tbuckley/cabot-search huggingface dataset:
Study on the mechanism of ginsenoside Rg5 attenuating radiation myocarditis through GDF11-SIRT1 pathway.
Authors: Hansong Bai, Tao Li
Journal: Journal of Clinical Oncology (2024)

e15098 Background: Radiation-induced Heart Disease (RIHD) refers to the damage caused by the radiation dose to the heart during radiotherapy for malignant tumors (especially chest tumors), generally including myocardial disease, pericardial disease, coronary artery disease, etc. It generally occurs during radiotherapy or within months to years after radiotherapy. It is reported that the incidence within 5-10 years after the end of radiotherapy is about 10%-30%. With the advancement of equipment and technology, radiotherapy has become increasingly involved in malignant tumors and has become one of the most important treatments for thoracic tumors. Radiation heart disease will significantly reduce the quality of life of patients with malignant tumors after radiotherapy. and survival rate. Although the incidence of RIHD can be reduced by optimizing radiotherapy technology, current technology cannot eliminate the risk of RIHD4. Therefore, it is of great clinical significance to explore how to reduce the incidence and severity of radiation heart disease. Methods: In vitro cultured cardiomyocyte model: used to analyze the impact of Rg5 on cardiomyocytes at the molecular level. Animal model: Construct an animal model of radiation heart disease to evaluate the protective effect of Rg5. Construction of iPCS organoid model to verify that Rg5 attenuates radiation heart disease mediated through Sirt1. Results: Immunohistochemistry, HE staining and Masson staining in early animal experiments showed that Rg5 can slow down radiation heart disease caused by radiotherapy. Immunohistochemistry results showed that SIRT1, HDAC3, PINK1, PARKIN, MFN2 and GDF11 showed obvious differences in expression, while SIRT6 and DRP1 did not. There were obvious differences. At the same time, immunofluorescence double staining of DRP1+SIRT1, MFN2+SIRT1, and HDAC3+SIRT1 was further performed to clarify their intracellular spatial relationship. After using iPSCs to induce cardiac endothelial cells, double immunofluorescence staining of mitochondrial markers and endothelial marker CD31 was performed. The results showed that radiotherapy can cause damage to vascular endothelial cells, reduce vascular integrity, reduce mitochondrial length, and impair function. Ginsenoside Rg5 can reduce this trend. From the common database of single-cell myocardial tissue, it was found that markers such as SIRT1, HDAC3, PINK1, MFN2, GDF11, and GPX4 have similar expression profiles in cardiomyocytes and are more likely to regulate each other. Conclusions: Ginsenoside Rg5 can regulate cardiac radiation injury through the HSP90α-HDAC3-GDF11-SIRT1 axis.It is expected to provide new therapeutic targets for the prevention and treatment of radiation heart disease, making ginsenoside Rg5 of great value in radiotherapy sensitization and radiation heart protection.
Patient-derived 3D bioprinting pan-cancer drug screening platform for personalized medicine.
