Publications by authors named "Keisuke Yokohama"

22 Publications

  • Page 1 of 1

Dysbiosis and liver diseases (Review).

Int J Mol Med 2021 Sep 30;48(3). Epub 2021 Jul 30.

The Second Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka 569‑8686, Japan.

Dysbiosis, a qualitative and quantitative aberrancy of gut microbiota, has attracted marked attention. At present, advances in molecular biological techniques have made it possible to analyze gut microbiota at the DNA and RNA levels without culturing, and methods such as 16S ribosomal RNA targeting analysis and metagenomic analysis using next‑generation sequencers have been developed. The relationship between gut microbiota and various diseases has been extensively examined. Gut microbiota are essential for the immune system, energy intake and fat storage, and humans use them to build complex immune regulatory mechanisms and to obtain energy from food. The liver is the first organ to be nourished by the portal blood flow of intestinal origin, and liver diseases can be strongly influenced by various factors of intestinal origin, such as intestinal bacteria, bacterial components, and intestinal bacterial metabolites. Rigorous research has revealed that the composition of the gut microbiota is altered and the diversity of bacteria is reduced in liver diseases. Significance of various factors transported to the liver by portal vein blood flow from the intestine has been extensively investigated. Gut microbiota in liver disease can be associated with disease progression regardless of disease etiology and even with carcinogenesis. The relationship between gut microbiota and liver diseases (hepatitis virus‑related diseases, autoimmune liver diseases, alcoholic liver disease, non‑alcoholic fatty liver disease, non‑alcoholic steatohepatitis, liver cirrhosis and hepatocellular carcinoma) and the treatments of dysbiosis (antibiotics, prebiotics, probiotics and fecal microbiota transplantation) in liver disease are outlined based on the current evidence.
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http://dx.doi.org/10.3892/ijmm.2021.5016DOI Listing
September 2021

Association between Administration of Antithrombotics and Intraperitoneal Hemorrhage in Patients Undergoing Percutaneous Interventions for Liver Diseases.

J Clin Med 2021 Jun 7;10(11). Epub 2021 Jun 7.

2nd Department of Internal Medicine, Osaka Medical College, Takatsuki 5698686, Japan.

Currently, percutaneous interventions are essential for diagnosis and treatment of liver diseases. The most frequent complication of percutaneous interventions is intraperitoneal hemorrhage. Recently, the number of patients with liver diseases on antithrombotics has been increasing. This retrospective cohort study aimed to evaluate the risk factors for intraperitoneal hemorrhage in patients after percutaneous interventions for liver diseases. This study included 1025 patients who underwent percutaneous interventions for liver diseases from April 2015 to March 2020. All interventions were performed using an ultrasound-guided approach. The influence of antithrombotic drug administration in patients, who underwent percutaneous interventions according to the guidelines for the American Association for the Study of Liver Disease, was evaluated. Intraperitoneal hemorrhage after percutaneous interventions was detected by computed tomography. Intraperitoneal hemorrhage occurred in nine patients (0.88%); however, these adverse events were not severe. We compared clinical characteristics between the patients with and without intraperitoneal hemorrhage. Although, there was no difference based on the administration of antithrombotics ( = 0.1961), seven of nine patients who showed intraperitoneal hemorrhage received percutaneous treatments (radio frequency ablation or microwave ablation). Therefore, we divided patients who underwent treatments and liver biopsy and then investigated the influence of antithrombotics on the intraperitoneal hemorrhage. After propensity score matching in each patient group, the administration of antithrombotics was not identified as a risk factor for hemorrhage in patients who underwent interventional treatments and patients who underwent liver biopsy. When the antithrombotics were discontinued, according to the guidelines, it may not increase the risk factor for hemorrhage in patients of liver disease who underwent percutaneous interventions.
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http://dx.doi.org/10.3390/jcm10112527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201393PMC
June 2021

Pathophysiology and mechanisms of primary sarcopenia (Review).

