Citations

Abstract Background: In breast cancer, the spatial relationship between immune and tumor cells is increasingly recognized as critical in determining the efficacy of neoadjuvant therapy (NAT). This study investigated how the distribution of immune cells, particularly CD8+ T cells, relative to tumor cells affects treatment outcomes. Methods: Biopsies from 104 breast cancer patients were examined, both pre- and post-NAT, using multiplex immunohistochemistry (mIHC). This study focused on the density and distribution of CD8+ T cells, CD68+ macrophages, FoxP3+ regulatory T cells, and other immune markers. Results: The spatial proximity of CD8+ T cells within 20 µm of cancer cells (N20-CD8+T) was strongly correlated with improved clinical outcomes across diverse tumor subtypes and NAT regimens. A significant post-NAT decrease in CD4+, CD68+, and FoxP3+ cells highlights notable shifts in the tumor immune landscape. A noteworthy finding was the positive correlation between CXCL9 expression and N20-CD8+T cells, suggesting a mechanism for immune cell recruitment and interaction within the tumor microenvironment. These results highlight the complex interplay among NAT, immune cell modifications, and patient outcomes. Conclusions: This study revealed that the proximity of N20-CD8+ T cells to tumor cells is consistently associated with favorable NAT outcomes, transcending tumor subtypes, and treatment differences. This highlights the potential of immune cell dynamics, especially CD8+ T cells, as predictive biomarkers for therapeutic responses in breast cancer, underscoring their vital role in tumor immunity.

Portal hypertension (PHTN) is a severe complication of liver cirrhosis and is associated with intrahepatic sinusoidal remodeling induced by sinusoidal resistance and angiogenesis. Collagen type IV (COL4), a major component of basement membrane, forms in liver sinusoids upon chronic liver injury. However, the role, cellular source, and expression regulation of COL4 in liver diseases are unknown. Here, we examined how COL4 is produced and how it regulates sinusoidal remodeling in fibrosis and PHTN. Human cirrhotic liver sample RNA sequencing showed increased COL4 expression, which was further verified via immunofluorescence staining. Single-cell RNA sequencing identified liver sinusoidal endothelial cells (LSECs) as the predominant source of COL4 upregulation in mouse fibrotic liver. In addition, COL4 was upregulated in a TNF-α/NF-κB–dependent manner through an epigenetic mechanism in LSECs in vitro. Indeed, by utilizing a CRISPRi-dCas9-KRAB epigenome-editing approach, epigenetic repression of the enhancer-promoter interaction showed silencing of COL4 gene expression. LSEC-specific COL4 gene mutation or repression in vivo abrogated sinusoidal resistance and angiogenesis, which thereby alleviated sinusoidal remodeling and PHTN. Our findings reveal that LSECs promote sinusoidal remodeling and PHTN during liver fibrosis through COL4 deposition.

Background . Despite the potential of palliative care (PC) to enhance the quality of life for patients with advanced dementia, there is limited knowledge of its inpatient utilization patterns. This study investigated inpatient PC consultation utilization patterns and evaluated its impact on hospital length of stay (LOS) and medical costs among older patients diagnosed with Alzheimer’s Disease and Related Dementia who were at a high risk of mortality (ADRD-HRM). Methods . Using the 2016-2019 National Inpatient Sample database, we conducted multivariable logistic regression analyses to identify individual and hospital characteristics influencing PC consultation utilization. We subsequently performed generalized linear models to estimate LOS (using Poisson distribution) and hospital charges (via log-transformation). Results . Our sample encompassed 965,644 hospital discharges (weighted n = 4,828,219) of patients aged 65 years and above with ADRD-HRM. Among them, 14.6% received inpatient PC. There was a notable uptrend in PC consultation utilization from 13.3% in 2016 to 16.3% in 2019 ( p trend<.001). Factors positively influencing and associated with PC utilization included patients that are older, non-Hispanic White, with higher income, receiving care from teaching hospitals, and facilitated with greater bed capacity (all P < .05). Although patients who received PC were more likely to have 3.0% longer LOS ( P < .001), they had 19.2% lower hospital charges ( P < .001). Conclusions . PC substantially reduced hospital expenditures for older patients with ADRD-HRM, but the prevalence remained low at 14.6% in the study period. Future studies should explore the unmet needs of patients with lower sociodemographic status and those in rural hospitals to further increase their PC consultation utilization.

