bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exploring demographic differences and outcomes in young-onset colorectal cancer.
Authors: Vadehra Deepak , Siromoni Beas , Groman Adrienne , Mukherjee Sarbajit 
Published: January 2023

35 Background: Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States (1). The incidence of young-onset CRC is on the rise based on recent data (2). Previous research on other cancers has shown that patients living in rural areas have worse outcomes (3). This study aimed to investigate the geographic and socio-demographic disparities in young-onset CRC patients. Methods: We conducted a retrospective study on colorectal cancer patients between 1975 and 2016 using the Surveillance, Epidemiology, and End Results (SEER) database. Both univariate and multivariable analyses were performed to evaluate overall survival (OS) and disease-specific survival (DSS). Socio-demographic factors, including the location of residence [metro area (MA) or rural area (RA)], gender, race, insurance status, and marital status, were analyzed. Young-onset colorectal cancer (CRC) was defined as the age of diagnosis less than 50 years. The program used for analysis was SAS software 9.4 (SAS Institute Inc., Cary, NC, USA.) Univariate and multivariable models were analyzed using Cox proportional models. Demographic differences between urban and rural population were assessed using Wilcoxon Rank Sum test (continuous variable) and Chi-square test (categorical variables). Results: A total of 73,378 [RA, N = 7,636(10.6%); MA, N = 64,605(89.4%)] young-onset CRC patients were included. RA had more Caucasian patients compared to MA (80.5% vs 60%, p < 0.001). Patients living in RA were more likely to be uninsured (4.8% vs 3%, p < 0.001) than MA. During the study period, the incidence and mortality rates were consistently higher in RA vs. MA. Univariate and multivariable analysis showed that RA had worse OS (multivariate HR = 1.14; p < 0.01) and DSS (multivariate HR = 1.15; p < 0.001) compared to MA. Similarly, males, single and uninsured patients had worse OS and DSS compared to females, married, and insured patients, respectively. Conclusions: Our study identified social and demographic disparities in young-onset CRC incidence and outcomes. Potential causes may include access to healthcare, diet, health behavior, and environmental factors. Future research is needed to understand and attenuate such disparities.
Ramucirumab beyond progression plus TAS 102 in patients with advanced or metastatic adenocarcinoma of the stomach or the gastroesophageal junction, after treatment failure on a ramucirumab-based therapy: Final results of the phase II RE-ExPEL study.
Authors: Goetze Thorsten Oliver , Stein Alexander , Lorenzen Sylvie , Habibzada Timorshah , Goekkurt Eray , Herhaus Peter , Sookthai Disorn , Ihrig Kristina , Pauligk Claudia , Al-Batran Salah-Eddin 
Published: January 2023

359 Background: Based on results of prior trials (TAGS, REGARD, RAINBOW), it seems promising to combine Ramucirumab (Ram) beyond progression (PD) with TAS-102 (trifluridine/tipiracil). The purpose of RE-ExPEL is to investigate the tolerability, safety and benefit of Ram beyond PD in combination with TAS-102 in advanced esophagogastric adenocarcinoma (EGA). Methods: This is a multicenter, non-randomized, open-label investigator initiated pilot trial. 20 ram-pretreated patients (pts) with advanced EGA were enrolled to a maximum of 4 cycles of ramucirumab 8mg/kg every two weeks (days 1, 15; qd28) plus TAS-102 35 mg/m2/p.o. bid (d1-5 and d8-12; qd28). Primary endpoint (EP) was tolerability and toxicity, defining a positive trial if SAE rate according (acc.) to CTCAE 5.0 will increase less than 30% (up to 55%) compared with results from TAGS (SAE-rate 43%). Secondary EPs are further safety data and efficacy data, OS, PFS and ORR. Results: 20 pts (20% female) were enrolled between Oct 2020 and Aug 2021, 20% gastric and 80% GEJ- cancers, 55% of pts with ECOG 0. Results of the final analysis showed that only 25% of pts had at least one SAE and the total no. of SAEs was 9, one with fatal outcome, all without relationship to systemic therapy and no SUSAR reported. RE-ExPEL was able to show a median OS of 9.07 mo (95% CI 5.42-10.09) and a DCR of 45%. 90% of pts got study medication in 3rd line whereas 10% were even further line pts. Conclusions: The safety data showed a favorable safety profile with a low rate of severe toxicity for ram+TAS-102, maybe due to the long disease stabilization and therefore less tumor associated symptoms. Regarding the primary safety endpoint, the trial was positive with even a numerically lower SAE rate compared with TAGS. Furthermore, RE-ExPEL was able to show very promising efficacy data for the combination ram plus TAS-102 with median OS of 9.07 mo. Ram+TAS-102 seems to be more effective than TAS-102 alone acc. to TAGS-trial respecting the limitation of the RE-ExPEL one arm study design with only 20pts. The combination needs further evaluation in a randomized phase III trial. Clinical trial information: NCT04517747 .
