Laparoscopic and open minor liver resection for hepatocellular carcinoma with clinically significant portal hypertension: a multicenter study using inverse probability weighting approach.

BACKGROUND: Liver resection offers substantial advantages over open liver resection (OLR) for patients with hepatocellular carcinoma (HCC) in terms of reduced intraoperative blood loss and morbidity. However, there is limited evidence comparing the indications and perioperative outcomes with the open versus laparoscopic approach for resection. This study aimed to compare postoperative outcomes between patients undergoing laparoscopic liver resection (LLR) and OLR for HCC with clinically significant portal hypertension (CSPH). METHODS: A total of 316 HCC patients with CSPH (the presence of gastroesophageal varices or platelet count < 100,000/ml and spleen diameter > 12 cm) undergoing minor liver resection at eight centers were included in this study. To adjust for confounding factors between the LLR and OLR groups, an inverse probability weighting method analysis was performed. RESULTS: Overall, 193 patients underwent LLR and 123 underwent OLR. After weighting, LLR was associated with a lower volume of intraoperative blood loss and the incidence of postoperative complications (including pulmonary complications, incisional surgical site infection, and paralytic ileus) compared to the OLR group. The 3-, 5-, and 7-year postoperative recurrence-free survival rates were 39%, 26%, and 22% in the LLR group and 49%, 18%, and 18% in the OLR group, respectively (p = 0.18). And, the 3-, 5-, and 7-year postoperative overall survival rates were 71%, 56%, and 44% in the LLR group and 76%, 51%, 44% in the OLR group, respectively (p = 0.87). CONCLUSIONS: LLR for HCC patients with CSPH is clinically advantageous by lowering the volume of intraoperative blood loss and incidence of postoperative complications, thereby offering feasible long-term survival.

Surgical management of right hepatectomy after coronary artery bypass grafting using the right gastroepiploic artery: a case report and literature review.

BACKGROUND: Coronary artery bypass grafting (CABG) using the right gastroepiploic artery (RGEA) is a well-established, safe procedure. However, problems with RGEA grafts in subsequent abdominal surgeries can lead to fatal complications. This report presents the first case of right hepatectomy for hepatocellular carcinoma after CABG using the RGEA. CASE PRESENTATION: We describe a case in which a right hepatectomy for an 81-year-old male patient with hepatocellular carcinoma was safely performed after CABG using a RGEA graft. Preoperatively, three-dimensional computed tomography (3D- CT) images were constructed to confirm the run of the RGEA graft. The operation was conducted with the standby of a cardiovascular surgeon if there was a problem with the RGEA graft. The RGEA graft had formed adhesions with the hepatic falciform ligament, necessitating meticulous dissection. After the right hepatectomy, the left hepatic lobe descended into the vacated space, exerting traction on the RGEA. However, this traction was mitigated by suturing the hepatic falciform ligament to the abdominal wall, ensuring stability of the RGEA. There were no intraoperative or postoperative complications. CONCLUSION: It is crucial to confirm the functionality and anatomy of the RGEA graft preoperatively, handle it gently intraoperatively, and collaborate with cardiovascular surgeons.

The Prognostic Value of Preoperative Serum Markers and Risk Classification in Patients with Hepatocellular Carcinoma.

BACKGROUND: Complex hepatocellular carcinoma (HCC) prognostic biomarkers have been reported in various studies. We aimed to establish biomarkers that could predict prognosis, and formulate a simple classification using non-invasive preoperative blood test data. METHODS: We retrospectively identified 305 patients for a discovery cohort who had undergone HCC-related hepatectomy at four Japanese university hospitals between January 1, 2011 and December 31, 2013. Preoperative blood test parameter optimal cut-off values were determined using receiver operating characteristic curve analysis. Cox uni- and multivariate analyses were used to determine independent prognostic factors. Risk classifications were established using classification and regression tree (CART) analysis. Validation was performed with 267 patients from three other hospitals. RESULTS: In multivariate analysis, α-fetoprotein (AFP, p < 0.001), protein induced by vitamin K absence or antagonist-II (PIVKA-II, p = 0.006), and C-reactive protein (CRP, p < 0.001) were independent prognostic factors for overall survival (OS). AFP (p = 0.007), total bilirubin (p = 0.001), and CRP (p = 0.003) were independent recurrent risk factors for recurrence-free survival (RFS). CART analysis results formed OS (CRP, AFP, and albumin) and RFS (PIVKA-II, CRP, and total bilirubin) decision trees, based on machine learning using preoperative serum markers, with three risk classifications. Five-year OS (low risk, 80.0%; moderate risk, 56.3%; high risk, 25.2%; p < 0.001) and RFS (low risk, 43.4%; moderate risk, 30.8%; high risk, 16.6%; p < 0.001) risks differed significantly. These classifications also stratified OS and RFS risk in the validation cohort. CONCLUSION: Three simple risk classifications using preoperative non-invasive prognostic factors could predict prognosis.

