Citations

Abstract Roux‐en‐Y gastric bypass (RYGB) surgery is a highly effective technique for treating obesity. However, it may result in nutritional deficiencies. Here we report the case of a 55‐year‐old woman presenting with chronic diarrhea lasting 2 years, accompanied by lower limb paresthesia, macrocytic anemia, leukopenia, and thrombocytopenia. Her medical history included hypothyroidism treated with levothyroxine, and RYGB surgery performed in 2014, with intermittent micronutrient supplementation. The patient developed copper and zinc deficiencies. To our knowledge, this is the first report of a patient presenting with both deficiencies simultaneously with pancytopenia 10 years after RYGB. This case underscores the need to verify adherence to existing preoperative screening recommendations involving preoperative micronutrient measurements to assess micronutrient deficiency risks and multidisciplinary postoperative follow‐up, the importance of monitoring micronutrient levels, close follow‐up of both symptomatic and asymptomatic patients and evaluating adherence to supplementation regimens.

Importance Clinical trials in cardiovascular medicine aim to deliver high-quality evidence with greater efficiency, including smaller sample sizes and shorter timelines. The selection of sensitive and reliable end points is central to this goal. Right ventricular (RV) structure and function play a critical role in many cardiovascular conditions; however, RV-specific parameters remain underused and inconsistently applied in interventional clinical trials. In this article, the current and emerging role of RV-focused imaging and hemodynamic parameters as end points in clinical trials are explored and a comprehensive framework for their development, validation, and broader implementation is proposed. Observations Across multiple disease domains, RV-focused parameters derived from echocardiography, cardiac magnetic resonance imaging, computed tomography, and right-sided heart catheterization demonstrate potential value in assessing the therapeutic effects of new medicines or devices across a wide range of conditions including heart failure, cardiomyopathies, valve diseases, pulmonary hypertension, and congenital heart conditions. However, their use is inconsistent, and feasibility challenges are common, particularly in multicenter clinical trial settings. Key limitations include variability in imaging acquisition, incomplete data capture, lack of standardized protocols, and insufficient validation linking short-term RV changes to long-term clinical outcomes. Emerging tools such as artificial intelligence may improve reproducibility and efficiency, while collaborative, multidisciplinary efforts are essential for advancing end-point development. Conclusions and Relevance RV-specific end points hold substantial promise for enhancing the sensitivity and mechanistic insight of clinical trials but remain inadequately integrated into current practice. Optimal end-point selection requires balancing clinical relevance, analytical validity, and operational feasibility, with consideration of disease-specific pathophysiology and trial design. Standardization of acquisition, validation of clinically meaningful changes, and centralized data analysis are important next steps. Broader adoption of robust RV metrics supported by technological innovation and cross-sector collaboration has the potential to improve trial efficiency, accelerate therapeutic development, and ultimately enhance patient outcomes.

Abstract Background In children with non-metastatic atypical teratoid/rhabdoid tumor (ATRT), proton therapy is increasingly utilized worldwide due to the radiosensitivity of afflicted young patients. General questions persist, however, surrounding dose and volume of radiotherapy. Methods Between 2009-2024, 39 children from a single institution with non-metastatic intracranial ATRT received focal proton therapy at a median age of 2.4 years (range 0.7-19). Twenty-two patients had supratentorial tumors and 27 had gross/near total resection prior to radiation. Most common chemotherapy regimens were ACNS0333 and SJYC07 (n = 10 each) and Dana-Farber (n = 6). Four patients received consolidative high-dose chemotherapy after radiation. The median radiation dose was 50.4 Gy (range, 50.4-54). The cumulative incidence method assessed freedom from selected endpoints.The Fine-Gray method assessed the level of statistical significance between levels of selected prognostic factors. Results With a median followup of 5.2 years (range 0.5-16.2), the 5-yr overall survival, progression-free survival, and local control was 63%, 64%, and 97%, respectively. Thirteen patients developed isolated leptomeningeal failure as first site of recurrence. Only subtotal resection was significantly associated with local recurrence (100% vs 92%, p < 0.05). Patient age, tumor site, extent of resection, radiation dose, and chemotherapy regimen were otherwise not significantly associated with disease control or survival. Four patients experienced symptomatic radiation necrosis, including 1 death: Three of 4 cases received 54 Gy and consolidative intrathecal methotrexate (n = 2) or high dose ACNS0333 intravenous chemotherapy (n = 1, fatal) after radiation. The other patient received 50.4 Gy and necrosis was immediately preceded by ventriculoperitoneal shunt failure. Six patients developed hearing loss requiring aids. One patient developed radiation-induced meningioma a decade following treatment. Conclusion This represents the largest experience reporting 5-year outcomes following focal radiation in children with non-metastatic intracranial ATRT. When applied with a variety of modern chemotherapy regimens in real-world settings, focal proton therapy at a dose of 50.4 Gy may offer the best therapeutic ratio but does not eliminate serious toxicity. If avoidance of craniospinal radiation remains an ongoing priority, further improvement in survival will depend upon systemic therapy.

