Background
A phase 3, multinational, randomized, non-inferiority trial (REFLECT) compared the efficacy and safety of lenvatinib (LEN) and sorafenib (SOR) in patients with unresectable hepatocellular ...carcinoma (uHCC). LEN had an effect on overall survival (OS) compared to SOR, statistically confirmed by non-inferiority OS: median = 13.6 months vs. 12.3 months; hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.79–1.06, and demonstrated statistically significant improvements in progression-free survival (PFS) and the objective response rate (ORR) in the overall population. The results of a subset analysis that evaluated the efficacy and safety of LEN and SOR in the Japanese population are reported.
Methods
The intent-to-treat population enrolled in Japan was analyzed.
Results
Of 954 patients in the overall population, 168 Japanese patients were assigned to the LEN arm (
N
= 81) or the SOR arm (
N
= 87). Median OS was 17.6 months for LEN vs. 17.8 months for SOR (HR 0.90; 95% CI 0.62–1.29). LEN showed statistically significant improvements over SOR in PFS (7.2 months vs. 4.6 months) and ORR (29.6% vs. 6.9%). The relative dose intensity of LEN and SOR in the Japanese population was lower than in the overall population. Frequently observed, related adverse events included palmar-plantar erythrodysaesthesia syndrome (PPES), hypertension, decreased appetite, and proteinuria in the LEN arm, and PPES, hypertension, diarrhea, and alopecia in the SOR arm.
Conclusions
The efficacy and safety of LEN in the Japanese population were similar to those in the overall population of REFLECT. With manageable adverse events, LEN is a new treatment option for Japanese patients with uHCC.
Trial registration ID
ClinicalTrials.gov. No. NCT01761266.
The fifth version of the Clinical Practice Guidelines for Hepatocellular Carcinoma was revised by the Japan Society of Hepatology, according to the methodology of evidence‐based medicine and partly ...to the Grading of Recommendations Assessment, Development and Evaluation system, which was published in October 2021 in Japanese. In addition to surveillance–diagnostic and treatment algorithms, a new algorithm for systemic therapy has been created, as multiple drugs for hepatocellular carcinoma can be currently selected. Here, new or revised algorithms and evidence on which the recommendations are based are described.
Liver cancer, which is most often associated with virus infection, is prevalent worldwide, and its underlying etiology and genomic structure are heterogeneous. Here we provide a whole-genome ...landscape of somatic alterations in 300 liver cancers from Japanese individuals. Our comprehensive analysis identified point mutations, structural variations (STVs), and virus integrations, in noncoding and coding regions. We discovered mutational signatures related to liver carcinogenesis and recurrently mutated coding and noncoding regions, such as long intergenic noncoding RNA genes (NEAT1 and MALAT1), promoters, CTCF-binding sites, and regulatory regions. STV analysis found a significant association with replication timing and identified known (CDKN2A, CCND1, APC, and TERT) and new (ASH1L, NCOR1, and MACROD2) cancer-related genes that were recurrently affected by STVs, leading to altered expression. These results emphasize the value of whole-genome sequencing analysis in discovering cancer driver mutations and understanding comprehensive molecular profiles of liver cancer, especially with regard to STVs and noncoding mutations.
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•Biliary tract cancers are clinically and genetically heterogeneous.•32 significantly mutated genes were identified, some negatively affecting prognosis.•A novel deletion of MUC17 at ...7q22.1 was detected.•Cell-of-origin predictions suggest hepatocyte-origin of hepatitis-related ICCs.•Deleterious germline mutations of cancer-predisposing genes were detected in 11% of patients with BTC.
Biliary tract cancers (BTCs) are clinically and pathologically heterogeneous and respond poorly to treatment. Genomic profiling can offer a clearer understanding of their carcinogenesis, classification and treatment strategy. We performed large-scale genome sequencing analyses on BTCs to investigate their somatic and germline driver events and characterize their genomic landscape.
We analyzed 412 BTC samples from Japanese and Italian populations, 107 by whole-exome sequencing (WES), 39 by whole-genome sequencing (WGS), and a further 266 samples by targeted sequencing. The subtypes were 136 intrahepatic cholangiocarcinomas (ICCs), 101 distal cholangiocarcinomas (DCCs), 109 peri-hilar type cholangiocarcinomas (PHCs), and 66 gallbladder or cystic duct cancers (GBCs/CDCs). We identified somatic alterations and searched for driver genes in BTCs, finding pathogenic germline variants of cancer-predisposing genes. We predicted cell-of-origin for BTCs by combining somatic mutation patterns and epigenetic features.
