bluuebunny/crossref_metadata_2025_split huggingface dataset:
Does non-alcoholic fatty liver disease increase the risk for pancreatic cancer? A multi-center retrospective cohort study.
Authors: Singh Rituraj Raj , O'Reilly Eileen M. 
Published: June 2024

4165 Background: Recent studies suggest that patients with non-alcoholic fatty liver disease (NAFLD) are at increased risk of hepatic and extra-hepatic gastrointestinal cancers. However, there is limited data exploring the risk of pancreatic cancer (PC) in patients with NAFLD. We aim to investigate the risk of PC in patients with biopsy proven NAFLD. Methods: We performed a multicenter retrospective cohort study utilizing an electronic health record database (TriNetX) to study the risk of PC in patients with NAFLD. The study group comprised adults ≥40 years with NAFLD who had undergone liver biopsy between January 2016 to December 2019. Comparison group was obese individuals (body mass index ≥30 kg/m2) without NAFLD. We excluded patients with other etiologies of chronic liver disease. The median follow up was 5 years. Patients who had follow up visits 1-4 years were selected. The primary outcome was a new diagnosis of PC. Results: We identified 18,513 patients with NAFLD and had undergone liver biopsy, predominantly white (75.3%) females (59.7%). Diabetes mellitus (29.4% vs. 18.8%), chronic pancreatitis (1.3% vs. 0.2%), pancreatic cyst (0.8% vs. 0.2%), tobacco use (9.4% vs. 7.7%), and a family history of GI cancers (2.7% vs. 1.5%) were observed more commonly in the NAFLD group compared with the obese control. After propensity score matching for confounding variables, the 5-year risk of developing PC was higher in NAFLD cohort (risk ratio, RR 2.18, 95% CI 1.56-3.03) compared with the control group. Overall, 5-year mortality was higher in the NAFLD cohort (8.2% vs 6.6%, RR 1.25, 95% CI 1.16-1.37). Conclusions: NAFLD probably increases the risk of pancreatic cancer in middle-aged and elderly individuals and the risk exists despite controlling for obesity and other known risk factors for PC. NAFLD should be considered in the risk stratification strategy for pancreatic cancer. Moreover, patients with NAFLD and advanced fibrosis who undergo screening for hepatoma may be considered for abdominal CT or MRI for pancreatic cancer screening if other risk factors exist. [Table: see text]
Independent blinded validation of a novel blood-based early pancreatic cancer detection test.
Authors: Strasser Patrick Christian , Bijlsma Maarten F. , Le Large Tessa Y.S. , Kazemier Geert , Thumfart Norbert , Schneider Maximilian 
Published: June 2024

4166 Background: Pancreatic ductal adenocarcinoma (PDAC) frequently presents at late stages, resulting in increased mortality. Early detection is crucial for enhancing survival rates; however, available screening methods are limited. This gap underscores the critical need for advancements in early PDAC detection. To address this, Wholomics developed a proprietary early detection assay, leveraging molecular signatures found in the blood, and has further validated its efficacy through a comprehensive blinded validation study. Methods: Wholomics conducted retrospective analysis of serum samples from the Amsterdam UMC Liquid Biopsy Center and the Bank of Biological Material of the Masaryk Memorial Cancer Institute. A training cohort included 290 control subjects, 12 patients with a confirmed diagnosis of chronic pancreatitis, and 71 patients with a histopathologically confirmed diagnosis of PDAC (20 stage I, 30 stage II, 13 stage III, 8 stage IV). A blinded validation cohort comprised samples from 20 control subjects, 24 patients with non-cancerous conditions (5 with benign tumors, 10 with IPMNs, 9 with chronic pancreatitis), and 60 patients with histologically confirmed PDAC. Peripheral blood samples of cancer patients were drawn before surgery or treatment. Wholomics used its proprietary NMR-based technology to quantitatively analyze serum samples. Disease-specific molecular signatures were identified and used to develop a computational biomarker specific to PDAC. A comparative analysis via 10-fold cross-validation and a blinded validation were conducted. The accuracy, specificity and sensitivity are reported. Results: In this study, a dual-cohort design, comprising both a training and a blinded validation cohort, was utilized to assess the capability of the Wholomics technology in detecting cancer-specific molecular signatures. In the training cohort, a 94.6% accuracy was achieved in distinguishing PDAC patients from non-cancer controls. A specificity of 95.7% and sensitivity of 90.7% were reached. A similar performance was observed in the blinded validation cohort, where the blood-based test accurately differentiated PDAC patients from controls with an accuracy of 92.5%. In more detail, a specificity of 95% (noting a single false positive) and a sensitivity of 91.7% were achieved. Conclusions: The collective findings of this research indicate that utilizing disease-specific molecular markers in peripheral blood offers a highly accurate method for differentiating between PDAC patients, healthy subjects, and those with pre-cancerous diseases. Should future studies across broader cohorts corroborate these results, this testing approach has potential for consideration as a screening mechanism for PDAC, aiming to facilitate early detection and consequently enhance patient prognoses.
Survival and prognosis of anus, anal canal and anorectal carcinoma: Analysis of National Surveillance, Epidemiology, and End Results database from 2000-2020.
Authors: Guragain Ashish , Inban Pugazhendi , Vaz Clint , Poudel Urusha , Cheriyath Pramil , Nookala Vinod , Kansakar Sajog , Shikhrakar Shreeja , Maroules Michael 
Published: June 2024

