Cedars-Sinai Medical Center

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer‐related mortality, largely due to late‐stage diagnosis. Reliable early detection methods are critically needed. PDAC‐derived extracellular vesicles (EVs) carry molecules that reflect their parental tumor cells and are detectable in early disease stages, offering a promising noninvasive diagnostic approach. Here, a streamlined PDAC EV Surface Protein Assay for quantifying PDAC EV subpopulations in 300‐µL plasma through a two‐step workflow is presented: i) click chemistry‐mediated EV enrichment using EV Click Beads and trans‐cyclooctene‐grafted antibodies targeting three PDAC EV‐specific surface proteins (MUC1, EGFR, and TROP2), and ii) quantification of enriched PDAC EVs through reverse transcription‐quantitative polymerase chain reaction. The three PDAC EV‐specific surface proteins are identified using a bioinformatics framework and validated on PDAC cell lines and tissue microarrays. The resultant PDAC EV Score, derived from signals of the three PDAC EV subpopulations, demonstrates robust differentiation of PDAC patients from noncancer controls, with area under the receiver operating characteristic curves of 0.94 in the training (n = 124) and 0.93 in the validation (n = 136) cohorts. This EV‐based diagnostic approach successfully exploits PDAC EV subpopulations as novel biomarkers for PDAC early detection, translating PDAC surface proteins into an EV‐based liquid biopsy platform.

Background Studies have shown mixed results regarding the association between irritable bowel syndrome (IBS) and metabolic syndrome (MS); This study aimed to assess the susceptibility of IBS patients to MS and its individual components. Methods PubMed, Scopus, Embase, and Web of Science were searched on 1/1/2023. Eligible studies were screened, and data on study characteristics, IBS diagnostic criteria, and metabolic syndrome components were extracted. Data were analysed in RevMan 5.4, with results reported as relative risk (RR) or mean difference (MD) and 95% confidence intervals. Statistical significance was set at p < 0.05. Results IBS was associated with an increased risk of MS (RR = 2.05, 95% CI = 1.50–2.79, p < 0.00001), with a higher risk among IBS‐D patients (RR = 3.09, 95% CI = 2.41–3.97, p < 0.00001). IBS patients showed increased HOMA‐IR (MD = 0.21, 95% CI = 0.15–0.26, p < 0.00001), higher obesity risk (RR = 1.46, 95% CI = 1.10–1.93, p = 0.009), elevated BMI (MD = 1.51, 95% CI = 0.98–2.03, p‐value < 0.00001), waist circumference (MD = 5.01, 95% CI = 1.29–8.72, p = 0.008), and an association with systolic hypertension (MD = −0.50, 95% CI = −0.60 to −0.40, p‐value < 0.00001). IBS was also linked to higher LDL (MD = 5.98, 95% CI = 0.91–11.05, p = 0.02), total cholesterol (MD = 12.21, 95% CI = 6.23–18.18, p < 0.0001), and triglycerides (MD = 11.93, 95% CI = 11.55–12.31, p < 0.00001). Conclusions This analysis indicates a potential association between IBS and metabolic syndrome, including its components such as obesity, hypertension, and lipid profile abnormalities. However, significant heterogeneity among studies limits the generalisability of these findings. Clinicians should remain aware of the possible link and consider individualised preventive and management strategies.

Clinical variant classification of pathogenic versus benign genetic variants remains a challenge in genetics. Current genomic foundation models have enhanced variant effect prediction (VEP) accuracy through weakly supervised or unsupervised training, yet these models lack disease specificity. Here, to address this, we propose DYNA (disease-specificity fine-tuning via a Siamese neural network), broadly applicable to all genomic foundation models for more effective VEPs in disease contexts. We applied DYNA to the coding VEP in cardiovascular diseases and the non-coding VEP of RNA splicing regulation. These two tasks cover a wide range of specific disease–gene relationships and disease-causing regulatory mechanisms; therefore, their performance will inform the general utility of DYNA. In both cases, DYNA fine-tunes various pretrained genomic foundation models on small rare-variant sets. The DYNA fine-tuned models show superior performance in held-out rare-variant test sets and are further replicated in large, clinically relevant variant annotations in ClinVar. Importantly, we observed that different genomic foundation models excel at different downstream VEP tasks, necessitating a universal tool such as DYNA to fully harness the power of genomic foundation models. Thus, DYNA offers a potent disease-specific VEP method for clinical variant interpretation.

