Background and Aims: Surgical resection is the primary treatment for HCC; however, it is associated with a high rate of recurrence and death. We conducted this phase 2 study to investigate the efficacy and safety of postoperative intensity‐modulated radiotherapy (IMRT) for HCC after narrow‐margin hepatectomy. Approach and Results: We designed a single‐arm, prospective phase 2 trial to evaluate overall survival (OS), disease‐free survival (DFS), recurrence patterns, and toxicity in patients receiving adjuvant radiotherapy. The eligibility criteria included the following: pathological diagnosis of HCC after hepatectomy, with narrow pathological margins (< 1 cm); age > 18 years; and Eastern Cooperative Oncology Group performance status score of 0 or 1. Patients received IMRT within 4‐6 weeks after surgical resection. This trial was registered at ClinicalTrials.gov (NCT01456156). Between 2008 and 2016, a total of 76 eligible patients who underwent narrow‐margin resection were enrolled. The median follow‐up duration was 70 months; the 3‐year OS and DFS rates were 88.2% and 68.1%, respectively; and the 5‐year OS and DFS rates were 72.2% and 51.6%, respectively. Intrahepatic recurrence was the primary recurrence pattern. No marginal recurrence was found. Intrahepatic, extrahepatic, and combined recurrences at the first relapse were found in 33, 5, and 1 patient, respectively. The most common radiation‐related grade‐3 toxicities were leukopenia (7.9%), elevated alanine aminotransferase (3.9%) and aspartate aminotransferase (2.6%) levels, and thrombocytopenia (1.3%). Classical or nonclassical radiation‐induced liver disease was not noted. Conclusions: Adjuvant radiotherapy is an effective, well‐tolerated, and promising adjuvant regimen in patients with HCC who have undergone narrow‐margin hepatectomy. Our trial provides evidence and a rationale for planning a future phase 3 trial.

Objective: Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), mostly characterised by HBV integrations, is prevalent worldwide. Previous HBV studies mainly focused on a few hotspot integrations. However, the oncogenic role of the other HBV integrations remains unclear. This study aimed to elucidate HBV integration-induced tumourigenesis further. Design: Here, we illuminated the genomic structures encompassing HBV integrations in 124 HCCs across ages using whole genome sequencing and Nanopore long reads. We classified a repertoire of integration patterns featured by complex genomic rearrangement. We also conducted a clustered regularly interspaced short palindromic repeat (CRISPR)-based gain-of-function genetic screen in mouse hepatocytes. We individually activated each candidate gene in the mouse model to uncover HBV integration-mediated oncogenic aberration that elicits tumourigenesis in mice. Results: These HBV-mediated rearrangements are significantly enriched in a bridge-fusion-bridge pattern and interchromosomal translocations, and frequently led to a wide range of aberrations including driver copy number variations in chr 4q, 5p ( TERT ), 6q, 8p, 16q, 9p ( CDKN2A/B ), 17p ( TP53 ) and 13q ( RB1 ), and particularly, ultra-early amplifications in chr8q. Integrated HBV frequently contains complex structures correlated with the translocation distance. Paired breakpoints within each integration event usually exhibit different microhomology, likely mediated by different DNA repair mechanisms. HBV-mediated rearrangements significantly correlated with young age, higher HBV DNA level and TP53 mutations but were less prevalent in the patients subjected to prior antiviral therapies. Finally, we recapitulated the TONSL and TMEM65 amplification in chr8q led by HBV integration using CRISPR/Cas9 editing and demonstrated their tumourigenic potentials. Conclusion: HBV integrations extensively reshape genomic structures and promote hepatocarcinogenesis (graphical abstract), which may occur early in a patient’s life.

Background: Microvascular invasion (MVI) is the most important risk factor associated with early postoperative recurrence in patients with hepatocellular carcinoma (HCC). However, the efficacy of postoperative adjuvant treatment for preventing recurrence in HCC patients with MVI has not been assessed. This study investigated the efficacy of postoperative adjuvant radiotherapy (RT) and transcatheter arterial chemoembolization (TACE) in HCC patients with MVI. Materials and methods: From July 2008 to December 2016, 117 hepatitis B virus (HBV)-related HCC patients with MVI were retrospectively divided into two groups based on postoperative adjuvant treatments. Propensity score matching (PSM) was performed to adjust for significant differences in baseline characteristics. Relapse-free survival (RFS) and overall survival (OS) of the two groups were analyzed before and after PSM. Results: Of all patients, the RT group had significantly smaller tumor size and milder MVI classification. PSM analysis created 46 pairs of patients. After matching, the two groups of patients were similar in baseline characteristics. Multivariate analysis indicated that tumor size, MVI classification, and postoperative treatment strategies were independently associated with RFS; tumor size and MVI classification were independently associated with OS. Similar multivariate analysis results were demonstrated after matching propensity score. Survival analysis revealed that the estimated median RFS and OS of patients with RT and TACE were 25.74±8.12 vs 9.18±1.67 months (P=0.003) and 60.69±7.36 vs 36.53±5.34 months (P=0.262), respectively. The RT group had significantly longer RFS than the TACE group. Conclusion: Postoperative adjuvant RT offers better RFS for HCC patients with MVI than TACE.

