bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterizing the genomic landscape of locally advanced pancreatic cancer.
Authors: Gonzalez Conchas Galileo Arturo , O'Kane Grainne M. , Denroche Robert Edward , Jang Gun Ho , Fischer Sandra , Dodd Anna , Picardo Sarah Louise , Holter Spring , Wilson Julie , Zogopoulos George , Elimova Elena , Prince Rebecca M. , Jang Raymond Woo-Jun , Moore Malcolm J. , Biagi James Joseph , Notta Faiyaz , Grant Robert C , Gallinger Steven , Tsang Erica S , Knox Jennifer J. 
Published: January 2024

697 Background: Locally advanced pancreatic cancer (LAPC) accounts for approximately 30% of pancreatic ductal adenocarcinomas (PDAC). Optimal management for LAPC is controversial and combination treatments are extrapolated from treatment guidelines for metastatic disease. The biological underpinnings of LAPC remain unclear, although the loss of tumor suppressor SMAD4 has been associated with metastatic disease. Here we characterize the genomic landscape of LAPC in a large series of prospectively sequenced PDAC. Methods: Clinical, genomic and survival data were obtained from the COMPASS trial (NCT02750657), a prospective multi-institutional study that included patients with treatment-naïve advanced PDAC, with predominantly metastatic cases due to ease of biopsy. Fresh tumor tissue was acquired by percutaneous core biopsy for real-time whole genome sequencing (WGS) and RNA sequencing (RNAseq). Laser capture micro-dissection was performed for all cases. Response to therapy was assessed every 8 weeks, and patients were followed prospectively. Results: Of 268 patients (268 with available WGS and 253 with RNAseq), 37 (14%) had LAPC. Baseline epidemiological variables were similar, with no differences between sex, age, smoking status, or history of diabetes. Patients with LAPC had a lower BMI (median 22 vs 24, p=0.005) and lower baseline CA19-9 (median 488 vs 2551, p=0.002) than metastatic cases. All patients with LAPC had a low (<2 points) Gustave Roussy Immune Score, previously shown to be prognostic in our dataset. Driver alternations were similar in LAPC and metastatic cases with no differences in SMAD4 loss between the two groups; however, major imbalances in mutant KRAS were absent in the LAPC group. The burden of SNVs, indels and SVs was significantly lower in LAPC (Table). All LAPC cases demonstrated a classical RNA subtype, compared to 23% in metastatic cases ( p=0.0008). Median OS measured 12.5 and 8.3 months for LAPC and metastatic cases, respectively (HR 0.65, 95% CI 0.48-0.89, p=0.003). In addition, when measuring CD8+ T cell infiltration by IHC using median cut-off values, primary site biopsies had a higher CD8+ T cell infiltrate compared to metastatic sites (77% vs 56% CD8-high, respectively, p=0.01). Conclusions: These integrated genomic, RNA subtyping and early immunophenotyping results suggest that LAPC demonstrate less genomic instability and classical programming. Further study will delineate how these genomic differences, along with better clinical features, may influence treatment decision-making and design of future clinical trials. Clinical trial information: NCT02750657 . [Table: see text]
Impact of site of metastases in pancreatic ductal adenocarcinoma.
