bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigation of prognostic factors for second-line treatment with nivolumab for unresectable or recurrent esophageal cancer.
Authors: Ogata Takashi , Machida Nozomu , Takahashi Kosuke , Kano Kazuki , Koumori Keisuke , Watanabe Hayato , Fujikawa Hirohito , Yamada Takanobu , Inokuchi Yasuhiro , Furuta Mitsuhiro , Kaneta Yoshihiro , Hayashi Kei , Ishida Ayaka , Oshima Takashi 
Published: June 2021

e16055 Background: Nivolumab, an immune-checkpoint inhibitor for unresectable or recurrent esophageal cancer is used as second-line treatment. On the other hand, the relationship between indicators of cancer immunity (GPS, NLR, PLR), indicators of nutritional status (PNI, BMI), and prognosis of patients treated with nivolumab is unclear. Methods: We investigated the prognostic factors of nivolumab for unresectable or recurrent esophageal cancer. The subjects were 62 patients who received nivolumab as a second-line or later treatment for unresectable or recurrent esophageal cancer before January 2021. Of these 13 patients had previously been treated with taxan. We used GPS (Glasgow prognostic score), NLR (Neutrophil-Lymphocyte Ratio: cutoff value is 3.5), PLR (Platelet-Lymphocyte Ratio: cutoff value is 200), PNI (Prognostic nutrition index: cutoff value is 40), BMI (Body mass index: cutoff value is 18.5 for under 70 years old, and 20 for over 70 years old defined by Asian GLIM standard) as prognostic indicators. We examined the association between age, gender, PS, GPS, NLR, PLR, PNI, BMI and prognosis in patients treated with nivolumab. And we also examined the relationship between the history of taxan administration, the presence of adverse events and the prognosis. Results: Of the 62 cases, 48 cases were male and 14 cases were female. The median age was 70 years. Median OS was 359 days, and median PFS was 97 days. OS in patients with no prior taxan treatment group was significantly longer (P<0.05). AE appeared in 49 cases (79%), and irAE appeared in 22 cases (35.5%). OS in patients with irAE was significantly longer (P<0.01). PS (0/1/2) was 27 cases/33 cases/2 cases, and GPS (0 point/1 point/2 point) was 41 cases/11 cases/10 cases. NLR high was 35 cases, and NLR low was 27 cases. PLR high was 31 cases and PLR low was 31 cases. PNI high was 46 cases and PNI low was 16 cases. BMI normal or high was 27 cases and BMI low was 35 cases. In univariate analysis of OS, GPS (P<0.001), NLR (P<0.01), PS (P<0.05), PNI (P<0.001) showed a significant difference in survival, and in multivariate analysis, PS (p<0.05) and PNI (P<0.05) were significant prognostic factors. Conclusions: PS and PNI were good prognostic factors with nivolumab after second or later treatment for unresectable or recurrent esophageal cancer.
TRG as indicator of efficacy of FLOT versus FOLFOX in perioperative chemotherapy for resectable gastric cancer patients (single institution experience).
Authors: Beliak Natalia P. , Orlova Rashida , Kutukova Svetlana , Zhukova Natalia V. , Balashov Pavel , Usmanov Nazif 
Published: June 2021

e16061 Background: Based on results German FLOT-4 study, the FLOT regimen could be considered the new standard chemotherapy regimen for perioperative strategy of resectable GC. Since more and more patients have received neoadjuvant treatment,the efficacy and side effect must be weighted before performing NACT. Two-drug regimens were preferred according to the NCCN guidelines in principle because of their lower toxicity. And three-drug regimens may be applied in medically fit patients with access to frequent evaluation during treatment, to ensure that they can still tolerate surgery after NACT. Methods: We analyzed the data of 79 patients with resectable locally advanced gastric cancer who received the FLOT or FOLFOX regimen as NACT. The group of patients with NAСT FLOT included 44 patients, including 32 men, 12 women. Age in the first group varied from 28 to 80 years, the median age was 59.0 (95% CI 54.1-62.0) The group of patients with the FOLFOX chemotherapy regimen included 35: 17 (48.6%) men and 18 women (51.4%). Age in the second group varied from 60 to 75 years, the median age in the second group was 67.5 (95% CI 62.2-71.0). The second group