Authors: Huiyu Yang, Jiangang Zhang, Ying Shan, Yanan Wang, Yaning Cao, Yuning Sun, Ying Jin, Lingya Pan, Chunhai Ke, Wei Cui, Mian Yang, Bo Zhou, Ziqi Jia, Heng Cao, Yu Wang, Wenbin Ma, Xiao Xu, Hai-Tao Zhao, Huayu Yang, Yilei Mao
Journal: Journal of Clinical Oncology (2024)

e15088 Background: Patient-derived tumor model offers an individualized approach to overcome interpatient heterogeneity in cancer therapy. 3D bioprinting (3DB) enables construction of in vitro model with high-throughput, high-fidelity, and high efficacy. We hereby report a pipeline of establishing pan-cancer patient-derived 3DB (PT-3DB) models with personalized drug sensitivity results in 148 patients from multiple medical centers. Methods: Tumor tissues of 148 patients were collected with informed consent at 4 medical centers in Beijing, Hangzhou and Ningbo from 2022-12 to 2023-12. Tumors were digested into cell suspension and mixed with GelMA, and PT-3DB was fabricated by extrusion-based bioprinter. A panel of chemotherapies and targeted therapies was selected based on first-line treatment of corresponding cancer type. PT-3DB was treated with drugs in dose gradient at DIV 5. Cell viability was measured by ATP quantification at DIV 8 and dose-response curve and IC 50 of each drug was calculated. Results: We have established PT-3DB in 148 patients with success rate of &gt; 95% and turnaround time of only 8 days. 137 were surgically resected samples and 11 were biopsy samples. Cancer types included ovarian cancer (OC, n = 52), colorectal cancer (CRC, n = 51), hepatobiliary cancer (HBC, n = 17), breast cancer (BC, n = 10), high-grade glioma (HGG, n = 10), cervical cancer (CC, n = 4), pancreatic cancer (PC, n = 2), and gastric cancer (GC, n = 2). A total of 27 drugs were screened, of which 15 were chemotherapies and 12 were targeted therapies. The median number of drugs tested for each patient was 5 (4-6) (Q25-Q75). Significant interpatient heterogeneous drug response was observed within each cancer type and between tumors with the same treatment regime. Representative data were presented in the attached table. Conclusions: We have successfully constructed pan-cancer PT-3DB platform for personalized drug screening in 148 cases, with outstanding stability across multiple centers. The timeline of 8 days preceded pathological diagnosis, which is the earliest start of systematic treatment, underscoring its high translational potential. PT-3DB has demonstrated interpatient heterogeneous response to systematic treatment, providing a strong foundation for precision medicine. Our ongoing research aims to correlate PT-3DB drug responses with clinical outcomes. [Table: see text]
EXPRESS study: A trial exploring the association of low level of genomic alteration with exceptional and unexpected response to targeted therapies in patients with advanced solid tumors.
Authors: Olivia Le Saux, Elodie Girard, Lori Leslie, Thomas Bachelot, Jean-Yves Pierga, Fabrice Barlesi, Laurence Albiges, Celeste Lebbe, Valerie Boige, Jean-Sebastien Frenel, Dominique Spaeth, Aline Guillot, Pierre Etienne Heudel, Miriam Gardner, Xavier Durando, Julien Peron, Maud Kamal, François Legrand, Amelie Lusque, Ivan Bieche
Journal: Journal of Clinical Oncology (2024)

e15140 Background: Small subsets of pts treated with targeted therapies (TT) present exceptional and unexpected response (1-10%), which could be driven and correlated by a low level of genomic alterations in genes identified as causally implicated in cancer. Conversely, the multiplication of the genomic alterations in such genes would decrease the oncogenic de-addiction process. Methods: EXPRESS is an exploratory, multicenter, prospective trial conducted in pts with locally advanced or metastatic solid tumors, who presented an exceptional and unexpected response to an antineoplastic TT. This research aimed to explore whether tumors with a low level genomic alteration (mutation, amplification, deletion) as assessed by whole exome sequencing (WES) are associated with exceptional and unexpected response. Secondary endpoints including the identification of novel candidate somatic molecular profiles and host immunologic characteristics susceptible to drive exceptional and unexpected response will be reported later. Results: 439 pts were identified over 32 centres from December 2016 to April 2021. Out of 270 pts confirmed with an exceptional response by our review committee of cases, 183 were included in the EXPRESS study. Exceptional responder population is summarised (Table). Out of 183, WES analysis was performed for 103 pts (56.3%). Genomic analysis failure was predominant in the breast and lung cohort (60.9% and 52.5%). The number of genomic alterations in the EXPRESS cohort was lower than in the TCGA control cohort (median[Q1-Q3]: 11[7-17] vs 19 [11-32], p&lt;0.001). A lower number of genomic alterations was also reported in the melanoma (8[5-13] vs 33[17-51], p&lt;0.001) and lung cancer cohort (8[5-17] vs 22[13-34], p&lt;0.001) but not in the breast and kidney cohorts (13[10-21] vs 17[10-29], p=0.41 and 12[9-14] vs 11[7-17], p=0.89). Conclusions: Compared to the TCGA cohort, a low level of genomic alteration is associated with exceptional response in pts with lung cancer and melanoma. A comparison with a matched population based on genomic criteria in the TCGA is undergoing and will be presented at the conference. Clinical trial information: NCT02701907 . [Table: see text]
Reasons for biomarker testing in NSCLC: An analysis of reasoning between 2021-2023 in early- vs. late-stage patients.