Authors: Arshad Adeel , Zhao Songzhu , Wei Lai , Stephens Julie , Manne Ashish , Noonan Anne M. , Rahman Shafia 
Published: January 2024

708 Background: Metastatic pancreatic ductal adenocarcinoma (mPDAC) has a 5-year survival rate of 3%. We examined the clinical significance of the metastatic site on outcomes in mPDAC using the Surveillance, Epidemiology, and End Results (SEER) database. Methods: We analyzed the data on mPDAC from SEER database from 2010-2020 and categorized into three groups: mPDAC with, liver-only (LO) metastasis (mets), multi-organ mets including the liver (IL), and multi-organ mets excluding the liver (EL). Patient demographics and disease characteristics were summarized using the mean for continuous variables and proportions for categorical variables. Overall survival (OS) was calculated from time of diagnosis to death or censored at a loss to follow-up. The survival curve was plotted using the Kaplan-Meier method and log-rank p-value was reported. The Cox regression model was used to study the association of site of distant metastasis on overall survival, controlling for potential confounders (age, race, treatment, etc.) Results: We identified 22642 patients with mPDAC; 15844, 4250, and 2548 with LO, IL, EL mets respectively. The mean age at diagnosis was 66 years with the majority being white (78.4%), non-Hispanic (87.1%), and from metropolitan counties (88.5%). The median OS was 4 months, 3 months, and 6 months (log-rank p<0.001) for LO, IL, and EL groups respectively, with 2-year survival being 4.84%, 2.56% and 7.89% respectively (log-rank p<0.001). Multivariate analysis showed a higher risk of mortality in LO (31.5%, hazards ratio (HR)=1.315, p<0.001) and IL groups (69.2% HR=1.692, p<0.001) than EL group (Table). Conclusions: The site of distant metastasis is an independent prognostic factor for survival in patients with mPDAC, with liver-only mets or multi-organ mets including liver having worse OS than extrahepatic mets. [Table: see text]
Gastrointestinal cancer trends in the Hispanic population: A SEER database population study (2000-2019).
Authors: Hechter Sharon , Nikiforov Ivan , Greenberg David B. 
Published: January 2024

725 Background: Cancer continues to be the leading cause of death in the Hispanic population. Gastrointestinal cancer surveillance data in Hispanic individuals has only recently become available in the last 3 decades. Differences in incidence rates among Hispanics and Non-Hispanic Whites (NHWs) need further elucidation. In this study, we analyzed trends in Hispanics and NHW populations across multiple gastrointestinal cancers. Methods: Gastrointestinal cancers (liver, colon and rectum, pancreas, esophagus, gallbladder, stomach, small intestine, anus, anal canal and anorectum) diagnosed between 2000-2019 were identified in the Surveillance, Epidemiology, and End Results Program (SEER) Database. We calculated incidence rates, confidence intervals and incidence rate ratios. Rates are per 100,000 and age adjusted to the 2000 US standard population. Rate ratios are the rounded rates in Hispanic individuals divided by the rounded rates in NHWs. Results: There was a higher incidence of liver, gallbladder, and stomach cancers among Hispanics when compared to NHWs between the years 2000-2019. Liver cancer incidence rate is (11.5 per 100,000) in Hispanics compared with (6.3 per 100, 000) in NHWs with an incidence rate ratio of 1.8. Gallbladder cancer incidence rate is (2.2 per 100,000) in Hispanics compared with (0.9 per 100,000) in NHWs with an incidence rate ratio of 2.4. Stomach cancer is (10.9 per 100,000) in Hispanics compared with (5.7 per 100,000) in NHWs with an incidence rate ratio of 1.9. The lowest incidence rate ratio was seen for anus, anal canal and anorectum cancers in Hispanics compared to NHWs. The incidence rate is (1.2 per 100,000) in Hispanics compared with (2.1 per 100,000) in NHWs with an incidence rate ratio of 0.6. Remaining cancers had incidence rate ratios less than 1.0 and were more likely to occur in NHWs. Conclusions: This study illustrates differing incidence rates of multiple gastrointestinal cancers among Hispanics compared to NHWs. Liver, gallbladder and stomach cancer incidence rates in Hispanics is double that of NHWs. Interestingly, the remaining gastrointestinal cancers had higher incidence rates among NHWs. Further research is warranted to understand the differences in cancer risk within the Hispanic population as well as healthcare access, language barriers and cultural differences that may play a role.[Table: see text]
Liquid biopsy-based comprehensive genomic profiling to reveal mutational landscape in real-world patients with gastrointestinal cancer.