e15501 Background: Anal cancer comprises about 2.5% of all gastrointestinal malignancies in the USA. The incidence of anal cancer is showing an increasing trend, however studies surrounding its prognostic factors and survival is limited. The aim of our study is to examine the prognostic factors and evaluate survival trends from 2000-2020 using the SEER database. Methods: SEER*Stat Version 8.4.3 software was used to extract anus, anal canal and anorectal carcinoma cases from SEER 17 registries (2000-2020). A total of 32315 patients were included in the study, data with unconfirmed histology were excluded. We analyzed overall mortality, and anal cancer specific mortality (CSM) using a Cox proportional hazards model. The survival analysis was carried out using the Kaplan–Meier method and the log-rank test was used to compare survival curves. Results: Crude analysis revealed a high overall mortality in patients above age 80 (HR = 11.085; 95% CI: 9.9113-13.485), p < 0.001), followed by age 60–79 (HR = 3.665, 95% CI: 3.303- 4.432, p < 0.003. Females were found to have better survival (HR = 0.705; 95% CI: 0.676-0.735). Non-Hispanic blacks were found to have the highest cancer-specific mortality compared to other ethnicities (HR = 1.294; 95% CI: 1.112-1.381). Patients who did not undergo surgical treatment had a significant cancer specific mortality (HR = 1.438; CI: 1.377-1.502). The highest cancer-specific mortality was observed in patients with distant metastases (HR = 2.461, 95% CI: 2.314– 2.616, p < 0.001). Irrespective of surgical status, patients who underwent either chemotherapy or radiation therapy had better survival rates. Multivariate cox proportional hazard regression analyses of CSM also revealed higher mortality among males and Non-Hispanic black patients. The mortality outcomes further become worse with advanced age and lack of application of available treatment options in the form of surgery, chemotherapy or radiotherapy. Conclusions: Our analysis indicated overall increased anal cancer specific mortality in Non-Hispanic blacks. Delayed diagnosis with distant metastasis and those who did not receive any of the available treatment modalities had worse prognosis. We recommend further research to develop better screening strategies for early diagnosis of anal cancer, identifying factors associated with increased mortality in certain ethnicities, and barriers to access available treatment modalities.
Efficacy and safety of nivolumab in pretreated patients with metastatic squamous cell carcinoma of anus: A real-world experience.
Authors: Conci Nicole , Rojas Llimpe Fabiola Lorena , Di Fabio Francesca , Di Odoardo Adriana , Danielli Linda , Seminerio Renata , Tortorella Carla , Guido Alessandra , Cuicchi Dajana , Laurenzi Andrea , Dalla Via Barbara , Tardio Maria Lucia , Rihawi Karim 
Published: June 2024