Sidedness and addition of chemotherapy associated with treatment outcomes of regorafenib for metastatic colorectal cancer (mCRC).
Authors: Wu Tsung-Che , Liang Yi-Hsin , Chen Kuo-Hsing , Chuang Chien Huai , Shao Yu Yun 
Published: January 2023

36 Background: Regorafenib is one of the options of salvage treatment for mCRC. We aimed to explore the prognostic factors of such regorafenib treatment. Methods: We searched the database of National Health Insurance, Taiwan for patients who initiated regorafenib treatment for mCRC from September 1, 2015, to December 31, 2018. Database interrogation of National Death Registry, Taiwan and Taiwan Cancer Registry was conducted for survival data and clinicopathological variables, respectively. Results: A total of 3,643 patients were included in the analysis. The median age was 61.2 years. The primary tumor was left-sided and KRAS mutant in 75.3% and 54.5% of patients, respectively; 28.9% of patients received chemotherapy simultaneously, with irinotecan as the most common companion. The median time to treatment discontinuation (TTD) was 2.3 months (95% confidence interval [CI]: 95% CI: 2.3-2.3), and the median overall survival (OS) was 7.2 months (95% CI: 6.9-7.4). Patients with left-sided primary tumors, compared with patients with right-sided tumors, exhibited significantly longer TTD (median, 2.4 vs. 2.1 months, p < 0.001) and OS (median, 7.6 vs. 6.1 months, p < 0.001). By contrast, TTD and OS of patients under regorafenib treatment were similar regardless the KRAS mutation status ( p = 0.415 and 0.643, respectively). Patients who received chemotherapy along with regorafenib, compared with patients who did not, also exhibited significantly longer TTD (median, 2.6 vs. 2.2 months, p < 0.001) and OS (median, 8.3 vs. 6.7 months, p < 0.001). In multivariate analysis adjusting age, sex, time from colorectal cancer diagnosis, hospital level, KRAS mutation, and initial regorafenib dose, left-sidedness of the primary tumor remained a predictor for better TTD (hazard ratio [HR]: 0.88, p = 0.002) and OS (HR: 0.92, p = 0.048), as well as addition of chemotherapy (for TTD, HR: 0.86, p < 0.001; for OS, HR: 0.76, p < 0.001). Due to the interaction between sidedness and KRAS mutation, we established separate Cox models and found that left-sided primary tumor was an independent predictor for better TTD and OS for KRAS wild-type tumors, but not for KRAS mutant tumors. Conclusions: In this population-wide cohort study, left-sided primary tumor and addition of chemotherapy were associated with better TTD and OS of regorafenib treatment for mCRC.
Emergence of RAS mutations in RAS wild type metastatic colorectal cancer patients receiving cetuximab as first-line treatment: A prospective study.
