bluuebunny/crossref_metadata_2025 huggingface dataset:
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.
Matched therapies for advanced gastric cancer based on genotype: A real-world study in China.
Authors: Liu Qin , Yang Ju , Wu Nandie , Liu Song , Zhang Yipeng , Chen Hui , Zhao Xiaochen , Bai Yuezong , Liu Baorui , Wei Jia
Published: June 2021

e16098

Background: Systemic therapy options for patients with advanced gastric cancer (GC) are limited. We here presented the efficacy results for advanced GC patients matched to targeted therapies or immunotherapies based on the identification of tumor tissue genotypes. Methods: We selected 30 patients diagnosed between 2014 and 2020 with advanced GC at Nanjing Drum Tower Hospital, the affiliated Hospital of Nanjing University Medical School identified with actionable alterations and received ≥1 matched therapies. Tumor biopsy specimens from the patients were analyzed using NGS and/or selected immunohistochemistry and fluorescence in situ hybridization. Results: In these 30 patients, median age at diagnosis was 63 years (range 28-83) and 6 (20%) were female. In total, 11 (37%) harbored c-MET amplification/overexpression (received savolitinib or crizotinib, cohort A), 9 (30%) harbored HER2 mutation/overexpression (received RC48-ADC or trastuzumab, cohort B), 6 (20%) dMMR/MSI-H/TMB-H (received sintilimab, pembrolizumab, tislelizumab or nivolumab, combined with antivascular or not, cohort C), 2 (7%) KIT mutation/amplification (received imatinib or anlotinib, cohort D), 1 (3%) BRAF V600E mutation (received vemurafenib, cohort E) and 1 (3%) EGFR mutation (received afatinib, cohort F). Except for three patients in cohort C, all patients received at least one previous line systemic therapy. In cohort A, three of 11 patients had an objective response (1 complete response and 2 partial responses, objective response rate (ORR) 27%), disease control rate (DCR) was 45%, median progression-free survival (mPFS) was 2.1 months, and median overall survival (mOS) was 3.7 months. In cohort B, ORR was 44% (4/9), DCR was 78% (7/9), mPFS and mOS was 3.1 months and 5.5 months, respectively. In cohort C, ORR was 17% (1/6), DCR was 67% (4/6), mPFS and mOS was 1.9 months and 6.8 months, respectively. In cohort D, no patient had objective response or disease control. In cohort E, the one patient had PR. Stable disease was observed in the patient in cohort F. In all cohorts, ORR was 30% (9/30), DCR was 60% (18/30), mPFS and mOS was 2.7 months and 5.8 months, respectively. Conclusions: Overall, 30 patients with advanced GC were treated with matched therapies according to specific genotype. These real-world outcomes suggested that matched therapies for advanced GC has promising efficacy, supporting the adoption of genotyping in treatment determination.
Phase II study of combining immunotherapy and pulsed low dose rate radiotherapy for abdominal metastasis of gastric cancer.
Authors: Yang Yang , Yan Jing , Liu Juan , Li Shuangshuang , Gao Shanbao , Wei Jia , Liu Baorui
Published: June 2021

e16099

Background: Immune-mediated responses against tumor antigens by checkpoint inhibitors (CPIs) may be enhanced by radiotherapy and the combination may hold therapeutic promise. Pulsed low dose rate radiotherapy (PLDR) is an effective strategy for abdominal tumor by taking advantage of low dose hyper-radiosensitivity with maximizing tumor response and minimizing adverse events by radiotherapy. In this phase II study, we prospectively analyzed the response and adverse events of the combination strategy of CPIs and PLDR for abdominal metastasis of gastric cancer. Methods: Eligibility criteria included pathologically confirmed advanced gastric adenocarcinoma with abdominal metastasis. Patients received XELOX regimen chemotherapy, anti-PD-1 toripalimab, and PLDR for abdominal metastasis, prescription dose was 50-56Gy/25-28f. The primary endpoint was objective response rate (ORR) and safety. Secondary endpoints were regional response rate (RRR) and regional controlled rate (RCR) for radiotherapy target tumor, progression-free survival (PFS), and overall survival (OS). Results: Between November 2018 and June 2020, 24 patients were enrolled and included in the efficacy analysis. 13 of them were first line therapy, and 11 of them were second line therapy. The ORR was 70.8% and the combination regimen were tolerable. The RRR was 83.3% and the RCR was 95.8%. The median PFS was 11.1 months and the median OS was not yet reached. Conclusions: In this phase II clinical trial, the combination of Immunotherapy and radiotherapy provided good response and toleration for abdominal metastasis of gastric cancer. It suggested clinical efficacy of this regimen in patients with advanced gastric cancer. Clinical trial information: NCT03061162.
Germline HLA-B evolutionary divergence to influence efficacy of immune checkpoint blockade therapy in gastrointestinal cancer.
Authors: Lu Zhihao , Shen Lin , Zhang Henghui , Chen Huan , Jiao Xi , Wang Yujiao , Wu Lijia , Sun Huaibo , Li Shuang , Gong Jifang , Li Jian , Zou Jianling , Yang Keyan , Mao Beibei , Zhang Lei , Zhang Xiaotian , Peng Zhi , Lu Ming , Wang Zhenghang
Published: June 2021

