bluuebunny/crossref_metadata_2025 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]
Clinical utility of immunotherapy hyperprogressive genes in hepatocellular carcinoma patients.
Authors: Wang Run , Lou Luyan , Guo Zhaoxia , Zhang Yanrui , Zhang Yun , Lou Feng , Cao Shanbo , Wang Huina
Published: June 2022

e16126

Background: Hepatocellular carcinoma (HCC) is the most common liver malignancy associated with poor prognosis. With the rapid development of systematic therapy for liver cancer, immunotherapy has been widely used in therapy of liver cancer. Hyperprogression of tumor is a phenomenon of accelerated tumor growth, which occurs in patients with liver cancer and other solid tumors receiving systematic treatment, and is mainly related to immunotherapy hyperprogression genes. However, it is still unclear about the genes of immune hyperprogression in HCC patients. Therefore, we studied the molecular characteristics of HCC patients, including the genes related to immunotherapy hyperprogression. Methods: From June 2019 to August 2021, 102 patients with HCC were inculded in this study. Matched tumor/normal DNA from HCC patients (N = 102) were analyzed by whole exome sequencing (WES) or Acornmed panel with 808 cancer-related genes. Results: Overall, 86.3% (88/102) patients exhibited genetic alterations. TP53 (50%), TERT (23%), CTNNB1 (18%) and KMT2C (14%) were the most commonly mutated genes in HCC. In addition, 8.9% patinets harbored at least one immunotherapy hyperprogressive gene mutations, including CCND1 (7%), FGF19 (6%), FGF3 (5%), FGF4 (5%) and MDM4 (2%). In addition, CCND1 and FGF19 were frequently mutated genes in patients with liver cancer, ranking ninth and tenth, respectively. Compared with the TCGA data, there was no significant difference in immunotherapy hyperprogressive genes (25% vs 32.3%, p = 0.18). Interesting, CCND1, FGF19, FGF3 and FGF4 mutations occurred simultaneously in most patients and were mutually exclusive with MDM4 (p = 0.057). Conclusions: This study contributes to understand the molecular characteristics of patients with HCC, which will be useful to guide immunotherapy and promote the clinical management in this population. Furthermore, the study suggested that both Chinese and Western populations should pay attention to immunotherapy hyperprogression genes in immunotherapy selection.
Does acute cholangitis impact outcomes of cholangiocarcinoma? Insights from a nationwide database.
Authors: Lee Raymond , Franco Diana , Farooq Umer , Chattaraj Asmi , Rehman Mohammad Ebad Ur , Anwer Faiz
Published: June 2022

e16138

Background: Cholangiocarcinoma is a malignancy associated with poor survival and outcomes. Structural abnormalities causing bile duct obstruction frequently lead to superimposed acute cholangitis (AC). We evaluated the impact of AC on hospitalized patients with cholangiocarcinoma. Methods: We investigated National Inpatient Sample 2019, employing International Classification of Diseases-10 (ICD-10) codes to include adult patients with cholangiocarcinoma. Analyses were performed using STATA (v 14.2), considering 2 sided P< 0.05 as statistically significant. Proportions were compared using Fisher exact test and continuous variables using Student’s t-test. Confounding variables were adjusted using multivariate logistic and linear regression analyses and included: gender, race, Charlson Comorbidity Index (CCI) score, median household income for patients’ zip codes, hospital location/region/ bedside, and insurance status. Results: A total of 36,900 patients were included in the analysis. Of those 15.26% (5,630) had AC on presentation (Table). Concomitant AC was associated with a higher adjusted length of stay (LOS) by 1.78 days and hospitalization cost by 3,028 USD in cholangiocarcinoma patients ( P< 0.01). There were higher adjusted odds of acute renal failure (Adjusted odds ratio (aOR) 1.31, P< 0.01) and lower odds of aspiration pneumonia while hospitalized in AC patients (aOR 0.37, P< 0.01). ERCP represented the primary technique of biliary drainage. No disparities were seen between the two groups undergoing ERCP or cholecystostomy tube, which resulted in comparable mortality trends ( P> 0.05). Rates of acute respiratory failure, mechanical ventilation, ICU admission, cardiac arrest, and sepsis were not different between the two groups ( P> 0.05). Conclusions: Unbiased and comparable biliary drainage via either ERCP or cholecystostomy resulted in observing no mortality differences between the two groups. However, superimposed AC in cholangiocarcinoma patients results in higher LOS driven by acute renal failure.[Table: see text]
Systematic literature review and meta-analysis of clinical outcomes for previously-treated patients with advanced biliary tract cancer.
Authors: Amonkar Mayur , Frederickson Andrew , Grira Torkia , Fox Grace , Gozman Alexander , Malhotra Usha , Malbecq William , Jin Fan , Abderhalden Lauren
Published: June 2022

