Citations

Abstract Circumscribed meningeal melanocytic neoplasms (CMMNs) represent a spectrum of rare central nervous system (CNS) tumors. Knowledge of their clinical behavior and molecular correlates remains limited. In this single‐institution retrospective study, we analyzed 31 patients (14 male, 17 female; median age, 59 years) diagnosed with CMMN between 2004 and 2025. In this patient cohort, based on the current World Health Organization Central Nervous System Tumor Classification (WHO CNS5) criteria, the majority of cases (18, 58.1%) fell into the intermediate‐grade melanocytic tumor (IMT) category based on histology, with either increased mitotic activity, CNS invasion, or both; 7 (22.6%) were melanocytomas, 5 (16.1%) melanomas, and 1 (3.2%) indeterminate case because of limited tissue. By next‐generation sequencing, mutations were identified in GNAQ/GNA11 in 21/24 cases, BAP1 in 5/23 (2 IMT, 3 melanoma), EIF1AX in 9/21 (1 melanocytoma, 8 IMT), and SF3B1 in 3/23 (2 IMT, 1 melanoma). Primary sites were spinal (20), posterior fossa (6), and supratentorial (5). During follow‐up, progression was observed in 5/6 melanocytomas, 9/13 IMTs, and 4/5 melanomas, suggesting a high frequency of progression across all groups. Two‐year progression‐free survival was 83.3% (95% confidence interval [CI], 53.5%–100.0%) for melanocytoma, 55.9% (95% CI, 26.7%–85.2%) for IMT, and 25.0% (95% CI, 0.0%–67.4%) for melanoma. Five‐year overall survival (OS) was 80.0% (95% CI, 44.9%–100.0%) for melanocytoma, 65.3% (95% CI, 37.0%–93.6%) for IMT, and 0.0% for melanoma. OS was significantly worse in melanoma compared with melanocytoma ( p = 0.002). BAP1 mutation correlated with worse OS (hazard ratio 8.73, p = 0.006). Upfront maximal safe resection appeared to be associated with improved outcomes in selected patients, whereas radiotherapy and systemic therapy did not demonstrate clear additional benefit in this cohort. In summary, our study shows that all CMMNs, irrespective of grade, have a high propensity to recur and melanoma histology and BAP1 mutation are associated with significantly worse OS.

Photodynamic priming (PDP), a fallout of photodynamic therapy, transiently modulates the tumor microenvironment (TME), enhances therapeutic susceptibility, and promotes immunogenic cell death through the release of damage-associated molecular patterns (DAMPs). Pancreatic ductal adenocarcinoma (PDAC) remains non-responsive to current therapies with a desmoplastic and immunosuppressive TME that limits drug delivery and blunts responses to immune checkpoint blockade. We investigated whether PDP could enhance anti-PD1 therapy responses in PDAC using patient-derived organoids (PDOs). PDOs were treated with Visudyne and red light (25, 75, and 100 J/cm²), followed by assessment of cytotoxicity, DAMP expression (HSP60, calreticulin, HMGB1), and transcriptomic changes. Monocyte-derived dendritic cells (mDCs) from healthy donors were cocultured with PDP-treated (25 J/cm 2 ) PDOs, then with matched naïve T cells. mDC and T cell activation markers were analyzed. Pembrolizumab (anti-PD1) was added to PDO-mDC-T cell cocultures to evaluate combined effects on PDO viability and T cell activation. PDP induced dose-dependent cytotoxicity and upregulated DAMPs. Gene profiling in PDOs showed increased IFN-γ , TNF-α , and CXCL12 , with reduced PD-L1 , TGF-β1 , and FOXP1 expression. mDCs exposed to PDP-treated PDOs upregulated CD40, CD86, and MHC-II, driving activation of CD4 + and CD8 + T cells, evidenced by elevated PD1 expression. Addition of pembrolizumab further decreased PDO viability and amplified effector cytokines ( IFN-γ , TNF-α , FASLG , granzyme B, IL-2 , IL-21 ). PDP was associated with modulation of the PDAC TME toward a more immunogenic phenotype by enhancing tumor immunogenicity, activating dendritic cells and T cells, and potentiating PD1 blockade. These findings provide mechanistic support for further preclinical and clinical evaluation of PDP combined with checkpoint inhibition in PDAC.

