bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gastric cancer burden: Evidence from a safety-net hospital.
Authors: Forlemu Arnold , Kosa Dimas , Findakly Dawood , Amar Surabhi 
Published: January 2021

187 Background: Gastric cancer is a leading cause of cancer-related deaths worldwide, with more than eleven thousand estimated gastric cancer deaths expected to occur this 2020 in the United States (US). Understanding the burden and trends in gastric cancer across demographics and different locations in the US is crucial to develop effective preventive strategies. This study describes, characterizes, and identifies high risk group gastric cancer patients, who may benefit the most from preventive and management strategies. Methods: A retrospective study was conducted between 2010 to 2019 at our institution to identify patients diagnosed with gastric cancer during that period. Data on demographics, risk factors, mode of presentation, pathology, site, type, and stage of gastric cancer were obtained. Chi-square was used to compare categorical variables. Regression analysis was used to evaluate factors associated with late-stage disease and cancer type. Results: A total of 111 patients were analyzed in this study. The median age of gastric cancer patients was 52 years (range 27 to 87 years). Most of the patients were Hispanic (70.3%), non-citizens (59.5%), were uninsured (69.4%), and 67.6% were living below the federal poverty level (FPL). Also, 31.5% of the patients had a family history of cancer, had diffuse-type adenocarcinoma (61%), late-stage disease (76.6%), 52.4% of the cancers were in the distal portion of the stomach. Uninsured patients were more likely to die compared to insured patients, however, this difference was not statistically significant (64.9% vs 47.1%, p = 0.077). Age below 40, Hispanic ethnicity, being uninsured, and living below FPL were associated with higher rates of late-stage disease and diffuse-type cancer (p < 0.05). Conclusions: Our data suggest a younger age at gastric cancer diagnosis than the national average. Moreover young, and uninsured Hispanics presented with advanced gastric cancer and may represent a high-risk target population for preventive strategies.
Serum pepsinogen as a biomarker for gastric cancer: A nested case-control study using the prostate, lung, colorectal, and ovarian (PLCO) cancer screening trial data.
Authors: In Haejin , Friedmann Patricia , Parides Michael , Sarkar Srawani , Castle Philip E. , Epplein Meira 
Published: January 2021

188 Background: Gastric cancer (GC) lacks specific symptoms, resulting in diagnosis at later stages and high mortality. Serum pepsinogen is a biomarker for atrophic gastritis, which is an intermittent phase in the development of GC. A serum based biomarker that indicates increased risk of GC would be useful for targeted prevention strategies. Methods: The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial is a large randomized trial conducted over 10 centers in the US between 1993 and 2001. Serum samples were collected at baseline and participants were followed for development of incident GC. ELISA-based pepsinogen tests were conducted on pre-diagnostic serum samples of patients who developed GC and age, sex, and race-matched controls. Pepsinogen negative (PG-) and positive (PG+) status was determined using pepsinogen I (PGI) and pepsinogen I to II ratio (PGR). Those with PGR ≥ 3 and PGI > 70µg/L were considered PG- while those with lower levels on either or both were considered PG+. Cox proportional hazard models were used to determine the hazard ratio (HR) and 95% confidence intervals (95%CI) of PG+ for GC. To examine the association of PG with non-cardia and cardia GC separately, propensity matching was used to create control subsets matched on age, sex, and race. Results: Pepsinogen test results were available on 105 GC cases (70 non-cardia and 35 cardia) and 220 matched controls. Median and range of time from pepsinogen measurement to incident GC diagnosis was 78.6 and 3.0-152.2 months, respectively. GC patients were more likely to be PG+ (31.4% vs 5.5%, p < 0.001) and current smokers (20.0% vs 7.7%, p = 0.004) at baseline than controls. Compared to PG-, PG+ were at an increased risk of any GC (HR = 3.77; 95%CI = 2.50-5.71). After adjusting for family history of GC, smoking, and BMI, PG+ were still at a significantly increased risk of GC compared to PG- (adjusted HR = 4.42; 95%CI = 3.14-6.21). For 138 controls matched to 70 non-cardia cancers, PG+ were at an increased risk of non-cardia GC compared to PG- (HR = 5.65, 95%CI = 3.67-8.70; adjusted HR = 7.26, 95%CI = 4.84-10.90). For 70 controls matched to 35 cardia cancers, PG+ were not at greater risk of cardia GC compared to PG- (HR = 1.79, 95%CI = 0.72-4.44; adjusted HR = 1.95, 95%CI = 0.81-5.37). Conclusions: Pre-diagnostic serum pepsinogen levels from a large prospective cohort study predicted development of non-cardia GC but not cardia GC. PG could be considered as a potential risk biomarker to identify individuals at higher risk of non-cardia GC for targeted screening or interventions.
The association of renal function with safety and efficacy of cisplatin plus S-1 (CS) therapy and docetaxel plus cisplatin plus S-1 (DCS) therapy in patients with advanced gastric cancer (AGC): An exploratory analysis of JCOG1013.
Authors: Hironaka Shuichi , Sadachi Ryo , Hashimoto Tadayoshi , Machida Nozomu , Iwasa Satoru , Yamada Yasuhide , Sasako Mitsuru , Boku Narikazu , Yoshikawa Takaki , Terashima Masanori 
Published: January 2021