e16143

Background: There is no standard chemotherapy available for previously treated, advanced (unresectable and/or metastatic) biliary tract cancer (BTC). This systematic literature review and meta-analysis were conducted to assess clinical outcomes of chemotherapies in this patient population. Methods: A systematic literature search was conducted through mid-2021 to identify relevant studies using Embase, MEDLINE, and Cochrane Central Register of Controlled trials (January 1, 2000–July 6, 2021) with additional searches of recent ASCO and ESMO conferences. Eligible study designs included randomized controlled trials, controlled clinical trials, and non-randomized clinical trials in patients (≥18 years age, Eastern Cooperative Oncology Group performance score 0 or 1) previously treated for advanced BTC and who had progressed on prior treatment (i.e., ≥2L). The outcomes of interest were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). A meta-analysis among chemotherapies was performed to obtain a pooled estimate of the efficacy of standard treatments in BTC. The ORR meta-analysis was performed using the Freeman-Tukey double arcsine transformation. For time-to-event outcomes, published Kaplan-Meier curves for OS and PFS were digitized to create pseudo- individual patient data. A meta-analysis of the resulting pooled survival curves for OS and PFS were conducted following the methodology of Combescure et al. (2014). Results: In total, 39 unique studies were identified. Seventeen studies representing 22 unique therapy arms evaluating chemotherapies among 903 patients were included in the meta-analysis for ORR. The random effects pooled estimate for ORR was 6.6% (95% confidence interval [CI]: 4.1-9.7%). Median PFS (12 studies; 16 survival curves) was 3.1 months (95% CI: 2.5-3.8) with PFS rates at 6 and 12 months of 26.7% (95% CI: 19.8-36%) and 6.9% (95% CI: 4.1-11.7%), respectively. Median OS (15 studies; 19 survival curves) was 6.8 months (95% CI: 5.9-7.5) with OS rates at 6, 12, and 24 months of 55.3% (95% CI: 49.9-61.3%), 24.6% (95% CI: 20.0-30.2%), and 2.0% (95% CI: 1.1-3.8%), respectively. Conclusions: The limited efficacy of clinical outcomes for chemotherapies used in the treatment of advanced BTC suggest an opportunity to explore the potential clinical benefits of newer treatments (e.g., immunotherapies).
Efficacy of camrelizumab and apatinib combination therapy versus apatinib only in treatment of advanced hepatocellular carcinoma: A meta-analysis.
Authors: Swed Sarya , Motawea Karam R , AbdelQadir Yossef Hassan , Gamal Mohamed , El-Sakka Amro A , Kandil Omneya A , Abdelazeem Basel , Abdelaziz Muhammad , Wahsh Engy A
Published: June 2022

