Norifumi Harimoto

Sarcopenia as a predictor of prognosis in patients following hepatectomy for hepatocellular carcinoma

Sarcopenia was identified recently as a poor prognostic factor in patients with cancer. The present study investigated the effect of sarcopenia on short‐ and long‐term outcomes following partial hepatectomy for hepatocellular carcinoma (HCC), and aimed to identify prognostic factors.

Histone deacetylase inhibitor trichostatin A induces cell-cycle arrest/apoptosis and hepatocyte differentiation in human hepatoma cells.

Remodeling of the chromatin template by inhibition of HDAC activities represents a potential transcriptional therapy for neoplastic disease. A number of HDAC inhibitors that modulate in vitro cell growth and differentiation have been developed. We analyzed the effects of TSA, a specific and potent HDAC inhibitor, on the human hepatoma cell lines HepG2 and Huh‐7. TSA increased levels of acetylated histones H3 and H4 in both HepG2 and Huh‐7. It inhibited cell proliferation in vitro and induced G0/G1 arrest in HepG2 and apoptosis in Huh‐7. Gene expression of liver‐specific functions and liver‐enriched transcription factors was upregulated by TSA. TSA upregulated the ammonia removal rate and the albumin synthesis rate of HepG2 and Huh‐7. Our results indicate that TSA can induce cell‐cycle arrest/apoptosis and hepatocyte differentiation in human liver cancer cell lines.

Preoperative neutrophil-to-lymphocyte ratio is a predictor of survival after hepatectomy for hepatocellular carcinoma: a retrospective analysis.

Objective: To clarify the prognostic value of the preoperative blood neutrophil-to-lymphocyte ratio (NLR) in patients undergoing hepatectomy for hepatocellular carcinoma (HCC). Background: Although a high NLR has been reported to be a predictor of poor survival in patients with various cancers, it has not been extensively examined in patients with HCC. Methods: This retrospective study enrolled 958 patients who underwent hepatectomy without preoperative therapy for HCC from 1996 to 2009. Clinicopathological parameters, including NLR, were evaluated to identify predictors of overall and recurrence-free survival after hepatectomy. Univariate and multivariate analyses were performed, using the Cox proportional hazards model. The best cutoff was determined with time-dependent receiver operating characteristic curve. To determine the mechanism of NLR elevation, immunohistological examination using CD163 staining was performed in 150 patients. Results: Univariate and multivariate analyses showed that NLR was an independent prognostic factor in overall and recurrence-free survival. The best cutoff of NLR was 2.81, and 238 of 958 patients (24.8%) had NLR of more than 2.81. The 5-year survival rate after hepatectomy was 72.9% in patients with NLR less than 2.81 and 51.5% in those with NLR 2.81 or more (P < 0.0001). CD163-positive cell counts were significantly higher in tumors in the group with NLR 2.81 or more than in the group with NLR less than 2.81 (P = 0.0004). Conclusions: Our results show that NLR is an independent predictor of survival after hepatectomy in patients with HCC. Accumulation of tumor-associated macrophages in the tumor is associated with a high NLR.

Sarcopenia is a prognostic factor in living donor liver transplantation

The aims of this study were to investigate sarcopenia as a novel predictor of mortality and sepsis after living donor liver transplantation (LDLT) and to evaluate the effects of early enteral nutrition on patients with sarcopenia. Two hundred four patients undergoing preoperative computed tomography within the month before LDLT were retrospectively evaluated. The lengths of the major and minor axes of the psoas muscle were simply measured at the caudal end of the third lumbar vertebra, and the area of the psoas muscle was calculated. A psoas muscle area lower than the 5th percentile for healthy donors of each sex was defined as sarcopenia. Ninety‐six of the 204 patients (47.1%), including 58.3% (60/103) of the male patients and 35.6% (36/101) of the female patients, were diagnosed with sarcopenia. Sarcopenia was independently and significantly associated with overall survival: there was an approximately 2‐fold higher risk of death for patients with sarcopenia versus patients without sarcopenia (hazard ratio = 2.06, P = 0.047). Sarcopenia was an independent predictor of postoperative sepsis (hazard ratio = 5.31, P = 0.009). Other independent predictors were a younger recipient age (P < 0.001) and a higher body mass index (P = 0.02). Early enteral nutrition within the first 48 hours after LDLT was performed for 24.2% in 2003‐2007 and for 100% in 2008‐2011, and the incidence of postoperative sepsis for patients with sarcopenia (n = 96) was 28.2% (11/39) in 2003‐2007 and 10.5% (6/57) in 2008‐2011 (P = 0.03). In conclusion, sarcopenia is an independent predictor of mortality and sepsis after LDLT. The incidence of postoperative sepsis was reduced even in patients with sarcopenia after the routine application of early enteral nutrition. Liver Transpl 20:401–407, 2014.