197 Background: JCOG1013, a phase III study comparing CS therapy with DCS therapy for AGC, failed to demonstrate the superiority of DCS to CS in overall survival (OS) (Yamada Y, Lancet GH 2019). Because cisplatin and gimeracil (an inhibitor of dihydropyrimidine dehydrogenase contained in S-1) are excreted in urine, it is speculated that renal dysfunction may affect the safety and efficacy of CS and DCS in patients (pts) with AGC. Methods: Among 741 all randomized pts, pts with serum creatinine level < 1.2 mg/dL were included in this study. Pts were categorized by creatinine clearance (CrCl) and treatment into A1 (CrCl ≥ 80 mL/min, CS), A2 (60 < CrCl < 80, CS), A3 (CrCl < 60, CS), B1 (CrCl ≥ 80, DCS), B2 (60 < CrCl < 80, DCS), and B3 (CrCl < 60, DCS). Adverse events, OS, progression-free survival (PFS), objective response rate (ORR) were compared by CrCl in group A (A1 vs. A2 vs. A3) and group B (B1 vs B2 vs B3), respectively, and between the treatment groups according to CrCl (A1 vs. B1, A2 vs. B2, A3 vs. B3). Results: Of 723 pts (169/136/57 in A1/A2/A3 and 170/138/53 in B1/B2/B3), the median CrCl was 94.1/71.9/53.4 mL/min in A1/A2/A3 and 98.2/70.0/55.6 mL/min in B1/B2/B3 group. The incidence of Grade (G) 4 hematological toxicity was 7.8/16.3/25.9% in A1/A2/A3 (P < 0.01), and 29.1/29.3/22.0% in B1/B2/B3 (P = 0.44), and that of G3-4 non-hematological toxicity was 46.1/64.4/64.3% in A1/A2/A3 (P < 0.01) and 54.6/64.7/74.5% in B1/B2/B3 (P < 0.01), respectively. The median OS was 15.4/15.5/15.4 months in A1/A2/A3 (P = 0.89) and 15.3/13.7/13.7 months in B1/B2/B3 (P = 0.72). The median PFS was comparable in A1/A2/A3 (7.1/6.8/6.2 months, P = 0.88) and B1/B2/B3 groups (7.5/7.2/7.8 months, P = 0.85). ORR showed no significant difference in A1/A2/A3 (58.9/57.8/46.9%, P = 0.31) and B1/B2/B3 groups (62.0/61.5/51.5%, P = 0.36). Comparisons between treatment arms according to CrCl (A1 vs. B1, A2 vs. B2, A3 vs. B3) did not show any significant difference in OS (P = 0.88, 0.65, 0.83) and PFS (P = 0.91, 0.63, 0.46). Conclusions: In this exploratory analysis of JCOG1013, CrCl might be associated with safety (G4 hematological toxicity for CS, and G3-4 non-hematological toxicity for CS and DCS), but not with efficacy in either group. Clinical trial information: 000007652.
RAINBOW-Asia: A randomized, multicenter, double-blind, phase III study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in the treatment of advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma following disease progression on first-line chemotherapy with platinum and fluoropyrimidine.
Authors: Xu Rui-hua , Zhang Yan-Qiao , Pan Hongming , Feng Ji Feng , Zhang Tao , Liu Tianshu , Qin Yanru , Han Rubing , Zhang Wanli , Shen Lin 
Published: January 2021

