bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence of MET aberration using next generation sequencing in oncology clinic: A real-world experience.
Authors: Ko Jihoon , Jung Jaeyun , Kim Kyoung-Mee , Kim Seung Tae , Kang WonKi , Lee Jeeyun
Published: June 2022

e16099

Background: MET has been known as an important therapeutic target in various solid cancer types. With the establishment of next-generation sequencing (NGS) in the oncology clinics, understanding the incidence of MET aberration in patients with metastatic cancer is critical for oncology drug development and efficacy. We investigated MET gene aberration in 2,239 oncology patients who underwent NGS in clinical practice with real-world data. Methods: From Nov. 2019 to Jan. 2021, 2,239 metastatic solid tumor patients who visited oncology clinic were enrolled in the NGS analysis. The NGS panel (TruSight Oncology 500 Assay, Illumina) was over 500 comprehensive sequencing using archival tissue specimen. In addition, PD-L1 22C3 assay results were available in 1,137 patients (50.8%) and 1,761(78.7%) patients had clinical record about 1st chemotherapy for overall survival analysis. Results: 2,239 patients with metastatic solid tumor (37 cancer types) received NGS as part of the clinical practice with an aim to be guided to targeted agents or immunotherapy. The most common cancer types were CRC (N = 702, 31.4%), followed by GC (N = 481, 21.5%), and sarcoma (N = 180, 8.0%). Of 2,239 patients, any MET aberrations (CNVs, fusions, and SNV) were detected in 212 patients. Of the 46 patients with MET amplification, 14 (30.4%) were GC followed by CRC (N = 10, 21.7%), melanoma (N = 7, 15.2%), CCC (N = 6, 13.0%), sarcoma (N = 2, 4.3%), HCC (N = 2, 4.3%), NSCLC (N = 2, 4.3%), pancreatic cancer (N = 2, 4.3%), and gallbladder cancer (N = 1, 2.2%). All MET-amplified tumors had microsatellite stable (MSS) status and 17.4 % patients (N = 8) were TMB-high status. And, 8 of MET-amplified patients concurrently showed MET-positive protein expression by IHC (2+ and 3+). Of note, MET fusion was detected in 0.4% (10 of 2,239) of the patients. The partner gene included ST7, TFEC, LRRD1, CFTR, CAV1, PCM1, HLA-DRB1 and CAPZA2. In survival analysis, patients having MET amplification or fusion had shorter OS and PFS than the others, suggesting MET aberration was an important key factor that could determine final response results to current chemotherapy. Conclusions: Based on our comprehensive NGS survey focused on MET aberration, we identified approximately 2.1% MET amplification and 0.4% MET fusion in patients with metastatic solid tumors. They showed worse response after chemotherapy and shorter OS and PFS.
Multi-omics analysis of locally advanced esophageal cell squamous carcinoma treated with radio-chemotherapy.
Authors: Li Hongwei , Li Jing , Zhang Xiaqin , Liang Hua , Ji Liyan , Gao Xuan , Xia Xuefeng
Published: June 2022