Ancestrally diverse and admixed populations, including the Hispanic/Latino/a/x/e community, are underrepresented in cancer genetic/genomic studies. Leveraging the Latino Colorectal Cancer Consortium (LC3) and other existing datasets, we analyzed whole exome sequencing data on tumor/normal pairs from 718 individuals with colorectal cancer to map somatic mutational features by ethnicity and genetic similarity. Global proportions of African, Asian, European, and Native American genetic ancestries were estimated using ADMIXTURE. Associations between these proportions and somatic mutational features were examined using logistic regression. APC, TP53, and KRAS were the top three mutated genes across all participants and in the subset of Latino individuals in LC3. In analyses examining recurrently mutated genes, tumors from patients of Latino ethnicity had fewer KRAS and PIK3CA mutations compared to tumors from non-Latino patients. Genetic ancestry overall was associated with CDC27 mutation status, and African genetic ancestry was associated with SMAD2 mutation status. In exome-wide analyses, African genetic ancestry was significantly associated with higher odds of mutation in KNCN and TMEM184B. Native American genetic ancestry was associated with a lower frequency of microsatellite instability-high (MSI-H) tumors. The SBS11 mutational signature was associated with Native American genetic ancestry as well as Latino ethnicity. In an independent replication dataset, MSK-IMPACT, estimates of association were largely consistent in direction, but non-significant. A meta-analysis of LC3 and MSK-IMPACT showed that African genetic ancestry was significantly associated with KRAS mutation status and MSI status. This work facilitates precision medicine initiatives by providing insights into the contribution of genetic ancestry to molecular features of colorectal tumors.

Aging is a known risk factor for melanoma, yet mechanisms underlying melanoma progression and metastasis in older populations remain largely unexplored. Aging might alter phenotypes of cells in the melanoma microenvironment, selecting for populations that support metastatic progression. Here, we demonstrated that age engenders the development of an immunosuppressive tumor microenvironment, which is linked to phenotypes associated with melanoma metastasis. Among cellular populations enriched by aging were macrophages with a tolerogenic phenotype expressing TREM2 and dysfunctional CD8+ T cells with an exhausted phenotype, while macrophages with a profibrotic phenotype expressing TREM1 were depleted. Notably, TREM1 inhibition decreased melanoma growth in young but not old mice, whereas TREM2 inhibition prevented lung metastasis in aged mice. These data identify age-related targets associated with melanoma metastasis and may guide aged-dependent immunotherapeutic strategies.

Background and Aims Based on liver stiffness measurement by vibration controlled transient elastography (LSM by VCTE), the Agile 3+ and 4 are novel noninvasive scores that accurately identify advanced fibrosis (≥ F3) and cirrhosis (F4), respectively. We investigated and compared the Agile 3+ and 4 scores’ performances in predicting adverse events to LSM alone, FIB-4 and Fibroscan-AST (FAST) score. Method This retrospective analysis included NAFLD patients with LSM by VCTE and laboratory testing from a tertiary care center from 2013 to 2022. Adverse events were defined as major adverse liver outcomes (MALO), hepatocellular carcinoma, liver transplant, and death. MALO was defined as ascites, hepatic encephalopathy, or esophageal variceal bleeding. We used the Cox proportional hazard rate model and the Harrell’s concordance (C) statistic to compare predictive performances. Results 733 total subjects with median follow-up of 27.0 months were included. Average age was 58.1 years and 32.8% had type 2 diabetes. Average alanine aminotransferase was 46.6 IU/L, aspartate aminotransferase: 34.5 IU/L, albumin: 4.4 g/dL, and platelets: 241.1 × 10⁹/L. Fourteen subjects had 21 adverse outcomes, including 10 MALO, 5 HCC, 4 liver transplants, 3 progression of MELD score, and 6 deaths. Agile 3+ and 4 respectively had the highest C stats of 0.911 (C stat SE 0.028) and 0.909 (C stat SE 0.029) compared to LSM (C stat 0.857, C stat SE 0.045), FIB-4 (C stat 0.843, C stat SE 0.037) or FAST (C stat 0.703, C stat SE 0.085). Conclusion The Agile 3+ and 4 scores had the highest likelihood of accurately predicting adverse outcomes including MALO and death compared to LSM alone, FIB-4 or FAST score.