Int J Mol Med 2021 Aug 29;48(2). Epub 2021 Jun 29.

The Second Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka 569‑8686, Japan.

Aging causes skeletal muscle atrophy, and myofiber loss can be a critical component of this process. In 1989, Rosenberg emphasized the importance of the loss of skeletal muscle mass that occurs with aging and coined the term 'sarcopenia'. Since then, sarcopenia has attracted considerable attention due to the aging population in developed countries. The presence of sarcopenia is closely related to staggering, falls and even frailty in the elderly, which in turn leads to the need for nursing care. Sarcopenia is often associated with a poor prognosis in the elderly. Therefore, it is crucial to investigate the causes and pathogenesis of sarcopenia, and to develop and introduce interventional strategies in line with these causes and pathogenesis. Sarcopenia can be a primary component of physical frailty. The association between sarcopenia, frailty and locomotive syndrome is complex; however, sarcopenia is a muscle‑specific concept that is relatively easy to approach in research. In the elderly, a lack of exercise, malnutrition and hormonal changes lead to neuromuscular junction insufficiency, impaired capillary blood flow, reduced repair and regeneration capacity due to a decrease in the number of muscle satellite cells, the infiltration of inflammatory cells and oxidative stress, resulting in muscle protein degradation exceeding synthesis. In addition, mitochondrial dysfunction causes metabolic abnormalities, such as insulin resistance, which may lead to quantitative and qualitative abnormalities in skeletal muscle, resulting in sarcopenia. The present review article focuses on age‑related primary sarcopenia and outlines its pathogenesis and mechanisms.
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http://dx.doi.org/10.3892/ijmm.2021.4989DOI Listing
August 2021

Outcomes of Sequential Therapy With Tenofovir Alafenamide After Long-term Entecavir.

Am J Gastroenterol 2021 06;116(6):1264-1273

Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan.

Introduction: Entecavir (ETV) and tenofovir alafenamide (TAF) are both first-line hepatitis B virus (HBV) therapies, but ETV-to-TAF switch outcome data are limited. We aimed to assess outcomes up to 96 weeks after ETV-to-TAF switch.

Methods: ETV-treated (≥12 months) chronic hepatitis B patients switched to TAF in routine practice at 15 centers (United States, Korea, Japan, and Taiwan) were included. Primary outcome was complete viral suppression (CVS) rate (HBV DNA <20 IU/mL).

Results: We analyzed 425 eligible patients (mean age 60.7 ± 13.2 years, 60% men, 90.8% Asian, 20.7% with diabetes, 27% with hypertension, 14.8% with cirrhosis, 8.3% with hepatocellular carcinoma, and mean ETV duration before switch 6.16 ± 3.17 years). The mean baseline estimated glomerular filtration rate (eGFR) was 89 ± 19 (chronic kidney disease [CKD] stages: 55.6% stage 1, 35.7% stage 2, and 8.8% stages 3-5). CVS rate increased from 91.90% at switch (from 90.46% 24 weeks before switch) to 95.57% and 97.21% at 48 and 96 weeks after (P = 0.03 and 0.02, respectively). Over the 96 weeks after switch, mean HBV DNA (P < 0.001) but not alanine aminotransferase or CKD stage decreased. Between switch and 96-week follow-up, 11% (26/235) of CKD stage 1 patients migrated to stage 2 and 8% (12/151) of stage 2 patients to stages 3-5, whereas 18% (27/151) from stage 2 to 1, and 19% (7/37) from stages 3-5 to 2. On multivariable generalized estimated equation analysis adjusted for age, sex, hypertension, diabetes, and cirrhosis, baseline eGFR, age (P < 0.001), and CKD stages 2 and 3-5 (vs 1) (both P < 0.001) were associated with lower follow-up eGFR.

Discussion: After an average of 6 years on ETV, CVS increased from 91.9% at TAF switch to 97.2% at 96 weeks later.
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http://dx.doi.org/10.14309/ajg.0000000000001157DOI Listing
June 2021

Treatment and Renal Outcomes Up to 96 Weeks After Tenofovir Alafenamide Switch From Tenofovir Disoproxil Fumarate in Routine Practice.