Authors: Tsai Hsiang-Lin , Wang Jaw-Yuan 
Published: January 2023

38 Background: Metastatic colorectal cancers (mCRC) with wild-type KRAS are often sensitive to anti-EGFR, but occasionally develop resistance within treatment. A major limitation of treatment that selectively target kinase signaling pathways is the emergence of secondary resistance. However, interlink between emergence of KRAS mutations and secondary resistance to anti-EGFR remains to be further elucidated. In this study, we investigate evolutional changes of KRAS mutations through liquid biopsy in mCRC patients under cetuximab-treatment. Methods: Patients enrolled to receive cetuximab plus FOLFIRI or mFOLFOX6 as first-line treatment. The treatment was anticipated to be continued until disease-progression, intolerable toxic effects, or withdrawal of consent. Blood samples from patients were collected before and every three months during the cetuximab-treatment, and were required at disease-progression. These samples were evaluated for KRAS mutation using the MassARRAY platform. The primary endpoint was the percentage of patients with KRAS mutation detected during treatment. The clinical outcomes of these patients with emergence of mutant KRAS were further analyzed. Results: 108 mCRC cetuximab-treated patients, 95 patients combined with FOLFIRI and 13 patients with mFOLFOX6, were enrolled between January 2018 and June 2020. The median follow-up time was 26.5 months [interquartile range (IQR), 17.0-37.0 months]. The median duration of cetuximab-treatment was 9.0 months (IQR, 5.0-12.0 months). The percentage of detected KRAS mutations during cetuximab-treatment was 9.26%. Median emergent time of KRAS mutation from initial treatment was 5.0 months (IQR, 2.0-7.5 months). The median duration from KRAS mutation to disease-progression was 3.0 months (IQR, 2.0-6.5 months). The median progression-free survival (PFS) and overall survival (OS) of emergent RAS mutations and RAS wild-type were 8.0 versus 19.0 months ( P = 0.002) and 20.0 versus not-reach months ( P = 0.027), respectively. Conclusions: The identified KRAS mutations as a predictor of early resistance during cetuximab therapy, indicating that emergence of KRAS-mutant clones can be detected 3 months prior to radiographic progression. Emergent RAS mutations were associated with less favorable patient outcomes. Clinical trial information: NCT03401957 .
Five-year follow-up results of a randomized phase III trial comparing 4 and 8 courses of S-1 adjuvant chemotherapy for pathological stage II gastric cancer: JCOG1104 (OPAS-1).
Authors: Nunobe Souya , Yoshikawa Takaki , Nishida Yasunori , Yamada Takanobu , Kaji Masahide , Takagane Akinori , Teshima Shin , Matsushita Hisayuki , Tanaka Ryo , Hihara Jun , Katayama Hiroshi , Mizusawa Junki , Fukuda Haruhiko , Boku Narikazu , Terashima Masanori 
Published: January 2023

381 Background: Postoperative S-1 (80 mg/m2/day for 4 weeks and 2 weeks rest in one course) for 1 year corresponding to 8 courses is a standard adjuvant chemotherapy for pathological stage (pStage) II gastric cancer. To shorten the duration of S-1 chemotherapy, we conducted a phase III trial to confirm non-inferiority in relapse-free survival (RFS) of 4 courses of S-1 to 8 courses of S-1 for pStage II gastric cancer. When 590 patients were enrolled, the study was closed at the first interim analysis because of futility. The RFS at 3 years was 89.8% for 4-courses and 93.1% for 8-courses (HR 1.84, 95% confidence interval (CI) 0.93-3.63). This is a final 5-year follow-up results of this study. Methods: Key eligibility criteria were pStage II except for T1 and T3N0 (7th edition of TNM), ECOG performance status 0-1, R0 resection with D2 lymph node dissection for >clinical stage (cStage) II or D1+ lymph node dissection for cStage I, within 7 weeks after surgery, and age between 20 and 80 years. The total sample size was determined to be 1,000 with a 3-year RFS