Citations

AimThe aim of this study was to compare the histopathologic features of MMF‐induced colitis and colonic GVHD and develop a digital tool using deep learning convolutional neural networks (CNNs) to semi‐automate the quantification of eosinophils.MethodsMMF and GVHD colitis cases were retrieved. A cohort of transplant patients who were at risk for developing GVHD and were on MMF at the time of biopsy was also identified. Cases were reviewed for histologic features and a deep learning CNN was trained to quantify lamina propria eosinophils. Clinical history was collected.ResultsNinety‐five patients were included in the study group: GVHD (n = 37), MMF (n = 25) and GVHD vs. MMF (n = 33). Within the GVHD vs. MMF group, one patient was thought to have definitive MMF colitis and one possible MMF colitis. The GVHD group had a significantly higher apoptotic count compared to the MMF group (median: 7 vs. 2, P = 0.03). Neuroendocrine aggregates were present in the GVHD (N = 12) and GVHD vs. MMF (N = 4) groups while absent in the MMF group. The MMF group had a higher semi‐quantitative eosinophil score and a higher automated eosinophil count as detected by the deep learning CNN (median eos/HPF: MMF 19.2, GVHD vs. MMF 3.6, GVHD 3.4, P < 0.001).ConclusionsLower eosinophil counts, higher apoptotic counts and neuroendocrine cell aggregates favour the diagnosis of GVHD. AI models for eosinophil quantification may serve as an ancillary tool for assessing this differential diagnosis. Given the rarity of MMF‐induced colitis in SCT patients, pathologists should have a high threshold for making this diagnosis in this population.

Objectives: To assess the long-term effects of 4 years of menopausal hormone therapy (mHT) on the brain’s white matter architecture in women who initiated mHT within 3 years of menopause onset. Methods: The Kronos Early Estrogen Prevention Study (KEEPS) was a multicenter, double-blind, randomized, placebo-controlled 4-year mHT trial with treatment arms of oral conjugated equine estrogens (oCEE), transdermal 17β-estradiol (tE2), and placebo in recently postmenopausal women. KEEPS Continuation was an observational follow-up of KEEPS participants. White matter integrity was evaluated in KEEPS Continuation participants 10 years after KEEPS completion using white matter hyperintensity volume, diffusion magnetic resonance imaging (dMRI) techniques, and cerebral infarcts. Linear regression models were fitted for each brain region to evaluate if there were differences in white matter between KEEPS treatment arms. Results: There was no evidence to suggest the long-term effects of 4 years of mHT on brain white matter in KEEPS Continuation participants [n=266, mean age 67 (58-73)]. No differences in dMRI metrics were found in each of the treatment arms (oCEE n=70; tE2 n=79) when compared to placebo (n=94), following a false discovery rate adjustment for multiple comparisons. There were no statistically significant differences in white matter hyperintensity volume or infarct occurrence when comparing each of the treatment arms to placebo. Conclusions: We found no evidence of the long-term effect of 4-year mHT on white matter integrity when compared to placebo, consistent with emerging evidence of the safety of short-term use of mHT in recently postmenopausal women.

ABSTRACT Background Multimodality therapy incorporating a combination of cytoreductive surgery (CRS), intraperitoneal (IP) and systemic therapy continues to evolve for peritoneal carcinomatosis (PC) However, treatment and outcomes vary depending on tumor of origin. Aims To develop Appropriate Use Criteria (AUC) guidelines to facilitate treatment decision‐making for patients with PC based on available evidence. Materials and Methods The American Radium Society (ARS) multidisciplinary expert panel performed a comprehensive systematic review. Preferred Reporting Items for Systematic Reviews and Meta‐analyses (PRISMA) methodology was used. These studies were used to inform the expert panel, which then rated the appropriateness of various treatments in seven representative clinical scenarios through a well‐established modified Delphi consensus methodology. Results Treatment of PC is often treated with a combination of CRS and IP ± systemic chemotherapy but specific recommendations exist for different tumor types and outcomes vary. Discussion Treatment of PC is complex and varies depending on origin of primary tumor and extent of disease. These AUC assist in patient and treatment selection for different clinical scenarios. Conclusion A summary of recommendations is outlined to guide practitioners on the management of PC from different tumor origins.

Background There is a global mismatch between the number of adults with congenital heart disease and adult congenital heart disease (ACHD) cardiologists, potentially impacting patient outcomes. This survey explores factors influencing trainees and cardiologists' career choices in ACHD. Methods An online, anonymous global survey on demographics, ACHD as a career choice, encouraging and deterring factors assessed via a 5‐point Likert scale and open‐ended questions on recommending ACHD was distributed through targeted emails and social media. Responses meeting a 75% completion criterion were analyzed using descriptive statistics and thematic analysis. Results Among 811 included responses, most were from women (53.5%), aged 31 to 40 years (48.3%), White individuals (43.3%), non‐Hispanic individuals (85%), from outside the ACHD field (79.0%), and from North America (42.7%). Only 30.9% of non‐ACHD physicians considered specializing in ACHD despite 78.9% recommending it. Encouraging factors included awareness of ACHD significance, mentor influence, and clinical exposure. Key deterrents were inadequate financial incentives, limited job opportunities, and lengthy training. Regional variations showed that longer training duration and lack of compensation incentives were the main deterrents in North America. Suggested solutions included structured training programs, salary improvements, and early ACHD exposure during medical education. Conclusions Less than a third of respondents considered ACHD as a career largely due to inadequate financial incentives, limited job opportunities, and long training duration. Addressing these barriers could enhance recruitment and help meet the growing demands of the ACHD population.

