Citations

Background: Radiologically Isolated Syndrome (RIS) is defined as incidentally found MRI abnormalities that are radiographically indistinguishable from multiple sclerosis (MS) and is considered a presymptomatic disease state of MS. Age <37 years, infratentorial or spinal cord lesions, gadolinium-enhancing lesions on index imaging, and positive cerebrospinal fluid oligoclonal bands have been identified as risk factors for conversion to MS. There are no existing guidelines regarding the role of disease-modifying therapy (DMT) in RIS patients. Objective: The objective of this study was to critically assess the current evidence regarding the impact of initiating DMT for patients with RIS on the time to first clinical attack of MS. Methods: The objective was addressed through the development of a structured critically appraised topic. This included a clinical scenario with a clinical question, literature search strategy, critical appraisal, results, evidence summary, commentary, and bottom-line conclusions. Participants included consultant and resident neurologists, medical librarian, and content experts in the field of neuroimmunology. Results: A multicenter, prospective, randomized, double-blind, placebo-controlled trial was chosen for critical appraisal. This trial examined the impact of treatment with dimethyl fumarate (DMF) versus placebo on the risk of conversion from RIS to MS over a 96-week study period. Patients in the DMF arm were found to have an 82% reduction in risk of clinical attack. DMF patients also had a smaller number of new/newly enlarging T2 hyperintense lesions compared with placebo. No subgroup analyses were performed to elucidate risk factors for conversion. Conclusions: While initiation of DMT in RIS does appear to reduce the time to first clinical attack of MS, the risk factors that should prompt initiation of DMT in this patient population require further study.

ABSTRACT Eccrine spiradenomas are benign sweat gland neoplasms that rarely undergo malignant transformation. Carcinosarcoma arising from an eccrine spiradenoma is exceptionally rare. A 41‐year‐old male presented with a rapidly growing neck/shoulder mass, progressive numbness, spasticity, and weakness. Further workup additionally revealed an epidural mass with spinal cord compression. Both masses were excised and predominantly showed morphologic features of high‐grade osteosarcoma, with overtly malignant spindled cells producing lace‐like osteoid. However, a single section from the upper back mass contained a roughly 2 mm focus of conventional eccrine spiradenoma, with an adjacent small focus having features of a poorly differentiated non‐small cell carcinoma. The final diagnosis was that of a high‐grade carcinosarcoma with heterologous osteosarcomatous differentiation, arising from a pre‐existing eccrine spiradenoma, with metastasis to the T4‐5 epidural region. The patient experienced rapid regrowth of the spinal mass and underwent radiotherapy but had unresectable metastatic disease at 2 months follow‐up. We describe what is to our knowledge only the 21st example of carcinosarcoma arising from eccrine spiradenoma, mimicking metastatic osteosarcoma. Awareness of this very rare entity, careful sampling, close microscopic examination, and, in selected cases, ancillary immunohistochemistry are the keys to making this challenging diagnosis.

Abstract Oral commensals such as Parvimonas micra are increasingly implicated in sporadic colorectal cancer (CRC). Several findings support an emerging notion that alterations in host DNA methylation constitute a mechanism by which P. micra adapts to the host microenvironment and contributes to pathogenic processes. However, multiple limitations hinder definitive conclusions, including the correlative nature of the human studies and the absence of human microbiota in mouse models. Here, we investigated how a complex human microbiome influences the adaptation and oncogenic potential of P. micra in a spontaneous mouse model of polyposis. Adult mice, following antibiotic conditioning, received fecal microbiota transplants (FMT) from a healthy human donor, with or without supplementation of P. micra. P. micra caused significant reshaping of the gut microbial community and altered co-occurrence network structures, which however largely recovered within 21 days post FMT. Despite the transient nature of these changes, P. micra caused a marked increase in both the number and invasive potential of intestinal polyps. Epigenomic profiling of polyp crypts revealed global DNA hypomethylation alongside gene-specific hypermethylation, accompanied by transcriptional changes in key oncogenic pathways. Affected pathways included Wnt signaling, epithelial-to-mesenchymal transition, circadian rhythm regulation, and host–microbe interactions. These findings demonstrate that P. micra exerts a profound influence on microbial ecology, host epigenetic programming, and tumorigenesis in a genetically predisposed host, highlighting its role as a microbial driver of intestinal carcinogenesis.

