Citations

INTRODUCTION: Colonoscopies reduce colorectal cancer incidence and mortality, but challenges remain in detecting all precancerous lesions. Operator fatigue, technique variability, and subtle lesions can lead to missed adenomas, highlighting the need for tools that standardize detection quality. Computer-aided detection (CADe) systems use artificial intelligence to enhance lesion detection and improve screening colonoscopy quality. This study evaluates the impact of CADe on key quality and efficiency metrics in a clinical setting. METHODS: A single-center retrospective study at an academic tertiary center analyzed 4,028 colonoscopies from October 2022 to December 2023. The CADe system was used in 4 of 8 endoscopy suites, creating a CADe and control group. Propensity matching accounted for age, sex, indication, and physician. Primary outcomes included adenoma detection rate (ADR) and polyp detection rate (PDR). Adenomas per colonoscopy (APC) and polyps per colonoscopy (PPC) were also measured. Per-polyp analyses were performed as a tertiary outcome. RESULTS: ADR was significantly higher in the CADe group (38.6%) vs control (34.2%) (rate ratio [RR] = 1.127, P < 0.05). PDR was significantly higher in the CADe group (67.2%) vs control (59.4%) (RR = 1.130, P < 0.05). APC was significantly higher in the CADe group (M = 0.406, SD 0.637) vs control (M = 0.359, SD 0.599) (RR = 1.131, P < 0.05). PPC was significantly higher in the CADe group (M = 1.297, SD 1.188) vs control (M = 1.046, SD 1.002) (RR = 1.240, P < 0.05). The increase in polyp resection with CADe was driven predominantly by ≤5 mm lesions, with comparatively smaller differences for larger polyps. DISCUSSION: Implementing CADe in clinical practice significantly improved ADR, PDR, APC, and PPC. However, the increase in ADR seems inflated by the detection of polyps ≤5 mm, whose clinical significance in reducing colorectal cancer remains uncertain.

Abstract Glioblastomas exhibit low immunogenicity and a highly immunosuppressive tumor microenvironment (TME) mediated by both tumor cells and tumor associated microglia/macrophages (TAMs). However, biomarkers that allow for specific detection, monitoring and therapy response assessment of the TAM phenotype in glioblastoma are still lacking. To address this gap, we characterized the dynamics of TAM clusters in the TME of experimental SB28 glioblastoma using single-cell RNA sequencing, immunofluorescence, and molecular imaging and identified Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) as a dynamic TAM-specific target. Consequently, we investigated a novel 64 Cu-labeled TREM2 radiotracer with a blood-brain barrier transport vehicle for translational mapping of TAMs in the TME of glioblastoma. We found strong and highly myeloid cell-specific PET signals that followed the trajectory of TREM2 gene expression from early- towards late-stage tumors. Transient myeloid cell depletion via CSF1R inhibition showed a reduction of TREM2 PET signals compared to placebo and prolonged survival in SB28 glioblastoma mice, while TREM2 stimulation led to increased TREM2 PET signals. Translation into a pilot cohort of patients with glioblastoma revealed strong TREM2 PET signals predominantly at lesion edges and high heterogeneity across individuals, matching with immunohistochemistry. In summary, TREM2 PET imaging has strong potential as an immune cell-specific biomarker for personalized assessment of the TAM phenotype in the TME of patients with glioblastoma.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Hodgkin lymphoma provide expert, multidisciplinary recommendations for the diagnosis and treatment of Hodgkin lymphoma. The panel convenes annually to update recommendations based on a review of recently published clinical trials. This selection from the NCCN Guidelines for Hodgkin Lymphoma focuses on the management of newly diagnosed and relapsed/refractory classic Hodgkin lymphoma in adults aged 18 to 60 years.

