Citations

ABSTRACT Objective Pituitary carcinoma (PC) is defined by the presence of metastasis from a pituitary tumour. PC is rare, therefore information regarding survival and factors influencing survival are limited. We sought to assess overall survival following the diagnosis of PC and to determine factors associated with outcome. Design Retrospective case series. Patients Patients with PC who attended the Mayo clinic between 1997 and 2025. Measurements Information regarding patient demographics, tumour characteristics, management and outcomes were extracted. Results In total 25 patients (11 women, 44%) were diagnosed with PC (median age 56 years, range, 44–78). The most common cell type was a corticotroph tumour ( n = 15, 60%). All but one patient had pituitary directed surgery and all received pituitary adenoma (PA) directed radiation therapy. Metastases were identified a median 6 years (range, 1–32) after initial PA diagnosis. At last follow‐up, 10 (40%) patients were alive, 12 (48%) died of PC, and 3 (12%) died from other causes. The median survival time of patients from PC diagnosis was 3 years. The 1‐, 5‐ and 10‐year survival rates were 59%, 37% and 15%, respectively. Increased survival probability was associated with temozolomide treatment ( n = 9) at some point in treatment plan ( p = 0.026), the use of systemic therapy vs locoregional treatment ( p = 0.045), female sex ( p = 0.011), and in nonfunctional tumours ( p = 0.023). Conclusion PC carries a poor prognosis, with a median survival of only 3 years. Improved survival was associated with temozolomide exposure, female sex, and nonfunctional tumour subtype and underscores the prognostic relevance of tumour biology and treatment approach.

Single-cell studies have defined immune states in inflammatory bowel disease (IBD), but how adaptive receptor histories organize circulating immunity remains unclear. We generated a single-cell transcriptomic atlas of peripheral blood from 249 participants with Crohn's disease, ulcerative colitis, or non-IBD control status, including 182 with productive TCR and BCR recovery. Expanded TCR clonotypes marked inflammatory-memory and cytotoxic states, while distinct but similar paired TCRs shared inflammatory programs across participants. BCR lineage maturation linked IgA-associated mucosal and plasma B cell programs to somatic mutation and class switching, distinguishing maturation-associated biology from clonal expansion. Helper, regulatory, and cytotoxic T-cell programs covaried with B-cell states, and inferred interactions nominated reciprocal antigen-presentation and helper pathways. Repertoire-based machine learning distinguished diagnosis, inflammation, and contemporaneous six-month treatment-response status. Together, this atlas connects receptor architecture to coordinated systemic immune remodeling, establishes a foundation for repertoire-informed patient stratification, and prioritizes candidate mechanisms of IBD pathogenesis.