e16147

Background: Recent studies have assessed the efficacy of some therapeutics in advanced hepatocellular carcinoma. Our aim is to perform a meta-analysis to compare the efficacy of Camrelizumab and Apatinib combination therapy versus Apatinib only in treatment of advanced hepatocellular carcinoma. Methods: We searched PubMed, WOS, Embase and Scopus databases. Inclusion criteria were clinical trials and cohort studies that evaluated the efficacy of Camrelizumab and Apatinib combination therapy or Apatinib only in treatment of advanced hepatocellular carcinoma. We excluded case reports, conference abstracts, editorials and animal studies. CMA software (version 3) was used to perform the meta-analysis. Continuous outcomes were presented as (mean and SD) and dichotomous outcomes as event ratio(ER), with 95% confidence interval (CI). Results: After complete screening, 12 studies were finally included in our study. 4 studies for combination of Camerlizumab and Apatinib while 8 studies investigated the role of Apatinib in patients with advanced hepatocellular carcinoma. The total number of patients included in the study is 844; 172 in combination group and 672 in Apatinib group. By indirect comparison, combination therapy is associated with a relatively better pooled survival rate (ER = 0.532, 95% CI [0.446, 0.615]) compared to Apatinib only therapy (ER = 0.262, 95% CI [0.218, 0.313]). Combination therapy was also associated with higher pooled rates of disease control (ER = 0.755, 95% CI [0.683, 0.815]) compared with Apatinib only (ER = 0.683, 95% CI [0.644, 0.720]). While the Combination therapy was associated with lower pooled rate of stable disease (ER = 0.13, 95% CI [0.339, 0.491]) than Apatinib (ER = 0.531, 95% CI [0.492, 0.570]). The overall survival time was significantly higher in combination therapy (Mean = 14.375, 95% CI [14.101, 14.649]) compared to the pooled mean survival time from Apatinib only therapy (Mean = 10.390, 95% CI [9.925, 10.855]). Conclusions: This study showed that Camrelizumab and Apatinib combination therapy is associated with increased survival rate, disease control and overall survival time in advanced hepatocellular carcinoma patients compared with Apatinib only. It revealed also that combination therapy is associated with lower stable disease than Apatinib only. Further multicenter clinical trials are needed to support our results.
Characterization analysis of gut and bile microbiota for cholangiocarcinomas.
Authors: Zhu Wenwen , Zhang Ningning , Wang Zeyu , Zhang Shuwen , Yue Xiaofen , Sun Linlin , Sun Jiao , Gong Lan , El-Omar Emad M , Lu Wei
Published: June 2022

e16150

Background: Cholangiocarcinomas (CCAs), which derive from the epithelial cells of the biliary tree, constitute a serious and growing health problem worldwide. Gut and bile microbiota have not been characterized in patients with CCA, and better noninvasive diagnostic approaches for CCA are essential to be established. CA19-9 was the most commonly used tumor marker for CCA; nevertheless, the forecasting performance of CA19-9 remains unsatisfactory. The aim of this study was to investigate the characteristics of gut and bile microbiota combined with CA19-9 in CCA patients. Methods: Fecal samples were collected from 42 CCA patients (16 of the total with Bile samples) and 16 healthy normal controls (HNC). 42 CCA patients were divided into three group according to CA19-9 levels: CCN (CA19-9 negative),CCP (CA19-9 positive: CPL (CA19-9 positive within 10 times) and CPH (CA19-9 positive over 10 times)) groups. DNA was extracted from fecal and bile samples and subjected to 16S rRNA gene analysis. The correlation between gut microbiota and clinical data in CCA group were further analyzed with Spearman rank correlation analysis. Results: Comparing with HNC group, the relative abundance of Firmicutes and Actinobacteriota were significantly decreased, whereas Proteobacteria and Bacteroidota were significantly enriched in CCA group at phylum level (all P < 0.01). Interestingly, Firmicutes/Bacteroidota (F/B) ratio significant decreased in CCA group compared to HNC group(P < 0.05). CA19-9 were inversely correlated with Bifidobacterium, which in turn was associated with Klebsiella in CCA patients. Especially the relative abundance of Klebsiella in CCP group was significantly enriched than CCN group(P < 0.05). Conclusions: Our findings provide evidence supporting Klebsiella may serve as a non-invasive intestinal microbiomarker for CCAs. Combinating with CA19-9, Klebsiella may improve the diagnosis of CCAs as non-invasive approach. Bifidobacterium is likely to be a potential protective factor for anti-tumorgenesis of CCAs.
Plasma cell-free DNA integrative analysis for early detection of hepatocellular carcinoma.
Authors: Nie Peiyao , Lv Fang , He Shuying , Han Tiancheng , Yang Shunli , Suxing Li , Liu Dan , Yang Ying , LI Yulong , Huang Yu S. , Hong Yuanyuan , Chen Weizhi , Yu Jianing , Tan Hai Dong
Published: June 2022

