Citations

Abstract: Melanoma exhibits a broad spectrum of histopathologic variations, including rare forms with neural differentiation. Neurotropism in melanoma encompasses both perineural invasion and neural-like transformation, but the prognostic implications of these features remain uncertain. Although (peri)neural invasion is well documented, true neural differentiation in melanomas is exceedingly rare. In this study, we describe an unusual case of primary cutaneous malignant melanoma exhibiting extensive Wagner–Meissner-like bodies, a feature more commonly associated with benign neural tumors and nevi. In this case, histopathology revealed a dual-component lesion with a neurotized and an epithelioid melanocytic component, both showing PRAME expression and p16 loss. Chromosomal microarray identified heterozygous loss of 9p22.1p13.1 (including CDKN2A / CDKN2B ), and loss of 10q22.2q26.3 (including PTEN ), supporting malignancy. These findings suggest that in this case, Wagner–Meissner-like bodies likely represent neurotization rather than a benign or collision lesion, highlighting the need for integrated histopathologic, immunohistochemical, and molecular analysis in challenging melanocytic neoplasms.

Background: A critical component of conducting systematic reviews or meta-analyses is assessing the methodological quality and bias of included studies. Several methodological quality assessment tools have been developed; however, these tools may not be relevant to observational sports medicine research, which carries numerous unique nuances and biases. Purpose: To develop the Sport Publication Observational Research Tool (SPORT), which evaluates and scores the methodological quality of observational sports medicine research. Study Design: Consensus statement. Methods: SPORT was developed through a modified Delphi approach involving members from the Herodicus Society and The FORUM. All active members were invited to participate in the process aimed at building consensus on SPORT content and scoring. After finalizing SPORT, a power analysis led to the independent selection of 55 observational clinical sports medicine studies, which were scored twice by 4 reviewers of varying training levels. Interrater and intrarater reliability for SPORT was assessed using intraclass correlation coefficients (ICCs). The distribution and percentiles for total SPORT score across the 55 studies were calculated. SPORT was also compared with the methodological index for non-randomized studies (MINORS), a commonly utilized quality assessment tool. Results: A total of 51 members participated and achieved 100%, 100%, 98.0%, and 98.0% completion rates for rounds 1 through 4, respectively. The final SPORT included 19 subscores related to methodological quality and bias and achieved 94% consensus approval. Mean SPORT completion time was 6 minutes and 19 seconds per study, which varied significantly by reviewer training level. The subscore "peer review" demonstrated unacceptable reliability and was removed. The remaining 18 subscores exhibited ICC ranges of 0.599 to 0.955 for interrater reliability and 0.530 to 0.936 for intrarater reliability. Total SPORT score demonstrated excellent agreement, for interrater (ICC, 0.967) and intrarater reliability (ICC, 0.966). Median SPORT score across the 55 studies was 20.0 and skewed toward lower scores. There was a moderate significant correlation between SPORT and MINORS ( r [53] = 0.575; P < .001). Conclusion: An objective tool to assess the methodologic quality of observational sports medicine research (SPORT) was successfully developed through a modified Delphi approach with numerous content experts in the field. This tool may be useful in assessing the methodological quality of primary observational sports medicine studies included in systematic reviews and meta-analyses.

OBJECTIVE Chordomas are rare, locally aggressive primary neoplasms. Resection with negative margins is the primary recommended therapeutic approach, while adjuvant radiotherapy and chemotherapy can also play a role in their treatment in certain situations, including lesions with positive margins or those that are poorly differentiated or dedifferentiated. Cervical spine chordomas pose significant surgical challenges given their proximity to critical anatomical structures and the mechanical constraints of the cervical spine. In the current case series, authors aimed to explore the clinical and patient-reported outcomes (PROs) of the surgical treatment of cervical chordomas in a large multicenter cohort. METHODS This multicenter case series analysis utilized data from the prospectively collected Primary Tumor Research and Outcomes Network (PTRON) registry, from its inception (May 16, 2016) to data extraction (February 29, 2024). The study population was restricted to patients with histologically confirmed cervical chordomas involving levels C0–7, who underwent surgical treatment at one of the participating centers, and for whom both the initially planned and postoperatively pathologically confirmed surgical margins were documented. Patient demographics, tumor characteristics, surgical and adjuvant treatments, local recurrence–free survival (LRFS), overall survival (OS), and perioperative adverse events were retrieved. PROs included the Spine Oncology Study Group Outcomes Questionnaire version 2.0 (SOSGOQ2.0), EQ-5D, and SF-36 version 2.0 (SF-36v2). RESULTS Thirty-eight patients were identified, 12 of whom underwent true en bloc resection (EBR), 18 of whom underwent deliberate intralesional resection, and 8 of whom underwent EBR after intralesional surgery or in whom EBR failed. True EBR led to better LRFS (92% vs 83% vs 63%, respectively) and OS (83% vs 39% vs 50%, respectively). Surgical adverse events within 1 year were more frequent with true EBR (100% vs 39% vs 75%, respectively). EQ-5D, SOSGOQ2.0, and SF-36v2 showed improvement with true EBR, whereas the trends for PROs from the other groups were more variable. CONCLUSIONS This multicenter case series analysis provides critical insights into the clinical outcomes and PROs in the largest cohort of surgically treated cervical spine chordomas described to date. It underscores the importance and challenges of wide resection for oncological control. It establishes the associated morbidity and provides an overview of PROs following surgery. These findings contribute valuable evidence to inform shared decision-making and optimize patient care.