e16101

Background: To date, although a number of biomarker-related investigations have focused on the intrinsic properties of tumor cells and immune microenvironment, how germline genetics influences efficacy of immune checkpoint inhibitors (ICIs) immunotherapy in gastrointestinal (GI) cancer is scarcely understood. Methods: Our investigation enrolled 94 metastatic GI cancer patients treated with ICIs recruited from Peking University Cancer Hospital (PUCH) between August 1, 2015, and May 24, 2019. A publicly available dataset from the Memorial Sloan Kettering (MSK) Cancer Center (MSK GI cohort) was used for validation. For the PUCH cohort, we performed HLA genotyping by whole exome sequencing (WES) analysis on the peripheral blood mononuclear cell (PBMC) from all 94 patients. Tumor tissues from 86 patients were subjected to WES analysis and immune oncology-related RNA profiling. Results: We assessed the clinic relevance of germline HLA heterozygosity and evolutionary divergence (HED, a quantifiable measure of HLA-I evolution) to immunotherapy in patients with advanced GI cancers from the PUCH cohort. Our data showed that neither HLA heterozygosity nor mean HED correlated with the overall survival (OS) in the PUCH cohort. However, patients with high HLA-B HED showed a better OS and durable clinic benefit (DCB) rate compared with the lower subgroup (p < 0.05 for all comparison). The prognostic value of HLA-B HED was consistently validated in the MSK GI cohort (N = 84). Notably, a combinatorial biomarker based on HLA-B HED and tumor mutation burden (TMB) could better stratify potential responders (86 patients with tumor samples). Survival analysis performed on the PUCH and MSK GI cancer datasets further demonstrated the potential joint utility of HLA-B HED and TMB for prognosis stratification. Moreover, HLA-B HED high subgroup was characterized with a lower prevalence of TP53 mutation and enrichment of multiple immune related pathways, indicating an immune-inflamed phenotype of this subgroup. Conclusions: Taken together, our data create an intriguing argument for the germline HLA-B sequence divergence and TMB as complementary biomarkers in guiding patient selection for GI cancer immunotherapy. Further investigation revealed a potential HLA-B restricted mutational pattern of TP53, and can be indicative of tumor immune microenvironment in GI cancer.
Predictors of 30-day readmission rate after total gastrectomy in patients with gastric malignancy.
Authors: Salazar Miguel , Gauto Estefania , Upadhyay Banskota Shristi Upadhyay , Palacios Pedro , Shrivastava Trilok , Baral Binav , Rodriguez Alarcon Pierre Alexander , Elsebaie Maha , Khanal Nabin
Published: June 2021

e16109

Background: Total gastrectomy with lymph node dissection is curative for early gastric malignancy which accounts for 1.5% of cancer cases in the U.S. Readmissions are common postoperatively, and are associated with increased morbidity, mortality, hospital costs and decreased quality of life. We hence aim to identify incidence, impact and independent predictors for readmission in patients who underwent total gastrectomy in gastric malignancy. Methods: We conducted a retrospective cohort study of the 2017 National Readmission Database (NRD) of adult patients readmitted within 30 days after an index admission for total gastrectomy with a concomitant diagnosis of gastric malignancy. T-test was used for continuous variables and chi square test was used for categorical variables. Multivariate regression was used to identify predictors for unplanned readmissions. ICD 10 codes were used to identify diagnoses and procedures. Results: A total of 1,779 patients with gastric malignancy underwent total gastrectomy. The 30-day readmission rate was 18.5%. Main causes for readmission were sepsis, ventricular fibrillation, recurrent STEMI. Readmitted patients were more likely to be on chemotherapy. (40.1% vs 27.2%; P<0.01) and more likely to be discharged to a skilled facility (13.5% vs 17.9%; P<0.01). The total health care in-hospital economic burden of readmission was $6.5 million in total charges and $25 million in total costs. Independent predictors of readmission were major bleeding, respiratory failure requiring mechanical ventilation, peripheral parenteral nutrition, history of non-alcoholic hepato-steatosis, and prolonged length of stay. Conclusions: Readmissions after gastrectomy in patients with gastric malignancies are associated with lower in-hospital mortality yet pose a substantial economic burden on healthcare. The lower mortality might be explained by the relatively stable course and lower comorbidities of patients who become eligible for discharge after surgery. Further studies are suggested. Modifiable risk factors like malnutrition and sepsis warrant special attention to decrease readmissions and improve overall outcomes.[Table: see text]
Clinical efficacy and safety of proton beam or photon radiation in combination with immune checkpoint inhibitors in patients with advanced hepatocellular carcinoma.
Authors: Su Chung Wei , Huang Pei-Wei , Chou Yung-Chih , Lin Chen-Chun , Hong Ji-Hong , Hou Ming-Mo
Published: June 2021