e16173

Background: Cell-free DNA (cfDNA) methylation, fragmentation patterns, chromosome instability, and chromatin accessiblity have been previously shown to be valid plasma biomarkers for non-invasive cancer detection. However, conventional whole-genome bisulfite sequencing (WGBS) is unable to simultaneously profile all these biomarkers due to bisulfite-induced DNA damages. Here we developed a machine learning approach to comprehensively integrate multiple types of cancer genomic markers from enzyme-conversion-based low-pass whole-methylome sequencing (WMS) of plasma cfDNA to non-invasively detect hepatocellular carcinoma. Methods: Plasma cfDNA sampels from 127 cancer patients and 568 healthy individuals were collected and were split into the discovery and independent testing cohort. The discovery cohort includes 90 cancer patients and 398 healthy individuals and the independent testing cohort includes 37 cancer patients and 170 healthy individuals. Whole methylome sequencing (WMS) libraries were generated from enzymatically converted cfDNA and were subsequently paired-end sequenced at ̃2X coverage. The genome-wide methylation density, fragmentation fingerprints, chromosome instability, and chromatin accessibility were extracted from the WMS data and individually modelled via machine learning methods such as SVM, LR, GBDT, random forest. The final predictive model is an ensemble model integrating all uni-modal models. All models were trained and fitted on the discovery cohort. Results: Data of different modalities provide complementary information in separating the cancer patients from the healthy individuals. Unsupervised clustering of the individuals showed clear separation between cancer patients and healthy individuals. The final predictive model achieved AUC =0.979 in the discovery cohort and AUC =0.98 in the independent testing cohort. Under a specificity of 96.23%(CI: 86% - 87%), sensitivity was 86% (CI: 85% - 88%) in the independent testing cohort. Separating the cancer patients into different stages, we found that the detection power is usuaul lower for early-stage cancer patients. Conclusions: These results demonstrate the first proof of principle on the feasibility of integrating multiple genomic cancer markers to non-invasively detect hepatocellular carcinoma from WMS plasma cell-free DNA. A large prospective cohort study is planned to further validate its clinical performance.
Biomarker analysis of first-line sintilimab plus gemcitabine and cisplatin in patients with advanced biliary tract cancers: Results from a phase II study.
Authors: Yuan Zhen-gang , Zeng Tian-mei , Tao Chen-jie , Yang Guang , Xu He-ming , Wei Wei , Chen Xi-yun , Cheng Zhuo , Dong Yu-long , Shang Pei-pei , Lou Cheng , Han Qin , Chen Dong-sheng , Song Yunjie
Published: June 2022

e16189

Background: The overall efficacy of immunotherapy for advanced biliary tract cancers (BTCs) was still poor, exploring the potential biomarkers associated with tumor response in advanced BTCs may further improve the clinical benefits from immunotherapy. Methods: Twelve patients from a phase 2 clinical trial (ChiCTR2000036652), which evaluated the efficacy and safety of sintilimab (anti-PD-1 antibody), plus gemcitabine and cisplatin as first-line treatment in advanced BTC patients, were included in the current biomarkers analysis. Exploratory points mainly focused on differentiated immune-related gene expression and immune pathway signatures using a 289-gene immune-related RNA panel sequencing on baseline tumor samples. Differential gene expression analysis was performed between responders (tumor regression) and non-responders (tumor extension) using Wilcoxon rank-sum test. Signature scores were calculated using the Gene Set Variation Analysis package with publicly available gene signatures. Results: Twelve patients (8 responders vs. 4 non-responders) who had available clinical response evaluations with RNA-sequencing data on baseline tumor samples were included in the current biomarkers analysis. Differential gene expression analysis revealed a significantly increased CXCL10, CXCL13 expression (p < 0.001) and decreased MAGEA12 expression (p < 0.001) in responder tumors compared with non-responder tumors. Differentiated genes were significantly enriched in cytokine-cytokine receptor interaction and interleukin-17 signaling pathway in responder tumors. Extensive analyses on immune pathway signatures showed that higher expression of IFN-γ-related genes (p = 0.048) and T cell-inflamed genes (p = 0.016) were associated with response to immunocombination therapy. Meanwhile, immune cell types score was also calculated, no notable differences were found between defined groups. Conclusions: Some differentially expressed genes were investigated in responder tumors compared with non-responder tumors. Higher expression of IFN-γ-related genes and T cell-inflamed genes could potentially predict the effect of immunocombination therapy. Potential biomarkers are needed to identify patients who respond to sintilimab plus gemcitabine and cisplatin in a larger validation cohort. Clinical trial information: ChiCTR2000036652.
Neutrophil-to-lymphocyte ratio (NLR), derived neutrophil-to-lymphocyte ratio (dNLR) and lymphocytes counts as a possible prognostic factor in neuroendocrine tumors of the gastrointestinal tract.
Authors: Androsova Alexandra , Orlova Rashida , Ivanova Anastasia , Beliak Natalia P. , Kutukova Svetlana
Published: June 2022