Authors: Ayse Levent, Pieter De Richter
Journal: Journal of Clinical Oncology (2024)

e15175 Background: Given the number of targeted therapies that are approved for non-small lung cancer (NSCLC), timely testing for biomarkers is critical to ensure eligible patients benefit from precision medicines. This study uses real-world data to explore how factors associated with routine and reflex testing in the US are influencing the decision to test for biomarkers. Methods: Ipsos’ MDx Monitor is a multi-stakeholder, physician-reported syndicated patient record database. Cancer-treating physicians in the US (2021 = 56, 2022 = 64, 2023 = 44) were screened for seniority and caseload and submitted data on 414 NSCLC patients (aggregate) who had been tested for biomarkers. Data were collected online in September-October of each year. Results: Comparing sampled physician-cited reasons for testing over time, standard procedure was mentioned more frequently in the reported 2023 cohort (87% in 2023 vs. 62% in 2021) as was lab performs this test as reflex (18% in 2023 vs. 2% in 2021). Testing because of patient histology or to inform treatment decision declined from 2021 to 2023. Reasons that were mentioned consistently more frequently among the reported early-stage patient cohorts vis-à-vis metastatic patients included histology, to inform treatment decision and, notably, patient request. The top cited reasons are shown in Table 1. Conclusions: Results from this study indicate that physicians’ approach to biomarker testing is evolving towards more routine procedures, rather than testing to inform a specific treatment decision, marked by a recorded increase in reflex and broader panel-based testing. Although guidelines focus on assessing metastatic patients’ eligibility for targeted therapies, early-stage patients also stand to benefit from more automated testing processes. Further investigation on time between diagnosis and implementation of biomarker testing, along with subsequent treatment outcomes, is warranted. [Table: see text]
Clinical validation of a novel circulating tumor DNA methylation assay for predicting recurrence of colorectal cancer in patients with curative-intent surgery by monitoring minimal residual disease.
Authors: Jin-Soo Kim, Yun Young Lee, Mi Young Kim, Joon An, Rumi Shin, Jin Hyun Park, Jinil Han, In Sil Choi, Seung Chul Heo, Youngho Moon
Journal: Journal of Clinical Oncology (2024)

3620 Background: Circulating tumor DNA (ctDNA)-based liquid biopsy has emerged as a promising tool for early detection and monitoring of cancer. In this study, we developed COLO eDX, a digital-PCR based colorectal cancer (CRC) diagnostic assay using a single CRC-specific methylation biomarker. This study aimed to evaluate the prognostic value as the universal assay for recurrence monitoring in CRC patients with curative-intent surgery. Methods: A total of 116 CRC patients who underwent surgery at Seoul National University Boramae Medical Center were enrolled in the study from Mar 2017 to January 2020. For each patient, postoperative plasma specimens were collected at 7 days and at each regular clinical follow-up visit up to 2 years. The enrolled patients were followed up with radiological and clinical measures for maximally 5 years after surgery. The primary outcome was recurrence-free survival (RFS) according to ctDNA status. Results: The majority of samples collected at 7 days after surgery were ctDNA positive by COLO eDX (65/83, 78.3%) and the ctDNA status was not significantly associated with RFS, suggesting that cancer signatures can still be detected in most cancer patients at least 1 week after surgery. However, ctDNA positivity at 1 month or later was associated significantly worse RFS. In plasma taken between 1- and 9-months after surgery, ctDNA positive group had a significantly higher recurrence rate than ctDNA negative group (hazard ratio [HR], 11.4, 95% confidence interval [CI], 3.8-34.4; P&lt;0.0001). Incorporating serial longitudinal samples, ctDNA status was significantly associated with recurrence (HR, 13.4, 95% CI, 4.3-40.6; P&lt;0.0001). Notably, ctDNA analysis by COLO eDX was a more powerful predictor for predicting recurrence than carcinoembryonic antigen (CEA) assessment (HR, 4.0, 95% CI, 1.4-11.8; P=0.0107 and HR, 1.5, 95% CI, 0.3-8.2; P=0.5949). Conclusions: Postoperative ctDNA monitoring using a CRC-specific epigenetic biomarker-based digital PCR assay is a promising strategy for recurrence prediction and personalized clinical management of CRC through early detection of minimal residual disease (MRD).