e16106

Background: The incidence rate of esophageal cell squamous carcinoma (ESCC) increases every year worldwide. Although the molecular characteristics of locally advanced esophageal carcinoma have been extensively studied, TCR evolution dynamics before and after treatment in patients with ESCC undergoing radical radiotherapy and chemotherapy are unknown. Methods: In this study, we performed whole-exome sequencing (WES) and RNA sequencing (RNA-seq) on tumor tissues from 11 ESCC patients who received radiotherapy and chemotherapy. T cell receptor (TCR) sequencing was performed in 33 ESCC blood samples, which included three time points: pre-treatment, on-treatment and post-treatment. We compared TCR clonality and Shannon index among the pre-treatment, on-treatment and post-treatment ESCC patients using paired samples Wilcoxon test. The t test was uesd for statistical analysis comparing the clonality and clonal frequency between patients with mutant and wild-type gene. Results: The median TMB is 3.32 mutations/Mb (range 1-6 muts/Mb). We identified nine significantly mutant genes including TP53 (100%), MUC17 (55%), FLG (45%), FLG2 (36%), FOXN1 (27%), HIST1H1E (18%), VN1R1 (18%), RIPK3 (9%), and ZNF628 (9%). Clonality was significantly increased from pre-treatment to post-treatment (p = 0.008) and from on-treatment to post-treatment (p = 0.04). Two patients exhibited an continuous increase of TCR CDR3 (CHCLPAED_AGGGELFF) frequency in post-treatment compared to on-treatment patients. Three patients had elevated level of CDR3 amino acid sequence (CASSLDSNQPQHF) after treatment. To explore the effect of the mutant gene on the TCR clonal pattern, we found that the baseline clonality and clonal frequency in mutant FAT1 (MUT) were significantly lower than that in wild-type (WT) patients (p = 0.044 and p = 0.013, respectively), while they were not significant after treatment between FAT1-MUT and WT patients. Intriguily, in FAT1-MUT patients, the clonality and clonal frequency underwent therapy were higher than that at baseline. The results suggested that the FAT1-MUT patients might be sensitive to treatment and FAT1 might contribute to immune response upon radio-chemotherpay. During radio-chemotherapy, the clonality and clonal frequency in INTS1-MUT and LCT-MUT patients had the similar phenomenon to the FAT1-MUT patients. Interestingly, a higher clonal frequency was observed after radiotherapy and chemotherapy than that of pre-treatment (p = 0.0086) in patients with mutant KMT2D (an epigenetic modifier coding lysine methyl transferase 2D). Conclusions: TCRs is clonal expansion after radiotherapy and chemotherapy in ESCC, suggesting an immune-activated microenvironment after radio-chemotherapy. Our multi-omics analysis provided the basic TCRs dynamics and its genomic and epigenomic association during the radio-chemotherapy of esophageal cell squamous carcinoma.
Non-hepatocellular carcinoma management: A SEER database analysis.
Authors: Legenza Ashton , Tupper Connor , Burdyny Michael , Silberstein Peter T.
Published: June 2022

e16108

Background: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy, however, chronic viral hepatitis and cirrhosis place patients at an increased risk for non-HCC malignancies as well. A major treatment option for these tumors is local tumor destruction via a number of minimally invasive techniques available to interventional radiologists. This study assessed the prognostic impact of various liver-directed local tumor therapies in the management of non-HCC liver cancer. Methods: We searched the SEER-18 database for malignant liver cancers not coded as HCC (8170-8175) that were diagnosed between 2000-2018. Patients were excluded if the cause of death was not associated with their cancer according to SEER’s cancer-specific death categorization. The SEER database tracks survival up to 60 months. SPSS was used for all descriptive and univariate survival statistics. Results: A total of 228 patients were collected from this search. 59.6% of cases were from males and the average age was 64 years old (median = 65). 60.1% were in non-Hispanic White patients, followed by Hispanic (16.2%), non-Hispanic Asian or Pacific Islander (14.0%), and non-Hispanic Black (9.2%) patients. Of the 170 patients with staging coded, 62.9% were local, 24.7% were regional, and 12.4% were distant. 36.8% of patients received some form of chemotherapy, while only 3.1% received radiation. When grouped by age range (< 49, 50-69, 70+), survival did not differ between groups. Sex also did not influence survival (p = .325). Patients that received chemotherapy had worse outcomes, likely due to worse staging which was negatively associated with survival (p < .05). Radiation did not significantly improve survival. Of the local tumor destruction therapies, Heat-Radio-Frequency ablation (RFA) (n = 150) improved survival significantly in comparison to: local tumor destruction not otherwise specified (n = 42), photodynamic therapy (n = 1), electrocautery (n = 4), cryosurgery (n = 4), and ultrasound or acetic acid (n = 15) (all p < 0.05). Laser surgery (n = 3) and intratumoral injection of alcohol (n = 9) had no significant outcome differences. RFA had an estimated mean survival time of 35.7 months while all other interventional radiology modalities combined had a mean estimated survival time of 21.4 months (p < .000). Conclusions: Though limitations of a small sample size and univariate statistical analyses were present in this study, RFA likely has improved survival compared to other interventional radiology modalities used in the treatment of non-HCC liver cancer.
Factors affecting outcomes in gallbladder cancer: A single institution retrospective analysis.
Authors: Hatic Haris , Li Peng , Paluri Ravi Kumar
Published: June 2022