Background Circulating tumor cells (CTCs) are pivotal in cancer progression, and in vitro CTC models are crucial for understanding their biological mechanisms. This study focused on the characterization of extracellular vesicles (EVs) from CTC lines derived from a patient with metastatic colorectal cancer (mCRC) at different stages of progression who progressed despite therapy (thus mirroring the clonal evolution of cancer). Methods and results Morphological and size analyses revealed variations among EVs derived from different CTC lines. Compared with the Vesiclepedia database, proteomic profiling of these EVs revealed enrichment of proteins related to stemness, endosomal biogenesis, and mCRC prognosis. Integrin family proteins were significantly enriched in EVs from CTC lines derived after therapy failure. The role of these EVs in cancer progression was analyzed by assessing their in vivo distribution, particularly in the liver, lungs, kidneys, and bones. EVs accumulate significantly in the liver, followed by the lungs, kidneys and femurs. Conclusions This study is a pioneering effort in highlighting therapy progression-associated changes in EVs from mCRC patients via an in vitro CTC model. The results offer insights into the role of metastasis initiator CTC-derived EVs in cancer spread, suggesting their utility for studying cancer tissue distribution mechanisms. However, these findings must be confirmed and extended to patients with mCRC. This work underscores the potential of CTC-derived EVs as tools for understanding cancer dissemination.

BACKGROUND Despite randomized data for survival benefit (with class 1 recommendations) for treating heart failure (HF) with reduced ejection fraction using quadruple medical therapy (QMT)—defined as evidence-based β-blockers, sodium-glucose cotransporter 2 inhibitor, preferably angiotensin receptor/neprilysin inhibitor, and mineralocorticoid receptor antagonist—it is underutilized. IMPLEMENT-HF is a multiregional HF quality improvement initiative to improve care and outcomes for patients with HF by enhancing the use of QMT in routine practice. METHODS This analysis of HF with reduced ejection fraction treatment in patients from hospitals participating in the American Heart Association’s Get With The Guidelines–HF who volunteered to participate in IMPLEMENT-HF in 7 US regions. IMPLEMENT-HF included multidisciplinary learning to share strategies for formulary changes, electronic health record tools, and patient resources with site-level feedback reports. Participants gathered QMT data at discharge and 30 days after discharge. We evaluated QMT utilization and variation, in addition to other prespecified performance measures, from Q1 2021 to Q2 2023. RESULTS The median (interquartile range) age of 43 558 admitted patients at 61 hospitals was 74 (63–83) years; 16 530 (38%) belonged to racial and ethnic minorities, and 22 228 (51%) were women. Between Q1 2021 and Q2 2023, defect-free QMT improved from 4.7% to 44.6% at discharge and from 0% to 44.8% at 30 days (both P <0.0001). There was also substantially improved incorporation of health-related social needs assessments. The magnitude of improvements was similar when stratified by sex or race and ethnicity, yet there was significant regional variation. CONCLUSIONS Among healthcare systems participating in IMPLEMENT-HF, there was a marked increase in QMT use among eligible patients over the course of the initiative. This quality improvement initiative supports a learning collaborative model to promote improvements in QMT use.