199 Background: Ramucirumab (RAM), a fully human IgG1 monoclonal antibody targeting vascular endothelial growth factor receptor 2, has been approved in combination with paclitaxel (PTX) in patients with advanced gastric cancer in the second-line setting outside of China in around 80 countries based on the significant overall survival (OS) benefit in the global phase 3 RAINBOW study. RAINBOW-Asia was a bridging study of RAINBOW to evaluate the efficacy and safety of RAM in a predominantly Chinese population. Methods: Patients with advanced gastric or gastro-esophageal junction (GEJ) adenocarcinoma who experienced disease progression on first-line chemotherapy (platinum plus fluoropyrimidine with or without an anthracycline) were randomized at a 2:1 ratio to receive RAM (8 mg/kg) on day 1 and 15 plus PTX (80 mg/m²) on day 1, 8, and 15 of a 28-day cycle or placebo (PL) plus PTX. Randomization was stratified by ECOG Performance Status (0 versus 1) and peritoneal metastases (yes versus no). The co-primary endpoints were PFS and OS. Results: From Mar 2017 to Jun 2020, 440 pts were randomized (RAM+PTX: 294; PL+PTX: 146). Median PFS was significantly improved with RAM+PTX compared to PL+PTX (4.14m vs. 3.15m; HR = 0.765 [95% CI: 0.613 to 0.955]; p = 0.0184). Median OS was 8.71m with RAM+PTX and 7.92m with PL+PTX (HR = 0.963 [95% CI: 0.771 to 1.203]; p = 0.7426). Grade ≥ 3 treatment-emergent adverse events (TEAEs) occurring in > 5% of patients with RAM+PTX were: neutrophil count decreased (54.3% RAM+PTX; 38.6% PL+PTX), white blood cell count decreased (43.3% vs. 29.0%), anaemia (15.7% vs. 16.6%), hypertension (7.2% vs. 6.2%), and febrile neutropenia (6.1% vs. 0.7%). Conclusions: The combination of RAM+PTX as 2nd-line therapy demonstrated a statistically significant PFS benefit, and OS benefit consistent with RAINBOW study in a predominantly Chinese population with advanced gastric and GEJ cancer. The safety profile of RAM was consistent with previous studies. No new safety signal was observed. Clinical trial information: NCT02898077.
A phase I/II trial of trifluridine/tipiracil in combination with irinotecan in patients with advanced gastric cancer refractory to fluoropyrimidine, platinum, and taxane.
Authors: Hara Hiroki , Mizukami Takuro , Minashi Keiko , Nishina Tomohiro , Takahashi Naoki , Amanuma Yusuke , Nakasha Akio , Takahashi Masaki , Nakajima Takako Eguchi 
Published: January 2021

210 Background: Trifluridine/tipiracil (FTD/TPI) or irinotecan is a treatment option in the heavily pretreated patients with advanced gastric cancer (AGC) with the limited efficacy. Thus, we investigated the recommended dose of trifluridine/tipiracil (FTD/TPI) and irinotecan for these patients. Methods: Patients who refractory to fluoropyrimidine, platinum and taxane were enrolled into four cohorts (Level 1A/1B/2A/2B) used a escalated dose of irinotecan [100 (Level 1) or 125 mg/m2 (Level 2) on Days 1 and 15 of a 28-day schedule] with 2 dosage schedules of FTD/TPI:35 mg/m2/dose, twice daily (bid), on days 1-5 and 8-12 of a 28-day cycle (Level A) or on days 1-5 and days 15-19 of a 28-day cycle (Level B). The primary objectives were the determination of the maximum tolerated dose, dose-limiting toxicities (DLTs), and recommended phase II dose (RP2D) for phase I part and the evaluation of disease control rate (DCR) targeting > 55% in all enrolled patients for phase II part. Results: Eleven patients were enrolled from 4 institutions in Japan; 2 at Level 1A, 3 at Level 1B and 6 at Level 2B. DLTs occurred in 2/2 patient at Level 1A (Grade 3 gum infection and Grade 3 febrile neutropenia on Day 29, outside the 28-day DLT assessment period, determined equivalent to DLT), and 2/6 patients at Level 2B (Grade 3 mucositis oral and Grade 3 febrile neutropenia). Grade 3 or higher treatment-related adverse events were neutropenia (90.9%), leukopenia (54.5%), anemia (45.5%) and febrile neutropenia (18.2%). One patient at Level 2B achieved partial response and the DCR was 72.7% (95% CI 39.0- 94.0%). The median progression-free survival and overall survival was 3.0 months (95% CI 0.92- not reached) and 10.2 months (95% CI 2.2- not reached), respectively. Conclusions: The RP2D was determined to be Level 1B although further investigation to explore optimal regimen is needed. Clinical trial information: UMIN000031346.
The preliminary efficacy and safety of KN046 plus concurrent chemoradiation therapy in recurrent and metastatic esophageal squamous cell carcinoma.
Authors: Qin Bing Song , Zhao Qi , Liu Dong Yan , Xue Jiao , Zhu Xing Jia 
Published: January 2021

