bluuebunny/crossref_metadata_2025_split huggingface dataset:
First-line (1L) nivolumab (NIVO) plus chemotherapy (chemo) vs chemo in patients (pts) with advanced gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma (GC/GEJC/EAC): CheckMate 649 Chinese subgroup analysis 4-year (yr) follow-up.
Authors: Shen Lin , Bai Yuxian , Lin Xiaoyan , Li Wei , Wang Jufeng , Zhang Xiaochun , Pan Hongming , Bai Chunmei , Bai Li , Cheng Ying , Zhang Jingdong , Zhong Haijun , Ba Yi , Hu Wenwei , Xu Rui-Hua , Guo Weijian , Qin Shukui , Wang Rui , McCraith Stephen , Liu Tianshu 
Published: January 2024

318 Background: NIVO + chemo demonstrated clinically meaningful improvement in overall survival (OS) and an acceptable safety profile vs chemo in previously untreated Chinese pts from CheckMate 649, consistent with the overall study population with advanced GC/GEJC/EAC. 1L NIVO + chemo is approved for advanced GC/GEJC/EAC in multiple countries, including China. We report 4-yr results of NIVO + chemo vs chemo in Chinese pts from CheckMate 649. Methods: Adults with previously untreated, unresectable advanced or metastatic, non-HER2+ GC/GEJC/EAC were enrolled regardless of programmed death ligand 1 (PD-L1) expression. Randomized pts received NIVO (360 mg Q3W or 240 mg Q2W) + chemo (XELOX Q3W or FOLFOX Q2W), NIVO + ipilimumab, or chemo. Dual primary endpoints for NIVO + chemo vs chemo were OS and progression-free survival (PFS) by blinded independent central review (BICR) in pts with PD-L1 combined positive score (CPS) ≥ 5. Results: 208 Chinese pts were randomized to NIVO + chemo or chemo. At 49-month (mo) minimum follow-up, NIVO + chemo continued to demonstrate OS and PFS benefit vs chemo in pts with PD-L1 CPS ≥ 5 and in all randomized pts (Table). The 4-yr OS rate was 25% with NIVO + chemo vs 11% with chemo in pts with PD-L1 CPS ≥ 5 and 21% vs 9% in all randomized pts. Objective response rate (ORR; 95% CI) per BICR in pts with PD-L1 CPS ≥ 5 who had measurable lesions at baseline was 68% (56–79) with NIVO + chemo vs 48% (36–60) with chemo; corresponding ORR in all randomized pts was 66% (55–76) and 45% (35–56). Responses were more durable with NIVO + chemo vs chemo both in pts with PD-L1 CPS ≥ 5 (median duration of response [mDOR; 95% CI] 12.5 mo [7.2–23.4] vs 6.9 mo [3.9–8.5]) and in all randomized pts (mDOR [95% CI] 12.5 mo [7.2–17.7] vs 5.6 mo [4.4–8.3]). No new safety signals were identified (Table). Conclusions: After 4 yrs of follow-up, NIVO + chemo continued to demonstrate clinically meaningful survival benefit and more durable responses vs chemo in Chinese pts, with an acceptable safety profile. These results are consistent with previous reports and with the overall study population with advanced GC/GEJC/EAC and further support NIVO + chemo as a standard 1L treatment option for Chinese pts. Clinical trial information: NCT02872116 . [Table: see text]
Benefit of immune checkpoint inhibitors (ICI) for patients with advanced esophageal squamous cell carcinoma and low PD-L1 expression: A systematic review and meta-analysis.
