bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endoscopic submucosal dissection in early gastric cancer with papillary histological type.
Authors: Lee Jung Hwan 
Published: January 2023

412 Background: Gastric papillary adenocarcinoma has been regarded as differentiated-type adenocarcinomas along with well- or moderately-differentiated tubular adenocarcinomas in current endoscopic submucosal dissection (ESD) indication. We aimed to investigate lymph node metastasis (LNM) and to verify the safety of ESD in patients with papillary early gastric carcinoma (P-EGC). Methods: 4,264 patients with early gastric cancer (EGC) underwent curative gastrectomy between October 2000 and December 2017 at National Cancer Center, Korea. Among them, 45 patients were pathologically confirmed with P-EGC. We compared clinicopathological factors among differentiated-type EGC except P-EGC (n=2,106), undifferentiated-type EGC (n=2,113), and P-EGC. Logistic regression model was used to investigate risk factors of LNM. Results: P-EGCs were frequently located in lower third of the stomach (71.1%, P < 0.001), and about half of them (46.7%, P < 0.001) had elevated morphology. Mucosal cancer of P-EGC (37.9%) was significantly lower than differentiated-type (48.8%) and undifferentiated-type EGC (22.2%, P < 0.001). Angiolymphatic invasion and LNM occurred most frequently in P-EGC (46.9% and 20.0%, respectively) compared to differentiated-type (18.9% and 9.2%, respectively) and undifferentiated-type EGCs (10.9% and 11.7%, respectively; P < 0.001 and P = 0.004, respectively). P-EGC that was not mixed with other pathological type tended to have increased risk of LNM referent to differentiated EGC. (Odd ratio [OR] 2.53, 95% confidence interval [CI], 0.99-6.50). Among 45 patients with P-EGC, 13 patients met the current ESD indication; 3 patients corresponded to absolute indication and 10 patients did expanded indication. One patient had LNM and met expanded criteria with submucosal invasion less than 500 μm. In multivariate analysis, OR for LNM meeting expanded indication of P-EGC was 40.67 (95% CI, 2.54-702.76) referent to that of absolute indication compared to LNM meeting expanded indication of non-papillary EGC (10.28, 95% CI, 1.37-77.04). Conclusions: When ESD was applied to P-EGC, it should be carefully performed because of high rate of submucosal invasion and high risk of LNM even in with submucosal invasion less than 500 μm.
LAG3-related factors to predict response to nivolumab monotherapy in advanced gastric cancer (WJOG10417GTR study).
Authors: Tsugaru Kai , Boku Narikazu , Kudo-Saito Chie , Shoji Hirokazu , Imazeki Hiroshi , Takahashi Naoki , Kawakami Takeshi , Amanuma Yusuke , Wakatsuki Takeru , Okano Naohiro , Narita Yukiya , Yamamoto Yoshiyuki , Kizawa Rika , Nagashima Kengo , Aoki Kazunori , Muro Kei 
Published: January 2023

425 Background: Blocking immune checkpoint (IC) pathways, particularly mediated by PD1 and PDL1, has attracted great attention as a promising strategy for treating gastrointestinal cancer. However, the clinical responses are low in many cases, and thus a new treatment strategy and its biomarker are urgently needed for improving the clinical outcome. Blocking other IC molecules, including LAG3, has been evaluated in many clinical trials, while the therapeutic efficacy and the predictive biomarkers remains to be determined due to the same issues as anti-PD1/PDL1 therapy. Methods: We analyzed soluble LAG3 (sLAG3) in sera by ELISA, and LAG3+ cells by flow cytometry, using fresh peripheral blood (PB) obtained from 91 patients with advanced gastric cancer (AGC) before and about one month after nivolumab monotherapy (2 courses) in the WJOG10417GTR study, according to the protocol approved by the IRB (August 2018 - November 2020). Progression-free survival (PFS) and overall survival (OS) were compared between high/low groups divided by the cutoff value determined by visually assessing the continuous trend and change point of log hazard ratios obtained by applying penalized splines to each molecular marker. This study was supported by ONO PHARMACEUTICAL CO., LTD. and Bristol Myers Squibb. Results: Posttreatment values were significantly more associated with patients’ prognosis rather than baseline values, and the sLAG3-high group showed significantly shorter PFS/OS