e16113

Background: Management of advanced hepatocellular carcinoma (HCC) remains a challenge. IMbrave150, a pivotal trial reported impressive overall survival benefit using combination strategy of atezolizumab and bevacizumab compared to sorafenib. We wonder the efficacy and safety when combining radiotherapy with immune checkpoint inhibitors (ICIs), which radiation might provide better local treatment and possible trigger abscopal effect. The aim of this study is retrospectively reporting the real-world efficacy and tolerability of proton beam or photon radiation plus ICIs in patients with advance stage HCC. Methods: We retrospectively reviewed all BCLC stage C HCC patients who have received combination therapy with ICIs plus proton or photon therapy with well documented basic characteristics and prompt treatment efficacy evaluation between 1st of January 2016 to 31st of October 2019 at a single medical center in Taiwan. 20 patients had ICIs plus proton and 32 patients had ICIs plus photon were included for analysis. Overall survival (OS) and progression free survival (PFS) were evaluated by Kaplan-Meier estimator. Results: Baseline characteristics were generally similar between ICIs plus proton or ICIs plus photon, while most patients in proton group did not receive prior systemic treatment and had less local therapies prior ICIs combine with radiotherapy. Median follow-up time was 10.7 months. The median Progression free survival (PFS) was not reached in ICIs plus proton group and 3.6 months (95% CI 2.7-4.6) in ICIs plus photon group (P = 0.007). The median OS was not reach in ICIs plus proton group and 12.1months (95% CI 6.4-17.7) in ICIs plus photon group (P = 0.007). Comparing ICIs plus proton group versus photon group, objective tumor response is 50% versus 9%, disease control rate is 80% versus 47% in each group. During follow-up, 7 patients (35%) in proton group achieved complete remission (CR). There was difference in radiation filed, 19 patients (95%) in proton group and 15 patients (47%) in photon group targeted on liver tumors, and more patient received > 50Gy treatment dose in proton group compared to photon group (90% versus 20%). Proton group has lower failure rate in both inner- or out-field compared to photon group. Grade 1 to grade 2 skin-dermatological and gastrointestinal toxicity remained the most frequent reported adverse events in both groups. There are only one therapy related grade 3 dermatitis in ICIs plus proton group and one grade 3 hepatitis, one grade 5 pneumonitis in ICIs plus photon group. Conclusions: This study reported real-world efficacy and safety of ICIs in combination with proton or photon therapy. Most adverse events were manageable. The combination of ICIs and proton therapy has impressive CR rate and OS benefit. Further prospective randomized trial is warranted for confirm our finding.
Triple combination therapy comprising angiogenesis inhibitors, anti-PD-1 antibodies, and hepatic arterial infusion chemotherapy in patients with advanced hepatocellular carcinoma.
Authors: Zhang Ti , Zhang Jinliang , Zhang Xihao , Mu Han , Yu Ge , Xing Wenge
Published: June 2021

e16124

Background: The effects of single-drug therapy for the systemic treatment of advanced unresectable hepatocellular carcinoma (HCC) remain unsatisfactory, promoting the emergence of multi-drug and combination therapies. Here we assess the safety and efficacy of a triple combination therapy for treating advanced HCC. Methods: This single-center retrospective study included patients with unresectable HCC treated with triple combination therapy comprising angiogenesis inhibitors (oral apatinib 250 mg/day, lenvatinib 8 mg/day, or sorafenib 400 mg BID), anti-programmed cell death 1 antibodies (iv camrelizumab or sintilimab, 200 mg every 3 weeks), and hepatic arterial infusion chemotherapy (FOLFOX every 4–8 weeks). Eligible patients had completed at least one cycle of therapy and had an imaging assessment. Treatment-related adverse events (TRAEs) were assessed according to the Common Terminology Criteria for Adverse Events. Efficacy data were summarized according to modified RECIST (mRECIST) and RECIST v1.1. Results: Of 34 patients who received triple combination therapy, 25 (19 men and 6 women; median age: 59 years [range: 49–78]) had an imaging assessment. TRAEs were manageable; 28.0% of patients experienced grade 3–4 TRAEs. Efficacy outcomes are summarized in the Table. The objective response rate was 96.0% (mRECIST), the median time to response was 50.5 days (95% CI: 31.02–64.00) and the surgical conversion rate was 56%, indicating a robust therapeutic effect. Overall, 12 patients (48.0%) achieved a complete response (CR), 12 (48.0%) achieved a partial response, and one (4.0%) had stable disease (mRECIST). Fourteen patients (56.0%) underwent surgical resection, after which seven (28.0%) achieved a pathologic CR. After a median follow-up of 9.67 months, no cases of post-operative recurrence or metastasis emerged. Conclusions: Triple combination therapy had a robust therapeutic effect with a high surgical conversion rate in patients with advanced HCC. TRAEs were acceptable, and long-term efficacy is reasonably expected. Summary of efficacy outcomes (n = 25).[Table: see text]
Preliminary results of the phase II ALTER-H004: Anlotinib combined with TACE as adjuvant therapy in hepatocellular carcinoma patients at high risk of post surgery recurrence.
Authors: Wu Zheng , Wang Zheng , Zhang Lei , Song Xiaojing , Du Xilin , Tan Kai
Published: June 2021

e16125

Background: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with high incidence and mortality worldwide. Presumably, adjuvant therapy is an efficient treatment for reducing recurrence in patients (pts) with hepatectomy, especially in those with high recurrence factors. Transarterial chemoembolization (TACE) can block the blood supply of the tumor, besides, high concentration of chemotherapeutic drugs can be accumulated within the tumor. It is recommended in several guidelines prophylactic TACE for pts with high recurrence risk factors after hepatectomy, which mainly include grade 1-2 microvascular invasion (M1-2) and portal vein tumor thrombus resection. Moreover, angiogenic inhibitors based therapy has constituted the crucial treatment strategy in HCC. As a novel multitarget tyrosine kinase inhibitor, anlotinib was demonstrated to be an effective first and second-line monotherapy for pts with advanced or recurrent HCC in China. The aim of this phase II trial was to evaluate the efficacy and safety of anlotinib as maintenance adjuvant treatment following inductional TACE in pts with HCC. Methods: A total of 48 histologically confirmed HCC pts who undertook hepatectomy within 1-2 months will be enrolled. The recruited pts who did not recieve any previous tumor-related treatment must have any of the following high risk factors: ≥5cm and <10cm of tumor diameter, tumor number ≥3, tumor microvascular invasion M1 or M2, portal vein tumor thrombus resection (Cheng’s classification Ⅰ/Ⅱ). Enrolled pts were received conventional TACE treatment with pirarubicin or epirubicin and platinum within 1-2 months after hepatectomy. On the 4th day after TACE treatment, oral anlotinib (12mg, qd, 2 weeks on 1 week off) was given until disease recurrence or unacceptable toxicity. The primary endpoint was disease free survival (DFS). Secondary endpoints included 1-year DFS rate, time to recurrence and safety. Results: By the cutoff date of January 26, 2021, 10 pts were enrolled and received at least once tumor assessment. According to RECIST version 1.1, 9 of them did not progress and 1 relapsed, in whom the DFS was 2.4 months. Most of treatment-related adverse events (TRAEs) were rash (20.0% Grade≤2), pain (20.0% Grade=1) and hypertension (10.0% Grade=1). Only one patient had grade 3 TRAE which was leukocytopenia (10.0%). No more grade 3 or above TRAEs occurred. Conclusions: The current results indicated that anlotinib combined with TACE as adjuvant therapy in HCC pts at high recurrence risk exhibited preliminary and implicational anti-tumor efficacy and manageable toxicity. The conclusion should be validated in more pts consecutively. Clinical trial information: NCT04213118.
Comprehensive molecular characterization of Chinese patients with intrahepatic and extrahepatic cholangiocarcinoma.
Authors: Yi Bin , Liu Lianke , Gu Dejian , Chen Rongrong , Xia Xuefeng , Jiang Xiaoqing
Published: June 2021