Abstract Background and Aims Fibroblast–neutrophil interactions are implicated in ulcerative colitis (UC) treatment resistance, but whether fibroblasts modify neutrophil inflammatory activity remains unclear. We investigated responses to fibroblast exposure, stromal depletion, and α5β1-directed treatment. Methods We integrated human and mouse colonic single-cell RNA sequencing (scRNA-seq), spatial protein profiling (CODEX), fibroblast–neutrophil coculture, and dextran sulfate sodium (DSS) mouse colitis with fibroblast activation protein (FAP) ablation or α5β1-directed treatment. Readouts included cellular representation and protein fluorescence via flow cytometry, neutrophil extracellular trap (NET)-associated elastase activity, RNA programs and epithelial responses using scRNA-seq. Results Inflamed UC tissue contained higher fractions of inflammatory fibroblasts and oncostatin M (OSM)- and CXCR4-associated neutrophils. Inflammatory fibroblasts had higher FAP–α5β1 module scores, and proximity to FAP-high fibroblasts was associated with higher neutrophil OSM and CXCR4 fluorescence. UC fibroblasts increased neutrophil OSM, CXCR4 and myeloperoxidase (MPO) fluorescence and NET-associated elastase activity relative to control fibroblasts, while α5β1-directed treatment attenuated these responses. Both mouse FAP ablation and α5β1 blockade in DSS colitis reduced histologic inflammation and overall neutrophil frequency. Ablation broadly reduced recovered neutrophil representation, whereas blockade increased OSM-positive and PADI4-positive percentages within neutrophils despite lower MPO fluorescence within these subsets. Both interventions were associated with lower epithelial chemokine scores but distinct absorptive and mucus/secretory responses. Conclusions Fibroblast exposure modifies neutrophil inflammatory phenotype and effector-associated activity, identifying candidate therapeutic pathways in UC. Evaluating these responses alongside neutrophil representation and tissue inflammation could inform pharmacodynamic assessment of stromal-directed therapies. Graphical Abstract What You Need to Know Background and Context Fibroblast–neutrophil interactions are associated with treatment resistance in ulcerative colitis. Whether fibroblast exposure modifies neutrophil inflammatory phenotype and effector activity, beyond its established recruitment role, remains unclear. New Findings UC fibroblasts increased neutrophil inflammatory proteins and NET-associated elastase activity; α5β1-directed treatment attenuated these responses. FAP ablation and α5β1-directed treatment reduced colitis and overall neutrophil frequency. α5β1-directed treatment lowered MPO within OSM-positive and PADI4-positive neutrophils despite higher marker-positive percentages. Epithelial single-cell RNA sequencing revealed reduced chemokine programs with both interventions but distinct barrier-associated and regenerative expression patterns. Limitations Cellular drug targets remain unresolved. Spatial associations and elastase activity do not establish direct contact, NET formation, or clinical efficacy. Clinical Research Relevance Fibroblast-associated pathways offer candidate therapeutic opportunities to modify neutrophil inflammatory phenotype and effector activity in UC. Coculture responses were pharmacologically modifiable, and stromal interventions reduced experimental colitis. Measuring neutrophil frequency, subset proteins, and effector activity alongside tissue inflammation could guide pharmacodynamic assessment. Clinical efficacy and treatment-selection utility require validation. Basic Research Relevance Human coculture provides experimental evidence that fibroblast exposure modifies neutrophil inflammatory proteins and NET-associated elastase activity. FAP+ stromal ablation and α5β1-directed treatment produced distinct patterns of neutrophil representation and subset proteins in colitis. Epithelial single-cell RNA sequencing revealed reduced chemokine programs with both interventions but differing barrier-associated and regenerative expression patterns. Together, these findings motivate mechanistic studies of how stromal recruitment cues, soluble signals, and matrix-associated interactions regulate neutrophil responses, and whether these changes contribute to reduced epithelial inflammation and tissue repair. Lay Summary Fibroblasts, support cells in the intestine, increased inflammatory activity in immune cells called neutrophils. Blocking a pathway involved in cell attachment reduced these responses in cultures. Targeting fibroblast-associated pathways also reduced experimental colitis, with changes in intestinal lining gene activity related to inflammation, barrier function, and repair. These findings suggest potential approaches to treating ulcerative colitis.

Background: Reliable access to postoperative guidance between clinic visits remains inconsistent, and the usefulness of large language models depends on how clinical knowledge is structured and retrieved. Knowledge graph-only (KG-only), vector retrieval-augmented generation (RAG-only), and hybrid graph-retrieval (GraphRAG) architectures have not been directly compared under controlled conditions for postoperative care. Objective: It was to compare these three pipelines on a curated postoperative question-answering benchmark using automated grounding metrics and blinded clinician review. Methods: A benchmark of 250 expert-authored questions (200 in-scope, 20 emergency-intent, 30 out-of-scope) was evaluated on an identical knowledge corpus using Gemini 2.5 Flash for generation and Gemini Embedding-001 for retrieval. Three blinded clinicians rated all 750 outputs; the primary outcome was majority-consensus accuracy across all 250 questions. GraphRAG is a multi-component pipeline that also includes query expansion, a second retrieval stage, evidence fusion, and a monotonic RAG fallback, and is therefore evaluated as a complete hybrid system rather than as graph retrieval in isolation. Results: Overall accuracy was 96.8% (95% CI: 93.8–98.4) for GraphRAG, 94.8% (95% CI: 91.3–96.9) for RAG-only, and 56.0% (95% CI: 49.8–62.0) for KG-only. Both retrieval-augmented systems outperformed KG-only (adjusted p < 0.001). The GraphRAG versus RAG-only difference was 2.0 percentage points, arose from five discordant question pairs and did not reach the Bonferroni-adjusted threshold (exact McNemar p = 0.062; adjusted p = 0.188). The monotonic RAG fallback determined 44.8% of GraphRAG outputs (112 of 250 queries). GraphRAG showed higher context recall (0.851 versus 0.796; adjusted p < 0.001), whereas RAG-only showed higher context precision. Estimated hallucination risk, derived from an LLM-as-a-judge procedure using Gemini 2.5 Flash rather than independent clinical adjudication, was 0.108, 0.132, and 0.436, respectively; the GraphRAG versus RAG-only difference was not significant (adjusted p = 0.771). Inter-rater agreement was high (Fleiss’ kappa = 0.854). Conclusions: Retrieval augmentation, rather than the choice of retrieval architecture, accounted for most of the difference observed. The incremental advantage of GraphRAG over a well-implemented RAG-only system was small, was not statistically significant after correction and reflects the complete hybrid system rather than graph augmentation alone. Emergency-intent accuracy was 75.0% for both retrieval-augmented systems; the architecture is therefore suited to supervised clinical workflows with clinician review, not autonomous patient-facing triage. Prospective validation on authentic patient messages and formal component ablations are required.