In vivo gene transfer into muscle via electro-sonoporation

Among the nonviral techniques for gene transfer in vivo, electroporation is simple, potent, inexpensive, and safe. To upregulate the expression levels of the transferred gene, we investigated the applicability of in vivo electro-sonoporation, which consists of a combination of electric pulse and ultrasound, for gene transfer using plasmid DNA encoding luciferase and mouse interleukin-12 (mIL-12). The quadriceps muscles of mice were injected with plasmid DNA, then sonoporated for 5 min, and electroporated by a pair of electrode plates at the middle of the duration of sonoporation. Three days later, mice that had undergone electro-sonoporation demonstrated twofold higher luciferase activity and low tissue damage in quadriceps muscle compared to mice having undergone electroporation alone. Serum mIL-12 levels in mice that had undergone electro-sonoporation (peaking at 25.5 ng/ml) were twofold higher after gene transfer than were those in mice having undergone electroporation alone (peaking at 14.3 ng/ml), and maintained high serum level of 13.9 ng/ml at 28 days after gene transfer. The efficacy of gene transfer via electro-sonoporation was superior when the plasmid DNA solution was 0.85% NaCl compared to albumin microbubble echo-contrast material. These results demonstrated that gene transfer into muscle via electro-sonoporation could provide a new potent nonviral technique for gene transfer in vivo.

New technique for the retraction of the liver in laparoscopic gastrectomy.

We developed a new technique for the retraction of the liver using a Penrose drain and a J-shaped retractor, which is both an easy and time-saving method that provides a good view during laparoscopic gastrectomy without damaging the liver.

Skeletal muscle area correlates with body surface area in healthy adults

Depletion of skeletal muscle mass (sarcopenia) predicts survival in patients with cancer or liver cirrhosis. Recently, many reports have used computed tomography (CT) to measure muscle area to define sarcopenia. However, the definition of sarcopenia using CT has not been fully determined. The aim of this study was to establish formulae to calculate the standard area of skeletal muscle.

Prognostic factors affecting survival at recurrence of hepatocellular carcinoma after living-donor liver transplantation: with special reference to neutrophil/lymphocyte ratio.

Background In living-donor liver transplantation (LDLT) for hepatocellular carcinoma (HCC), it is important to predict not only who may be susceptible to recurrence but also who may survive longer. The neutrophil/lymphocyte ratio (NLR) is useful to properly assess the patient without decreasing the long-term survival after LDLT. In this study, we investigated the relationship between NLR and prognosis of patients with recurrent HCC after LDLT. Methods In total, 167 LDLTs for HCC were enrolled in this study. Clinicopathologic factors for HCC recurrence after LDLT were investigated and prognostic factors were examined with respect to survival. Results The following factors were found to be significant in patients with HCC recurrence compared with the controls: &agr;-fetoprotein ≧300 ng/mL, des-&ggr;-carboxyprothrombin ≧300 mAU/mL, NLR ≧4, tumor number >3, tumor size ≧5 cm, duration of last treatment of HCC to LDLT <3 months, Milan criteria exceeded, histologic tumor number ≧10, histologic tumor size >5 cm, poor differentiation, presence of histologic vascular invasion, adjuvant chemotherapy, and interferon therapy against patients with hepatitis C virus. Male sex, interferon therapy against patients with hepatitis C virus, &agr;-fetoprotein ≧300 ng/mL at recurrence, NLR ≧4 at recurrence, and nonsurgical resection for recurrent HCC were significantly related to poor prognosis. The 3-year survival rate after recurrence was 0% in patients with NLR ≧4 and 43.6% in patients with NLR <4. NLR was reelevated after LDLT in patients who later died; however, NLR gradually decreased in surviving patients. Conclusion NLR at recurrence is a prognostic factor affecting survival after recurrence in LDLT for HCC.