Hepatology 2021 Aug 22;74(2):656-666. Epub 2021 May 22.

Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA.

Background And Aims: Real-world data for treatment effectiveness and renal outcomes in chronic hepatitis B (CHB) patients who were switched to the new and safer prodrug tenofovir alafenamide (TAF) from tenofovir disoproxil fumarate (TDF) are limited. Therefore, we aimed to evaluate treatment and renal outcomes of this population.

Approach And Results: We analyzed 834 patients with CHB previously treated with TDF for ≥12 months who were switched to TAF in routine practice at 13 US and Asian centers for changes in viral (HBV DNA < 20 IU/mL), biochemical (alanine aminotransferase [ALT] < 35/25 U/L for male/female), and complete (viral+biochemical) responses, as well as estimated glomerular filtration rate (eGFR; milliliters per minute per 1.73 square meters) up to 96 weeks after switch. Viral suppression (P < 0.001) and ALT normalization (P = 0.003) rates increased significantly after switch, with a trend for increasing complete response (P = 0.004), while the eGFR trend (P  > 0.44) or mean eGFR (P > 0.83, adjusted for age, sex, baseline eGFR, and diabetes, hypertension, or cirrhosis by generalized linear modeling) remained stable. However, among those with baseline eGFR < 90 (chronic kidney disease [CKD] stage ≥2), mean eGFR decreased significantly while on TDF (P = 0.029) but not after TAF switch (P = 0.90). By week 96, 21% (55/267) of patients with CKD stage 2 at switch improved to stage 1 and 35% (30/85) of CKD stage 3-5 patients improved to stage 2 and 1.2% (1/85) to stage 1.

Conclusions: Overall, we observed continued improvement in virologic response, ALT normalization, and no significant changes in eGFR following switch to TAF from TDF.
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http://dx.doi.org/10.1002/hep.31793DOI Listing
August 2021

Diabetes mellitus does not influence results of hepatectomy in hepatocellular carcinoma: case control study.

Contemp Oncol (Pozn) 2020 4;24(4):211-215. Epub 2021 Jan 4.

Department of General and Gastroenterological Surgery, Osaka Medical College Mishima-Minami Hospital, Takatsuki City, Osaka, Japan.

Introduction: Patients with diabetes mellitus undergoing hepatectomy for hepatocellular carcinoma (HCC) are at high risk of acquiring perioperative infections. Herein, we investigate the peri-operative impact of diabetes on hepatectomy.

Material And Methods: The surgical outcomes in 363 patients who underwent laparoscopic and open hepatic resection for HCC, with or without diabetes mellitus, were reviewed retrospectively. The association of diabetes mellitus with surgical outcomes and remnant liver regeneration was analyzed. The Student's and χ tests, Mann-Whitney's U test, Wilcoxon's signed-rank test, or Fisher's exact test were used in the statistical analysis.

Results: Of the 363 patients, 136 (37.5%) had diabetes, while 227 (62.5%) did not. After propensity score matching, there were no significant differences between the groups in surgical outcomes such as surgery duration, bleeding amount, and postoperative complication rate. No significant differences were observed between the groups in terms of incidence rates of not only infectious complications, including surgical site infection and remote site infection, but also postoperative complication (Clavien-Dindo grade > IIIA), post-hepatectomy liver failure, and massive ascites. There were no differences in the remnant liver regeneration at 7 days and 1, 2, 5, and 12 months following the surgery between the groups ( = 0.076, 0.368, 0.864, 0.288, and 0.063, respectively). No significant differences between the groups in the overall and recurrence-free survival were observed ( = 0.613 and 0.937).

Conclusions: Remnant liver regeneration in diabetic patients was not morphologically and functionally delayed compared to that in non-diabetic patients. Moreover, diabetes has no effect on the short- and long-term prognosis.
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http://dx.doi.org/10.5114/wo.2020.102825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836278PMC
January 2021

The Management of Recurrence of Hepatocellular Carcinoma Occurring Within 6 Months After Hepatic Resection: A Comparative Study Using a Propensity Score Matching Analysis.

