Yosuke Kasai

Type D Personality Is Associated with Psychological Distress and Poor Self-Rated Health among the Elderly: A Population-Based Study in Japan

We investigated the association between Type D personality, psychological distress, and self-ratings of poor health in elderly Japanese people. In August 2010, questionnaires were sent to all residents aged ≥65 in three municipalities (n = 21232) in Okayama Prefecture, Japan, and. 13929 questionnaires were returned (response rate: 65.6%). To assess mental and physical health outcomes, we used the Kessler Psychological Distress Scale and a single item question regarding perceived general health. We analyzed 9759 questionnaires to determine odds ratios (ORs) and 95% confidence intervals (CIs) for several health outcomes, adjusting for sex, age, smoking status, frequency of alcohol consumption, overweight status, educational attainment, socioeconomic status, and number of cohabiters. The multiple imputation method was employed for missing data regarding Type D personality. The prevalence of Type D personality in our sample was 46.2%. After adjusting for covariates, we found that participants with Type D personality were at 4–5 times the risk of psychological distress, and twice the risk of poor self-rated health. This association was stronger in participants aged 65–74 years (psychological distress; OR: 5.80, 95% CI: 4.96–6.78, poor self-rated health; OR: 2.84, 95% CI: 2.38–3.38) than in those aged over 75 years (psychological distress; OR: 4.54, 95% CI: 3.96–5.19, poor self-rated health; OR: 2.05, 95% CI: 1.79–2.34). Type D personality is associated with adverse health status among Japanese elderly people in terms of mental and physical risk; therefore, further research into the implications of this personality type is warranted.

Prediction of the Remnant Liver Hypertrophy Ratio after Preoperative Portal Vein Embolization

Background: Portal vein embolization (PVE) is considered to improve the safety of major hepatectomy. Various conditions might affect remnant liver hypertrophy after PVE. The aim of the present study was to clarify the factors that affect remnant liver hypertrophy and to establish a prediction formula for the hypertrophy ratio. Methods: Fifty-nine patients who underwent preoperative PVE for cholangiocarcinoma (39 patients), metastatic carcinoma (10 patients), hepatocellular carcinoma (8 patients), and other diseases (2 patients) were enrolled in this study. For the prediction of the hypertrophy ratio, a formula with stepwise multiple regression analysis was set up. The following parameters were used: age, gender, future liver remnant ratio to total liver (FLR%), plasma disappearance rate of indocyanine green (ICGK), platelet count, prothrombin activity, serum albumin, serum total bilirubin at the time of PVE and the maximum value before PVE (Max Bil), as well as a history of cholangitis, diabetes mellitus, and chemotherapy. Results: The mean hypertrophy ratio was 28.8%. The 5 parameters detected as predictive factors were age (p = 0.015), FLR% (p < 0.001), ICGK (p = 0.112), Max Bil (p < 0.001), and history of chemotherapy (p = 0.007). The following prediction formula was established: 101.6 - 0.78 × age - 0.88 × FLR% + 128 × ICGK - 1.48 × Max Bil (mg/dl) - 21.2 × chemotherapy. The value obtained using this formula significantly correlated with the actual value (r = 0.72, p < 0.001). A 10-fold cross validation also showed significant correlation (r = 0.62, p < 0.001), and a hypertrophy ratio <20% was predictable with a sensitivity of 100% and a specificity of 90.9%. Moreover, technetium-99m-diethylenetriaminepentaacetic acid-galactosyl human serum albumin scintigraphy showed a significantly smaller increase in the uptake ratio of the remnant liver in patients with prediction values <20% than in those with values ≥20% (6.8 vs. 20.8%, p = 0.030). Conclusions: The prediction formula can prognosticate the hypertrophy ratio after PVE, which may provide a new therapeutic strategy for major hepatectomy.

Regorafenib suppresses sinusoidal obstruction syndrome in rats.

BACKGROUND Sinusoidal obstruction syndrome (SOS), a form of drug-induced liver injury related to oxaliplatin treatment, is associated with postoperative morbidity after hepatectomy. This study aimed to examine the impact of regorafenib, the first small-molecule kinase inhibitor to show efficacy against metastatic colorectal cancer, on a rat model of SOS. METHODS Rats with monocrotaline (MCT)-induced SOS were divided into two groups according to treatment with either regorafenib (6 mg/kg) or vehicle alone, which were administered at 12 and 36 h, respectively, before MCT administration. Histopathologic examination and serum biochemistry tests were performed 48 h after MCT administration. Sinusoidal endothelial cells were evaluated by immunohistochemistry and electron microscopy. To examine whether regorafenib preserved remnant liver function, a 30% hepatectomy was performed in each group. RESULTS The rats in the vehicle group displayed typical SOS features, whereas these features were suppressed in the regorafenib group. The total SOS scores were significantly lower in the regorafenib group than in the vehicle group. Immunohistochemistry and electron microscopy showed that regorafenib had a protective effect on sinusoidal endothelial cells. The postoperative survival rate after 7 d was significantly better in the regorafenib group than that in the vehicle group (26.7% versus 6.7%, P < 0.05). Regorafenib reduced the phosphorylation of extracellular signal-regulated kinase, which induced matrix metalloproteinase-9 (MMP-9) activation and decreased the activity of MMP-9, one of the crucial mediators of SOS development. CONCLUSIONS Regorafenib suppressed MCT-induced SOS, concomitant with attenuating extracellular signal-regulated kinase phosphorylation, and MMP-9 activation, suggesting that regorafenib may be a favorable agent for use in combination with oxaliplatin-based chemotherapy.