Objectives: To describe changes in the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) exam in sublesional motor and sensory domains following short-term epidural electrical stimulation of lumbosacral spinal segments in individuals with spinal cord injury (SCI). Methods: Twenty individuals with SCI underwent implantation of percutaneous epidural spinal cord stimulation followed by stimulation parameter optimization and 10-12 sessions of stimulation-enabled motor training. Pre-/postintervention ISNCSCI exams were compared to determine changes in motor/sensory scores for regions within 3 levels of the neurological level of injury (NLI) and caudal to this, with subanalyses per motor/sensory complete versus incomplete baseline status. Results: Individuals with motor complete SCI gained 6% ± 3% of available motor points within 3 levels of NLI and 1% ± 0% of motor points caudal to this ( P = .08). Motor incomplete individuals gained 9% ± 22% of available motor points within 3 levels of NLI and lost 4% ± 7% of motor points caudal to this ( P = .63). Following stimulation, changes in motor scores with potential high functional impact occurred in 3 individuals (5 total muscle groups with conversion from baseline <3/5 strength to ≥3/5 at completion). Individuals with sensory complete SCI had fewer sensory gains within 3 levels of NLI (6%) compared to those with sensory incomplete SCI (30%, P = .02). Discussion: Spinal cord stimulation after SCI rapidly induces changes in both motor and sensory domains that are retained after stimulation is removed. These changes primarily occur within 3 levels of the NLI and occur to a greater degree in those with incomplete SCI.

Importance Obesity is associated with a higher risk of recurrence, mortality, comorbidities, treatment-related adverse effects, and poor quality of life in patients with breast cancer. Scalable interventions are needed to promote weight loss in this population. Objective To evaluate the impact of a remotely delivered weight loss intervention (WLI) on weight change at 1 year in patients with breast cancer and obesity and to explore factors associated with weight change. Design, Setting, and Participants The Breast Cancer Weight Loss trial is a phase 3, randomized clinical trial evaluating the impact of a telephone-based WLI on invasive disease–free survival and other outcomes in women with obesity and early breast cancer at 637 sites across the US and Canada. Participants were enrolled to the study between August 2016 and February 2021. Participants included women with stage II to III, ERBB2 -negative breast cancer and a body mass index (BMI) of 27 or higher. Interventions Participants were randomized to a 2-year, telephone-based WLI plus health education or health education alone control group. Main Outcome and Measures The primary end point for this prespecified secondary analysis was weight change at 1 year. Weight was measured at baseline and 1 year, and changes in weight were compared between groups. Weight change was evaluated with a linear mixed-effects model including treatment group, weight over time, a time-by-group interaction, menopausal status, race and ethnicity, and hormone receptor status. Results A total of 3180 women with breast cancer and BMI of 27 and higher were included in the study; 1591 were randomized to the WLI and 1589 to the control group. At baseline, the mean (SD) age of participants was 53.4 (10.6), and the mean (SD) BMI was 34.4 (5.6). The racial and ethnic breakdown included 406 (12.8%) Black, 231 (7.3%) Hispanic or Latino, 2906 (91.4%) non-Hispanic, and 2555 (80.3%) White participants. WLI participants lost a mean of 4.3 kg (95% CI 3.9-4.6 kg), or 4.7% (95% CI, 4.3%-5.0%) of baseline body weight at 1 year vs control participants, who gained 0.9 kg (95% CI, 0.5-1.3 kg), or 1.0% (95% CI 0.1%-1.4%) of baseline body weight ( P &amp;lt; .001). Participants randomized to WLI experienced significant weight loss (vs control group participants) across demographic and tumor factors. WLI effect differed significantly by menopausal status, with postmenopausal participants having greater weight loss than premenopausal participants, and by race and ethnicity, with Black and Hispanic participants having less weight loss compared to other races and ethnicities. Conclusions and Relevance In this secondary analysis of a randomized clinical trial, a telephone-based WLI induced significant weight loss in patients with breast cancer with overweight and obesity across demographic and treatment factors. Further follow-up of the Breast Cancer Weight Loss trial will evaluate whether the WLI improves disease outcomes. Trial Registration ClinicalTrials.gov Identifier: NCT02750826

Abstract Background and Aims Type 1 short QT syndrome (SQT1) is a genetic channelopathy caused by gain-of-function variants in KCNH2, resulting in shortened cardiac repolarization and QT intervals, which predispose patients to ventricular arrhythmias and sudden cardiac death. This study aimed to investigate the therapeutic efficacy of KCNH2-specific suppression-and-replacement (KCNH2-SupRep) gene therapy in a transgenic rabbit model of SQT1. Methods KCNH2-SupRep was developed by combining a KCNH2-shRNA with its corresponding shRNA-immune KCNH2-cDNA into an AAV9 vector, delivered directly into the aortic root (1 × 1010 vg/kg). Therapeutic efficacy was evaluated in vivo by electrocardiogram, ex vivo by optical mapping, and at cellular levels by patch-clamp, calcium imaging, and qPCR in ventricular cardiomyocytes (VCMs). Results In vivo, KCNH2-SupRep normalized the heart rate-corrected QT interval (QTc) in SQT1 rabbits, without affecting repolarization heterogeneity. Ex vivo, KCNH2-SupRep corrected the action potential duration (APD90) and resolved the increased apicobasal APD90 heterogeneity observed in untreated (UT)-SQT1 hearts, supporting an antiarrhythmic effect, which was further validated by reduced re-entry formation in silico. At cellular levels, KCNH2-SupRep prolonged APD90 in VCMs from SupRep-SQT1 rabbits closer to wildtype levels compared with UT- and sham-SQT1. Additionally, KCNH2-SupRep restored the cellular surrogate of the electro-mechanical window and normalized IKr in nearly 50% of VCMs, in line with a 50%–60% suppression of the mutant KCNH2 transcript. Conclusions This proof-of-concept study is the first to demonstrate the efficacy of gene therapy for SQT1 in a medium-sized animal model. KCNH2-SupRep gene therapy successfully corrected the pathologic phenotype in vivo, ex vivo, and at cellular levels in transgenic SQT1 rabbits.