OBJECTIVE The optimal surgical treatment for lumbar spinal stenosis (LSS) with degenerative spondylolisthesis (DS) remains controversial. Posterior lumbar facet arthroplasty preserves motion after decompression and may address some of the limitations of fusion techniques. The Total Posterior Spine System (TOPS) investigational device exemption trial compared decompression with facet arthroplasty to decompression plus fusion (open with interbody). This study reports the 3-year outcomes from this trial. METHODS This randomized, controlled, multicenter trial enrolled 321 patients with LSS and grade I DS across 37 sites (2:1 randomization of arthroplasty to fusion). Eligible patients were 35–80 years old, had failed ≥ 6 months of nonsurgical treatment, and met thresholds for disability and leg pain. The primary endpoint was a composite clinical success score at 36 months, defined by four criteria: 1) no reoperation or lumbar injection, 2) no major device adverse events, 3) ≥ 15-point improvement in the Oswestry Disability Index (ODI), and 4) no new/progressive neurological deficit. Secondary outcomes included the ODI score, visual analog scale (VAS) scores for back and leg pain, the Zurich Claudication Questionnaire (ZCQ), device-related adverse events, and reoperations. RESULTS One hundred seventy-nine patients in the arthroplasty (TOPS) group and 74 in the fusion group were eligible for the 36-month analysis. The composite clinical success achievement rate was significantly higher in the arthroplasty group (76.0%) than in the fusion group (56.8%; p = 0.0038). The rate of reoperation or lumbar injection was significantly lower for the arthroplasty group (14.0%) compared to the fusion group (25.3%; p = 0.0222). Arthroplasty was associated with a significantly higher minimal clinically important difference (MCID) achievement rate for VAS back pain score compared with fusion (85.2% vs 72.2%; p = 0.041). Although there was no significant difference in ODI score, VAS leg pain score, or ZCQ component scores between groups, the arthroplasty group trended toward higher MCID achievement rates across all patient-reported outcome measures. There was no significant difference in reoperation failure rates between groups (5.8% for arthroplasty vs 9.5% for fusion; p = 0.329). CONCLUSIONS Decompression and dynamic stabilization with lumbar facet arthroplasty was associated with statistically significantly superior clinical outcomes and lower rates of secondary invasive procedures, including reoperations and injections, compared with decompression and fusion. Long-term follow-up is critical in defining the role of lumbar facet arthroplasty for the treatment of DS.

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal, rapidly progressive neurodegenerative disease of motor neurons for which therapeutics are limited. Improved biomarkers are imperative to improve patient care and therapeutic development. Here, we employed 35-plex isobaric tandem mass tag labeling based on isobutyl-proline reporter group (TMTpro) to perform unbiased proteomic analysis of cerebrospinal fluid (CSF) and plasma from control (n= 28, n= 31) and sporadic ALS (sALS) (n= 39, n= 41), from the Target ALS Global Natural History Study (TALS GNHS). We identified 2,875 proteins in CSF and 1,118 proteins in plasma and identified known and novel differentially expressed proteins (DEPs) between controls and sALS, some of which were orthogonally validated using immunoassay. Comparison of TMTpro-MS and Olink proximity extension assay proteomics revealed common and non-overlapping differentially expressed proteins illustrating strengths unique to each platform. This initial cross-sectional proteomic study of biofluids from the TALS GNHS, with unrestricted availability of study results to the research community, highlights the potential of this resource as a potent platform for ALS biomarker discovery.

