bluuebunny/crossref_metadata_2025_split huggingface dataset:
Real-world effectiveness and safety of trifluridine/tipiracil plus bevacizumab in metastatic colorectal cancer: A retrospective observational study using an administrative database.
Authors: Shinozaki Eiji , Kagawa Yoshinori , Okude Ryota , Tone Takuma , Kunitomi Yuji , Nakashima Masayuki 
Published: January 2023

44 Background: Trifluridine/tipiracil (FTD/TPI) and regorafenib (REG) are standard of care for refractory metastatic colorectal cancer (mCRC). Several phase II trials of FTD/TPI plus bevacizumab (BEV) have been conducted, showing promising efficacy with manageable safety, and it is widely used for patients with refractory mCRC in Japan. No result has been reported for large-scale real-world data directly comparing FTD/TPI plus BEV with FTD/TPI or REG monotherapy. Here, we evaluated the efficacy and safety of FTD/TPI plus BEV in real-world clinical practice. Methods: We used a nationwide claims database provided by Medical Data Vision Co., Ltd. (Tokyo, Japan) in Japan. Eligible patients were aged 20 years or older in mCRC who received their first dose of FTD/TPI or REG between May 2014 and January 2021. The primary outcome was overall survival (OS) in a propensity score matching (PSM) population that was performed matching using a 1:1 ratio for FTD/TPI plus BEV and control group (FTD/TPI or REG) by propensity score. To enhance robustness, sensitivity analyses of OS were performed using the inverse probability treatment weighted (IPTW) approach and the analysis in all eligible population. Main secondary outcomes were OS for subgroups, time to treatment discontinuation (TTD), adverse events (assessed in all eligible population), and post-treatment. Results: The eligible population was 2,369 for FTD/TPI plus BEV and 9,318 for control group (FTD/TPI: 6,500 and REG: 2,818). The PSM population was 1,787 for FTD/TPI plus BEV and 1,787 for control group (FTD/TPI: 1,252 and REG: 535). Median OS (mOS) was 17.0 months for FTD/TPI plus BEV and 11.6 months for control group (HR: 0.70; 95% CI: 0.63–0.78; P < 0.001) in PSM population. Similarly, mOS was longer for FTD/TPI plus BEV compared to that for control group in IPTW analyses (HR: 0.68; 95% CI: 0.65–0.71; P < 0.001) and in all eligible population (HR: 0.68; 95% CI: 0.63–0.73; P < 0.001). In all eligible population, mOS were 17.6 months for FTD/TPI plus BEV and 12.6 months for control group (FTD/TPI: 12.9 months and REG: 12.1 months). Median TTD was 101 days for FTD/TPI plus BEV and 56 days for control group in PSM population (Wilcoxon rank-sum test P < 0.001). The incidence of hand-foot syndrome was significantly higher in REG compared with that in FTD/TPI plus BEV (Fisher's Exact test P < 0.001. Leukopenia incidence was significantly higher in FTD/TPI plus BEV than that in REG (Fisher's Exact test P < 0.001. Granulocyte colony-stimulating factor was administered to 20.6%, 16.5%, and 1.1% of patients in FTD/TPI plus BEV, FTD/TPI, and REG, respectively. Conclusions: The real-world data showed that FTD/TPI plus BEV had significantly longer OS and TTD than FTD/TPI or REG in mCRC. Thus, FTD/TPI plus BEV may be a favorable regimen for refractory mCRC in clinical practice.
Molecular landscape and clinical implication of CCNE1-amplified esophagogastric cancer.
