Citations

Context.— Generative artificial intelligence (GAI) is a promising new technology with the potential to transform communication and workflows in health care and pathology. Although new technologies offer advantages, they also come with risks that users, particularly early adopters, must recognize. Given the fast pace of GAI developments, pathologists may find it challenging to stay current with the terminology, technical underpinnings, and latest advancements. Building this knowledge base will enable pathologists to grasp the potential risks and impacts that GAI may have on the future practice of pathology. Objective.— To present key elements of GAI development, evaluation, and implementation in a way that is accessible to pathologists and relevant to laboratory applications. Data Sources.— Information was gathered from recent studies and reviews from PubMed and arXiv. Conclusions.— GAI offers many potential benefits for practicing pathologists. However, the use of GAI in clinical practice requires rigorous oversight and continuous refinement to fully realize its potential and mitigate inherent risks. The performance of GAI is highly dependent on the quality and diversity of the training and fine-tuning data, which can also propagate biases if not carefully managed. Ethical concerns, particularly regarding patient privacy and autonomy, must be addressed to ensure responsible use. By harnessing these emergent technologies, pathologists will be well placed to continue forward as leaders in diagnostic medicine.

Abstract DNMT3A and TET2 are epigenetic regulator genes commonly mutated in age-related clonal hematopoiesis (CH). Despite having opposed epigenetic functions, these mutations are associated with increased all-cause mortality and a low risk for progression to hematologic neoplasms. Although individual impacts on the epigenome have been described using different model systems, the phenotypic complexity in humans remains to be elucidated. Here, we make use of a natural inflammatory response occurring during coronavirus disease 2019 (COVID-19), to understand the association of these mutations with inflammatory morbidity (acute respiratory distress syndrome [ARDS]) and mortality. We demonstrate the age-independent, negative impact of DNMT3A mutant (DNMT3Amt) CH on COVID-19–related ARDS and mortality. Using single-cell proteogenomics we show that DNMT3A mutations involve myeloid and lymphoid lineage cells. Using single-cell multiomics sequencing, we identify cell-specific gene expression changes associated with DNMT3A mutations, along with significant epigenomic deregulation affecting enhancer accessibility, resulting in overexpression of interleukin-32 (IL-32), a proinflammatory cytokine that can result in inflammasome activation in monocytes and macrophages. Finally, we show with single-cell resolution that the loss of function of DNMT3A is directly associated with increased chromatin accessibility in mutant cells. Hence, we demonstrate the negative prognostic impact of DNMT3Amt CH on COVID-19–related ARDS and mortality. DNMT3Amt CH in the context of COVID-19, was associated with inflammatory transcriptional priming, resulting in overexpression of IL32. This overexpression was secondary to increased chromatic accessibility, specific to DNMT3Amt CH cells. DNMT3Amt CH can thus serve as a potential biomarker for adverse outcomes in COVID-19.

Abstract Context A national assessment of osteoporosis drug therapy (ODT) use can inform the extent of underdiagnosis and undertreatment of osteoporosis. Objective The aim was to describe trends in ODT use by age, sex, fragility fracture, and documented osteoporosis. Methods This was a retrospective analysis of patient-quarter observations for adults aged ≥50 years with commercial or Medicare Advantage health insurance in the OptumLabs Data Warehouse between 2011 and 2022. The primary outcome was the proportion of patient-quarter observations with ODT use stratified by age, sex, fragility fracture, and documented osteoporosis. Cuzick tests were performed to assess trends ODT use. Results Analysis of 166 673 420 patient-quarter observations revealed that over 70% of patients with fragility fractures did not have documented osteoporosis. Among women aged ≥65 years with documented osteoporosis, ODT fill rates increased between 2011 and 2022 from 36.3% to 50.1% for women without fragility fractures (P < .001) and from 30.8% to 43.7% for women with fragility fractures (P < .001). However, ODT fill rates declined (9.2% to 7.4% between 2011 and 2022) for women with fragility fractures and no documented osteoporosis (P = .015). Similar trends were observed among women aged 50-64 years and men. Conclusion ODT use for patients with documented osteoporosis has increased but remains low. Low rates of ODT use for patients with fragility fractures in the absence of documented osteoporosis suggests that underdiagnosis of osteoporosis contributes to underuse of ODTs.