as compared to the low group divided by the median: median PFS (mPFS) 51.5 vs 95.5 days (HR = 2.04, P = 0.002), and median OS (mOS) 188 vs 393 days (HR = 1.81, P = 0.032). Patients with high levels of LAG3+ PBCs after treatment showed worse prognosis as compared to those with low levels divided by the cutoff values: a CD3+CD4+LAG3+ T-cell subset, mPFS 43 vs 72 days (HR = 2.23, P = 0.015) and mOS 178 vs 282 days (HR = 1.56, P = 0.249); a CD3+CD8+LAG3+ T-cell subset, mPFS 57 vs 69 days (HR = 1.89, P = 0.012) and mOS 228 vs 303 days (HR = 1.40, P = 0.233); and a CD56+LAG3+ NK subset, mPFS 57 vs 88 days (HR = 2.15, P = 0.003) and mOS 217 vs 409 days (HR = 1.88, P = 0.031). Patients with sLAG3-high/CD56+LAG3+ NK-high levels showed markedly worse prognosis than those with low/low levels (mPFS-HR = 10.55, P < 0.001; and mOS-HR = 4.59, P < 0.001). Conclusions: Patients with posttreatment high levels of sLAG3 and LAG3+ cells in PB showed poor prognosis of AGC patients after the nivolumab therapy, suggesting that these are useful predictive biomarkers. LAG3 may be a promising target in immunotherapy for AGC. Clinical trial information: UMIN000032686 .
The role of serial circulating tumor DNA for predicting clinical outcomes of chemotherapy in patients with advanced gastric cancer.
Authors: Kim Sheehyun , Lim Yoojoo , Kang Jun-Kyu , Kim Hwang-Phill , Kim Tae-You , Kim Tae-Yong 
Published: January 2023

433 Background: Serial circulating tumor DNA (ctDNA) analysis enables us to detect minimal residual disease, to estimate recurrence and to trace evolution of cancer. However, the role of ctDNA in patients with advanced gastric cancer (AGC) who received palliative chemotherapy is still unclear. We performed this study to evaluate if serial ctDNA can predict clinical outcomes of chemotherapy and propose evolutionary findings during chemotherapy. Methods: The patients with histopathologically confirmed AGC and who received palliative chemotherapy were enrolled. Serial blood sample for ctDNA sequencing were obtained at baseline (BL) (before first-line chemotherapy), after first cycle and every 2-3 months until disease progression. ctDNA sequencing was performed for all samples using the next-generation sequencing (NGS) platform with a targeted gene panel including 106 genes. Single nucleotide variants (SNVs), insertions and deletions (Indels), and copy number variants (CNVs) were identified by ctDNA sequencing while serial ctDNA were monitored by tracing changes in the variants. ctDNA clearance was defined as no detection of any kind of variants or variant allele frequency (VAF) less than 0.1%. Results: A total of 50 patients were registered and 248 samples were collected. Median age was 62. HER2-positive GC were 5 (10.0%) and 49 received fluoropyrimidine plus platinum (1 did not receive chemotherapy). Response rate and median progression-free survival (PFS) were 42.9% and 10.7 months (95% CI, 7.9-13.6). Among 40 who were available for BL ctDNA, patients who were detected with ctDNA variant (D group) were 21 (52.5%). TP53 mutation was the most frequently observed genetic alteration in BL ctDNA (76.2%) and median copy numbers of ERBB2 in HER2-positive GC were 28 (range 2-42). D group were more frequently observed in tubular or papillary adenocarcinoma than in poorly cohesive carcinoma (69.0% vs. 9.1%, p = 0.001). Patients who were not detected with any kind of ctDNA variant (ND group) showed a trend in longer PFS, compared to D group, however it was not significant (10.5 vs 7.9 months, p = 0.29). In serial analysis during first-line chemotherapy, ctDNA clearance was observed in 14 (70.0%) out of 20 in D group. Patients with ctDNA clearance showed significantly longer PFS, compared with patients without ctDNA clearance (9.8 vs. 3.6 months, p < 0.001). Among 32 patients who had disease progression, increased VAF or re-development of previous BL ctDNA variants were observed in 16 (50.0%). Increased VAF or re-development of BL ctDNA were detected in 2.1 months earlier than clinical or radiologic deterioration. Conclusions: Serial ctDNA could predict clinical outcomes of chemotherapy and detect disease progression earlier than clinical or radiological findings in AGC. Further study for serial ctDNA is needed to find out the resistant mechanism and evolutionary process in cancer.