ABSTRACT Post‐translational modifications, such as glycosylation and phosphorylation, play a critical role in protein trafficking, interactions, and stability. Disruptions in these pathways can lead to glycosylphosphatidylinositol (GPI) deficiencies, which present with a spectrum of clinical features, including congenital anomalies, dysmorphic features, developmental delay, hypotonia, and epilepsy. Biallelic variants in PIGV , a key mannosyltransferase in GPI biosynthesis, cause Hyperphosphatasia with Impaired Intellectual Development Syndrome 1 (HPMRS1), a rare disorder characterized by hyperphosphatasia, seizures, developmental delay, hypotonia, abnormal MRI findings, and distinct facial dysmorphisms. Fewer than 30 cases have been reported to date. We conducted a case study and literature review; with clinical data obtained from medical records. A 2‐year‐old female presented with developmental delay, myoclonic epilepsy, hypotonia, and mild facial dysmorphism. Laboratory results showed elevated alkaline phosphatase (899 U/L) and low pyridoxal 5′‐phosphate levels in cerebrospinal fluid (CSF). Brain MRI revealed diffuse cerebral volume loss and ventriculomegaly. Trio genome sequencing identified two PIGV variants: c.1415T>C‐p.(Leu472Pro) and c.524T>C‐p.(Leu175Pro). Functional studies using PIGV ‐knockout HEK293 cells transfected with wild‐type or mutant PIGV constructs demonstrated reduced GPI‐anchored protein (GPI‐AP) expression under weaker promoters, indicating impaired enzymatic activity. We report two novel PIGV variants associated with HPMRS1, emphasizing the value of functional assays in variant interpretation. Our findings also highlight the diagnostic relevance of alkaline phosphatase measurement in patients with refractory seizures.

Key Points Significant heterogeneity in patient characteristics, urine metabolic studies, and kidney outcomes exist among enteric hyperoxaluria patients from diverse etiologies. Structurally induced malabsorption and exocrine pancreatic insufficiency have the highest kidney stone event rates. Patients with structurally induced malabsorption have up to 18% ESKD incidence at 5 years. Background Enteric hyperoxaluria (EH) is a risk factor for calcium oxalate nephrolithiasis and kidney disease. The study compares patient characteristics and urine metabolic profiles at the time of EH diagnosis and kidney stones and ESKD events during follow-up in a cohort with diverse causes of EH. Methods Adult patients with newly documented elevated urinary oxalate excretion >40 mg/24 h between January 1, 2010, and October 10, 2023, and a known enteric diagnosis including inflammatory bowel disease, exocrine pancreatic insufficiency (EPI), celiac disease, structural intestinal malabsorption (SIM), or malabsorptive bariatric surgery (Bariatric) were identified. Event rates and cumulative incidence of kidney stones and ESKD were assessed. Results Among 814 identified patients, the most common enteric etiology was Bariatric ( n =524, 64%). Patients with ulcerative colitis had the highest prevalence of kidney stones at EH diagnosis (93.6%) compared with other enteric etiologies ( P = 0.002). Patients with SIM had the highest urinary oxalate, lower urinary citrate, and volume, compared with other enteric etiologies ( P < 0.05). Calcium oxalate supersaturation was similar among the enteric groups ( P = 0.67). Median stone event rate for the overall cohort was 0.70 stone events/year during a mean (SD) follow-up of 5.0 (3.9) years. The SIM and EPI groups experienced the highest stone events (median [IQR] 1.24 [0.28–2.40] and 1.20 [0.41–1.99] events/year, respectively) while the Bariatric group had the lowest event rates (median [IQR] 0.45 [0.00–1.66 events/year]; P < 0.001). The SIM group had the highest ESKD incidence (17.8% 5 years postdiagnosis; log-rank test P < 0.001). Conclusions We describe a large EH cohort from diverse enteric etiologies. Significant heterogeneity exists in patient characteristics, urine metabolic risk factors, and adverse kidney outcomes. Patients with SIM and EPI experienced the highest kidney stone events and patients with SIM had the highest ESKD incidence. This study highlights the urgent need for more granular information regarding the natural history and risk factors for kidney complications for patients with EH to support interventional trials to improve outcomes.