80 (0.74-0.87) and OR[grade1] = 0.75 (0.63-0.88) per 5 units, and with higher PR-positivity and higher grade in postmenopausal women (p-trend<0.001 and <0.001), with OR[PR+] = 1.08 (1.03-1.14) and OR[grade 3] = 1.10 (1.04-1.17) per 5 units. Conclusion This pooled analysis of 15,731 cases showed that nulliparity, age at menopause, MHT, and BMI have independent, dose-response associations with ER, PR, and grade, clarifying patterns of etiologic heterogeneity. Associations with HER2, KI67 and TP53, or other risk factors did not meet our threshold for strong evidence.

Background: Chemotherapy-induced peripheral neuropathy (CIPN) and cancer-related myelopathy often cause pain, numbness, and mobility impairment. While treatments such as medications typically target positive sensory symptoms (eg, burning or tingling), negative symptoms such as numbness and proprioceptive loss remain difficult to manage and significantly affect balance and gait. This study evaluated the feasibility of using textured insoles as a noninvasive approach to improve these symptoms. Methods: A prospective feasibility study was conducted with adult patients with cancer experiencing negative sensory symptoms due to CIPN or myelopathy. Participants were provided with textured insoles designed to enhance plantar sensory input and instructed to wear them during daily activities for 1 month. Outcomes were measured pre- and postintervention using the 4-Stage Balance Test, Timed Up and Go test, and patient-reported assessments of balance and mobility. Results: Twenty participants were enrolled: 70% reported numbness, 45% gait impairment, 40% balance impairment, and 35% pain. Objective improvements in balance and gait were observed with the use of insoles, with significant Timed Up and Go gains at both initial ( P < .001) and follow-up ( P = .01) visits, adjusting for additional therapy. Sixteen participants reported improved stability and confidence after 1 month. Adherence was high, and no adverse events occurred. Conclusion: Textured insoles are a feasible, well-tolerated supportive intervention for patients with negative sensory symptoms from CIPN or cancer-related myelopathy. By enhancing sensory feedback, insoles may improve balance, mobility, and quality of life. Larger controlled trials are warranted to confirm efficacy and long-term outcomes.

Pulmonary developmental disorders comprise a heterogeneous group of congenital abnormalities involving the airways, lung parenchyma, pulmonary vasculature, or overlapping developmental pathways. Although these conditions commonly present during infancy or childhood, many remain clinically silent until adulthood, when they are discovered incidentally or manifest with recurrent respiratory symptoms such as infection, hemoptysis, or progressive dyspnea. These abnormalities may be broadly categorized into airway, vascular, parenchymal, and mixed developmental anomalies. Airway abnormalities include congenital tracheobronchomegaly, branching anomalies of the tracheobronchial tree, bronchial atresia, bronchogenic cysts, congenital pulmonary airway malformations (CPAM), and bronchopulmonary sequestration (BPS). Vascular anomalies include pulmonary artery sling, proximal interruption of the pulmonary artery, Scimitar syndrome, and meandering pulmonary veins. Parenchymal disorders encompass congenital lobar overinflation and pulmonary hypoplasia. Increasing recognition of overlapping lesions, particularly combinations of CPAM, sequestration, and bronchial atresia, has challenged traditional compartmental classification systems and supports a developmental spectrum model. This review synthesizes contemporary concepts regarding embryologic mechanisms, pathogenesis, imaging findings, and management of these entities in adults. Particular emphasis is placed on imaging evaluation with CT and MRI, updated terminology, evolving molecular understanding of CPAMs, including lesions with malignant potential, and distinctions between congenital sequestration and pseudosequestration. Recognition of these disorders and their associated anomalies is essential for accurate diagnosis, appropriate management, and surgical planning in adult patients.