CA125 kinetics as a potential biomarker of prognosis in nivolumab monotherapy for patients with advanced gastric cancer and peritoneal metastasis.
Authors: Ando Takayuki , Yuki Satoshi , Kito Yosuke , Ueda Akira , Motoo Iori , Ito Ken , Sakumura Miho , Ueda Yuko , Kajiura Shinya , Nakada Naokatsu , Nakajima Koji , Hosokawa Ayumu , Harada Kazuaki , Kawamoto Yasuyuki , Komatsu Yoshito , Yasuda Ichiro 
Published: January 2023

445 Background: The ascites develop in large proportion of patients during salvage-line chemotherapy for advanced gastric cancer (AGC). Serum CA125 is reported to be potential biomarker in peritoneal metastasis and associate with prognosis in first-line treatment for AGC. Therefore we aimed to clarify the association between serum CA125 and therapeutic efficacy for AGC treated with third of later-line nivolumab monotherapy (Nivo). Methods: This multicenter retrospective study comprised AGC patients who received Nivo in third line or later setting between Jun. 2015 to May 2019. Patient background and treatment outcome was assessed in CA125 elevated and non-elevated group before Nivo (cut-off, 37 U/ml). The CA125 kinetics after chemotherapy was calculated based on baseline and first measure of CA125. Further, the association between CA125 kinetics and ascites burden during chemotherapy were evaluated based on optimal cut off value calculated receiver operating characteristic (ROC) curve analysis. Results: A total 50 patients from 5 hospitals were assessable. The proportion of poor PS, moderate/severe peritoneal effusion, low albumin was significantly larger in CA125 elevated group (n=29) than those in non-elevated group. The median value of CA125 before Nivo was elevated according to ascites burden (none, 31.0 U/ml; mild, 49.4 U/ml; moderate/severe, 187.0 U/ml; p<0.001). The overall survival was significantly shorter in elevated group than that in non-elevated group (median, 3.2 vs. 9.4 months, p=0.035). After Nivo, first-time measure of CA125 was performed in a median of day 27. The median change of CA125 was correlated with ascites response (CR/PR, 0.04%/day; SD, 2.06%/day; PD, 4.17 %/day, p=0.013). ROC curve analysis showed that the optimal cut-off value of CA125 kinetics for ascites progression was 2.4%/day (specificity 75%, sensitivity 70%). The progression free survival in increased group was significantly shorter than that of non-increased group in patients with peritoneal dissemination (median, 1.4 vs 3.3 months, p=0.016). Conclusions: The serum CA125 before Nivo was associated with ascites burden. Further, CA125 kinetics after Nivo was associated with prognosis in AGC patients with peritoneal dissemination.
Analysis of the role of tumor microenvironment on clinical outcomes of chemotherapy in patients with advanced gastric cancer using high plex digital spatial profiling.