Abstract Background: Nutritional and inflammatory factors collected in routine cancer labs, neutrophil percentage to albumin ratio (NPAR), neutrophil lymphocyte ratio (NLR), monocyte lymphocyte ratio (MLR), and platelet lymphocyte ratio (PLR), have been shown feasible in identification of patients at risk of increased treatment complications, decreased cognition, anxiety and depression, and increased mortality. These have proven sensitive to multiple cancer types and stages, though little is known about causal pathways. The Vitamin/Mineral and Inflammatory Correlations To Understand Chronic Stress in the U.S. (The VICTUS Study) sought to elucidate a relationship between diet and food insecurity within these panels. Methods: Using NHANES 2017/2018 surveys, adults &gt; 18 years without renal or hepatic disorders, pregnancy, alcohol, or supplement use were included. NPAR, NLR, MLR, and PLR were categorized as quartiles and compared to demographic, food security, plasma micronutrient statuses [vitamins A, B9, C, D, E, calcium (Ca), ferritin (Fe), phosphorus (P), potassium (K), sodium (Na)], and smoking, activity level, and sun exposure, using chi-square and ANOVA. ANOVA models compared food security and poverty to NPAR, NLR, MLR, and PLR means. Results: From 3,317 participants, 50.2% were male, 54.3% non-Hispanic White, 33.7%, food insecure, 51.1% food stamp recipients, 27.7% smokers, with a mean age of 42.5 (SD 0.44), poverty to income ratio 2.79 (SD 0.08), CRP 3.90 (SD 0.18), NPAR 14.1 (SD 0.14), NLR 2.07 (SD 0.04), MLR 0.28 (SD 0.003), and PLR 118.7 (SD 1.61). CRP was found to be statistically significantly associated with all biomarker ratios (p &lt; 0.018). Significant micronutrient biomarker-inflammatory biomarker associations were identified in Fe [NPAR, MLR, PLR (p &lt; 0.001)], P [NPAR, NLR, MLR, PLR (p &lt; 0.033)], C [NPAR, NLR (p &lt; 0.008)], E [MLR, PLR (p &lt; 0.016)], K [NPAR, NLR, MLR, PLR (p &lt; 0.015)], Ca [NPAR, PLR (p &lt; 0.04)], A [NPAR (p &lt; 0.023)] and D [NLR (p &lt; 0.035)]. Significant micronutrient intake-inflammatory biomarker associations were detected in vitamin A [NPAR, PLR (p &lt; 0.013)], lycopene [NLR, PLR (p &lt; 0.035)], and B12 [NLR, PLR (p &lt; 0.031)]. Age [NPAR, NLR, MLR, PLR (p &lt; 0.001)], gender [NPAR, MLR, PLR (p &lt; 0.001)], ethnicity [NPAR, NLR, MLR (p &lt; 0.006)], and sedentariness [MLR, PLR (p &lt; 0.039)] were also associated with inflammatory markers. Poverty was significantly associated with NPAR, NLR, MLR, and CRP (p &lt; 0.018). Food insecurity was significantly associated with NPAR (p &lt; 0.001) and CRP (p &lt; 0.001). Discussion: Food insecurity and poverty were significantly associated with NPAR, a ratio implicated in overall poorer cancer health outcomes. Multiple inadequate micronutrient intakes and plasma biomarkers were associated with inflammatory panels, though neither nutritional biomarker nor food insecurity statuses and their contributions to inflammatory processes are routinely surveilled within cancer disease and treatment. Citation Format: Jennifer Crook, Eunkyung Lee, Rui Xie, Opeyemi Bolajoko, Victoria Loerzel. Nutritional mediators of inflammation: A cause for increased surveillance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2171.