Abstract Pancreatic ductal adenocarcinoma (PDAC), the most common subtype of pancreatic cancer, is a deadly disease with a complex tumor microenvironment (TME). Cytotoxic combination chemotherapy treatments are the mainstay of PDAC therapy, but patients rapidly develop chemoresistance, highlighting the need to elucidate how chemotherapy alters the TME and whether these changes drive chemoresistance. Here, we examined matched pre- and post-treatment tissue specimens using single-cell RNA-sequencing and found near-universal enrichment after treatment of axonal guidance genes in cancer-associated fibroblasts (CAFs). These neural CAFs were enriched near sites of perineural invasion, coinciding with regions of increased tumor cell proliferation, and were enriched in tumor areas distant from nerves after chemotherapy. Metastatic recurrent lesions had the highest prevalence of neural CAFs versus primary tumors and untreated metastases. Neural CAFs showed elevated non-canonical WNT mediators and axonal guidance genes, which complemented matching cognate binding partners in tumor epithelial cells, suggesting a role in tumor-stroma crosstalk. Additionally, in vitro studies revealed enrichment of axonal guidance genes in patient-derived CAF lines upon exposure to chemotherapy or tumor cells. Altogether, these findings implicate fibroblast-derived axonal-guidance genes in promoting PDAC invasion and point to a promising therapeutic target for this disease.

Abstract Introduction Conversion of sleeve gastrectomy (SG) to Roux-en-Y gastric bypass (RYGB) is performed for gastroesophageal reflux disease (GERD), recurrent weight gain, and suboptimal clinical response. We compared early safety, weight loss, and healthcare utilization across indications. Methods We retrospectively analyzed adults undergoing SG-to-RYGB conversion in the 2023 MBSAQIP Participant Use File linked to the Long-Term Follow-Up file. Patients were grouped by indication as GERD, recurrent weight gain, suboptimal clinical response, or other. Baseline, operative, 30-day, and 6-month outcomes were compared using unadjusted analyses. Results Among 12,350 patients, indications were GERD in 59.2%, recurrent weight gain in 24.7%, suboptimal clinical response in 10.5%, and other in 5.6%. Patients with weight-related indications had higher baseline BMI. Major 30-day complications were uncommon and did not differ significantly across groups. Among 8,797 patients with 6-month weight data, mean percent total weight loss (%TWL) was 14.2% for recurrent weight gain, 13.3% for suboptimal clinical response, and 12.7% for both GERD and other indications (P < 0.001). The maximum absolute difference was 1.5 percentage points. Six-month intervention rates were 6.4% for GERD and 6.8% for other indications, compared with 4.2% for recurrent weight gain and 2.8% for suboptimal clinical response (P < 0.001); mortality remained uncommon. Conclusion SG-to-RYGB conversion was associated with low short-term complication rates across indications. Six-month weight loss and healthcare utilization differed in unadjusted comparisons, but weight-loss differences were modest and may reflect baseline case-mix differences.