e16109

Background: Gallbladder cancer is one of the highest fatal malignancy. We conducted a retrospective analysis to study the outcomes of gallbladder malignancy in an academic care setting. Methods: Data was collected retrospectively on patients treated at University of Alabama at Birmingham between January 2005 and June 2015 from the electronic medical record using a standardized data collection tool (Redcap). We evaluated for predictors of overall survival (OS) and progression-free survival (PFS). Results: Of the 93 patients in this study, 66% were female. Adjuvant chemotherapy (CT) was given to 11% and adjuvant chemoradiation (CRT) to 14%. On multivariate analysis, albumin > 3.5, uninvolved margins, absence of lymphovascular/peri-neural invasion were independent predictors of OS and PFS (Table). The overall median survival was 24.3 months with a 5-year median OS at 23.7%. Surgery with CRT for the full cohort had a median OS of 54.4 vs 15.6 (p = 0.0048) months compared to surgery CT alone. The OS in stage 3-4 patients with surgery alone vs surgery & CT was 5.5 versus 28.7 months respectively (p = 0.0052). The PFS for the same group was 17.5 vs 4.6 months (p = 0.0052). Conclusions: The dismal survival rates of gallbladder cancer made. adjuvant therapy (CT or CRT) critically important. Concurrent chemoradiation needs to be evaluated in randomized clinical trials for potential improvement in clinical outcomes compared to currently approved standard of care, adjuvant CT alone. [Table: see text]
A retrospective study on the efficacy and safety of regorafenib or regorafenib combined with immune-checkpoint-inhibitors (ICIs) after first-line therapy in patients with advanced hepatocellular carcinoma.
Authors: Yan Tao , Peng Caiyun , Yu Lingxiang , Duan Xuezhang , Ji Dong , Zhang Linzhi , Cheng Jiamin , Wu Tong , Su Guodong , Jing Yi , Li Yinyin , Lu Yinying
Published: June 2022

e16115

Background: The efficacy of first-line ICIs combination therapy patients with advanced hepatocellular carcinoma (HCC) was better than that of TKIs alone. This study was conducted to explore whether regorafenib combined with ICIs has better efficacy in second-line therapy. Methods: This retrospective study included 101 patients who have received regorafenib after the failure of at least one molecular-targeted therapy evaluated between March 2017 to November 2021. The patients were divided into two groups based on receiving regorafenib (cohort A) or regorafenib combined with ICIs(cohort B). The primary endpoint was Progression-Free Survival (PFS), and the secondary endpoints included the Objective Response Rate (ORR), Disease Control Rate (DCR), Overall Survival (OS), and safety. Results: 29 patients were in the cohort A and 72 were in the cohort B. There were no significant differences in age, gender, weight, ECOG performance status, Child-Pugh, BCLC staging, and the proportion of previous therapy regimens between the two cohorts. Among them, the first-line therapy mainly includes sorafenib, lenvatinib with or without ICIs. The median PFS (4.0 months), 6 months PFS rate (25.66%) and DCR(65.52%) of cohort A were poor than that of cohort B (8.7 months, 83.33%, 74.13%), (P＜0.05). OS data was not yet available. First-line therapy, use of TKI with ICIs (n = 31) or TKI without ICIs(n = 27) (PFS 8.70m VS 8.37m，P = 0.84), use of sorafenib with or without ICIs (n = 22), or lenvatinib with or without ICIs (n = 33)(PFS 8.87m VS 7.60m，P = 0.77), didn’t affect the PFS and ORR of the later line therapeutic regimens. In the cohort B, the ORR of the second-line (29.31%) was better than that of the third-line (0), (P = 0.03). Adverse events (AEs) of all grades were statistically different between the two groups (P = 0.03), but there was no significant difference in the incidence of grade 3-4 AE. Conclusions: In the later-line therapy, regorafenib combined with ICIs therapy showed better curative effect, especially in the second-line. Regorafenib combined with ICIs is recommended as early as second-line therapy to benefit patients. Different regimens of first-line therapy have no effect on PFS in second-line therapy.[Table: see text]
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.
Application of circulating tumor DNA for prediction and surveillance of tumor recurrence after liver transplantation: A pilot study.
Authors: Huang Ao , Guo De-Zhen , Zhang Xuan , Sun Ying , Zhang Xin , Fu XiuTao , Wang Yupeng , Yang Guo-Huan , Sun Qiman , He Yifeng , Song Kang , Huang Xiao-Wu , Liu Wei-Ren , Ding Zhen-Bing , Shi Ying-Hong , Fan Jia , Zhou Jian
Published: June 2022