Authors: Kim Tae-Yong , Lee Hye Seung , Bae Jihong , Park Yujun , Oh Do-Youn , Yoon Jeesun , Nam Soo Kyung , Kwak Yoonjin 
Published: January 2023

456 Background: Tumor consists of not only cancer cells but also various immune cells or stromal cells. And tumor microenvironment (TME) is known to be associated with response and resistance to treatment. However, the role of TME in the response to chemotherapy in advanced gastric cancer (AGC) remains unclear. We evaluated whether TME can affect the survival in patients with AGC who received first-line chemotherapy using high plex digital spatial profiling (DSP). Methods: Patients with AGC who received first-line chemotherapy were registered. Archival tumor tissue before first-line chemotherapy were obtained and tissue microarrays (TMAs) were made. Regions of interest (ROIs) were selected on each TMA and high plex DSP including RNA transcript was performed in all ROIs using GeoMx DSP (Whole Transcriptome Atlas) after masking by cytokeratin (CK) immunofluorescence. Differentially expressed gene (DEG), geneset enrichment analysis (GSEA), gene ontology (GO) and cell subsets were analyzed separately in CK-positive and CK-negative areas, using EdgeR, mSigDb, DAVID and CIBERSORT. Results: Thirty-three tumor tissues from 33 patients and 5 normal tissues were analyzed. All patients received fluoropyrimidine and platinum doublet chemotherapy. HER2+ was 15.2% and all with HER2+ AGC received trastuzumab plus chemotherapy. Five received nivolumab plus chemotherapy. Response rate was 48.5% and progression-free survival (PFS) was 9.8 months (95% CI, 6.85-NA). In CK-positive area, high expression of PIGR (polymeric Immunoglobulin receptor gene) (FDR q=0.013) and low expression of IFNE (FDR q=0.027) were associated with long PFS. Response to interferon beta (FDR q=0.044), cytokine-cytokine receptor interaction (FDR q=0.014) and antigen processing and presentation pathway (FDR q=0.015) were less activated in patients with long PFS in GO and GSEA. Although the density of CD8+ T cell did not affect PFS (6.9 vs. 10.8, p=0.25), high density of CX3CR1+memory CD8+T cells (Tmem) showed longer PFS (18.3 vs. 6.6 months, p=0.01), compared with low density of CX3CR1+CD8+Tmem. In CK-negative area, low density of CD8+ T cells were associated with longer PFS (6.3 vs. 18.3 months, p= 0.008). Conclusions: TME particularly in CK-positive area might affect survival for chemotherapy in AGC. PIGR and CX3CR1+CD8+Tmem were suggested as good candidate markers for predicting clinical outcomes of chemotherapy, indicating further analysis of TME will be needed especially in patients with AGC who received immune checkpoint inhibitors.
Development of a postoperative nomogram to predict overall survival in gastric cancer using variables the AJCC recommends for collection and registration.
Authors: Bando Etsuro , Ji Xinge , Kattan Michael W. , Koseki Yusuke , Furukawa Kenichiro , Fujiya Keiichi , Tanizawa Yutaka , Terashima Masanori 
Published: January 2023

468 Background: The American Joint Committee on Cancer (AJCC) has increasingly recognized the need for individual risk prediction model for the era of tailored therapy. This study aimed to develop a postoperative gastric cancer nomogram for prediction of overall survival (OS). Methods: The nomogram was developed using data of 4,990 patients with primary gastric cancer who underwent macroscopically complete resection (residual tumor: R0 or R1) at Shizuoka Cancer Center (Shizuoka, Japan), and it was created with a multivariable Cox proportional hazard regression model. Fifteen pathological or host-related variables (age, sex tumor location, tumor size, macroscopic type, histology, depth (pT), number of positive nodes (pN), number of negative nodes, location of positive nodes, lymphovascular invasion, lavage cytology (CY), tumor margin, serum CEA and serum CA19-9) were collected. They are recommended to collect and register by the AJCC. The model was validated internally using measures of discrimination (Harrell’s C-index), calibration and decision curve analysis. A stage-specific subset survival analysis of the three risk groups (low, intermediate, high) calculated using the nomogram was performed. Results: In the development procedure, multivariable analysis for OS selected 11 variables for constructing the nomogram. The developed nomogram showed good discrimination, with a C-index of 0.812; that of the American Joint Committee on Cancer (AJCC) pathological stage was 0.756. The nomogram performed well in the calibration and decision curve analyses. A stage-specific subset survival analysis of the three risk groups calculated using the nomogram also showed the superiority of nomogram-prediction when compared to AJCC ordinal staging. Conclusions: This new postoperative risk model accurately predicts OS in gastric cancer and can be used for patient counseling in clinical practice and clinical trial eligibility determination.
Tislelizumab versus sorafenib in first-line treatment of unresectable hepatocellular carcinoma: Impact on health-related quality of life in RATIONALE-301 population.