J Gastrointest Cancer 2021 Jan 20. Epub 2021 Jan 20.

Department of General and Gastroenterological Surgery, Osaka Medical College Mishima-Minami Hospital, 8-1 Tamagawa-shinmachi, Takatsuki City, Osaka, 569-0856, Japan.

Background: Hepatectomy is currently recommended as the most reliable treatment for hepatocellular carcinoma. However, the association between the choice of treatment for recurrence and the timing of recurrence remains controversial.

Methods: Three-hundred thirty-nine patients who underwent hepatectomy were retrospectively analyzed using a propensity score matching analysis for the risk factors and outcomes for early recurrences within 6 months. The remnant liver volumes and laboratory data were measured postoperatively using multidetector computed tomography on days 7 and months 1, 2, and 5 after surgery. The Student's t test and chi-square test, the likelihood-ratio test, Fisher's exact test, Mann-Whitney U test, or Wilcoxon signed-rank test were used in the statistical analyses.

Results: Early recurrence developed in 41/312 patients (13.1%). Vascular invasion and non-curative resection were independent risk factors for the occurrence of early recurrence (P < 0.001 and < 0.001, respectively). Patients with early recurrence had a poorer prognosis than patients who developed later recurrences (P < 0.001). Patients who underwent surgery or other local treatments had better outcomes (P < 0.001). The changes in remnant liver volumes and laboratory data after postoperative month 2 were not significantly different between the two groups.

Conclusion: Patients with early recurrence within 6 months had a poorer prognosis than patients who developed a later recurrence. However, patients who underwent repeat hepatectomy for recurrences had a better prognosis than did those who underwent other treatments, with good prospects for long-term survival.
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http://dx.doi.org/10.1007/s12029-021-00585-2DOI Listing
January 2021

Safety and Efficacy of Laparoscopic Liver Resection for Colorectal Liver Metastasis With Obesity.

Am Surg 2021 Jun 7;87(6):919-926. Epub 2020 Dec 7.

Department of Internal Medicine, Osaka Medical College Mishima-Minami Hospital, Japan.

Introduction: Laparoscopic liver resection (LLR) in obese patients has been reported to be particularly challenging owing to technical difficulties and various comorbidities.

Methods: The safety and efficacy outcomes in 314 patients who underwent laparoscopic or open nonanatomical liver resection for colorectal liver metastases (CRLM) were analyzed retrospectively with respect to the patients' body mass index (BMI) and visceral fat area (VFA).

Results: Two hundred and four patients underwent LLR, and 110 patients underwent open liver resection (OLR). The rate of conversion from LLR to OLR was 4.4%, with no significant difference between the BMI and VFA groups ( = .647 and .136, respectively). In addition, there were no significant differences in terms of operative time and estimated blood loss in LLR ( = .226 and .368; .772 and .489, respectively). The incidence of Clavien-Dindo grade IIIa or higher complications was not significantly different between the BMI and VFA groups of LLR ( = .877 and .726, respectively). In obese patients, the operative time and estimated blood loss were significantly shorter and lower, respectively, in LLR than in OLR ( = .003 and < .001; < .001 and < .001, respectively). There was a significant difference in the incidence of postoperative complications, organ/space surgical site infections, and postoperative bile leakage between the LLR and OLR groups ( = .017, < .001, and < .001, respectively).

Conclusion: LLR for obese patients with CRLM can be performed safely using various surgical devices with no major difference in outcomes compared to those in nonobese patients. Moreover, LLR has better safety outcomes than OLR in obese patients.
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http://dx.doi.org/10.1177/0003134820952448DOI Listing
June 2021

Hepatectomy and liver regeneration in the results of treatment of colorectal liver metastasis.