CancerHallmarks.com: A tool for the enrichment analysis of the cancer hallmarks.
Authors: Balazs Gyorffy, Otilia Menyhart, William Kothalawala, Libero Santarpia
Journal: Journal of Clinical Oncology (2024)

e15079 Background: The "Hallmarks of Cancer" concept is a useful framework for understanding the fundamental principles that are shared among different types of cancers. However, the lack of agreement on a specific set of genes for these hallmarks makes it difficult to compare and integrate data, leading to varying interpretations of the biological processes involved in cancer across different studies. In this study, we created a consensus set of cancer hallmark genes by combining data from multiple mapping resources and the scientific literature. Methods: We identified 6,763 candidate cancer hallmark genes associated with ten cancer hallmarks by consolidating information from seven studies. There was a considerable variation in the number of genes within the available resources, ranging between 91 and 7,779. We observed a sizable variation in the number of genes connected to each hallmark. The number of genes across cancer hallmarks ranges between 574 („enabling replicative immortality”) and 3,574 ("sustaining proliferative signaling"). The least number of genes are associated with the more recent hallmarks, published in 2011, and the hallmarks „enabling replicative immortality” and „sustaining angiogenesis”. We identified six genes linked to each of the ten cancer hallmarks: TP53, AKT1, MAP2K1, CTNNB1, HRAS, and PIK3CB. Results: As a practical utility of the hallmark concept, we analyzed the enrichment of cancer hallmarks by evaluating genes associated with overall survival. Only genes with a false discovery rate below 0.01, a hazard rate over 1, and a cutoff value over 100 were analyzed to ensure sufficient robustness of the gene sets. The hallmark "genome instability" was most prominent in liver (p=1.0E-05), lung (p=1.0E-05), and pancreatic cancers (p=0.00164). Renal cancer had higher “invasion and metastasis” (p=0.002). Both pancreatic cancer and lung adenocarcinomas were enriched for “resisting cell death” (p=0.00096 and p=0.037, respectively). Overall, while eight cancer types had no significant hallmark enrichment among druggable genes, pancreatic cancers had the most enriched hallmarks (5 out of 10), emphasizing the disease's complexity. These results highlight the usefulness of the hallmark concept as a valuable tool for organizing information, especially in establishing a direct link between genes and biological functions. Conclusions: We have created a unified list of genes linked to cancer hallmarks. We integrated the data into an easily accessible online tool (accessible at www.cancerhallmarks.com) that enables users to identify the most pertinent cancer-associated “candidate hallmark genes” in their own datasets.
COVID-19 breakthrough infections in patients with colorectal cancer: A propensity-matched score analysis.
