bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of clinical pathological features, surgical treatments and prognosis of Gallbladder Neuroendocrine Neoplasms between Chinese and American population: Based on a nationwide multicenter study and SEER database.
Authors: Sun Xuheng , Liu Yingbin , WANG Yijun 
Published: June 2022

e16119 Background: Gallbladder Neuroendocrine Neoplasm (GB-NEN) is an extremely rare type of gallbladder neoplasms and its characteristics and prognosis varies widely. The focus of this study was to analyze and compare the clinical pathological features, surgical treatments and prognosis of patients with GB-NEN between Chinese and American population. 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. Patients diagnosed with GB-NEN according to the 2019 WHO classification between 2010 and 2017 were assembled from CRGGC study and National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database. Chi-square test for categorical variables and the overall survival outcomes were analyzed by the Kaplan–Meier method in the two groups before and after a propensity score matching (PSM) with 1:1 ratio. Results: In this study, we assembled totally 84 patients from CRGGC study and there were 217 patients with GB-NEN diagnosed during the same period from National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database. After the PSM using sex, age, American Joint Committee on Cancer stage 7th Edition, liver invasion status and types of surgical treatment, 19 pairs of patients were included. Chinese patients from the CRGGC with GB-NENs presents more liver invasion (c²= 22.621, P = 0.000), higher diagnosed age (c²= 37.313, P = 0.000) and cancer stage (c²= 13.298, P = 0.021) totally than those from the SEER database. Radical surgical treatments were performed in 51(60.714%) and 96(44.240%) patients among patients from the CRGGC study and the SEER database respectively and the surgical treatment model shows a difference between these two groups (c²= 85.729, P = 0.000). Compared with propensity score matched American patients with GB-NENs from SEER database, Chinese patients from the CRGGC study had similar overall survival(c²= 0.480, P = 0.489) instead of longer overall survival than patients from the SEER database before PSM(c²= 6.408, P = 0.011). Conclusions: Chinese and American patients with GB-NEN form the CRGGC study and the SEER database present no difference in overall survival after PSM. However, heterogeneity of pathological features, surgical treatments between those groups of GB-NEN patients prompt that different methods could be referred for the improvement in the survival of GB-NEN patients.
Combining stereotactic radiotherapy with anti-PD-1 for advanced hepatocellular carcinoma patients with portal vein tumor thrombus.
Authors: Zhou Bin , Sun Xiangdong 
Published: June 2022

e16121 Background: Immunotherapy has attracted extensive attention in advanced hepatocellular carcinoma. For unselected patients, the efficacy of PD-1 monotherapy is less than 20%. The addition of radiotherapy to local lesions can significantly enhance the effectiveness of PD-1. However, the efficiency of SBRT combined with PD-1 in the treatment for portal vein tumor thrombus in patients with hepatocellular carcinoma remains unclear. Methods: This phase II study enrolled 17 patients with advanced liver cancer with portal vein tumor thrombus after 1-line or multi-line treatment in our single center, between June 2018 and June 2021. SBRT was delivered to the carcinoma thrombus with or without primary intrahepatic tumor，with a median total dose of 60Gy/10fx (range of 50Gỹ70Gy). Camrelizumab was administered within 2 weeks after SBRT, in cycles of every 3 weeks, until disease progression or patient intolerance. The primary endpoints were overall survival (OS), progression-free survival (PFS) and overall response rate (ORR). Results: At 3 months after SBRT, 6 patients had complete responses (35.3%) and 11 patients had partial responses (64.7%), with an ORR of 100%. The 1-year OS rate was 100%, and 1-year PFS was 84.8%. None of the patients had radiation response. Four patients (23.5%) were unable to tolerate immunotherapy, with one patient stopping after 12 cycles due to frequent preventricular phase contraction (in a double couplet rhythm) and 3 owing to upper gastrointestinal bleeding. Conclusions: SBRT combined with immunotherapy can improve local control and bring survival benefit, suggesting that SBRT could be considered in patients with portal vein tumor thrombus in hepatocellular carcinoma after 1-line or multi-line treatment. Moreover, the adverse reactions were mild. Clinical trial information: ChiCTR1900026188.
Preliminary data of a prospective study on the safety and efficacy of donafinib combined with anti-PD-1 antibody as adjuvant therapy for patients with hepatocellular carcinoma (HCC).
