tbuckley/cabot-search huggingface dataset:
CAF-macrophage crosstalk in tumour microenvironments governs the response to immune checkpoint blockade in gastric cancer peritoneal metastases
Authors: Yuanfang Li, Yongqiang Zheng, Jiaqian Huang, Run-Cong Nie, Qi-Nian Wu, Zhijun Zuo, Shuqiang Yuan, Kai Yu, Cheng-Cai Liang, Yi-Qian Pan, Bai-Wei Zhao, Yuhong Xu, Qihua Zhang, Yashang Zheng, Junquan Chen, Zhao-Lei Zeng, Wei Wei, Ze-Xian Liu, Rui-Hua Xu, Hui-Yan Luo
Journal: Gut (2024)

Background Peritoneal metastasis is the most common metastasis pattern of gastric cancer. Patients with gastric cancer peritoneal metastasis (GCPM) have a poor prognosis and respond poorly to conventional treatments. Recently, immune checkpoint blockade (ICB) has demonstrated favourable efficacy in the treatment of GCPM. Stratification of best responders and elucidation of resistance mechanisms of ICB therapies are highly important and remain major clinical challenges. Design We performed a phase II trial involving patients with GCPM treated with ICB (sintilimab) combined with chemotherapy. The samples of primary tumours, GCPMs and peripheral blood from patients were collected for single-cell sequencing to comprehensively interpret the tumour microenvironment of GCPM and its impacts on immunotherapy efficacy. Results The GCPM ecosystem coordinates a unique immunosuppressive pattern distinct from that of primary GC, which is dominated by a stroma-myeloid niche composed of SPP1+tumour-associated macrophages (TAMs) and Thrombospondin 2 (THBS2)+matrix cancer-associated fibroblasts (mCAFs). Consequently, this stroma-myeloid crosstalk is the major mediator of ICB resistance in patients with GCPM. Mechanistically, the accumulated THBS2+mCAFs facilitate the recruitment of peritoneum-specific tissue-resident macrophages and their transformation into SPP1+TAMs via the complement C3 and its receptor C3a receptor 1 (C3AR1), thereby forming a protumoral stroma-myeloid niche. Blocking the C3-C3AR1 axis disrupts the stroma-myeloid crosstalk and thereby significantly improves the benefits of ICB in in vivo models. Conclusion Our findings provide a new molecular portrait of cell compositions associated with ICB resistance in patients with GCPM and aid in the prioritisation of therapeutic candidates to potentiate immunotherapy.
Correlation of safety and efficacy of atezolizumab therapy across indications
Authors: Gonzalo Durán-Pacheco, G Scott Chandler, Vidya Maiya, Mark A Socinski, Guru Sonpavde, Javier Puente, Laurent Essioux, Corey Carter, Jose Vicente Cardona, Rajat Mohindra, Jarushka Naidoo
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background The association between safety and efficacy of immune checkpoint inhibitors is known, but the correlation between severity and impact of specific organ involvement by immune-related adverse events (irAE) and cancer outcomes is poorly understood. Most irAEs are mild-to-moderate but severe irAEs may pose clinical management challenges and affect patient outcomes. Methods We assessed the association between irAE grade (G) and specific organ involvement with overall survival (OS) in 9,521 patients across 14 studies involving atezolizumab as mono (IO) or with chemo/targeted (C-IO) therapy as compared with chemo/targeted therapy (C) in advanced non-small cell lung, small-cell lung, renal cell, urothelial, and triple-negative breast cancers. We used a mixed-effect Cox proportional hazard model for time-varying covariates to address immortal-time bias; adjusted for baseline factors associated with irAEs and OS to control for confounding bias; and focused on five common irAEs (dermatologic, thyroid dysfunction, hepatitis, pneumonitis, and colitis) to avoid low statistical power for rare events. Results For patients treated with IO or C-IO, G1-2 irAEs were associated with improved OS (HR=0.65, p&lt;0.01) and G3-4 irAEs showed a slight increased risk of death (HR=1.18, p=0.10) versus patients without irAEs. By specific irAE, G1-2 cutaneous irAEs, thyroid dysfunction, or pneumonitis were associated with improved OS (p&lt;0.05), while G3-4 pneumonitis and colitis were associated with worse OS (p&lt;0.01). There was no association between hepatitis and OS by any grade. Findings were consistent across indications. Conclusions This analysis demonstrates a correlation between irAEs and improved OS with atezolizumab by severity grade and the most common irAEs by organ involvement. Low-grade irAEs are significantly associated with improved OS, while specific high-grade irAEs are associated with poorer OS, underscoring the importance of early recognition and management of toxicity to optimize benefit/risk balance.
