Citations

Hematologic malignancies, including leukemias, lymphomas, and multiple myeloma, are diseases of older adults (age ≥ 60 years). Treatment decisions in older adults with cancer are heavily influenced by patient fitness: the ability of an individual patient to tolerate the off-target effects of anti-cancer therapy. Sarcopenia, defined as low muscle mass and strength, is increasingly recognized as an important marker of fitness. Furthermore, sarcopenia is known to be modifiable with nutrition and exercise interventions in older adults without cancer, but such evidence is limited for patients with cancer. Much of the literature on sarcopenia in older adults with cancer has focused on patients with solid tumors. However, there is an increasing body of literature on the impact of sarcopenia in older adults with hematologic malignancies. In this comprehensive review, we attempt to (i) describe the most up-to-date diagnostic criteria and diagnostic approach to sarcopenia, (ii) summarize the prognostic impact of sarcopenia among older adults with hematologic malignancies, (iii) discuss the proposed mechanisms of sarcopenia and its pathogenesis, (iv) review the evidence for interventions targeting sarcopenia, and (v) provide future directions for the advancement of sarcopenia management among older adults with hematologic malignancies.

Background: It is not clear if changes in lesion volume might represent a clinically relevant and statistically advantageous outcome parameter in early phase trials of novel drugs aimed at preventing bleeding in cerebral cavernous malformations (CCM). Methods: We analyzed the modified intention to treat cohort (33 patients receiving atorvastatin and 31 placebo) who contributed at least one paired imaging biomarker in the recently completed double-blinded randomized controlled AT CASH EPOC trial (clinicaltrials.gov NCT02603328). We examined prospective changes in CCM lesion volume and correlated these with symptomatic hemorrhage (SH) events. We contemporaneously assessed changes in lesional iron content by quantitative susceptibility mapping (QSM) on MRI, and objective (mRS) and subjective (EQ-VAS) functional status. We also simulated sample sizes needed to detect potential effects of a drug on lesion volume. Results: There was excellent correlation between independently assessed maximum lesion diameter and CCM lesion volume (R 2 = 0.68, P<0.0001). The mean (SD) percentage change in lesion volume per year was +6 (65) and +18 (94) in atorvastatin and placebo patients, respectively (P= 0.43). All cases with SH had increases in lesion volume as well as increases in mean lesional iron content by QSM, and most had declines in functional status on mRS and EQ-VAS. But there were many cases with increases in lesion volume with improved functional status or decreased mean lesional QSM, and other cases with worsening in function or increased lesional QSM and decreased lesion volume. There were no significant correlations of changes in lesion volume with concomitant changes in mean lesional QSM, mRS or EQ-VAS (all R/R 2 <0.5 and Bonferroni corrected P>0.05), including in brainstem lesions analyzed separately. Sample size simulations indicate larger numbers of cases needed to demonstrate a drug effect on changes in lesion volume than those needed to detect an effect on QSM change with a=0.05 and b=0.8, and even larger samples to detect effects on the proportion of cases with increased or decreased lesion volume. Conclusion: Changes in lesion volume occur frequently in CCM lesions after recent SH, but do not correlate with measures of bleeding in the lesions, nor appear to reflect functional changes. And they are not statistically advantageous in comparison to QSM measures for detecting potential drug effects.

Abstract INTRODUCTION The vascular endothelial growth factor (VEGF) signaling family plays a role in neurodegenerative diseases, including Alzheimer's disease (AD). Previous work has shown widespread effects of the members FLT1 , FLT4 , and VEGFB on AD outcomes. However, these analyses have focused within the non‐Hispanic White (NHW) population. METHODS The goal of this study was to analyze the effects of the VEGF family in underrepresented populations, leveraging large and diverse bulk RNA sequencing and tandem mass tag–mass spectrometry (TMT‐MS) proteomic data. Outcomes included measures of AD pathology and diagnosis. RESULTS Within underrepresented populations, we replicated previously reported effects of FLT1 and FLT4 , whereby higher protein abundance was observed in the AD brain and was associated with higher neuropathology burden. In stratified analyses, these associations were largely consistent across race and ethnicity. DISCUSSION This multi‐omic study on the role of the VEGF family in AD emphasizes the need for more representative studies focused on therapeutic targets for AD. Highlights Vascular endothelial growth factor (VEGF) genes and proteins were quantified in four different brain regions. Samples included participants from four different populations. Previously observed effects were replicated in diverse populations. This study is the largest multi‐omic study of the vascular endothelial growth factor (VEGF) genes among Alzheimer's disease (AD) participants from diverse populations.

