Citations

ABSTRACT This case highlights the diagnostic challenges posed by rare oropharyngeal neurofibromas, their potential to mimic other conditions, and the novel application of transoral robotic surgery (TORS) for the management of an oropharyngeal neurofibroma. A 47‐year‐old female presented with a 1‐year history of a left tonsillar mass. Clinical evaluation, imaging, and biopsy results were inconclusive but raised suspicion for a neoplasm. The patient underwent robotic‐assisted tonsillectomy and mass resection. Subsequent histopathological evaluation confirmed a benign spindle cell tumor consistent with neurofibroma. Oropharyngeal neurofibromas may present diagnostic challenges due to their resemblance to common tonsillar pathologies. Imaging and biopsies may not always provide definitive diagnoses, necessitating surgical excision for accurate characterization. This case demonstrates the utility of TORS, offering improved visualization and access while minimizing patient morbidity.

ABSTRACT Clinical pharmacists are increasingly recognized as vital contributors to acute stroke care, yet their role remains inconsistently defined and underutilized across health care systems. This consensus statement explores the expanding presence of clinical pharmacists within interdisciplinary stroke teams, particularly in the management of both acute ischemic stroke ( AIS ) and hemorrhagic stroke. This consensus statement panel was composed of clinical pharmacists, emergency medicine physicians, and a vascular neurologist. The Grading of Recommendations, Assessment, Development, and Evaluation ( GRADE ) approach was used to assess the level of certainty and strength of recommendations. We focused on two questions regarding the clinical pharmacist's role in caring for adult patients presenting to the emergency department ( ED ) with AIS or hemorrhagic stroke. Despite the very low level of evidence, a consensus was reached for the following recommendations: (1) clinical pharmacist involvement in AIS care for adult patients presenting to the ED and (2) clinical pharmacist involvement in hemorrhagic stroke care for adult patients presenting to the ED . Based on the available literature, we believe optimizing the clinical pharmacist role is a critical factor in improving time‐sensitive treatment and equity in care delivery.

Importance Tofersen is a disease-modifying antisense oligonucleotide therapeutic for people living with SOD1 –amyotrophic lateral sclerosis ( SOD1 -ALS). Autopsy tissue donors have provided the first opportunity to study the distribution of intrathecally administered tofersen in human central nervous system tissues. Objectives To determine the tissue distribution of tofersen and to provide the first estimates of SOD1 reduction in human somatic motor systems tissues. Design, Setting, and Participants This was a cross-sectional autopsy tissue case series conducted between 2018 and 2026. Autopsies were performed at 3 US academic medical institutions. Tissue samples from 8 deceased patients who lived with SOD1 -ALS, participated in tofersen clinical trials (ClinicalTrials.gov Identifiers NCT02623699 [An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)] and NCT03070119 [Long-Term Evaluation of BIIB067 (Tofersen)]) or the Expanded Access Program, and whose families authorized autopsies were eligible for this study. All autopsy tissue donors known at the time of this study were included (none were excluded). Analyses were conducted between August 2020 and January 2026. Exposures Participants received multiple intrathecal 20- to 100-mg tofersen doses. Main Outcomes and Measures Tofersen tissue concentrations were measured using hybridization enzyme-linked immunosorbent assay (ELISA). SOD1 messenger RNA (mRNA) and protein reduction estimates, defined as percentage SOD1 levels in this study’s recently treated autopsy tissue donors compared to a cohort of samples from tofersen-naive SOD1 -ALS autopsy tissue donors, were measured using quantitative reverse transcription polymerase chain reaction (PCR) and ELISA. Histological localization of tofersen and SOD1 transcripts were studied using immunohistochemistry and in situ hybridization assays. Results In 8 tofersen-treated autopsy tissue donors (5 male and 3 female donors; age range, 42-66 years), spinal cord and motor cortical tissue tofersen concentrations strongly correlated with predictions based on individual dosing histories and a preclinical pharmacokinetic model. For 3 recently treated autopsy tissue donors, reductions in lumbar spinal cord tissue SOD1 mRNA and protein levels ranged from 45% to 84% despite not having been administered 1 to 2 scheduled doses before autopsy. Residual somatic motor neurons demonstrated tofersen transduction and low SOD1 mRNA probe hybridization. Misfolded SOD1 protein inclusions were detected in residual motor neurons of tofersen-naive SOD1- ALS tissue donor controls and tofersen-treated tissue donors. Meningeal and perivascular lymphocytic immune responses were observed in 5 recently treated tissue donors but were not apparent in tissue donors with remote final tofersen doses. Conclusions and Relevance This case series presents the first emerging autopsy tissue data confirming the predicted distribution of tofersen and robust SOD1 protein reduction in human somatic motor systems tissues.