Authors: Bai Xueli , Chen Yiwen , Liang Tingbo 
Published: June 2022

e16131 Background: Surgical resection is one of the most effective treatments for HCC. However, the recurrence rate after hepatectomy is still very high with the 5-year recurrence rate of 60̃70%, which is even higher in patients with high-risk recurrence factors (the cumulative 1-year recurrence rate was about 50% without intervention). Here investigators intended to explore the safety and efficacy of donafenib combined with anti-PD-1 antibody as adjuvant therapy for HCC patients with high risks of recurrence. Methods: In this single-center study, eligible HCC patients with high-risk recurrence factors after radical surgery were recruited to receive donafenib combined with anti-PD-1 antibody for six months. The starting dose of donafenib was 100 mg PO BID in the first six patients and then reduced to 100 mg PO QD at the investigator’s discretion on tolerability in the adjuvant setting. For patients who started with donafenib 100 mg QD, the dose could be escalated to 100 mg BID from the second 21-day cycle if there were no experience grade ≥2 major adverse reactions (i.e. hand-foot syndrome, abnormal liver or kidney function, and blood cell decreased) reported in cycle 1. The primary endpoint was the cumulative 1-year recurrence-free survival rate. The secondary endpoints were recurrence-free survival (RFS), overall survival, quality of life (QoL) measured with FACT- Hepatobiliary questionnaire, and adverse events (AEs). Results: Between June 2020 and December 2021, thirteen patients with BCLC stage A-B HCC were enrolled. 11/13 (84.6%) patients had microvascular invasion (8 w/ M1 and 3 w/ M2). 11/13 (84.6%) patients had one tumor. 4/13 (30.8%) patients had tumor size ≥5 cm and 4/13 (30.8%) had satellite nodules. The median tumor size was 3.00 cm (IQR 2.60 to 6.00) and 3.29 cm (IQR 2.20 to 6.50) based on pathological findings and image, respectively. Eleven patients were included in efficacy analysis (two were excluded due to ineligibility). The median duration of follow-up was 8.30 months (IQR 2.90-14.40). Two patients experienced recurrence. The cumulative 1-year recurrence-free survival rate was 80% (90%CI, 49% to 93%). The median RFS was not reached. QoL showed a trend of improvement after 9 weeks of treatment. Among all the patients who received donafenib plus anti-PD-1 antibody, grade 3 treatment-related AEs (TRAEs) occurred in 7/13 (53.8%) patients (no grades 4 or 5 were reported). Common TRAEs included alanine aminotransferase increased (53.8%), aspartate aminotransferase increased (53.8%), blood bilirubin increased (38.5%), white blood cell decreased (38.5%), platelet count decreased (38.5%), rash (38.5%). No deaths were reported. Conclusions: The combination of donafinib and anti-PD-1 antibody as adjuvant therapy was well tolerated and demonstrated promising efficacy in HCC patients with high risks of recurrence. Clinical trial information: NCT04418401.
Surgical intervention of hepatocellular carcinoma with wedge versus segmental resection: A SEER database analysis.
Authors: Legenza Ashton , Tupper Connor , Burdyny Michael , Silberstein Peter T. 
Published: June 2022

e16136 Background: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy, constituting 75-85% of liver cancer cases globally. In recent years there have been developments in both the clinical treatment methods and surgical approaches to HCC treatment, however, the prognosis for patients with HCC remains dismal. Two of the major surgical treatment options for HCC are wedge resections and segmental resection with the latter having up to three segments of the liver being removed. This study assessed the prognostic impact between these two surgical treatment options in the management of HCC liver cancer. Methods: We searched the SEER-18 database for HCC cases (histology codes 8170-8175) diagnosed between 2000-2018. Patients were excluded if their cause of death was not associated with their HCC diagnosis according to SEER’s cancer-specific death categorization. The SEER database tracks survival up to 60 months. Using SPSS, we performed analyses on the association between surgical subtype and survival, which is tracked up to 60 months in the SEER database. Results: A total of 3919 patients were collected from this search. Of that patient collection, 643 patients received a wedge resection and a total of 2609 patients received a segmental resection. There were 366 patients that received a segmental resection with local tumor destruction. 667 patient resections were not differentiated between segmental or wedge resections. The segmental resection of an unspecified number, the one segment resection, and the two segments resection groups all had better mean survival compared to the wedge resection group and segmental resection with local tumor destruction group (all p < 0.05). The three segments resection compared to wedge resection had no difference in survivability (p > 0.05). The three-segment resection had worse survivability when compared to both one and two-segment resections (p < 0.01). The one-segment resection had no difference in survivability when compared to the two-segment resection procedure (p > 0.05). Conclusions: Though limitations of small sample size and univariate statistical analyses were present in this study, one or two segment resection is associated with improved survival compared to wedge resection, the three segment resection and the segmental with local tumor destruction approach used in the treatment of HCC.[Table: see text]
External beam and stereotactic radiation in the treatment of fibrolamellar carcinoma.