Contemp Oncol (Pozn) 2020 30;24(3):172-176. Epub 2020 Oct 30.

Department of General and Gastroenterological Surgery, Osaka Medical College Hospital, Takatsuki City, Osaka, Japan.

Introduction: Hepatectomy is currently the most reliable treatment modality for colorectal liver metastases (CRLM). This paper describes and discusses the outcomes of initial versus repeat hepatic resection for CRLM.

Material And Methods: Between January 2008 and December 2018, we retrospectively analyzed the data of 385 patients who underwent initial and repeat hepatic resection for CRLM at a single institution with respect to surgical outcomes and remnant liver regeneration. The remnant liver volume was postoperatively measured via computed tomography on postoperative day 7 and at 1, 2, 5, 12, and 24 months postoperatively.

Results: The liver regeneration rate peaked at 1 week postoperatively, and gradually decreased thereafter. Remnant liver volume plateaued around 1-2 months postoperatively, when regeneration was almost complete. There was no difference in the rate of liver volume regeneration during the entire postoperative period between initial and repeat hepatic resection ( 0.708, 0.511, 0.055, 0.053, 0.102, and 0.110, respectively). After 2 months postoperatively, the laboratory data showed recovery toward near normal levels, and none of the data exhibited significant differences. There were also no significant differences in morbidity rate, mortality rate, overall survival, and recurrence-free survival after hepatic resection ( 0.488, 0.124, 0.071 and 0.387, respectively).

Conclusions: Initial and repeat hepatectomy showed similar outcomes of remnant liver regeneration and short- and long-term prognoses.
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http://dx.doi.org/10.5114/wo.2020.100272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670187PMC
October 2020

Efficacy and safety of laparoscopic hepatectomy for hepatocellular carcinoma comorbid with cirrhosis.

Prz Gastroenterol 2020 19;15(3):225-233. Epub 2020 Sep 19.

Department of General and Gastroenterological Surgery, Osaka Medical College Hospital, Osaka, Japan.

Introduction: Laparoscopic hepatectomy (LH) is very difficult to perform in patients with cirrhosis because of the haemorrhagic and fibrotic nature of the liver, although there are various advantages to laparoscopic surgery.

Aim: To investigate the surgical outcomes, and efficacy and safety of LH versus open hepatectomy (OH) for hepatocellular carcinoma (HCC) resection.

Material And Methods: A total of 112 patients with cirrhosis, who underwent hepatectomy, were analysed retrospectively. We investigated the safety and efficacy of LH for HCC with cirrhosis. Student's and χ tests, Mann-Whitney's test, Wilcoxon's signed-rank test, and Fisher's exact test were used in the statistical analysis.

Results: Seventy-one patients underwent LH, and 41 underwent OH. The conversion rate from LH to OH was 12.7%. After propensity score matching, the estimated blood loss was significantly lower in the LH group than in the OH group (25 vs. 310 ml; < 0.001), and there was a significant difference between the groups in the operative time ( = 0.091). The LH group had complication rates of 3.6% and 0% for refractory ascites and pleural effusion, respectively, while those were 17.9% and 10.7%, respectively, in the OH group ( = 0.019 and = 0.005, respectively). The LH group had no mortality, whereas the OH group had a mortality rate of 10.7% ( = 0.038). The postoperative length of stay was significantly longer in the LH group than in the OH group (9 days vs. 14 days) ( = 0.002).

Conclusions: LH can be performed safely for HCC with cirrhosis. More favourable results are achieved with LH than with OH in terms of surgical outcomes.
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http://dx.doi.org/10.5114/pg.2020.99039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509897PMC
September 2020

The Effects of Allogeneic Blood Transfusion in Hepatic Resection.

Am Surg 2021 Feb 15;87(2):228-234. Epub 2020 Sep 15.

13010 Department of General and Gastroenterological Surgery, Osaka Medical College Hospital, Takatsuki, Osaka, Japan.

Background: Hepatectomy has a high risk of perioperative bleeding due to the underlying disease. Here, we investigated the postoperative impact of allogeneic blood transfusion during hepatectomy.