e16128

Background: Cholangiocarcinoma (CCA) is a heterogeneous disease arising from a complex interaction between host-specific genetic background and multiple risk factors. Globally, CCA incidence rates exhibit geographical variation, with much higher incidence in parts of the Eastern world compared to the West. Therefore, understanding the molecular characteristics of Chinese CCA patients is helpful for individualized treatment of patients. Methods: We reviewed 397 Chinese cholangiocarcinoma patients, including 125 extrahepatic and 272 intrahepatic, with paired tumor-normal samples sequenced by a 1021 gene panel. Tumor mutational burden(TMB) was defined as the number of somatic non-synonymous mutations per megabase of the panel region. Results: The genomic profiling was analyzed and indicated that TP53 and KRAS were the most frequently mutated gene, which were detected in 47% and 27% samples. The common targets gene of FGFR2 and IDH1 were detected in 6% and 4% patients in our cohort. Meanwhile, the prevalence of gene mutated was compared between intrahepatic and extrahepatic cholangiocarcinoma. The TP53 mutation was more frequently prevalence in intrahepatic cholangiocarcinoma (51% vs 36%, p = 0.0048); and the FGFR2 fusion more detected in extrahepatic cholangiocarcinoma (4% vs 10%, p = 0.0214). The TMB was also analyzed in our study and ranged from 1 to 194 (median:5). No difference was found between intrahepatic and extrahepatic cholangiocarcinoma in TMB. Besides, the TP53 mutations showed significant association with higher TMB (p < 0.0001), both intrahepatic and extrahepatic cholangiocarcinoma; and KRAS mutations showed significant association with higher TMB (p = 0.029) in intrahepatic cholangiocarcinoma. Interesting, KRAS mutations was also association with TMB in extrahepatic cholangiocarcinoma; The KRAS-mutated & TP53-wildtype(wt) patients showed higher TMB than double-wt patients (5.5 vs 4, p = 0.048) and the only TP53-mutated patients showed higher TMB than double-mutated patients (8 vs 6, p = 0.047). Conclusions: In conclusion, the genomic profiling and molecular characterization were difference between intrahepatic and extrahepatic cholangiocarcinoma, which may helpful in clinical diagnosis and treatment.
Real-world effectiveness of lenvatinib monotherapy among previously treated unresectable hepatocellular carcinoma patients in United States clinical practices.
Authors: Singal Amit G. , Nagar Saurabh P , Hitchens Abigail , Iyer Shrividya
Published: June 2021

e16129

Background: In the United States (U.S.), lenvatinib monotherapy was approved in August 2018 for first-line treatment of patients with unresectable hepatocellular carcinoma (uHCC) based on the pivotal trial, REFLECT. Treatment patterns in uHCC are evolving with recent approvals. The main objective of our real-world data (RWD) study was to assess treatment patterns and clinical effectiveness of lenvatinib among previously treated uHCC patients in U.S. clinical practices. Methods: A retrospective patient chart review study was conducted among U.S. adult patients (≥18 years) with uHCC and ECOG status of 0 or 1, who initiated lenvatinib monotherapy as second- or later-line systemic therapy between Aug 2018 and Sept 2019. Data were extracted from individual patients’ electronic health records and captured in electronic case report forms. Clinical outcomes assessed include provider-reported best response, progression-free survival (PFS) and overall survival (OS). PFS and OS were estimated using Kaplan-Meier methods. For PFS, patients were censored at end of treatment or end of follow-up in case of ongoing treatment, while censoring occurred at end of follow-up for OS. Results: Of 164 patients, median age was 62 years, majority were male (72%), and most were Caucasian (56%) followed by African American (23%). The most common liver disease etiologies were alcohol-related (32%), hepatitis C (26%), non-alcoholic steatohepatitis (21%) and hepatitis B (15%). Only one-third (31%) had Child Pugh A cirrhosis, with nearly half (49%) having Child Pugh B cirrhosis. Most patients had Barcelona Clinic Liver Cancer Stage B (24%) or C (38%) disease. Median body weight was 77 kg, and the median starting dose of lenvatinib was 12 mg daily. Median duration of lenvatinib treatment was 6.9 months, with 43% of patients remaining on lenvatinib at end of follow-up. RECIST v1.1 was reported as the criteria used to assess response in 60% of patients. Provider-reported best response was complete response (CR):9%, partial response (PR):45% and stable disease (SD): 26%. Median PFS and median OS were estimated to be 12.5 months and 14.0 months respectively. At 6 and 12 months, landmark PFS was 71% and 52%, respectively and landmark OS was 84% and 58%, respectively. PFS and OS estimates were consistent in subgroup analyses among those who had received lenvatinib in the second-line (81%, n=133) or treated with lenvatinib post immunotherapy (66%, n=109) (Table). Conclusions: Results from this retrospective real-world study affirm the clinical effectiveness of lenvatinib monotherapy among previously treated uHCC patients, including those with prior immunotherapy.[Table: see text]
Conversion hepatectomy for hepatocellular carcinoma with inadequate future- remnant- liver after portal vein ligation in combination with apatinib plus camrelizimab: A single-arm prospective pilot study (PLACES).
Authors: Zeng Zhiming , Zhu Guangzhi , Huang Huasheng , Jiang Yangfeng , Ye Xinping , Zeng Jie , Liu Cuizhen , Su Hao , Su Ming , Mo Ning , Liao Xiwen , Ma Fuchao , Peng Minhao , Ma Jie , Peng Tao
Published: June 2021