e16207

Background: The aim of our study was to investigate the prognostic role of the neutrophil to lymphocyte ratio (NLR), derived neutrophil to lymphocyte ratio (dNLR), platelet to lymphocyte ratio (PLR), and lymphocyte to monocyte ratio (LMR) in PFS and OS of patients with neuroendocrine tumors (NETs) of the gastrointestinal tract. Methods: We analyzed medical records of 69 patients with stage I - IVB NETs of the gastrointestinal tract (25 men, 44 women; median age is 57 years [44.75-66.00]). All patients were treated according to the standard protocols from 2015 till 2020. We examined demographics, clinical stage, tumor morphology, and baseline levels of leukocytes, neutrophils, lymphocytes, monocytes, and PLT. We also analyzed the calculated value of NLR, dNLR, PLR and LMR. Results: The ROC analysis made it possible to determine that the factors, that have a significant impact on the PFS indicator are: absolute (cut-off: ≤2.26; p = 0.0274) and relative (cut-off: ≤30; p = 0.0158) lymphocyte count, NLR (cut-off: 1.85; p = 0.0230) and dNLR (cut-off: 1.40; p = 0.0209). The median PFS of patients whose baseline absolute lymphocyte count 2.26x109/l or less was 34.0 months and was significantly (61%) less than the median PFS in the group of patients with an absolute lymphocyte count greater than cut-off value (p = 0.0122; HR = 0.39: 95% CI 0.19-0.81). The median PFS of patients with relative lymphocyte count £30% was 25.0 months and was significantly (61%) less than the median PFS in the group of patients with lymphocyte count > 30% (p = 0.0082; HR = 0.39: 95% CI 0.20-0.79). The median PFS of patients with NLR > 1.85 was 26.0 months and was significantly (60%) less than the median PFS in the group of patients with NLR1≤.85 (p = 0.0095; HR = 0.40: 95% CI 0.21-0.80). The median PFS of patients with dNLR > 1.40 was 20.0 months and was significantly (60%) less than the median PFS in the group of patients with dNLR≤140 (p = 0.0120; HR = 0.40: 95% CI 0.20-0.82). In multivariant analyses, which contained all significance factors by univariate analysis, count of lymphocytes: lymphocytes≤30% significantly increased the risk of disease progression: p = 0.0344; HR = 0.97; 95% CI 0.94-0.99. Conclusions: Systemic inflammatory markers have demonstrated their diagnostic and predictive value in patients with neuroendocrine tumors of the gastrointestinal tract.
Anlotinib for the treatment of locally advanced or metastatic pheochromocytoma and paraganglioma: A retrospective study.
Authors: Tian Rui , Yao Xiaochen , Wang Jun , Fu Jingjing , Song Jieping , Shi Liang , Yu Fei , Zhang Pengjun , Ni Yudan , Wang Feng
Published: June 2022

