bluuebunny/crossref_metadata_2025_split huggingface dataset:
Classification of esophageal adenocarcinoma into subgroups that are associated with patient survival using RNA-seq and immunohistochemistry.
Authors: Sharma Sowmya , Naeini Marjan , Aoude Lauren G , Bonazzi Vanessa F , Gartside Michael G , Loffler Kelly A , Patel Kalpana , Newell Felicity , Lampe Guy , Brosda Sandra , Thomas Janine , Smithers Mark , Simes John , Watson David I. , Pearson John , Barbour Andrew , Waddell Nic 
Published: June 2022

e16028 Background: : Prognosis of oesophageal adenocarcinoma (OAC) remains poor globally. Traditional histopathology classifications have minimal impact on clinical management and outcomes. To improve patient outcomes, prognostic and therapeutic stratification is required within this cohort of morphologically homogenous cancers. Identification and validation of candidate prognostic and therapeutic biomarkers may contribute to personalisation of therapy for patients with OAC. Methods: We used RNAseq of OAC tumour tissues to classify OAC into subgroups which were associated with patient survival and the immune infiltrate in the tumour micro-environment. We identified genes that discriminate each group and selected thirteen to perform IHC against the protein products of these genes using the same OAC samples. The IHC markers that best discriminate the immune-clusters were applied to an independent set of OAC in tissue micro-arrays (TMAs) to validate the prognostic significance of the immune-clusters. Results: Using RNA-seq we identified four candidate immune-clusters namely, immune hot, immune cold, immune suppressed and immune moderate, that correlate with progression free and overall patient survival. IHC revealed a correlation of five of thirteen of these IHC markers with the RNAseq data, and the IHC was able to corroborate the classification of OAC immune-clusters. The best markers predictive of these immune-clusters underwent IHC in an independent OAC TMA cohort to confirm the prognostic significance of these markers. The TMAs contain matched primary and nodal disease, so we will also report on the presence of the four subgroups within nodal disease. To date, two of the IHC markers are associated with survival benefit in the TMAs patient group. Conclusions: We anticipate that validating IHC markers to reliably identify the four immune-clusters of OAC will be useful in predicting prognosis, survival and therapeutic classification of OAC in precision oncology of the OAC.
Effect of hepatic impairment on the pharmacokinetics of ripretinib.
Authors: Li Xiaoyan , Psoinos Charles M , Shelton Mark Joel , Abane Farida , Matson Mark A. , Oberstein Samuel , Ruiz-Soto Rodrigo 
Published: June 2022

e16031 Background: Ripretinib is a tyrosine kinase inhibitor indicated for the treatment of patients with advanced gastrointestinal stromal tumor who have received prior treatment with ≥3 kinase inhibitors, including imatinib. Ripretinib and its active metabolite (DP-5439) are CYP3A substrates and coadministration with itraconazole (CYP3A inhibitor) increased exposure to each analyte by ̃100%. Therefore, we studied ripretinib in subjects with varying degrees of hepatic impairment (HI). Methods: Subjects with mild, moderate, and severe HI based on Child-Pugh, and matched healthy subjects received a single oral dose of ripretinib (50 mg, fasting) with 8 days of PK sampling. Concentrations of ripretinib and DP-5439 in plasma were measured by a liquid chromatography–tandem mass spectrometry (LC-MS/MS) assay. PK parameters were calculated using Phoenix WinNonlin, and the geometric least squares mean ratios and corresponding 90% confidence intervals of Cmax, AUC0-t, and AUC0-∞ (total and unbound) were calculated. Unbound concentrations were assessed at Tmax and 24 hours postdose. Results: Eight subjects with mild HI, 8 with moderate HI, 4 with severe HI, and 13 healthy matches were enrolled. As shown in the table, total ripretinib and DP-5439 PK was comparable for mild HI vs. healthy matches. For moderate HI, total ripretinib AUC was ̃100% higher (Cmax was comparable), whereas DP-5439 AUC was marginally higher (Cmax was 32% lower). For severe HI, total ripretinib AUC0-t was ̃160% higher and Cmax was ̃24% lower, whereas DP-5439 AUCs were ̃50% lower and Cmax was 78% lower. Unbound fraction was < 0.6% for ripretinib and 0.2-1.4% for DP-5439, with no clear trend with HI severity. The safety profile in HI subjects was similar to healthy matches; common adverse events (in ≥2 subjects) included increased lipase or amylase, diarrhea, and headache. Conclusions: Consistent with current labeling, mild HI had no impact on total PK. In this study, moderate and severe HI increased ripretinib AUC ̃100% and 163%, respectively. PK exposure to DP-5439 and combined ripretinib + DP-5439 was impacted to a lesser extent. Dose recommendations in moderate and severe HI are currently under development.[Table: see text]
Comparison of response evaluation criteria in solid tumors and tumor regression grade in evaluating the effect of preoperative systematic therapy of gastric cancer.
Authors: Qiu Miaozhen , Lai Mingyu , Guan Wen-Long , Sun Yu-Ting 
Published: June 2022

