bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regorafenib joins immune checkpoint inhibitors (ICIs) for previously ICIs plus TKIs failed advanced hepatocellular carcinoma (HCC) patients: A retrospective study.
Authors: Zhao Jie , Yang Chao , Han Guoyong , Zhang Long , Jiang Chuanwei , Ding Wenzhou , Hu Yuanchang , Ni Ming , Wu Chen , Xia Yongxiang 
Published: June 2022

e16118 Background: The development of ICIs has promoted a major breakthrough in the field of cancer therapy. A number of patients experience primary or acquired resistance to ICIs based first line therapy. Because of the similar mechanisms, PD-(L)1 inhibitors replacement after PD-(L)1 inhibitors-based therapy resistance is difficult to sustain benefits. Therefore, whether suspending immunotherapy, or maintenance immunotherapy and switching the combination drugs in the follow-up strategy is worth to explore. Regorafenib is an oral multikinase inhibitor that blocks the activity of protein kinases involved in angiogenesis, oncogenesis and metastasis. Besides, regorafenib could regulate the immune microenvironment. This retrospective trial aims to evaluate the efficacy of regorafenib in combinations with previous ICI in advanced HCC patients who failed to previous ICI-TKI treatment. Methods: In this study, eligible patients were advanced HCC, who failed to previous treatment with TKIs and PD-1 inhibitors. 17 patients were received PD-1 inhibitor the same as the first-line treatment (dosage and mode of administration according to instructions) and regorafenib (40, 80, 120mg/m2, po, qd, d1-21) every 4 weeks, until disease progression, intolerable toxicities, or physician/patient withdrawal. The safety and efficacy were assessed by investigators per CTCAE v5.0 and RECIST v1.1, respectively. The primary endpoint was objective response rate (ORR), the secondly endpoints were progression-free survival (PFS), disease control rate (DCR), overall survival (OS), duration of response (DOR) and safety. Results: From Nov 15, 2020 to Jan 31, 2022, 17 patients with advanced HCC, Child-Pugh class A liver disease, and ECOG PS 0-1 (16 male vs. 1 female, 13 second-line recipients vs. 4 third-line recipients, median age of 55 years) had been enrolled. 52.94% of the patients had BCLC stage B and others had BCLC stage C. The median follow-up was 8.8 months (range, 2.7-14.7). Confirmed ORR and DCR were 41.2% and 64.7%, respectively. The median PFS was 5.21 months (95% CI, 2.65-7.77). For 13 second line patients, confirmed ORR and DCR were 46.2% and 69.2%, respectively. Median OS and DOR had not yet been reached. 12 recipients had treatment-related adverse events (TRAEs). Most frequent TEAEs (≥5%) included fatigue (15.8%), diarrhea (15.8%), periodontal disease (10.5%), hypertension (10.5%), albuminuria (5.3%). Grade 3 TRAEs occurred in 3 (17.6%) patients included gastrointestinal bleeding, hand-foot syndrome and albuminuria. No Grade 4 TRAE and new safety signal were identified. Conclusions: Regorafenib plus PD-1 inhibitor showed a promising efficacy with favorable safety in HCC patients with PD-1 inhibitor resistance, especially in the standard second line patients. Moreover, the strategy showed a higher ORR than RESORCE study (46.2% vs. 10.6%).
Efficacy and safety of anlotinib with PD-1 blockades in the treatment of advanced biliary tract cancer: A real-world study.