AbstractMacitentan is a dual endothelin receptor antagonist (ERA) approved for treating pulmonary arterial hypertension (PAH). SOPRANO evaluated the efficacy and safety of macitentan versus placebo in pulmonary hypertension (PH) patients after left ventricular assist device (LVAD) implantation. SOPRANO was a phase 2, multicenter, double‐blind, randomized, placebo‐controlled, parallel‐group study. Patients with an LVAD implanted within the prior 90 days who had persistent PH (i.e., mean pulmonary arterial pressure ≥25 mmHg, pulmonary artery wedge pressure [PAWP] ≤18 mmHg, and pulmonary vascular resistance [PVR] >3 Wood units [WU]) were randomized (1:1) to macitentan 10 mg or placebo once daily for 12 weeks. The primary endpoint was change in PVR. Secondary endpoints included change in right‐heart catheterization hemodynamic variables, N‐terminal prohormone of brain natriuretic peptide levels, World Health Organization functional class, and safety/tolerability. Fifty‐seven patients were randomized to macitentan (n = 28) or placebo (n = 29). A statistically significant reduction in PVR from baseline to Week 12 was observed with macitentan versus placebo (placebo‐corrected geometric mean ratio, 0.74; 95% confidence interval, 0.58–0.94; p = .0158). No statistically significant differences were observed in secondary endpoints. In a post‐hoc analysis, 66.7% of patients receiving macitentan achieved PVR <3 WU versus 40.0% receiving placebo (p = .0383). Macitentan was generally well tolerated; adverse events were consistent with those in previous PAH studies with macitentan. In conclusion, macitentan showed promising tolerability and significantly reduced PVR in PH patients with persistently elevated PVR after LVAD implantation. ClinicalTrials. gov identifier: NCT02554903.

Importance Neoadjuvant therapy (NT) is an increasingly used treatment strategy for patients with localized pancreatic ductal adenocarcinoma (PDAC). Little research has been conducted on cancer care delivery during NT, and the standards for optimal delivery of NT have not been defined. Objective To develop consensus best practices for delivering NT to patients with localized PDAC. Design, Setting, and Participants This study used a modified Delphi approach consisting of 2 rounds of voting, and a series of virtual conferences (from October to December 2023) to reach expert consensus on candidate best practice statements generated from a systematic review of the literature and expert opinion. An interdisciplinary panel was formed including 47 North American experts from surgical, medical, and radiation oncology, radiology, pathology, gastroenterology, integrative oncology, anesthesia, pharmacy, nursing, cancer care delivery research, and nutrition as well as patient and caregiver stakeholders. Main Outcome and Measures Statements that reached 75% agreement or greater were included in final consensus statements. Results Of the 47 participating panel members, 27 (57.64%) were male, and the mean (SD) age was 47.6 (8.2) years. Physicians reported completing training a mean (SD) 14.6 (8.6) years prior and seeing a mean (SD) 110.6 (38.4) patients with PDAC annually; 35 (77.7%) were in academic practice. Final consensus was reached on 82 best practices for delivering NT. Of these, 38 statements focused on pre-NT practices, including diagnosis and staging (n = 15), evaluation and optimization (n = 20), and decision-making (n = 3); 29 statements defined best practices during NT, including initiation (n = 3), delivery of therapy (n = 8), restaging practices (n = 12), and management of complications during NT (n = 6); and 15 best practices were identified to guide treatment post-NT, focusing on surgery (n = 7), pathology (n = 4), and follow-up (n = 3). Conclusions Using a modified Delphi consensus technique, best practice guidelines were developed focusing on the optimal standards for delivering NT to patients with localized PDAC. Given the prognostic importance of completing multimodality therapy, efforts to standardize and optimize the delivery of NT represent an immediate opportunity to decrease care variation and improve outcomes for patients with PDAC. Future research should focus on validating and implementing best practice standards into clinical practice.

