tbuckley/cabot-search huggingface dataset:
Disparities in diagnosis and access to care in patients with young-onset rectal cancers in northeast Ohio.
Authors: Rohan Patel, Alex Price, Emily Steinhagen-Golbig, Madison Conces, Jennifer Anne Dorth, Jennifer Miller-Ocuin, J. Eva Selfridge, Amr Mohamed, Sakti Chakrabarti, Amit Mahipal, David L Bajor, Lauren E. Henke, Melissa Amy Lumish
Journal: Journal of Clinical Oncology (2024)

e15521 Background: The rising incidence of young-onset colorectal cancers (YO-CRC) in individuals &lt; 50 years old is alarming. Despite the updated USPSTF recommended age for CRC screening ( &lt; 45) in 2021, disparities in receiving proper care for YO-CRC remained largely under addressed. We sought to identify modifiable disparities to be addressed with future interventions for patients with YO-rectal cancer (YO-RC). Methods: We analyzed a cohort of patients with newly diagnosed YO-RC from 2001 to 2023 at a large academic center in Northeast Ohio. Demographic data included sex, race, age, smoking status, and poverty index. A retrospective chart review was completed to assess diagnosis date and time from symptom onset to diagnosis. Access to guideline-concordant care was assessed via clinic visits with specialty providers in medical oncology, radiation oncology, colorectal surgery, genetics, and onco-fertility. Chi-square testing and Cox regression modeling was used for statistical analyses. Results: We identified 83 patients with YO-RC, 52% female (n = 43) and 48% male (n = 40), of which 76% were White (n = 63), 21% Black (n = 17), 2% Hispanic (n = 2), and 1% Asian (n = 1). Median age at diagnosis was 44 years (IQR[39-49]). Non-White (NW) patients had a greater delay from symptom onset to diagnosis compared to White (W) patients, with an average time of 6.9mo vs 1.3mo (p &lt; 0.00001). Colonoscopy completion rates after symptom onset for NW and W patients at 2-months was 11% vs 81% and 33% vs 98% at 4-months (p &lt; 0.0001, respectively). Rate of access to specialty care once diagnosed was not statistically significant for either groups, but there is a lower percentage of all YO-RC patients who accessed onco-fertility (13%, n = 11) or genetics services (46%, n = 38). The median 1-year overall survival was 50% for NW patients vs 85.7% for W patients, which was statically significant on univariate analysis (p = 0.04), but not on multivariate analysis. Conclusions: We found significant disparities for YO-RC from symptom onset to diagnosis with longer delays noted in NW patients. Such delays in diagnosis may lead to higher staging upon presentation and impact survival. Once a diagnosis was made, access to specialty oncology care rates was similar across groups. This study encourages further evaluation and consideration of socioeconomic factors and care access patterns to address disparities in diagnosis, access, and treatment of YO-CRC. [Table: see text]
Robotic versus laparoscopic surgery for middle and low rectal cancer (REAL): Primary outcome of a multicenter randomized controlled trial.
Authors: Jianmin Xu, Weitang Yuan, Taiyuan Li, Bo Tang, Baoqing Jia, Yanbing Zhou, Wei Zhang, Ren Zhao, Cheng Zhang, Longwei Cheng, Xiaoqiao Zhang, Fei Liang, Guodong He, Ye Wei, Qingyang Feng
Journal: Journal of Clinical Oncology (2024)

3617 Background: Robotic surgery for rectal cancer is gaining popularity, but persuasive evidence on long-term oncological outcomes is lacking. This multicenter randomized controlled trial compared robotic and conventional laparoscopic surgery regarding surgical quality and long-term oncological outcomes among patients with middle and low rectal cancer. Previously the short-term outcomes of this trial had been reported that robotic surgery had significantly lower circumferential resection margin positivity rate, lower postoperative complication rate, and better postoperative recovery. Now the long-term oncological outcomes were reported. Methods: This superiority trial was undertaken at 11 hospitals in 8 Chinese provinces. Patients with middle (&gt; 5–10 cm from anal verge) or low (0–5 cm from anal verge) rectal adenocarcinoma, cT1–T3 N0–1 or ycT1–T3 Nx after preoperative radio-/chemoradiotherapy, and no evidence of distant metastasis were enrolled and randomly assigned in a 1:1 ratio to receive robotic or conventional laparoscopic surgery. The 3-year locoregional recurrence rate was the primary outcome and was compared using modified intention-to-treat (mITT) analysis. Secondary outcomes included disease-free survival and overall survival. All time-to-event outcomes were calculated using Kaplan-Meier method with log-rank test. This trial was registered with ClinicalTrials.gov (NCT02817126). Results: Between July 2016 and December 2020, 1240 patients were enrolled, and 1171 were included in the mITT analysis (586 in robotic and 585 in laparoscopic group). The pathological TNM stage of the mITT population was 73 (6.2%) patients with complete response, 346 (29.5%) with stage I, 368 (31.4%) with stage II, 384 (32.8%) with stage III. And the median follow-up time was 43.0 months (interquartile range = 36.7 to 60.0), with 34 (2.9%) patients lost to follow-up. The 3-year locoregional recurrence rate in robotic group (1.5%) was significantly lower than in laparoscopic group (4.0%, log-rank p=0.025, hazard ratio = 0.451, 95% confidence interval = 0.221 to 0.921). Robotic group also had significantly higher 3-year disease-free survival rate (87.3% vs. 83.6%, log-rank p=0.035). No significant difference was observed in 3-year overall survival rate (94.8% vs. 93.1%, log-rank p=0.155). Conclusions: Robotic surgery for middle and low rectal cancer significantly reduced locoregional recurrence and improved disease-free survival, compared with conventional laparoscopic surgery. Clinical trial information: NCT02817126 .