Abstract SV40 Large T antigen (LT) is essential for viral replication and a key determinant of host range. This host-range function is mediated by the C-terminal domain (LT-C) through binding to the host serine protease FAM111A, but the underlying mechanism has remained unclear. Here, we report the X-ray crystal structure of the FAM111A serine protease domain in complex with LT-C, revealing the structural basis for direct inhibition of FAM111A. LT-C uses a previously unrecognized zinc-binding motif and a P1-like phenylalanine residue to engage the FAM111A active site through a substrate-mimicking mechanism while avoiding proteolytic cleavage and covalent complex formation. Mutations disrupting either feature abolish FAM111A inhibition and impair SV40 propagation in cells. Consistent with this mechanism, SV40 host restriction requires FAM111A protease activity, which must be antagonized by LT-C for productive infection. Together, these findings define a zinc-dependent, cleavage-avoiding mechanism of protease inhibition that highlights an evolutionary arms race between SV40 and host antiviral proteases.

Heart rate variability (HRV) is a widely utilized approach for investigating cardiovascular health and human performance. Methodological approaches, analyses, and interpretations of HRV can vary extensively, and scientific debates on HRV reliability and utility remain. These debates have been amplified in recent years by the rapid growth and ubiquity of wearable devices, and their incorporation into scientific research studies. The present guidelines paper takes an evidence-based approach to propose more consistent and rigorous measurement and interpretation of HRV within human cardiovascular research and application. First, HRV has some utility as a cardiovascular risk stratification tool, but is not appropriate to employ as a specific marker of cardiac sympathetic outflow or sympathovagal balance. While time-domain and spectral analysis can more accurately reflect respiratory modulation of cardiac vagal (parasympathetic) activity, caution is necessary to avoid overinterpretation, particularly with respect to the concept of “vagal tone”. Numerous experimental, demographic, and environmental factors influence HRV assessment, interpretation, and reliability. Specifically, it is critical to account for non-modifiable (age, sex, race/ethnicity, etc.) and modifiable (i.e., exercise, physical fitness, etc.) factors within participant samples. Furthermore, technical approaches such as the HRV input signal (e.g., electrocardiography vs. photoplethysmography), length of recording, location of recordings (i.e., laboratory vs. field), respiratory rate and depth, and analytical approaches (i.e., time vs. frequency domain) can all impact rigor, reliability, and study interpretations. Finally, with respect to the rapid advancements of HRV assessment using wearable technology, investigators should interpret and contextualize findings within the limitations outlined in this guideline review.