Methods: The surgical outcomes in 385 patients who underwent hepatic resection for hepatocellular carcinoma were retrospectively reviewed. The association of allogeneic blood transfusion with surgical outcomes and remnant liver regeneration data was analyzed.

Results: Eighty-six patients (24.0%) received an allogeneic blood transfusion and 272 patients (76.0%) did not. After propensity score matching, the incidence rates of postoperative complication (Clavien-Dindo grade >IIIA), posthepatectomy liver failure, and massive ascites were significantly higher for the group that received a blood transfusion than for the group that did not receive blood transfusion ( < .001, = .001, and <.001, respectively). Postoperative measures of total bilirubin, albumin, platelet count, prothrombin time, aspartate aminotransferase, and alanine aminotransferase were significantly more favorable in patients without blood transfusion until day 7 after surgery. There were no correlations in the remnant liver regeneration at 7 days, and 1, 2, 5, and 12 months postoperatively between the 2 groups ( = .585, .383, .507, .261, and .430, respectively). Regarding prognosis, there was no significant difference in overall and recurrence-free survival between the 2 groups ( = .065 and .166, respectively).

Conclusion: Allogeneic transfusion during hepatectomy strongly affected remnant liver function in the early postoperative period; however, this was not related to the remnant liver regeneration volume. Despite that the allogeneic transfusion resulted in poorer postoperative laboratory test results and increased postoperative complication and mortality rates, it had no effect on the long-term prognosis.
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http://dx.doi.org/10.1177/0003134820950285DOI Listing
February 2021

Liver dysfunction is associated with poor prognosis in patients after immune checkpoint inhibitor therapy.

Sci Rep 2020 09 2;10(1):14470. Epub 2020 Sep 2.

Second Department of Internal Medicine, Osaka Medical College, 2-7, Daigakumachi, Takatsuki, Osaka, 569-8686, Japan.

Immune-related adverse events (irAEs) are induced by immune checkpoint inhibitors (ICIs). Liver is one of the main target organs which irAEs occur and we investigated the influence of liver dysfunction on prognosis of patients after ICIs. From July 2014 to December 2018, 188 patients with diverse cancers who received ICIs (nivolumab or pembrolizumab) were enrolled. Twenty-nine patients experienced liver dysfunction of any grades after ICIs. Progression-free survival (PFS) was significantly shorter in the liver dysfunction-positive group than in the liver dysfunction-negative group, and a similar result was obtained for Overall survival (OS). Multiple logistic regression analysis revealed liver metastasis and alanine aminotransferase before ICIs were associated with a higher incidence of liver dysfunction after ICIs. Regardless of liver metastasis, PFS and OS were significantly shorter in the liver dysfunction-positive group. In conclusion, this study suggests liver dysfunction is associated with poor prognosis in patients after ICIs with diverse cancers.
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http://dx.doi.org/10.1038/s41598-020-71561-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468148PMC
September 2020

Post-Progression Treatment Eligibility of Unresectable Hepatocellular Carcinoma Patients Treated with Lenvatinib.

Liver Cancer 2020 Jan 18;9(1):73-83. Epub 2019 Oct 18.

oDepartment of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan.

Background/aim: Post-progression treatment following tyrosine-kinase inhibitor (TKI) failure in patients with unresectable hepatocellular carcinoma (u-HCC) is important to prolong post-progression survival (PPS), which has a good correlation with overall survival (OS). This study aimed to elucidate the clinical features of progressive disease (PD) in patients treated with lenvatinib (LEN).

Materials/methods: From March 2018 to June 2019, 156 u-HCC patients with Child-Pugh A were enrolled (median age: 71 years, Child-Pugh score 5:6 = 105:51, BCLC A:B:C = 8:56:92, modified albumin-bilirubin grade (mALBI) 1:2a:2b = 59:42:55, past history of sorafenib:regorafenib = 57:17). Clinical features were retrospectively evaluated.