Authors: Lopes Mario Machado , Alencar Viviane , Sousa Isadora Martins de , Marin Comini Ana Carolina , Camandaroba Marcos Pedro Guedes 
Published: January 2024

346 Background: Immunotherapy has improved survival for patients with advanced esophageal squamous cell carcinoma (aESCC) and currently is the standard of care for patients with a positive PD-L1 status (CPS ≥10; TPS ≥1%) in the first-line setting. For PD-L1 negative/low, treatment options are limited, and chemotherapy is usually the first choice and associated with adverse events that may impair quality of life. Immunotherapy trials harbor conflicting results in this subgroup of patients, therefore, we performed a systematic review and meta-analysis to evaluate the potential benefit of ICI as single treatment for patients with aESCC and a PD-L1 expression negative/low. Methods: Studies that enrolled patients with aESCC treated with ICI versus chemotherapy in first and second-line settings and provided separate outcomes for patients with PD-L1 negative/low were identified by searching the EMBASE, PubMed and Cochrane databases. The outcomes evaluated were Overall Survival (OS), Progression Free-Survival (PFS) and Treatment-Emergent Adverse Events (TEAE). We pooled hazard ratio (HR) for PFS and OS endpoints and odds ratio (OR) with 95% confidence intervals (CI) for TEAE. Statistical analyses were performed using Revman 5.4 and a random-effects model. I² analysis was used to assess heterogeneity. This meta-analysis was recorded on Prospero ID CRD42023411251. Results: We included 6 randomized clinical trials with a total of 674 individuals in the final analysis. Most studies (5/6) included previously treated patients. ICI monotherapy in aESCC patients and PD-L1 expression negative/low was associated with a better OS (HR 0.86; 95% CI 0.76-0.97; p = 0.02; I² = 0%) and worse PFS (HR 1.37; 95% CI 1.10-1.71; p = 0.005; I² = 0%). Regarding the safety profile, it showed higher grade 3-5 toxicity rates (OR 1.8; 95% CI 1.17-2.78; p = 0.007; I² = 85%) for chemotherapy. Conclusions: ICI is effective for patients with aESCC and low/negative PD-L1 expression with an improvement in OS and a favorable safety profile.
Anlotinib plus TQB2450 as adjuvant therapy in patients with esophageal squamous cell carcinoma: A phase II study (ALTER-E005).
Authors: Guo Changying , Chen Shengjia , Ye Yongqiang , Li Xiao-Bing , Mao Weimin 
Published: January 2024

347 Background: There is currently a limited range of therapeutic options available for postoperative patients (pts) with esophageal squamous cell carcinoma (ESCC), emphasizing the urgent requirement to investigate more efficient and safer postoperative treatment regimens for resectable ESCC. TQB2450, a novel PD-L1 blockade, has shown promising activity when combined with anlotinib, an antiangiogenic agent, in the treatment of various tumors, including advanced ESCC,1 and biliary tract cancer.2 The ALTER-E005 study aimed to evaluate the efficacy and safety of combining anlotinib with TQB2450 as adjuvant therapy in pts with ESCC. Methods: This was a single-arm, multi-center phase II clinical trial. 30 pts (≥18 years) with histologically confirmed T1-2N1-3M0 or T3-4NanyM0 ESCC who had undergone radical (R0) resection with no recurrence 6 to 12 weeks after surgery and ECOG PS ≤ 1 would been rolled. Enrolled pts received oral anlotinib 12 mg on days 1-14 and intravenous TQB2450 1200 mg on day 1every 3 weeks for up to 16 cycles, until disease recurrence. The primary endpoint was disease recurrence free (DFS). The secondary endpoints included safety, 1-year DFS rate, 3-year DFS rate, 1-year overall survival (OS) rate, and 3-year OS rate. Results: Between August 18, 2022, and August 25, 2023, a total of 12 patients were enrolled. Out of the 12 surgically resected cases of ESCC, 11 (91.7%) had an ECOG score of 1, 10 (83.3%) were male, and 6 (50%) were under the age of 65. According to the eighth edition of the AJCC Cancer Staging Manual, 7 (58.3%) were classified as stage II, and 5 (41.7%) were classified as stage III. As of the data cut-off date (August 25, 2023), the median follow-up time was 5.1 months (95% CI: 3.4-6.8). 2 pts experienced disease recurrence, and the median duration of DFS has not yet been reached. Currently, 9 pts are still undergoing therapy, with treatment durations ranging from 0.3 months to 9.6 months. 2 pts discontinued therapy due to adverse events (AE), which subsequently improved after treatment. One patient experienced immune-related myocarditis, while the other patient had mouth ulcers and hand-foot syndrome. Additionally, one patient voluntarily withdrew from the study. Out of the total 12 patients, 3 (25%) experienced grade 3 treatment-emergent adverse events (TEAEs). There was no grade 4 or higher TEAEs reported. The grade 3 TEAEs included hand-foot syndrome (16.7%), abnormal liver function (8.3%), and immune-related hepatitis (8.3%). Conclusions: The study demonstrated the preliminary efficacy and safety of combining anlotinib with TQB2450 as adjuvant therapy in patients with ESCC who had undergone radical (R0) resection and showed no recurrence 6 to 12 weeks after surgery. 1. Zhi-Ye Zhang, et al. poster 4041: ASCO 2023. 2. Zhou J, et al. Hepatology 2022. Clinical trial information: NCT05252078 .