BACKGROUND: The Commission on Cancer (CoC) implemented 6 operative standards to reduce technical variation in cancer surgery. Although designed to guide surgeons in performing key oncologic techniques, these standards also provide a framework for teaching high-quality cancer surgery to trainees. We assessed surgical trainees’ familiarity with the CoC Operative Standards and the underlying principles of cancer surgery to identify knowledge gaps and opportunities for improved education. STUDY DESIGN: The American College of Surgeons Cancer Surgery Standards Program distributed an anonymous survey to general surgery residents and surgical fellows across the US. Questions addressed the CoC Operative Standards and cancer surgery principles, with scores calculated on the basis of correctness. Univariate logistic regression evaluated associations between trainee or program characteristics and knowledge. Trainees were also asked about their role in procedural documentation, given the synoptic operative report requirements of the standards. RESULTS: A total of 244 surveys were completed by 205 residents and 39 fellows. Fellows reported greater familiarity with the CoC Operative Standards (68% vs 24%, p < 0.001). Only 30% of trainees reported receiving a formal curriculum on the standards. Correct response rates were 30% for CoC Operative Standards questions vs 50% for cancer surgery principles, with minimal association between knowledge and trainee or program characteristics. Most residents (71%) reported contributing to operative documentation. CONCLUSIONS: Surgical trainees demonstrated limited knowledge of the CoC Operative Standards, highlighting the need for multifaceted educational strategies at the national and institutional levels. Incorporating education about the CoC Operative Standards into surgical training can help emphasize the importance of performing and documenting critical elements of cancer operations.

What was done? A review of artificial intelligence (AI) applications for the imaging of uterine fibroids, endometriosis, and adenomyosis. What was found? AI models can assist with the recognition, segmentation, and localization of uterine fibroids, and the differentiation of benign fibroids and sarcomas. Models can aid in the diagnosis of adenomyosis and endometriosis, and the prediction of the impact of endometriosis on fertility. What the findings mean? Deployed thoughtfully, AI tools could reduce variability, shorten read times, and add objective measurements to routine care. Studies evaluating these models are limited by single-institution designs and continued reliance on expert sonologists and radiologists.

Abstract Chimeric antigen receptor (CAR) T-cell therapy enriched for a memory-like phenotype may persist and function longer than a nonenriched product, thereby improving duration of response (DOR). We conducted a phase I study with bb21217 (NCT03274219), an anti–B-cell maturation antigen CAR T-cell therapy manufactured in the presence of the phosphoinositide 3-kinase inhibitor bb007 to enrich for T cells with a memory-like phenotype, in patients with relapsed/refractory multiple myeloma (N = 72). No new safety concerns were raised with bb21217 therapy (three cases each of grade ≥3 cytokine release syndrome and grade ≥3 neurotoxicity were observed). The objective response rate was 69.4% and the median DOR was 23.8 (95% confidence interval, 16.8–34.8) months. Analysis of the drug product established an association between early memory phenotype and robust expansion and depth of response. Examination of baseline characteristics indicated that tumor burden and prior therapies influenced DOR. The data indicate that generation of CAR T cells early in a disease course when tumor burden is lower and source material exhibits a more naïve phenotype may maximize the clinical benefit potential of the drug product.

ABSTRACT Background Despite histologic remission (HR) being important in management of ulcerative colitis, the impact of endoscopic sampling on newer scoring systems remains uncertain. This study examines the outcome of applying PICaSSO Histologic Remission Index (PHRI) scoring on biopsies collected during routine clinical care and investigates the impact of endoscopic sampling variation on PHRI scoring and HR status. Methods A retrospective survey of UC endoscopic biopsies ( N = 128, 559 bites, 1–13 bites/biopsy) was evaluated using standard H&E stain and myeloperoxidase (MPO) immunohistochemistry to aid neutrophil identification. Convolutional neural networks (CNN), trained on colonic tissue architecture and cytomorphology features, were deployed alongside pathologist interpretations. In silico modeling of bite‐derived virtual biopsies ( N = 19,760) was investigated to determine the impact of sampling variation on PHRI scores and compared with ground truth clinical samples. Results PHRI MPO scoring displayed improved sensitivity and specificity for identifying neutrophils, compared with PHRI H&E . CNN‐derived PHRI scoring was most accurate for chronic active and chronic active with ulceration categories, with greatest variability observed in chronic inactive biopsies. Virtual patient biopsies comprised of < 5 endoscopic bites were impacted most by sampling permutations. Limited variability in PHRI scores was observed in samples consisting of ≥ 5 bites. Conclusions HR status (PHRI = 0) determination was slightly impacted by sampling. Biopsies consisting of < 5 endoscopic bites exhibited the most variability. Conservative sampling of 5–7 endoscopic bites may produce more accurate assessments of microscopic heterogeneity in clinical studies employing quantitative histologic measurements to assess disease activity and remission. Additionally, incorporating MPO increased the sensitivity and specificity of detecting active inflammation for PHRI scoring.