We identified 32 significantly and commonly mutated genes including TP53, KRAS, SMAD4, NF1, ARID1A, PBRM1, and ATR, some of which negatively affected patient prognosis. A novel deletion of MUC17 at 7q22.1 affected patient prognosis. Cell-of-origin predictions using WGS and epigenetic features suggest hepatocyte-origin of hepatitis-related ICCs. Deleterious germline mutations of cancer-predisposing genes such as BRCA1, BRCA2, RAD51D, MLH1, or MSH2 were detected in 11% (16/146) of BTC patients.
BTCs have distinct genetic features including somatic events and germline predisposition. These findings could be useful to establish treatment and diagnostic strategies for BTCs based on genetic information.
We here analyzed genomic features of 412 BTC samples from Japanese and Italian populations. A total of 32 significantly and commonly mutated genes were identified, some of which negatively affected patient prognosis, including a novel deletion of MUC17 at 7q22.1. Cell-of-origin predictions using WGS and epigenetic features suggest hepatocyte-origin of hepatitis-related ICCs. Deleterious germline mutations of cancer-predisposing genes were detected in 11% of patients with BTC. BTCs have distinct genetic features including somatic events and germline predisposition.
Genes generate transcripts of various functions by alternative splicing. However, in most transcriptome studies, short-reads sequencing technologies (next-generation sequencers) have been used, ...leaving full-length transcripts unobserved directly. Although long-reads sequencing technologies would enable the sequencing of full-length transcripts, the data analysis is difficult. In this study, we developed an analysis pipeline named SPLICE and analyzed cDNA sequences from 42 pairs of hepatocellular carcinoma (HCC) and matched non-cancerous livers with an Oxford Nanopore sequencer. Our analysis detected 46,663 transcripts from the protein-coding genes in the HCCs and the matched non-cancerous livers, of which 5,366 (11.5%) were novel. A comparison of expression levels identified 9,933 differentially expressed transcripts (DETs) in 4,744 genes. Interestingly, 746 genes with DETs, including the LINE1-MET transcript, were not found by a gene-level analysis. We also found that fusion transcripts of transposable elements and hepatitis B virus (HBV) were overexpressed in HCCs. In vitro experiments on DETs showed that LINE1-MET and HBV-human transposable elements promoted cell growth. Furthermore, fusion gene detection showed novel recurrent fusion events that were not detected in the short-reads. These results suggest the efficiency of full-length transcriptome studies and the importance of splicing variants in carcinogenesis.
Background
To evaluate the efficacy and safety of cabozantinib in Japanese patients with advanced hepatocellular carcinoma (HCC) who had progressed following one or two lines of systemic therapy ...including sorafenib. An exploratory evaluation in sorafenib-naïve patients was performed.
Methods
In this open-label, single-arm, phase 2 trial, patients received oral cabozantinib 60 mg once daily. The primary endpoint was progression-free survival (PFS) rate at Week 24. Secondary endpoints included PFS, overall survival (OS), objective response rate (ORR, best response of complete/partial response), disease control rate (DCR, objective response or stable disease) and safety.
Results
Thirty-four patients received cabozantinib across 17 centers (prior sorafenib cohort,
n
= 20; sorafenib-naïve cohort,
n
= 14). PFS rate at 24 weeks was 59.8% 90% confidence interval (CI) 36.1–77.2% in the prior sorafenib cohort, 16.7% (90% CI 4.0–36.8%) in the sorafenib-naïve cohort and 40.1% (90% CI 24.8–55.0%) overall. Median PFS was 7.4 months for the prior sorafenib cohort, 3.6 months for the sorafenib-naïve cohort, and 5.6 months overall. OS rate at 6 months was 100.0%, 78.6% and 91.1%, respectively; DCR was 85.0%, 64.3% and 76.5%, respectively. The ORR was 0.0% for both cohorts. All patients required dose modifications due to adverse events, the most common of these were palmar–plantar erythrodysesthesia syndrome and diarrhea. Three patients (8.8%) discontinued due to adverse events other than disease progression.
Conclusions
Cabozantinib 60 mg/day has a favorable benefit/risk profile for Japanese patients with advanced HCC who have previously received one or two lines of systemic anticancer therapy including sorafenib. (Clinical trial registration: NCT03586973)
This contingency guide was formulated on the premise that delivering standard treatment for hepatocellular carcinoma (HCC) has come under strain due to the coronavirus (COVID‐19) pandemic. Measures ...required are likely to vary largely across regions and individual institutions, depending on the level of the strain imposed by the pandemic (e.g., number of inpatients infected with COVID‐19 and the availability of resources, including personal protective equipment and inpatient beds). In addition, models suggest that the second and third waves of COVID‐19 will occur before effective vaccines and medicines become widely available in Japan (expected time, 2–3 years). This guide should serve as a good reference for best practices in the management of HCC, which is in light of the possible risk of impending collapse of the healthcare system due to a surge in COVID‐19 infections.