Authors: Tang Haoran , Zhang Xiaogang , Xie Feng , Zhang Yue , Jia Shidong 
Published: January 2024

735 Background: Molecular characteristics hold substantial clinical significance in cancer. Previous research has elucidated the molecular classification of gastrointestinal (GI) cancers, leveraging biomarkers like gene alterations, MSI, EBV status, and chromosomal instability. However, most of these studies relied on tissue biopsies. Limited investigations have been documented regarding the characterization of molecular profiles through liquid biopsy. Here we present a comprehensive genomic profiling study conducted on advanced GI cancer patients using blood samples. Methods: This prospective study is a part of a global initiative focused on molecular biomarker screening across various solid tumors. Here we report the early result of 106 unresectable GI cancer patients, encompassing those with advanced disease or experiencing relapse after prior treatments. The cohort comprises 66 colorectal cancer (CRC) patients, 34 gastric cancer (GC) patients, and 6 esophageal cancer (EC) patients. Each patient contributed a 10-mL blood sample for comprehensive circulating tumor DNA (ctDNA) analysis. The study employed PredicineCARE, a 152-gene, NGS-based liquid biopsy assay, to profile somatic gene variations within this patient population. Results: The study revealed a total of 1,597 somatic mutations, with 1,077 occurring in CRC, 448 in GC, and 72 in EC. Additionally, 722 gene copy number variants were identified, with 288 in CRC, 351 in GC, and 83 in EC patients. In CRC, the most frequently altered genes (prevalence > 20%) included TP53 (58%), APC (45%), KRAS (33%), and BRCA2 (22%). Conversely, in GC, the most altered genes were TP53 (59%), TERT (35%), FAT1 (29%), ARID1A (26%), and FGFR4 (24%). Among the 6 EC patients, 3 carried TP53 variations, with variations in APC (N=2), ERCC5 (N=2), FAT1 (N=2), and EGFR (N=1) also observed. The mutation burden in CRC (median 3.73 mut/Mb) and GC (median 3.57 mut/Mb) displayed no significant differences. However, the mutation burden in CRC was significantly higher than that in EC (2.24 mut/Mb) (p=0.04). A similar pattern was observed between GC and EC but did not reach statistical significance (p=0.10) due to limitations in cohort size. Furthermore, the assay identified patients carrying both germline and somatic mutations related to homologous recombination deficiency (HRD). In CRC patients, 5 had MLH1 germline mutations, 6 had MSH2 mutations (5 were germline), 4 had MSH6 germline mutations, 2 had PMS2 somatic mutations, and 1 had an EPCAM germline mutation. While in GC patients, 2 had MLH1 germline mutations, 1 had an MSH6 mutation, and 1 had a PMS2 somatic mutation. Conclusions: This study elucidated the comprehensive mutational landscape of advanced gastrointestinal cancer through liquid biopsy, thereby contributing novel biomarkers for clinical diagnosis and facilitating targeted therapy mechanism investigations.
Role of proton pump inhibitors in immune checkpoint inhibitor colitis.
