Citations

SUMMARY Intraductal oncocytic papillary neoplasms (IOPNs) are rare tumors that develop from biliary and pancreatic ductal epithelium and progress to lethal cancers. Human IOPNs and IOPN-associated carcinomas are known to harbor the DNAJB1-PRKACA gene fusion, however the role of the oncogenic fusion in carcinogenesis is poorly understood. We developed a Cre-inducible mouse model of human DNAJB1-PRKACA expression and substantiated that the DNAJB1-PRKACA fusion gene is a bona fide driver of IOPN-associated biliary and pancreatic carcinoma. By analyzing the unique histopathologic and transcriptional changes that occur at each stage of tumor development, we found that these murine tumors closely mimic human DNAJB1-PRKACA driven tumors. Furthermore, we identified that many of the salient features of invasive carcinoma are established at the pre-invasive stage, including evidence of tumor cell metabolic dysregulation, immunosuppressive tumor stroma and expression of genes strongly associated with invasive DNAJB1-PRKACA driven cancer in humans. Finally, we found that Slc16a14 , a characteristic DNAJB1-PRKACA regulated super-enhancer associated gene, serves as a robust biomarker of malignant transformation from IOPN to invasive carcinoma.

OBJECTIVE Frailty is a known predictor of adverse outcomes in pituitary surgery, yet its impact regarding craniopharyngioma remains unclear. The authors assessed preoperative frailty, measured by the 11-factor modified frailty index (mFI-11), and its association with perioperative morbidity among adult patients undergoing craniopharyngioma surgery. METHODS Using the Registry for Adenomas of the Pituitary and Related Disorders (RAPID) database, the authors performed a retrospective cohort study of the records of patients ≥ 18 years of age who underwent craniopharyngioma surgery between June 2007 and November 2024. Patients were stratified into the following categories according to their numeric mFI-11 score: fit (scores 0 and 1), managing well (scores 2 and 3), and mildly frail (scores 4–6). Primary outcomes included hospital length of stay (LOS) and discharge disposition. Secondary outcomes included 90-day readmission, surgical outcomes, and complications. Multivariable analyses were performed to identify independent predictors of hospital LOS and non-home discharge, adjusting for age, surgeon experience, American Society of Anesthesiologists class, complications, and surgical approach. RESULTS Among 278 patients (221 fit, 43 managing well, 14 mildly frail), higher-frailty patients were older (mean age 47.8 ± 16.1 years in fit vs 60.1 ± 12.5 years in managing well vs 67.6 ± 8 years in mildly frail, p < 0.001) and more likely to present urgently (24.2% vs 36.4% vs 78.6%, p = 0.001). Gross-total resection was achieved less frequently in frail patients (44.8% vs 24.3% vs 23.1%, p = 0.030). Overall complication rates were similar; however, increasing frailty was associated with higher rates of postoperative mortality (0% vs 2.8% [1/36] vs 7.7% [1/13], p = 0.018), pneumonia (0.5% [1/195] vs 2.8% [1/36] vs 15.4% [2/13], p = 0.006), and reintubation (2.6% [5/195] vs 2.8% [1/36] vs 30.8% [4/13], p = 0.002). Higher frailty was associated with a stepwise rise in median [IQR] LOS (5 [3–8] days vs 7 [4–12] days vs 13 [6.5–21.8] days, p < 0.001) and remained an independent predictor of extended LOS on multivariable analysis (β = 1.729 per point, p = 0.006). Rates of non-home discharge showed a similar pattern (9.2% vs 30.0% vs 64.3%, p < 0.001), with frailty independently predicting non-home discharge (OR 2.352, 95% CI 1.527–3.822). Unplanned 90-day readmission rates were significantly higher in the mildly frail cohorts (22.5% vs 45.7% vs 53.8%, p = 0.002). CONCLUSIONS The mFI-11 scores independently predicted perioperative morbidity following craniopharyngioma resection. Incorporating frailty screening into preoperative screening may improve risk stratification, family and patient counseling, and discharge planning.