Abstract Endocytosis regulates receptor trafficking and signaling, yet its role in colorectal cancer (CRC) remains unclear. We analyzed transcriptomic data from 15,025 CRC tumors to evaluate gene expression in clathrin-mediated endocytosis (CME) and the endosomal sorting complexes required for transport (ESCRT) pathway. Pathway-level signatures were compared across consensus molecular subtypes (CMS) and examined in relation to oncogenic signaling programs, while individual endocytosis-related genes were evaluated for associations with clinical outcomes in an independent randomized trial cohort. Expression of CME and ESCRT pathways varied by CMS, with the highest expression in CMS4 and the lowest in CMS3. Endocytosis signatures correlated with multiple oncogenic signaling pathways, including MAPK, TGF-β, WNT, PI3K, NOTCH, and angiogenesis, suggesting broad links between endocytic activity and tumor biology. In the randomized phase III CALGB/SWOG 80405 trial, low expression of AP2M1 —a core adaptor in the CME complex—was significantly associated with longer overall survival and progression-free survival in patients treated with anti-EGFR agents, but not in those receiving anti-VEGF agents. These findings suggest that endocytic trafficking may be associated with oncogenic signaling and differential therapeutic benefit in patients with metastatic CRC. The endocytosis pathway reflects biologically relevant heterogeneity in CRC and may help guide therapeutic stratification.

Abstract Background The multicentre ALaCaRT and ACOSOG Z6051 randomized trials were unable to demonstrate non-inferiority of laparoscopic versus open surgery for rectal cancer with respect to a composite pathology metric indicating successful resection. Neither trial was individually powered to detect differences in long-term recurrence or survival. This planned meta-analysis determined long-term oncological outcomes of laparoscopic versus open proctectomy for rectal adenocarcinoma. Methods This prospective meta-analysis included individual patient data from patients with cT1–3 N0–2 M0 rectal adenocarcinoma enrolled in the ALaCaRT and ACOSOG Z6051 trials. Pathologically successful resection was defined as complete or near-complete total mesorectal excision, a clear circumferential resection margin (CRM; > 1 mm), and a clear distal resection margin (> 1 mm). The non-inferiority margin for disease-free survival (DFS) was an absolute difference of 5% at least 3 years after surgery. Results The combined data set included 935 patients (65.6% men, mean age 60.7 years, mean body mass index 26.7 kg/m2) randomized to open (457 patients) or laparoscopic (478 patients) proctectomy. Pathologically successful resection was lower in the laparoscopic than open group (85.1% versus 89.9%, respectively; pooled estimate 4.6% difference; 95% confidence interval (c.i.) −8.6% to −0.5%). The median follow-up was 60.2 (interquartile range 49.9–61.1) months. Three-year DFS was 75.2% (95% c.i. 71.1% to 79.2%) and 76.5% (95% c.i. 72.5% to 80.6%) for the laparoscopic and open groups, respectively (pooled estimate difference −1.5%; 95% c.i. −7.2% to 4.2%). Non-inferiority of laparoscopic surgery was not demonstrated because the lower one-sided 95% c.i. (−6.3% to 100%) crossed −5%. Three-year locoregional recurrence was higher in laparoscopic than open group (5.4% (95% c.i. 3.3% to 7.5%) versus 2.0% (95% c.i. 0.7% to 3.4%), respectively; pooled estimate 3.1% difference (95% c.i. 0.6% to 5.6%)). A clear CRM was the most significant and only pathological predictor of both DFS (P < 0.0001) and overall survival (P < 0.0001). Conclusion Laparoscopic proctectomy led to a lower rate of pathologically successful resection and a higher rate of locoregional recurrence at 3 years. The possibility of subsequent poorer DFS or overall survival rate requires further evaluation, because this analysis was not specifically powered for these endpoints.

ABSTRACT Patients requiring permanent pacing after tricuspid valve intervention present challenges due to the need to cross tricuspid valve prostheses. We report three cases of successful dual coronary sinus (CS) lead implantation for biventricular pacing following a range of tricuspid interventions—surgical tricuspid annuloplasty, transcatheter edge‐to‐edge repair, and transcatheter tricuspid valve replacement. The approach avoided tricuspid valve traversal, was technically feasible and resulted in satisfactory pacing performance without procedural complications. Dual CS lead configurations were individualized based on CS anatomy and pacing characteristics. The degree of QRS narrowing achieved varied according to lead location and ventricular activation patterns, highlighting the importance of individualized lead placement strategies and device programming. Dual CS lead pacing may represent a viable alternative for biventricular pacing in selected patients with prior tricuspid valve interventions. Larger studies are needed to evaluate long‐term outcomes and define the optimal role of this approach among available pacing strategies in this patient population.