Authors: Szeszko Filip , Kim Thomas , Stockwell Tom , Patel Anushka Harish , Kent Paul 
Published: June 2022

e16137 Background: Fibrolamellar Carcinoma (FLC) is an extremely rare (< 50 cases/year US), distinct type of primary liver cancer, unrelated to hepatocellular carcinoma (HCC), affecting healthy children and young adults that often presents at an advanced stage. Surgery is the only known cure, but is only possible in half of patients, and, even with surgery, there is an 80% relapse rate. Loco-regional therapies can make surgery possible or replace surgery, allow systemic therapy time to work, and prolong life. However because of the paucity of data and the common misunderstanding of treating FLC as a “variant of hepatocellular carcinoma (HCC)” it is often assumed to be radio-resistant. For example, the 2021 NCCN Guidelines give no specific recommendations for radiation in FLC but classifying FLC as a “variant of HCC'' recommend 25 1.8Gy fractions (45Gy) with a boost to 50-60 Gy for external beam radiation(EBRT) and 3-5 10Gy fractions for stereotactic body radiation (SBRT). In their HCC reviews, the New England Journal of Medicine (2020), ASCO (2019), and the Fibrolamellar Cancer Summit (2017) do not discuss radiation. This is the largest collection of FLC patients treated with radiation in the literature to date and will hopefully inform clinicians of the option to use radiotherapy in this difficult to treat cancer. Methods: We reviewed the literature for cases of FLC treated with radiation after 2000. With IRB approval, (ORA#19071603), we collected data on all Rush FLC patients treated with radiation. Descriptive statistics were used to characterize this group of patients. Results: We found 29 instances of EBRT or SBRT treating FLC: 3 case reports, 21 of our patients (two had multiple (2 and 4) distinct treatments). Of these 24 (13F/10M/1 Unknown), median age at diagnosis/start of treatment 17(11-40)/23(13-45) underwent radiation with a median dose of 36 Gy (20-50). Ten of 27 were considered “palliative” treatments. High fraction therapy (> 10 fractions) was used 9 times while low fraction therapy (≤ 10 fractions) 16. Biological Equivalent Dose median was 0.36108(0.2008-0.505). Six patients were treated concurrently with nivolumab. Mean prior systemic therapies was 2.6 (0-10) and 5 patients received prior radiation. Fourteen patients underwent SBRT, 10 conventional, 2 IMRT, and 2 unknown. Best response by RECIST 1.1 of the 27 instances with outcome data, was 21 CR, 2 PR, 2 PD, and 2 SD, for a objective response rate (CR + PR) of 85% and a cancer control rate (CR + PR + SD) of 93% at a median follow up of 13 months. In 18 out of 29 instances (62%), surgery was avoided after radiation. Late recurrence was noted in 2 out of 26 instances (8%). Conclusions: FLC is a rare disease lacking radiation guidelines. Our data strongly suggest radiotherapy can be effective with a variety of doses and strategies. We hope our report will encourage clinicians to consider EMRT/SBRT as part of a multi-modal approach to this difficult to treat cancer.
The immunosuppressive landscape of the NOTCH gene family in hepatocellular carcinoma (HCC).