Aim
To compare the efficacy and safety of edoxaban and warfarin for treatment of portal vein thrombosis (PVT) following danaparoid sodium in patients with liver cirrhosis.
Methods
Fifty cirrhotic ...patients with PVT treated initially for 2 weeks with danaparoid sodium were enrolled in this retrospective cohort study. Treatment was later switched to either edoxaban (n = 20) or warfarin (n = 30). We compared the efficacy and safety of edoxaban and warfarin for up to 6 months. The PVT volume was measured by dynamic computed tomography before treatment, at 2 weeks, and at 1, 3, and 6 months.
Results
There were no significant differences in the clinical characteristics of patients in the two groups. Treatment with edoxaban reduced the volume of PVT from 1.42 cm3 at 2 weeks to 0.42 cm3 at 6 months, and prevented exacerbation of PVT at 6 months after treatment with danaparoid sodium (P = 0.016). In contrast, treatment with warfarin resulted in increased PVT volume from 1.73 cm3 at 2 weeks to 2.85 cm3 at 6 months, despite the control of the international normalized ratio in 57% of the patients (P = 0.005). Multivariate regression analysis identified edoxaban therapy as the single significant and independent determinant of PVT reduction at 6 months (P = 0.0014, hazard ratio 6.400). Clinically significant gastrointestinal bleeding was encountered in 3 of 20 (15%) patients of the edoxaban group and 2 of 30 (7%) of the warfarin group (P = 0.335).
Conclusion
Edoxaban following danaparoid sodium is an effective anticoagulant and could be potentially considered as one of the treatment options for PVT in cirrhotic patients.
BACKGROUND： Early recurrence （ER） after hepatic resection （HR） is a poor prognostic factor for patients with hepatocellular carcinoma （HCC）. This study aimed to identify the clinico- pathological ...features, outcomes, and risk factors for ER after HR for small HCC in order to clarify the reasons why ER is a worse recurrence pattern. METHODS： We retrospectively examined 130 patients who underwent HR for small HCC （___30 mm）. Recurrence was clas- sifted into ER （〈2 years） and late recurrence （LR） （_〉2 years）. The clinicopathological features, outcomes, and risk factors for ER were analyzed by multivariate analysis. RESULTS： ER was observed in 39 patients （30.0%）. The sur- vival rate of the ER group was significantly lower than that of the LR group （P〈0.005）, and ER was an independent prognos- tic factor for poor survival （P=0.0001）. The ER group had a significantly higher frequency （P=0.0039） and shorter interval （P=0.027） of development to carcinoma beyond the Milan criteria （DBMC） compared with the LR group, and ER was an independent risk factor for DBMC （P〈0.0001）. Multi-nodularity, non-simple nodular type, and microvascular invasion were independent predictors for ER （P=0.012, 0.010, and 0.019, respectively）.CONCLUSIONS： ER was a highly malignant recurrence pattern associated with DBMC and subsequent poor survival after HR for small HCC. Multi-nodularity, non-simple nodular type, and microvascular invasion predict ER, and taking these factors into consideration may be useful for the decision of the treatment strategy for small HCC after HR.
Aim
Pembrolizumab has been quickly approved in many countries for the treatment of patients with unresectable or metastatic, microsatellite instability‐high (MSI‐H) solid tumors, which have ...progressed following previous treatment and who have no satisfactory alternative treatment options. We aimed to determine the incidence of MSI‐H tumors in Japanese patients with advanced hepatocellular carcinoma (HCC).
Methods
We investigated the incidence of MSI‐H tumors in 82 consecutive Japanese patients with unresectable HCC that had progressed after standard of care treatment. Using a companion diagnostic sequencing kit (polymerase chain reaction analysis of five microsatellite markers: BAT25, BAT26, NR21, NR24 and MONO27), we analyzed 49 biopsy specimens and 33 resection specimens. Responses to pembrolizumab were assessed with the modified Response Evaluation Criteria in Solid Tumors.
Results
MSI‐H tumors were found in only two patients (2.4%), in whom all five markers showed slight shortening. One patient had a complete response to pembrolizumab for over 10 months, and the other was a non‐responder.
Conclusions
MSI‐H tumor status was found in only two of 82 (2.4%) Japanese patients with advanced HCC, one of whom had a complete response to pembrolizumab. Thus, MSI status should be assessed in patients with HCC who progress after standard of care treatment.
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