Diarrhea and related factors among passengers on world cruises departing from Japan

BACKGROUND Despite growth in the number of cruises worldwide, evidence about diarrhea experienced by cruise ship passengers remains sparse. We investigated rates of diarrhea and related factors among passengers on world cruises departing from Japan. METHODS Targeting passengers on five world cruises (n = 4180) from 2012 to 2013 (85-103 travel days), we calculated rates of health seeking behavior for diarrhea by sex, age group, and number of roommates for each cruise. We estimated rate ratios and 95% confidence intervals, using the group aged 20-39 years, women, and 2-4 roommates as referent categories. RESULTS We found 5.04-6.00 cases per 10,000 person-days in the five cruises, with an elevated number after calling at ports. Older passengers (>60 years) and passengers with fewer roommates had an elevated risk of health seeking behavior for diarrhea, although passengers aged <20 years had an elevated risk on one cruise. After controlling for covariates (including cruise), significant associations remained for passengers aged >60 years and without roommates. CONCLUSIONS Older passengers and passengers with fewer roommates may be more likely to seek medical treatment for diarrhea during travel on a world cruise, and should take preventive measures.

CAAT/enhancer binding protein–homologous protein deficiency attenuates liver ischemia/reperfusion injury in mice

Ischemia/reperfusion injury (IRI) is one of the main causes of liver dysfunction after liver surgery. Involvement of endoplasmic reticulum (ER) stress in various diseases has been demonstrated, and CAAT/enhancer binding protein–homologous protein (CHOP) is a transcriptional regulator that is induced by ER stress. It is also a key regulator of ER stress‐mediated apoptosis. The aim of this study was to investigate the role of CHOP in liver IRI. Wild type (WT) and CAAT/enhancer binding protein–homologous protein knockout (CHOP–/–) mice were subjected to 70% liver warm ischemia/reperfusion for 60 minutes. At different times after reperfusion, liver tissues and blood samples were collected for evaluation. Induction of ER stress including CHOP expression was ascertained. Liver damage was evaluated based on serum liver enzymes, liver histology, and neutrophil infiltration. Hepatocyte death including apoptosis was assessed. Liver warm IRI induced ER stress in both WT and CHOP–/– mice. In addition, CHOP expression was up‐regulated in WT mice. At 6 hours after reperfusion, liver damage was attenuated in CHOP–/– mice. On the basis of terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick‐end labeling staining, apoptotic and necrotic cells were significantly reduced in CHOP–/– mice. CHOP deficiency also reduced the cleavage of caspase 3 and expression of the proapoptotic protein B cell lymphoma 2–associated X protein. Liver IRI induces CHOP expression, and CHOP deficiency attenuates liver IRI by inhibiting apoptosis. Elucidation of the function of CHOP in liver IRI may contribute to further investigation for a therapy against liver IRI associated with the ER stress pathway. Liver Transplantation 24 645–654 2018 AASLD.

Proposal of selection criteria for operative resection of hepatocellular carcinoma with inferior vena cava tumor thrombus incorporating hepatic arterial infusion chemotherapy