Dorsal vs ventral approach to the middle hepatic vein during laparoscopic left hemihepatectomy: multicenter retrospective observational study.

BACKGROUND: Left hemihepatectomy requires exposure of the middle hepatic vein (MHV) at the cutting-surface. Two procedures are used to approach the MHV: a conventional ventral approach and a laparoscopy-specific dorsal approach. This multicenter retrospective observational study aimed to evaluate the perioperative outcomes of these two procedures. METHODS: Clinical records of 38 consecutive patients that underwent laparoscopic left hemihepatectomy in four university hospitals between 2016 and 2021 were retrospectively reviewed. Outcome measurements were operative blood loss, operating time, trend of postoperative laboratory data within 7 days after hepatectomy, and postoperative complications. Quality of MHV exposure was also evaluated and compared by three-grade evaluation (excellent/good/poor) using recorded still images of the cut-surface of the remnant liver (n = 35). RESULTS: Dorsal and ventral approaches were performed in 9 and 29 patients, respectively. Median operating time was 316 min (dorsal) and 314 min (ventral) (P = 0.71). Median operative blood loss was 45 ml (dorsal) and 105 ml (ventral) (P = 0.10). Two patients in the ventral approach group had bleeding in excess of 500 ml, which was not seen in the dorsal approach group. Excellent/good/poor MHV appearance on the cutting-surface was observed in 5/3/1 patients in the dorsal approach group, respectively, and in 7/8/11 patients in the ventral approach group, respectively (P = 0.03). In the ventral approach group, significant increases of aspartate aminotransferase (on postoperative day 1 and day 4/5) and of alanine aminotransferase (on postoperative day 2/3 and 4/5) were observed (P < 0.05). Postoperative complications were observed only in the ventral approach group (n = 3). CONCLUSIONS: The dorsal approach could achieve safe and precise anatomical left hemihepatectomy with operation time and operative blood loss comparable to the conventional ventral approach.

Treatment strategy for resectable colorectal cancer liver metastases from the viewpoint of time to surgical failure.

PURPOSE: The efficacy of pre or postoperative chemotherapy for resectable colorectal cancer liver metastases (CRLM) is disputed. This study aimed to examine the risk factors for time to surgical failure (TSF) and analyze the efficacy of pre or postoperative chemotherapy prior to liver resection for CRLM. METHODS: The clinicopathological factors of 567 patients who underwent initial hepatectomy for CRLM at 7 university hospitals between April 2007 and March 2013 were retrospectively analyzed. The prognostic factors were identified and then stratified into two groups according to the number of preoperative prognostic factors: the high-score group (H-group, score 2-4) and the low-score group (L-group, score 0 or 1). RESULTS: Patients who experienced unresectable recurrence within 12 months after initial treatment had a significantly shorter prognosis than other patients (p < 0.001). Multivariate analysis identified age ≥ 70 (p = 0.001), pT4 (p = 0.015), pN1 (p < 0.001), carbohydrate antigen 19-9 ≥ 37 U/ml (p = 0.002), Clavien-Dindo grade ≥ IIIa (p = 0.013), and postoperative chemotherapy (p = 0.006) as independent prognostic factors. In the H-group, patients who received chemotherapy had a better prognosis than those who did not (p = 0.001). CONCLUSION: Postoperative chemotherapy is beneficial in colorectal cancer patients with more than two of the following factors: age ≥ 70, carbohydrate antigen 19-9-positivity, pT4, and lymph node metastasis.

Superiority of CRP-albumin-lymphocyte index (CALLY index) as a non-invasive prognostic biomarker after hepatectomy for hepatocellular carcinoma.