Authors: Pradeep Roshini , Moshtaghi Afsheen , Khan Hamza , Walenga Ann K , Rocca Neychelle , Kudelka Andrzej Piotr 
Published: January 2024

743 Background: Proton pump inhibitors (PPIs) are known to be beneficial in symptomatic control of gastroesophageal reflux disease and gastritis which can be a common complication of various cancers specifically gastrointestinal (GI) cancers. Microscopic colitis development has been studied to be associated with PPI use. Immune checkpoint Inhibitor (ICI) colitis is a known adverse effect of Inhibitors of Programmed cell death 1 (PD-1) and its ligand (PD-L1). Previous studies have also shown use of PPIs and NSAIDs are common risk factors which can exacerbate ICI Colitis caused by Inhibitors of PD-1 and PD-L1. This study is designed to observe association of certain drugs especially PPIs in ICI colitis. Methods: This is a single center, retrospective, and observational study that investigated patients treated with PD-1 and PD-L1 Inhibitors for management of any type of cancer between January 2022- September 2023. A list of patients treated with PD-1 and PD-L1 inhibitors was obtained from Inpatient pharmacy records followed by retrospective chart review to look for symptoms of colitis and other medications used by each patient. Primary outcome was to observe the role of PPIs in ICI colitis. Secondary outcomes were to observe the number of patients with GI cancers on PPIs who developed colitis. We also observed the effect of NSAIDs use as a potential risk factor in the population with ICI colitis. Results: The data consisted of 93 patients of which 17 (18.3%) developed colitis. Among this population 13 (76.5%) was ICI colitis, 2 (11.7%) was diverticular colitis and 2 (11.7%) was Infectious colitis. PPI use was seen in 3 out of 13 patients (23%) with ICI colitis. Patients with any type of GI cancer who developed colitis was 5 (25%) and PPI use in ICI colitis was seen in 2 out of these 5 patients. NSAIDs use was seen in 3 (23%) patients with ICI colitis. Conclusions: We did not observe significant association between PPI use and ICI colitis. ICI use becoming increasingly common in oncologic population, larger studies may be needed to further evaluate risk factors associated with ICI colitis in this population.
Phase Ib adaptive study of dasatinib for the prevention of oxaliplatin-induced neuropathy in patients with gastrointestinal (GI) cancers receiving FOLFOX chemotherapy with or without bevacizumab.
Authors: Noonan Anne M. , Schnell Patrick , Trunzo Danielle , Thornton Wendy , Malalur Pannaga G. , Manne Ashish , Abushahin Laith I. , Rahman Shafia , Jin Ning , Hays John L. , Elkhatib Rifat T. , Mittra Arjun , Roychowdhury Sameek , Lustberg Maryam B. , Sparreboom Alex , Hu Shuiying 
Published: January 2024

745 Background: Neurotoxicity is one of the most significant and disabling side effects of oxaliplatin (OX) and frequently limits the amount of OX that can be used. OX uptake by organic cation transporter 2 (OCT2) into mouse and rat dorsal root ganglia is a prerequisite for OX-induced peripheral neuropathy (OIPN). Preclinical data in rat and mouse models from our group showed that by inhibiting YES1, pre-treatment with dasatinib (D) inactivated OCT2 and prevented acute and chronic OIPN. A phase I trial is ongoing investigating addition of D prior to OX to prevent OIPN. Methods: This was a Bayesian Phase 1b dose-finding study with adaptive dose selection using efficacy-toxicity trade-offs in patients (pts) with GI cancers who are candidates for mFOLFOX6 ± bevacizumab [NCT04164069]. Pts received chemotherapy on day 1 and 15 schedule, every 28 days. D was administered at one of 2 dose levels – 100mg or 140mg PO, given 24 hours and 30 mins prior to OX on C1D14, C1D15 respectively and repeated on C1D28 and C2D1. During cycle 1, pharmacokinetic and pharmacodynamic data was obtained at baseline, during, and up to 24 hours after D or OX administration. Recommended Phase 2 dose (RP2D) was defined as the lowest intermittent dose of D that affects serum biomarkers of OCT2, including methylnicotinamide (NMN) and creatinine, by ≥2-fold without influencing the clearance of oxaliplatin by ≥20%. CIPN20 questionnaire was completed prior to each dose of FOLFOX on screening through to C3D1. Weakly informative Jeffreys priors were used for response and toxicity probabilities, with the latter constrained to be increasing with dose. Results: 13 pts were screened. 5 pts enrolled in cohort 1 (D 100 mg), 2 in cohort 2 (D 140 mg) and 2 in cohort 3 (D 140mg). 6 pts were not evaluable for the efficacy and toxicity endpoints due to screen failure or early study discontinuation. 7 patients were evaluated for efficacy biomarkers and 6 pts were evaluated for both efficacy biomarkers and toxicity. There were no DLTs observed in any cohort. 4/7 pts had ≥2-fold increase in AUC of NMN, and 3/7 pts had ≥2-fold increase in AUC of creatinine. 6/7 pts had ≤20% change in the clearance of OX. Conclusions: Addition of D 100mg or 140mg to traditional FOLFOX regimen was safe and in the majority of pts appeared to alter serum biomarkers of OCT2 in a manner suggesting inhibition of OX uptake in the DRG. 140mg was the chosen RP2D. A randomized phase II study is planned using D to prevent OPIN. Clinical trial information: NCT04164069 . [Table: see text]
Use of tumor-informed ctDNA across gastrointestinal cancers.