ABSTRACT Background Long‐term outcome data for stiff person spectrum disorder (SPSD) remain limited and sustained response to treatment varies. Methods In this retrospective cohort study, we included patients with probable or definite SPSD (Mayo Clinic criteria), evaluated at Mayo Clinic (12/1995‐07/2024) with ≥ 5 years of follow‐up after diagnosis. Primary outcome measures included the modified Rankin scale (mRS) and use of gait aids. Results Fifty‐four patients were included, 41 (76%) were female; median age at onset was 45 years (16–78). Most were antibody‐positive (51 [94%]), with high‐titer (serum, ≥ 20 nmol/L) GAD65‐IgG in 45 (83%). Nine patients had a stiff‐limb presentation (17%). The median interval from onset to diagnosis was 2 years (0–34), and median follow‐up was 9 years (5–26). Most patients (46 [85%]) received immune therapy; 37 (82%) reported improvement. All patients had significant impairment (mRS ≥ 2) at nadir, with 31 (57%) losing functional independence (mRS ≥ 3) and 40 (75%) requiring bilateral gait assistance. The median time from onset to nadir was 6 years (0–39). At last follow‐up, most (37 [69%]) were functionally independent (mRS ≤ 2), including 8 (15%) with minimal restrictions (mRS ≤ 1). Bilateral gait assistance was needed in 22 (41%). Among 40 patients with ≥ 10 years of follow‐up, 22 (56%) had an mRS ≤ 2 and 25 (63%) required a gait aid at last follow‐up. Poor outcome in this population was associated with bilateral gait assistance at nadir and older age ( p < 0.05). Conclusions Although over half of SPSD patients lose functional independence at disease nadir, many regain independence and achieve well‐controlled symptoms.

Abstract Background Emerging evidence suggests irreversible electroporation (IRE) with standard-of-care (SOC) chemotherapy may improve survival in patients with Stage 3 pancreatic ductal adenocarcinoma (PDAC) when compared to SOC alone. This study evaluates the overall survival (OS) and progression-free survival (PFS) of Stage 3 PDAC patients treated with SOC plus IRE with the NanoKnife System versus SOC alone. Methods This prospective, multicenter study included two cohorts from the DIRECT registry: an IRE cohort from sites offering IRE as part of clinical care, and a comparator SOC cohort of prospectively enrolled and contemporaneous retrospective patients. Enrollment spanned 08/05/2019 to 02/05/2023, with follow-up through at least 24 months, death, or loss to follow-up. Included were 137 patients (99 IRE; 38 SOC), aged ≥18 years with Stage 3 PDAC and no progression after three months of SOC therapy. Results Median (interquartile range) time from diagnosis to enrollment was 8 (6-10) months for IRE and 4 (3-6) for SOC (p<0.0001). Median OS and PSF from enrollment were 18 (95% confidence interval [CI]: 15-24) months and 9 (95% CI: 7-12) months for IRE, and 10 (95% CI: 8-14) months and 6 (5-8) months for SOC, respectively (p<0.0001 and p=0.009). Adverse events occurred in 80% (79/99) of IRE patients and 95% (36/38) of SOC patients; 29% (29/99) of the IRE cohort experiencing an IRE-related adverse event. Conclusions IRE was associated with improved OS versus SOC alone and may be an effective consolidative treatment for Stage 3 PDAC after three months of induction chemotherapy.