Abstract Exercise training improves cardiovascular health and reduces the risk for future cardiovascular events and mortality. However, emerging evidence suggests that Masters athletes may have a higher prevalence of cardiovascular abnormalities, such as atrial arrhythmias, coronary atherosclerosis, aortic dilatation, and myocardial fibrosis, compared to their less active peers. The clinical management of Masters athletes may be challenging as available guidelines for such conditions are generally based on data derived from symptomatic sedentary patients, limiting their applicability to highly trained individuals. Other unique challenges in the clinical assessment of Masters athletes include differences in symptomatic presentations compared to sedentary individuals, potential resistance to the initiation of pharmacologic treatment, and the increasing availability of consumer wearable health data that may provide relevant information on their cardiovascular health status. The purpose of this joint EAPC/ESC and ACC Clinical Consensus Statement is to provide an in-depth update on the current state of knowledge on abnormal cardiovascular findings in Masters athletes. We present an expert-based approach on the diagnostic assessment, management, and prognosis of (i) atrial fibrillation, (ii) bradyarrhythmias, (iii) ventricular arrhythmias, (iv) coronary atherosclerosis, (v) aortic dilatation, (vi) myocardial fibrosis, and (vii) exercise-induced arrhythmogenic cardiomyopathy. Clinical challenges, areas of ongoing controversy, and uncertainty and the potential underlying mechanisms are discussed. We also present future perspectives and research directives to further refine current best practice strategies. This includes the need for clinical outcome studies, dedicated randomized controlled trials in athletes, and international registries with diverse populations and longitudinal follow-up to evaluate the natural history of cardiac abnormalities and facilitate development of evidence-based approaches in the clinical management of Masters athletes with cardiovascular abnormalities.

619 Background: Well-differentiated G3 GEP-NETs are rare and heterogeneous diseases, limiting phase III trials and definition of clear standards of care. Building upon our preliminary cohort of 76 patients (pts), we present an updated and expanded retrospective analysis across three Mayo Clinic tertiary centers. Methods: We included pts with histologically confirmed well-differentiated G3 GEP-NETs diagnosed since 2017 (new WHO classification) from the three Mayo Clinic sites (Rochester, Phoenix, Jacksonville). Endpoints were ORR, DCR, PFS, and OS across treatment lines. PFS/OS were estimated by Kaplan-Meier. OS was defined from treatment start. Multivariate Cox regression was used to evaluate the association of clinic-pathologic features (age, sex, tumor functionality, Ki-67, primary tumor site, stage at diagnosis, presence of liver metastasis, number of metastatic sites at diagnosis) with OS (p<0.05). Results: 111 pts (median age 62 y, range 22–83). Primary sites were pancreas (58%), small bowel (19%), unknown (9%), and rectum (5%). Most tumors were G3 at diagnosis (88%); the remainder evolved from prior G1/G2. Ki-67 was 20–55% in 83% of cases. Most were nonfunctional (70%); functional subtypes included carcinoid (13%) and gastrinoma (8%). Median plasma 5-HIAA was 38.5 ng/ml (5–1394). Advanced disease was present in 85%. Common metastatic sites included liver (85%), lymph nodes (32%), bone (26%), peritoneum (10%), and lung (9%). Median number of metastatic sites was 1 (range 0–5). Median number of systemic treatment lines was 2 (range 0–8). The most frequent regimens and outcomes are shown in the Table. Insulin-secreting tumors (HR 2.16, 95% CI 1.33–25.73, p=0.019) and ≥2 metastatic sites (HR 2.13, 95% CI 1.05–4.31, p=0.035) were associated with inferior OS. Conclusions: This represents one of the largest real-world datasets of well-differentiated G3 GEP-NETs and provides a deeper evaluation of treatment strategies and prognostic factors. CAPTEM, SSAs, and PRRT with Lu-177 emerged as the most commonly used therapies, with PRRT showing the most favorable outcomes. Insulin secretion and higher metastatic burden were confirmed as adverse prognostic factors. CAPTEM SSAs PRRT Lu-177 Carboplatin plus etoposide FOLFOX Everolimus Sunitinib N of pts (%) 64 (58) 44 (40) 37 (33) 24 (19) 18 (13) 11 (10) 8 (7) Line of therapy (%) First 36 (56.3) 27 (61.4) 5 (13.5) 13 (59.2) 5 (7.2) 1 (9.0) 1 (12.5) Second 15 (23.4) 13 (29.5) 13 (35.2) 3 (13.6) 5 (35.7) 3 (27.3) 2 (37.5) Third or higher 13 (20.3) 4 (9.1) 19 (51.3) 6 (27.2) 8 (57.1) 7 (63.7) 5 (62.5) DCR (%) 60.9 56.8 75.0 52.2 71.4 45.5 37.5 ORR (%) 34.4 13.6 44.4 30.4 35.7 18.2 12.5 mPFS (95% CI) 8.0 (5.3-10.6) 6.2 (2.8-9.5) 11.2 (9.1-13.3) 7.3 (2.8-11.8) 4.4 (2.4-6.4) 3.9 (2.2-5.6) 3.9 (1.54-6.26) mOS (95% CI) 40.1 (23.0-57.2) 50 (22.6-77.4) 76.1 (16.3-135.8) 33.0 (21.0-45.0) 21.1 (15.0-27.2) NE NE