e16063 Background: Both Response Evaluation Criteria in Solid Tumors (RECIST) and tumor regression grade (TRG) play key roles in evaluating tumor response. However, the consistency of these two methods has not been determined. Therefore, we compared the prognostic value of TRG and RECIST 1.1 for gastric cancer (GC) patients and analyzed their consistency. Methods: Patients with gastric cancer who received preoperative chemotherapy or chemotherapy combined with immunotherapy and had record of TRG from December 2013 to October 2021 were enrolled retrospectively. TRG 0-1 is considered as consistent with CR or PR in RECIST 1.1 and TRG 2-3 corresponds to SD or PD in RECIST 1.1. The primary endpoints were disease free survival (DFS) and overall survival (OS). The consistency of RECIST and TRG was examined by kappa statistics. Kaplan-Meier method and Cox proportional hazards regression models were used for survival analysis. Results: We enrolled 157 GC patients, including 125 patients with preoperative chemotherapy, and 32 patients with preoperative chemotherapy combined with PD-1 inhibitors. Among them, 56 patients had measurable lesions. Only 19.6% (11/56) of the patients had consistent results of RECIST 1.1 and TRG. The pCR rate was 13.4% and the overall response rate (ORR) was 52.6% according to RECIST 1.1. Preoperative chemoimmunotherapy had a significantly higher pCR rate than chemotherapy alone, 34.4% vs 8.0%, P< 0.001. TRG was significantly correlated with both OS and DFS (P = 0.0162 and 0.0259, respectively) while response according to RECIST1.1 was not significantly related with OS and DFS ( P= 0.8598 and 0.2288, respectively). The median DFS had not reached in the TRG 0-1 group and was 16.13 months in TRG 2-3 group. Young patient, peritoneal metastasis or liver metastasis was correlated with TRG 2-3. Conclusions: Our results showed that TRG was in poor agreement with RECIST 1.1. TRG was better than RECIST 1.1 in predicting DFS and OS for GC patients who received neoadjuvant therapy.
Comparison of neoadjuvant chemotherapy and postoperative adjuvant chemotherapy in the treatment of Borrmann type IV gastric cancer.
Authors: Huang Xingmao , Pengfei Yu , Fang Jingquan , Cao Yang , Ye Zeyao , Chai Tengjiao , Du Yian , Cheng Xiangdong 
Published: June 2022

e16064 Background: Borrmann type IV gastric cancer is highly malignant and prone to peritoneal metastasis, including peritoneal dissemination (P1) and positive peritoneal cytology (CY1) causing a dismal prognosis. This study is to compare the efficacy of neoadjuvant chemotherapy and postoperative adjuvant chemotherapy in patients with Borrmann type IV gastric cancer and analyze the prognostic factors of these patients. Methods: According to different therapies, patients diagnosed with Borrmann type IV gastric cancer in Zhejiang Cancer Hospital from June 2010 to June 2020, were divided into two groups: neoadjuvant chemotherapy group (NCT group) and non-neoadjuvant chemotherapy group (NNCT group). Both of two groups were subjected to the propensity score matching (PSM) at a ratio of 1:2 and then the treatment completion rate and overall survival (OS) time were analyzed. Results: A total of 240 cases were included after propensity score matching and 80 patients and 160 patients were enrolled in the NCT group and NNCT group, respectively. Neoadjuvant chemotherapy and postoperative adjuvant chemotherapy were based on platinum combined with fluorouracil. For the efficacy of treatment, R0 resection was performed on 92.2% patients in the NCT group and 88.1% in the NNCT group, but there was no statistical difference (P=0.463). 3-year survival rate was 35.0% in the NCT group compared with 29.4% in the NNCT group (P=0.427), and the 5-year survival rate was 28.7% and 25.6%, respectively (P=0.460). For patients with and without R0 resection, the 3-year survival rate was 34.3% and 7.4% (P<0.001), and the 5-year survival rate was 30.0% and 0%, respectively (P<0.001). Hyperthermic intraperitoneal chemotherapy (HIPEC) was conducted on 40 patients (16.7%), and the survival rate of HIPEC group was better than that of non-HIPEC group (3 year survival rate: 55.0% vs 26.5%, P=0.073; 5 year survival rate: 45.0% vs 23.0%, P=0.174), but the difference was not statistically significant. Conclusions: Borrmann type IV gastric cancer was characterized by poor differentiation and high incidence of peritoneal metastasis. The efficacy of the neoadjuvant chemotherapy based on platinum combined with fluorouracil is limited. A combination of HIPEC and system chemotherapy may effectively improve the prognosis of these patients.
Genomic alteration in chromatin remodeling genes as a potential predictive biomarker for immunotherapy in gastric cancer.
Authors: Jia Yongning , Yuan Hongling , Xin Yaqun , Xing Xiaofang , Li Ziyu , Zhu Honglin 
Published: June 2022