Abstract Background Breast cancer is etiologically heterogeneous, but which risk factors differ in their associations across tumor subtypes remains unclear. We conducted a large, pooled analysis to evaluate independent, dose-response associations between breast cancer risk factors and quantitative tumor features. Methods Analyses of 15,731 invasive breast cancers from 24 studies evaluated associations (p-trend) between reproductive and hormonal factors, body mass index (BMI), alcohol, smoking, and family history in relation to quantitative immunohistochemistry measures on tissue microarrays (ER, PR, HER2, KI67, TP53) and tumor grade. Analyses in a subset of 10 population-based studies estimated subtype-specific odds ratios (ORs) comparing cases to controls. A Bayesian False Discovery Probability (BFDP) <0.2 was used to identify associations with strong statistical evidence. Results Nulliparity and later age at menopause were associated with higher ER-positivity (p-trend=0.021 and 0.001, respectively), with corresponding OR[ER+] (95% CI) = 1.49 (1.16-1.90) for nulliparous vs. parous and 1.07 (1.03-1.11) per 5 years. Current combined menopausal hormone therapy (MHT) use was associated with lower grade (p-trend<0.001), with OR [grade1] = 3.37 (2.69-4.21) for current vs. never users. Higher BMI was associated with lower ER-positivity and higher grade in premenopausal women (p-trend<0.001 and <0.001), with OR[ER+] = 0.80 (0.74-0.87) and OR[grade1] = 0.75 (0.63-0.88) per 5 units, and with higher PR-positivity and higher grade in postmenopausal women (p-trend<0.001 and <0.001), with OR[PR+] = 1.08 (1.03-1.14) and OR[grade 3] = 1.10 (1.04-1.17) per 5 units. Conclusion This pooled analysis of 15,731 cases showed that nulliparity, age at menopause, MHT, and BMI have independent, dose-response associations with ER, PR, and grade, clarifying patterns of etiologic heterogeneity. Associations with HER2, KI67 and TP53, or other risk factors did not meet our threshold for strong evidence.

Background: Midfoot arthritis can cause debilitating dorsal midfoot pain and functional limitation. Deep peroneal nerve (DPN) neurectomy is a minimally invasive surgical option that addresses pain through selective denervation. Although favorable midterm outcomes have been reported, long-term durability remains unclear. The purpose of this study was to evaluate changes in patient-reported physical function and pain interference between midterm and long-term follow-up after DPN neurectomy using validated Patient-Reported Outcomes Measurement Information System (PROMIS) instruments. Methods: A retrospective review identified patients who underwent isolated DPN neurectomy for midfoot arthritis between 2017 and 2021 and completed PROMIS Physical Function (PF) and Pain Interference (PI) questionnaires at midterm and long-term follow-up. Mean follow-up was 2.9 years (midterm) and 6.1 years (long-term). PROMIS scores were compared using paired t tests. Clinically meaningful improvement was defined using established minimal clinically important difference (MCID) thresholds (+5.88 for PF, −5.49 for PI). Results: The final cohort included 32 patients (81.2% female, mean age 68.4 ± 7.3 year). PF improved from 37.7 ± 6.2 to 39.0 ± 7.5 (Δ = +1.3, 95% CI [−0.7 to +3.4], P = .188), whereas PI decreased from 62.6 ± 8.8 to 59.2 ± 9.0 (Δ = −3.4, 95% CI [−6.3 to −0.5], P = .020). Clinically meaningful improvement was achieved by 7 of 32 (21.9%) for PF and 15 of 32 (46.9%) for PI. Five patients experienced clinically meaningful worsening, including patients with stroke, chronic pain syndrome, or contralateral foot and ankle pathology or surgery. Conclusion: DPN neurectomy was associated with stable longitudinal PROMIS outcomes through extended follow-up, with a nonsignificant mean PF change of +1.3 points and a statistically significant but sub-MCID mean PI decrease of −3.4 points over approximately 6 years. Outcomes were heterogeneous; fewer than half of patients achieved clinically meaningful improvement in pain interference, and a subset experienced worsening. These findings suggest that DPN neurectomy may provide durable symptom stability in appropriately selected patients with refractory dorsal midfoot pain, although clinically meaningful benefit at the individual level is not universal. Level of Evidence: Level III, comparative series.