Authors: Finn Richard S. , Qin Shukui , Kudo Masatoshi , Meyer Tim , Boisserie Frederic , Li Songzi , Chen Yaxi , Barnes Gisoo , Abdrashitov Ramil , Zhu Andrew X. , Vogel Arndt 
Published: January 2023

495 Background: RATIONALE-301 (NCT03412773), a global Phase 3 study, comparing tislelizumab (TIS) to sorafenib (SOR) as 1L treatment in adult patients (pts) with unresectable HCC (uHCC), met its primary endpoint of OS non-inferiority. This analysis examined the HRQoL outcomes in pts in both arms. Methods: Systemic therapy-naïve adults with histologically confirmed uHCC were randomized 1:1 to receive TIS (200 mg IV Q3W, n=342) or SOR (400 mg PO BID, n=332). HRQoL was assessed using EORTC QLQ-C30, QLQ-HCC18 and EQ5D-5L. A mixed model for repeated measures using key pre-specified PRO endpoints of global health status/quality of life (GHS/QoL), physical functioning and fatigue scales of the QLQ-C30, and HCC18 index score, fatigue and pain scores at the key pre-specified clinical cycles 4 and 6 were performed. Time to deterioration was examined with the Kaplan-Meier method using the PRO endpoints. Results: At both cycles, TIS had better HRQoL outcomes than SOR, as indicated by LS mean differences in GHS/QoL, physical functioning, fatigue and HCC symptom index, but not for pain. TIS had a lower risk for deterioration of QLQ-C30 GHS/QoL (hazard ratio [HR] 0.68 [95% CI, 0.49-0.94]), physical functioning (0.53 [0.39-0.73]) and fatigue (0.48 [0.37, 0.63]) as well as for deterioration in the HCC18 index (0.53 [0.34-0.81]) and fatigue (0.60 [0.46-0.80]). Both arms had a similar risk for deterioration in pain (HR 0.78 [0.56-1.09]). TIS maintained while SOR declined EQ-5D-5L VAS (general health status) scores at cycle 4 (mean change from baseline =-0.4 [SD = 14.52] vs -4.3 [12.92]) and cycle 6 (-0.2 [17.03] vs -5.4 [13.09]). Conclusions: Pts with HCC treated with 1L TIS had better HRQoL outcomes compared with pts treated with SOR, particularly in terms of fatigue and physical functioning. These results, along with effects an overall survival, response rate, and a favorable safety profile, support the benefit of TIS as a potential 1L treatment option for uHCC. Clinical trial information: NCT03412773 .[Table: see text]
Utility of AST to platelet ratio index (APRI) score in predicting post-surgical outcomes in patients with cholangiocarcinoma.
Authors: Aslam Faaiq , Loveday Tristan , Uson Junior Pedro Luiz Serrano , Borad Mitesh J. 
Published: January 2023

502 Background: Cholangiocarcinoma (CCA) is an epithelial malignancy of the intrahepatic or extrahepatic biliary tree, primarily driven by chronic inflammation and fibrosis. Given fibrosis has shown to correlate with malignancy and the aminotransferase-platelet ratio index (APRI) score, a marker for hepatic fibrosis, has shown to be useful in prognosticating hepatocellular carcinoma, this study aimed to assess the utility of APRI score in prognosticating post-surgical outcomes in CCA patients. Methods: 152 CCA patients at the Mayo Clinic that underwent surgical resection were retrospectively analyzed. Statistical analyses were then conducted to determine the relationship between APRI score and demographic factors, laboratory values (CA19-9, albumin, bilirubin, INR, alkaline Phosphatase, ALT, AST, and platelet count), pathology features, and outcome data. Results: When looking at demographic factors, no relationship between APRI score and age (r = -0.19, p = 0.02), sex (2-sample t-test p = 0.16) and race (ANOVA p = 0.81) were identified. There was a negative correlation between APRI score and albumin (m = -0.35, r = -0.35, p < 0.01) and a positive correlation with bilirubin (m = 0.13, r = 0.23, p = 0.01) and ALT (m = 0.01, r = 0.47, p < 0.01). No correlation between the other laboratory values analyzed was identified. Similarly, there was no relationship between APRI score and pathology features (tumor grade t-test p = 0.41, N Stage ANOVA p = 0.94, Vascular Invasion t-test p = 0.59, and Perineural invasion t-test p = 0.14), except for T3 stage which had a higher APRI score compared to T1, T2, and T4 (ANOVA p = 0.01). Likewise, APRI also did not correlate with post-surgical outcomes like recurrence (t-test p = 0.22) and mortality (t-test p = 0.39). Conclusions: In summary, despite being driven by chronic inflammation, APRI score, a marker for hepatic inflammation and a surrogate for liver fibrosis, did not serve as a reliable prognostication tool of post-surgical outcomes in CCA patients. These data suggest that although chronic inflammation is thought to be one of the primary drivers of disease, the role of other factors such as genetic and cellular signaling abnormalities may play a more prominent role in patients with CCA. In conclusion, APRI score did not serve as a useful prognostication tool in surgically resected CCA patients. Future studies should focus on other prognostic factors such as genomic and transcriptomic biomarkers in CCA.