Strategies for Successful Left-Lobe Living Donor Liver Transplantation in 250 Consecutive Adult Cases in a Single Center

BACKGROUND Living donor liver transplantation (LDLT) using left-lobe grafts was not generally recognized as feasible due to the problem of graft size. STUDY DESIGN We retrospectively evaluated strategies for successful left-lobe LDLT in 250 consecutive cases stratified into 2 eras: Era 1 (n = 121), in which surgical procedures were continually refined, and Era 2 (n = 129), in which established procedures were used. RESULTS Graft volume (GV) did not affect the incidence of graft function or survival. Era 2 patients had decreased portal vein (PV) pressure at closure (16.0 ± 3.5 mmHg vs 19.1 ± 4.6 mmHg, p < 0.01), increased PV flow/GV (301 ± 125 mL/min/100g vs 391 ± 142 mL/min/100g, p < 0.01), and improved graft survival rate (1-year: 90.6% vs 81.8%. p < 0.01) despite the smaller GV/standard volume (SLV) ratio (36.2% ± 5.2% vs 41.2% ± 8.8%, p < 0.01) compared with Era 1. Patients in Era 2 had lower PV pressure and greater PV flow (y = 598-5.7 x, p = 0.02) at any GV/SLV compared with cases in Era 1 (y = 480-4.3 x, p < 0.01), representing greater graft compliance. Univariate analysis for graft survival showed that Era 1, Model for End-Stage Liver Disease (MELD) score ≥ 20, inpatient status, closing portal venous pressure ≥ 20 mmHg, no splenectomy, and operative blood loss ≥ 10 L were the risk factors for graft loss, and multivariate analysis showed that Era 1 was the only significant factor (p < 0.01). During Era 2, development of primary graft dysfunction was associated with inpatient recipient status (p = 0.02) and donor age ≥ 45 years (p < 0.01). CONCLUSIONS The outcomes of left-lobe LDLT were improved by accumulated experience and technical developments.

Long-term favorable surgical results of laparoscopic hepatic resection for hepatocellular carcinoma in patients with cirrhosis: a single-center experience over a 10-year period.

BACKGROUND We first performed laparoscopic hepatic resection (Lap-Hx) for hepatocellular carcinoma (HCC) in 1994. Here we review the long-term surgical results of Lap-Hx for HCC in patients with cirrhosis over a 10-year period at a single institution. STUDY DESIGN Between January 2000 and December 2013, 99 patients with cirrhosis underwent open hepatic resection (Open-Hx) and 63 underwent Lap-Hx for primary HCC within the Milan criteria. We compared the operative outcomes and patient survival between the 2 groups. RESULTS There were no significant differences regarding patient background characteristics or tumor-related factors between the 2 groups. The morbidity rate of the Lap-Hx group was significantly lower than that of the Open-Hx group (26% vs 10%; p = 0.0459), and the complication rate of ascites was significantly lower (7% vs 0%; p = 0.0077). The mean duration of hospital stay of the Lap-Hx group was significantly shorter than that of the Open-Hx group (16 vs 10 days; p = 0.0008). There were no significant between-group differences regarding overall or disease-free survival. CONCLUSIONS Laparoscopic-Hx for HCC in patients with cirrhosis is associated with less morbidity and shorter hospital stays, with no compromise in patient survival. It may be time to consider changing the standard operation for primary HCC within the Milan criteria to Lap-Hx in patients with cirrhosis.