Background The optimal management of biochemical recurrence (BCR) after radical prostatectomy (RP) remains controversial, particularly in the absence of clinical or radiographic evidence of disease. Salvage radiotherapy (SRT) remains standard of care, but it is unclear whether SRT benefits patients when modern imaging with a multiparametric magnetic resonance imaging (mpMRI) and prostate‐specific membrane antigen‐positron emission tomography/computed tomography (PSMA‐PET/CT) are negative for local recurrence. Retrospective data comparing SRT to observation for such patients is fraught with selection bias, underscoring the need for a prospective randomised controlled trial. Study Design and Methods The Biochemical Recurrence Irradiation or Observation (BRIO) is a randomised study under the DIVINE trial framework (NCT06378866) enrolling men with BCR (prostate‐specific antigen [PSA] level ≥0.2, up to 1.5 ng/mL) after RP with no radiographic evidence of recurrence on mpMRI and PSMA‐PET/CT. Major inclusion criteria include age ≥18 years, biochemically recurrent prostate cancer after RP with a PSA level between 0.2 and 1.5 ng/mL, and no local or metastatic recurrence on imaging. A total of 312 patients will be enrolled. Participants are randomised 1:1 to standard‐of‐care SRT followed by surveillance (Group A), or initial observation with subsequent image‐guided therapy at radiographic progression (Group B). Based on historical analysis, a total of 30 metastasis events provides 80% power to detect a significant improvement (hazard ratio 0.5 corresponding to a 5‐year metastasis‐free proportion of 80.7% in the control group and 89.8% in the experimental group with one‐sided type I error rate of 0.15). All participants undergo baseline blood collection to measure prostate cancer‐extracellular vesicles and cell‐free DNA for biomarker development. Participants are followed in a 16‐week cycle with serial PSA measurements, repeat imaging if PSA doubles, safety assessment, and patient‐reported outcomes. Endpoints The primary endpoint is distant recurrence‐free survival at 5‐years using a 12‐month landmark to mitigate bias arising from differing assessment schedules for patients receiving optional 6 months of androgen deprivation therapy. Key secondary outcomes include time to hormone therapy, quality of life measures, adverse effects, and novel blood and urine biomarkers. Conclusion The BRIO study will clarify the clinical benefit of immediate SRT vs observation with image‐guided intervention in mpMRI and PET‐negative BCR after RP.

Background: Total knee arthroplasty (TKA) is the treatment of choice for end-stage knee osteoarthritis in many patients. In younger patients with predominantly medial compartment disease, high tibial osteotomy (HTO) is performed as a joint-preserving treatment. However, concerns remain regarding potentially compromised outcomes of TKA after previous HTO given the axial deviation, osteotomy site, secondary surgery, previous hardware, and instrumentation. Therefore, this study compared long-term implant survival, revision, and infection rates, and patient-reported outcomes between patients undergoing TKA after HTO and matched TKA-only controls. Methods: Postoperative complications and revision surgeries were prospectively recorded in patients who underwent TKA from 2000 to 2023 at a single academic center. Patients with previous ipsilateral HTO formed the study group and were propensity matched 1:2 to TKA-only patients without a previous osteotomy based on age, sex, and body mass index. Knee Society Scores (KSS) were collected prospectively. Implant survivorship was analyzed using Kaplan-Meier survival curves and Cox proportional hazards models. Results: The study included 134 HTO-TKA and 268 matched TKA-only patients, with a mean follow-up of 10.5 ± 6.4 years (range: 0-24 years) after TKA. Both groups showed significant postoperative improvements in KSS (p < 0.02) with comparable clinical outcomes (HTO-TKA: 79.0 (6.0), TKA-only: 79.0 (11.8)). Revision arthroplasty rates were 5.2% for HTO-TKA and 4.5% for TKA-only (p = 0.69); the mean time to revision was 8.1 ± 8.7 years vs. 4.4 ± 3.5 years, respectively (p = 0.30). Infection rates were 2.2% and 1.1%, respectively (p = 0.74). Conclusions: Revision and infection rates were comparable between HTO-TKA and matched TKA-only patients, with no statistically significant differences. Our findings demonstrate comparable patient-reported outcomes in both groups. These findings indicate that a previous HTO does not adversely affect TKA implant longevity or clinical outcomes when compared with matched primary TKA patients within the US population. Level of Evidence: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

Summary Cancer genome sequencing is essential for understanding tumor evolution and advancing precision medicine. 1 However, reference gaps and germline variants obscure detection of small and large somatic variants and methylation in repetitive regions. 1–3 It is common for tumor cells to gain or lose chromosome arms due to somatic structural changes that occur inside highly repetitive satellite DNA sequences in the centromeres. 4 To identify the full spectrum of somatic variants, including complex rearrangements, we construct and curate near-complete, haplotype-resolved assemblies of the most recent common ancestor of an early-passage broadly-consented hypodiploid pancreatic cancer cell line and matched normal tissues. The tumor assembly completely recapitulates all 35 tumor chromosomes observed with karyotyping, with multiple translocation-induced hybrid chromosomes. The hybrid chromosomes contain putative functional dicentric and fused centromeres, nested foldback inversions causing 14 breakpoints with a haplotype switch in a single event, and centromeric satellite tandem duplications up to 136 kbp. Direct comparison of tumor and normal assembly haplotypes uncovers >7,000 variants altering >1 Mbp of sequence in repetitive regions that have been hidden by reference gaps and germline variants. 44 % of somatic small variants change representation because they alter germline variants on GRCh38, impacting mutational signatures and kataegis/omikli clusters. Most somatic LINE insertions originate from two hypomethylated non-reference germline LINE insertions, highlighting their impact on insertion mutation burden. These assemblies demonstrate that centromeric, acrocentric, and telomeric regions conventionally excluded from analysis harbor extensive somatic and epigenetic changes. Resolving complete tumor genomes enables a deeper understanding of cancer structural plasticity and the endpoints of breakage-fusion-bridge cycles. These assembled, curated paired normal-tumor benchmarks will serve as a critical foundation for developing future algorithms to characterize the most intractable regions of cancer genomes.