Authors: Chen Kehe , Huang Xianshi , Yu Lei , Hou Encun , Ou Mei , Wang Junping , Huang Xiao , Pan Deng , Liu Yu , Huang Min , Zhong Wenhe , Pan Zhuang , Zhang Shijie , Li Bin , Nong Xiansheng , Chen Kefan 
Published: June 2022

e16129 Background: Several clinical trials have demonstrated that antiangiogenic drugs combined with PD-1 blockades are effective for patients with advanced biliary tract cancer (BTC). However, the efficacy of this combination in real-world patients needs to be explored. Anlotinib is a novel oral multi-targeted tyrosine kinase inhibitor for tumor angiogenesis and proliferation, which had been licensed for treatment of considerable malignancies in China. The aim of this study was to investigate the efficacy and safety of anlotinib combined with PD-1 blockades in the treatment of advanced BTC in real world. Methods: This is a multi-center prospective real-world study. Patients with advanced BTC receiving anlotinib combined with PD-1 blockades were recruited. Clinical efficacy was summarized, and adverse events were documented. Tumor response was assessed by investigator according to RECIST version 1.1. The primary endpoint was overall survival (OS), secondary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) and safety. Results: From May 2020 to Sep 2021, a total of 14 eligible pts were recruited. 1 patient was in stage IIIa, 4 pts in stage IIIb, and 9 pts in stage IV. Among them, 10 pts received anlotinib as first-line treatment, 3 pts as second-line treatment and 1 pts as third-line treatment. DCR was 85.71% (57.19%, 98.22%). At the data cut-off date, 7 pts discontinued treatment due to disease progression, the preliminarily prognostic results indicated that the median OS was 8.21 months (95%CI: 5.88, NA) and the median PFS of the 14pts was 6.28 months (95%CI: 3.17-8.21). The safety profile suggested that the most common drug-related adverse events were hypertension (21.43%), decreased white blood cell count (21.43%), decreased platelet count (21.43%), hypoalbuminemia (14.29%), vomit (14.29%), gastrointestinal bleeding (14.29%). The common grade 3 adverse event were gastrointestinal bleeding (7.14%), anemia (7.14%), biliary infection (7.14%). Conclusions: Present study indicated that the combination of anlotinib and PD-1 blockades exhibited potential efficacy and manageable adverse events in the treatment of advanced BTC in the real world. The conclusion should be validated in more patients included subsequently. Clinical trial information: NCT04954521.
Construction and validation of the prognostic model for patients with gallbladder neuroendocrine neoplasm-based a nationwide retrospective registry study.
Authors: Sun Xuheng , WANG Yijun , Liu Yingbin 
Published: June 2022

e16140 Background: Gallbladder neuroendocrine neoplasm (GB-NEN) is an extremely rare type of gallbladder neoplasm and the prognosis of patients with GB-NENs varies widely. The focus of this study was to construct and validate a prognostic model of GB-NENs based on the data from a nationwide retrospective multicenter registry cohort. Methods: The Chinese Research Group of Gallbladder Cancer (CRGGC) study is a multicenter retrospective registry cohort study reviewing the electronic medical records from 76 tertiary and secondary hospitals across 28 provinces in China. We assembled patients with GB-NEN diagnosed between 2010 and 2017 in 24 tertiary hospitals from CRGGC study. Influential factors of recurrence free survival (RFS) and overall survival (OS) were identified using Least absolute shrinkage and selection operator (LASSO) regression and Cox predicting model was constructed for predicting RFS and OS. The prognostic model was validated both internally and externally. Performance of the model was assessed by concordance index (C-index) and calibration curves stratified by risk categories. Results: A total of 84 patients with GB-NEN was extracted from CRGGC study, among which 3 were diagnosed with GB-NEN Grade 1, 8 were diagnosed with GB-NEN Grade 2 and 35 with GB-NEN Grade 3. Of the 35 patients with GB-NEN Grade 3, 3 had poorly differentiated small-cell neuroendocrine carcinomas (SC-NECs) and 8 patients had Mixed neuroendocrine–non‐neuroendocrine neoplasms (MiNENs). 53 patients were included in the training group (median survival, 21.1 months; 95% confidence interval (CI), 13.8-37.6 months) and 31 patients in the validation cohort (median survival, 34.3 months; 95% CI, 9.63-58.97months). A Cox predicting model was built, including 5 variables (age, TNM stage, surgery, metastasis at liver, proportion of positive lymph nodes examined). The C-index was 78.1 (95% CI, 63.9-92.3), with a good calibration, and these results were confirmed in the internal validation cohorts. Conclusions: We have built a clinical model for GB-NEN patients and clinical doctors for prognosis prediction based on age, TNM stage, surgery, metastasis at liver, proportion of positive lymph nodes examined which can be easily obtained in one’s case history. It can be used to determine subgroups of patients who may have poorer prognosis and assist individualized and precise treatment for GB-NEN.
Immune checkpoint inhibitors (ICIs) plus CAPOX in the treatment of unresectable advanced or recurrent biliary tract carcinoma (BTC): A retrospective study.