Background: Upfront resectable pancreatic ductal adenocarcinoma (PDAC) is defined by the NCCN as disease with ≤180° portomesenteric vein (PMV) abutment. However, the clinical significance of PMV abutment in this cohort remains unexplored, and we sought to investigate its impact. Methods: This multi-institutional study included patients who underwent pancreatoduodenectomy (PD) for upfront resectable PDAC from 2002 to 2023. Patients with PDAC with ≤180° PMV abutment were compared with those without. Overall survival (OS) was compared and stratified based on whether patients underwent upfront surgery or neoadjuvant therapy (NAT). Results: Among 1,446 patients included, 521 (36.0%) had PMV abutment. Median OS for patients with PMV abutment was 28.8 months compared with 31.2 months for those without ( P =.17). In a stratified analysis of patients who underwent upfront surgery, patients with PMV abutment had worse OS (19.2 vs 27.6 months; P <.05) and lower R0 resection rates (63.1% vs 87.2%; P <.05) compared with those without. However, in patients who underwent NAT, this difference in R0 resection rate was not observed (91.4% vs 94.0%, respectively; P =.27). Furthermore, there was no significant difference in median OS with NAT (42.5 vs 51.6 months, respectively; P =.48). Conclusions: In this largest cohort to date of patients with upfront resectable PDAC, PMV abutment was associated with worse OS compared with no PMV abutment when an upfront resection strategy was used. The use of NAT in patients with PMV abutment mitigated this survival difference with increased R0 resection rates. These findings suggest that patients with upfront resectable PDAC with PMV abutment benefit from a NAT approach for optimal survival outcomes, and that the current criteria guidelines need to be redefined.

Background: Aggressive non-Hodgkin lymphoma (aNHL) commonly occurs in older adults. However, geriatric assessments (GAs), which are associated with both survival and treatment-related toxicity, are infrequently performed due to logistical constraints. In this study, we examined how the brief, self-reported Vulnerable Elders Survey-13 (VES-13) screening tool and a comprehensive GA relate to clinical outcomes in this population. Methods: We conducted a longitudinal study of 105 adults aged ≥65 years who were initiating upfront chemoimmunotherapy for aNHL at 2 academic medical centers and their community affiliates between September 2020 and January 2023. Baseline frailty was evaluated using the Fondazione Italiana Linfomi (FIL) GA, which classifies patients as fit, unfit, or frail. The VES-13 was assessed both continuously and by categorizing patients as vulnerable (score ≥3). Using logistic regression controlling for covariates, we examined the association of VES-13 with grade ≥3 nonhematologic toxicity (toxicity), unplanned hospitalization within 6 months of treatment initiation, decline in quality of life (QoL) 1 year after therapy initiation, and death within 1 year of treatment initiation. In addition, we calculated the sensitivity and specificity of both the VES-13 and the FIL GA in identifying patients at risk for these outcomes. Results: The median patient age was 73 years (range, 64–99 years), with 42% aged ≥75 years. GA classified 40% of patients as fit, 10% as unfit, and 51% as frail, while 46% of patients had a VES-13 score ≥3, indicating vulnerability. VES-13 score was significantly associated with toxicity (odds ratio [OR], 1.18; P =.026), unplanned hospitalization (OR, 1.16; P =.043), QoL decline at 1 year (OR, 1.22; P =.027), and death within 1 year (OR, 1.49; P =.010). Using the VES-13 to define vulnerability (score ≥3), sensitivity and specificity were 59% and 61% for predicting toxicity, and 100% and 59% for predicting death within 1 year, respectively. FIL GA frailty had a sensitivity of 63% and specificity of 56% for predicting toxicity, and 100% sensitivity and 54% specificity for predicting death within 1 year. Conclusions: We found that VES-13 score was associated with survival, toxicity, health care utilization, and QoL decline, demonstrating similar sensitivity and specificity to the FIL GA. These findings underscore the potential utility of VES-13 as a screening instrument to identify older patients with aNHL at risk for adverse clinical outcomes.

Abstract Repetitive injury is hypothesized to lead to progressive tissue fibrosis and end-stage organ failure. Whether tissue-resident mesenchymal cell populations retain epigenetic memory of prior injuries that contribute to this pathological process is unknown. Here we used a genetic lineage labeling approach to mark the lung mesenchyme prior to injury, then performed multimodal analyses on isolated lung mesenchyme during the initiation, progression, and resolution of the fibrotic response. Our results demonstrate the remarkable epigenetic and transcriptional plasticity of the lung mesenchyme during fibrotic activation and de-activation. Despite this plasticity, we also find that the lung mesenchyme exhibits an enhanced fibrotic program upon reinjury. We identify RUNX1 as a critical driver of both fibrotic activation and fibrotic memory. Comparison of fresh isolated and cultured lung mesenchyme demonstrates that RUNX1 is spontaneously activated in standard culture conditions, previously masking these roles of RUNX1. Targeted knockdown of RUNX1 dampens fibrotic mesenchymal cell activation immediately after cell isolation, but with reduced efficacy after only days of culture, confirming its functional importance to both early activation and long-term memory. Collectively, our findings implicate RUNX1 in the initiation and memory of fibrotic mesenchymal cell activation that together prime enhanced mesenchymal cell responses upon repeated injury.