Background. Because operative resection of hepatocellular carcinoma with inferior vena cava tumor thrombus has been associated with a substantial risk of recurrence and postoperative morbidity, adequate patient selection for resection is necessary. Our aim was to propose selection criteria for resection of hepatocellular carcinoma with inferior vena cava tumor thrombus. Methods. Long‐term outcomes were analyzed retrospectively in 39 operative cases of hepatocellular carcinoma with inferior vena cava tumor thrombus (1996–2015). Since 2003, preoperative hepatic arterial infusion chemotherapy instead of immediate resection has been performed in patients with advanced inferior vena cava tumor thrombus, defined as those patients with suspected extrahepatic metastasis, who will need extracorporeal circulation, or who have marginal liver function and/or multiple bilobar tumors. Indication for resection has been based on the tumor response to hepatic arterial infusion chemotherapy thereafter. Results. The median survival time for all patients was 15.2 months. Multivariate analysis revealed that preoperative hepatic arterial infusion chemotherapy (hazard ratio: 0.30), use of extracorporeal circulation (3.12), and extrahepatic metastasis (2.67) were independent prognostic factors for overall survival. Among patients with initially advanced inferior vena cava tumor thrombus, preoperative hepatic arterial infusion chemotherapy was associated with a much more favorable prognosis compared with no hepatic arterial infusion chemotherapy (median survival time: unreached vs 8.3 months, P = .007). Overall survival was significantly worse in patients with uncontrolled, advanced inferior vena cava tumor thrombus than in those without advanced inferior vena cava tumor thrombus or with advanced inferior vena cava tumor thrombus controlled by preoperative hepatic arterial infusion chemotherapy (median survival time: 10.4 vs 26.1 months, P = .039). Conclusion. An effective response to hepatic arterial infusion chemotherapy and subsequent operative resection salvaged patients with initially advanced inferior vena cava tumor thrombus. Our results suggest that operative resection should be indicated only in patients without advanced inferior vena cava tumor thrombus or with advanced inferior vena cava tumor thrombus controlled by preoperative hepatic arterial infusion chemotherapy.

Chronological profiling of plasma native peptides after hepatectomy in pigs: Toward the discovery of human biomarkers for liver regeneration

Liver regeneration after partial hepatectomy (PHx) is a time-dependent process, which is tightly regulated by multiple signaling cascades. Failure of this complex process leads to posthepatectomy liver failure (PHLF), which is associated with a high rate of mortality. Thus, it is extremely important to establish a useful biomarker of liver regeneration to help prevent PHLF. Here, we hypothesized that alterations in the plasma peptide profile may predict liver regeneration following PHx and hence we set up a diagnostic platform for monitoring posthepatectomy outcome. We chronologically analyzed plasma peptidomic profiles of 5 partially hepatectomized microminipigs using the ClinProtTM system, which consists of magnetic beads and MALDI-TOF/TOF MS. We identified endogenous circulating peptides specific to each phase of the postoperative course after PHx in pigs. Notably, peptide fragments of histones were detected immediately after PHx; the presence of these fragments may trigger liver regeneration in the very acute phase after PHx. An N-terminal fragment of hemoglobin subunit α (3627 m/z) was detected as an acute-phase-specific peptide. In the recovery phase, the short N-terminal fragments of albumin (3028, 3042 m/z) were decreased, whereas the long N-terminal fragment of the protein (8926 m/z) was increased. To further validate and extract phase-specific biomarkers using plasma peptidome after PHx, plasma specimens of 4 patients who underwent PHx were analyzed using the same method as we applied to pigs. It revealed that there was also phase-specificity in peptide profiles, one of which was represented by a fragment of complement C4b (2378 m/z). The strategy described herein is highly efficient for the identification and characterization of peptide biomarkers of liver regeneration in a swine PHx model. This strategy is feasible for application to human biomarker studies and will yield clues for understanding liver regeneration in human clinical trials.

Nardilysin promotes hepatocellular carcinoma through activation of signal transducer and activator of transcription 3

Nardilysin (NRDC) is a metalloendopeptidase of the M16 family. We previously showed that NRDC activates inflammatory cytokine signaling, including interleukin‐6‐signal transducer and activator of transcription 3 (STAT3) signaling. NRDC has been implicated in the promotion of breast, gastric and esophageal cancer, as well as the development of liver fibrosis. In this study, we investigated the role of NRDC in the promotion of hepatocellular carcinoma (HCC), both clinically and experimentally. We found that NRDC expression was upregulated threefold in HCC tissue compared to the adjacent non‐tumor liver tissue, which was confirmed by immunohistochemistry and western blotting. We also found that high serum NRDC was associated with large tumor size (>3 cm, P = 0.016) and poor prognosis after hepatectomy (median survival time 32.0 vs 73.9 months, P = 0.003) in patients with hepatitis C (n = 120). Diethylnitrosamine‐induced hepatocarcinogenesis was suppressed in heterozygous NRDC‐deficient mice compared to their wild‐type littermates. Gene silencing of NRDC with miRNA diminished the growth of Huh‐7 and Hep3B spheroids in vitro. Notably, phosphorylation of STAT3 was decreased in NRDC‐depleted Huh‐7 spheroids compared to control spheroids. The effect of a STAT3 inhibitor (S3I‐201) on the growth of Huh‐7 spheroids was reduced in NRDC‐depleted cells relative to controls. Our results show that NRDC is a promising prognostic marker for HCC in patients with hepatitis C, and that NRDC promotes tumor growth through activation of STAT3.