included significantly older patients U = 137.0; p = 0.0001. Results: The severity of drug pathomorphosis was assessed in a standard way according to the Mandard system, in the first group there were 5 patients - TRG1 (11.4%), 7 patients - TRG2 (15.9%), 9 patients - TRG3 (20.5%), 15 patients TRG4 (34.0%), 5 patients - TRG5 (11.4%), 3 patients it was not evaluated (6.8%). In the second group, 6 patients - TRG1 (17.1%), 2 patients - TRG2 (5.7%), 2 patients - TRG3 (5.7%), 16 patients - TRG4 (45.8 %), 7 patients - TRG5 (20.0%), for 2 patients it was not evaluated (5.7%). Complete pathomorphosis was not statistically different in both groups (p = 0.47). TRG 2 was not statistically different (p = 0.16). The number of registered cases of TRG3 in the first group exceeded (p = 0.06). The frequency of TRG4 and TRG 5 did not differ (p = 0.29). Major pathological regression (TRG1 + TRG2) was 27.3% in the first group and 22.8% (p = 0.65). A decrease in the stage in the first group occurred in 22 patients (50.0%), and in the second group - in 19 patients (54.3%), p = 0.70. yp≤ T2 was diagnosed in 21 out of 79 patients (26.6%), in the first group in 11 patients (25%), in the second group in 10 (28.6%), p = 0.72. Conclusions: the FOLFOX regimen showed similar efficacy in the tumor response grade rate compared to the FLOT regimen, therefore, these two regimes are interchangeable, especially among patients of the older age group or in patients with high risks of a four-component regimen.
Profiling genomic characteristics related to immunotherapy for gastric cancer with amplified MET.
Authors: Yu Yiyi , Li Wei , Yu Shan , Wang Yan , Zhu Mengxuan , Yi Zhao , Liu Tianshu 
Published: June 2021

e16066 Background: Gastric cancer (GCA) is one of the most deadly cancers all over the world, with an estimate of 26,560 new cases and 11,180 deaths in United States according to the cancer statistics of 2021. As immunotherapy has become available for GCA, it is necessary to distinguish patients who might be resistant to it. Methods: We identified 41 patients with amplified MET from a large Chinese cohort including 934 GCA (4.4% out of them) according to the ratio of purity adjusted copy number of MET and chromosome 7. Then, we comprehensively profiled genomic characteristics related to immunotherapy for GCA with amplified MET and compared them with other GCA. Results: First, mutated RNF43 and AXIN1 were much more prevalent in GCA with amplified MET. These two genes are components of Wnt pathway, whose aberrance is associated with resistance to immunotherapy. Second, carrier ratios of amplified CDK6 and CCND1 were much higher in GCA with amplified MET. These two genes play important roles in cell cycle pathway, while amplification of CCND1 has been recognized as a negatively predictive biomarker for immunotherapy. Third, we calculated mutational load of immunotherapy-related positively (mutated ATM, BRCA1, BRCA2, CHEK2, ERCC2, ERCC4, FANCA, KRAS, MLH1, MSH2, MSH6, NRAS, PALB2, PBRM1, PMS2, POLD1, POLE, RAD50 and TP53; deleted POLE) and negatively (mutated B2M, CTNNB1, DNMT3A, EGFR, JAK1, JAK2 and STK11; amplified CCND1, EGFR, FGF19, FGF3, FGF4, MDM2 and MDM4; deleted B2M, JAK2, PTEN and STK11) predictive biomarkers for GCA with amplified MET. We defined the mutational load as mean carrier ratio of point mutations or copy number variations (CNVs) appeared in a gene set. As is expected, the mutational load of point mutations in 19 positively predictive biomarkers in GCA with amplified MET was much lower than that in other GCA, whereas the mutational load of CNV in 11 negatively predictive biomarkers in GCA with amplified MET was much higher than that in other GCA. Finally, we found GCA with amplified MET possessed lower tumor mutational burden (TMB) and microsatellite instability (MSI), depleted somatic signature of defective DNA mismatch repair and higher copy number instability (CNI). Conclusions: Genomic characteristics of GCA with amplified MET are associated with adverse response to immunotherapy and thus it should be carefully evaluated when these patients are treated with immunotherapy.
Optimizing the program of sequential chemotherapy for advanced gastric cancer based on gene-level CNVs called from ctDNA.