Authors: Reilley Matthew , Kunk Paul Raymond , Le Tri Minh , Rehman Muneeb 
Published: January 2024

758 Background: In colorectal cancer (CRC), the use of ctDNA for the purpose of early recurrence detection and prognostication is established, and multiple studies are testing its utility for guiding adjuvant therapy decisions. Tumor informed testing can be performed in clinical situations where adequate tissue is available for next-generation sequencing (NGS). Increasingly, ctDNA testing is being used clinically for colorectal cancer patients and other gastrointestinal (GI) cancers when there is an appropriate clinical scenario and adequate tumor tissue is available for sequencing. Methods: We identified GI cancer patients treated at our institution where Signatera (Natera) testing was ordered and performed between 2020 – 2023. We included all patients for whom testing was ordered. Then, among patients with any result further analyzed results by disease type, stage, and results. We examined clinical rationale for testing and whether results informed subsequent decisions. Results: A total of 99 GI cancer patients for whom ctDNA testing was ordered were identified. 80 patients had at least 1 ctDNA result including 68 colorectal patients and 12 other GI cancers (anal, bile duct, esophagogastric, pancreatic, and small bowel). Among patients with measurable ctDNA, at the most recent testing timepoint 16 had levels that met criteria for positive detection, while 64 were undetectable. Most commonly, testing was ordered in stage II/III CRC patients for post-operative surveillance. Other clinical use scenarios included 1) surveillance/treatment monitoring in oligometastatic CRC, 2) surveillance in non-metastatic esophagogastric cancer, 3) treatment monitoring in MSI-H/immunotherapy sensitive GI cancers. For at least 18 patients, results were a factor in shared clinical decision making between patients and providers. Conclusions: We found ctDNA monitoring is most commonly used in the adjuvant setting for CRC patients which is best supported by existing studies. Our data demonstrates that tumor informed testing can be successful in other GI cancers for both surveillance and therapy monitoring. Given the broad and rapid adoption of this technology, there needs to be continued efforts for both prospective validation studies and retrospective real world studies to guide clinical practice.
Gender disparities in the National Institutes of Health funding for gastrointestinal oncology.