of 85% in both arms and non-inferiority margin of hazard ratio (HR) of 1.37, with one-sided alpha of 5% and 80% power. Results: Between Feb 2012 and Mar 2017, 590 patients, 295 for each arm, were enrolled. When closing the study, the patients who were allocated to the 4-courses arm were informed of the primary results and the recommendation to continue S-1 until 8 courses as an off-protocol when they were receiving S-1. The cut-off date for the final follow-up data was March 22, 2022 with a median follow-up period for surviving patients of 6.0 years (IQR; 5.0-7.2). In 4-courses arm, 27 patients were receiving S-1 when the study was closed at the interim analysis. Among them, 22 patients expressed their will to continue until 8 courses. The RFS at 3/5 years was 90.1%/85.6% for 4-courses and 92.2%/87.7% for 8-courses (HR 1.27, 95% CI 0.85-1.89). The overall survival at 3/5 years was 93.2%/88.6 for 4-courses and 94.9%/89.7 for the 8-courses (HR 1.12, 95% CI 0.72-1.75). The HR of the cumulative incidence of the recurrence was 1.38 (95% CI 0.85-2.24) for the 4-courses against 8-courses. Recurrence was frequently observed in patients who received up to 4 courses of S-1 (38 for 4-courses vs. 28 for 8 courses). The HR of the cumulative incidence of the peritoneal recurrence was 1.54 (95% CI 0.82-2.89) for the 4-courses against 8-courses. Conclusions: This final follow-up data confirmed the primary results presented at the interim analysis. S-1 adjuvant chemotherapy for 1 year for pStage II gastric cancer is highly recommended. Clinical trial information: 000007306 .
The effect of potassium-competitive acid blocker tegoprazan on gastric cancer cells.
Authors: Lee Sang Kil 
Published: January 2023

385 Background: Proton pump inhibitors (PPI) and potassium-competitive acid blocker (P-CAB) are both effective gastric acid secretion blockers. PPI was reported to inhibit proliferation and induce apoptosis of gastric cancer. However, no study on the effect of Tegoprazan, a novel P-CAB, on gastric cancer have been attempted. Methods: In this study, the anti-cancer effect of tegoprazan in gastric cancer cell line AGS and MKN74 were analyzed with esomeprazole (PPI) as a control. After treatment with tegoprazan and esomeprazole, AGS cells were analyzed with with RNA sequencing and Ingenuity Pathway Analysis (IPA). MTT assays, AnnexinV-FITC/PI staining, flow cytometry and western blot were used for subsequent analysis. The wound-healing assay, matrigel chamber assays, colony forming assay, and western blot of epithelial-mesenchymal transition (EMT) markers were used for analysis of oncogenic and migratory ability. Results: In RNA sequencing and subsequent IPA analysis, tegoprazan significantly increased the pathways involved in cell death of gastric cancer cell compared to esomeprazole. MTT assays proved that tegoprazan inhibits proliferation of AGS and MKN74 cells in dose-dependent manner. AnnexinV-FITC/PI staining and western blot demonstrated that tegoprazan stimulates apoptosis of gastric cancer cells. PI staining and flow cytometry confirmed that tegoprazan blocks G1/S phase entry, finally leading to cell cycle arrest. Moreover, wound-healing assay, matrigel chamber assays, colony forming assay, and western blot of epithelial-mesenchymal transition (EMT) markers indicated that tegoprazan inhibits cell migration, invasion, colony formation, and EMT. To determine key molecule of anti-cancer effect of tegoprazan, upstream regulator analysis in IPA was done and cMYC has strong effect on G1/S phase entry, through PI3K/AKT/GSK3β signaling pathway in this experiment. In this study, the experimental results for tegoprazan showed significant changes compared to esomeprazole. Conclusions: Our findings showed that tegoprazan has more evident anti-cancer effect than esomeprazole. cMYC could be a key molecule for anti-cancer effect through PI3K/AKT/GSK3β signaling pathway by tegoprazan in gastric cancer.