Phase I study of C-CAR031, a GPC3-specific TGFβRIIDN armored autologous CAR-T, in patients with advanced hepatocellular carcinoma (HCC).
Authors: Qi Zhang, Qihan Fu, Wanyue Cao, Hongkan Wang, Xingyuan Xu, Jiaqi Huang, Andy Zou, Judy Zhu, Hui Wan, Yihong Yao, Eric Tu, John Stone, Attilio Bondanza, Benedetto Farsaci, Tingbo Liang
Journal: Journal of Clinical Oncology (2024)

4019 Background: GPC3 is a surface antigen overexpressed in HCC and virtually absent on healthy tissues. Chimeric antigen receptor (CAR) T cells targeting GPC3 offer a promising option for advanced unresectable HCC treatment. C-CAR031 is an autologous GPC3-directed CAR-T armored with dominant negative TGF-b receptor II. Here we report the safety and preliminary efficacy of C-CAR031 in advanced HCC patients (pts). Methods: The first-in-human, open-label dose-escalation trial employs an accelerated titration plus i3+3 design. GPC3+ advanced HCC pts who failed ≥ 1 line systemic treatments received a single i.v. infusion of C-CAR031 post standard lymphodepletion. Primary endpoints are safety and tolerability, others include pharmacokinetics and preliminary efficacy. Adverse events (AEs) were graded by CTCAE 5.0, and cytokine release syndrome (CRS) / immune effector cell-associated neurotoxicity syndrome (ICANS) were assessed per ASTCT 2019 criteria. Objective response was assessed by investigator per RECIST 1.1. Results: As of Jan 5 th , 2024, a total of 24 pts received C-CAR031 infusion at 4 dose levels (DLs). All pts had BCLC stage C HCC, 83.3% (20/24) had extrahepatic metastasis. The median number of prior lines of therapy was 3.5 (range 1-6), 23 (95.8%) pts received ICIs (immune checkpoint inhibitors) and TKIs (tyrosine kinase inhibitors). All pts were evaluable for safety. No dose-limiting toxicity and ICANS was observed. CRS was observed in 22 (91.7%) pts with only 1 (4.2%) grade (G) 3 CRS. The most common ≥G3 AEs were lymphocytopenia (100%), neutropenia (70.8%), thrombocytopenia (37.5%) and transaminase elevation (16.7%). One pt (4.2%) had G4 myelosuppression and 1 pt (4.2%) had G3 interstitial pneumonitis at DL4 caused by G3 CRS. All AEs were reversible. 22 pts were evaluable for efficacy. Tumor reductions were observed in 90.9% pts, not only in intrahepatic lesions but also extrahepatic ones with a median reduction of 44.0% (range, 3.4%-94.4%). The disease control rate was 90.9% and the objective response rate (ORR) was 50.0% for pts of all DLs. In DL4, the ORR was 57.1%. Conclusions: The study showed a manageable safety profile and encouraging anti-tumor activity of C-CAR031 in heavily treated advanced HCC patients. Clinical trial information: NCT05155189 . [Table: see text]
Association of gut microbe and stress-related cancer metastasis and oleic acid degradation.