Authors: Abushukair Hassan Mohammed , Al-Kraimeen Leen Mohammad , Saeed Anwaar 
Published: June 2022

e16139 Background: Despite the recent addition of atezolizumab to advanced HCC first-line treatment, response biomarkers are not well studied. The involvement of the NOTCH gene family in HCC tumorigenesis has been previously discussed, yet insights on its effect on the immune microenvironment are still lacking. Methods: We systematically analyzed differentially expressed genes (DEGs) in the KEGG NOTCH pathway across HCC transcriptomics datasets from the HCCDB platform. Immune and prognostic analyses were done using The Cancer Genomic Atlas (TCGA) HCC cohort (n = 372). The TIMER 2.0 tool was used to assess immune infiltration. cBioportal was used for tumor mutational burden (TMB) and microsatellite instability (MSI) correlations. The TIDE tool assessed T cell dysfunction and DEGs efficacy predictive value using the only trial administering atezolizumab (IMvigor210, n = 348). Results: Four DEGs were identified: NCSTN, APH1A, NOTCH3, HDAC2. All four genes were significantly directly associated (spearman’s ρ > 0.1, P < 0.05) with immunosuppressive cells: Tregs, macrophage M2 cells, cancer-associated fibroblasts (CAF), and myeloid-derived suppressor cells (MDSC). HDAC2 was associated with higher T cell dysfunction (z score = 2.07, P = 0.04). High NOTCH3 and low HDAC2 expression served as favorable overall survival (OS) prognostic markers (HR: 0.66, 95% CI: 0.48 - 0.90, P = 0.008 & HR: 1.52, 95% CI: 1.12–2.07, P = 0.006, respectively). Stratification based on the expression of these two genes and strongly associated immunosuppressive cells’ infiltration levels (ρ > 0.5), revealed two unique patients’ subsets with worse OS marked by “low NOTCH3 expression with high CAF levels” and “high HDAC2 expression with high MDSC levels”. Regarding immune checkpoint genes expression, NOTCH3 and HDAC2 expression levels were directly correlated with CTLA-4, PD-1, and TIM-3, whereas NCSTN and APH1A were inversely related with PD-L1, LAG-3, and TIM-3 after correction for multiple hypothesis testing (ρ > 0.2, Q value < 0.05). TMB count was inversely associated with NOTCH3 expression (ρ = - 0.2, P < 0.001), as for the MSI sensor score, NOTCH3 (ρ = -0.29) and APH1A (ρ = 0.29) expression had inverse and direct significant associations, respectively (P < 0.0001). Exploratory subgroup analysis from the IMvigor210 trial on metastatic urothelial carcinoma patients on atezolizumab showed a significant difference in OS favoring low NOTCH3 expression (P = 0.003) and high APH1A expression (P = 0.049). Conclusions: DEGs from the NOTCH family seem to impose an immunosuppressive effect on HCC’s microenvironment. High NOTCH3 and low HDAC2 expression were identified as potential favorable prognostic markers. Interestingly, high NOTCH3 expression translated into worse OS in patients on anti-PD-L1 which could be owed to the inverse relation with TMB and MSI described in our study, thus deserving further translational investigations.
Hepatic arterial infusion chemotherapy versus trans-arterial chemoembolization in unresectable hepatocellular carcinoma: A systematic review and meta-analysis.
Authors: Beran Azizullah , Abuhelwa Ziad , Abdulsattar Waleed , Alloghbi Abdurahman , Alqahtani Ali , Hamouda Danae M. 
Published: June 2022

e16141 Background: Trans-arterial chemoembolization (TACE) has been one of the standard options for patients with unresectable hepatocellular carcinoma (HCC). Recent studies have shown that liver arterial infusion chemotherapy (HAIC) has favorable outcomes in these patients, but its use has been limited due to the need for technical expertise. In this systematic review and meta-analysis, we compared the efficacy and safety of HAIC vs. TACE for unresectable HCC. Methods: We performed a comprehensive literature search of PubMed, Embase, and Cochrane databases through January 12, 2022, for all peer-reviewed studies that compared the outcomes of HAIC vs. TACE in patients with large, unresectable HCC. Our primary outcomes were the objective response rate (ORR), disease control rate (DCR), and progressive disease (PD). The secondary outcomes were overall survival (OS), progression-free survival (PFS), and grade ≥3 adverse events (AEs). Pooled risk ratio (RR) and hazard ratio (HR) with the corresponding 95% confidence intervals (CIs) were obtained by the Mantel-Haenszel method within a random-effect model. Heterogeneity was assessed using the Higgins I2 index. Results: Six studies (one randomized controlled trial [RCT], two non-randomized trials, and three retrospective cohort studies) were eligible for final analysis. A total of 899 patients were included for the final evaluation. HAIC was associated with significantly higher ORR (RR 2.70, 95% CI 2.06-3.55, P < 0.001, I2= 10.1%) and DCR (RR 1.42, 95% CI 1.19-1.70, P < 0.001, I2= 54.5%) and substantially reduced PD (RR 0.55, 95% CI 0.40-0.75, P < 0.001, I2= 56.6%) compared to TACE. The median OS was significantly longer in the HAIC group, ranging from 11.4 to 23.1 months vs. TACE, ranging from 4 to 16.1 months (HR 0.49, 95% CI 0.28-0.85, P = 0.01 I2= 84.7%). The median PFS was significantly longer in the HAIC group, ranging from 5.5 to 9.6 months, vs. TACE, ranging from 1.5 to 5.4 months (HR 0.45, 95% CI 0.26-0.79, P = 0.001, I2= 84.6%). Notably, the incidence of grade≥3 AEs was lower in the HAIC group than in TACE (RR 0.61, 95% CI 0.47-0.80, P < 0.001, I2= 16.4%). Conclusions: Compared to TACE, HAIC significantly improved ORR, DCR, and OS in unresectable HCC with a significantly better safety profile. However, our meta-analysis is hampered by the limited number of studies. Future large-scale multicenter RCTs are warranted to further evaluate the outcomes of HAIC vs. TACE in the management of unresectable HCC.