Differences in the pathological, transcriptomic, and prognostic implications of lymphoid structures between primary and metastatic cutaneous melanomas
Authors: Lilit Karapetyan, Aofei Li, Danielle Vargas De Stefano, Hassan M Abushukair, Ayah N Al-Bzour, Andrew Knight, Caroline Layding, Hong Wang, Jin Xu, Jiqiang Yao, Xiaofei Song, Marion Joy, Jonathan Nguyen, Carlos Moran-Segura, Sabrina Bruno, Cindy Sander, Jane Messina, James J Mule, Walter J Storkus, John M Kirkwood
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background While the prognostic role of tertiary lymphoid structures (TLS) has been well studied in solid cancers, the prevalence and impact of immature precursor lymphoid structures known as lymphoid aggregates (LA) remain unresolved in relation to the disease process. In this study, we examined characteristics and the prognostic utility of LA and TLS status in histological samples from patients with melanoma. Methods We assessed The Cancer Genomic Atlas-skin cutaneous melanoma digital slides and melanoma specimens from the University of Pittsburgh for the presence of LA and TLS using H&amp;E staining, multiplex immunofluorescence (mIF) and transcriptomic analyses. Cox proportional hazard regression models were used to assess the prognostic value associated with the presence of lymphoid structures in melanomas. Results A total of 278 evaluable samples were analyzed and split into primary melanomas in skin (N=195) and metastatic melanomas involving skin/subcutaneous/soft tissue sites (N=83). 72% of tumor specimens contained histologically defined LA located in peritumoral (34%), intratumoral (5.6%) or stromal (6.1%) locations, with the remaining samples (54.3%) exhibiting LA in multiple locations. In contrast to LA which tended to form more commonly in primary melanoma samples, TLS with germinal centers predominantly formed in peritumoral (45.2%) or stromal (35.5%) locations in metastatic melanomas (p=0.02), with TLS observed in 11% of all melanoma specimens evaluated. mIF analyses revealed cellular heterogeneity of lymphoid structures, with CD20 + (B) cells present in nodule-shaped and stromal locations where they exhibited a high degree of colocalization with CD4 + and CD8 + T cells. A previously defined 12-chemokine gene expression score was significantly higher in samples with evidence of LA versus none (p&lt;0.001), and samples without LA/TLS were enriched with pigmentation/neural network gene signatures. The presence of LA was significantly associated with tumor-free regional lymph node status (p=0.002). In multivariable analysis, after adjusting for age, sex, sample type, and stage, the presence of LA was associated with improved patient overall survival (OS) (HR=0.52, 95% CI 0.31 to 0.87, p=0.01). Conclusion Melanoma frequently contains LA, which tends to form in diverse locations in the tumor microenvironment in association with improved overall survival and tumor-free regional lymph node status in patients with primary disease.
Abstract 4138794: Risk Factors of Cumulative Limb Amputation in Patients with Thromboangiitis Obliterans (Buerger's Disease): Insights from Nationwide Inpatient Sample
Authors: Shuo Zheng, Yi Yang, Fangqin Wu, Danyang Ling, Ziwei Chen, Zhizhi Hu, Lisha Ai, Guanhua Su, Qi Wang, Wenzhu Li
Journal: Circulation (2024)

Background: Thromboangiitis obliterans (TAO) is a rare, nonatherosclerotic, inflammatory disease that typically onsets in male patients at young age with heavy smoking. TAO commonly affects small and medium-sized arteries in extremities, and up to 1/3 of patients with TAO will experience limb amputation. However, the role of social determinants of health (SDoH) are not well studied in TAO patients with limb amputation in a real-world dataset. Methods: A cross-sectional study was performed in Nationwide Inpatient Sample (NIS) of United States, from calendar year 2016-2021. The diagnosis of diseases was identified by ICD-10-CM codes. Univariable logistic regression analysis was performed to identify characteristics associated with cumulative limb amputation (CLA). Stepwise multivariate logistic regression model was further employed to analyze association between significant characteristics and CLA. Results: In this study, 33.3% (N=432) patients with TAO (N=1297) had CLA. Variables showed significant association with CLA identified by univariable analysis were further included in stepwise multivariate logistic regression model. In the multivariate model, middle-age patients had higher risk of CLA than young patients (OR=1.41, 95% CI=1.00-1.99, p=0.050). Female showed lower CLA risk than male patients (OR=0.53, 95% CI=0.41-0.69, p&lt;0.001). Black patients showed higher CLA risk than White (OR=1.82, 95% CI=1.24-2.68, p=0.002). Compared to Medicare insurance, self-pay (OR=0.51, 95% CI=0.30-0.87, p=0.014) and Private insurance (OR=0.69, 95% CI=0.49-0.97, p=0.035) patients had lower CLA risk. Higher socioeconomic status associated with lower CLA risk, and patients in the 3 rd percentile had significantly lower CLA risk than those in the 1 st percentile (OR=0.68, 95% CI=0.49-0.95, p=0.028). Patients with tobacco smoking showed higher CLA risk (OR=2.11, 95% CI=2.49-3.00, p&lt;0.001). Conclusions: The CLA rate was up to 33.3% among the TAO patients in NIS 2016-2021. SDoH like age, sex, race, insurance type and socioeconomic status showed significant association with CLA risk in TAO patients. Further studies are warranted to explore mechanism, health equity and multidisciplinary care to decrease CLA for patients with TAO.