Authors: Khan Sara , Sohail Aruba , Ukrani Janta , Zahid Ibrahim , Eshaghi Faraz , Khan Kainat , Thakore Shaival , Jaglal Michael Vishal , Farooq Muhammad Zain 
Published: January 2024

763 Background: Traditionally, there has been an under-representation of women in academic fields, thus making them less likely to receive grants. This study examines the trend of funding allocation of R01 grants in Gastrointestinal oncology by the National Institutes of Health with specific focus on the distribution of funding between gender. Methods: The data were retrieved from the NIH RePORTER (Research Portfolio Online Reporting Tools Expenditure) using gastrointestinal oncology-related search terms from 2018-2021. The gender was categorized using Genderize. The number of citations, publications, H-index, and seniority were obtained from Scopus and Web of Science in December 2022. Consumer Price Index was used to adjust funding amount to 2021 equivalent U.S. dollars. Linear regression was used for analysis. Results: A total of 1426 NIH-funded R01 grants amounting to 626.6 million were awarded for gastrointestinal oncology research. Women (n=391; 27.4% [95% CI: 25.1%-29.7%]) received fewer grants than men (n=1035; 72.6% [95% CI: 70.3%-74.9%]). From 2018-2021, there was no significant difference in the number of grants awarded among both men (263 to 259, p=0.65) and women (90 to 105, p=0.12). Similarly, there was no significant change in the grant amount (in millions) awarded among men (114.7 to 111.2, p=0.86) and women (39.8 to 47.9, p=0.19). Colorectal cancer accounted for the greatest proportion of grants (n=528; 37.0% [95% CI: 34.5%-39.5%]), amounting to 235.9 million. Of the 481 co-PIs, 405 (84.2% [95% CI: 80.9%-87.5%]) were men and 76 (15.8% [95% CI: 12.5%-19.1%]) were women. Male PIs as compared to female PIs had a higher h-index (52 vs 40, p<0.001), a higher number of publications (160 vs 111, p<0.001), and were cited more (13324 vs 6371, p<0.001). Funding amount was significantly associated with gender (β=0.06, p=0.02), number of publications (β=0.17, p<0.01) and institution (p<0.01). Conclusions: Our analysis shows continued gender disparity as only 27% of total R01 grants towards gastrointestinal oncology were granted to females during the fiscal years of 2018-2021. Thus, a collaborative effort is needed to close the divide and advance gender equality. [Table: see text]
Real-world adoption of 3 months of adjuvant oxaliplatin chemotherapy in patients with stage III colorectal cancer (CRC).
Authors: Krishnan Tharani , Solar Vasconcelos Joao Paulo , Lim Howard J , Loree Jonathan M. , Davies Janine Marie , Gill Karamjit , Gill Sharlene 
Published: January 2024

83 Background: Based on the IDEA analysis, 3 months (mos) of adjuvant chemotherapy (ACT) with CAPOX has emerged as an option for both low-risk and high-risk stage III CRC. This has resource utilization, cost and toxicity benefits (particularly less neurotoxicity) without compromising efficacy. This study examines the patterns of uptake of CAPOX vs FOLFOX and duration of ACT in a contemporary post-COVID real-world cohort of patients (pts) in the province of British Columbia (BC), Canada. Methods: The provincial pharmacy database was used to identify pts with resected stage III CRC who received adjuvant CAPOX or FOLFOX between January 2021 and December 2022. Pts with rectal cancer requiring neoadjuvant chemotherapy or radiotherapy were excluded. Demographic, tumor, and treatment information was collected. “High-risk features” were defined as pT4 or pN2 tumors. “Urban” setting was defined based on the population size of the regional health authority. Descriptive statistical analyses were performed to examine baseline characteristics and Fisher’s exact test was used to examine univariate associations. Results: 452 pts were included, of which 234 (52%) and 218 (48%) were planned to receive 3 and 6 mos of ACT respectively (see table). Within the 3 mos group, 226 (97%) received CAPOX. Within the 6 mos group, there was a 51%/49% split between CAPOX/FOLFOX. By univariate analysis, factors associated with 3 mos of CAPOX vs 6 mos of ACT were age >70y (P=0.039), low/intermediate grade (P=0.005) and low-risk stage III disease (P<0.0001). 29% of pts planned for 6 mos of oxaliplatin ACT had low-risk disease, with 52% of these receiving CAPOX. Conclusions: 3 mos of adjuvant CAPOX is an accepted option for nearly all pts with stage III disease with consequent less neurotoxicity and fewer treatment visits. Yet, in this contemporary cohort, use of 3 mos of adjuvant CAPOX remains low and is associated with older age and low-risk disease. 6 mos of oxaliplatin is still being offered to pts with low-risk disease. Exploration of patient preferences, real-world treatment and time toxicities, and resource costs may improve more widespread adoption of 3 mos of adjuvant CAPOX in stage III CRC. [Table: see text]