Abstract Background Methylation class pleomorphic xanthoastrocytoma (mcPXA) comprises tumors with the DNA methylation signature of classical PXA but with a wider histologic spectrum, including overlap with glioblastoma (GBM). Methods To clarify the histologic and molecular scope of mcPXA and characterize its clinical behavior, a cohort of 469 tumor samples from 458 patients matching to mcPXA by the DKFZ classifier (v12.6 score ≥0.85) was interrogated. Results Patient median age was 23 years (range 1-73 years) with a female predominance (259 female/199 male). CDKN2A/B homozygous deletion was observed in 406 of 469 (87%) samples. In samples tested for BRAF p.V600E mutations (n = 279), 240 (86%) harbored the mutation. A chr7+/chr10− pattern was observed in 103 of 469 (22%) samples. Among samples tested for TERT promoter mutations (n = 143), 32 (22%) harbored the mutation. Progression-free and overall survival of patients with mcPXA were comparable to patients with methylation class IDH-mutant astrocytoma, low grade, but a GBM-like subset (ie, cases with a pre-methylation working diagnosis of GBM) showed shorter survival. Histologic features of high grade, including palisading necrosis and microvascular proliferation, were prognostic in mcPXA. Compared to patients with BRAF p.V600E-altered GBM, patients with mcPXA were younger and had a lower frequency of TERT promoter mutations. Conclusion Tumors in mcPXA share molecular characteristics with histologically defined PXA, and high-grade histologic features can help predict their clinical behavior. The use of an epigenetic classification of PXA reveals that this group of tumors is more common than previously appreciated and warrants in-depth study to identify efficacious therapeutic options.

Abstract Parkinson’s disease (PD) is the fastest growing neurodegenerative disease in the world1. Gastrointestinal (GI) dysfunction can occur decades before motor impairments and in up to 80% of individuals living with PD2,3,4. We investigated peripheral relationships that may underlie environmental contributions to mechanisms along the gut-blood axis that contribute to PD pathogenesis. Single-cell multiomic spatial molecular imaging (SMI) of colonic tissue localized inflammatory injury within epithelial cells that appear to be associated with iron mishandling in both inflammatory bowel disease (IBD) and PD biosamples. We found that both the single-cell SMI of RNA and protein revealed parallel cross-modal dysregulation in the gut epithelium, in both IBD and PD biosamples. These data are accompanied by plasma (PD) and stool (IBD) protein depletion of CCL22. Our findings suggest iron mishandling along the gut barrier likely contributes to systemic inflammation, which may be the catalyst that primes circulating immune cells to body-first PD pathogenesis.

ABSTRACTIntroductionDry epicardial access to facilitate epicardium mapping and ablation is a well described technique with increasing use in modern electrophysiology. However, traditional percutaneous access can be challenging is obese patients or those with anatomical variations.Methods and ResultsWe report on a case where a subxiphoid cut down was utilized for epicardial access in a patient with morbid obesity. This approach allows us to reach the epicardial space when traditional needles do not suffice and enables a more controlled access, potentially minimizing the risk of damage to nearby structures.ConclusionSubxiphoid cut down to facilitate percutaneous epicardial access is a simple and effective option when traditional epicardial access is not feasible due to morbid obesity or anatomical variations.

Abstract Background and Aims There is a paucity of data on arrhythmia burden in patients with congenitally corrected transposition of the great arteries (ccTGAs). The present study sought to quantify the incidence of atrial arrhythmia (AA), ventricular arrhythmia (VA), and complete atrioventricular block (CAVB) in patients with ccTGA and identify associated factors. Methods An international, multi-centre, retrospective cohort study was conducted in 29 tertiary hospitals (six countries) between 1990 and 2018. Primary analyses consisted of determining the incidence of a combined outcome consisting of AA, VA, or CAVB, along with its individual components. Factors associated with the different types of arrhythmias were assessed by uni-variable and multi-variable Cox regression analyses. Results A total of 1131 patients with ccTGA were followed for 9.0 (interquartile range 4.0–17.2) years. Cumulative rates of the primary endpoint at 10, 15, and 20 years were 44.5%, 51.0%, and 58.8%, respectively. AA, VA, and CAVB occurred in 2.1, 1.4, and 2.0 cases per 100 person-years, respectively. In multi-variable analyses, surgery/intervention conferred a greater than three-fold higher risk of AA [hazard ratio (HR) 3.01, 95% confidence interval (CI) 1.90–4.78, P &lt; .001]. Furthermore, surgery/intervention was significantly associated with a greater risk of VA (HR 1.73, 95% CI 0.98–3.05, P = .003) and CAVB (HR 3.65, 95% CI 2.20–6.05, P &lt; .001). The left bundle branch block was associated with a higher risk of VA (HR 4.03, 95% CI 1.59–10.23, P = .003) and the right bundle branch block with a higher risk of CAVB (HR 3.71, 95% CI 1.81–7.63, P &lt; .001). Conclusions The arrhythmia burden in patients with ccTGA is substantial, with a high incidence of AA, VA, and CAVB.