Abstract Purpose This study synthesizes and characterizes pregnancy outcomes and complications among US female physician trainees. Method In this systematic review, the PubMed, Embase, Scopus, Web of Science, and Cochrane databases were searched in May 2024 and May 2025 for peer-reviewed, English-language articles published from January 2000 to May 2025 reporting pregnancy outcomes in US female residents or fellows. Medical Subject Headings and keywords for pregnancy complications, pregnancy outcomes, and women or female physicians were used. Cross-sectional, retrospective, prospective, and case-control studies were included. Opinion articles, editorials, systematic or scoping reviews, and other non–peer-reviewed articles were excluded. Abstracts and full-text articles were screened by 3 investigators. Extracted data were documented in standardized forms. Risk of bias was assessed regarding study population and outcome reporting and summarized using standardized quality assessment tools. Results Of 792 titles and abstracts screened, 10 articles involving 4,891 trainees were included. Eight of these 10 studies described pregnancy outcomes specifically in surgical trainees; all were cross-sectional surveys. The numbers of trainees experiencing pregnancy complications ranged from 38.9% to 56.0%. The most frequently described complication was preterm labor (9 of 10 studies), affecting 5.3% to 22.9% of surveyed trainees. The most cited fetal complication was miscarriage (5 of 10 studies), affecting 20.0% to 28.0% of trainee pregnancies. Other commonly reported complications included preeclampsia or eclampsia, hyperemesis gravidarum, and gestational hypertension. Conclusions Although pregnancy complications appear to be common among female physician trainees, current data on obstetric outcomes in this population remain limited. Most studies focus specifically on surgical trainees and rely on self-reported data, limiting generalizability. Residency programs may consider findings from this review to enhance support for childbearing trainees, although prospective studies are needed to better discern the impact of medical training on maternal and fetal outcomes.

Thiopurine methyltransferase (TPMT) and Nudix hydrolase 15 (NUDT15) are key enzymes that catabolize thiopurines. Decreased or no‐function alleles in TPMT and NUDT15 are associated with reduced or no enzyme activity and predictive of pronounced adverse effects, including severe myelosuppression, that may occur among individuals treated with standard doses of thiopurines. Genetic variants in these genes are present in all world populations; however, their frequency varies by ancestry. In this updated guideline, we provide recommendations for adjusting starting doses of mercaptopurine, thioguanine, and azathioprine based on TPMT and NUDT15 genotypes, including for individuals with variants in both genes (updates on www.clinpgx.org ).

This study uncovers a previously unrecognized role for NAV3 in TGF-β1-driven cardiac fibroblast activation. We show that NAV3 facilitates profibrotic remodeling through noncanonical signaling and cell cycle arrest, independently of SMAD2/3. These findings position NAV3 as a novel regulator of fibroblast phenotype and a potential modulator of cardiac fibrosis.

Background: The management of asymptomatic high-grade carotid stenosis remains challenging, particularly in identifying individuals at highest risk for hypoperfusion-related stroke. Impaired cerebrovascular reactivity (CVR) has emerged as a potential predictor of future cerebrovascular events. Objective: To perform a systematic review and meta-analysis to quantify the association between impaired CVR and the risk of ipsilateral ischemic stroke or TIA in patients with asymptomatic high-grade carotid stenosis/occlusion. Methods: A systematic literature search of PubMed, Embase and Scopus was conducted from inception till July 2025. Eligible studies included asymptomatic patients with ≥70% carotid stenosis or occlusion who underwent CVR assessment and reported ipsilateral ischemic stroke or TIA outcomes. Pooled relative risks (RR) with 95% confidence intervals (CIs) were calculated using a random-effects model. Forest plots were generated, and heterogeneity was assessed using the chi-square test and the I 2 statistic. Results: Six prospective observational studies including a total of 361 patients with asymptomatic high-grade carotid stenosis/occlusion (mean age 70.4 years; 73.6% male; 71.2% with hypertension; 28.6% with diabetes; 29.6% current or former smokers) were included in the analysis. Of these, 120 patients had impaired CVR and 241 had preserved CVR. Transcranial Doppler (TCD) was the most frequently used modality to assess CVR, with acetazolamide or CO 2 as the vasodilatory stimulus. Following CVR assessment, patients were monitored for a weighted mean follow-up of 26.2 months (range: 21.5 to 42.5 months). The incidence of ipsilateral ischemic stroke or TIA was 14.2% in patients with impaired CVR versus 2.1% in those with preserved CVR (RR 3.98; 95% CI 1.62–9.76; P = 0.003; Figure 1). When limited to ipsilateral ischemic stroke alone, the incidence was 21.4% in the impaired CVR group compared to 4.3% in the preserved CVR group (RR 3.35; 95% CI 1.54–7.25; P = 0.002; Figure 2). Conclusions: Impaired CVR is associated with a 3- to 4-fold increased risk of ipsilateral ischemic stroke or TIA in patients with high-grade carotid stenosis/occlusion. CVR assessment may help stratify risk and guide individualized management in this population.