e16209

Background: Pheochromocytomas (PCC) and paragangliomas (PGL) are rare hyper-vascular neuroendocrine tumors derived from the adrenal medulla and paraganglia, respectively. In previous studies, the overall survival at 5 years for patients (pts) with metastatic disease was only 50% to 60% after the diagnosis of metastases. Anlotinib is a novel multikinase inhibitor targeting VEGFR, PDGFR, FGFR, and c-Kit. This study investigated the efficacy and safety of anlotinib monotherapy or in combination with other therapies in treating locally advanced or metastatic (LA/M) PCC and PGL. Methods: Pts with histologically or cytologically confirmed unresectable or progressive LA/M PCC or LA/M PGL were enrolled from March 2020 to October 2021. The inclusion criteria contained: (a) age 18 or older, (b) ECOG performance status 0–2, (c) adequate organ and marrow function. Eligible pts received anlotinib monotherapy or in combination with peptide receptor radionuclide therapy (PRRT) or 131I-MIBG. Anotinib was given orally 12 mg once daily (d1-d14, q3w) until the disease progression or the intolerable toxicities. Tumor response was assessed according to RECIST1.1. Results: 35 pts were enrolled (Table) and 25 were assessed for tumor response. Among them, 17 received anlotinib alone, others were treated with the combination regimen, including 6 with PRRT, and 2 with 131I-MIBG respectively. At the data cut-off date on January 15th, 2022, 4 pts progressed and 1 died. The median duration of treatment was 8.5 months. 10 pts (40%) achieved partial response (PR) and the stable disease (SD) was observed in 13 pts (52%). The objective response rate (ORR) for 25 pts was 40% and the disease control rate (DCR) was 92%. For pts with PCC and PGL, the ORR was 33.3% and 46.2%, respectively. All pts were assessed for safety. The most common adverse events (AEs) included: malaise (23 pts, 65.7%), palmar-plantar erythrodysesthesia syndrome (PPE) (23 pts, 65.7%), hypertension (22 pts, 62.9%) and oropharyngeal pain (17 pts, 48.6%). The most common grade 3 or worse AEs were hypertension (15 pts) and PPE (4 pts), which were claimed tolerable by the pts. Conclusions: This single-center retrospective study indicated that anlotinib monotherapy or in combination with radionuclide therapy showed promising efficacy and favourable safety profile in the treatment of LA/M PCC and PGL, which is worthy of further exploration.[Table: see text]
Association between metastatic pancreatic cancer and environmental quality index.
Authors: Ozer Muhammet , Goksu Suleyman Yasin , Khatib Jude , Al Mutar Salwan , Aguilera Todd Anthony , Zeh Herbert , Beg Shaalan Shaalan , Kazmi Syed Mohammad Ali
Published: June 2022

e16232

Background: Pancreatic cancer ranks as the 3rd leading cause of cancer mortality. Overall more than 50% of patients have metastatic disease at diagnosis. In this study, we evaluated the association between the national level Environmental Quality Index (EQI) and metastatic pancreatic cancer in the US. Methods: Adult patients with pancreatic cancer in the SEER database from 2010-2016 were included in this study. The unknown stage was excluded. Patients were categorized into two groups: metastatic vs. non-metastatic disease. EQI provides county-level environmental quality data from 2005-2010 and presents five domains (built, sociodemographic, air, water, land). EQI was categorized into quintiles, with the 5th quantile representing a poorer environmental quality. We used the multivariable logistic regression analysis to assess the association between EQI quintiles and metastatic pancreatic cancer adjusting by age, gender, and race (White, Black, and Others). In addition, the SEER*Stat was used to evaluate the age-adjusted incidence rate, and the correlation coefficient between EQI domains and incidence rate was calculated. Results: A total of 75,461 pancreatic cancer patients were included; 55% had metastatic disease. In the adjusted multivariable analysis, metastatic pancreatic cancer was associated with poor built EQI (OR 1.06 [1.01-1.11]). Among metastatic pancreatic cancer patients, poor overall EQI was strongly associated with age > 50 years (OR 1.06 [1.01-1.11]) and Black race (OR 1.29 [1.10-1.51]). Lower built EQI domain was associated with > 50 (OR 1.07 [1.02-1.12]) and White race (OR 1.07 [1.02-1.12]). The incidence rate of metastatic pancreatic cancer was positively correlated with total EQI (rho = 0.02, p < 0.001), sociodemographic EQI (rho = 0.23, p < 0.001), land EQI (rho = 0.14, p < 0.001), and air EQI (rho = 0.34, p < 0.001). Conclusions: Using population-based environmental data, we found built EQI to be associated with metastatic pancreatic cancer. Among metastatic pancreatic cancer patients, total environmental quality was associated with older age at diagnosis and the Black race, while built EQI domain was associated with older age at diagnosis and the White race. Environmental quality was positively correlated with the incidence rate of metastatic pancreatic cancer.