Efficacy and safety of anlotinib as first-line treatment and followed by tyrosine kinase inhibitors (TKIs) combined with PD-1 blockades regimen after disease progression for advanced hepatocellular carcinoma (HCC): A real-world exploratory study.
Authors: Li Qing-Qing , Ma Sheng-Li , Zhang Lu , Zhang Xian-Qiang , Gao Xiao-Juan , Pan Yan-Feng 
Published: June 2022

e16146 Background: The prognosis of traditional treatments for patients with HCC was dismal. Small-molecule anti-angiogenic targeted drugs and PD-1 blockades have been shown superior efficacy in advanced HCC. As a novel oral multitarget TKI, anlotinib monotherapy or combined with PD-1 blockades has preliminary efficacy in the treatment of HCC. Consequently, this study was to explore the efficacy and safety of anlotinib as first-line treatment and followed by TKIs combined with PD-1 blockades regimen after disease progression for advanced HCC in real-world. Methods: Patients with advanced HCC with BCLC stage B or C were recruited in this study. Eligible patients received anlotinib (8/10/12mg, po, d1̃14, q3w. Dosage is determined by the clinician) as first-line treatment until disease progression or intolerable toxicity. For those with progressive disease, treatment was administrated with TKIs (anlotinib, apatinib, lenvatinib, or regorafenib) and PD-1 blockades (camrelizumab or sintilimab) until disease progression again or intolerable toxicity. The primary endpoint was PFS (RECIST v 1.1) in the first-line treatment. Secondary endpoints were ORR, DCR, OS and safety. Results: From Feb 2019 to Nov 2021, a total of 62 eligible patients were enrolled. The patients were 55 (38̃78) years of age, including ECOG PS 0 (82.3%) or 1 (17.7%), BCLC stage B (32.3%) or C (67.7%). In the first line treatment, there were 12 CR (19.4%), 17 PR (27.4%), 25 SD (40.3%) and 8 PD (12.9%). Consequently, ORR was 46.8% (95%CI: 34.0%̃59.9%) and DCR was 87.1% (95%CI: 76.1%̃94.3%). At the cut-off date, 41 patients experienced disease progression, the preliminary median PFS was 7.37 months (95%CI: 5.88-8.86), and the median OS was not yet reached. Of the 41 patients with disease progression, 11 patients received TKIs plus PD-1 blockades regimen. There were 3 CR (27.3%), 1 PR (9.1%), 3 SD (27.3%) and 4 PD (36.4%). Therefore, ORR was 36.4% (95%CI: 10.9%̃69.2%) and DCR was 63.6% (95%CI: 30.8%̃89.1%). The safety profile suggested that the most common treatment-emergent adverse events were thrombocytopenia (51.6%), leukopenia (50%), hypertension (46.8%), neutropenia (46.8%), fatigue (43.5%) and hand-foot syndrome (41.9%). The common grade ≥3 treatment-emergent adverse events were hypertension (12.9%), elevated bilirubin (9.7%) and neutropenia (7.9%). Unfortunately, one patient died from gastrointestinal bleeding. Conclusions: The present study indicated that anlotinib as first-line treatment and followed by TKIs combined with PD-1 blockades regimen after disease progression for advanced HCC exhibited potential efficacy and tolerable safety profile in real-world setting. The conclusion should be validated in more pts included subsequently.