Authors: Zhen He, Chen Liu, Ping Lan
Journal: Journal of Clinical Oncology (2024)

e15517 Background: Cancer patients often face psychological distress. Cancer metastasis is critical for prognosis. Recent research highlights the link between chronic stress and metastasis. However, the underlying mechanisms is far from known. Methods: Animal models of cancer metastasis were used to explore the effect of chronic stress in promoting tumor metastasis. A combination of antibiotic cocktail treatment, fecal microbiota transplantation and germ-free mice were carried out to confirm whether the pro-metastatic ability of chronic stress was dependent on gut microbiota. 16S rDNA sequencing and liquid chromatography mass spectrometry were parallelly performed on mice stools to investigate alterations in microbiota and metabolites. Additionally, we assessed hormone changes post-stress and demonstrated the correlation between glucocorticoid elevation and gut microbiota through in vivo and in vitro experiments. Finally, we validated our hypothesis using a prospective colorectal cancer cohort. Results: Mice undergone chronic stress had significantly increased cancer metastasis compared with stress-free control mice. Gut microbial dysbiosis was observed in mice undergone chronic stress, with Bifidobacterium being significantly depleted. Stress hormone, corticosterone could alter intestinal epithelium metabolism, and thus inhibit the growth of Bifidobacterium. Metabolomic analysis showed increased Oleic Acid (OA) in the colonic contents from chronic stress-treated mice, and the pro-metastatic role of OA were examined in vitro and in vivo experiments. Supplement of Bifidobacterium animalis (isolated from feces of the stress-free control mice) could decrease the level of OA and inhibit pro-metastasis effect of stress in mice. OhyA which encoded oleate hydratase was identified in Bifidobacterium animalis by whole genome sequencing. Heterogeneous expression of OhyA in Escherichia coli BL21 showed that supplement of OhyA could decrease the level of OA and abrogate the pro-metastatic effect of chronic stress. We found that glucocorticoid secretion increases during chronic stress, promoting the nuclear translocation of glucocorticoid receptors in epithelial cells and activating the transcription of downstream target genes. Through integrated metabolomic analysis, we demonstrated that glucocorticoids degrade guanine, reducing its concentration in the intestine and thereby inhibiting the growth of Bifidobacterium. Furthermore, our investigation into clinical cohorts revealed that patients with higher stress scores are more prone to tumor metastasis, accompanied by a decrease in the abundance of Bifidobacterium in the gut and an increase in serum and fecal oleic acid levels. Conclusions: Chronic phycological stress promotes cancer metastasis by inhibiting the growth of probiotic microbe Bifidobacterium through modulating epithelium purine metabolism and increasing the level of OA.
Quality indicators in the care of patients with rectal cancer in social security in Guatemala: Results of a retrospective population study.
Authors: Pedro Luis López, Hugo Raul Castro-Salguero, Jorge Luis Ranero Meneses, Stefany Jerusa Peralta de León
Journal: Journal of Clinical Oncology (2024)

e15518 Introduction: Rectal cancer is a serious condition affecting a significant number of patients worldwide. However, in the Guatemalan population, the epidemiology and clinical characteristics of this disease have not been widely studied. This study aims to address this knowledge gap by retrospectively analyzing patients with rectal cancer treated at the Guatemalan Social Security Institute between 2013 and 2018. Methods: A retrospective analysis of eighty-eight patients with rectal cancer treated at the Guatemalan Social Security Institute during the mentioned period was conducted. Descriptive statistical techniques, such as chi-square, as well as survival analysis using Cox regression and Kaplan-Meier, were employed to assess the relationship between clinical stages, treatments, and overall survival. Results: The mean age at diagnosis was 70 years +/- 20 years, and 71% of the patients were male. At the time of diagnosis, 14.28% of the patients had localized disease, 58.86% had regional spread, and 26.86% had metastatic disease. Patients in clinical stage I showed a 5-year survival rate of 100%, with a p-value &lt; 0.001 and an HR of 0.01. Additionally, the combination of chemotherapy, radiotherapy, and surgery was found to be significantly associated with improved survival, with a p-value of 0.03 and an HR of 0.82. Conclusions: This study provides crucial information on the clinical characteristics and survival of Guatemalan patients with rectal cancer. The findings underscore the importance of early detection and multimodal treatment, including chemoradiotherapy followed by surgery, to improve outcomes in these patients. Sharing these results is essential to promote access to standard treatment and enhance survival outcomes in patients with rectal cancer in Guatemala.
Tumor microbiome differences in early-onset versus average-onset pancreatic adenocarcinoma.
