Histone methyltransferase SUV420H1/KMT5B contributes to poor prognosis in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) has a high rate of recurrence and poor prognosis, even after curative surgery. Multikinase inhibitors have been applied for HCC patients, but their effect has been restricted. This study aims to clarify the clinical impact of SUV420H1/KMT5B, one of the methyltransferases for histone H4 at lysine 20, and elucidate the novel mechanisms of HCC progression. We retrospectively investigated SUV420H1 expression using HCC clinical tissue samples employing immunohistochemical analysis (n = 350). We then performed loss-of-function analysis of SUV420H1 with cell cycle analysis, migration assay, invasion assay and RNA sequence for Gene Ontology (GO) pathway analysis in vitro, and animal experiments with xenograft mice in vivo. The SUV420H1-high-score group (n = 154) had significantly poorer prognosis for both 5-year overall and 2-year/5-year disease-free survival than the SUV420H1-low-score group (n = 196) (p < 0.001 and p < 0.05, respectively). The SUV420H1-high-score group had pathologically larger tumor size, more tumors, poorer differentiation, and more positive vascular invasion than the SUV420H1-low-score group. Multivariate analysis demonstrated that SUV420H1 high score was the poorest independent factor for overall survival. SUV420H1 knockdown could suppress cell cycle from G1 to S phase and cell invasion. GO pathway analysis showed that SUV420H1 contributed to cell proliferation, cell invasion, and/or metastasis. Overexpression of SUV420H1 clinically contributed to poor prognosis in HCC, and the inhibition of SUV420H1 could repress tumor progression and invasion both in vitro and in vivo; thus, further analyses of SUV420H1 are necessary for the discovery of future molecularly targeted drugs.

Progressive Massive Splenomegaly in an Adult Patient with Kabuki Syndrome Complicated with Immune Thrombocytopenic Purpura.

Kabuki syndrome is characterized by multiple systemic anomalies and intellectual disability. It is complicated with immunodeficiencies and autoimmune disorders. The syndrome is caused by a mutation in the KMT2D gene. We herein report a case of a Kabuki syndrome with developing immune thrombocytopenic purpura (ITP) and progressive splenomegaly. Laparoscopic splenectomy was performed and the patients' symptoms quickly disappeared with platelet recovery. After this operation, the patient had no severe complications. A sequence analysis of the KMT2D gene identified a pathogenic mutation frequently associated with ITP. Laparoscopic splenectomy is therefore considered to be a good therapeutic option for recurrent ITP and symptomatic splenomegaly with Kabuki syndrome.

Prognostic impact of adjuvant chemolipiodolization and treatment frequency on patients with hepatocellular carcinoma after hepatectomy: Prospective study with historical control group.

BACKGROUND: Reducing or minimizing metastatic recurrence is a consideration in prolongation of survival of patients with hepatocellular carcinoma. We previously proposed single adjuvant chemolipiodolization (ACL) as a possible adjuvant treatment. The current study aims to further improve prognosis by performing ACL three times (sequential-ACL). METHODS: We examined the prognostic impact of sequential-ACL compared with our historical cohort groups: resection alone (non-ALC) and single-ACL. We evaluated recurrence-free survival (RFS), recurrence pattern, and overall survival. Multivariate prognostic analyses were used to adjust baseline bias between three treatment groups. RESULTS: Non-ACL (n = 64), single-ACL (n = 137), and sequential-ACL (n = 95) showed 40, 54, and 62% of two-year RFS rates (P = 0.03 and P = 0.007 compared with non-ACL). Recurrence pattern beyond Milan criteria was frequently observed in the non-ACL group (P = 0.003). Five-year overall survival rates of these three groups were 53, 69, and 77% (P = 0.02 and 0.002 compared with non-ACL). Single- and sequential-ACL were selected as independent favorable factors for five-year overall survival; their hazard ratios (95% confidence interval) were 0.61 (0.37-0.99) and 0.48 (0.26-0.86). However, compared with single-ACL, there was no additional prognostic effects of sequential-ACL. CONCLUSIONS: Single- and sequential-ACL treatment both showed better RFS and overall survival with minimized recurrence patterns than resection alone. There was not sufficient additional benefit by sequential-ACL, however, over single-ACL. Single-ACL might therefore be appropriate as an adjuvant therapy.

Effective Response of Intrahepatic Cholangiocarcinoma to Pembrolizumab: A Case Report.

BACKGROUND/AIM: The efficacy of pembrolizumab for intrahepatic cholangiocellular carcinoma (IHCCC) is not widely reported. CASE REPORT: We began pembrolizumab treatment in a 69-year-old male with recurrent IHCCC at 18 months after his surgery because of the proven microsatellite instability (MSI)-high status. The patient had partial response, with an 82.5% reduction at the end of 18 courses. Immunostaining of the primary tumor revealed intra-tumoral infiltration of both PD-1+ and CD8+ T cells, and a low expression of PD-L1. CONCLUSION: Intra-tumoral infiltration of both PD-1+ and CD8+ T cells may be a predictive factor of the efficacy of pembrolizumab. Expression of PD-L1 did not correlate with a therapeutic effect, but the tumor microenvironment of our patient's recurrent lesions may have been modified by conventional chemotherapy and CD8+ T cells.