Local recurrence after curative resection of early gastric cancer by endoscopic submucosal dissection.
Authors: Joo Moon Kyung , Park Jong-Jae , Lee Beom Jae , Kim Sunsuk , Chun Hoon Jai 
Published: January 2023

388 Background: We investigate the local recurrence rate and its risk factors among patients who underwent endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) and are judged as curative resection. Methods: We enrolled patients who were diagnosed as EGC and underwent ESD during 2006 and 2020. Local recurrence after ESD was confirmed by histopathologic evaluation by endoscopic biopsy at ESD site during endoscopic surveillance. Results: A total of 936 patients underwent ESD for EGC, achieved curative resection and were followed up more than 12 months. Among them, 14 cases of local recurrence were found (14/936, 1.5%) during 53.2 months of follow-up. Compared with patients without local recurrence, those with local recurrence showed male-predominance (677/922 vs. 14/14, P=0.025), frequent presence of synchronous tumor (123/922 vs. 6/14, P=0.001) and larger tumor size (16.3 vs. 26.3 mm, P=0.001). Kaplan-Meier graph also showed that local recurrence significantly occurred in subgroup with male, presence of synchronous tumor and tumor size ≥ 20 mm ( P=0.028, 0.009 and <0.001 by log rank test, respectively). After propensity score matching for gender, age and comorbidities with 1:5 ratio, tumor size ≥ 20 mm was the only significant factor for local recurrence (odds ratio: 3.886, 95% confidence interval: 1.012-14.922, P=0.048) Conclusions: Endoscopists need to be cautious for local recurrence at ESD site even after curative resection of EGC, especially for large tumor size.
Tislelizumab combined with anlotinib and chemotherapy (XELOX) in the treatment of advanced gastric carcinoma: Preliminary results of a single-arm, open-label phase I/IIa trial (TALENT study).
Authors: Chen Xiaofeng , Wang Deqiang , Yuan Yuan , Tang Jie , Guo Fen , Chen Yizhang , Ding Junli , Hong Tingting , Lu Binbin , Li Wei , Wang Rong , Tian Yitong , Pan Lanlan , Zhang Jiaguang , Zhang Xinyi , Xu Tongpeng , Xu Hao , Shu Yongqian 
Published: January 2023

396 Background: PD-1 inhibitor combined with chemotherapy is one of the standard regimens for first line gastric. The addition of anti-vascularization agents has been reported to help improve the overall survival (OS) in GC/GEJC patients (pts) through vascular-normalization in the microenvironment. In this phase I/IIa study, we aim to explore the safety and efficacy of tislelizumab combined with anlotinib and XELOX (TAXE regimen) as first line treatment for advanced GC/GEJC. Methods: This prospective, multicenter, phase I/IIa study planned to enroll 9 patients in phase I and 57 patients in Phase IIa. The aim of this Phase 1 study was to determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD) and safety of 8 mg, 10 mg or 12 mg anlotinib in combination with XELOX and tislelizumab. The maximum tolerable dosage (MTD) would be administered to all pts in phase II. The primary and objective response rate(ORR). Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), OS, and safety. The exploring endpoint was to evaluate the association between the efficacy and the expression of biomarkers including PD-L1, microsatellite instability profile, and genome stability (GS). Results: From march 2021 to August 2022, 38 pts were enrolled (9 pts in phase 1). Phase 1 was completed without dosage limiting toxicities (DLTs). 12mg anlotinib was recommended for phase 2. Thirty two (84.21%) pts had at least one treatment-related adverse events (TRAEs), and 7 patients (18.42%) had at least one grade 3/4 TRAEs. Anemia (15 pts, 39.47%), leukopenia (12 pts, 31.58%) and fatigue (10 pts, 26.32%) were the most common TRAEs. Two pts achieved complete response (CR), 20 pts achieved partial response (PR), and 7 pts achieved stable disease (SD). The ORR was 75.86% (95% CI: 57.89%-87.78%), and the DCR was 100%. Conclusions: The preliminary results of this Phase I/IIa trial by using tislelizumab combined with anlotinib and XELOX had shown great potential in improving the response rate in advanced GC/GEJC patients with manageable toxicity. Clinical trial information: NCT04963088 .