Abstract Semaglutide (Smg), a GLP‐1 receptor agonist (GLP‐1RA), shows renal protective effects in patients with diabetic kidney disease (DKD). However, the exact underlying mechanism remains elusive. This study employs transcriptome sequencing and identifies β ‐Klotho (KLB) as the critical target responsible for the role of Smg in kidney protection. Smg treatment alleviates diabetic kidney injury by inhibiting ferroptosis in patients, animal models, and HK‐2 cells. Notably, Smg treatment significantly increases the mRNA expression of KLB through the activation of the cyclic adenosine monophosphate (cAMP) signaling pathway, specifically through the phosphorylation of protein kinase A (PKA) and cAMP‐response element‐binding protein (CREB). Subsequently, the adenosine monophosphate‐activated protein kinase (AMPK) signaling pathway is activated, reprograming the key metabolic processes of ferroptosis such as iron metabolism, fatty acid synthesis, and the antioxidant response against lipid peroxidation. Suppression of ferroptosis by Smg further attenuates renal inflammation and fibrosis. This work highlights the potential of GLP‐1RAs and KLB targeting as promising therapeutic approaches for DKD management.

Background/Objectives: Spinal astrocytomas (SA) represent 30–40% of all intramedullary spinal cord tumors (IMSCTs) and present significant clinical challenges due to their aggressive behavior and potential for recurrence. We aimed to pool the evidence on SA and investigate predictors of regrowth or recurrence after surgical resection. Methods: A systematic review and meta-analysis were conducted on peer-reviewed human studies from several databases covering the field of SA. Data were collected including sex, age, tumor location, extent of resection, histopathological diagnosis, and adjuvant therapy to identify predictors of SA recurrence. Recurrence was defined as failure of local tumor control or regrowth after treatment. Results: A total of 53 studies with 1365 patients were included in the meta-analysis. A postoperative deterioration in neurological outcomes, as assessed by the modified McCormick scale, was noted in most of the patients. The overall recurrence rate amounted to 41%. On meta-analysis, high-grade WHO tumors were associated with higher odds of recurrence (OR = 2.65; 95% CI: 1.87, 3.76; p = 0.001). Similarly, GTR was associated with lower odds of recurrence compared to STR (OR = 0.33; 95% CI: 0.18, 0.60; p = 0.0003). Sex (p = 0.5848) and tumor location (p = 0.3693) did not show any significant differences in the odds of recurrence. Intraoperative neurophysiological monitoring was described in 8 studies and adjuvant radiotherapy in 41 studies. Conclusions: The results highlight the significant importance of tumor grade and extent of resection in patient prognosis. The role of adjuvant radiotherapy remains unclear, with most studies suggesting no differences in outcomes, with limitations due to potential confounders.

ABSTRACTObjectiveAlcohol‐related liver disease (ALD) has emerged as a significant public health concern, particularly among younger populations. ALD remains the leading cause of alcohol‐attributable deaths. This study aims to forecast ALD mortality trends up to 2030, focusing on individuals under 55 years.MethodsWe utilized data from the CDC WONDER database (1999–2022) to examine ALD‐related deaths, identified by ICD‐10 codes (K70.0–K70.9). Crude mortality rates (CMRs) per 100 000 were analyzed and temporal trends were assessed using annual and average annual percent changes (APC/AAPC) with empirical quantile confidence intervals. An Autoregressive Integrated Moving Average (ARIMA) model was employed to project mortality rates until 2030, validated through time series cross‐validation.ResultsFrom 1999 to 2022, there were 181 862 ALD‐related deaths among individuals under 55, with mortality rates increasing from 3.9 per 100 000 in 1999 to 9.7 per 100 000 in 2022 (AAPC 4.66%, 95% CI: 3.90%–5.86%). Projections suggest rates will continue to rise, reaching 14.4 per 100 000 by 2030. From 1999 to 2022, the 25–34 age group experienced the highest increase, with an AAPC of 10.27% (95% CI: 9.19%–11.35%), while the 35–44 and 45–54 age groups showed more moderate increases, with AAPCs of 5.03% and 4.38%, respectively. Projections indicate an AAPC of 3.86% for ages 25–34, 3.90% for ages 35–44, and 6.17% for ages 45–54 by 2030.ConclusionForecasts indicate a continued rise in ALD mortality among individuals under 55, necessitating immediate public health strategies to mitigate this trend.