e15502 Background: Squamous cell carcinoma of the anus (SCCA) is a rare malignancy with limited treatment options for metastatic patients. Immune checkpoint inhibitors (ICI) have been studied on few prospective trials, but its efficacy seems low. Methods: We retrospectively collected clinical, radiological, and laboratory data from patients (pts) diagnosed with metastatic SCCA who received nivolumab as 2nd or 3rd line therapy at the Oncology Unit of Bologna University Hospital from October 2017 to November 2023. We analyzed the correlation of clinical-pathological features with the overall response rate (ORR), overall survival (OS), and progression-free survival (PFS). Results: We enrolled 15 pts diagnosed with relapsed/metastatic SCCA; pts characteristics are summarized in Table 1. Nivolumab was administered as a 2nd line treatment in 13 pts, while 2 pts received ICI in the 3rd line. Overall, median OS was 8.3 months (mo.) (95% CI 4.37-NA) and median PFS was 4.37 mo. (95% CI 3.67-NA). Of note, ORR was 40%, compared with the 10% ORR seen in the few prospective phase II trials available. Pts with ECOG PS ≥ 2 showed a lower ORR and resulted in worse OS and PFS. ECOG PS 0 pts showed a median OS of 19.17 mo., PFS of 5.17 mo., and ORR of 75%. ECOG PS 1 pts had an OS of 10.73 mo., a PFS of 4.98 mo., and an ORR of 38%, while ECOG PS 2 pts showed 4.37 mo. of OS and PFS with no response seen. The number of metastatic sites at baseline has been shown to be associated with OS. Pts with ≥ 3 metastatic sites showed an OS of 5.17 vs 10.73 mo. for pts with < 3 sites. Overall, no complete response was seen; however, we identified 4 long-responders with a median treatment duration of 15.8 mo. (8.3 - 26.5). All long-responders were HPV-positive and had no liver metastases at the time of treatment initiation. PD-L1 evaluation and molecular characterization is ongoing. Nivolumab was well-tolerated with 5 pts experiencing immune-related adverse events: 4 pts showed G1 toxicities according to the CTCAE, version 5.0 (thrombocytopenia, hypothyroidism and rash) while 1 patient had G4 myopathy caused a treatment discontinuation. Conclusions: ICI is a possible treatment option with a favorable safety profile in pretreated SCCA although a better selection of patients is required. [Table: see text]
Paradoxical association of B7H3 with clinical outcomes in patients with colorectal cancer.
Authors: Huang Yan , Qi Xiaohua , Acuna-villaorduna Ana , Gali Radhika , Maitra Radhashree , Lin Juan , Maia Catarina , Zhang Wei , Zhang Chenxin , Zang Xingxing , Liu Qiang , Goel Sanjay 
Published: June 2024

e15508 Background: Immune related biomarkers (IRB) are important predictors of outcome to immune checkpoint inhibitor (ICI) therapy; however, their role is unclear in early-stage colorectal cancer (CRC). This study aimed to evaluate the expression of novel protein IRB among CRC patients to predict clinical outcomes. Methods: A CRC tumor microarray (TMA) was constructed from a multiracial patient population, and expression of HHLA2, B7-H3, PD-L1, CK7, CK20, and CDX2 determined. Comprehensive clinical information was extracted. For curable cancers, associations between biomarker expression and relapse risk were assessed using logistic regression analysis. For metastatic(m) cancers, Kaplan Meier curves were plotted, and Cox proportional hazards regression analysis was performed to evaluate association with overall survival (OS). Results: Among 388 patients, 150 had de novo metastatic disease, 108 experienced relapses from localized cancer, and 130 patients had cured localized disease. The median age was 62.4 years, with a female predominance (53%). The majority were racial/ethnic minorities. Among curable cancers, patients with high B7-H3 expression experienced a 73% lower risk of relapse (OR 0.27, 95%Cl 0.09-0.76, p = 0.015) exceeding the relevance of nodal(N) and tumor(T) stage in predicting relapse. High HHLA2 (OR 4.79, 95%CI 1.74-14.5, p = 0.003) was associated with a higher risk of relapse. Among mCRC, low expression of both PD-L1 and B7-H3 was associated with better OS (HR 1.73; 95%CI 1.08-2.76, p = 0.023). Conclusions: In this multiracial TMA of CRC, high B7-H3 expression was associated with lower risk of relapse. Post validation, routine B7-H3 testing may enable clinicians to make more informed decisions regarding adjuvant therapy.
Evaluating peripheral myeloid-derived suppressor cells as factor for the diagnosis and treatment efficiency of patients with colorectal cancer.
Authors: Zhou Cong , He Lina , Gu Yi , Shi Bisheng , Cheng Xiaojiao , Zhangyuan Ruohan , Shen Yuguang , Shen Wei , Wang Zheng , Tu Shuiping 
Published: June 2024