A phase II biomarker-oriented study to evaluate paclitaxel, olaparib, and durvalumab combination in patients with advanced gastric cancer.
Authors: Kim Tae-Yong , Yoon Jeesun , Lee Dae-Won , Im Seock-Ah , Nam Ah-Rong , Bang Ju-Hee , Oh Kyoung-Seok , Kim Jae-Min , Jeong Yoojin , Choo Sea Young , Kim Hyo Jung , Lee Su In , Oh Do-Youn 
Published: January 2023

404 Background: DNA damage response (DDR) gene alterations are observed in 27% of gastric cancer (GC), therefore, targeting DDR might be an interesting strategy in GC. Olaparib plus paclitaxel showed numerically improved overall survival (OS) compared to paclitaxel in 2L GC patients (pts), even though it did not meet the endpoint. (Lancet Oncol 2017). Besides DNA damage repair, olaparib induces immune modulation. The role of immune checkpoint inhibitor (ICI) is established in 1L and 3L+ GC. The combination of cytotoxic chemotherapy, DDR acting agent and ICI might have synergistic effects in GC, which has not been tested in clinical studies. Here, we report biomarker-oriented phase II study of paclitaxel/olaparib/durvalumab combination in 2L GC. (NCT03579784). Methods: Advanced GC pts who have failed to 1L chemotherapy were enrolled. During 1st cycle, paclitaxel (80 mg/m2, D1, 8, 15 Q 4wk) and olaparib (150mg bid, D1-28) was administered. From 2nd cycle, durvalumab (1500 mg, D1 Q 4wk) was added on them. Tumor biopsy (pretreatment, after 1st cycle, at disease progression) and blood collection (every cycle) was mandatory. Primary endpoint was the disease control rate (DCR). Secondary endpoints included ORR, DoR, PFS, OS and safety. For biomarker study, multiplex IHC, NGS, ctDNA, and cytokines and angiogenic factors analysis were performed. Efficacy analysis set (ES) and safety analysis set (SS) were defined as pts who underwent at least one tumor assessment and all pts who received cycle1 day1 or more, respectively. Results: Fifty pts were enrolled (6 screening fail or withdrawal of consent, 44 in SS, 38 in ES) HER2+ GC were 13.2%. Among 38 in ES, DCR and ORR were 84.1% (95% CI, 72.5-95.7) and 39.5% (95% CI, 24.0-55.0) (1 CR, 14 PR and 17 SD). PFS, DoR and OS were 6.7 (95% CI, 4.5-10.3), 6.5 (95% CI, 5.1-10.7) and 11.4 (95% CI, 9.2-13.2) months. Homologous recombination repair (HRR) genetic alterations (9.6 vs. 5.9 in PFS, p=0.037), high CD8/CD3 ratio (8.8 vs. 3.7 in PFS, p=0.008), high PD-L1 (CPS≥10) (9.6 vs 5.1 in PFS, p=0.031), low ATM IHC (13.3 vs. 9.8 in OS, p=0.066), and low serum IL-6 (12.9 vs. 8.3 in OS, p=0.001) were associated with prolonged PFS or OS. In SS, most adverse events (AEs) were mild, and Gr 3/4 leukopenia and anemia were observed in 52.2% and 31.8%. There were no treatment related AEs resulted in study discontinuation. Conclusions: Paclitaxel/olaparib/durvalumab is a promising combination in 2L GC, and is worth to be further explored, especially in biomarker-enriched patients with HRR, specific T-cells subsets, high PD-L1, low ATM and IL-6. Clinical trial information: NCT03579784 .