Purpose: To describe a case of locally invasive conjunctival squamous cell carcinoma (SCC) refractory to plaque radiotherapy. Case Description: A 69-year-old man presented with a recurrent conjunctival tumor after 6 previous cycles of topical 5-fluorouracil chemotherapy and excisional biopsy showing invasive SCC with positive margins. There was a mild anterior chamber reaction. By the time of repeat excisional biopsy, the conjunctiva had ulcerated with underlying scleralysis associated with histopathologic evidence of scleral involvement by SCC. After subsequent tectonic scleral patch grafting, plaque radiotherapy was applied after which the disease appeared to be controlled for 9 months. The eye then developed progressive conjunctival ulceration and scleralysis with progressive ectropion. Exenteration was performed, revealing locally invasive SCC into palpebral conjunctiva, ciliary body, and choroid. Conclusions: Conjunctival SCC can be locally invasive with destruction of the globe, despite plaque radiotherapy. Clinicians should be suspicious of invasive diseases in cases of ocular surface squamous neoplasia that are poorly responsive to topical chemotherapy. Associated anterior chamber cell and progressive scleralysis should also raise concern for invasive malignancy.

Objective Our objective was to identify and describe the clinical characteristics and outcomes in patients with pre‐existing idiopathic inflammatory myopathies (IIMs) in the Veterans Health Administration (VHA) treated with immune checkpoint inhibitors (ICIs). Methods All veterans receiving ICI infusions were identified. Patients with at least two International Classification of Disease codes for IIM before first ICI infusion underwent chart review to identify patients with confirmed IIM by American College of Rheumatology/EULAR criteria. The demographics, cancer diagnoses, laboratory findings, clinical course, and mortality rates were reported. IIM cases were also reviewed to determine if patients developed IIM flare following ICI treatment. Results We identified 29,539 veterans who received at least one ICI infusion in the VHA between June 6, 2011, and February 14, 2023. The eight patients with confirmed IIM before ICI treatment were mostly White men with an average age of 71.7 years at first ICI infusion. The IIM diagnoses were dermatomyositis in three patients, polymyositis in two, antisynthetase syndrome in two, and one rheumatoid arthritis (RA)/myositis overlap. Cancer diagnoses were lung (two), melanoma (two), head and neck (two), kidney/other urinary (one), and mesothelioma (one). Diagnosis of IIM was made on average 3.1 years before ICI treatment. One patient had an IIM flare after ICI. No IIM flares were identified in other patients. Conclusion Our findings show that an IIM flare after ICI therapy can occur, but most patients did not develop a flare. These observations suggest ICIs can be considered as an option in patients with cancer with IIM with shared decision‐making and close monitoring.

Background: Whether robot-assisted cholecystectomy reduces bile duct injury compared with laparoscopic cholecystectomy remains uncertain because prior studies have inadequately accounted for disease severity and have rarely classified injury severity using standardized criteria. This study compared perioperative outcomes after robot-assisted and laparoscopic cholecystectomy across a large healthcare system while adjusting for operative complexity. Study Design: Adults undergoing robot-assisted or laparoscopic cholecystectomy within the Mayo Clinic Enterprise (2014–2025) were retrospectively evaluated. Propensity score weighting adjusted for demographics, surgeon case volume, learning curve, and disease severity using the Tokyo Guidelines and Parkland grading system in patients with acute cholecystitis. The primary outcome was bile duct injury; secondary outcomes included general and procedure-specific complications. Results: Among 23,513 patients (19,998 laparoscopic; 3,515 robotic), robot-assisted cholecystectomy was used more frequently for Parkland grade ≥3 disease. Overall, 227 bile duct injuries occurred (204 laparoscopic; 23 robotic), corresponding to absolute risks of 1.02% and 0.65%, respectively (absolute risk difference −0.37%, 95% CI −0.72% to −0.02%; number needed to treat, 273). Robot-assisted cholecystectomy was associated with lower odds of conversion to open surgery, 30-day readmission, and mortality, shorter hospital stay (β −0.56, 95% CI −0.66 to −0.45; P<0.001), and a 5-minute longer median operative time. In acute cholecystitis, robot-assisted cholecystectomy was associated with lower adjusted odds of bile duct injury (aOR 0.29, 95% CI 0.07–0.78; P=0.011). Conclusions: After adjustment for disease severity and surgeon-related factors, robot-assisted cholecystectomy was associated with lower odds of bile duct injury in acute cholecystitis and improved perioperative outcomes, including shorter hospitalization and lower conversion rates, despite greater use in more complex cases.