e16149

Background: Emerging data suggest that circulating tumor DNA (ctDNA) could detect minimal residual disease (MRD) and reflect tumor recurrence after radical resection in hepatocellular carcinoma (HCC). However, most reported ctDNA measurements are based on hotspot mutations and their predictive value in liver transplantation (LT) are still undetermined. We conducted a pilot study investigate ctDNA fingerprint as the detection marker of MRD in HCC patients undergoing LT. Methods: We enrolled 74 patients in HCC and monitored their ctDNA changes along the course of treatment at both pre- and post-operation by serial sampling of peripheral blood. All of the patents were treated by LT, and their ctDNA variations were used to assess the recurrence. We analyzed the correlation between ctDNA levels and recurrence-free survival (RFS) of the patients. Results: We monitored the ctDNA value of each patient before and after LT and found that the ctDNA-positive group was associated with higher recurrence rate (31.7% vs 11.5%), and has a shorter RFS than that of the ctDNA-negative group at baseline (preopreation) (HR, 3.25; CI 95% 1.18-8.97; p = 0.019). The conclusion also stands in patients at first timepoint follow-up after LT (postoperation) (recurrence rate, 46.2% vs 21.3%; HR, 4.26; CI 95% 1.62-11.2; p = 0.010). Moreover, changes of ctDNA were associated with RFS during the course after LT, both the ctDNA-decreased group and ctDNA-negative group have favorable clinical benefit than ctDNA-increased group. Conclusions: This study confirming the association between baseline levels of ctDNA and RFS in HCC undergoing LT. More importantly, it suggests the change of ctDNA level in plasma is a promising biomarker of MRD detection and patient prognosis in early HCC.
Lenvatinib plus PD-1 inhibitors in 378 unresectable hepatocellular carcinoma: A large real-world study from two centers.
Authors: Yang Xu , Chen Bowen , Wang Yanyu , Wang Yunchao , Long Junyu , Zhang Nan , Xue Jinnan , Xun Ziyu , Zhang Linzhi , Cheng Jiamin , Lei Jin , Pan Jie , Hu Ke , Guan Mei , Huo Li , Mao Yilei , Sang Xinting , Lu Yinying , Zhao Hai-Tao
Published: June 2022

e16155

Background: Combining lenvatinib (a multikinase inhibitor) with programmed cell death protein-1 (PD-1) inhibitor has been explored in Unresectable hepatocellular carcinoma (uHCC) in phase 1b trials. This study aimed to investigate the real-word efficacy and safety of lenvatinib plus PD-1 inhibitor for large Chinese patients uHCC cohorts. Methods: BCLC stage B or C uHCC patients were included. Data was collected from Oct 2017 to Nov 2021 retrospectively. Patients were treated with lenvatinib and PD-1 inhibitor (pembrolizumab or nivolumab or camrelizumab or sintilimab or toripalimab or tislelizumab). The primary endpoint was overall survival (OS) and secondary endpoints were progression-free survival (PFS) and objective response rate (ORR) evaluated by RECIST v1.1 criteria. Adverse events (AEs) were assessed using CTCAE v5.0. Prognostic factors of survival were also analyzed. Results: 378 uHCC patients of BCLC stage B (12.7%) and C (87.3%) from two medical centers were included in China. The median age was 55 (range 18-89) years and 86.5% patients were male. ECOG scores were 0 (43.7%), 1 (43.4%) and 2 (13.0%), while Child-pugh grade were A (77.5%) and B (22.5%) respectively. The median OS was 17.8 (95% CI 14.0-21.6) months. The median PFS was 6.9 (95% CI 6.0-7.9) months. The best objective response rate (ORR) and disease control rate (DCR) was 74/378 (19.6%) and 278/378 (73.5%) respectively. Child-pugh grade (A vs. B), ECOG score (0 vs. 1-2), BCLC stage (B vs. C) and achieve response (yes vs. no) were the prognostic factors for both OS and PFS. All (100%) experienced all-grade adverse events (AE). The most frequent AEs were fatigue, diarrhea, hypertension, decreased appetite. The most common ≥Grade 3 AEs were hypertension (13.2%), fatigue (7.1%), decreased platelet count (6.3%), increased blood bilirubin (6.1%), diarrhea (6.1%) and gastrointestinal hemorrhage (4.8%). Conclusions: This real-world study of lenvatinib plus PD-1 inhibitors achieved long survival and considerable ORR for uHCC patients in China. The tolerability of combination therapy was acceptable but should be still monitored closely. Clinical trial information: NCT03892577. [Table: see text]
Genetic profile and survival outcomes in a modern cohort of patients with biliary tract cancers (BTC): Single center experience in New York City.
Authors: Kaur Anahat , Bteich Fernand , Brodin Patrik , Kabarriti Rafi , Goel Sanjay , Kaubisch Andreas
Published: June 2022