BACKGROUND: We aimed to investigate whether a novel biomarker incorporating albumin, lymphocytes, and CRP can predict the prognosis for hepatocellular carcinoma (HCC) after hepatectomy. METHODS: Between January 2011 and December 2013, 384 patients who underwent hepatectomy in four university hospitals in Japan were investigated as a discovery cohort. The CRP-Albumin-Lymphocyte (CALLY index) was defined as (Albumin × Lymphocyte)/(CRP × 104). Patients with a CALLY index ≥5 (n = 200) were compared to those with an index <5 (n = 184). Next, validation was performed using 267 patients from three other university hospitals (external validation cohort). RESULTS: The number of TNM Stage III and IV patients was significantly higher in the CALLY <5 group than the ≥5 group (p = 0.003). There was a significant difference in the 5-year survival rate (CALLY ≥5: 71% vs. <5: 46%; p < 0.001). Multivariate analysis identified the CALLY index as an independent factor of overall survival. Similarly, there was a significant difference in the 5-year survival rate between the CALLY ≥5 (73%) and <5 (48%) groups (p < 0.001), and the CALLY index was identified as an independent prognostic factor in the external validation cohort. CONCLUSION: The CALLY index derived from CRP, albumin, and lymphocyte values is a promising predictive biomarker for postoperative prognosis of patients with HCC.

Association Between Neoadjuvant Chemoradiotherapy and Intractable Serous Ascites After Pancreaticoduodenectomy for Pancreatic Cancer.

BACKGROUND: Intractable serous (not chylous) ascites (IA) that infrequently develops early following pancreaticoduodenectomy (PD) for pancreatic cancer is a life-threatening problem. The relationship between neoadjuvant chemoradiotherapy (NACRT) for pancreatic cancer and the incidence of IA following PD has not been evaluated. This study aims to identify the risk factors associated with IA that develops early after PD for pancreatic cancer. METHODS: We retrospectively identified 94 patients who underwent PD for pancreatic cancer at the Department of General and Gastroenterological Surgery, Osaka Medical College Hospital, Osaka, Japan, from April 2012 to March 2020. Data on 29 parameters were obtained from medical records. Univariate and multivariate analyses were conducted to identify independent risk factors. Levels of serum albumin were compared before and after NACRT to analyze its effect. Survival analysis was also conducted. RESULTS: Of the 92 patients included in this study, 8 (8.70%) were categorized into the IA group. Multivariate analysis identified NACRT [odds ratio (OR) 27, 95% confidence interval (CI) 1.87-394, p = 0.016)] and hypoalbuminemia (≤ 1.6 g/dl) just after the operation (OR 50, 95% CI 1.68-1516, p = 0.024) as risk factors. The level of serum albumin was significantly decreased following NACRT. The IA group had poorer prognosis than the control group. CONCLUSIONS: IA is a serious problem that aggravates patient's prognosis. Postoperative lymphatic leak might be a trigger of IA. NACRT was a major risk factor, followed by hypoalbuminemia caused by various reasons. These factors may act synergistically and cause IA.

Chymase as a Novel Therapeutic Target in Acute Pancreatitis.

Acute pancreatitis is still a life-threatening disease without an evidenced therapeutic agent. In this study, the effect of chymase in acute pancreatitis and the possible effect of a chymase inhibitor in acute pancreatitis were investigated. Hamsters were subcutaneously administered 3.0 g/kg of L-arginine to induce acute pancreatitis. Biological markers were measured 1, 2, and 8 h after L-arginine administration. To investigate the effect of a chymase inhibitor, a placebo (saline) or a chymase inhibitor TY-51469 (30 mg/kg) was given 1 h after L-arginine administration. The survival rates were evaluated for 24 h after L-arginine administration. Significant increases in serum lipase levels and pancreatic neutrophil numbers were observed at 1 and 2 h after L-arginine administration, respectively. Significant increases in pancreatic neutrophil numbers were observed in the placebo-treated group, but they were significantly reduced in the TY-51469-treated group. A significant increase in the pancreatic tumor necrosis factor-α mRNA level was observed in the placebo-treated group, but it disappeared in the TY-51469-treated group. Chymase activity significantly increased in the placebo-treated group, but it was significantly reduced by treatment with TY-51469. The survival rate significantly improved in the TY-51469-treated group. A chymase inhibitor may become a novel therapeutic agent for acute pancreatitis.

Is Postoperative Adjuvant Transcatheter Arterial Infusion Therapy Effective for Patients with Hepatocellular Carcinoma who Underwent Hepatectomy? A Prospective Randomized Controlled Trial.