e15510 Background: Colorectal cancer (CRC) is one of the most common malignant tumors in the world. As the main immunosuppressive cells in tumor microenvironment (TME), the diagnostic value of myeloid-derived suppressor cells (MDSCs) in periphery of CRC patients and their treatment-related clinical significance are still ambiguous. Methods: Here, blood samples and clinical information were collected from 210 CRC patients and 102 healthy individuals. The frequencies of MDSCs were detected by flow cytometry. Immune-related cytokines were detected by Cytometric Beads Array. Paired blood samples before and after treatment were collected from another 175 CRC patients to assess the effect of therapeutic regimens on MDSCs. Results: Compared with healthy individuals, the proportions of total MDSCs (1.34 vs. 9.20, p< 0.0001), monocyte-MDSCs (Mo-MDSCs) (0.13 vs. 0.60, p< 0.0001) and polymorphonuclear-MDSCs (PMN-MDSCs) (0.87 vs. 7.32, p< 0.0001) were increased, while early-MDSCs (eMDSCs) were decreased (0.02 vs. 0.01, p< 0.0001). The sensitivity, specificity, and AUC of total MDSCs for CRC diagnosis were 80.5%, 90.2% and 0.90. The sensitivity, specificity, and AUC of total MDSCs combined with CEA were 89.5%, 89.0%, and 0.94, respectively. Correlation analysis showed that peripheral MDSCs were significantly correlated with leukocytes (r = 0.24~0.37), immune-related cytokines [especially IL-2 (r = 0.25~0.27), IL-5 (r = 0.26), IL-6 (r = 0.22~0.44), IL-8 (r = 0.18~0.32)], and biomarkers of gastrointestinal tumors (r = 0.24~0.41). Additionally, first-line chemotherapy FOLFOX and XELOX, or chemotherapy plus targeted therapy can effectively reduce total MDSCs (13.30 vs. 2.81, p< 0.001; 15.09 vs. 3.31, p< 0.001) and PMN-MDSCs (13.21 vs. 2.14, p< 0.001; 13.78 vs. 2.22, p< 0.001). Conclusions: This study disclosed that peripheral MDSCs have important diagnostic value and clinical significance for CRC.
Mutational landscape and evolutionary pattern of peritoneal metastases in colorectal cancer.
Authors: Wang Yuzhuo , Xu Xianfeng , Zheng Jinyu , Xu Lu , Zhu Yuping , Xu Rui , Shen Yan , Xu Guifang , Zhu Weiyou , Fu Zan , Sun Jing 
Published: June 2024

e15533 Background: Peritoneal metastases occur in approximately 10% of all colorectal cancer (CRC) patients, which are associated with significant morbidity and worse clinical outcome. To date, the evolutionary pattern and molecular mechanisms of peritoneal metastases remains largely unknown, which provided little insights into the prevention and treatment of this subgroup of CRC patients. Methods: We performed whole-exome sequencing (WES) on 49 samples of matched primary tumors, peritoneal metastases, and lymph node metastases from 11 CRC patients. Phylogenetic reconstruction and evolutionary analyses were performed to investigate the mode and route of metastatic dissemination. The timing of metastatic dissemination was inferred using SCIMET. Metastases-associated driver events were analyzed and validated in two independent cohorts. Finally, therapeutic actionability of somatic alterations was assessed. Results: A characterization of metastatic dissemination found that 3 out of 11 patients displayed monoclonal dissemination. Whereas the other 8 patients exhibited polyclonal dissemination, of which 6 were monophyletic and 2 were polyphyletic. In five patients, we observed evidence for the metastasis-seeding-metastasis mode among peritoneal metastases. Additionally, the peritoneal metastases were mainly seeded by the primary tumor rather than the lymph node metastases. Metastatic timing inference found that most (9 out of 11) of the peritoneal metastases occurred early before the primary tumor became clinically detectable. Genetic alterations associated with peritoneal metastases were identified, including somatic mutations in TP53, SMAD4, KRAS, RNF43, and SMARCB1, as well as focal amplifications (8p24) and losses (17p12). Analysis of therapeutic actionability identified potentially targetable oncogenic alterations in all patients. Conclusions: Our results provided important insights into the evolutionary features of peritoneal metastases, which had profound implications for the prediction, prevention, and treatment of peritoneal metastasis in CRC.
Benefits for adjuvant chemotherapy of resected colon carcinoma examined by Artificial Intelligence Laboratory (NCI-Br) through synthetic data and machine learning: A tribute to Prof. Charles George Moertel.
Authors: Kesley Rubens , Castro Leonaldson Dos Santos , Correa José Humberto Simões 
Published: June 2024