e16132

Background: A variety of staged hepatic resection has been applied in patients (pts) with hepatocellular carcinoma (HCC) who had an inadequate future-remnant-liver (FRL), but the clinical outcomes remain unsatisfactory. Based on the clinical data of apatinib (a highly selective VEGFR-2 inhibitor) and camrelizimab (anti‐PD‐1 antibody) in HCC pts, we therefore evaluated the safety and efficacy of portal vein ligation (PVL) in combination with apatinib plus camrelizimab for primary HCC with insufficient residual liver volume. Methods: Pts aged 18-75, with HCC, Child-Pugh A status, BCLC stage A-C, preoperative indocyanine green retention rate at 15 min < 10%, and preoperative FLR/standardized liver volume (SLV) < 30% (for pts without cirrhosis ) and < 40% (for pts with cirrhosis ) were enrolled. Pts received PVL followed by camrelizimab (200mg, iv, d1 q2w) plus apatinib (250mg, po, pd, q2w) until surgical criteria were met. Pts underwent second-stage hepatic resection 4 weeks after treatment discontinuation, and continued treatment with apatinib plus camrelizimab for 1 year or endpoints occurred. The primary endpoints were resection rate of conversion surgery and ORR (objective response rate). Results: Between Apr 21, 2020 to Jan 20, 2021, 14 pts were enrolled in this trial. The estimated median preoperative FLR/SLV for all pts was 34.6%. Among the 10 evaluable pts, 7 met the criteria for surgery and 5 completed second-stage hepatectomy except for 2 pt who refused and waited for surgery, respectively. The median interval time of the two stages of surgery was 138.8 days. ORR was 40%, and disease control rate (DCR) was 100% (4 pts with partial response and 6 pts with stable disease). The other 4 pts are waiting for the evaluation. No adverse events (AEs) of grade 3 or worse occurred after PVL. The most common treatment-related AEs in pts during treatment with apatinib plus camrelizimab included hypoalbuminemia (36%), increased aspartate aminotransferase (AST) (100%) and rash (29%). Major AEs in pts underoing second-stage hepatectomy were pneumonia (100%), increased AST (100%), increased alanine transaminase (100%) and anemia (100%). One patient died of postoperative pulmonary infection. Conclusions: PVL in combination with apatinib plus camrelizimab followed by staged resection may be a safe and effective treatment option for HCC pts with insufficient FLR. Clinical trial information: ChiCTR2000033692.
A phase 2 trial of apatinib combined with intensity modulated radiation therapy for patients with unresectable hepatocelluar carcinoma.
Authors: Ke Shaobo , Qiu Hu , Peng Jin , Cai Gaoke , Zhangcai Yutian , Cheng Hao , Cai Yuxin , Xia Lingling , Luo Xixi , Wu Yong , Gong Yi , Wang Jing , Shi Wei , Chen Jiamei , Zhao Wensi , Ruan Shasha , Chen Yongshun
Published: June 2021

e16136

Background: To estimate the clinical outcomes and safety for patients with unresectable advanced hepatocelluar carcinoma (HCC) treated with apatinib in combination with intensity modulated radiation therapy (IMRT). Methods: This study was an open-label, single-arm, phase 2 clinical trial of apatinib combined with IMRT for treatment of patients with unresectable advanced HCC. Patients aged between 18 and 75 years with adequate hematologic, liver, and renal functions, and ECOG performance status of 1 or less were included in the study between March 2017 and September 2020. Patients received IMRT (biologically effective dose(BED): 46-60Gy), and continuous apatinib (250-500 mg/d) orally until disease progression or unacceptable toxic effects. The primary end point was progression-free survival(PFS), the secondary end points included overall survival(OS), disease control rate (DCR), objective response rate(ORR) and safety. The data were analyzed for this report with cutoff on February 1, 2021. Results: A total of 46 patients were screened and 33 were enrolled in this study. The cohort had a median age of 56.7 years (range 21-77), 28(84.85%) were men. 25(75.76%) patients had hepatitis B, 32(96.7%) were BCLC stage B-C, 31(93.9%) were Child-Pugh A-B，and 8(24.2%) had portal vein involvement. Receiving first-line and second- or later-line treatment were 21(63.6%) and 12(36.4%), respectively. At a median follow-up of 11.6 months, the median PFS was 7.68 months(95% confidence interval:5.39-9.76) .The 6-month and 12-month overall survival rates were 100% and 96.2%, respectively. According to Response Evaluation Criteria in Solid Tumors Version 1.1, the ORR and DCR were 15% and 82%, respectively. There were 15 (15.2%) grade 3-4 treatment-related adverse events including neutropenia, thrombocytopenia, hypertension, proteinuria and hand and foot syndrome. There were no treatment-related deaths. Conclusions: Apatinib in combination with IMRT was safe and effective in improving PFS and DCR, and suggested an encouraging anti-tumor activity in patients with unresectable advanced HCC. Clinical trial information: ChiCTR-OPC-17011890.
Acceleration of blood-based circulating cell-free DNA epigenetic age among HIV-infected patients with hepatocellular carcinoma in Nigeria.
Authors: Zheng Yinan , Hawkins Claudia , Okeke Edith , Lesi Olufunmi A. , Qu Yishu , Roberts Lewis R. , Gursel Demirkan , Abdulkareem Fatimah Biade , Akanmu Alani , Imade Godwin , Wei Jian-Jun , Kocherginsky Masha , Kim Kwnag-Youn , Adeyemo Wasiu Lanre , Wehbe Firas Hazem , Achenbach Chad , Sagay Atiene , Ogunsola Folasade , Murphy Robert , Hou Lifang
Published: June 2021