FLOT compared to FOLFOX/XELOX as a neoadjuvant chemotherapy in locally advanced gastric cancer: Experience of two clinics.
Authors: Semenov Nikolay , Dalgatov Kamil , Izrailov Roman , Zhukova Lyudmila 
Published: January 2024

361 Background: The optimal regimen of neoadjuvant chemotherapy (NCT) in locally advanced gastric cancer (GC) remains controversial, especially whether triplet (FLOT) or duplet (FOLFOX/XELOX) regimen is superior since escalation does not always lead to significant clinical improvement. The aim of this study is to assess efficacy of triplet and duplet chemotherapy regimens as a neoadjuvant approach in locally advanced GC via retrospective data. Methods: We queried the data for 334 patients with locally advanced GC (cT2-4 or cN+) diagnosed in 2016–2023 yy administered with multi-agent NCT: FLOT or XELOX/FOLFOX. The primary endpoints were the ratio of patients with disease progression on NCT, rates of ypN0, and rates of pathological complete response (pCR). Secondary endpoints included progression free survival (PFS) and overall survival (OS). Results: 156 patients (out of total 334 included in the study) received doublet NCT (FOLFOX/XELOX, 8/6 cycles respectively), 61.5% were males, median age was 67.4 (range 21.3-85.4) years, 88.2% had cT3-4. and 22.4% had locally advanced gastroesophageal junction (GEJ) adenocarcinoma. 177 patients were treated with triple NCT (FLOT, 8 cycles), 62.1% were males, median age was 59.9 years, 89.2% had cT3-4, and locally advanced GEJ adenocarcinoma was diagnosed in 21.0%. At a median follow up of 34.7 months (mth) using FLOT regimen as NCT was associated with better clinical outcomes. The ratio of patients who have progressed on NCT was 21.5% and 31% in triplet and doublet arms, respectively (p=0.098). Rates of ypN0 were 50.5% in FLOT arm and 43.7% in XELOX/FOLFOX arm (p=0.36). pCR was achieved in 8.2% and 6.3% in FLOT and XELOX/FOLFOX arms, respectively (p=0.59). Median PFS was 20.3 mth in FLOT arm in comparison to 15.7 mth in FOLFOX/XELOX arm (p=0.012). Median OS was not reached (NR) for triplet arm and was 25.1 mth for doublet arm (p= 0.003). Patients who conversed resectable disease had median PFS of 34.5 and 23.1 months for FLOT and FOLFOX/XELOX arms, respectively (p=0.024). Median OS in these subgroups was NR and 37.0 mth (p=0.003). Conclusions: We report that triplet regimen (FLOT) in comparison with doublet (FOLFOX/XELOX) regimen is the more favorable option as a neoadjuvant setting in locally advanced gastric cancer. FLOT NCT is associated with increased ypN0, pCR and shows statistically significant difference in PFS and OS.
Safety and efficacy of neoadjuvant docetaxel, cisplatin, and 5-fluorouracil (Neo DCF) therapy for locally advanced esophageal cancer: Real world data analysis.