Background Irritable bowel syndrome (IBS) is a complex disorder of gut-brain interaction, with heterogeneous symptoms, no available biomarkers and limited pathogenetic insight. Objective To identify genetic risk factors and actionable mechanisms for future clinical translation in IBS. Design We conducted a genome-wide association study (GWAS) meta-analysis of IBS in 2 775 539 individuals from 22 biobanks. IBS genetics was studied across multiple ancestries, different case definitions and symptom-related subtypes. Heritability and genetic correlations with other traits were estimated, and Mendelian randomisation was used to test causal relationships. GWAS data were functionally annotated and fine-mapped to prioritise tissues, cell types, pathways, candidate genes, specific mechanisms and druggable targets. Results Significant heritability was only detected in individuals of European ancestry, with near-identical genetic architecture across case definitions. Genetic correlations with GI, psychiatric and cardiometabolic traits were observed, including causal relationships with triglyceride (TG) levels. Functional annotation of IBS risk loci highlighted cell types and pathways relevant to brain, enteric neuro-glial and cardiometabolic domains, as well as actionable targets like GCKR, a regulator of TG metabolism. Druggability analyses converged on cardiometabolic mechanisms, including TG modulation. IBS polygenic risk scores were derived and showed a significant association with case status in an independent case-control dataset, supporting further evaluation in external population-based and clinically ascertained cohorts. Conclusions This study provides the most comprehensive assessment of IBS genetics to date, demonstrating reproducible polygenic inheritance. We link IBS risk to convergent neurogastrointestinal and novel cardiometabolic mechanisms, highlight specific biological pathways and actionable mechanisms and outline translational opportunities emerging from integrated computational analyses.

The NCCN Clinical Practice Guidelines for Breast Cancer include recommendations for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget’s disease, Phyllodes tumor, inflammatory breast cancer, and management of breast cancer during pregnancy. The panel convenes annually to update recommendations based on a review of recently published clinical trials. This selection from the NCCN Guidelines for Breast Cancer focuses on the recommendations for the management of recurrent or stage IV (M1) metastatic breast cancer. It summarizes the treatment strategies stratified by tumor biology, including hormone receptor status and HER2 expression, as well as clinical factors such as prior therapy and disease-free interval. Throughout all treatment lines, supportive care, quality of life preservation, toxicity minimization, and clinical trial participation are emphasized as integral components of patient care.

Importance High-quality evidence guiding opioid prescribing decisions for acute pain across common diagnoses is lacking. Objective To describe pain trajectories and patterns of opioid and nonopioid treatment use among individuals who were offered opioids for the treatment of acute pain. Design, Setting, and Participants This was a prospective cohort study of patients recruited from 5 US health systems between September 2020 and March 2023 in emergency departments (EDs), primary care clinics, dental practices, or after cesarean delivery or knee replacement. Eligible patients were opioid-naive adults aged 18 years or older at all study sites, as well as adolescents aged 15 to17 years undergoing impacted molar extraction at 1 site, who were offered an opioid prescription for acute pain. Analysis was conducted April 2023 through February 2026. Exposure Offer of a prescription for an opioid analgesic. Main Outcomes and Measures Time to pain resolution (3 consecutive reports of no pain), patterns of opioid and nonopioid treatment use, and opioid-related adverse effects, ascertained from digital questionnaires. Results Among 1708 enrolled patients (median age, 38 years [IQR, 28-52 years]; 615 [36.0%] reporting race or ethnicity underrepresented in studies of acute pain management) followed up for 180 days, 915 (53.6%) were recruited in EDs, 307 (18.0%) in primary or urgent care, 263 (15.4%) in dental settings, and 223 (13.1%) in inpatient settings. Pain sources included dental (302 patients [17.7%]), trauma or injury (302 [17.7%]), obstetric (176 [10.3%]), musculoskeletal (131 [7.7%]), and low back (100 [5.9%]). Among 1502 patients reporting pain level at least once, median time to pain resolution irrespective of the treatment approach was 20 days (IQR, 8-88 days), with longer durations for surgical pain (74 days [IQR, 30 days to not reached]) and low back pain (69 days [IQR, 18 days to not reached]). The median time to opioid discontinuation among 1189 patients (69.6%) who reported any opioid use was 7 days (IQR, 2-31 days); an estimated 10.0% (95% CI, 7.7%-12.7%) of patients used opioids for at least 90 days, with higher rates in people reporting frequent pain before enrollment. Of 1482 patients (86.8%) completing at least 1 survey during the first 2 weeks of follow-up, 1153 (77.8%) reported using any opioids and 1287 (86.8%) reported using acetaminophen or ibuprofen. Among 619 (52.1%) patients with any opioid use who reported the dose of opioids taken in the first 15 days, daily doses were low (median, 10 [IQR, 5-15] morphine milligram equivalents). Most respondents reported leftover opioids (657 of 982 responding [66.9%]). Conclusions and Relevance In this cohort study of opioid-naive patients with acute pain, opioid use was generally low dose and of short duration, although some patients reported prolonged opioid use; most reported achieving pain resolution within 3 weeks, with longer times for surgical and low back pain. The findings suggest current guidelines for multimodal treatment and for short-duration opioid prescriptions if needed will serve many but not all patients, and treatment should be tailored to address individual patients’ needs.