Previous studies have suggested routine preoperative laboratory assessment may be unnecessary or excessive. The primary aim of this study was to determine the association between abnormal preoperative laboratory screening tests on allogeneic transfusion in pediatric patients receiving posterior spinal fusion for idiopathic scoliosis correction. The NSQIP Pediatric database for years 2016–2022 was used. Patients who were (1) < 18 years old, (2) received posterior arthrodesis for idiopathic scoliosis correction, and (3) had recorded preoperative laboratory tests were included in this study. Preoperative bloodwork values of interest were hematocrit, albumin, platelet count, international normalized ratio (INR), and partial thromboplastin time (PTT). Descriptive statistics were used to characterize patient demographics, surgical metrics, and preoperative laboratory values. Rate of allogeneic transfusion was stratified by laboratory value cut-offs and compared using G-test. Standardized cut-offs were used to define abnormal values. A multivariable logistic regression analysis was used to assess the impact of abnormal bloodwork values on rate of allogeneic transfusion. There were 6057 patients included in this study. The mean age was 13.8 years. There were 13.6% that received allogeneic transfusion. The mean transfusion volume was 62.1 mL. Patients with abnormal preoperative INR (13.1% vs. 20.0%; p < 0.001), hematocrit < 35 (12.4% vs. 25.9%; p < 0.001), and albumin < 3.4 (13.4% vs. 25.8%; p = 0.004) had higher rates of transfusion. In the multivariable logistic regression analysis, INR > 1.2 (OR 1.4, p = 0.023) and hematocrit < 35 (OR 2.3, p < 0.001) were significantly associated with higher odds of allogeneic transfusion. Preoperative INR and hematocrit values can aid in risk stratification for allogeneic transfusion requirements. PTT and platelet count did not significantly impact perioperative transfusion rates or volumes.

Background Current guidelines and expert consensus recommend lifelong single antiplatelet therapy for patients undergoing transcatheter aortic valve replacement who have no indication for anticoagulation or dual antiplatelet therapy. However, there is no direct evidence from randomized controlled trials supporting this practice. Furthermore, the optimal duration of antiplatelet therapy in this population has not been adequately investigated. Methods and Results CREATE (A Multicenter Randomized Controlled Study to Evaluate Cessation of Antithrombotic Therapy at 1 Year in TAVR Patients–The CREATE Study) is a prospective, multicenter, open‐label, randomized controlled trial for patients who have undergone successful transcatheter aortic valve replacement and have no indication for long‐term oral anticoagulation or antiplatelet therapy. Eligible patients are free from major bleeding and ischemic events for 1 year postprocedure before being randomized 1:1 to single antiplatelet therapy (control group) or no antiplatelet therapy (experimental group). The primary efficacy end point is the incidence of bleeding events, defined by the VARC‐3 (Valve Academic Research Consortium‐3) criteria, at 1‐year postrandomization. The primary safety end point is a composite of cardiac death, myocardial infarction, and ischemic stroke at 1 year. The trial is powered for both superiority in efficiency and noninferiority in safety. Accordingly, a total of 3380 patients will be enrolled. Conclusions The CREATE trial aims to assess if stopping antiplatelet therapy at 1‐year after transcatheter aortic valve replacement reduces bleeding risk without increasing ischemic events in patients not requiring chronic antithrombotic therapy. Registration URL: https://www.chictr.org.cn ; Unique identifier: ChiCTR2400087454.