Authors: Zhao Jie , Yang Chao , Ding Wenzhou , Han Guoyong , Zhang Long , Jiang Chuanwei , Wu Chen , Ni Ming , Xia Yongxiang 
Published: June 2022

e16144 Background: Patients with advanced or unresectable BTC have limited treatment options and poor prognosis. The combination of ICIs with chemotherapy has demonstrated promising antitumor activity with manageable safety in the first- or second-line in treatment of patients with advanced or unresectable BTC, but only a subset of patients with BTC derive benefit. The standard systemic treatment for BTC has been gemcitabine (800-1250 mg/m2, i.v., d1 and d8, q3w) in combination with oxaliplatin/cisplatin. The regimen is associated with high frequency of intravenous injection or more hospital days. All above highlights the need for new combinations. Therefore, we conducted a retrospective trial to evaluate ICIs combined with CAPOX (more convenient dosing regimen) in patients with advanced or recurrent BTC who were treatment-naive or failed to previous treatment. Methods: In this study, eligible patients were diagnosed as unresectable advanced or recurrent BTC, therapy-naive or failed to previous treatment with chemotherapy, inhibitors of VEGFR or PD-1/PD-L1. In therapy phase, 28 patients were given with ICIs (dosage and mode of administration according to instructions, d1), oxaliplatin (130 mg/m2, i.v., d1), and capecitabine (1000mg/m2, po, bid, d1-14) every 3 weeks, until disease progression, intolerable toxicities, or physician/patient withdrawal. The safety and efficacy were assessed by investigators per CTCAE v5.0 and RECIST v1.1, respectively. The primary endpoint was progression-free survival (PFS), the secondly endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response (DOR) and adverse events (AEs). Results: From Dec 24, 2019 to Aug 6, 2021, 28 patients had been enrolled to receive therapy. The patients were characterized with a median age of 58 years (range 53-79), 75% intrahepatic cholangiocarcinoma (ICC) and 25% gallbladder cancer (GBC), 25% lymph node metastasis, 25% liver metastases, 54% with history of surgery, and 57% with therapy-native. As of Jan 23, 2022, with a median follow-up of 9.0 months (range, 2.1-23.4), safety and efficacy were assessed in 26 evaluable patients, with response of 12 PR and 6 SD. Confirmed ORR and disease control rate (DCR) were 46.2% (95% CI, 27.1%-66.2%) and 69.2% (95% CI, 48.1%-84.9%), respectively. The median PFS, median OS and median DOR were 6.1 months (95% CI, 4.9-7.3), 16.5 months (95% CI, 5.0-28.0) and 5.0 months (95% CI, 2.0-8.0), respectively. Grade 3-4 treatment-related adverse events occurred in 32.1% of patients, with thrombocytopenia and bone marrow depression ranking the most frequent. No new safety signal was identified. Conclusions: In this study, ICIs combined with CAPOX not only showed high level of safety and efficacy, but also provided convenience in the treatment of unresectable advanced or recurrent BTC.
Regorafenib combined with PD-1 monoclonal antibody in the second-line setting for hepatocellular carcinoma (HCC): A retrospective, real-world study in China.
Authors: Li Zhongchao , Li Lei , Zhong Jingtao , Cui Kai , Zhang Chengsheng , Shi Xuetao , Sun Pengfei 
Published: June 2022

e16145 Background: In China, the first-line TKI therapy for advanced HCC is a common standard treatment modality. Meanwhile regorafenib combined with anti-PD-1 antibodies (PD-1) exerted promising effects on unresectable hepatocellular carcinoma (uHCC). Still，more clinical evidence is needed to optimize second-line treatment for uHCC. In this single-center, retrospective real-world study, we look forward to further clinical benefits of regorafenib combined with PD-1 monoclonal antibody as second-line treatment of uHCC in China. Methods: We reviewed the medical data of 55 patients with HCC and received regorafenib combined with PD-1 monoclonal antibody for second-line treatment from April 2019 to April 2021. Patients were treated with regorafenib combined with PD-1 monoclonal antibody for at least 1 cycle (21days). The progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR) were observed. Results: The median age was 52 years (range 29-72), 89.1% were male, 78.2% patients had hepatitis B. At study entry, the proportions of patients with Child–Pugh A/B class were 61.8%/36.4% (unknown: 1.8%); the proportions of patients with ECOG performance status 0/1/2 were 70.9%/21.8%/7.3%; the proportions of patients with BCLC stage A/B/C class were 5.5%/9.1%/83.6% (unknown: 1.8%); For prior targeted therapy, the proportion of patients with sorafenib/ lenvatinib / apatinib were 85.5%/9.1%/1.8% (unknown:1.8%), 1patient did not receive targeted therapy. Regorafenib combined with PD-1 monoclonal antibody was used for second-line systemic therapy, the PD-1s used mainly were sintilimab (n = 23), camrelizumab (n = 21), tislelizumab (n = 10); The median initial daily dose was 120 mg (rang,40-160),and the proportions of patients with the initial daily regorafenib dose 160mg/120mg/80mg/40mg were30.9%/16.4%/43.6%/1.8% (unknown :7.3%). The median PFS was 7.9 month (95%CI:5.1, NA), ORR was 27.3%, DCR was 56.4%. Conclusions: The preliminary results of this retrospective real-world study, indicate that regorafenib combined with pd-1 therapy as second-line treatment provide clinical benefits in uHCC patients with a manageable toxicity in Chinese patients. Data will be further collected to reduce bias caused by small sample size and baseline differences.