Background: Although surgical resection provides a cure for patients with intrahepatic cholangiocarcinoma (ICC), the risk of mortality and recurrence remains high. Several biomarkers are reported to be associated with the prognosis of ICC, including Beclin-1, ARID1A, carbonic anhydrase IX (CA9) and isocitrate dehydrogenase 1 (IDH1), but results are inconsistent. Therefore, a histopathological retrospective study was performed to simultaneously investigate the relationship of these four potential biomarkers with clinicopathological parameters and their prognostic values in patients with ICC. Methods: A total of 113 patients with ICC were enrolled from Cancer Hospital of Chinese Academy of Medical Sciences between January 1999 and June 2015. The expression of Beclin-1, ARID1A, IDH1 and CA9 were determined by immunohistochemical staining. The prognostic values of the four biomarkers were analyzed by Cox regression and the Kaplan-Meier method. Results: Beclin-1, ARID1A, CA9 and IDH1 were highly expressed in ICC tumor tissues. Higher mortality was positively associated with Beclin-1 expression (HR = 2.39, 95% CI = 1.09–5.24) and higher recurrence was positively associated with ARID1A expression (HR = 1.71, 95% CI = 1.06–2.78). Neither CA9 nor IDH1 expression was significantly associated with mortality or disease recurrence. Kaplan-Meier survival curves showed that ICC patients with higher Beclin-1 and ARID1A expression had a lower survival rate and a worse recurrence rate than patients with low Beclin-1 and ARID1A expression (p < 0.05). Conclusions: High Beclin-1 and ARIDIA expression are strongly associated with poor prognosis in ICC patients, and thus Beclin-1 and ARID1A should be simultaneously considered as potential prognostic biomarkers for ICC patients.

Background/Aim: The purpose of this study was to investigate the clinical, pathological, and prognostic differences between adenocarcinoma (ADC) and mucinous adenocarcinoma (MUC) in colorectal cancer (CRC). Patients and Methods: This was a retrospective study of a Japanese high-volume cancer Center over a 10-year period. From April 2007 to December 2016, a total of 3,296 patients with primary CRC were included in the study. The clinical characteristics of MUC and ADC were compared. Then, propensity score matching was performed according to a 1:2 ratio. Multivariate analysis was used for independent risk factors related to prognosis. The overall survival (OS) and disease-free survival (DFS) of 126 cases of MUC and 256 cases of ADC were studied, as well as the survival rate of each stage. Results: MUC accounts for 3.82% of the total CRC. Compared to ADC, MUC is more common in female patients (47.62% vs. 38.77%; p=0.045), with higher carcinoembryonic antigen levels (56.35% vs. 34.95%; p<0.001), more ulcerative and infiltrative types (82.54% vs. 72.93%; p=0.016), higher incidence of perineural infiltration (51.59% vs. 41.04%; p=0.018), deeper infiltration (T3-T4: 90.48% vs. 65.84%; p<0.001), and more advanced cancer (stage III-IV: 59.52% vs. 44.79%; p=0.001). MUC is also more likely to recur (24.6% vs. 14.32%; p=0.001). Regarding the long-term survival rate, the OS (p<0.001) and DFS (p=0.05) is consequently worse. After propensity score matching, multivariate analysis showed that MUC was a common independent risk factor for DFS [odds ratio (OR)=4.277; 95% confidence interval (CI), 0.327-0.97; p=0.039], and also for OS (OR= 6.836; 95% CI, 0.274-0.831; p=0.009). In MUC, OS and DFS were still relatively worse (OS: p=0.017; DFS: p=0.038). However, only significant statistical differences were shown in stage II (OS: p=0.003; DFS: p=0.007). No significant differences were noted in the stages I, III, or IV. Conclusion: MUC is a high-risk factor for stage II CRC. Adjuvant chemotherapy should be routinely recommended for patients with MUC stage II, and special attention should be paid during their follow-up.