BACKGROUND: The effectiveness of adjuvant transcatheter arterial chemo- or/and chemoembolization therapy after curative hepatectomy of initial hepatocellular carcinoma (HCC) is controversial. This study aimed to evaluate whether hepatectomy combined with adjuvant transcatheter arterial infusion therapy (TAI) for initial HCC has better long-term survival outcomes than hepatectomy alone. METHODS: From January 2012 to December 2014, a prospective randomized controlled trial of patients with initial HCC was conducted. Then, 114 initial HCC patients were recruited to undergo hepatectomy with adjuvant TAI (TAI group, n = 55) or hepatectomy alone (control group, n = 59) at our institution. The TAI therapy was performed twice, at 3 and 6 months after curative hepatectomy (UMIN 000011900). RESULTS: The patients treated with TAI had no serious side effects, and operative outcomes did not differ between the two groups. No significant differences were found in the pattern of intrahepatic recurrence or time until recurrence between the two groups. Moreover, no significant differences were found in the relapse-free survival or overall survival. Low cholinesterase level (< 200) had been identified as a risk factor affecting relapse-free survival. Furthermore, compared with surgery alone, adjuvant TAI with hepatectomy improved the overall survival for lower-cholinesterase patients. CONCLUSIONS: Adjuvant TAI is safe and feasible, but it cannot reduce the incidence of postoperative recurrence or prolong survival for patients who underwent curative hepatectomy for initial HCC.

Laparoscopic versus open liver resection for hepatocellular carcinoma in elderly patients: a multi-centre propensity score-based analysis.

BACKGROUND: The frequency of liver resection in elderly patients has been increasing. However, data are limited regarding the safety of laparoscopic liver resection (LLR) compared with that of open liver resection (OLR) for hepatocellular carcinoma (HCC) in elderly patients. The present study aimed to compare short-term outcomes between LLR and OLR in elderly patients with HCC using propensity score matching. METHODS: The study included 630 patients (age, ≥ 75 years) who underwent liver resection for HCC at nine liver centres between April 2010 and December 2017. Patients were divided into LLR and OLR groups, and perioperative outcomes were compared between the groups. In addition, subgroup analysis was performed according to age (75-79 and ≥ 80 years). RESULTS: Of the 630 patients, 221 and 409 were included in the LLR and OLR groups, respectively. After propensity score matching, 155 patients were included in each group. Intraoperative blood loss and the transfusion, post-operative overall complication and major complication rates were lower in the matched LLR than the matched OLR group (P < 0.001, P = 0.004, P < 0.001 and P < 0.001, respectively). Moreover, post-operative pulmonary and cardiovascular complications were less frequent in the matched LLR group (P = 0.008 and P = 0.014, respectively). In subgroup analysis, among octogenarians, the post-operative major complication rate was lower and hospital stay was shorter in the matched LLR than the matched OLR group (P < 0.001 and P < 0.001, respectively). CONCLUSION: LLR for HCC is associated with good short-term outcomes in patients aged ≥ 75 years compared with OLR. LLR is safe and feasible in selected octogenarians with HCC.

The Management of Recurrence within Six Months after Hepatic Resection for Colorectal Liver Metastasis.

BACKGROUND: Hepatectomy is currently recommended as the most reliable treatment for colorectal liver metastases. However, the association between the choice of treatment for recurrence and the timing of recurrence remains controversial. METHODS: Two-hundred ninety-five patients who underwent hepatectomy were retrospectively analyzed for the risk factors and the outcomes for early recurrence within 6 months. The remnant liver volumes (RLVs) and laboratory data were measured postoperatively using multidetector computed tomography on days 7 and months 1, 2, and 5 after the operation. RESULTS: Early recurrence developed in 88/295 patients (29.8%). Colorectal cancer lymph node metastasis, synchronous liver metastasis, and multiple liver metastases were independent risk factors for the occurrence of early recurrence (p < 0.001, 0.032, and 0.019, respectively). Patients with early recurrence had a poorer prognosis than did patients who developed later recurrence (p < 0.001). Patients who underwent surgery or other local treatment had better outcomes. The changes in RLV and laboratory data after postoperative month 2 were not significantly different between the 2 groups. CONCLUSION: Patients with early recurrence within 6 months had a poorer prognosis than did patients who developed later recurrence. However, patients who underwent repeat hepatectomy for recurrence had a better prognosis than did those who underwent other treatments, with good prospects for long-term survival.

Initial pulmonary metastasis after pancreatectomy for pancreatic ductal adenocarcinoma.