Results: The median observation period was 8.5 months. Median OS was not obtained, while median time to decline to Child-Pugh B (CPB) was 11.4 months, median time to progression (TTP) was 8.4 months, and the period of LEN administration was 7.3 months. When we compared predictive values for time to decline to CPB based on Child-Pugh score and mALBI, values for Akaike information criterion (AIC) score and c-index of mALBI were superior as compared to Child-Pugh score (AIC: 592.3 vs. 599.7) (c-index: 0.655 vs. 0.597). Of the 73 patients with PD, 32 (43.8%) showed no decline to CPB or death. After excluding 3 without alpha-fetoprotein data at PD determination, only 14 (20.0%) of 70 showed REACH-2 eligibility. Non-mALBI 1/2a at the start of LEN was a significant risk factor for decline to CPB during LEN treatment (HR 2.552, 95% CI: 1.577-4.129; < 0.001).

Conclusion: Introduction of TKI therapy including LEN for u-HCC patients with better hepatic function (mALBI 1/2a: ALBI score ≤-2.27), when possible, increases the chance of undergoing post-progression treatment, which can improve PPS.
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http://dx.doi.org/10.1159/000503031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024896PMC
January 2020

Analysis of factors associated with the prognosis of cirrhotic patients who were treated with tolvaptan for hepatic edema.

J Gastroenterol Hepatol 2020 Jul 14;35(7):1229-1237. Epub 2020 Jan 14.

Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan.

Background And Aim: The prognosis of cirrhotic patients with hepatic edema is poor. Although several short-term predictors of tolvaptan (novel diuretic agent) treatment for such patients have been reported, the factors related to long-term survival are still unclear.

Methods: Among 459 patients with hepatic edema enrolled in a retrospective, multicenter collaborative study, we analyzed 407 patients who received tolvaptan.

Results: Patients consisted of 266 men and 141 women, with the median age of 68 years (range, 28-93 years). The frequency of short-term responders to tolvaptan was 59.7% (243/407). In the Cox regression analysis, short-term response to tolvaptan, low average dosages of furosemide and spironolactone during tolvaptan treatment, Child-Pugh classification A and B, and absence of hepatocellular carcinoma were independent factors contributed to 1-year survival. The 1-year and long-term cumulative survival rates in short-term responders were significantly higher than those in non-responders (P = 0.011 and 0.010, respectively). Using a receiver operating characteristic curve analysis, the optimal cut-off values of average daily dosages of furosemide and spironolactone for predicting 1-year survival were 19 and 23 mg/day, respectively. The long-term cumulative survival rates in patients who received a mean dosage of spironolactone < 23 mg/day during tolvaptan treatment were significantly higher than those receiving a mean dosage of ≥ 23 mg/day (P = 0.001).

Conclusions: The present study suggests that the short-term response to tolvaptan and low dosages of conventional diuretics during tolvaptan treatment might improve the 1-year and long-term survival rates in cirrhotic patients with hepatic edema.
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http://dx.doi.org/10.1111/jgh.14965DOI Listing
July 2020

The Relationship Between the Number of Ports and Surgical Outcomes in Laparoscopic Hepatectomy.

Surg Laparosc Endosc Percutan Tech 2020 Feb;30(1):85-90

Department of General and Gastroenterological Surgery.

Introduction: Reduced port surgery (RPS) has been garnering interest as a novel minimally invasive surgery lately.

Aim: The authors examined the relationship between the number of ports and surgical outcomes after laparoscopic hepatectomy (LH).

Materials And Methods: Between January 2012 and April 2019, 209 patients who underwent laparoscopic partial resection and lateral sectionectomy were retrospectively analyzed with respect to operative variables and surgical outcomes. Patients were divided into 5 groups by the number of ports used. Student's t test, the χ test, the likelihood-ratio test, Fisher exact test, or Mann-Whitney U test were used to analyze the data.