Authors: Xi Wenqi , Zhou Chenfei , Zhang Shouwei , Yi Zhao , Chen Yawei , Ji Jun , Ma Tao , Wu Junwei , Shangguan Chengfang , Zhu Zhenggang , Zhang Jun 
Published: June 2021

e16068 Background: Tumor evolutionary trade-offs under treatment pressure can be utilized to optimize therapy. We aimed to profile the dynamic pattern of gene-level copy number variations (CNVs) for advance gastric cancer (GCA) patients who underwent sequential chemotherapy and optimized the therapy program. Methods: 27 chemo-naive advanced GCA patients with distant metastasis were enrolled. Peripheral blood samples were collected at different time points, including pre-therapy and disease progression on a specific regimen. Gene-level CNVs were called from ctDNA of blood samples and drug modified score (DMS) was defined as the ratio of CNV value between samples of pre- and post-treatment for each gene. Positive and negative DMS of a gene represented its resistance and sensitivity to a selected regimen, respectively. Then, the best initial regimen was selected and the optimal program of sequential chemotherapy was designed for each patient. Results: DMS of gene was calculated for four chemotherapy regimens, including platinum-based doublet regimen (Pt-2d), oral-fluorouracil prodrug (O-FP), paclitaxel-based regimen (PTX) and irinotecan-based regimen (CPT-11). Based on DMS distribution, resistant and sensitive genes were determined for each regimen through a heuristic method. Functional enrichment analysis showed that resistant genes mainly involved in cellular response to oxygen-containing compound and regulation of cell proliferation, while sensitive genes mainly involved in positive regulation of macromolecule biosynthetic process and regulation of apoptotic process. Then, drug resistant score (DRS, defined as DMS weighted sum of CNV values of resistant genes) was calculated and the regimen with the lowest DRS was selected as the best initial treatment for each patient. The best initial treatment of 16 patients was CPT-11, of 8 patients was O-FP, of 2 patients was Pt-2d and of 1 patient was PTX. Following that, the optimal program of sequential chemotherapy was designed according to the percentage of shared resistant genes between regimens for each patient, where two regimens with the lowest percentage were recommended to use one by one. Finally, prognostic analysis showed that differences between the optimal and practical program of sequential chemotherapy were negatively correlated to overall survival of patients. Conclusions: Based on gene-level CNVs called from ctDNA of blood samples, we determined the best initial treatment and designed the optimal program of sequential chemotherapy for advanced GCA patients, pacing a key step toward precision medicine in GCA field.
Effect of ethnicity and chemotherapy (mFOLFOX6) on zolbetuximab pharmacokinetics in patients with claudin 18.2-positive locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma (G/GEJ).
Authors: Lee Keun-Wook , Klempner Samuel J , Yang Jianning , Desai Amit , Yamada Akihiro , Ueno Yoko , Wojtkowski Tomasz , Park Jung Wook , Pavese Janet , Loupakis Fotios , Bang Yung-Jue , Shitara Kohei 
Published: June 2021

e16078 Background: Zolbetuximab is a chimeric IgG1 monoclonal antibody that targets Claudin 18.2 (CLDN18.2), a tight junction protein that is normally confined to gastric mucosa but is retained in G/GEJ. A phase 2 (NCT01630083, FAST) trial demonstrated significantly prolonged survival with zolbetuximab + EOX (epirubicin, oxaliplatin, capecitabine) vs EOX in G/GEJ. Two global phase 3 studies are ongoing, comparing zolbetuximab + chemotherapy vs chemotherapy as first-line treatment in CLDN18.2-positive G/GEJ. This study assessed the influence of ethnic differences and chemotherapy on the pharmacokinetics (PK) of zolbetuximab in patients (pts) with G/GEJ and the potential effect of zolbetuximab on chemotherapy PK. Methods: In the Japanese phase 1 and global phase 2 studies, adult pts with CLDN18.2-postitive G/GEJ received zolbetuximab 800 mg/m2 IV on Cycle 1 Day 1 (Cycle 1 Day 3 in Cohort 2 of phase 2) then 600 mg/m2 Q3W. Phase 1 and Cohort 1A of the phase 2 study assessed zolbetuximab monotherapy in 21-day cycles. Cohort 2 of the phase 2 study assessed zolbetuximab + mFOLFOX (5-FU, folinic acid, oxaliplatin; 4 cycles) in 42-day cycles (Q2W from Cycle 1 Day 1). Blood samples for zolbetuximab PK following single and multiple doses, and for chemotherapy (5-FU and oxaliplatin) PK alone or with zolbetuximab were collected. Maximum serum drug concentration (Cmax) and area under the concentration-time curve from 0-21 days (AUC0-21) were assessed. Potential ethnic differences in zolbetuximab exposures across Japanese, other Asian (Korean and Taiwanese), and Western pts, and the potential drug-drug interaction between zolbetuximab and chemotherapy were evaluated. Results: Zolbetuximab concentration profiles and PK parameters were generally comparable across Japanese, other Asian, and Western populations (Table). Zolbetuximab PK properties were similar between monotherapy and combination therapy cohorts (Table). Chemotherapy PK was comparable with and without zolbetuximab. Conclusions: The analyses suggest no apparent ethnic differences in zolbetuximab PK across Japanese/Asian and Western pts and no PK interactions between zolbetuximab and mFOLFOX6. These results support the use of zolbetuximab and mFOLFOX without the need for dose adjustment in global phase 3 trials. Clinical trial information: NCT03505320, NCT03528629. [Table: see text]
Role of adjuvant therapy in esophageal cancer patients after neoadjuvant therapy and curative esophagectomy: A systematic review and meta-analysis.
Authors: Lee Yung , Samarasinghe Yasith , Lee Michael H , Thiru Luxury , Shargall Yaron , Finley Christian , Hanna Wael , Levine Oren Hannun , Juergens Rosalyn A. , Agzarian John 
Published: June 2021

e16083 Background: While neoadjuvant therapy followed by esophagectomy is the standard of care for locally advanced esophageal cancer, the role of adjuvant therapy is uncertain. As such, this review aims to analyze esophageal cancer patients who previously underwent neoadjuvant therapy followed by a curative resection (negative margins) to determine whether additional adjuvant therapy is associated with improved survival outcomes. Methods: MEDLINE, EMBASE, and CENTRAL databases were searched up to August 2020 for studies comparing patients with esophageal cancer who underwent neoadjuvant therapy and curative resection with and without adjuvant therapy. Primary outcome was overall survival (OS), and secondary outcomes were disease-free survival (DFS), locoregional recurrence, and distant recurrence at 1 and 5-years. Random effects meta-analysis was conducted where appropriate. Grading of recommendations, assessment, development, and evaluation (GRADE) was used to assess the certainty of evidence. Results: Ten studies involving 6,462 patients were included. 6,162 (95.36%) patients from 7 studies received adjuvant chemotherapy, whereas 296 (4.58%) patients from 3 studies underwent either adjuvant radiotherapy or chemoradiotherapy. When compared to patients who received neoadjuvant therapy and esophagectomy alone, adjuvant therapy groups experienced a significant overall survival benefit by 48% at 1-year (RR 0.52, 95%CI 0.41-0.65, P < 0.001, moderate certainty). This reduction in mortality was consistent at long-term 5-year follow-up (RR 0.91, 95%CI 0.87-0.96, P < 0.001, moderate certainty). Subgroup analysis on pathologic node positive patients demonstrated a consistent survival benefit at 1-year (RR 0.57, 95% CI 0.42-0.77, P < 0.001, moderate certainty) and 5-year (RR 0.89 95%CI 0.84-0.95, P < 0.001, moderate certainty). While adjuvant therapy presented no benefit for the T0-2 stage subgroup, patients with T3-4 disease experienced a significant reduction in mortality with the addition of adjuvant therapy at both 1-year (RR 0.51, 95% CI 0.41-0.63, P < 0.001, moderate certainty), and 5-years (RR 0.91, 95% CI 0.85-0.97, P = 0.005, moderate certainty). Due to incomplete reporting, the added benefit of adjuvant therapy was uncertain regarding DFS, locoregional recurrence, and distant recurrence. Conclusions: Adjuvant therapy after neoadjuvant treatment and curative esophagectomy provides improved OS at 1 and 5 years, but the benefit for DFS and locoregional/distant recurrence was uncertain due to limited reporting of these outcomes.
The epidemiological trend of esophageal cancer in Mumbai, India over the past two decades.