e16137

Background: Hepatocellular Carcinoma (HCC) is the leading cause of cancer-related mortality in Nigeria. HIV and viral hepatitis B (HBV) and C (HCV) co-infection are common in Nigeria that significantly accelerates liver disease progression including HCC. Aging-related DNA methylation signatures obtained in liquid biopsy, such as circulating cell-free DNA (ccfDNA) extracted from serum/plasma are promising minimally-invasive biomarkers that may inform HIV-associated HCC. We examined the epigenetic age acceleration (EpiAgeAccel) in ccfDNA in HCC patients with HIV. Methods: The study included three groups of participants: a) HIV positive with HCC (n=7); b) HIV positive and cancer-free (n=45); and c) HIV negative with HCC (n=33). Epigenetic age was estimated by Horvath’s calculator using genome-wide ccfDNA methylation data profiled by Illumina EPIC array. EpiAgeAccel was computed as the residuals of a linear model of epigenetic age on chronological age, namely the unexplained portion of epigenetic age by chronological age. We used multiple linear regression to compare EpiAgeAccel between HIV/HCC groups, adjusting for sex, age, education, alcohol intake, and HBV/HCV infection. Results: Among HIV positive participants, there was a higher percentage of men (57% vs. 22%, p<0.001), HBV infection (29% vs. 11%, p=0.004), and HCV infection (57% vs. 2%, p<0.001) in the HCC group compared to the cancer-free group. EpiAgeAccel was 4.8 years higher in HIV positive patients with HCC compared to cancer-free HIV positives (p=0.02). Among HCC patients, EpiAgeAccel was 2.1 years higher in HIV positives compared to HIV negative but not statistically significant. Conclusions: Epigenetic age in ccfDNA is accelerated in HIV-positive HCC patients. EpiAgeAccel measured in ccfDNA may be developed into a surrogate biomarker for minimally invasive HCC detection among HIV-infected patients in low- and middle-income countries.
Utilization of hepatocellular carcinoma surveillance programs in patients with cirrhosis: A systematic review and meta-analaysis.
Authors: Singh Jameel Kenneth , Ramai Daryl , Tartaglia Nicola , Ambrosi Antonio , Khan Shahab R. , Chandan Saurabh , Facciorusso Antonio
Published: June 2021

e16141

Background: Patients with cirrhosis are advised to undergo hepatocellular carcinoma (HCC) surveillance every six months. Routine screening is associated with early tumor detection and improved survival. However, surveillance is underutilized. We aimed to characterize the impact of HCC surveillance interventions on patient uptake and concomitant detection of HCC. Methods: We performed a comprehensive literature search of major databases (from inception to October 2020) to identify studies which assess the impact of HCC surveillance programs in patients with cirrhosis. Our primary endpoint was uptake of screening defined as having an abdominal sonogram every at least every 6 months. Secondary endpoint was the detection of HCC following screening. Pooled data was assessed using a random-effects model expressed in terms of odds ratio (OR) and 95% confidence interval (CI). Results: Nine studies were included for meta-analysis which involved 5,021 patients with cirrhosis. Patients with a history of hepatitis B or C accounted for 40.5% of the study cohort. Comparing both screening and control groups, patients were 5 times more likely to undergo abdominal sonography if they participated in surveillance programs versus usual care (OR 4.69; CI: 2.41 – 9.13, I2: 94%). Overall, the mean difference in patients who did undergo screening versus those who did not participate in surveillance was 30.6% (CI: 19.2% – 41.9%, P < 0.001). Comparing both screening and control groups, patients were 1.5 times more likely to be diagnosed with HCC if they participated in surveillance programs (OR 1.49; CI: 0.57 – 3.89, I2: 65%). On subgroup analysis, comparing type of intervention program, dedicated surveillance programs showed a higher uptake compared to clinical reminders, though not statistically significant (dedicated programs OR 62.6, CI: 1.53 – 2559.5 vs clinical reminders OR 2.63, CI: 1.82 – 3.79). Conclusions: Patient uptake in HCC surveillance remains underutilized. Interventions such as dedicated surveillance programs and clinical reminders systems can significantly increase uptake of abdominal sonography and cancer detection.
Evaluation of somatic and germline mutations in Chinese patients with gallbladder carcinoma reveals clinically actionable targets.
Authors: Yang Wenhui , Liu Si , Li Xiaomo , Gao Hongjian , Ma Tonghui , Liu Rong
Published: June 2021