223 Background: Definitive or palliative chemoradiation therapy has been employed in the management of esophageal squamous cell carcinoma (ESCC). Immune checkpoint inhibitor has improved outcomes in metastatic stage IV pts. Here we report the addition of KN046, a PD-L1/CTLA-4 bispecific antibody, to concurrent chemoradiation (CRT) therapy to determine the safety and efficacy of this approach (ChiCTR2000031544). Methods: Pts with recurrent or metastatic ESCC, not been treated by CRT or other systemic treatment within 6 months, were recruited and received palliative CRT consisting of cisplatin (75 mg/m2 IV Q3W for 4~6 cycles), paclitaxel (135~175 mg/m2 IV Q3W for 4-6 cycles) and radiation (SBRT or conventional and dose are determined at the investigator’s discretion according to institutional standard). KN046 at ascending doses of 1, 3 and 5 mg/kg Q3W was added within 7-14 days after the completion of radiation therapy (RT) and concurrently with chemotherapy, followed by KN046 Q2W maintenance. Dose limiting toxicities (DLTs) were assessed for the first treatment cycle of KN046. Anti-tumor activity was assessed according to RECIST 1.1 every 6 weeks within the first year, and every 12 weeks thereafter. Results: As of June 30, 2020, 18 subjects were enrolled and received KN046 treatment (1mg/kg, n = 3; 3mg/kg, n = 11; 5mg/kg, n = 4). The median KN046 exposure was 11.5 weeks. No DLT was reported. 3 (16.7%) subjects experienced Grade 3, KN046 related adverse events (1 Grade 3 pneumonitis and 2 Grade 3 colitis recovered after steroid and antibiotic Tx). For 18 evaluable subjects, the disease control rate and objective response rate were 94.4% and 44.4%, respectively. DOR and PFS were not matured yet as of cutoff date. At 3 mg/kg, objective response was observed in 5 out of 9 subjects (55.6%) with measurable disease and disease control rate was 100%; 7/9 (77.8%) subjects experienced further tumor reduction after initiation of KN046 treatment. It is worth to note that, 2 subjects at 3mg/kg achieved complete response after receiving KN046 treatment. Conclusions: The addition of KN046 to CRT was well tolerated and showed promising efficacy signal in recurrent or metastatic ESCC. This pilot study enables further investigation of a new treatment modality of KN046 with CRT in this detrimental disease with poor prognosis. Clinical trial information: 2000031544.
Human oral microbiome dysbiosis as a novel tool for detecting noninvasive biomarkers for colorectal cancer.
Authors: Kong Cheng 
Published: January 2021

23 Background: The oral microbiome may play an important role in colorectal carcinogenesis. However, few studies have investigated the association between oral microbiome and the development of colorectal cancer (CRC). We aimed to investigate whether oral health–colorectal tumor association has an underlying microbial basis, in the quest for novel non-invasive biomarkers for CRC. Methods: We collected oral swab samples from 161 patients with CRC, 34 patients with colorectal adenoma (CRA), and 58 healthy volunteers. The oral microbiota was assessed using 16S rRNA sequencing. The oral microbiome was characterized, microbial markers were identified, and colorectal tumor (CRA and CRC) classifiers were constructed and validated. Results: Oral microbial composition and diversity were significantly different among the three groups; the CRA group had the highest diversity. Analysis of the functional potential of oral microbiota demonstrated that the pathway involving cell motility was overrepresented in the CRA and CRC groups relative to that in the healthy controls. Moreover, a random forest model was constructed based on oral microbial markers, which could distinguish the colorectal tumor groups from the healthy controls and achieve a powerful classification potential in the discovery and validation cohorts. Conclusions: This study suggests a potential association between oral microbiome dysbiosis and colorectal cancer. Oral microbiota-based biomarkers may be helpful in predicting the risk of developing CRA and CRC.
Impact of tumor location on effectiveness of first-line 5-FU-based palliative doublet chemotherapy in patients with metastatic gastroesophageal cancer.
Authors: Goksu Suleyman Yasin , Alterio Rodrigo , McGehee Elizabeth , Beg Muhammad Shaalan , Kazmi Syed Mohammad Ali , Porembka Matthew R. , Wang Sam C. , Sanford Nina Niu , Wang David H. , Sanjeevaiah Aravind 
Published: January 2021

