BackgroundHepatocellular carcinoma (HCC) is a heterogeneous disease with various etiological factors, and ranks as the second leading cause of cancer-related mortality worldwide due to multi-focal recurrence. We herein identified three major subtypes of HCC by performing integrative analysis of two omics data sets, and clarified that this classification was closely correlated with clinicopathological factors, immune profiles and recurrence patterns.MethodsIn the test study, 183 tumor specimens surgically resected from HCC patients were collected for unsupervised clustering analysis of gene expression signatures and comparative analysis of gene mutations. These results were validated by using genome, methylome and transcriptome data of 373 HCC patients provided from the Cancer Genome Atlas Network. In addition, omics data were obtained from pairs of primary and recurrent HCC.FindingsComprehensive molecular evaluation of HCC by multi-platform analysis defined three major subtypes: (1) mitogenic and stem cell-like tumors with chromosomal instability; (2) CTNNB1-mutated tumors displaying immune suppression; and (3) metabolic disease-associated tumors, which included an immunogenic subgroup characterized by macrophage infiltration and favorable prognosis. Although genomic and epigenomic analysis explicitly distinguished between HCC with intrahepatic metastasis (IM) and multi-centric HCC (MC), the phenotypic similarity between the primary and recurrent tumors was not correlated to the IM/MC origin, but to the classification. Interpretation: Identification of these HCC subtypes provides further insights into patient stratification as well as presents opportunities for therapeutic development.FundMinistry of Education, Culture, Sports, Science and Technology of Japan (16H02670 and 18K19575), Japan Agency for Medical Research and Development (JP15cm0106064, JP17cm0106518, JP18cm0106540 and JP18fk0210040).

At present, molecular markers of colorectal cancer (CRC), including KRAS, NRAS and BRAF mutations, and the microsatellite status are evaluated for the development of personalized treatments. However, clinicopathological and molecular characteristics and the prognostic role of NRAS mutations remain unclear. In the present study, a total of 1,304 consecutive stage 0-IV CRC tumor samples were analyzed for KRAS (exon 2, 3 and 4), NRAS (exon 2 and 3) and BRAF (exon 15) mutations. Multivariate analysis was performed to assess the prognostic impact of NRAS mutations. KRAS, NRAS and BRAF mutations were identified in 553 (42.4%), 35 (2.7%), and 59 (4.5%) of 1,304 CRC cases, respectively. Tumors with NRAS mutations were more frequently located in the distal colorectum compared with those with KRAS or BRAF mutations. Multivariate analysis indicated that KRAS and BRAF mutations were found to be associated with poor prognosis [hazard ratio (HR)=1.44, 95% confidence interval (CI), 1.18-1.76 and HR=2.09; 95% CI, 1.33-3.28, respectively], whereas NRAS mutations were associated with a trend toward favorable prognosis (HR=0.53; 95% CI, 0.27-1.03). Characteristics and prognosis of CRC with NRAS mutations are different from those with KRAS or BRAF mutations.

Objectives Pancreatic fistula after distal pancreatectomy (DP) remains an unsolved problem, and postoperative CT imaging often demonstrates fluid collection (FC) around the pancreatic remnant. This study sought to clarify the clinical implications of FC. Methods This study enrolled 146 patients who underwent DP. FC was defined as a cyst-like lesion C 10 mm in diameter on CT imaging at postoperative day (POD) 7. FC size, irregularity of FC margin, and air bubbles in FC were investigated. In addition, clinical data were retrospectively collected, and useful predictive factors for postoperative pancreatic fistula (POPF) were analyzed. Results Clinically relevant POPF was observed in 26 patients (17.8%), and FC was detected in 136 patients (94.4%). Multivariate analysis identified FC size and drain amylase levels on POD3 as significant risk factors for POPF. Cutoff values were determined by ROC analyses, and the levels of the FC size and drain amylase on POD3 were determined as 41 mm and 1026 IU/L, respectively. The sensitivity and specificity of FC diameters [ 41 mm were 76.9% and 75.0%, respectively, while those of drain amylase levels [ 1026 IU on POD3 were 73.1% and 75.8%, respectively. Conclusions While treating some FCs after DP was necessary for the management of POPF, others did not require any intervention since most of them spontaneously disappeared. FC size and drain amylase levels on POD3 were found to be significantly associated with POPF and could potentially help to determine appropriate treatment.

Our results indicate that sunitinib is as effective for NET-G3 as for NET-G1/2.

Although genomic analysis have recently discovered the malignant subtype of human pancreatic ductal adenocarcinoma (PDAC) characterized by frequent mutations of histone demethylase KDM6A, the biological and molecular roles still remain obscure. We herein elucidated the clinical and biological impacts of KDM6A deficiency on human PDAC and identified the therapeutic potential by pathological and molecular evaluation. Immunohistochemical analysis suggested that loss of KDM6A in cancerous tissues was an independent prognostic factor for both recurrence‐free and overall survival in the 103 tumor specimens surgically resected from patients with PDAC. We established KDM6A knocked out cells by using the CRISPR/Cas9 system and KDM6A‐expressed cells by doxycycline‐inducible system from each two human PDAC cell lines, respectively. KDM6A knockout enhanced aggressive traits of human PDAC cell lines, whereas KDM6A overexpression suppressed them. Microarray analysis revealed reduced expression of 22 genes including five well‐known tumor suppressors, such as CDKN1A, and ChIP‐PCR analysis displayed depleted enrichment of histone H3 lysine 27 acetylation (H3K27ac) at the promoter regions of the five candidates. The epigenetic alterations were induced by the impaired recruitment of histone acetyltransferase p300, which cooperatively interacted with KDM6A. Consistent with these results, the KDM6A knockout cells demonstrated higher vulnerability to histone deacetylase (HDAC) inhibitors through the reactivation of CDKN1A in vitro and in vivo than the KDM6A wild‐type. In conclusion, KDM6A exhibited essential roles in human PDAC as a tumor suppressor and KDM6A deficiency could be a promising biomarker for unfavorable outcome in PDAC patients and a potential surrogate marker for response to HDAC inhibitors.