Abstract 4138792: A Case of Right Coronary Artery Chronic Total Occlusion in a Transplanted Heart: To Stent or Not to Stent?
Authors: Hussein Krayem, Richard Cooke, Nayef Abouzaki, Issa Kutkut
Journal: Circulation (2024)

Background: Cardiac Allograft Vasculopathy (CAV) is commonly seen in transplanted hearts. Due to the absence of innervation, many transplanted patients have no symptoms despite extensive disease. This poses a challenge in deciding when to perform coronary interventions. We present a case of significant CAV on surveillance angiogram that posed a challenge in management. Case: A 67-year-old female presented for her fifth surveillance coronary angiography nine and a half years after her heart transplant. The angiogram revealed ostial right coronary artery (RCA) chronic total occlusion (CTO) with left-to-right collaterals as well as diffuse irregularities in the left anterior descending (LAD) and left circumflex arteries. The patient was asymptomatic and two years prior to that, her angiogram revealed no significant disease. Biopsies for the past nine years showed no evidence of allograft rejection. She was subsequently referred for coronary intervention. Due to concern of CTO being a sign of rapidly progressing CAV, it was decided to undergo revascularization of the RCA. Antegrade approach was performed with guidance from contralateral injections. Three overlapping drug-eluting stents were deployed proximally-distally using intravascular ultrasound guidance. Surveillance angiography nine months later showed patent RCA stents with no significant disease otherwise. Eighteen months later, angiography demonstrated CTO of the mid LAD and patent RCA stents with mild in-stent restenosis in the most distal RCA stent. The patient remained asymptomatic. Discussion: CAV develops in fifty percent of transplanted hearts within 10 years and requires close surveillance. In this case, revascularization of the RCA CTO resulted in maintaining graft function for at least two additional years as the development of LAD CTO may have resulted in graft failure had the RCA CTO not been intervened upon. CTO revascularization in CAV has the potential to prolong graft viability and delay the need for re-transplantation. Further studies related to CTO revascularization, especially in asymptomatic transplanted patients, are needed to understand the impact on morbidity and mortality in this patient population.
Abstract 4138782: A Meta-Analysis Comparing Same-Day Discharge to Later-Day Discharge in Transcatheter Aortic Valve Replacement
Authors: Hritvik Jain, Jyoti Jain, Aman Goyal, Amanpreet Wasir, Mushood Ahmed, Nandan Patel, Ashish Yadav, Janhvi Shah, Aryan Mehta, Siddhant Passey
Journal: Circulation (2024)

Background: One of the benefits of transcatheter aortic valve replacement (TAVR) over surgical aortic valve replacement (SAVR) is the possibility of same-day discharge, allowing for early mobilization and reduced total hospital stay. However, there is limited evidence comparing same-day discharge to later-day post-TAVR discharge. This meta-analysis aimed to compare the outcomes of same-day and later-day discharge post-TAVR in patients with aortic stenosis. Methods: A systematic bibliographic search was conducted using electronic databases, including PubMed, Embase, and the Cochrane Library, from inception to May 23, 2024. We pooled the risk ratios (RR) with 95% confidence intervals (CI) using the inverse-variance random-effects model. Statistical significance was set at p &lt;0.05. Results: Six studies were included with 71,550 patients undergoing TAVR (2215: same-day discharge; 69335: later-day discharge). The mean age for the same-day and later-day discharge groups was 77.3 ± 8.3 and 78.3 ± 8.5, respectively. Same-day discharge for patients post-TAVR was associated with a higher risk of 30-day stroke [RR: 1.93; 95% CI: 1.14, 3.27] and 30-day major vascular complications [RR: 1.82; 95% CI: 1.02, 3.24] as compared to later-day discharge post-TAVR. However, no significant differences in the risks of 30-day mortality [RR: 0.30; 95% CI: 0.06, 1.57], 30-day readmission [RR: 0.93; 95% CI: 0.66, 1.32], 30-day major bleeding [RR: 0.86; 95% CI: 0.52, 1.42], 30-day new permanent pacemaker [RR: 1.00; 95% CI: 0.81, 1.22], 30-day acute kidney injury [RR: 1.04; 95% CI: 0.73, 1.49], and 30-day valve reintervention [RR: 5.77; 95% CI: 0.60, 55.39] were noted between the two groups. Conclusion: This meta-analysis concluded that same-day discharge post-TAVR is associated with a higher risk of 30-day stroke and 30-day major vascular complications than later-day discharge after TAVR. Same-day discharge was comparable to later-day discharge post-TAVR in terms of 30-day mortality, 30-day readmission, 30-day major bleeding, 30-day new permanent pacemaker, 30-day acute kidney injury, and 30-day valve reintervention. This study underscores the possibility of same-day discharge after uncomplicated TAVR in select patients. Further randomized studies are required to evaluate the safety and feasibility of the same-day discharge protocols.
