UNASSIGNED: The aim of the study was to evaluate the efficacy and safety of adjuvant sorafenib treatment compared with placebo in patients with hepatocellular carcinoma who underwent local ablation.
UNASSIGNED: The SORAMIC trial is a randomised controlled trial with diagnostic, local ablation, and palliative sub-study arms. After initial imaging within the diagnostic study, patients were assigned to local ablation or palliative arms. In the local ablation cohort, patients were randomised 1:1 to local ablation + sorafenib vs. local ablation + placebo. The primary endpoint was time-to-recurrence (TTR). Secondary endpoints were local control rate and safety in terms of adverse events and quality-of-life.
UNASSIGNED: The recruitment was terminated prematurely after 104 patients owing to slow recruitment. One patient was excluded because of a technical failure. Fifty-four patients were randomised to local ablation + sorafenib and 49 to local ablation + placebo. Eighty-eight patients who underwent standardised follow-up imaging comprised the per-protocol population. The median TTR was 15.2 months in the sorafenib arm and 16.4 months in the placebo arm (hazard ratio 1.1; 95% CI 0.53-2.2; p = 0.82). Out of 136 lesions ablated within the trial, there was no difference in local recurrence rate between sorafenib (6/69, 8.6%) and placebo groups (5/67, 5.9%; p = 0.792).Overall (92.5% vs. 71.4%, p = 0.008) and drug-related (81.4% vs. 55.1%, p = 0.003) adverse events were more common in the sorafenib arm compared with the placebo arm. Dose reduction because of adverse events were common in the sorafenib arm (79.6% vs. 30.6%, p <0.001).
UNASSIGNED: Adjuvant sorafenib did not improve in TTR or local control rate after local ablation in patients with hepatocellular carcinoma within the limitations of an early terminated trial.
UNASSIGNED: Local ablation is the standard of care treatment in patients with early stages of hepatocellular carcinoma, along with surgical therapies. However, there is a risk of disease recurrence during follow-up. Sorafenib, an oral medication, is a routinely used treatment for patients with advanced hepatocellular carcinoma. This study found that sorafenib treatment after local ablation in people with early hepatocellular carcinoma did not significantly improve the disease-free period compared with placebo.
UNASSIGNED: EudraCT 2009-012576-27, NCT01126645.

UNASSIGNED: Hepatocellular carcinoma (HCC) is one of the most common malignant tumours worldwide. Clarification of the somatic mutational landscape of important genes could reveal new therapeutic targets and facilitate individualized therapeutic approaches for HCC patients. The mutation and expression changes in the ARID1A gene in HCC remain controversial.
UNASSIGNED: First, cBioPortal was used to visualize genetic alterations and DNA copy number alterations (CNAs) in ARID1A. The relationships between ARID1A mutation status and HCC patient clinicopathological features and overall survival (OS) were also determined. Then, a meta-analysis was performed to evaluate the effect of ARID1A mutation or expression on the prognosis of HCC patients. Finally, the role of ARID1A in HCC progression was verified by in vitro experiments.
UNASSIGNED: ARID1A mutation was detected in 9.35% (33/353) of sequenced HCC cases, and ARID1A mutation decreased ARID1A mRNA expression. Patients with ARID1A alterations presented worse OS than those without ARID1A alterations. Meta-analysis and human HCC tissue microarray (TMA) analysis revealed that HCC patients with low ARID1A expression had worse OS and relapse-free survival (RFS), and low ARID1A expression was negatively correlated with tumour size. Then, ARID1A gain-of-function and loss-of-function experiments demonstrated the tumour suppressor role of ARID1A in HCC in vitro. In terms of the mechanism, we found that ARID1A could inhibit HCC progression by regulating retinoblastoma-like 1 (RBL1) expression via the JNK/FOXO3 pathway.
UNASSIGNED: ARID1A can be considered a potential prognostic biomarker and candidate therapeutic target for HCC.

UNASSIGNED: To evaluate efficacy of S-1 (tegafur/gimeracil/oteracil), an active novel fluoropyrimidine, as compared to UFT (tegafur/uracil) as a postoperative adjuvant therapy in patients with node-negative non-small cell lung cancer (NSCLC).
UNASSIGNED: Eligible patients had undergone complete resection of p-stage I (T1 with tumor diameter >2 cm or T2-N0M0 by 5th edition Union for International Cancer Control TNM) NSCLC, and were randomized to receive oral UFT 250 mg/m2/day for 2 years (Arm A) or oral S-1 80 mg/m2/day for 2 weeks with a 1-week rest period, for 1 year (Arm B). The primary end point was relapse-free survival (RFS), with 80% power and a one-sided type I error of 0.05.
UNASSIGNED: From November 2008 to December 2013, 963 patients were enrolled (Arm A: 482, Arm B: 481). Toxicities (hematologic/nonhematologic) of grade 3 or more were observed in 15.9 (1.5/14.7)% in Arm A, and in 14.9 (3.6/12.1)% in Arm B, respectively. At data cut-off in December 2018, the hazard ratio for RFS was 1.06 (95% confidence interval, 0.82-1.36), showing no superiority of S-1 over UFT. The hazard ratio of overall survival (OS) was 1.10 (95% confidence interval, 0.81-1.50). The 5-year RFS/OS were 79.4%/88.8% in Arm A and 79.5%/89.7% in Arm B, respectively. The original NSCLC accounted for 58%/53%, respectively, of the Arm A/Arm B OS events. Secondary malignancies were observed in 85 (17.8%) and 84 (17.8%) individuals in Arm A and Arm B, respectively.
UNASSIGNED: S-1 was not superior to UFT as postoperative adjuvant therapy in node-negative NSCLC. Future investigation should incorporate identification of high-risk populations for recurrence.

Recent studies have shown that cancers arise as a result of the positive selection of driver somatic events in tumor DNA, with negative selection playing only a minor role, if any. However, these investigations were concerned with alterations at nonrepetitive sequences and did not take into account mutations in repetitive sequences that have very high pathophysiological relevance in the tumors showing microsatellite instability (MSI) resulting from mismatch repair deficiency investigated in the present study.
We performed whole-exome sequencing of 47 MSI colorectal cancers (CRCs) and confirmed results in an independent cohort of 53 MSI CRCs. We used a probabilistic model of mutational events within microsatellites, while adapting pre-existing models to analyze nonrepetitive DNA sequences. Negatively selected coding alterations in MSI CRCs were investigated for their functional and clinical impact in CRC cell lines and in a third cohort of 164 MSI CRC patients.
Both positive and negative selection of somatic mutations in DNA repeats was observed, leading us to identify the expected true driver genes associated with the MSI-driven tumorigenic process. Several coding negatively selected MSI-related mutational events (n = 5) were shown to have deleterious effects on tumor cells. In the tumors in which deleterious MSI mutations were observed despite the negative selection, they were associated with worse survival in MSI CRC patients (hazard ratio, 3; 95% CI, 1.1-7.9; P = .03), suggesting their anticancer impact should be offset by other as yet unknown oncogenic processes that contribute to a poor prognosis.
The present results identify the positive and negative driver somatic mutations acting in MSI-driven tumorigenesis, suggesting that genomic instability in MSI CRC plays a dual role in achieving tumor cell transformation. Exome sequencing data have been deposited in the European genome-phenome archive (accession: EGAS00001002477).