Standardization of surgical procedures for laparoscopic Spiegel lobectomy: A single-institutional experience.

INTRODUCTION: Surgical techniques for Spiegel lobectomy remain technically difficult because of its deep anatomical location. Laparoscopic Spiegel lobectomy has not yet been standardized or widely reported. In the current study, we introduce technical improvements, including the liver hanging maneuver, to laparoscopic Spiegel lobectomy. Additionally, we demonstrate the safety and feasibility of this procedure. MATERIALS AND SURGICAL TECHNIQUE: We performed consecutive laparoscopic Spiegel lobectomy on six patients: five with hepatocellular carcinoma and one with colorectal liver metastasis. As preparation before liver parenchymal resection, necessary and sufficient mobilization of the Spiegel lobe was performed. A few Glissonian pedicles of the Spiegel lobe were exposed from the hilar plate and divided to reduce the inflow to the Spiegel lobe. After that, vessel tape was used in the hanging maneuver. The tape was pulled forward to give the cutting plane moderate tension during liver parenchymal resection. Lifting this tape provided better exposure for determining the correct cutting plane during liver parenchymal transection. The median operation time was 207 min (range, 147-240 min) and the median intraoperative blood loss was 35 mL (range, 15-85 mL). There were no severe postoperative complications. DISCUSSION: We safely performed laparoscopic Spiegel lobectomy. To maintain a sufficient surgical view, especially during liver parenchymal resection, the hanging maneuver may be a useful technique. This single-center investigation into standardized laparoscopic Spiegel lobectomy featuring improvements in technique showed potential for favorable results.

Overexpression of KDM5B/JARID1B is associated with poor prognosis in hepatocellular carcinoma.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) has high potential for recurrence, even in curative operative cases. Although several molecular-targeting drugs have been applied to recurrent HCC, their effectiveness has been limited. This study therefore aims to develop novel cancer drugs through protein methylation. METHODS: We investigated the role of KDM5B/JARID1B, a member of JmjC histone demethylase, in HCC. Expression profiles of KDM5B were examined by immunohistochemical analysis in 105 HCC clinical tissue samples. To examine functional effects of KDM5B using HCC cell lines, we performed loss-of-function analysis treated with KDM5B-specific small interfering RNAs (siKDM5B). RESULTS: All HCC cases were divided into KDM5B-positive expression group (n=54) and negative expression group (n=51). In five-year overall survival, KDM5B-positive group had poorer prognosis than KDM5B-negative (61% vs 77%, p=0.047). KDM5B-positive group had much poorer prognosis than that of the negative group, especially in HCC derived from persistent infection of hepatitis B virus (HBV) or hepatitis C virus (HCV) (54% vs 78%, p=0.015). Multivariate analysis indicated that KDM5B was the strongest risk factor for poor prognosis, especially in HCC derived from HBV/HCV. Inhibition of KDM5B could significantly suppress HCC cell proliferation through no promotion from G1 to S phase. Real-time PCR and Western blotting demonstrated that E2F1/E2F2 were downstream genes of KDM5B. CONCLUSIONS: Overexpression of KDM5B results in poor prognosis in HCC that especially derived from HBV/HCV. KDM5B appears to be an ideal target for the development of anti-cancer drugs.

Detection of needle tract implantation and peritoneal seeding after radiofrequency ablation using intraoperative near-infrared fluorescence system for recurrent hepatocellular carcinoma: a case report.

BACKGROUND: Radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) is already fully established worldwide. Needle tract implantation and peritoneal seeding occasionally occur by RFA, and the prognosis of these cases is thought to be poor. In this study, intraoperative real-time near-infrared fluorescence (NIRF) system by indocyanine green (ICG) incidentally detected both needle tract implantation and peritoneal seeding. As the utility of this system for identification of implanted and disseminated lesions after RFA for HCC has not been widely reported, we report a case of successful detection by real-time ICG-NIRF imaging and subsequent resection. CASE PRESENTATION: A 76-year-old man originally underwent medial sectionectomy for HCC in 2009. When repeated intrahepatic recurrence occurred, he underwent RFA and transcatheter arterial chemoembolization (TACE) for recurrent HCC twice at segment III and once at segment IV. In 2013, the second hepatectomy for recurrent HCC at segment VIII was performed. In 2016, he had recurrent HCC at segment III around a previous RFA and TACE scar; therefore, left lateral sectionectomy was planned. ICG-NIRF system was used to observe a main intrahepatic metastasis at segment III and to search for other tumors in the remnant liver. Although there was no signal on the surface of the remnant liver, tiny signals were observed in the abdominal wall and greater omentum. These tumors were on the needle tract of the previous RFA; both lesions, therefore, were resected. These tumors were pathologically proven to be HCC metastases. The patient has had no recurrence 14 months after the last hepatectomy. CONCLUSIONS: ICG-NIRF system might be helpful in the detection of not only intrahepatic lesions but also needle tract implantations or peritoneal seeding. RFA should be avoided in patients with high risk of needle tract implantation and peritoneal seeding.