Authors: Moy Ryan H. , Wu Sharon , Xiu Joanne , Walker Phillip , Korn Wolfgang Michael , Lou Emil , Shields Anthony Frank , Goel Sanjay , Saeed Anwaar , Bass Adam Joel 
Published: January 2023

440 Background: Cyclin E1 ( CCNE1) amplification ( CCNE1Amp) drives chromosomal instability (CIN) and is associated with immune cell exclusion, liver metastasis, therapeutic resistance, and poor survival in gastric adenocarcinoma (GA). However, the clinical relevance of CCNE1Amp in a larger real-world population is unknown. Therefore, we profiled the molecular landscape of CCNE1-amplified (amp) esophagogastric cancer (EGC) and explored treatment response outcomes. Methods: Tumors were analyzed by next-generation sequencing (NGS) of DNA (592 genes, NextSeq; WES, NovaSeq) and RNA (WTS, NovaSeq) (Caris Life Sciences, Phoenix, AZ). Deficiency in mismatch repair or microsatellite instability (dMMR/MSI-H) was tested by fragment analysis, IHC, and NGS. Tumor mutational burden (TMB) was measured by totaling somatic mutations per tumor (high>10 mt/MB). PD-L1 was tested by IHC (22C3, 1+). Real world overall survival (OS) was extracted from insurance claims and calculated from first of treatment to last contact using Kaplan-Meier survival curves for molecularly defined cohorts. Statistical significance was determined using chi-square and Mann-Whitney U test with p-values adjusted for multiple comparisons (q<0.05). Results: CCNE1Amp (copy number, CN ≥6) was identified in 142/2276 (6.2%) esophageal adenocarcinoma (EA), 101/1449 (7.0%) esophagogastric junction carcinoma (EJC), 109/2607 (4.2%) GA, and 6/751 (0.8%) esophageal squamous cell carcinoma (ESCC) samples. Metastatic sites such as lymph node and liver showed higher frequency of CCNE1Amp compared to primary sites. TMB, dMMR/MSI-H, and PD-L1 expression were similar in CCNE1-amp vs non-amp tumors. CCNE1Amp was enriched in CIN type tumors (defined by increased TP53 and ERBB2 amp) and was associated with decreased mutation of CDKN2A and CDH1. In addition, CCNE1-amp tumors showed increased HER2 positivity/ ERBB2 amplification by IHC (14.3% vs 10.1%) or CN analysis (19.1% vs 10.3%). Differential gene expression analysis demonstrated increased liver X receptor/retinoid X receptor (LXR/RXR) pathway activation in tumors harboring CCNE1Amp. While there were no differences in OS between CCNE1-amp vs non-amp GA, CCNE1Amp was associated with worse OS after trastuzumab in the IHC HER2+ cohort (N=9 vs 28; HR (95% CI): 2.95 (1.18 – 7.34), p = 0.015). By contrast, there was a trend toward improved OS after immunotherapy in CCNE1-amp GA (N=9 vs 194; HR (95% CI): 0.34 (0.11 –1.07), p = 0.054). Conclusions: CCNE1Amp is associated with a distinct molecular profile in EGC and resistance to HER2-targeted therapy. While CCNE1-amp tumors are thought to be generally “immune-cold,” CCNE1-amp GA demonstrated potentially improved outcomes with immunotherapy. Further investigation of CCNE1Amp as a predictive biomarker is warranted, particularly as novel therapeutics selectively targeting CCNE1Amp are under clinical investigation.
Examination of antagonistic metabolic reactions and nicotinamide/methylnicotinamide as a biomarker in gastric cancer.