Authors: Saqr Alsakarneh, Hana Qasim, Yazan Sallam, Ibrahim Khamees, Ammar Al-Obaidi, Mohammad Adam
Journal: Journal of Clinical Oncology (2024)

e15655 Background: Previous data showed that cancer patients are more prone to have severe outcomes due to SARS-CoV-2 infection. While there are promising data on anti-mRNA antibodies titer post-COVID-19 vaccination in solid malignancies, concerns arise regarding durability of this immune response. We aim to evaluate the risk of breakthrough COVID-19 infection in colorectal cancer patients (CRC). Methods: We conducted a retrospective cohort study using TriNetX, a population-based database that sources data from electronic medical records (EHRs) of 61 health care organizations in the US. Using ICD-10 codes, we created two cohorts of patients with vaccination against COVID-19: with CRC and without CRC. Within each cohort, we collected data on demographics, and several risk factors for COVID-19. We performed propensity score matching (PSM) of 44 variables to control for confounding. Primary aim of our study was to compare the risk of COVID-19 breakthrough infection between CRC patients and control group. Odds ratio (OR) and 95% confidence interval (CI) were used to report associations for the propensity-matched cohorts. Results: A total of 6,152 vaccinated CRC patients were identified (mean age = 68.3 ± 12.7, females: 47.4%). In CRC vaccinated patients, (68.9%) were White, (12.50%) were African Americans, (8.3%) were Hispanics/Latino individuals. 6051 received 2 doses, and 2087 received 3 doses of COVID-19 messenger RNA vaccine. Vaccinated CRC patients were found to be at significantly higher risk for breakthrough COVID-19 infections compared to patients without CRC (adjusted odds ratio [aOR] = 1.46; [95% confidence interval (CI): 1.33 - 1.59]). Sub-group analysis based on the number of vaccines administered revealed consistent findings, with aOR of 1.39 [1.27 - 1.52] after 2 doses, and 1.36 [1.18 - 1.57] after 3 doses. There were no differences in risk of breakthrough infection based on gender or age groups in patients with CRC (P &gt; 0.05). Conclusions: Our study showed that CRC patients are at a significantly elevated risk of breakthrough COVID-19 infections. Our study provides a valuable finding that may enlighten public health measures and clinical interventions for this vulnerable patient population. Further research is warranted to investigate the biological mechanisms that contribute to the breakthrough infections COVID-19 among CRC patients. [Table: see text]
Utilizing comprehensive next-generation sequencing to determine the clinical significance of copy number variation in advanced/metastatic non-small cell lung cancer.
Authors: Aya EL Helali, Elaine Yee-Ling Ko, Charlene Hoi Lam Wong, David Jen-Hao Shih, Jason Wong, Matthew Chiu, Victor Ho-Fun Lee
Journal: Journal of Clinical Oncology (2024)

e15174 Background: Large population-based comprehensive tumor genomic profiling using next-generation sequencing (NGS) technology offers insight into the detection of copy number variation (CNV) in advanced/metastatic solid cancers. However, the significance and role of CNV in advanced-stage non-small cell lung cancer (NSCLC) is limited. In this analysis, we investigated the incidence and impact of CNV on patient outcomes. Methods: Patients were recruited as part of an ongoing real-world multicentre prospective NSCLC Precision Oncology Programme in Hong Kong. All patients underwent tissue and liquid NGS using Foundation One CDx and Foundation One Liquid CDx, respectively. Patients were classified into two groups based on CNV status: group 1 (CNV+) was defined as tumors with CNV reported; group 2 (CNV-) was defined as tumors with no CNV reported. The association of clinical factors with CNV was reported using Chi-square tests. The overall survival (OS) was calculated from the date of diagnosis of advanced-stage cancer to the date of death or the last follow-up date. Survival analysis was estimated using the Kaplan-Meier method with the log-rank test. Results: 353 patients were included in this analysis. NGS was performed in 216 (61%) tumor tissues, and 137 (39%) liquid specimens. 37% (n = 129) were female, and 50% (n = 175) were ever-smoker. 63% (n = 223) of our patient cohort harbored druggable mutations. The detection rate of CNV was 74% in tissue and 14% in liquid specimens. Patients with brain, liver, or bone metastasis (p = 0.018) and/or TMB-high (TMB-H) (p = 0.0014) were associated with CNV+. Next, we assessed the impact of CNV on treatment outcomes. Among patients who received immunotherapy ± chemotherapy, CNV+ was associated with a median OS of 20.4 months compared to 31.4 months in the CNV- group (HR:2.09, 95% CI: 1.05-4.16, p = 0.034). In contrast, there was no statistically significant difference in OS among the CNV+ and CNV- patient groups treated with chemotherapy alone. Although not significant, there was a trend towards poorer OS to immunotherapy ± chemotherapy in the TMB-H CNV+ cohort (23.6 months versus 31.4 months; p = 0.082). Conclusions: We demonstrate the significance of CNV as a prognostic tool for the prediction of survival outcomes among lung cancer patients. Our data suggests that CNV represents a distinct entity in advanced/metastatic NSCLC, associated with poorer survival outcomes to immunotherapy.