e15537 Background: Data is considered the basis of the modern economy and the production of synthetic data can revolutionize the applicability of artificial intelligence in healthcare. However, there are few synthetic databases in biostatistics and few mechanisms capable of generating them. The objective of the study is to develop a synthetic database based on the seminal article by Moertel et al (1990) entitled: Levamisole and Fluoracil for adjuvant therapy of resected colon carcinoma, which revolutionized oncological treatment. Methods: An algorithm with probabilistic and logical methods and specialized knowledge was used to reconstruct the dataset with the variables studied by Moertel et al (1990). Based on the percentages observed in the study and logical programming rules in R language, we propose to create a model capable of simulating the original dataset with the epidemiological (age and sex) and anatomopathological (tumor location, depth of tumor invasion, involvement of adjacent organs, obstruction, perforation, peritoneal implants, number of metastatic lymph nodes and histological differentiation type). Using the decreasing exponential function it was possible to simulate the decay of the probability density function of the original sample for recurrence and survival. The synthesized data was subjected to traditional statistical analysis and machine learning, using decision trees. Results: Statistical analyzes of the independent exploratory variables of relapse (invasion, metastatic lymph nodes, cellular differentiation) and survival (tumor location, invasion, metastatic lymph nodes, cellular differentiation) demonstrated statistical significance (p = 0.001). The behavior of the exploratory variables for recurrence and survival was similar to the recurrence and survival curves observed by the Kaplan-Meier statistical method (p = 0.001). Decision trees were created with amplified samples that demonstrated the importance of the variables number of lymph nodes, tumor invasion and chemotherapy. Conclusions: The proposed algorithm showed that it is possible to recreate a dataset with statistical similarities to the original, based on detailed analysis, knowledge in Data Science and Analytics, mathematical methods and rules determined by the domain expert. The study of synthetic dataset allows evaluating the quality of the article studied, amplifying or reducing the sample, mapping interrelationships between explicative and dependent variables, and analyzing the synthetic dataset according to artificial intelligence, demonstrating that artificial intelligence laboratories are essential for analyzing the health data.
Use of epigenetic inhibitor screen to identify HDAC1/2 inhibitor as a pro-differentiation therapy in colorectal cancer.
Authors: Likasitwatanakul Pornlada , Li Zhixin , Spisak Sandor , Doan Paul , Bala Pratyusha , Liow Priscilla , Papanastasiou Malvina , Qi Jun , Sethi Nilay S. 
Published: June 2024

e15538 Background: Impaired differentiation is a key mechanism by which neoplastic cells persist and eventually progress to malignancy in the renewing colonic epithelium. Our group recently demonstrated that SOX9 functionally prevents differentiation to promote colorectal cancer (CRC) development; however, we have yet to convert this knowledge for therapeutic gains. Methods: To this end, we developed a discovery platform by genome-engineering SOX9 (stem cell activity) and KRT20 (differentiation) genomic loci of CRC cell lines to express two fluorescent markers simultaneously. Epigenetic modulators play an essential role in intestinal epithelium differentiation, and drug-targeting epigenetic regulators are emerging as a novel therapy class. Hence, we applied a small molecule screen targeting epigenetic regulators to our platform, searching for perturbations that induce differentiation, reduce stem cell activity, and suppress viability, and ultimately converged on a selective HDAC1/2 inhibitor. Results: CRC cell lines, patient-derived organoids, and ApcKO mice treated with selective HDAC1/2 inhibitors illustrated induction of differentiation and suppression of stem cell activity by transcriptional and chromatin accessibility profiling. Streptavidin bead pulldown of a biotinylated HDAC1/2 inhibitor (using an inactive version as a control) followed by mass spectrometry confirmed specific interaction with HDAC1/2, ensuring on-target activity. By testing several HDAC inhibitors in CRC cell lines, we found that HDAC1, 2, and/or 3 inhibition is required for the differentiation phenotype. To identify the mechanism of action, we pursued unbiased global histone modification profiling upon HDAC1/2 inhibitor treatment and observed increased acetylation (ac) of H3K9, H3K27, and H4K8. To elucidate how acetylation of these specific histones induced differentiation, we performed chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq) in CRC cell lines treated with two HDAC1/2 inhibitors. Intriguingly, only regions with increased H3K27ac bound by HDAC1/2 were significantly associated with differentiation transcriptome and chromatin accessibility profiles. Blocking H3K27ac by degrading EP300/CBP reversed the differentiation phenotype induced by HDAC1/2 inhibition, confirming its necessity. Conclusions: Despite HDAC inhibitors being unsuccessful with previous CRC clinical trials, our HDAC1/2 inhibitor demonstrated synergistic killing and differentiation effect with 5-fluorouracil, the backbone of the most common treatment regimens for GI cancers. Romidepsin, an HDAC1/2 inhibitor approved for cutaneous T-cell lymphoma, reproduced similar phenotypes in CRC cell models. These preclinical studies highlight the possibility of using a small molecule HDAC1/2 inhibitor as a pro-differentiation therapy in colorectal cancer.