Patients who undergo pancreatectomy for pancreatic ductal adenocarcinoma (PDA) develop relatively early recurrence, but pulmonary metastasis from PDA is rare. Between January 2008 and December 2016, a total of 120 consecutive patients underwent pancreatectomy for primary PDA at Osaka Medical College Hospital. Among these, 13 patients developed pulmonary metastasis and 6 patients underwent pulmonary metastasectomy. Among these patients, the median disease-free survival following initial pancreatic surgery was 26.1 months, and the median overall survival (OS) interval was 39 months. On the other hand, seven patients did not undergo pulmonary resection. The median OS interval of these patients was 33 months. The 1-, 3-, and 5-year OS rates were 100%, 80%, and 60%, respectively, for patients who underwent pulmonary metastasectomy and 100.0%, 42.8%, and 0%, respectively, for those who did not undergo the procedure. Our experience has shown that surgical resection may lengthen the survival time of patients who tolerate surgery.

Surgical treatment of gastric venous congestion in association with extended resection of pancreas: a case report.

BACKGROUND: Total pancreatectomy is performed for chronic pancreatitis, tumors involving the entire pancreas or remnant pancreas after pancreatectomy. Gastric venous congestion and bleeding may be associated with total pancreatectomy. We report the case of a patient who underwent left gastric vein to splenic vein bypass to relieve gastric venous congestion during total pancreatectomy for remnant pancreatic cancer. CASE PRESENTATION: A 60-year-old woman underwent subtotal stomach-preserving pancreaticoduodenectomy for cancer of the pancreatic head. A follow-up computed tomography revealed a low-density tumor of the remnant pancreas. The pathological diagnosis was adenocarcinoma on endoscopic ultrasound-fine needle aspiration. Total resection of the remnant pancreas was performed for the tumor 3 years after the initial surgery. We ligated the splenic vein at the point of distal side of the left gastric vein confluent. Immediately, the vein congestion around the stomach was confirmed. We found the stenosis of the confluent between the left gastric vein and splenic vein. We subsequently anastomosed the left gastric vein and splenic vein, following which the gastric venous congestion was relieved. CONCLUSION: In cases wherein all the drainage veins from the stomach are removed, an anastomosis between the left gastric vein and splenic vein can be effectively used to prevent gastric venous congestion and bleeding after total pancreatectomy.

Is neoadjuvant chemotherapy appropriate for patients with resectable liver metastases from colorectal cancer?

PURPOSE: Neoadjuvant chemotherapy (NAC) for resectable liver metastasis from colorectal cancer (CRLM) is used widely, but its efficacy lacks clear evidence. This study aimed to clarify its worth and develop appropriate treatment strategies for CRLM. METHODS: We analyzed, retrospectively, the clinicopathological factors and outcomes of 137 patients treated for resectable CRLM between 2006 and 2015, with upfront surgery (NAC- group; n = 117) or initial NAC treatment (NAC+ group; n = 20). RESULTS: The time to surgical failure (TSF) and overall survival (OS) after initial treatment were significantly worse in the NAC+ group than in the NAC- group (P = 0.002 and P = 0.032, respectively). At hepatectomy, the NAC+ group had a lower median prognostic nutrition index (PNI), higher rates of a positive Glasgow Prognostic Score (P = 0.002) and more perioperative blood transfusions (P = 0.027) than the NAC- group. Moreover, the serum albumin (P = 0.006), PNI (P ≤ 0.001) and lymphocyte-to-monocyte ratio (P ≤ 0.001) were significantly decreased and the GPS positive rate was increased from 15 to 35% in the NAC+ group. The OS rates did not differ significantly according to the NAC response (5-year OS rates-CR/PR 67%, SD 60%, PD 38%). CONCLUSIONS: Patients with resectable CRLM should undergo upfront hepatectomy because NAC did not improve OS after initial treatment in these patients.

A Concealed "Natural Orifice": Umbilicus Anatomy for Minimally Invasive Surgery.

INTRODUCTION: A recent development in minimally invasive surgery (MIS) is single-port surgery, where a single large multiport trocar is placed in the umbilicus. All medical schools require that students complete an anatomy course as part of the medical curriculum. However, there is limited instruction regarding the detailed parts of the "umbilicus." In several famous anatomy atlases, the umbilicus is not dissected at all and is merely represented as a button. Until now, the true nature of the umbilicus has not been anatomically demonstrated. METHODS: Five cadavers were obtained from the Osaka Medical College medical student anatomy class. The umbilicus was dissected in the anatomy laboratory, to demonstrate all the layers. A detailed dissection was performed, focusing on the exact center of the umbilicus, in order to ascertain whether there exists a "natural orifice" or a fascial defect. RESULTS: In all cadavers, a small defect of fascia was identified just below the center of the umbilicus. Yellow fatty tissue was present just below the skin in the exact center of the umbilicus. A probe placed exactly in the middle of this defect passes easily through into the abdominal cavity. CONCLUSIONS: With the widespread use of MIS, umbilical incision is commonly used to reduce pain and improve cosmetic results. This study consistently revealed a natural defect of fascia in the center of the umbilicus. Therefore, the umbilicus can be called a concealed "natural orifice." It is important to recognize and utilize this defect effectively to minimize unnecessary tissue trauma during MIS.