e16143

Background: Gallbladder cancer (GBC) is an aggressive gastrointestinal cancer and the median survival of GBC patients is less than one year. Given the rarity of this disease, there is no enough evidence to guide the precision therapy for GBC patients. Therefore, it is urgent to identify therapeutic targets in GBC to help physicians to enroll patients in clinical trials. In this study, we aimed to characterize clinically actionable mutations in a large cohort of patients with GBC. Methods: To characterize therapeutic targets in 118 Chinese GBC patients, a deep sequencing panel (OncoPanscan, Genetronhealth) was applied to explore somatic alterations including point mutations, indels, copy number alterations and gene fusions, as well as possible pathogenic germline variants respectively from their tumor tissues and matched genomic DNA sample. Results: Recurrent somatic mutations were identified in TP53 (65%), ERBB2 (18%), ARID2 (13%), ELF3 (13%), CDKN2A (12%), ARID1A (10%), KRAS (10%) and KMT2C (10%). Of the entire cohort, the most frequently mutated genes were in the ErbB pathway including EGFR, ERBB2, ERBB3, and ERBB4. For the patients with ERBB2 genetic aberrations, 67% (14/21) patients had gene amplification and 29% (6/21) patients had the oncogenic S310F/Y (n = 6) mutation which may be eligible for HER2-targeted therapy clinical trial. Importantly, 9% (10/118) patients carried activating PIK3CA mutations including P104L, E110del, E545K/Q/G, E542K, E726K and T1025S which may be targeted by PIK3CA inhibitor alpelisib. Additionally, patients with loss-of-function mutation in NF1 (n = 6), STK11 (n = 5) and PTEN (n = 2) can be respectively targeted with MEK inhibitor and mTOR inhibitor. Furthermore, patients with MET amplification (n = 3) may be eligible for clinical trials of MET inhibitor carbozantinib. There were four patients (3.4%) carried loss-of-function germline mutations in DNA repair genes ( BRCA1, BRCA2 and PALB2) and 19 patients (16%) harbored somatic loss-of-function mutations in BRCA1 (n = 2), BRCA2 (n = 2), ARID1A (n = 12) and ATM (n = 3). These patients may benefit from platinum chemotherapy or targeted therapy with PARP inhibitors. Interestingly, 13% (15/118) patients in our cohort carried ELF3 inactivating mutations which was reported as a potential GBC vaccine candidate. Taken together, at least 54 (46%) patients in our cohort had actionable genetic alterations. Conclusions: Our results indicated that activating mutations in the ErbB and PI3K signaling pathways are the major driving events of GBC. The results of genomic profiling can guide physicians to enroll a significant portion of GBC patients into genomically matched clinical trials.
Treatment patterns and outcomes of locally advanced gall bladder cancer: A National Cancer Database (NCDB) analysis.
Authors: Kancharla Pragnan , Alnimer Lynna , Samhouri Yazan , Shankar Karthik , Bakalov Veli , Jayakrishnan Thejus Thayyil , Peterson Chelsea , Huffman Deanna , Wegner Rodney E. , Monga Dulabh K.
Published: June 2021

e16147

Background: Gall bladder (GB) cancer is rare but an aggressive disease especially when presenting at an advanced stage. There is controversy regarding the best treatment approach for locally advanced disease. In this NCDB analysis, we aim to study treatment patterns for T3, T4, and/or N1 GB cancer and estimate survival for each treatment modality. We also sought to investigate clinical and socioeconomic predictors of treatment selection. Methods: We conducted a retrospective cohort analysis using de-identified data accessed from the NCDB. The NCDB provided records of 39,229 patients diagnosed with GB cancer between 2004-2017. We excluded patients who were not treated at the reporting facility, those with no histologic confirmation of the diagnosis, those with no survival data available and those with T1, T2 and metastatic disease. We did exploratory analysis and divided patients into six arms based on treatment modality (Table). Stepwise multivariable regression models were used to analyze predictors of treatment selection. Survival estimates were calculated using the Kaplan Meier and proportional Cox hazard regression methods. Results: We identified 7,004 patients with GB cancer who fulfilled the inclusion and exclusion criteria. Median age was 68 years. There were 69.5% females, and the majority of patients were white (66.1%). Receiving treatment at an academic/research center (OR 0.37, 95% CI 0.19-0.73, p <0.01), black patients (OR 0.55 95% CI 0.36-0.85, p <0.01) and higher education (OR 0.58, 95% CI 0.37-0.91, p 0.02) decreased the odds of receiving surgery. Meanwhile, the presence of lymphovascular invasion was seen more amongst patients with receipt of surgery. For patients who underwent radiation, increasing age (OR 0.97, 95% CI 0.97-0.98, p <0.01) and higher histologic grade (OR 0.65, CI 0.46-0.92, p .02) were associated with less radiation use. Median income between $50,354-$63,332 (OR 1.28, 95% CI 1.02-1.60, p 0.04) was associated with more radiation use. Patient who received triple therapy had improved survival compared with other modalities (HR 0.51, CI 0.46-0.57, p <0.01). Median overall survival (OS) for the whole population was 13.0 months (CI 12.6-13.5) (Table) Conclusions: American patients with T3, T4, and/or N1 GB cancer received variable treatment modalities. Patients who underwent triple-modality therapy in our analysis had improved adjusted-overall survival compared with other modalities. Limitations include unmeasured confounding factors, selection bias and the retrospective design. We also identified clinical and socioeconomic factors that affect treatment selection.[Table: see text]
The comparative efficacy of atezolizumab and bevacizumab versus lenvatinib in patients with unresectable hepatocellular carcinoma (uHCC).
Authors: Trueman David , Liu Yifeng , Lucero Melanie , Meier Genevieve
Published: June 2021