Authors: Tamba Mikako , Osumi Hiroki , Fukuoka Shota , Ogura Mariko , Okamura Akihiko , Kanamori Jun , Imamura Yu , Takahari Daisuke , Yoshino Koichiro , Udagawa Shohei , Wakatsuki Takeru , Shinozaki Eiji , Watanabe Masayuki , Yamaguchi Kensei , Chin Keisho , Ooki Akira 
Published: January 2024

365 Background: Neoadjuvant chemotherapy with docetaxel, cisplatin plus 5-FU (Neo DCF) is one of the standard treatments for locally advanced esophageal squamous cell carcinoma (ESCC) in Japan based on the results of the JCOG1109 NExT study. As Neo DCF is both highly effective and high rate of adverse events, it is important to confirm clinical outcomes in the clinical practice and to explore clinical factors that predict treatment efficacy and adverse events (AEs) for treatment optimization. Methods: ESCC patients who were treated with Neo DCF between July 2016 and May 2023, were enrolled. Three courses of DCF (DTX [day 1]: 70 mg/m2, CDDP [day 1]: 70 mg/m2, 5-FU [continuous infusion on days 1-5]: 750 mg/m2, every 3 weeks) were planned, and prophylactic antibiotics was administered on days 5-15. We retrospectively assessed disease free survival (DFS), pathological response, AEs. Pathological response was assessed according to the Becker’s Criteria. Subgroup analyses of clinical factors related to the pathological response and AEs were also performed. Results: In total, 91 patients (median age, 62.3 years) were enrolled. Clinical stages of this cohort were 8.8% (I),16.4% (II), 69.2% (III), and 5.5% (IVA), respectively. After Neo DCF treatment, 90 patients (98.9%) underwent curative surgery. Median DFS and 3-year DFS rate were not reached and 76.9%. The incidence of pathological complete response (pCR) and major pathological response (MPR) were 11.1% (10/90) and 35.6% (32/90), respectively. There were no cases of recurrence in patients with pCR and MPR. The most common grade 3 or 4 AEs were neutropenia (58/91, 63.7 %), diarrhea (15/91, 16.5%), and thrombosis (9/91, 9.9%), respectively. Febrile neutropenia occurred in 33 patient (36.2%). Clinical T stage was significantly associated with pCR (P = 0.033). Conclusions: Neo DCF was effective and tolerable in the real-world ESCC patients in Japan.
Proportion and distribution of PD-L1 expression and associated clinicopathologic features in patients with microsatellite instability-high gastric cancer.
Authors: Lee Sun Mi 
Published: January 2024

387 Background: The frequency of microsatellite instability-high (MSI-H) phenotype in sporadic gastric cancers (GCs) widely varies from 8% to 20%. From prior data, MSI-H phenotypes are significantly associated with female sex, older age, antral location of the tumor, well to moderate differentiation, intestinal type, non-signet ring cell component, mucinous histologic type, a moderate to severe lymphoid stromal reaction, and a lower TNM stage. This study investigated the proportion and distribution of PD-L1 expression of MSI-H GCs compared to microsatellite stable (MSS) GCs. Methods:The study consists of 847 cases of unselected GC. MSI analysis was performed on all GC cases by immunohistochemistry for mismatch repair proteins followed by multiplex polymerase chain reaction. Among them, 72 GCs were found to be an MSI-H phenotype. After matching the T category of GCs, 200 cases of GC with MSS phenotype were selected for a control group. Immunohistochemistry for PD-L1 (SP263) was performed on 72 