Authors: Shi Min , Jiang Yu , Wang Yawen , Huang Qiong , Wu Qijing , Chen Guofeng , Liang Bishan , Wang Jiao , Li Shaowei , Wu Jianhua , Sun Li , Guo Jian , Liao Wangjun 
Published: January 2023

442 Background: Immune checkpoint inhibitors (ICIs) have revolutionized the therapy pattern of advanced gastric cancer (GC), but the efficacy is still unsatisfactory. The role of metabolism in the immune landscape of tumor microenvironment (TME) has been emphasized for the past few years. As the mediators of cellular interactions in TME, more metabolic biomarkers and their predictive value remain to be revealed. Methods: Metabolite activity scoring gene sets were constructed based on metabolite-protein interaction network. Integrated metabolite profile was collected from metabolic reactions in KEGG database. Transcriptome of ACRG (n=299) and anti-PD-1 cohort (PRJEB25780, n=45) were utilized to generate metabolite activity scores via GSVA algorithm. Cox regression was performed to calculate the hazard ratio (HR) to overall survival of metabolites in each metabolic reaction. Plasma samples (n=55) were obtained to measure nicotinamide metabolites from GC patients in Nanfang Hospital before and after ICIs treatment. Results: 78 metabolic reactions (78/6429) with opposite prognostic value among metabolic substrates and products were identified via the antagonistic metabolism screening workflow. Notably, nicotinamide (NAM)-methylnicotinamide (MNAM) (KEGG REACTION: R01269) showed significant antagonistic relationship (NAM, HR=0.76, 95% CI: 0.64-0.89, P<0.001; MNAM, HR=1.28, 95% CI: 1.09-1.49, P=0.002). NNMT, the rate-limiting enzyme catalyzing the formation of MNAM from NAM, was also correlated with poor prognosis (log-rank P=0.013). In terms of therapeutic prediction, NAM/MNAM ratio in plasma of GC patients was significantly correlated with anti-PD-1 response (PR vs SD/PD, median NAM/MNAM ratio (ng·mL-1/ng·mL-1) = 26.76 vs 10.40, P<0.0001). Compared with baseline, decreased plasma NAM/MNAM ratio was found in all (7/7) PR patients ( P=0.0011), while 73.33% (11/15) of non-responders showed a higher NAM/MNAM ratio after ICIs treatment ( P=0.0283). Correlation analysis of key metabolites with TME cells revealed that MNAM activity score was positively correlated with fibroblasts, MDSCs and M2 macrophages infiltration (Pearson correlation: R=0.60, P<0.001; R=0.42, P<0.001; R=0.34, P<0.001), suggesting that MNAM has a potential impact on immune-suppressive cells recruitment and functions. Conclusions: Nicotinamide metabolism was an indicator of prognosis in GC patients. Circulating NAM/MNAM ratio can be a novel metabolic biomarker in dynamic monitoring for ICIs therapy.
Serum IL-6 level to predict survival and treatment response in gastric and gastroesophageal junction cancer.
Authors: Karalis John D , Ju Michelle R , Yoon Lynn Y , Castro-Dubon Esther C , Hammer Suntrea , Porembka Matthew R. , Wang Sam C. 
Published: January 2023

444 Background: There are few biomarkers to guide treatment for gastric and gastroesophageal junction adenocarcinoma (G+GEJ). The systemic inflammatory response, which is reflected by circulating serum cytokine levels, of G+GEJ patients is associated with survival. In this study, we evaluated the relationship of circulating serum cytokine levels with overall survival (OS) and pathologic tumor regression grade (TRG) in G+GEJ patients. Methods: A retrospective review of a prospectively maintained biobank was performed to identify patients diagnosed with G+GEJ from 2016-2022. Pre-treatment serum was collected at the time of diagnosis. For patients who received neoadjuvant therapy, an additional serum sample was collected immediately prior to surgical resection. A multivariable Cox proportional hazards model was used to assess the association of cytokine concentration with OS. In patients who received neoadjuvant therapy, we assessed whether the change in IL-6 (ΔIL-6) after therapy was associated with TRG. Results: We first measured the pre-treatment levels of 17 different cytokines in a 67-patient cohort to determine if certain circulating cytokines were prognostic for OS. In a multivariable analysis adjusted for clinical stage and the expression level of the other cytokines, the only circulating cytokine level that was independently associated with OS was IL-6 (HR: 1.06 per 1 pg/ml increase, 95% CI: 1.04-1.08). We then analyzed the serum IL-6 level in an additional 134 patients, resulting in a final cohort of 201 patients. Serum IL-6 level ranged from 0.3-196.7 pg/ml. In a multivariable analysis adjusted for age, sex, clinical stage, pathologic differentiation, Lauren classification, H. pylori status and neutrophil-to-lymphocyte ratio, IL-6 level was independently associated with OS (HR: 1.012 per 1 pg/ml increase, 95% CI: 1.006-1.019). Patients in the top tercile of pre-treatment IL-6 level had worse median OS (10.6 months) compared to patients in the intermediate (17.4 months) and bottom tercile (35.8 months, p < 0.0001). Among patients who received neoadjuvant therapy (n = 50), ΔIL-6 ≤ 0 had a sensitivity of 80% and specificity of 80% for predicting complete or near-complete pathologic tumor regression (TRG 1). Conclusions: Pre-treatment serum level of IL-6 is a promising prognostic biomarker for patients with G+GEJ. ΔIL-6 may predict response to neoadjuvant therapy.