e16083 Background: Gastric cancer (GC) is the fifth most incident and the fourth deadliest cancer worldwide, and currently immune checkpoint inhibitors have been approved for the treatment of patients with recurrent/metastatic GC. Studies have reported that the inactivation of chromatin remodeling complex may be a promising biomarker for immune checkpoint inhibitors (ICI) treatment. The aim of this study was to investigate the predictive value of chromatin remodeling genes on the response of ICIs in GC. Methods: We analyzed next-generation sequencing (NGS) data from three cohorts: the Chinese cohort (from GenetronHealth, n = 1013), the TCGA cohort (n = 434) and the ICI cohort (from the Memorial Sloan Kettering Cancer Center, n = 39). The abundance of tumor immune infiltrates was estimated by the tumor immune estimation resource (TIMER) 2.0 algorithm using gene expression data, and the Kaplan–Meier curves were used to determine survival differences. Results: In this study, we defined a set of chromatin remodeling genes containing PBRM1, ARID1A, ARID1B and ARID2. The loss-of-function mutations of these chromatin remodeling genes (CRGLOF), including frameshift, nonsense and splice were identified in 176/1013 (17.4%) patients with GC in the Chinese cohort, which was significantly lower than those in the TCGA cohort (17.4% vs 27.6%, p = 0.00001). In both cohorts, patients with CRGLOF mutations exhibited higher tumor mutational burden (TMB) (all p < 0.001) and PD-L1 expression (p < 0.001 in the TCGA; p = 0.037 in the Chinese) than those without CRGLOF mutations. Next, we further analyzed the differences in tumor infiltrating lymphocytes (TILs) between CRGLOF and non-CRGLOF patients in the TCGA cohort, and the results showed that TILs level of CD8+ T cells (p < 0.001), Dendritic cells (p = 0.0012) and Neutrophil cells (p < 0.001) were all significantly higher in CRGLOF samples than non-CRGLOF ones. In addition, survival analysis found that CRGLOF mutation conferred no significant effect on patient outcome in the TCGA cohort, while in the ICI cohort, GC patients with CFGLOF mutations had significantly better prognosis after immunotherapy than patients with non-CRGLOF mutations(p = 0.042). Conclusions: Loss of chromatin remodeling subunits may impact response to immune checkpoint therapy and may predict patient outcomes in GC. Further study in larger cohorts of immunotherapy-treated patients and functional characterization of the CRGLOF mutations in the context of the tumor-immune microenvironment were needed.
Efficacy and safety of sintilimab plus XELOX as neoadjuvant therapy in patients with locally advanced gastric cancer: A single-arm open-label phase II trial.
Authors: Guo Honghai , Ding Ping'an , Yang Peigang , Tian Yuan , Liu Yang , Zhang Ze , Zheng Tao , Zhang Zhidong , Wang Dong , Tan Bibo , Zhao Xuefeng , Li Yong , Zhao Qun 
Published: June 2022