Perioperative allogenic blood transfusion is a poor prognostic factor after hepatocellular carcinoma surgery: a multi-center analysis.

PURPOSE: The influence of allogenic blood transfusion on the postoperative outcomes of hepatocellular carcinoma (HCC) surgery remains controversial. This study aims to clarify the clinical impacts of perioperative allogenic blood transfusion on liver resection outcome in HCC patients. METHODS: We analyzed data collected over 5 years for 642 patients who underwent hepatectomy for HCC at one of the five university hospitals. We investigated the impact of allogenic blood transfusion on postoperative outcome after surgery in all patients and in 74 matched pairs, using a propensity score. RESULTS: Of the 642 patients, 198 (30.8%) received perioperative allogenic blood transfusion (AT group) and 444 (69.2%) did not (non-AT group). Overall survival was lower in the AT group than in the non-AT group in univariate (P < 0.001) and multivariate analyses (risk ratio 1.521, P = 0.011). After matching the different distributions using propensity scores, perioperative blood transfusion was found to be a poor prognostic factor for HCC patients. CONCLUSIONS: In this multi-center study, perioperative blood transfusion was an independent factor for poor prognosis after curative surgery for primary HCC in the patient group and in pairs matched by propensity scores.

The utility of the subcuticular suture in hepatic resection.

AIM OF THE STUDY: Despite recent technical progress and advances in the perioperative management of liver surgery, postoperative surgical site infection (SSI) is still one of the most common complications that extends hospital stays and increases medical expenses following hepatic surgery. MATERIAL AND METHODS: From 2001 to 2017 a total of 1180 patients who underwent hepatic resection for liver tumours were retrospectively analysed with respect to the predictive factor of superficial incisional SSI, using a propensity score matching by procedure (subcuticular or mattress suture). RESULTS: The incidence of superficial and deep incisional SSIs was found to be 7.1% (84/1180). By propensity score matching (PSM), 121 of the 577 subcuticular suture group patients could be matched with 121 of the 603 mattress suture group patients. Multivariate analysis demonstrated wound closure technique as the only independent risk factor that correlated significantly with the occurrence of superficial incisional SSIs (p = 0.038). C-reactive protein (CRP) levels on postoperative day 4 were significantly higher in patients with incisional SSIs than in those without (p < 0.001). CONCLUSIONS: Wound closure technique with subcuticular continuous spiral suture using absorbable suture should be considered to minimise the incidence of incisional SSIs. Moreover, wounds should be carefully checked when CRP levels are high on postoperative day 4.

Chymase inhibitor prevents the development and progression of non-alcoholic steatohepatitis in rats fed a high-fat and high-cholesterol diet.

The effect of the chymase inhibitor TY-51469 on the development and progression of non-alcoholic steatohepatitis (NASH) was evaluated in rats fed a high-fat and high-cholesterol (HFC) diet. To evaluate the preventive effect of TY-51469 on the development of NASH, stroke-prone spontaneously hypertensive rat 5 (SHRSP5)/Dmcr rats were fed either a normal or HFC diet for 8 weeks, and concurrently administered either placebo or TY-51469 (1 mg/kg per day). To evaluate the effect of TY-51469 on the survival rate, TY-51469 was administered either concurrently with HFC diet (pretreated group) or 8 weeks after HFC diet at which point NASH had developed (posttreated group). Eight weeks after HFC diet, significant increases of steatosis, fibrosis and chymase-positive cells were observed in liver from the placebo-treated rats. Significant increases of myeloperoxidase, transforming growth factor-ß, matrix metalloproteinase-9, and collagen I mRNA levels were also observed. However, all parameters were significantly attenuated in the TY-51469-treated group. A survival rate of the placebo-treated group fed the HFC diet was 0% at 14 weeks. In comparison, the rates of TY-51469-pretreated and TY-51469-posttreated groups were 100% and 50% at 14 weeks, respectively. Chymase inhibitor may be applicable to preventing the development and progression of NASH.