Proposal of a coagulation score to predict postoperative survival of patients undergoing neoadjuvant therapy followed by subtotal esophagectomy for squamous cell carcinoma of the esophagus.
Authors: Sugiyama Fumitake , Shimizu Dai , Kanda Mitsuro , Tanaka Chie , Takami Hideki , Inokawa Yoshikuni , Hattori Norifumi , Hayashi Masamichi , Nakayama Goro , Fujiwara Michitaka , Kodera Yasuhiro 
Published: January 2023

448 Background: Despite advances in multimodality treatment of esophageal squamous cell carcinoma (ESCC), the recurrence rate after curative resection remains high. Assessment of the risk of disease recurrences after curative resection of ESCC will be helpful for optimization of individual patient management. The close association between coagulation status and progression of malignant tumors has been previously reported. We herein sought to identify sensitive prognostic factors in ESCC by combining multiple coagulation markers. Methods: A total of 200 patients who underwent curative subtotal esophagectomy after neoadjuvant treatment for ESCC between January 2012 and December 2020 were included in the analysis. We retrospectively evaluated the correlation of preoperative plasma D-dimer (upper limit of normal, 1.0 μg/mL), fibrinogen (upper limit of normal, 350 mg/dL) levels and the coagulation score, which is calculated by combining levels of D-dimer and fibrinogen, with postoperative prognosis. The coagulation score was determined as follows. 0, neither D-dimer nor fibrinogen were elevated; 1, either D-dimer or fibrinogen was above the upper limit of normal; 2, both were elevated. Results: There was no significant difference in postoperative recurrence-free survival between the high and low groups for either preoperative D-dimer alone or preoperative fibrinogen alone. 59 patients (29.5%), 99 patients (49.5%) and 42 patients (21%) were categorized into coagulation score 0, 1 and 2, respectively. Patients in the coagulation score 1-2 group had a significantly shorter recurrence-free survival time than those in the coagulation score 0 group (hazard ratio 1.99, P = 0.0223). Conclusions: The coagulation score combining with plasma D-dimer and fibrinogen levels was suggested to be a simple predictor of postoperative recurrences in patients undergoing curative subtotal esophagectomy after neoadjuvant treatment for ESCC.
Clinical significance of D-amino acid profile for cancer detection in early stage and prediction of efficacy of nivolumab in gastric cancer.