Abstract Diffuse hemispheric glioma, H3 G34‐mutant (DHG‐H3 G34) has been primarily molecularly characterized by methylation profiling and sequencing studies. We describe an integrated histomolecular evaluation including high‐resolution copy number profiling of a series of 60 DHG‐H3 G34 to further our understanding of the spectrum of genetic changes associated with this tumor type. Cases were clinically tested using an 187‐gene mutation and fusion targeted neuro‐oncology next‐generation sequencing panel ( n = 60) and Oncoscan chromosomal microarray ( n = 26) by a single laboratory (2018–2022). A subset of cases had immunohistochemical results for OLIG2 ( n = 42), p53 ( n = 48), and ATRX ( n = 46), and methylation array data ( n = 8). Median age at testing was 21 years (range, 12–50). No significant difference was noted in clinical, histopathological, and mutational profile between pediatric and adult patients. H3‐3A G34 mutations included G34R ( n = 56; 94%), G34V ( n = 3), and a non‐canonical G34E ( n = 1). Concurrent mutations most often involved TP53 ( n = 55; 92%), ATRX ( n = 50; 83%), and PDGFRA ( n = 34; 57%). A reportedly primary tumor was confirmed to be hypermutant and had a PMS2 mutation. A single case also showed an FGFR3::FAM184B fusion. All cases with available chromosomal microarray data had unbalanced genomes, which were often complex (14/26; 54%). The most frequent recurrent copy number abnormalities were losses involving 3q, 4q, 10q, 13q, and 18q, and 17p copy‐neutral loss of heterozygosity (cnLOH) encompassing TP53 . This copy number profile was reminiscent of that seen in Grade 4 IDH‐mutant astrocytomas. Collectively, a TP53 abnormality at copy number (12/26, all cnLOH), sequence (55/60) and protein expression (46/48) level was detected in all 60 cases. In conclusion, integrated high‐resolution copy number and histomolecular analysis expanded the spectrum of genetic changes associated with DHG‐H3 G34, including the presence of universal TP53 abnormalities with frequent cnLOH—a copy number abnormality that has been largely unrecognized—for this new 2021 World Health Organization central nervous system tumor type.

BACKGROUND: Bicuspid aortic valve (BAV) is a frequent congenital heart defect with a high heritability. Despite this, only a limited number of genes have been associated with the disease, and the molecular mechanisms remain unexplained in most cases. This study aimed to further understand the genetic architecture of BAV. METHODS: A genome-wide association study meta-analysis including 9631 cases among 65 677 participants was performed. Genes were prioritized using transcriptomic analyses based on RNA sequencing in relevant tissues, including human fetal and adult aortic valves. The impact of the knockdown or knockout of 4 candidate genes on cardiac development was verified in zebrafish. A polygenic risk score was developed, its association with BAV was evaluated in an independent cohort, and its association with a wide range of phenotypes (n=976) was evaluated in UK Biobank (n=355 618 individuals). RESULTS: Thirty-six genomic loci were identified, including 32 that were not described previously. Among the prioritized genes, KANK2 and ERBB4 were identified as potentially causal through transcriptomic analyses, colocalization, and Mendelian randomization based on gene expression in human aortic valves (n=484), whereas PRDM6 and STRN were prioritized using similar analyses from aortic (n=326) and left ventricular tissues (n=326), respectively. Targeting 4 candidate genes ( WNT4 , LEF1 , STRN , and KANK2 ) in zebrafish led to disruption in cardiac development. A polygenic risk score was associated with an odds ratio of 2.07 (95% CI, 1.90–2.25; P =5.43×10 -62 ) per SD for BAV and significantly associated with thoracic aortic aneurysm and atrial fibrillation in UK Biobank. CONCLUSIONS: This study supports a significant polygenic contribution to BAV, where the combination of multiple common variants in genes involved in heart morphogenesis disrupts aortic valve development.