Extending surgical resection for hepatocellular carcinoma beyond Barcelona Clinic for Liver Cancer (BCLC) stage A: A novel application of the modified BCLC staging system.
Authors: Wee Ian , Moe Fiona , Sultana Rehena , Ang Reiko , Quek Pearly , Goh Brian , Chan Chung Yip , Cheow Peng Chung , Chung Alexander , Raj Prema , Koh Ye Xin , Mack Peter , Ooi London Lucien , Tan Ek Khoon , Teo Jin Yao , Kam Juinn Huar , Chua Jacelyn , Ng Ashley , Goh Jade , Chow Pierce K. H. 
Published: January 2023

503 Background: Intermediate hepatocellular carcinoma is a heterogenous group of disease. We aimed to prognosticate survival after surgical resection of HCC stratified by stage with amalgamation of the modified Barcelona Clinic Liver Cancer (BCLC) staging system and location of tumour. Methods: This single-institutional retrospective cohort study included patients with HCC who underwent surgical resection between 1st January 2000 to 30th June 2016. Participants were divided into 6 different subgroups based on the Milan Criteria (MC), the “Up-to-7” criteria, and location of lesions: A-u) Within MC with Unilobar lesions; A-b) Within MC + Bilobar lesions; B1-u) Out of MC + within Up-To-7 + Unilobar lesions; B1-b) Out of MC + within Up-to-7 + Bilobar lesions; B2-u) Out of MC + Out of Up-To-7 + Unilobar lesions; B2-b) Out of MC + Out of Up-To-7 + Bilobar lesions. A separate survival analysis was conducted for solitary HCC lesions according to three subgroups: A-S (Within MC); B1-S (Out of MC + within Up-To-7); B2-S (Out of MC + out of Up-To-7). The respective primary and secondary time-to-event outcomes were overall survival (OS) and recurrence-free survival (RFS). Results: 794 of 1043 patients with surgical resection for HCC were analysed. Groups A-u (64.6 %), A-b (58.4 %) and B1-u (56.2 %) had 5-year cumulative overall survival (OS) rates above 50% after surgical resection and median OS exceeding 60 months (P=0.0001). The 5-year cumulative recurrence-free survival rates (RFS) were 40.4% (group A-u), 38.2% (group A-b), 36.3% (group B1-u), 24.6% (group B2-u), and 7.3% (group B2-b)(P=0.0001). For solitary lesions, the 5-year OS for the subgroups were A-S (65.1%), B1-S (56.0%) and B2-S (47.1%) (P=0.0003). Compared to A-S, there was also a significant trend towards relatively poorer OS as the lesion sizes increased in B1-S (HR 1.46, 95%CI 1.03 – 2.08) and B2-S (HR 1.65, 95%CI 1.25 – 2.18). Conclusions: We adopted a novel approach combining the modified BCLC B sub-classification and dispersion of tumour to show that surgical resection may be curative in a select subgroup of patients with intermediate HCC that fall outside BCLC Stage A, specifically those with unilobar lesions and are within the “up-to-7” criteria. Furthermore, We found that size prognosticates resection outcomes in solitary tumours.