e16151

Background: Hepatocellular carcinoma (HCC) is the most common type of liver cancer, comprising 90% of all cases. In the phase III IMbrave150 trial, combination of atezolizumab and bevacizumab (atezo+bev) resulted in improved overall survival (OS) and progression-free survival (PFS) compared with sorafenib for patients with unresectable hepatocellular carcinoma (uHCC). In the phase III REFLECT trial, lenvatinib met the primary endpoint of non-inferiority in OS versus sorafenib, and demonstrated superiority in secondary endpoints; PFS, time to progression and objective response rate (ORR). Furthermore, post-hoc analyses strongly suggest that the original non-inferiority trial likely underestimated the true effect of lenvatinib on OS due to imbalances in baseline prognostic covariates and the comparatively greater use of post-treatment anti-cancer therapies in the sorafenib arm. In the absence of a head-to-head comparison between atezo+bev and lenvatinib, the objective of this analysis was to estimate their comparative efficacy as first-line treatments for patients with uHCC. Methods: A network meta-analysis (NMA) was conducted based on a de novo systematic literature review which identified evidence for licensed therapies in first-line uHCC. This was supplemented with data from the extended IMbrave150 study findings (clinical cut-off on 31 August 2020). Median hazard ratios (HR) with corresponding 95% credible intervals (CrI) were estimated for OS and PFS. HRs for OS and PFS from REFLECT were taken from multivariable analyses which adjusted imbalances in baseline prognostic covariates. All analyses were conducted in a Bayesian generalised linear model framework. Model selection was based on deviance information criterion (DIC). Results: Four eligible phase III studies (REFLECT, SHARP, Asia-Pac and IMbrave150) were included. Using a fixed-effects model, the estimated median HRs for atezo+bev compared with lenvatinib were 0.81 (95%CrI: 0.61, 1.08; posterior p=0.078) and 0.99 (95%CrI: 0.76, 1.28; posterior p=0.454) for OS and PFS, respectively. The results obtained were similar to those observed by Vogel et al, who reported an OS HR of 0.63 (95% CI: 0.32, 1.25), and a PFS HR of 0.91 (95% CI: 0.23, 3.65). Conclusions: While the NMA respects the randomization of the included studies, it does not represent direct evidence and should therefore be considered exploratory in nature. The results of this NMA suggest that the benefit of atezo+bev is not statistically significant compared to lenvatinib, as the differences between atezo+bev and lenvatinib fell within the Bayesian range of equivalence (upper limit of Crl ≥ 1 for OS and PFS) and were subject to a high degree of uncertainty. The results of the NMA were consistent for all the publicly available data cuts from IMbrave150.
Combined treatment with iodine-125 (125I) seed strand and transarterial chemoembolization (TACE) plus lenvatinib with anti-PD-1 antibodies in patients with unresectable hepatocellular carcinoma (uHCC) and portal vein tumor thrombus (PVTT): Real-world experience in China.
Authors: Zhang Zi-Han , Zhang Wen , Liu Qing-Xin , Liu Ling-Xiao , Luo Jian-Jun , Qu Xu-Dong , Yan Zhi-Ping
Published: June 2021

e16152

Background: We reviewed real-world outcomes for patients with uHCC and PVTT receiving TACE with 125I seed and stent implantation combined with lenvatinib plus anti-PD-1 antibodies. Methods: We retrospectively reviewed medical records from 62 consecutive adult (≥18 to ≤75 years) patients with HBV-related HCC and type III and IV PVTT with Child-Pugh class A or B liver function and ECOG performance status of 0-2 who received 125I seed strand and stent implantation combined with TACE at our center between November 2018 and May 2020. Patients were divided into two groups; those who had received adjuvant lenvatinib plus anti-PD-1 inhibitors, initiated 3 days after the first interventional procedure (Group A; n=18), and those who only received locoregional therapy (Group B; n=44). Propensity score matching (PSM) with a 1:1 ratio was used to reduce selection bias. Tumor response, progression-free survival (PFS, time from the first interventional procedure to progression or death for both Group A and Group B) and time-to-progression (TTP) were assessed using the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Time to untreatable progression (TTUP) and overall survival (OS) were also assessed. Adverse events (AEs) were graded according to the Common Toxicity Criteria for Adverse Events (CTCAE) v4.0. Results: PSM resulted in 15 matched pairs of patients, and baseline demographic parameters were comparable between the two groups. The median follow-up time was 12.4 ± 4.6 and 9.4 ± 4.8 months for patients in Groups A (n=15) and B (n=15) after PSM, respectively. Compared with patients in Group B, those in Group A had a higher overall response rate (66.7 vs. 18.2%; p=0.001) and disease control rate (72.2 vs. 43.2%; p=.038) and a longer median PFS, TTP, TTUP and OS (Table). No serious complications related to locoregional procedures were reported in either group. In Group A, 13% (n=2) of patients experienced ≥1 AE but the majority were Grade <3; one patient had Grade 2 hyperthyroidism and one had Grade 2 enteritis, which were both considered related to immunotherapy. Conclusions: These real-world data show that 125I seed strand and stent implantation combined with TACE plus adjuvant lenvatinib and anti-PD-1 antibodies led to better treatment responses and survival outcomes compared with locoregional treatment alone in patients with uHCC and PVTT, with an acceptable safety profile. Summary of survival outcomes in propensity score matched groups.[Table: see text]