BACKGROUND/OBJECTIVES Pediatric hospital medicine (PHM) is a growing field with a unique scholarly perspective and evolving role in academic leadership. Since the last systematic assessment of PHM research in 2009, predating subspecialty certification in 2016 and fellowship accreditation in 2020, the research infrastructure within PHM has not been reevaluated. We sought to assess the current state of PHM research by assessing the number, scope, and scholarly domains of research faculty, as well as research funding and support. METHODS Using the Pediatrics Research in Inpatient Settings Network, we distributed a cross-sectional survey to PHM group leaders across the United States and Canada. The 16-item instrument, adapted from prior PHM and adult hospital medicine surveys, assessed program demographics, faculty effort allocation, research support, funding, and scholarly domains. Surveys were distributed via REDCap with follow-up reminders. Descriptive statistics were used. RESULTS 49 programs responded (51% response rate), representing 1702 faculty (∼40% of US pediatric hospitalists). Fewer than half of programs (n = 21, 43%) reported faculty with more than 50% research effort. One-hundred and ninety faculty members (11%) had dedicated research time, and 72% of those conducting quality improvement research did so without any protected effort. Most PHM programs (n = 27, 55%) received less than $100 000 in total annual research funding. CONCLUSIONS Despite recent PHM subspecialty designation and pediatric hospitalist desire to conduct research, dedicated time and associated supports are uncommon in PHM groups. Improvements in the PHM research pipeline will require understanding institutional financial constraints and diversifying and strengthening research funding.

Background: Real-time intraoperative discrimination of malignant tissue during pediatric solid tumor resection is limited, constraining margin optimization; the utility of indocyanine green (ICG) fluorescence in this population remains incompletely defined. Study Design: Prospective, observational, multi-institutional study (2019–2023) of pediatric, adolescent, and young adult patients undergoing resection of intra-abdominal solid malignancies following preoperative ICG administration. The primary endpoint was diagnostic accuracy of ICG fluorescence for tumor-containing specimens; secondary endpoints included association with margin status and surgeon-perceived intraoperative benefit. Results: Forty-three operations in 42 patients yielded 55 specimens, of which 47 (85%) were malignant. Diagnostic performance was highest in hepatic tumors (sensitivity 83%, positive predictive value 83%) and lower in adrenal and heterogeneous tumor types. ICG avidity was not associated with improved negative margin rates (86% vs 75%, p=0.47). Surgeons reported intraoperative benefit in 67% of cases, most commonly improved visualization. No ICG-related adverse events occurred. Conclusions: ICG fluorescence provides reliable tumor identification in hepatic malignancies but does not correlate with margin-negative resection, indicating limited utility for margin guidance. These data support tumor-specific application and further investigation of optimized fluorescence strategies, including dosing, timing, and alternative fluorophores, in pediatric oncologic surgery.

Importance Little is known about how factors external to the workplace, such as spousal support, influence physician attrition. Objectives To explore associations of spousal support among married/partnered physicians with both ‘hard’ attrition ((HA), considering leaving academic medicine within 2 years) and ‘soft’ attrition ((SA), having ever considered part-time work), before and after adjusting for demographic variables, burnout and satisfaction with work-life integration (WLI). Design This cross-sectional survey study was conducted among faculty physicians employed at Mayo Clinic. Outcomes and measures Survey items measured demographics, spousal support (five items), HA, SA, satisfaction with WLI (single-item measure) and burnout (two-item measure). Check-all-that-apply questions explored reasons for considering attrition. We investigated associations of spousal career support with attrition consideration using logistic regression analyses, adjusting for demographic variables then for WLI satisfaction and burnout. Results 739/2103 physicians responded (response rate 35.1%); 666 (90.1%) were married or partnered and responded to the HA question. 42.5% (283/666) reported considering HA and 60.9% of full-time employees (288/473) had ever considered SA. 65.5% (437/666) considered any attrition (AA). Respondents reporting more frequent spousal career support had lower odds of HA (OR 0.80, 95% CI 0.68 to 0.94, p=0.006), though this was not significant when considering AA (OR 0.85, 95% CI 0.71 to 1.01, p=0.07). Neither association was significant after adjusting for WLI satisfaction and burnout (OR 1.01, 95% CI 0.80 to 1.29, p=0.91 (HA), OR 1.10, 95% CI 0.86 to 1.37, p=0.45 (any attrition)). Conclusions While spousal support was no longer significantly associated with attrition after adjusting for WLI satisfaction and burnout, it may mitigate attrition.