Importance TMEM106B is a frontotemporal lobar degeneration (FTLD) genetic susceptibility factor, and TMEM106B protein aggregates are a feature of aging and neurodegeneration. Whether TMEM106B protein levels are associated with clinical features is unknown. Objective To investigate the clinical associations of cerebrospinal fluid (CSF) TMEM106B in FTLD. Design, Setting, and Participants This cross-sectional study was conducted in 2 independent frontotemporal dementia (FTD) cohorts (recruitment from April 2009 through July 2023, with analyses from January 2025 through April 2026), with a 2-year follow up. This multicenter clinical study integrated clinical, genetic, biomarker, and neuroimaging data. Individuals were recruited through the University of California, San Francisco (n = 3733), or ALLFTD (n = 2343). Participants with available CSF were included. A discovery cohort (n = 271) included participants with sporadic neuropathology-confirmed FTLD; presymptomatic or symptomatic carriers of pathogenic variants in C9orf72 , GRN , or MAPT ; or controls. An independent validation cohort (n = 383) included participants with clinically diagnosed sporadic FTD, Alzheimer disease (AD), and controls. Exposures CSF samples for TMEM106B quantification with aptamer proteomics (SomaScan version 3.0 [discovery cohort] and SomaScan version 4.1 [validation cohort]). Main Outcomes and Measures Parametric tests compared the primary outcome, CSF TMEM106B, by disease severity, TMEM106B rs1990622 genotype, sex, clinical syndrome, pathological diagnosis, and pathogenic variant and determined associations with brain volume. Results In the discovery (n = 271; 136 women [51%]; median [IQR] age, 59 [38-80] years) and validation (n = 383; 183 women [48%]; median [IQR] age, 64 [50-78] years) cohorts, lower CSF TMEM106B was associated with more severe disease (β, −0.15; 95% CI, −0.24 to −0.04; P = .003), lower frontotemporal brain volumes (β, 0.42; 95% CI, 0.24-0.61; P < .001), and faster clinical progression (β, −2.21; 95% CI, −3.70 to −0.72; P = .001). Associations of TMEM106B with clinical disease severity were independent of those with neurofilament light chain. TMEM106B levels were influenced by TMEM106B rs1990622 genotype, where individuals with the protective G/G genotype had lower levels than the risk A/A genotype. CSF TMEM106B levels did not differentiate between FTLD subtypes or between FTLD and AD. Conclusions and Relevance Per the results of this cross-sectional study, TMEM106B is detectable in CSF and levels reflect disease severity in sporadic and genetic FTLD and AD, but levels are also influenced by the TMEM106B rs1990622 genotype. CSF TMEM106B could support further studies to understand the mechanisms of disease and develop clinical tools in FTLD and other neurodegenerative diseases.

Abstract Multiple myeloma (MM) is a heterogenous cancer that remains mostly incurable. A unifying feature of MM cells is a highly interconnected network of transcription factors and co-factors that coordinate the activity of super-enhancers to enforce myeloma cell identity. Targeting this network offers a promising avenue for therapeutic intervention across genetically diverse myeloma sub-types. Using integrated molecular and functional genomic approaches we identified Menin as a key driver of oncogenic gene expression in MM cells. Menin and its co-factor KMT2A bind at super-enhancers and maintain expression of essential myeloma genes, including IRF4. We demonstrate that Menin inhibitors, which have recently been approved for treatment of acute myeloid leukaemia, are highly active in myeloma cell lines and in vivo models. Combining Menin inhibitors with other super-enhancer targeting therapies such EP300/CREBBP inhibitors or immunomodulatory drugs (IMiDs) overcomes epigenetic plasticity in cells resistant to single agent treatment.