MSI-H GCs and 200 MSS GCs. Results: Patients with MSI-GC were significantly associated with advanced age (p <0.001), advanced tumor (p=0.0173), antral location of the tumor(p=0.0018), and T2 and T3 category (p=0.0031) but not T1 or T4 category. Histologically, MSI-H GCs occurred frequently in ulcerofungating mass (45.8%, p < 0.0001)), intestinal type (73.6%, p=0.0102), well to moderately differentiated tumor (56.9%, p=0.0102), tubular histologic type (66.7%, p=0.0013), tumor necrosis (18.1%, p <0.0001), and peritumoral neutrophilic infiltrate (40.3%, p <0.001) compared to those of 200 MSS GCs. In the evaluation of PD-L1, 55 (76.4%) MSI-H tumors revealed PD-L1 expression with ≥ 1 CPS. The predominant PD-L1 staining was found in intratumoral and peritumoral immune cells (66.7%) than within tumor cells (9.7%). The distribution of positive immune cells was predominantly located in the periphery of the tumor (37.5%) than within the tumor (9.7%). According to the criteria for PD-L1 positivity as at least 10 CPS, approximately 50% of MSI-H GCs were considered PD-L1 positive tumors with at least 10 CPS. Conclusions: In this study, the prevalence of MSI-H phenotype is approximately 8.5% of unselected GCs. Approximately 76% of patients with MSI-H tumors showed PD-L1 expression with at least 1 CPS, and 50% revealed PD-L1 expression with at least 10 CPS, who can respond better to immune checkpoint inhibitors with promising therapeutic benefits. Due to the peritumoral expression of immune cells in PD-L1 positive GCs with MSI-H phenotype, different endoscopic approaches to obtain tumor tissues for PD-L1 evaluation would be considered, such as sampling tissues at the tumor periphery.
The usefulness of ctDNA and exosome DNA as biomarkers in esophageal squamous cell carcinoma.
Authors: Nakai Tomoki , Kitahata Yuji , Nakamura Yuki , Motobayashi Hideki , Takemoto Norio , Ojima Toshiyasu , Hayata Keiji , Iwaya Takeshi , Hiraki Hayato , Nishizuka Satoshi , Kawai Manabu 
Published: January 2024

388 Background: Recently, the usefulness of exosome DNA (exo-DNA) for prognostic analysis of various solid tumors has also been reported. In this study, we investigated the usefulness of ctDNA and exo-DNA as biomarkers for esophageal squamous cell carcinoma. Methods: Patients with esophageal squamous cell carcinoma undergoing standard treatment had ctDNA and exo-DNA collected over time. NGS analysis was performed on biopsy or surgical specimens, and mutated genes in individual cases were followed by ddPCR over time. Results: NGS analysis was performed on 16 patients. 12 of 16 cases showed mutations, In 8 cases, ctDNA and exo-DNA could be measured by ddPCR over time. In one case of Stage IVA. both ctDNA and exo-DNA were useful to determine the efficacy of chemotherapy and radiotherapy, and in one case of Stage II, both ctDNA and exo-DNA were useful to predict postoperative recurrence. Conclusions: In esophageal squamous cell carcinoma, ctDNA and exo-DNA may be useful in determining treatment response and predicting recurrence. We will further investigate the usefulness of ctDNA and exo-DNA in esophageal squamous cell carcinoma, including prognostic prediction. Clinical trial information: UMIN000045311 .
Concordance among three programmed death-ligand 1 (PD-L1) scoring methods and their association with clinical outcomes of tislelizumab (TIS) monotherapy in esophageal squamous cell carcinoma (ESCC).