Authors: Thejus Jayakrishnan, Naseer Sangwan, Kanika G. Nair, Suneel Deepak Kamath, Mehrie Patel, Daniel Joyce, Matthew Walsh, Robert Simon, Deepak Vadehra, Renuka V. Iyer, Christos Fountzilas, Alok A. Khorana
Journal: Journal of Clinical Oncology (2024)

4016 Background: The rise in early-onset gastrointestinal cancers includes an increased risk of pancreatic adenocarcinoma (PDAC), but the underlying pathogenesis is incompletely understood. The tumor microbiome is an increasing focus of research given its impact on tumor pathogenesis and outcomes. We evaluated microbiome profiles in resected specimens from early-onset PDAC (eoPDAC) and average-onset PDAC (aoPDAC). Methods: PDAC specimens were selected consecutively from Cleveland Clinic and Roswell Park Cancer Institute biorepositories and categorized on age at diagnosis ( &lt; 50 years defined as eoPDAC, and &gt; 50 years as aoPDAC). The tissue microbiome was characterized using shotgun metagenomic sequencing. Alpha diversity, denoting the richness and evenness of microbial species within a specific sample, was compared using the Wilcoxon rank-sum test. The differential test of Beta-diversity distances (Bray Curtis distance), representing microbial taxonomic differences between the specimens was performed using Permutational MANOVA. All p-values were adjusted for multiple testing. Results: The study comprised 44 individuals with resected PDAC (24 eoPDAC and 20 aoPDAC). After quality checks, 63 tissue specimens were selected for analysis (13 tumor and 10 adjacent normal specimens for eoPDAC, 20 each of tumor and adjacent normal specimens for aoPDAC). eoPDAC tumor demonstrated significantly higher alpha diversity compared to adjacent normal tissue (P = 0.02) and aoPDAC (P = 0.0062) while aoPDAC did not (tumor vs normal alpha diversity P = 0.31). Beta diversity analysis demonstrated significantly different diversity of genera between all the groups (P &lt; 0.05). Consistent with this finding, the majority of the species - 259/302 (85.8%) in eo vs aoPDAC comparison and 262/366 (71.6%) for eoPDAC vs normal comparison did not overlap. Differential abundance analysis revealed a significant variation of tumor microbiome in eoPDAC vs aoPDAC (P &lt; 0.05). Prevalent bacterial genera (tumor specimens) are listed in the Table. eoPDAC tumor tissues were enriched in Enterobacter, Neisseria,and Escherichia genera, while aoPDAC tumor tissues were enriched in Klebsiella and Bacillus genera. Conclusions: eoPDAC has a distinct microbiome profile compared to aoPDAC. The correlation with several microbial genera associated with pancreatic diseases is a significant finding and warrants further exploration. This is relevant considering the rising incidence of eoPDAC of unknown etiology, and ongoing efforts to develop microbiome-based biomarkers for screening and treatment. [Table: see text]
Effect of tocotrienol and tocopherol regulation by the microbiome on colitis-associated cancer.
Authors: Amanda Stafford, Jie (James) Min Lam, Amedra Basgaran, Eva Lymberopoulos, Mohammad Tanweer, Michael Hobbs, James Arney, Dionisios Korovilas, David Delanoue, Stephen Moore, Muhannad Alomari, Nikhil Sharma
Journal: Journal of Clinical Oncology (2024)

e15512 Background: The association between inflammatory bowel disease (IBD) and a higher risk of colorectal cancer (CRC) has been well established, and is commonly attributed to chronic inflammation and a predisposition to genomic instability ( Feagins et al., 2009 ). Independently, an altered gut microbiome has been evidenced in both IBD ( Halfvarson et al., 2017 ) and CRC ( Marchesi et al., 2011 ). It is unknown whether the altered the IBD-associated microbiome is able to directly influence carcinogenesis via an inflammation-independent mechanisms. Methods: Microbiome analysis was performed using BioCorteX’s industry-leading knowledge graph and integrated proprietary engines v20240126_153156. 