e16157

Background: BTCs are the second most common primary hepatobiliary malignancy with rising incidence and mortality worldwide. Individual characterization of BTCs at a genomic level is critical to tailor management strategies. Currently available data stem from studies in predominantly White populations. We conducted a retrospective study to determine the demographic, clinical and survival profiles of patients with BTCs seen in our center, who had been tested for genomic alterations. Methods: We identified 69 patients with BTCs diagnosed between 2015-2022 who had tissue-based genomic results available. Chi-square test was used to compare frequency distributions. Univariate analysis with cox regression model and multivariate cox proportional hazards test were conducted. Kaplan-Meier curves were used to assess overall survival (OS). Results: Median age at diagnosis was 67 years and median follow-up time was 15.5 months. Racial and ethnic minority populations were highly represented with 41% Hispanic, 29% Black and 17% White patients. ECOG performance status (PS) ranged between 0-2 at diagnosis. Most patients (40%) had stage IV BTC, with intrahepatic cholangiocarcinoma (CCA) being most prevalent (48%). On univariate modeling, variables associated with a shorter OS were age (HR 1.03, 95% CI 1.00-1.07, p = 0.05) and ECOG PS of 2 (HR 7.03, 95% CI 1.49-33.3, p = 0.014). In a multivariate model, ECOG PS 2 was independently associated with a shorter OS. The most common mutations (N, %) found on NGS were TP53 (28, 41%), KRAS (13, 19%), ARID1A (11, 16%), PIK3CA (9, 13%), ERBB2 (5, 7%) and FGFR2 (5, 7%). Median tumor mutation burden (TMB) was 4 Mut/Mb, with 18.9% having hypermutated (≥10 Mut/Mb) BTCs. Potentially actionable targets were found in 40 (58%) patients, 5.8% of which received targeted therapies with a median OS of 27 months (median OS of entire cohort was 22.8 months). KRAS mutation was significantly less common in intrahepatic CCA compared to the other BTC subtypes (p = 0.016). Race or ethnicity were not found to have a significant association with mutation frequency (Table). TP53 and ARID1A mutations were associated with a trend towards reduced OS in univariable analysis, with HR = 1.46 (p = 0.29) and HR = 1.64 (p = 0.28) respectively. Conclusions: Extensive genomic diversity was observed among BTC patients in our center which serves a large minority population. Studies with larger sample size are required to expand our understanding of the genomic spectrum in BTCs, its therapeutic and survival implications. [Table: see text]
Biomarker analysis of first-line camrelizumab plus apatinib in patients with advanced biliary tract cancers: Results from a phase II study.
Authors: Rao Jian-hua , Chen Dong-sheng , Song Yunjie
Published: June 2022