Authors: Shu Yongqian , Wang Jufeng , Chen Zhendong , Kim Sung-Bae , Lin Chen-Yuan , Kato Ken , Van Cutsem Eric , Du Wenting , Shi Jingwen , Xia Tianyu , Huang Ruiqi , Li Qiao , Zhang Yun , Shen Zhirong , Shen Lin 
Published: January 2024

390 Background: Multiple scoring methods and cutoffs have been developed to evaluate tumor PD-L1 expression status in patients with ESCC, and PD-L1 expression level has been associated with the degree of response to anti-programmed cell death protein 1 (PD-1)/PD-L1 therapy. Here, we retrospectively investigated concordance between three PD-L1 scoring methods and their association with clinical outcomes in RATIONALE-302, a phase 3 study of the anti-PD-1 antibody TIS vs investigator-chosen chemotherapy (ICC) as second-line treatment for advanced unresectable/metastatic ESCC (NCT03430843). Methods: Patients enrolled in RATIONALE-302 with evaluable PD-L1 expression by the tumor area positivity (TAP) score (based on visual estimation of positive tumor cells [TCs] and tumor-associated immune cells [ICs]) using the VENTANA PD-L1 (SP263) assay were categorized at a 10% cutoff. Stained slides from those patients were rescored post hoc using both combined positive score (CPS; based on counting positive TCs and ICs) at cutoff 10 and TC (based on counting positive TCs only) score at a 1% cutoff, thresholds currently used in ESCC for anti-PD-(L)1 therapy. Concordance at these thresholds was investigated. Clinical efficacy (overall survival [OS]) for PD-L1 subgroups was assessed. Results: Of 512 pts enrolled, 364 had evaluable TAP scores (TIS, n=180; ICC, n=184), of whom 355 had evaluable post-hoc CPS and TC scores (TIS, n=175; ICC, n=180). TAP score and CPS showed high concordance in terms of overall percentage agreement (OPA; 90% [95% confidence interval (CI): 86, 93]) and Cohen’s Kappa (0.79 [95% CI: 0.72, 0.85]), while TAP and TC scores had lower concordance (OPA: 78% [95% CI: 73, 82]; Cohen’s Kappa: 0.56 [95% CI: 0.47, 0.64]). OS benefit with TIS vs ICC in PD-L1 subgroups defined by TAP, CPS, and TC score cutoffs were generally similar (Table). Conclusions: OS subgroup analysis showed comparable treatment effect by TAP score at 10% cutoff, CPS at cutoff 10, and TC score at 1% cutoff based on SP263 staining. TAP score and CPS at these cutoffs exhibited substantial concordance. The results indicate that the less time-consuming, visually estimated TAP score and CPS may be interchangeable for clinical measurement of PD-L1 expression in patients with ESCC. Clinical trial information: NCT03430843 . [Table: see text]
Circulating exosomal microRNA signature to predict peritoneal metastasis in patients with advanced gastric cancer.
Authors: Wada Yuma , Nishi Masaaki , Yoshikawa Kozo , Takasu Chie , Tokunaga Takuya , Nakao Toshihiro , Kashihara Hideya , Yoshimoto Toshiaki , Shimada Mitsuo 
Published: January 2024

396 Background: Despite of radical operation, about half of gastric cancer (GC) patients with advanced GC develop peritoneal metastasis (PM) and the patients with PM has poor prognosis. However, because staging laparoscopy was high invasive procedure for the patients, identification of PM by using liquid biopsy can be useful in patients with GC. Methods: We analyzed two genome-wide miRNA expression profiling datasets (GSE164174 and TCGA). We prioritized biomarkers in pretreatment plasma specimens from clinical training and validation cohorts of patients with GC. We developed an integrated exosomal miRNA panel and established a risk-stratification model, which was combined with miRNA panel and currently used tumor markers (CEA, CA19-9, CA125, and CA72-4 levels). Results: Our comprehensive discovery effort identified a 4-miRNA panel that robustly predicted the metastasis, with an excellent accuracy in TCGA dataset (AUC=0.86). We successfully established a circulating exosomal miRNA panel with remarkable diagnostic accuracy in the clinical training (AUC=0.85) and validation (AUC=0.86) cohorts. Moreover, the predictive accuracy of the panel was significantly superior to conventional clinical factors (P<0.01), and the risk-stratification model was dramatically superior to the panel and currently used clinical factors for predicting PM (AUC=0.94, univariate: OR = 77.00, P < 0.01; multivariate: OR = 57.71, P = 0.01). Conclusions: Our novel risk-stratification model for predicting PM has a potential for clinical translation as a liquid biopsy assay in patients with GC. Our findings highlight the potential clinical impact of our model for improved selection and management of patients with this malignancy.