A multiplexed immunohistochemical consecutive staining on single slide (MICSSS) analysis of the immune microenvironment of bile duct cancers (BDC) pre and post neoadjuvantchemotherapy (NACT).
Authors: Dharmapuri Sirish , Cabal Rafael , Ioannou Giorgio , Ozbey Sinem , Paulsen John , Ang Celina , Sarpel Umut , Sung Max W. , Kozuch Peter , Schwartz Myron E. , Cohen Deirdre Jill , Gnjatic Sacha , Pintova Sofya 
Published: June 2022

e16151 Background: NACT is increasingly being used in the management of locally advanced BTC. Emerging evidence suggests a potential key contributing role of tumor infiltrating immune cells in the prognosis & response to therapy. We set out to characterize immune modulation of tumor immune microenvironment composition in BTC following NACT. Methods: Patients (pts) with locally advanced BTC who underwent a diagnostic biopsy, then NACT followed by resection between 2014 & 2018 were identified & consented after IRB approval. MICSSS, a sample-sparing chromogenic consecutive multiplex tissue staining method, was performed with a series of immune markers (Table), to characterize T cell subsets, B cells, macrophages, mature dendritic cells (DCs), and immune checkpoints on pre & post NACT formalin-fixed paraffin-embedded tumor tissue sections. Density was calculated for each marker (+ve cells/mm2) following annotation of tissues by tumor, fibrosis, necrosis, stromal & tumor infiltrating lymphocyte-enriched areas. Results: Nine pts were enrolled. Final analysis included 5 pts with adequate tissue. Median age = 48 (41-56), with 4 female, 4 intrahepatic cholangiocarcinomas & 1 gallbladder. All pts received Gemcitabine/Cisplatin as NACT with a median of 5 (4-7) cycles. Median time from diagnosis to surgery was 4.3 (1.4-7.8) months & last cycle to surgery was 0.9 (0.6-1.5) month. All pts were MMR proficient, 1 Her2+ & 2 with FGFR2 amplification. NACT on average produced a depletion of all immune markers (Table). Given the small N, each pt was considered their own control & changes in mean cell densities post NACT were calculated. Pt2 with a 40-fold increase in PDL1 expression & 5-fold decrease in CD8:FOXP3 ratio notably had the shortest disease-free interval (DFI). Pt3 with the longest DFI had the largest increase in CD8:FOXP3 by about 8-fold combined with a decrease in PDL1. Conclusions: Preliminary results suggest NACT may modulate immune microenvironment despite overall immune cell depletion. Future studies should focus on strategies to expand immune modulation of the tumor microenvironment in BTC by NACT, including immune oncology agent priming prior to or after NACT.[Table: see text]
The association of chromosome 11q13 amplification with the hyperprogressive disease in unresectable hepatocellular carcinoma patients underwent the immunotherapy.
Authors: Zhang Haibin , Yan Kai , Zhang Ding , Chen Yanan , Huang Mengli , Fu Yong , Lu Wenfeng 
Published: June 2022

e16156 Background: Hyperprogressive disease (HPD) is characterized by an acceleration of tumor growth during systemic therapy, which usually refers to immunotherapy. The incidence of HPD in patients with hepatocellular carcinoma (HCC) is reported to be 12.7%. Amplification of the chromosome 11q13 locus, including cyclin D1 (CCND1), FGF3, FGF4 and FGF19, is frequent in many cancers and correlates with inferior outcomes with immunotherapy. However, little is known about the association between chromosome 11q13 amplification and HPD of HCC. Methods: 58 HCC patients who underwent the next-generation sequencing (NGS) in our institution from September 2017 to April 2018 were enrolled in this study. Among them, 30 patients had unresectable advanced or recurrent HCC and received anti-tumoral therapy, including 18 cases (Group 1) receiving programmed cell death-1 (PD-1) monoclonal antibody immunotherapy (with or without tyrosine kinase inhibitors, TKIs) and 12 cases (Group 2) receiving local regional therapy (with or without TKIs). Based on radiological surveillance, HPD was defined as: 1. Tumor growth kinetics (TGK) or tumor growth rate (TGR) > 2; 2. Time to treatment failure < 2 months. Results: In our dataset, chromosome 11q13 amplification (11q13 Amp) was seen in 11 patients (19.0%). 11q13 Amp was associated with worse clinical baseline, with a significant concentration in patients with BCLC C stage, tumor numbers of ≥ 3 and ECOG 1 score. Group 1 had an objective response rate (ORR) of 50.0% and Group 2 had an ORR of 54.5%. There was no significant difference in progression-free survival (PFS) between these two groups. 3 patients showed HPD in Group 1, all of whom carried 11q13 Amp. Compared to non-11q13 Amp patients, patients with 11q13 Amp had worse PFS (log-rank P= 0.001) in Group 1. While there was no significant difference of PFS between 11q13 Amp and non-11q13 Amp patients in Group 2. We further investigated the efficacy of different treatment strategies based on 11q13 Amp status. These 11q13 Amp patients in Group 1 showed worse PFS, compared to Group 2 (log-rank P= 0.025). However, patients with non-11q13 Amp showed similar outcomes between these two groups (log-rank P= 0.70). Conclusions: Our findings suggested that 11q13 Amp was associated with HPD of HCC. PD-1 monoclonal antibody showed poor efficacy in patients with 11q13 Amp, therefore targeted treatment strategies might be more suitable for such patients. Meanwhile, the role of 11q13 Amp as putative predictive biomarkers of HPD needs further validation in larger cohorts.