Authors: Tsugaru Kai , Sujino Tomohisa , Mita Masashi , Sasabe Jumpei , Chida Akihiko , Harada Yosuke , Hirata Kenro , Sukawa Yasutaka , Kato Motohiko , Kawakubo Hirofumi , Hamamoto Yasuo , Kanai Takanori 
Published: January 2023

453 Background: Some metabolites from gut microbiota are reported to associate with immunotherapy response. D-amino acids (D-AAs), enantiomer of L-amino acids (L-AAs), mainly produced by gut microbe and brain, are rare but important metabolite in mammals. Little is known about their biological and immunological significance in cancer patients (pts) as its difficulty of stable measurement. Methods: We first analyzed L/D-AAs in plasma of pts with each disease stage of gastric cancer (GC) before treatment, then compared with healthy control (HC). Second, we analyzed L/D-AAs in plasma of advanced GC pts planned nivolumab (NIVO) monotherapy, and compared among two groups divided based on treatment efficacy of progressive disease (PD) or non-PD. All pts with GC and HC were recruited in Keio University Hospital from October 2017 till March 2022. Concentration of L/D-AAs was measured with Two-Dimensional HPLC-MS/MS System. Results: In the first part, 108 pts with GC before treatment and 87 HC were recruited. D-Ser, D-Asn, D-Ala, D-Pro were detected in plasma of both pts with GC and HC, and their concentration was significantly higher in GC pts rather than in HC, even in pStage 1 ( p<0.0001 of each D-AA, values in table). D-Ser showed an increasing trend as the disease stage progressed. The AUC value of ROC curve to discriminate Stage 1 GC pts from HC were 0.976 with D-AAs. In the second part, 28 pts with advanced GC before NIVO monotherapy were recruited. The best response was PD in 10 pts, and non-PD in 18 pts. D-Ser and D-Asn in plasma were significantly higher in PD group rather than non-PD group ( p=0.0025 and p=0.0158, respectively). The AUC value of the ROC curve discriminating NIVO PD was highest for the equation mainly with D-Ser at 0.933. Pts with poor progression free survival (PFS) and overall survival (OS) could be distinguished by the determined cutoff value of the equation [median PFS: 1.1m vs 3.8m, HR 5.1 ( p=0.0003), median OS: 3.4m vs 18.9m, HR 7.1( p=0.0010)]. Conclusions: D-AAs in plasma significantly increased in pts with GC rather than HC even in early stage. Moreover, higher D-Ser in plasma associated with poor efficacy and prognosis of NIVO in GC pts. We firstly reported D-AA is a novel biomarker of both cancer detection and efficacy of NIVO.[Table: see text]
Unique microbial profile identified in patients with gastric cancer with pathologic response to neoadjuvant chemotherapy.
Authors: Drebin Harrison M. , Abate Miseker , Fei Teng , Tang Laura H. , Laszkowska Monika , Maron Steven Brad , Shimada Shoji , Vardhana Santosha , Vanderbilt Chad , Strong Vivian E. 
Published: January 2023

458 Background: Microbial dysbiosis has been shown to be associated with the pathogenesis of gastric cancer (GC). However, the relationship between the GC microbiome and response to systemic therapy, such as neoadjuvant chemotherapy (NAC), is largely unknown. This study aims to explore changes in the microbiome after neoadjuvant chemotherapy, by analyzing the microbial profile of patients who received NAC and comparing differences among those with varied pathologic response to therapy. Methods: A microbiome bioinformatics pipeline using multiple next generation sequencing platforms was developed and used for analysis. GC tissue from patients who received NAC (n=101) and those who did not (n=85) were acquired at the time of surgical resection. Shannon alpha diversity plot and enrichment analyses by odds ratio were used to compare the microbial differences of the treatment cohorts. The microbial profiles of patients with pathologic response to NAC (>20% response) were characterized. Results: Of patients who received NAC, 66 (65.3%) experienced a greater than 20% response to NAC, and 35 (34.6%) demonstrated a 20% or lower response. Patients with a pathologic response to NAC were enriched for Rhizobium, Streptomyces, Comamonas, Sphingomonas, Micrococcus, Mycobacterium, Thauera, Hyphomicrobium, and Sinorhizobium (OR>4). There were no statistically significant differences in alpha diversity (p>0.05). Conclusions: Our results demonstrate that patients with a greater than 20% pathologic response to NAC have a distinct microbial enrichment compared to those with a poor pathologic response. Given the variable NAC treatment responses in GC, understanding unique microbial signatures in tumors will provide the landscape to explore key microbial contributors to GC NAC treatment response that may improve our understanding of treatment response variability among patients. [Table: see text]
Body composition assessment in patients with gastric cancer.