Abstract Background: It is a common practice to monitor trastuzumab-related cardiac toxicity (TRCT) using left ventricular ejection fraction (LVEF) in patients who receive trastuzumab-containing therapy for human epidermal growth factor receptor 2 (HER2)-positive cancers. However, this monitoring approach does not appear cost effective in patients with HER2-positive gastrointestinal (GI) cancers given poor overall survival (OS). Here, we aim to examine the incidence of clinically significant TRCT in this target population. Methods: This is a retrospective cohort study of patients with advanced HER2-positive GI cancers who received trastuzumab-containing therapies (trastuzumab +/- pertuzumab, chemotherapy +/- immunotherapy + trastuzumab, trastuzumab deruxtecan) between 2011 and 2023. HER2 status was determined by immunohistochemistry, fluorescent in situ hybridization, and/or next generation sequencing. LVEF was estimated by serial transthoracic echocardiograms (TTE). Continuous variables were summarized as median and interquartile range (IQR). Paired Wilcoxon signed rank test was used to compare serial LVEF. OS was estimated using Kaplan-Meier method. Results: A total of 243 patients were included in this study with a median age of 64 (IQR: 55-70) years. 139 (57%) patients had esophageal or GEJ adenocarcinoma; 45 (19%) patients had gastric cancer; 37 (15%) patients had colorectal cancer; and the rest had other GI cancers. Median follow-up time was 18.6 (IQR: 9.2-36) months. Median OS from cancer diagnosis and the first dose of trastuzumab-containing therapy were 24.1 (95%CI: 20.2-30.2) and 11.7 (95%CI: 10.4-15.6) months, respectively. Patients received a median of 13 cycles of trastuzumab-containing therapy for a median duration of 4.1 (IQR: 1.4-10.1) months. The median number of TTE each patient had throughout therapy was 2 (IQR: 1-4). Median baseline LVEF was 61% (IQR: 56-65%) which was significantly higher (p&lt;0.001) than the median lowest LVEF of 58% (IQR: 53-62%) during therapy, but not different (p=0.14) from the most recent median LVEF of 60% (IQR: 56-64%) after discontinuation of trastuzumab. Among 176 patients with serial LVEF data, 16 (9%) had &gt; 10% LVEF drop; 7 (44%) of these 16 patients had LVEF recovery. None of the cardiovascular risk factors prior to trastuzumab treatment including hypertension, diabetes, hyperlipidemia, peripheral arterial disease, coronary artery disease, and stroke were significantly associated with the development of TRCT. Conclusion: The incidence of clinically significant LVEF drop appears low in patients with advanced GI cancers as post-treatment LVEF recovery to baseline was observed at the population level. The value of using TTE to monitor TRCT in these patients with short OS should be further assessed in the perspective of cost effectiveness. Citation Format: Samual R. Kosydar, Matteo Castrichini, Mojun Zhu, Hao Xie. The value of routine trastuzumab-related cardiac toxicity monitoring in gastrointestinal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6298.

Abstract Background: Benefit from single-agent immune checkpoint inhibitor has been observed in 5-10% of the patients with microsatellite stable (MSS) gastrointestinal (GI) cancers. However, a reliable predictive marker to immune checkpoint inhibitor has not been discovered in this patient population. We sought to assess the incidence of mismatch repair (MMR) gene alterations and their association with tumor mutational burden (TMB) in MSS GI cancers. Methods: This is a retrospective cohort study of patients with advanced GI cancer who had molecular profiling of the tumor using either Guardant360 blood-based or Tempus tissue next generation sequencing (NGS) platforms between 2020 and 2023. We assessed four MMR genes including MLH1, MSH2, MSH6 and PMS2 for alterations. Continuous variables were summarized as median and interquartile range (IQR) and compared using Mann-Whitney test. Categorical variables were summarized as counts and proportions and compared using Fisher’s exact test. Results: A total of 2920 patients with Guardant360 were included with a median age of 65 (IQR: 56-73) years. 870 (30%) patients had pancreas cancer; 846 (29%) patients had colorectal cancer; 688 (24%) patients had biliary tract cancers; and the rest had other GI cancers. Among patients evaluable for microsatellite instability (MSI) status, 58 patients (2%) had MSI-high GI cancers, 31 (53%) of whom had MMR gene alterations. 2445 (98%) patients had MSS GI cancers, 130 (5.3%) of whom had MMR gene alterations. Patients with MSS GI cancers bearing MMR gene alterations had a median age of 70 (IQR: 62-75) years, significantly older than those without MMR gene alterations (p&lt;0.001). In addition, patients with MMR gene alterations had significantly higher median blood TMB of 11 (IQR: 7.4-16) mut/Mb compared to 7.7 (IQR: 4.8-11) mut/Mb in patients without MMR gene alterations. In MSS GI cancers, MMR gene alterations are more commonly associated with the presence of alterations in APC (p=0.03), TP53 (p=0.01), CTNNB1 (p&lt;0.001) and SMAD4 (p=0.01). 1453 patients with GI cancer and Tempus tissue NGS data were included as a validation cohort. They had comparable demographics with the Guardant360 cohort. 14 (1.6%) of 896 patients with MSS GI cancers had MMR gene alterations, significantly fewer (p&lt;0.001) than those found in the Guardant360 cohort. Patients with MMR gene alterations and wild type POLE had significantly higher (p=0.001) median TMB of 9.8 (IQR: 4.8-14) mut/Mb compared to 4.7 (IQR: 3.2-6.3) mut/Mb in patients without MMR gene alterations. Conclusions: MMR gene alterations can be identified by clinical NGS platforms in a small proportion of patients with MSS GI cancers. They are associated with elevated TMB, which may suggest a hypermutated profile serving as a basis for potential role of immune checkpoint inhibitor in MSS GI cancers. Citation Format: Conor D. O'Donnell, Mojun Zhu, Hao Xie. The association of mismatch repair gene alterations with elevated tumor mutational burden in microsatellite stable gastrointestinal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6469.