Study Design. Post hoc analysis of prospectively-collected data. Objective. To identify factors predicting the most (and least) satisfaction following surgery for cervical spondylotic myelopathy (CSM). Summary of Background Data. Patient satisfaction affects long-term outcomes after surgery but the preoperative factors that influence postoperative satisfaction have not been well studied in patients with CSM. Methods. We conducted a post hoc analysis of prospectively-collected data from the Quality Outcomes Database (QOD) CSM registry cohort. Baseline and surgical characteristics were compared for patients with CSM reporting the most [North American Spine Society Satisfaction Score (NASS) 1] and least (NASS 4) satisfaction 24 months postoperatively. A multivariable logistic regression model was constructed using backward stepwise elimination to determine significant predictors of most versus least satisfaction. Twenty-four-month patient-reported outcomes (PROs) were compared. Results. Overall, 1141 patients were prospectively enrolled with 948 (83.1%) reaching 24-month follow-up. Of these, 699 met prespecified inclusion criteria: 610 (87.3%) were most satisfied and 89 (12.7%) were least satisfied. Though there were mean improvements in all 24-month PROs for the most satisfied cohort ( P <0.001), there were no significant improvements in 24-month PROs for the least satisfied cohort ( P >0.05). Using multivariable logistic regression modeling, a preoperative symptom of upper extremity weakness (OR=2.5, P =0.003), subjective myelopathy (OR=2.0, P =0.04), absence of numbness complaints (OR=2.2, P =0.003), symptom duration under 12 months (OR=1.6, P =0.047), Caucasian race (OR=2.3, P =0.001), participation in activities outside of the home (OR=2.0, P =0.04), anterior approach (OR=2.3, P <0.001), and higher baseline quality of life (OR=4.0, P =0.01) were predictive of the most satisfaction. Conclusion. Compared with the least satisfied, those most satisfied following surgery for CSM more often had a preoperative symptom of arm weakness, subjective myelopathy, the absence of numbness complaints, symptom duration under 12 months, higher baseline quality of life, and participation in activities outside of the home. Compared with a posterior approach, an anterior approach was associated with the most satisfaction. Taken together, early surgical treatment--before myelopathic symptoms significantly impact one's quality of life--may be considered to optimize patient satisfaction following CSM surgery.

ABSTRACT Background Eosinophilic esophagitis is associated with epithelial barrier dysfunction. Epidemiologic studies suggest environmental factors promote disease pathogenesis. The common household detergent sodium dodecyl sulfate (SDS) induces epithelial barrier dysfunction and eosinophilic inflammation in mice. We hypothesized that acute SDS exposure would compromise the esophageal mucosal barrier in humans. Methods Healthy adults brushed with 2 g of an SDS‐containing toothpaste. Esophageal impedance was measured continuously pre‐/post‐toothbrushing to assess the effect of toothpaste on epithelial barrier function. SDS was measured in saliva using a methylene blue anionic substances assay. Participants completed 1‐h esophageal string tests (ESTs) pre‐/post‐toothbrushing and protein isolates from EST eluates from the proximal and distal esophagus were analyzed by tandem mass tag mass spectrometry. Results Ten of twelve subjects completed the clinical study. SDS in the initial expectorate measured immediately after toothbrushing varied markedly (median: 321.40 μg/mL; range: 169.90–1243.00 μg/mL) and was detectable in saliva in 80% of subjects (median: 9.55 μg/mL; range: 0–123.40 μg/mL) at 60 min post toothbrushing. Esophageal mucosal impedance decreased within 30 min of toothbrushing ( p < 0.01). Toothbrushing increased salivary viscosity and proteins associated with mucosal defense in EST eluates. The tight junction pathway was downregulated while the salivary secretion and complement and coagulation cascades pathways were upregulated in the proximal esophagus. Conclusion In healthy individuals, SDS remained detectable in saliva for a prolonged period after toothbrushing at concentrations previously shown to disrupt esophageal epithelial barrier function in vitro. Toothbrushing with an SDS‐containing toothpaste was associated with reduced esophageal mucosal impedance, altered salivary properties, and activated mucosal immune responses.

ABSTRACT Background Inflammatory bowel disease (IBD) and myeloproliferative neoplasms (MPNs) share chronic inflammation and immune dysregulation. Aim We evaluated the incidence of MPNs among patients with IBD and clinical outcomes of IBD–MPN coexistence. Methods Two retrospective cohort analyses were conducted using the TriNetX database. First, adults with ulcerative colitis (UC) or Crohn's disease (CD) were compared with matched non‐IBD controls to estimate incident MPN risk. A coexistence second analysis included patients with UC or CD who developed MPNs and then were matched to IBD without MPN controls to assess 5‐year outcomes, including IBD‐related complications, surgical interventions, colorectal cancer (CRC) and primary sclerosing cholangitis (PSC). Medication subgroup analyses were performed to evaluate associations with MPN risk. Results After matching, 3873 patients with UC–MPN and 3474 patients with CD–MPN were included. Compared with matched non‐IBD controls, incident MPN risk was higher in UC (HR 1.60, p = 0.01) and CD (HR 1.56, p < 0.001). In CD, MPN coexistence was associated with higher risks of CRC (HR 1.52, p = 0.012), intestinal fistula (HR 2.84, p < 0.001), obstruction (HR 2.05, p < 0.001), perforation (HR 2.37, p < 0.001), small bowel resection (HR 3.69, p < 0.001) and colectomy (HR 2.10, p < 0.001). In UC, MPN coexistence was associated with higher risks of CRC (HR 1.50, p = 0.001), PSC (HR 1.75, p = 0.03) and pouchitis (HR 1.68, p = 0.003). Exposure to thiopurines (HR 1.28, p < 0.001) was associated with increased MPN risk, whereas TNF, IL‐23 and JAK inhibitors were not. Conclusions IBD is associated with increased MPN risk, and IBD–MPNs coexistence is associated with worse IBD‐related complications and malignancy risk.