240 Background: While gastroesophageal cancers with different primary tumor locations can have distinct molecular characteristics and clinical outcomes, the efficacy of palliative chemotherapy in tumors with different locations is unknown. Using primary tumor location as a surrogate for molecular subtype, we investigated the differential efficacy of first-line doublet chemotherapy in metastatic gastroesophageal adenocarcinomas. Methods: We performed a retrospective review of patients with metastatic gastroesophageal adenocarcinoma who received first-line palliative chemotherapy at the University of Texas Southwestern Medical Center and the Dallas County Safety Net Parkland Hospital diagnosed between 2011-2019. Cases were identified using cancer registries. We categorized the tumor location as proximal or distal based on endoscopy and imaging studies. Disease response was assessed on the first staging scan and classified as ‘disease shrinkage, stability, or progression.’ Overall and progression-free survival were evaluated using Kaplan-Meier and Cox proportional hazards methods. Results: 99 patients were identified; 58.6% had proximal tumors. Patients with proximal tumors were more likely to be white (38% vs. 13%, p = 0.008) and older with age ≥ 50 years (71% vs. 51%, p = 0.04) and less likely to have peritoneal metastasis (48% vs. 78%, p = 0.003) than distal tumors. Patients with proximal tumors had a higher disease shrinkage than patients with distal tumors (53% vs. 21%, p = 0.004). Patients with proximal tumors also had better overall survival (median 12.5 vs. 8.7 months) and progression-free survival in response to 5-FU based chemotherapy (median 5 vs. 4 months) compared to patients with distal tumors, but this was not statistically significant. On multivariable analysis, tumor location was not independently predictive of progression-free survival after adjusting for age, gender, presence of signet rings, diffuse, intestinal histology, and peritoneal metastasis (HR 1.22 95% CI 0.74-2.00), but pretreatment albumin was (HR 0.63 95% CI 0.43-0.94). Conclusions: Proximal gastroesophageal cancers have a better clinical response to first-line 5FU containing chemotherapy than distal cancers. Currently, there is no platform to determine molecular subgroups that is commercially available. Until testing for this becomes available, differences in response rates to palliative chemotherapy in gastroesophageal cancers with different anatomical locations should be recognized and studied further.
Regulation of p14ARF by Siva1 in H. pylori-infected gastric epithelial cells.
Authors: Palrasu Manikandan , Zaika Elena , Wael El-Rifai , Peek Richard , Zaika Alexander 
Published: January 2021

243 Background: Helicobacter pylori ( H. pylori) is the strongest known risk factor for gastric cancer. Bacterial degradation of tumor suppressor proteins affect the host microbe’s interactions and host cellular response, which contribute to tumorigenesis. p14ARF, a crucial tumor suppressor protein that activates p53 protein under oncogenic stress plays a major role in oncogenic stress response (OSR) regulation. However, little is known about the mechanism of ARF and OSR regulation in H. pylori-infected gastric epithelial cells. Methods: The expression of p14ARF and cytotoxin-associated gene A (CagA) were analyzed in gastric cells co-cultured with H. pylori strains isolated from high-gastric risk and low-gastric risk areas by immunoblotting. To investigate the potential role of CagA in regulation of p14ARF, we employed isogenic cagA− and cagE− H. pylori mutants in gastric epithelial cells, and C57BL/6 mice (n = 10). We also analyzed the expression of Siva1 in human individual infected with cagA-positive (n = 13) and cagA-negative (n = 13) bacteria as well as uninfected human subjects (n = 6). siRNA was used to inhibit activity of Siva1 protein. Results: In this study, H. pylori strains expressing high levels of CagA virulence factor and associated with a higher gastric cancer risk more strongly suppress p14ARF compared with low-risk strains in vivo and in vitro. We found that degradation of p14ARF induced by CagA is mediated by E3 ubiquitin ligase Siva1, which works in concert with another E3 ubiquitin ligase TRIP12. Decreased expression of Siva1 protein and consequent up-regulation of p14ARF was also found in gastric mucosa of H. pylori-infected mice and human individuals. Tumorigenic strain 7.13 was more potent in upregulation of Siva1 and downregulation of p14ARF than non-tumorigenic strain B128. Inhibition of p14ARF protein by H. pylori causes inhibition of autophagy in infected cells. Conclusions: Our results provide first evidence that carcinogenic H. pylori strains significantly alter the host tumor suppressor protein p14ARF, leading to suppression of host OSR and autophagy, which may affect host-bacteria interactions and tumorigenic alteration in the stomach.