Abstract 4138745: Blockade of Mineralocorticoid Receptor by Esaxerenone Improves Insulin Sensitivity in Obese Mice
Authors: Oyunbileg Bavuu, Masataka Sata, Daiju Fukuda
Journal: Circulation (2024)

Background: Aldosterone regulates blood pressure and electrolyte balance. However, overactivation of the mineralocorticoid receptor (MR) and elevated aldosterone levels are implicated in the pathogenesis of cardiometabolic disorders, though the underlying mechanisms are not fully understood. In this study, we investigated whether a novel, non-steroidal selective MR blocker, esaxerenone, ameliorates the development of metabolic disorders in obese mice models and examined the underlying mechanism. Methods: Esaxerenone (3 mg/kg/day) was orally administered to high-fat diet (HFD)-fed C57BL/6J or normal chow-fed db/db mice. Metabolic parameters, tissue morphology, and effects of esaxerenone on insulin sensitivity were assessed. Gene expression and insulin signaling, determined by Akt phosphorylation, were examined using quantitative RT-PCR and western blotting, respectively. In in-vitro experiments, insulin targets cell lines such as 3T3-L1 adipocytes, HepG2 cells, and C2C12 myotubes were used. Insulin-responsive cells were treated with 10 nM or 100 nM esaxerenone or eplerenone for 30 minutes before 4-hour 1000 nM aldosterone stimulation. Insulin signaling was assessed 15 minutes after stimulation with 17 nM insulin. Results: Esaxerenone improved insulin sensitivity (P&lt;0.05) without altering metabolic parameters in HFD-induced obese and db/db mice. Esaxerenone suppressed fat accumulation, adipocyte size, and liver lipid droplets compared with the vehicle-treated group (P&lt;0.01). In adipose tissue, esaxerenone reduced macrophage infiltration (P&lt;0.01) and the expression of inflammatory molecules (P&lt;0.05). In in-vitro experiments, aldosterone significantly decreased the expression levels of PPARγ and adiponectin in 3T3-L1 adipocytes. Moreover, aldosterone attenuated insulin-induced Akt phosphorylation in 3T3-L1 adipocytes, HepG2 cells, and C2C12 myotubes in a dose-dependent manner (P&lt;0.01). Pretreatment with esaxerenone reversed the effect of aldosterone, whereas eplerenone, an MR antagonist, did not show a similar effect at the same dose. Conclusion: Inhibition of MR by esaxerenone improved insulin sensitivity in HFD-induced obese and genetically diabetic mice. The reduction of inflammation and fat accumulation and enhancement of insulin signaling were suggested to be underlying mechanisms. Esaxerenone might be a beneficial therapeutic approach for managing metabolic disorders.