e16091 Background: Neoadjuvant chemotherapies have been widely recommended by clinical guidelines for patients with locally advanced gastric cancer. However, the evidence of combining neoadjuvant chemotherapy with anti-programmed death 1 (anti-PD-1) antibody therapy for patients with locally advanced gastric cancer is inadequate. Thus, we conducted a single-arm phase II trial to evaluate the efficacy and safety of anti-PD-1 antibody sintilimab and XELOX regimen (capecitabine plus oxaliplatin) in patients with locally advanced gastric adenocarcinoma. Methods: Patients with locally advanced(cT3-4 N+ M0, CY0,P0) were enrolled and received four preoperative cycles of XELOX (oxaliplatin 130mg/m2, IV, d1 with capecitabine 1000mg/m2, bid, d1-d14, q21d) and sintilimab (200mg, IV, q21d). Surgery was performed within 3-4 weeks after completion preoperative therapy. After surgery, patients received four cycles of XELOX. The primary endpoint was the pathological complete response (pCR) rate and the secondary endpoints were major pathologic response (MPR) rate, R0 resection rate, safety, disease-free survival (DFS) and overall survival (OS). This clinical trial is registered at ChiCTR.gov.cn: ChiCTR2000030414. Results: From March 2020 to July 2021, 30 patients were enrolled, with median age 62 years (range30-72), males 18, cT3/T4: 8/22, cN1/2/3: 10/14/6, intestinal diffuse type (Lauren classification):17/13, ECOG PS 0/1/2: 19/8/3. There were 19(63.3%) patients with PD-L1 CPS≥1. All patients were available for preoperative response evaluation, the objective response (ORR) rate was 70.0% (95% CI, 50.6%-85.3%) and the disease control (DCR) rate was 100% (95% CI, 88.4%-100%). All (100%) achieved R0 resection. 10 patients (33.3%) achieved pCR (TRG 0) and 19 patients (63.3%) had MPR (TRG 0-1). Common treatment-related adverse events (TRAEs) were anemia (36.7%), leukopenia (36.7%), neutropenia (30.0%), diarrhea (26.6%), ALT increase (23.3%), AST increase (13.3%), thrombocytopenia (10.0%), vomiting (10.0%). The potential immune-related adverse events (irAEs) were dermatitis (6.7%), hypothyroidism (3.3%), pneumonia (10.0%). Most of the TRAEs and potential irAEs were grade 1 or 2. Grade3 TRAEs and irAEs included ALT increase (3.3%), AST increase (3.3%), dermatitis (3.3%). There were no severe complications and death related to the operation. The median postoperative hospital stay was 8 days (range6-23 days). Conclusions: Sintilimab plus XELOX as neoadjuvant therapy showed an encouraging pCR rate, MPR rate and manageable safety. This combination regimen might provide a new option for patients with locally advanced gastric cancer. Clinical trial information: ChiCTR2000030414.
Efficacy and safety of IBI110 in combination with sintilimab in first-line advanced HER2-negative gastric cancer or gastroesophageal junction cancer: Preliminary results from a phase Ib study.
Authors: Mao Chenyu , Qian Jiong , Gao Yuan , Liu Ying , Zhang Tao , Cui Jiuwei , Liu Ying , Chen Yiwei , Zhao Li , Xu Nong 
Published: June 2022

e16097 Background: Sintilimab plus XELOX has been proven to be efficacious in the first line treatment of gastric cancer. Dual inhibition of PD-1 and lymphocyte-activation gene 3 (LAG-3) may improve anti-tumor effect synergistically. IBI110 (anti-LAG-3 mAb) plus sintilimab (anti-PD-1 mAb) has shown preliminary antitumor activity in advance solid tumors. This phase Ib cohort study evaluated the safety and efficacy of IBI110 in combination with sintilimab and XELOX regimen for advanced HER2-negative gastric or gastroesophageal junction adenocarcinoma (G/GEJ AC) in first-line setting. Methods: This phase Ib study enrolled patients with previously untreated, unresectable, locally advanced or recurrent/metastatic HER2-negative GC/GEJAC. Patients received IBI110 200mg IV Q3W and sintilimab 200mg IV Q3W plus oxaliplatin and capecitabine (XELOX) until disease progression, unacceptable toxicity or death. The primary objective was to evaluate the safety and tolerability, and efficacy of the combination therapy. Results: As data cutoff January 20th 2022, 18 patients were enrolled, 6 patients had locally advanced/recurrent tumors, and 12 had metastatic tumors. The median follow up time was 4 weeks (range, 0-20). The median exposure of combination therapy was 9.4 weeks (range, 3-24). Any grade TRAEs occurred in 16 pts (88.9%); most commonly white bloo4d cell count decreased (n = 6; 33.3%), neutrophil count decreased (n = 6; 33.3%), and aspartate aminotransferase increased (n = 6; 33.3%). Grade ≥ 3 TRAEs occurred in 5 pts (27.8%), including neutrophil count decreased (n = 2; 11.1%), platelet count decreased (n = 2; 11.1%) and hepatic function abnormal (n = 2; 11.1%), platelet count decreased (n = 2; 11.1%) and hepatic function abnormal (n = 2; 11.1%). Immune-mediated AEs occurred in 7 pts (38.9%); most commonly amylase increased (n = 2; 11.1%). One patient discontinued treatment because of the coronary artery disease. There were no treatment-related death. For 15 evaluable patients, the ORR and DCR were 60% (9 PR) and 100% (9 PR,6 SD), respectively. The median duration of response (DOR) and median progression free survival (PFS) were not reached. As data cutoff, 17 patients were still in treatment. Conclusions: In this phase Ib study, IBI110 in combination with sintilimab and chemotherapy was well tolerated in the first line treatment of G/GEJ AC and the clinical benefit need more follow up time to be elucidated. Clinical trial information: NCT04085185.
Spatial transcriptomics characterization of hepatocellular carcinoma using Molecular Cartography.
Authors: Franses Joseph Wang , Bhan Irun , Ferrone Cristina R. , Boland Genevieve Marie , Ting David Tsai 
Published: June 2022