Background Pituitary neuroendocrine tumors (PitNETs) that progress following surgery and radiotherapy are in need of additional treatment options. Responses to immune checkpoint inhibitors (ICIs) have been described; however, the feasibility of ICI therapy and biomarkers of response have not been formally assessed. Methods We performed a single center, prospective, phase 2 trial investigating the activity of ipilimumab and nivolumab in PitNET patients. The primary endpoint was objective response using the iRANO response criteria. We then explored genetic biomarkers of response to ICI in 13 patients with PitNETs, who were treated with ICI, on or outside of the trial. Results 10 patients with a PitNET were enrolled, including 5 corticotroph, 4 lactotroph, and 1 somatotroph tumor; of which 9/10 (4 metastatic and 5 non-metastatic) patients were evaluable for the primary endpoint. While no objective responses were observed, tumor shrinkage was seen in 2/9 patients. In a biomarker discovery cohort, comprised of 7 tumors treated on trial and 6 tumors treated off trial, temozolomide hypermutation and mismatch repair deficiency (MMRd) were associated with immunological response. In 3 tumors sequenced pre- and post-ICI treatment, we identified evidence of immunoediting, characterized by loss of MMRd and/or a decrease in tumor mutational burden. Conclusion This study demonstrates the safety and feasibility of ICI treatment in aggressive PitNETs. We also identified MMRd and temozolomide hypermutation as potential biomarkers of response to ICI. Overall, our data suggests that ICIs might provide an additional treatment option for PitNET; this should be evaluated more broadly in future studies.

Purpose High‐quality fat suppression is essential for various MRI applications. In musculoskeletal imaging, poor fat suppression caused by severe B0 inhomogeneity can obscure important lesions, potentially leading to inaccurate diagnoses. This problem is particularly exacerbated in off‐isocenter imaging, where conventional shimming using second‐order spherical harmonic shim coils often proves inadequate due to elevated B0 inhomogeneity. To address this challenge, we configured a simple local shim insert to provide additional localized B0 shimming for off‐isocenter regions, offering a practical hardware solution. Methods We designed and constructed a seven‐channel shim coil and evaluated its performance in comparison to conventional second‐order spherical harmonic shimming within a targeted volume near the scanner bore. The coil was tested with both phantom and in vivo studies using a clinical 3 T MRI scanner. Results The improved B0 homogeneity achieved with the local shim coil significantly enhanced fat saturation (fat–sat) uniformity across the imaged volumes. This improvement was particularly beneficial for areas far from the scanner isocenter, where B0 inhomogeneity is most severe. Our results indicated a 40% reduction in RMS error of the B0 field for elbow imaging and 35% for hand imaging, highlighting substantial improvements in B0 field homogeneity. Additionally, the image quality score increased by 1 point for both hand and elbow images, reflecting enhanced fat–sat quality. Conclusion The simple local shim insert we configured improves fat–sat capability in both hand and elbow imaging. It offers the potential for improving off‐isocenter musculoskeletal MRI.

Background While alcohol is known to sensitize the pancreas to acute injury, the role of short‐term episodic drinking in regular drinkers is unknown. Methods We conducted a case‐crossover study to (1) determine the hazardous period of drinking prior to a first episode of acute pancreatitis (FAP) or recurrent acute pancreatitis (RAP) and (2) evaluate the dose–response association between short‐term drinking and FAP/RAP. Patients hospitalized for FAP/RAP with an AUDIT‐C score of ≥3 were enrolled. Recent and lifetime drinking history were collected through interviews. Drinking prior to the index pancreatitis attack was compared to that of an asymptomatic control period. Conditional logistic regression quantified the association of heavy drinking and FAP/RAP. Results Of 141 patients who completed a short‐term drinking questionnaire, 77 had RAP, and 64 experienced FAP. We found that both FAP and RAP patients drank at moderate‐to‐heavy levels regularly, with modest day‐to‐day variation (intraclass correlation of drinks/day 67%–82%). Alcohol consumption increased 2 days preceding the onset of the index pancreatitis attack as compared to the week prior. Stratifying by prior AP history, heavy drinking in the hazard period was associated with RAP (OR = 3.79, 95% confidence interval [CI] 1.57–9.12). Each drink was associated with 1.22‐fold (95%CI 1.10–1.35) increased odds of RAP. Short‐term heavy drinking was not associated with a FAP (OR = 1.06, 95%CI 0.43–2.57). Conclusion In summary, we found that patients with a prior history of AP face a higher risk of RAP due to excess drinking. Drinking intensity did not increase prior to a FAP, which may have been triggered by other cofactors warranting further examination.