Characterization of molecular and immune landscape of microvascular invasion in hepatocellular carcinoma and prognostic significance.
Authors: Zhang Kai , Tao Changcheng , Wu Fan , WANG Liming , Zheng Linlin , Wang Yaru , Wu Anke , Wu Jianxiong , Xiao Ting , Rong Weiqi 
Published: June 2022

e16162 Background: Partial hepatectomy is potentially curative treatment in selected patients (pts) with hepatocellular carcinoma (HCC). Microvascular invasion (MVI) is one of the strongest predictors of prognosis and recurrence of HCC. In this study, we analyzed the gene mutation signature and immune factors associated with MVI, and the prognostic value. Methods: Pts who were diagnosed with HCC between Jan 2018 and Sep 2020 in Cancer Hospital of Chinese Academy of Medical Sciences were retrospectively enrolled in this study. Next-generation sequencing (NGS) was performed on tumor tissues after radical partial hepatectomy. The different immune makers (PD1, PD-L1, CD3, CD8, CD68, and CD163) of tumor-infiltrating lymphocytes (TILs) were identified with immunofluorescence-based microenvironment analysis panel (MAP). Results: In the MVI+ group (n = 39, 59.1 %), there were significantly more pts with larger tumor size, and capsules invasion by tumors. The mutation spectra revealed that 61 (92.4%) pts harbored somatic mutations and the most frequently mutated gene was telomerase reverse transcriptase (TERT), which was present in 31.8% (n = 20) HCC pts. Mutations in the promoter of TERT were found in 95.2% (20/21) pts. 90.0% (18/20) had one hotspot point mutation located 124bp upstream of the translation start site. The mutation frequency in the TERT promoter was significantly higher in the MVI+ group compared with the MVI- group (41.0% vs. 14.8%, p < 0.05). Pts with TERT promoter mutations tend to be MVI+ rather than MVI- and more HCC driver mutations were detected in MVI+ pts with TERT promoter mutations (p < 0.05). Based on MAP, we found MVI+ pts had significantly lower CD3+ TILs (p < 0.05). The multivariable analysis indicated that pts with copy number variations (CNV, hazard ratios [HR] 2.62, 95% confidence interval [CI] 1.07-6.40; p = 0.028), elevated PT/INR (HR 0.29, 95% CI 0.11-0.77; p = 0.008), and lower serum prealbumin concentration (PALB, HR 3.03, 95% CI 1.08-8.51; p = 0.027) had significantly shorter recurrence-free survival (RFS) after surgery. Similar findings were also observed for immune factors within cancer parenchyma, including CD68+ (HR 7.14, 95% CI 0.95-53.55; p = 0.025), CD163+ (HR 3.07, 95% CI 1.10-8.53; p = 0.023), CD68+/CD163- (HR 11.35, 95% CI 1.51-85.05; p = 0.003), CD68+/CD163+ (HR 3.51, 95% CI 1.4-8.79; p = 0.004), which indicated tumor-associated macrophage (TAM) infiltration was independent risk factor for RFS. Conclusions: In this study, we characterized the molecular and immune landscape of MVI in HCC patients. MVI presence highly correlated with adverse biological markers, mutations in the promoter of TERT, and higher CD3+ TILs. Some risk factors of HCC recurrence were identified, including CNV, PT/INR, CA 19-9, PALB, and TAM. Transcriptional alterations and immune tumor microenvironment change may contribute to MVI in HCC.