e16164

Background: The prognosis of immunotherapy for patients with unresectable or metastatic biliary tract cancers (BTCs) was not very optimistic, exploring the potential biomarkers associated with tumor response in advanced BTCs may further improve the clinical benefits from immunotherapy. Methods: Fourteen advanced BTCs patients from the single-arm phase II study (ChiCTR2000034283) receiving camrelizumab (anti-PD-1 antibody) plus apatinib (VEGFR2 inhibitor) as first-line combination therapy, were included for the current biomarkers analysis. Exploratory points mainly focused on differentiated immune-related gene expression and immune pathway signatures using a 289-gene immune-related RNA panel sequencing on baseline tumor samples. Differential gene expression analysis was performed between responders (tumor regression) and non-responders (tumor extension) using Wilcoxon rank-sum test. Signature scores were calculated using the Gene Set Variation Analysis package with publicly available gene signatures. Results: Of all enrolled patients with clinical response evaluations, twelve patients had available RNA-sequencing data (6 responders vs. 6 non-responders) on baseline tumor samples. Differential gene expression analysis revealed a significantly higher BRCA2, RAD51, BRIP1 expression (p < 0.001) and decreased TGF β 1, IT GAX, ITGB2 expression (p < 0.001) in responder tumors compared with non-responder tumors. Differentiated genes were significantly enriched in receptor metabolic process pathway in responder tumors. Extensive analyses on immune cell types score were also calculated, CD8 positive T cells (p = 0.022) were significantly increased in baseline responder tumors, and Macrophages M2 cells (p = 0.008) were significantly increased in baseline non-responder tumors. Conclusions: Some differentially expressed genes and immune-related cell types were founded in defined groups, both immune- and tumor-intrinsic factors may be considered for validation in a larger study. Clinical trial information: ChiCTR2000034283.
Sintilimab plus bevacizumab as maintenance therapy for patients with unresectable hepatocellular carcinoma treated with transarterial chemoembolization: A phase Ib study.
Authors: Cai Mingyue , Liang Wei , Huang Wensou , Guo Yongjian , Liang Licong , Zhou Jingwen , Lin Liteng , Deng Haihui , Zhu Kangshun
Published: June 2022

e16165

Background: Sintilimab (a PD-1 inhibitor) plus bevacizumab (Sin-Bev) has been demonstrated to confer a significant survival benefit over sorafenib in patients with unresectable hepatocellular carcinoma (uHCC). This phase Ib study (NCT04592029) aimed to evaluate the safety and efficacy of Sin-Bev for patients with uHCC who received transarterial chemoembolization (TACE). Methods: The key eligibility criteria were: age ≥ 18 years; BCLC B/C stage uHCC; no prior systemic therapy and non-curative local treatments; Child-Pugh score ≤7; ECOG PS ≤1. This study included dose escalation and dose expansion stages. In the dose escalation stage, a 3+3 design was employed to determine the safety of a standard dose of sintilimab (200 mg Q3W) plus two possible doses of bevacizumab (group A: 7.5 mg/kg Q3W; group B: 15.0 mg/kg Q3W) after TACE. In the dose expansion stage, additional 30 patients were randomized 1:1 to each group. Sintilimab and bevacizumab was started at 3-7 days after the first TACE (TACE was repeated on demand). The primary endpoints were the incidence of adverse events (AEs) and progression free survival (PFS). The secondary endpoints included objective response rate (ORR), disease control rate (DCR) and overall survival (OS). Results: At the time of data cutoff (January 20th, 2022), 36 patients were enrolled (18 in each group). One patient in group A withdrew from the study after the first cycle of treatment. Of the remaining 35 patients, 20 (57.1%) had disease at BCLC C stage, 15 (42.9%) had macroscopic vascular invasion and 11 (31.4%) had extrahepatic metastasis. The mean largest tumor size was 10.5±5.2 cm. The median follow-up was 9.57 (range, 4.4-15.6) months. Thirty-one patients (86.1%, n=36) had treatment-related AEs (83.3% in group A vs. 88.9% in group B, P=1.000). All the AEs were mild (<grade 2) and manageable. During follow-up, 19 patients (54.3%) experienced disease progression (per RECIST 1.1 or mRECIST). The median PFS was 7.2 (95% CI 3.6-10.8) months (6.7 [95% CI 4.7-8.8] months in group A vs. 8.4 [95% CI 3.9-12.8] months in group B, P=0.832). The median PFS in this report was immature due to some later enrolled patients were censored. Thus, it is likely to improve with longer follow-up. The ORR per RECIST 1.1 and mRECIST was 37.1% (41.2% in group A vs. 33.3% in group B, P=0.733) and 80.0% (88.2 in group A vs. 72.2% in group B, P=0.402), respectively. The DCR per RECIST 1.1 or mRECIST was 91.4% (94.1% in group A vs. 88.9% in group B, P=1.000). The median OS was not reached. Conclusions: Sin-Bev showed preliminary clinical benefits and an acceptable safety profile in uHCC patients treated with TACE. The study is still ongoing and further follow-up is required to obtain the final survival results. Clinical trial information: NCT04592029.