Inflammatory bowel disease (IBD) is driven by a breakdown in immune regulation and epithelial barrier function, yet the contribution of eosinophils to this process has remained poorly defined and controversial. While eosinophils infiltrate the intestinal mucosa during both flares and remission, their role in shaping disease outcomes is unclear. Our RNA-seq analyses of colonic eosinophils isolated from dextran sulfate sodium (DSS)-treated mice revealed a significant upregulation of cyclooxygenase (COX)-2 (gene name, Ptgs2 ). Eosinophil-specific deletion of COX-2 (Ptgs2 fl/fl eoCre +/− ) reduced IL-22 production and exacerbated DSS- and trinitrobenzene sulfonic acid (TNBS)-induced colitis, characterized by greater weight loss, higher disease activity, colon shortening, and epithelial injury. Administration of recombinant IL-22 reversed these phenotypes. Mechanistically, eosinophil-derived COX-2 enhanced IL-22 production by type 3 Innate lymphoid cells (ILC3s) through prostaglandin E2 (PGE 2 ) signaling. Consistently, Ptgs2 fl/fl eoCre +/− mice exhibited reduced colonic PGE 2 levels, while PGE 2 analog treatment restored IL-22 production and mucosal protection. Our findings identify eosinophil-derived COX-2 and PGE 2 as a critical regulator of IL-22 production during colitis, uncovering a eosinophil–ILC3 cross talk that safeguards the intestinal barrier and represents a promising therapeutic target in IBD.

Abstract The discovery of pathogenic neuroglial surface-directed autoantibodies (NGSAbs) has fundamentally transformed clinical neurology, by enabling molecular-level diagnoses in potentially treatable, yet previously unrecognized, diseases. Annual descriptions of novel CNS-targeting antibodies create a continuous stream of new conditions in which to evaluate distinct phenotypes, specific tumour associations and immunotherapy responses. Alongside this clinical growth, increasing basic knowledge has highlighted origins and mechanisms underlying disease causation, most comprehensively interrogated in the well-established autoantibody-mediated conditions of autoimmune encephalitis (AE), neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). The corresponding most common ‘big six’ autoantigens are LGI1, the N-methyl-D-aspartate (NMDA) receptor, CASPR2, IgLON5, in forms of AE, AQP4 and MOG. Each of these autoantigens associates with a homogenous set of basic clinical features, across age, sex, tumour associations and ethnicities, coupled with partly distinctive profiles of triggers and predispositions, paradigms of immune tolerance escape in the periphery, how cells and autoantibodies gain access to the CNS, and discrete mechanisms by which the CNS autoantibodies induce neuroglial dysfunction. These observations lead us to reconstruct a proposed chronological series of events as the ‘cascade to pathogenicity’, which together culminate in a rare CNS disease. By extension, we hypothesize elucidating the underlying biology of each condition will present differing precision medicine approaches to optimize patient care. Despite distinctions, there are also clinical and biological overlaps between these diseases, collectively creating opportunities to compare and contrast their individual features. Here, in each condition, we review current knowledge regarding the similarities and differences between the triggering events, underlying immunological processes and pathogenic mechanisms of autoantibodies. In some instances, we identify scientific clues that drive hypothetical pathways of pathogenesis and, for others, highlight striking observations that aim to generate hypothesis-driven next steps. Our aim is to construct a model across the major autoantibody-mediated CNS diseases to highlight distinct components of cascades to pathogenicity, which may offer targeted therapeutic approaches to improve patient outcomes, and identify key areas and questions for future research.