2,081 stool samples from adults with IBD and 2,000 stool samples from healthy adults were included. Shannon’s Diversity Index was used to consider within-sample diversity, and PERMANOVA and dimensional scaling based (MDS) on Bray-Curtis diversity was used to consider between-sample diversity. Differential abundance analysis was used to identify species significantly associated with IBD, and a database built on existing literature was used to consider their metabolic products and interactions with known human oncogenes and tumour suppressor genes. Results: Our results show a clearly separation of the IBD microbiome from the healthy population (PERMANOVA p = 0.01), as well as a collapse in Shannon diversity (p &lt; 2.2e-16). Compared to the healthy microbiome, 79 species were significantly (FDR &lt; 0.01) enriched in the IBD stool microbiome, including: Bacteroides fragilis, Bacteroides vulgatus, Bacteroides uniformis, Escherichia coli, Veillonella parvula, Enterococcus faecalis, Fusobacterium mortiferum, and Fusobacterium ulcerans, all of which have previously been evidenced to be enriched in CRC ( Randa et al., 2023 , Bi et al., 2022 , Du et al., 2022 ). Conversely, 115 species were enriched in healthy subjects, including several bacteria with probiotic and anti-tumourigeneic potential such as: Segatella copri, Roseburia inulinivorans, Lactobacillus rogosae, and Coprococcus comes ( Sarah et al., 2022 , Kang et al., 2023 , Campisciano et al., 2020 , Yang et al., 2019 ) Two of the bacteria enriched in the healthy group are producers of both delta-tocotrienol and gamma-tocopherol. These vitamin E isoforms have been implicated in suppression of cancer invasion and proliferation ( Ya et al., 2008 ), in part through NFkB signalling ( Ling et al., 2012 ). Conclusions: This work suggests that that IBD-associated microbiome may contribute to colorectal cancer risk via the suppression of vitamin E isoform signalling, a mechanism that is independent from inflammation. This could present a highly targetable way of mediating CRC-risk in the IBD population.
Individualized tumor-informed circulating tumor DNA analysis for molecular residual disease detection in predicting recurrence and efficacy of adjuvant chemotherapy in colorectal cancer.
Authors: Di Cao, Qiaoxia Zhou, Xuning Fan, Jinyu Yang, Cong Li, Fulong Wang, Rongxin Zhang, Xiaojun Wu, Liren Li, Zhenhai Lu, Zhizhong Pan, Junzhong Lin, Miaoqing Wu, Yifan Liu, Guangzhao Lv, Fujun Qiu, Haoyang Xin, Yu Xu, Guoqiang Wang, Gong Chen
Journal: Journal of Clinical Oncology (2024)

3615 Background: Molecular residual disease (MRD) using circulating tumor DNA (ctDNA) may identify recurrent risk and guide adjuvant chemotherapy (ACT) in colorectal cancer (CRC). This study explored the feasibility of a tumor-informed personalized approach to predict recurrence, comparing with tumor-informed (TI) and tumor naïve (TN) fixed panel approaches. Methods: Patients with stage I-IV CRC eligible for R0 resection were recruited. Blood samples were collected preoperatively, at postoperative day 7 and 30 (POD7/30), and every 3-6 months thereafter, which were tested by brPROPHET assay, using up to 50 highly ranked variants identified by whole-exome sequencing of surgical tissue samples. A fixed 168-gene panel was applied for TI and TN fixed panel tests. Results: A total of 214 patients were enrolled. With a median follow-up of 13.2 months, 20 (9.3%) participants relapsed. The brPROPHET assay had a positivity rate of 96% in preoperative samples. ctDNA positivity indicated by brPROPHET predicted worse recurrence-free survival (RFS) at both POD7 (hazard ratio [HR]=7.35, 95% confidence interval [95% CI], 3.04-17.78, P&lt;0.001) and POD30 (HR=5.18, 95% CI, 2.00-13.38, P&lt;0.001). Higher mean tumor molecules (MTM) level &gt;0.0316/mL was observed in surveillance of 15 relapsed patients, which was associated with worse RFS (HR=44.47, 95% CI, 12.83-154.12, P&lt;0.001). In ctDNA positive patients at POD7, patients benefit from ACT (HR=0.23, 95% CI, 0.05-1.00, P=0.03), which was not observed in ctDNA negative patients (HR=1.80, 95% CI, 0.48-6.81, P=0.38). Among the patients with results of all three approaches (n=168), the brPROPHET assay outperformed TI and TN fixed-panel assays in predicting RFS at POD7 (HR, 7.52 vs 3.43 and 5.60). Of note, the brPROPHET assay identified 6 additional relapsed patients beyond the fixed panels, with more than 87.5% of the positive sites derived from personalized designs. Conclusions: The individualized tumor-informed brPROPHET assay effectively identified postoperative patients with high risk of recurrence and benefit from ACT. Using a personalized tumor-informed panel that covers sites outside fixed panels may improve the utility of MRD detection. [Table: see text]