Abstract 4138739: Insulin Resistance as a Marker of Multivessel Coronary Artery Diseases in Patients With Cardiovascular-Kidney-Metabolic Risk: Inshight From Invasive Coronary Angiography
Authors: NAOKI FUJISAWA, Kenichiro Otsuka, Hiroki Yamaura, Akihiro Okamoto, Tomohiro Yamaguchi, Shunsuke Kagawa, Takenobu Shimada, Atsushi Shibata, Asahiro Ito, Takanori Yamazaki, Daiju Fukuda
Journal: Circulation (2024)

Background: Cardiovascular-Kidney-Metabolic (CKM) syndrome is the concept of a combined diseases, including diabetes and chronic kidney disease (CKD), to stratify patients at cardiovascular risks. However, whether CKM components and insulin resistance differ in risk for coronary artery disease (CAD) severity is unknown. Purpose: This study aimed to investigate the association of distinct CKM risks and insulin resistance with CAD severity. Methods: In this study, we included 849 patients (74% male, 69±10 years of age) who underwent coronary angiography to assess chronic CAD. We assessed CKM risks using following components: (1) BMI ≥23 kg/m 2 , (2) diabetes, (3) hypertension and dyslipidemia, and (4) CKD. According to the number of CKM risk components, patients were categorized into four groups (Group A as having 0 or 1, Group B as 2, Group C as 3, and Group 4 as 4 risks). Insulin resistance was assessed by HOMA-IR and triglyceride-glucose index (TyG index) calculated as Ln (fasting plasma glucose × triglyceride/2). Coronary artery stenosis was categorized into single-vessel or multi-vessel CAD (MVD) per AHA classification. Gensini score was calculated to assess CAD extent. Logistic regression analysis was performed to determine independent predictors of MVD among CKM risk components. Results: MVD was diagnosed in 26.3% (n = 223) patients (mean Gensini score was 58±40 points). Among the four groups, there were significant differences in age, body mass index, hemoglobin A1c levels, TyG index, HOMA-IR, and Gensini score. Compared with Group A as reference, Group C (odds ratio [OR], 1.58; 95% confidence interval [CI] 1.03–2.42) or Group D (OR, 1.75; 95%CI, 1.06–2.89) but not Group B (OR, 1.09; 95%CI, 0.70–1.71) had higher risk for MVD (Figure). In a logistic regression model adjusting for age, male, smoker, and CRP ≥2 mg/dL, independent predictor of MVD was diabetes (OR, 2.15; 95%CI,1.55–2.99; p &lt; 0.001; model 1 in Table). In addition, when adjusting for age, male, smoker, and CRP ≥2 mg/dL, HOMA-IR&gt;2.5 was an independent predictor of MVD (model 2 in Table). Similarly, TyG index, an alternative marker of insulin resistance, remained as an independent predictor of MVD (model 3 in Table). Conclusions: In chronic CAD patients who underwent coronary angiography, subgroups stratified by the CKM risk components exhibit distinctly different insulin resistance, CAD severity and risk for MVD. Insulin resistance and diabetes were independent risks for MVD in this population.
Abstract 4138701: Phenotypic clustering of HFpEF using cardiac magnetic resonance imaging
Authors: Mariana Garcia-Arango, Yimin Chen, Aditya Sahai, Wanxin Tu, Ahmed El Shaer, Aria Kenarsary, Arthur Gallegos, Kathryn Jones, Anas Abed, Abdul Wahab Arif, Yeonhee Park, Farhan Raza
Journal: Circulation (2024)

Background: Improved understanding of the high-risk features associated with HFpEF may facilitate risk stratification. Cardiac magnetic resonance (CMR)-based strain and structural data can define detailed myocardial structure, which can be leveraged to define heterogenous HFpEF phenotypes. This study used phenotypic clustering integrating CMR-based strain and structural data to identify a high-risk HFpEF phenotype. Methods: Retrospective analyses of 48 HFpEF participants, who underwent cardiac MRI and invasive cardiopulmonary exercise testing (median time between the two studies=40 days), was performed. We conducted unsupervised and unbiased K-means clustering analyses using CMR-based strain and myocardial structural variables. We associated two identified clusters with mortality using Cox proportional hazards modeling and constructed Kaplan-Meier survival curves. A p-value was considered significant if &lt; 0.05. Results: We identified a low (n=32) and high-risk (n=16) cluster. Patients in the identified clusters had similar ages and comorbidities. The high-risk cluster had more male participants and hemodynamically had a higher exercise mPAP/CO and PAWP/CO slope, which are metrics of pulmonary vascular disease. The high-risk cluster displayed greater LV mass, worse biventricular longitudinal strain, decreased right ventricular ejection fraction, and greater interventricular septal angle (all P&lt;0.05) as characterized by CMR as compared to the low-risk cluster (Table 1, Figure 1A). Mortality for the high-risk cluster was 5.43 times that for the low-risk cluster at 12 months (95% CI 1.69-17.42, Figure 1B). Conclusions: Using clustering analyses with CMR strain and structural variables, we identified a high-risk HFpEF phenotype with increased LV mass, reduced biventricular strain, and reduced RV ejection fraction.