Authors: Nakamura Shun , Kanetaka Kengo , Matsumoto Ryo , Hashimoto Yasumasa , Kobayashi Shinichiro , Arai Junichi , Kobayashi Kazuma , Ito Shinichiro , Hidaka Masaaki , Nagayasu Takeshi , Eguchi Susumu 
Published: January 2023

460 Background: The number of overweight patients with gastric cancer who underwent gastrectomy has increased in Japan. In addition to obesity, sarcopenia is a risk factor of severe surgical complication. The study aimed to elucidate the relationship between body composition and surgical outcome of gastrectomy for gastric cancer. Methods: This study was a retrospective, cohort study that include 701 patients who underwent gastrectomy in our institution between May 2008 and July 2017. Using preoperative computed tomography (CT), body composition such as psoas muscle index (PMI) and visceral fat area (VFA) were measured in the third lumber section. The patients were divided into two groups according to PMI (cut-off value 5.2 cm2/m2 in male and 3.5 in female) or VFA (cut-off value 155 cm2 in male and 116 in female), respectively. Surgical outcomes and postoperative complications were compared between the low and high groups for each PMI and VFA value. Results: There were 53 severe complications (14 anastomotic leakage, 14 pancreatic fistula, 8 respiratory failure, and 7b intraabdominal abscess) in this cohort. Some 701 patients were included in the study, 528 of whom were classified as normal PMI and 173 were as low PMI. In addition, 528 of whom were classified as normal VFA and 173 were as low PMI. In multivariate analysis, age and gender were independent risk factor for severe postoperative complication, however, low PMI was not. Conclusions: Our analysis showed no relationship between preoperative low PMI and postoperative complications. [Table: see text]
Immunohistochemistry-based molecular classification of gastric cancer in India: How are we different?
Authors: Dubashi Biswajit , L Charles , Nisha Yadav , Ganesh Rajesh Nachiappa , Kate Vikram , Penumadu Prasanth , Selvarajan Sandhiya , Raja Kalayarasan , Kayal Smita , Ganesan Prasanth 
Published: January 2023

462 Background: TCGA and ACRG have classified gastric cancer (GC) into molecular subgroups using genomics. We attempted to classify GC from our region using IHC (Immunohistochemistry) to understand its prognostic significance and compare with similar data from other parts of the world. Methods: This was a retrospective cohort of GC patients from years 2017-18. EBV (LMP), MSI (MLH1, MSH2, PMS2, MSH6),p53, E-cadherin and PIK3CA were assessed by IHC. Clinicopathological characteristics and survival were evaluated for association with molecular subtypes as defined by TCGA and ACRG classification system. Results: A total of 191patients were included with EBV positivity 35 (18.3 %), MSI 33(17.3 %), p-53 aberration 25(13.1%), E-cadherin negative (29.3%). On univariate analysis, p53 aberration was associated with higher age (>60 yrs), E- cadherin negative with diffuse histology & antro-pyloric region as predominant site. MSI with intestinal histology & antro-pyloric region as predominant site with MSI. The TCGA classification revealed EBV 35 (18%), MSI 28 (15 % ), GS 48 (25 %) and CIN 80 (42% ) subtypes respectively. CIN subtype was seen predominantly above 40 yrs of age (P=0.04), GS subtype was frequently associated with diffuse histology P<0.0001. The ACRG classification revealed MSI 33(17%), MSS/EMT 51 (26.7%), MSS/ p53 normal 91 (47.6%) and MSS/p53 aberrant 16 (8.4) subtypes. MSS/E-cad- subtype was associated with diffuse histology. PIK3CA positivity was higher in CIN (TCGA )& MSI (dmr) (ACRG) respectively. The median OS in MSI was 35 and 32 months higher compared to other subtypes (P<0.0001) in TCGA and ACRG classification respectively. Conclusions: The TCGA and ACRG classification identified molecular subtypes based on IHC from our region and significantly correlated with clinical factors and survival. PIK3CA as an additional marker may be further explored to be included in the classification system. Abbreviation: EBV - Epstein–Barr-virus, MSI – Microsatellite-Instability, GS- Genomic-instability, CIN- Chromosomal-instability, MSS- Microsatellite-stable, EMT-Epithelial-mesenchymal-transition.[Table: see text]