Abstract Background: Though widely recognized in cancer pathogenesis, inflammatory pathways of allostatic load remain vaguely understood. A partial explanation may be found within the realm of food insecurity and micronutrient inadequacies, defined as nutrient intake less than the estimated average requirement. Many micronutrient deficiencies contribute to pro-inflammatory and immunocompromised milieus. Inadequacies, however, which may present without overt symptoms, are not currently well studied. The purpose of this study was to examine relationships between known inflammation-associated nutritional biomarkers of micronutrients and biomarker variables of allostatic load. Methods: Using NHANES 2017/2018 surveys, adults &gt; 18 years without renal or hepatic disorders, pregnancy, alcohol, or supplement use were included. Plasma levels of vitamins A, B9, C, D, E, calcium (Ca), ferritin (Fe), phosphorus (P), potassium (K) and sodium (Na) were grouped into deficiency, inadequate and adequate groups based on clinically recognized standards. Micronutrient prevalence was assessed and variables of allostatic load [blood pressure, glucose, albumin, creatinine, red cell distribution width (RDW), high density lipoprotein (HDL), low density lipoprotein (LDL), cholesterol and triglycerides] were analyzed for mean differences among micronutrient groups, food security and poverty. Results: From 3,317 unique participants, inadequacy prevalence percentages were quantified as: vitamins A (0.4%), B9 (12.2%), C (58.3%), D (39.6%), E (21.0%), P (11.4%), K (3.4%), Na (24.2%), Ca (59.5%), and Fe (37.4%) [p &lt; 0.001]. Statistically significant differences were identified in age [C, D, E, Ca, Fe, P, Na (p &lt; 0.004)], race/ethnicity [B9, C, D (p &lt; 0.006)], gender [C, E, Ca, Fe, P, K, Na (p &lt; 0.018)], poverty [A, B9, C, D, E, Fe, K (p &lt; 0.025)], and food security [B9, C, D, E, P (p &lt; 0.032)]. Associations to allostatic load were discovered in: albumin [A, C, D, Ca, Fe, P, Na (p &lt; 0.025)], glucose [C, E, Fe, P, Na (p &lt; 0.009)], HDL [C, D, E, Fe, P, K (p&lt;0.045)], LDL [E, Ca, Fe, Na (p&lt;0.028)], creatinine [C, D, Ca, Fe (p&lt;0.001)], triglycerides [B9, D, E, Fe (p&lt;0.033)], cholesterol [C, D, E, Ca, Fe, Na (p&lt;0.006)], B/P [C, E, Fe, P, Na (p &lt; 0.035)], and RDW [C, D, Ca, Fe (p &lt; 0.001)]. Poverty was significantly associated with all variables of allostatic load (F = 2.85, p = 0.002). Food security was significantly correlated with albumin (p &lt; 0.001), glucose (p = 0.005) and HDL (p &lt; 0.001). Conclusion: Allostatic load, poverty, and food security were significantly associated with subclinical micronutrient statuses, which may not present with signs of deficiency and are not currently well assessed. Similarly, poverty was significantly associated with all variables of allostatic load, though food security was only identified to be associated with albumin, glucose, and HDL, suggesting that food security may not be currently adequately defined for surveillance. Citation Format: Jennifer M. Crook, Eunkyung Lee, Opeyemi Bolajoko, Rui Xie. Poverty, food insecurity, and nutritional inflammatory mediators of allostatic load [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2198.

Clarkson disease, or monoclonal gammopathy–associated idiopathic systemic capillary leak syndrome (ISCLS), is a rare, relapsing-remitting disorder featuring the abrupt extravasation of fluids and proteins into peripheral tissues, which in turn leads to hypotensive shock, severe hemoconcentration, and hypoalbuminemia. The specific leakage factor(s) and pathways in ISCLS are unknown, and there is no effective treatment for acute flares. Here, we characterize an autonomous vascular endothelial defect in ISCLS that was recapitulated in patient-derived endothelial cells (ECs) in culture and in a mouse model of disease. ISCLS-derived ECs were functionally hyperresponsive to permeability-inducing factors like VEGF and histamine, in part due to increased endothelial nitric oxide synthase (eNOS) activity. eNOS blockade by administration of N (γ)-nitro-l-arginine methyl ester (l-NAME) ameliorated vascular leakage in an SJL/J mouse model of ISCLS induced by histamine or VEGF challenge. eNOS mislocalization and decreased protein phosphatase 2A (PP2A) expression may contribute to eNOS hyperactivation in ISCLS-derived ECs. Our findings provide mechanistic insights into microvascular barrier dysfunction in ISCLS and highlight a potential therapeutic approach.