Background: Previous studies have reported the mean difference in homocysteine level in patients with and without silent brain infarction. However, evidence regarding the rate of silent brain infarcts in the presence versus absence of hyperhomocysteinemia remains limited. Objective: We aim to perform a systematic review and meta-analysis to compare the rate of silent brain infarcts in patients with hyperhomocysteinemia compared with patients with normal or low homocysteine levels. Methods: A systematic search of PubMed, Embase, Web of Science, Scopus were searched from inception to June 18, 2025. Eligible studies compared the rate of image-confirmed silent brain infarcts in patients with hyperhomocysteinemia versus those with normal homocysteine levels. The primary outcome was the rate of silent brain infarcts; the secondary outcome was cognition assessed by the Mini-Mental State Examination (MMSE). Pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated using a random-effects model, and heterogeneity was assessed using I 2 statistics. Subgroup analyses were performed according to increasing hyperhomocysteinemia cutoffs (>12 μmol/L and 9–12 μmol/L) as defined in the included the studies. Results: Four observational studies involving 2331 patients were included (mean age was 58.0±6.4 years, 45.8% women). Of these, 1087 had hyperhomocysteinemia and 1244 had normal levels. The rate of silent brain infarcts was 23.3% (253/1087) in patients with hyperhomocysteinemia versus 22.8% (284/1244) in controls (OR 1.82; 95% CI 1.11-3.00; P = 0.02, Figure 1A). The association was higher in studies using a > 12 µmol/L cutoff (OR 3.08; 95% CI 1.85-5.11; P < 0.0001, Figure 1B). Patients with hyperhomocystinemia had lower MMSE score compared with controls (mean difference of -1.55; 95% CI -3.60-0.50; P = 0.14, Figure 2). Conclusions: Hyperhomocysteinemia is associated with increased risk of silent brain infarcts and numerically lower cognitive performance. Findings suggest a possible dose-dependent relationship between homocysteine level and silent stroke risk. Prospective studies are needed to determine whether homocysteine is a modifable therapeutic tharget for reducing silent infarcts and cognitive decline.

Background: Stroke is a leading cause of death and disability despite advances in risk factor management. Many risk factors for stroke have also been implicated as risk factors for mild cognitive impairment (MCI) and dementia. Given these shared risk factors, cognitive impairment (CI) may represent an accumulation of neurological injury that is associated with an elevated risk of stroke. In ARIC-NCS, we aimed to 1) understand the independent relationship between pre-stroke CI (MCI or Dementia) and incident stroke; 2) explore mortality differences in stroke patients with vs without pre-stroke CI; and 3) evaluate modifiers of these relationships. Methods: 5434 stroke-free participants were evaluated for cognitive status at an in-person visit in 2011-13 (visit 5; ages 66-90), based on cognitive testing and informant interviews. Incident definite or probable strokes (ischemic or hemorrhagic) from visit 5 through 2022 were identified via ongoing surveillance (semi-annual telephone calls, with expert classification). Using Cox proportional hazards regression models adjusted for demographics and vascular risk factors, we evaluated associations between CI (MCI or dementia) and incident stroke, and between CI and death among individuals with stroke. Finally, we tested effect modification by age at visit 5, sex, education, and race, via stratified models and formal interaction terms. Results: Compared to those without CI, individuals with CI (23%) were older (77 vs 75 years, p<0.001), and more frequently male (48% vs 40%). Over 10+ years, CI was independently associated with an increased risk of incident stroke (HR:1.52, 95% CI:1.18-1.96). Among individuals with stroke, risk of death was also higher in CI vs non-CI patients (HR 1.78, 95% CI 1.27-2.50). In stratified analysis, we found a significant interaction by sex (p-interaction=0.04): in males, CI was associated with elevated stroke risk (HR:2.01, 95% CI:1.39-2.91) without a similar risk in females (HR:1.22, 95% CI:0.85-1.75). Interactions by race, age, and educational level were not statistically significant, but effect sizes were qualitatively larger in White participants and individuals with more education. Conclusion: CI is associated with incident stroke independent of shared risk factors, especially in men. This work adds to our understanding of populations at risk for stroke, thus aiding efforts to optimize stroke prevention in at-risk populations.