e16110 Background: The microenvironment within hepatocellular carcinoma (HCC) tumors is composed of interacting cancer cells, endothelial cells and other stromal cells, and immune cells. The emerging field of spatial transcriptomics enables the measurement of gene expression in specific regions within a tissue sample. This technique retains the spatial context of intact tissue, can provide deep biological insights into cell-cell interactions, tumor microenvironment, and tumor progression. Methods: Resolve Biosciences’ Molecular Cartography platform was used on serial fresh frozen sections obtained from treatment naïve, HCC samples, and matched non-cancerous control liver tissues. Results: Given the high sensitivity, single-cell resolution, and specificity of the platform, the gene profiles of the hepatic endothelial, mesenchymal and parenchymal cell were studied in-depth to characterize the tumor microenvironment. The data obtained from the analyses revealed several local interactions between cancer cells, endothelial cells, and immune cells. These interactions include both known immune checkpoints and angiogenesis drivers and novel interactions. Conclusions: A deeper in situ understanding of the interacting cellular components of the HCC microenvironment may give insight into the natural history (prognosis) of the disease, predict response to therapies that target the immune system and vasculature, and define novel targets for the next generation of drug development.
Efficacy and safety in advanced hepatocellular carcinoma using atezolizumab plus bevacizumab combined with interventional therapy: A retrospective analysis of real-world evidence.
Authors: Cheng Jiamin , Chen Bowen , Jing Yi , Lu Yinying 
Published: June 2022

e16112 Background: Recently, atezolizumab plus bevacizumab (A+T) has shown promising effects on hepatocellular carcinoma (HCC). So far, no study explored the effectiveness and safety of A+T combined with interventional therapy in patients with HCC. This study aimed to explore short-term efficacy and safety of A+T combined with interventional therapy in first-line treatment of advanced HCC. Methods: In this retrospective study, 13 advanced HCC patients received first-line A+T combined with interventional therapy from September 2020 to September 2021 were enrolled. Liver function was evaluated by Child-Pugh score. Objective response rate (ORR), disease control rate (DCR), progression free survival (PFS) and adverse events (AEs) were recorded in accordance with RECIST v1.1 and CTCAE v5.0. The PFS was defined as the time from first dosing of A+T or first time of interventional therapy until disease progressive or death. Results: A total of 13 HCC patients with Barcelona Clinic Liver Cancer (BCLC) stage C were reviewed. The liver function of 8 patients was Child-Pugh A while the other 5 patients was Child-Pugh B. Median time of following up was 8.9 (5.2-12.6) months. The ORR and DCR were 30.8% and 84.6%, respectively. One patient was able to conduct hepatectomy after treatment. And CR was confirmed by pathological report after surgery. The median PFS was 9.7 (7.3-12.1) months. The 3-month PFS rate was 84.6%. Nearly all patients suffered from AEs. The most frequency AE were hyperthyroidism (6 of 15), following hypertension (4 of 15), weight loss (4 of 15). While platelet-cell- decrease (3 of 15) turn out to be the most frequent serious AE, but it could be well managed. No AE-related death happened. Total two patients died, of progression of tumor and septic shock respectively. Conclusions: A+T combined with interventional therapy showed potential short-term anti-tumor effect and tolerance on advanced HCC.[Table: see text]