Authors: Sekar Anbarasan , Rajendra Akhil , Noronha Vanita , Mokal Smruti , Patil Vijay Maruti , Menon Nandini , Chopade Sunil , Dikshit Rajesh , Banavali Shripad Dinanath , Prabhash Kumar 
Published: June 2021

e16095 Background: There has been a definite histopathological shift in esophageal cancer in the West over the past few decades, with adenocarcinoma overtaking squamous cell carcinoma as the commonest type. Asian countries with a high human development index like China have also reported an increased incidence of esophageal adenocarcinoma. Data on the epidemiology of esophageal cancer in India are limited. Methods: We retrospectively evaluated the data of all patients with histologically proven esophageal cancer at Tata Memorial Hospital, from 2003 to 2018. We excluded non-squamous and non-adenocarcinoma histologies. Results: Of a total of 7,874 patients with esophageal cancer, 5,092 (64.7%) were men, for a male to female ratio of 2.5:1. The median age was 57 years (IQR, 50-65); 4,465 (56.7%) were below 60 years old. Of the 4912 patients in whom a history of tobacco or alcohol use had been elicited, there were 1,360 (27.7%) patients with no history of substance use. The site of the primary was the upper third in 906 (12.8%), middle third esophagus in 2,942 (41.5%), lower third in 2,331 (32.8%) and gastroesophageal junction in 917 (12.9%) patients. The predominant histology was squamous cell carcinoma in 6,413 (81.4%) patients and adenocarcinoma in 1461 (18.6%). There was no change in the histologic pattern over the period of the study; squamous cell carcinoma constituted 78.5% of the cases in 2003, and 85.5% in 2018; Chi square test for the year wise trend in histologic patterns was not significant, p=0.143. Evaluation of the histologic subtype according to sex revealed that in the male patients, there were 3890 (76.4%) squamous and 1202 (23.6%) adenocarcinoma cases, while in female patients, there were 2523 (90.7%) squamous and 259 (9.3%) adenocarcinoma cases. On a uni variate analysis, male sex (p<0.001), a history of tobacco or alcohol use (p<0.001), and the presence of comorbidity (p<0.007) were associated with an increased risk of squamous cell carcinoma. Multivariate analysis by logistic regression model revealed that female sex and use of tobacco or alcohol were positively associated with squamous cell carcinoma, while the presence of comorbities and primary in lower esophagus/GEJ were positively associated with adenocarcinoma. Conclusions: Squamous cell carcinoma continues to be the commonest esophageal cancer histologic subtype in over 80% Indian patients. The mid esophagus is the most common site (42%). There is no evidence of an epidemiological shift or an increase in the occurrence of adenocarcinoma or of lower esophageal/GEJ malignancy over the past two decades.
Phase I study of liposomal irinotecan (LY01610) in patients with advanced esophageal squamous cell carcinoma.
Authors: Liu Yun , Zhang Bo , Xu Jianping , Wang Xingyuan , Tang Jialin , Huang Jing 
Published: June 2021

e16097 Background: This phase I trial was performed to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), preliminary efficacy, and pharmacokinetics (PK) of LY01610, a novel liposome-encapsulated irinotecan, in patients with advanced esophageal squamous cell carcinoma (ESCC). Methods: This trial was conducted in two stages. In the dose-escalation stage, patients with advanced ESCC refractory or intolerant to previous chemotherapy received escalating doses of LY01610. A recommended dose based on patient tolerance was then expanded in the second stage. LY01610 was administered intravenously every 2 weeks, except that the first cycle in dose-escalation was three weeks to allow observation of DLTs. Results: Twenty-four patients were enrolled across four dose levels (30, 60, 90 and 120 mg/m2). The DLTs included vomiting and febrile neutropenia, and the MTD was 90 mg/m2. The most common grade 3/4 adverse events were leukopenia in six patients (25.0 %), anemia in six patients (25.0 %) and neutropenia in five patients (20.8 %). One patient achieved complete response, and four had partial response, including one patient receiving LY01610 at the starting dose of 30 mg/m2. Compared with conventional irinotecan, the PK profile of LY01610 was characterized by increased and prolonged exposure of total irinotecan and the active metabolite SN-38 in plasma. Conclusions: LY01610 demonstrated manageable toxicity and promising antitumor activity in patients with advanced ESCC. Future clinical development of LY01610 as single agent or in combination with other anti-cancer agents in treating ESCC patients is warranted. Clinical trial information: NCT04088604.