Abstract Background Artificial intelligence enhanced electrocardiograms (AI-ECG) have matured over the past 10 years. More recently, the AI-ECG estimate of biological sex has shown potential as a novel tool for cardiovascular risk stratification among women. Cardiovascular disease is a leading cause of pregnancy-related mortality; however, there have been limited approaches for estimating the physiological demands of pregnancy and its impact of maternal cardiovascular outcomes. Purpose To estimate pregnancy-related changes on AI-ECG-based sex and age estimation in a prospective cohort of otherwise healthy, complication free pregnant women. Methods This secondary analysis of the SPEC-AI Nigeria Clinical Trial identified pregnant women without any pregnancy-related complications (at baseline or during follow-up) who had at least two 12 lead ECGs recorded during the study. The ECGs were analyzed with previously-developed algorithms to predict age and biological sex. To address bias in the AI-ECG age estimate, a reference cohort of 25,144 healthy patients was analyzed using quantile regression to estimate the 75th percentile of the reference distribution as a function of age. The estimate of biological sex was used to determine a sex discordance score with a discordance of 0.2 considered clinically relevant. To simplify the trends in the data, the ECGs were categorized as during pregnancy (&lt;=28 days prior to birth), peripartum (+/- 28 days of birth), and postpartum (28+ days after birth), and mixed effects models with a random intercept were used for analysis. Results A total of 207 females with a median age of 31 years (IQR 28 to 36 years) and normal blood pressures (systolic: 110 (IQR 10 to 120); diastolic: 70 (IQR 60-77); mmHg) were included from 5 clinical sites in Nigeria. The majority (73%, 150/207) of participants were in their second trimester at time of enrollment and the median number of ECGs per participant was 3 (max 7). The sex discordance score was elevated in 38% of the women at baseline and this percentage fell to 23% postpartum; which resulted in a decrease in the mean discordance score of 0.03 (95% CI: -0.06 to 0.0; p=0.028). Conversely, the percentage of patients with elevated age prediction increased from 35% to 41% over the course of pregnancy. This resulted in an increase in the bias-corrected AI-ECG age of 3.0 years (95% CI: 1.5 to 4.6 years; p&lt;0.001). Conclusion This study demonstrates the preliminary utility of serial AI-ECG based assessment as a marker for the biological effects of pregnancy. The increase in sex discordance score during pregnancy may be related to changes in cardiac structure, such as increased ventricular mass and chamber dilation which often reverses postpartum. However, the impact on age estimation appeared to persist in the early postpartum period. Further study is warranted to associate any changes observed with long term maternal or fetal outcomes.Figure

Abstract Background Ischemic heart disease is the leading cause of death among women. Non-obstructive coronary disease (NOCAD), often identified by a positive stress test and negative coronary angiogram result, is linked to adverse outcomes, particularly among women. Purpose This study evaluated the impact of discordant Single Photon Emission Computed Tomography (SPECT) Myocardial Perfusion Imaging (MPI) stress test and coronary angiogram results on repeat invasive angiography and survival, while assessing sex-related differences. Methods Data were extracted from a single health system for patients who underwent a SPECT MPI stress test, and invasive coronary angiography performed within 3 months from September 2002 to July 2018. Discordance was defined as: Profile A – a positive stress test with negative angiography (epicardial coronary vessel stenosis &lt;50%); Profile B – a negative stress test with positive angiography (at least one epicardial coronary vessel stenosis &gt;=50%). To assess the association between discordance and all-cause mortality, Cox-proportional hazards regression was used to analyze the most recent stress/angiogram pair (adjusting for race, age, and number of prior angiograms). For repeat invasive angiography, where mortality was considered a competing event, the Fine-Gray proportional hazards model for the sub-distribution of a competing risk was used to analyze the first stress/angiogram pair (adjusting for race and age). Hazard ratios (HRs), sub-distribution hazard ratios (SHRs), and corresponding 95% confidence intervals (CIs) were reported. Results 5,179 were included in the final analysis, median age was 67.9 years and 32.7% were female. Approximately 15% and 24% were classified as Profile A and B respectively. Patients with a negative stress/negative angiogram were designated as the reference group. Profile A was not significantly associated with mortality or repeat invasive testing in both sexes. Profile B was associated with the highest risk of death (female aHR: 1.58, P&lt;.001; male aHR: 1.54, P&lt;.001) followed by those with a positive stress/positive angiogram (female aHR: 1.39, P=.009; male aHR: 1.25, P=.05) compared to the reference group. Profile B was significantly associated with repeat invasive testing and a stronger association was seen in females (female aSHR: 9.84, P&lt; .001; male aSHR: 3.42, P&lt;.001). A similar pattern was seen for those with a positive stress/positive angiogram. Conclusion Discordant Profile A showed no significant association with mortality or repeat invasive testing. Discordant Profile B was associated with the highest mortality risk in both sexes and showed a stronger association with repeat invasive testing among females. These findings underscore the importance of careful patient selection for stress testing, the need for improved stress testing options (especially in females), and prompt coronary evaluation in patients with a negative stress test and persistent symptoms or high-risk features.