Results: Operative duration was significantly longer in patients with a larger number of ports than in those with a smaller number of ports. Chronological pain scores according to the visual analog scale (VAS) on postoperative days 1, 2, 4, and 7 were not associated with the number of ports and wound length in the umbilical region. The frequency of using additional analgesic agents was not significantly different between the groups. VAS scores and the number of additional analgesic agents used were smaller in patients in whom non-steroidal anti-inflammatory drugs were regularly administered postoperatively than in those in whom the drug was not regularly administered postoperatively. LH had a 3.4% complication rate (Clavien-Dindo classification >IIIA); however, this was not significantly different between the groups.

Conclusions: No significant difference in postoperative pain was observed between RPS and conventional methods, although operative durations were shorter with RPS. However, RPS for LH may be associated with excellent cosmetic results compared with conventional methods.
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http://dx.doi.org/10.1097/SLE.0000000000000750DOI Listing
February 2020

The preventive effect of the impaired liver function for antiemetic therapy against chemotherapy-induced nausea and vomiting in hepatocellular carcinoma patients.

J Clin Biochem Nutr 2017 Nov 19;61(3):222-227. Epub 2017 Oct 19.

2nd Department of Internal Medicine, Osaka Medical College, 2-7 Daigakumachi, Takatsuki, Osaka 569-8686, Japan.

Transarterial chemoembolization and hepatic arterial infusion chemotherapy are recommended for the treatment in patients with intermediate stage of hepatocellular carcinoma. Impaired liver function was sometime observed in patients with hepatocellular carcinoma after transarterial chemoembolization or hepatic arterial infusion chemotherapy. However, what kinds of factors deeply influence in impaired liver function are not clear. A retrospective study was performed to evaluate the risk factors of impaired liver function in cisplatin-naïve patients treated with these therapies using cisplatin. Prior to and 2 months after these therapies, we analyzed the liver function by Child-Pugh score in these patients. For assessing the severity of chemotherapy-induced nausea and vomiting, we utilized the Common Terminology Criteria for Adverse Events ver. 4.0. In hepatocellular carcinoma patients received these therapies using cisplatin, the cancer stage and treatment without neurokinin-1 (NK) antagonist were found to be independent risk factors of the impaired liver function. The treatment with NK antagonist was effective in reducing chemotherapy-induced nausea and vomiting and patients treated with NK antagonist kept their liver functions after cisplatin-used these therapies. The treatment with NK antagonist was effective in chemotherapy-induced nausea and vomiting and prevented the impaired liver function associated with cisplatin-used these therapies in hepatocellular carcinoma patients.
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http://dx.doi.org/10.3164/jcbn.17-57DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5703785PMC
November 2017

A long-lasting dipeptidyl peptidase-4 inhibitor, teneligliptin, as a preventive drug for the development of hepatic steatosis in high-fructose diet-fed ob/ob mice.

Int J Mol Med 2017 Apr 20;39(4):969-983. Epub 2017 Feb 20.

Second Department of Internal Medicine, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan.

Non-alcoholic fatty liver disease (NAFLD) occurs in patients with components of metabolic syndrome such as type 2 diabetes mellitus (T2DM). At present, the central pathophysiological problem in patients afflicted with NAFLD is insulin resistance. In this study, we aimed to determine the effects of a dipeptidyl peptidase-4 (DPP-4) inhibitor, teneligliptin, on the development of NAFLD in ob/ob mice. Five-week-old male ob/ob mice were divided into 4 experimental groups as follows: a group in which they were fed a high carbohydrate diet (HCD) for 8 weeks (n=8) as controls (control group 1), a group in which they were fed HCD supplemented with 0.018% teneligliptin for 8 weeks (n=8) (teneligliptin group 1), a group in which they were fed HCD for 12 weeks (n=8) as controls (control group 2), and another group in which they were fed only HCD for 4 weeks, and the HCD was then supplemented with 0.018% teneligliptin for 8 weeks (n=8) (teligliptin group 2). Hepatic steatosis was observed in all mice in the control group fed the HCD, but only mild hepatic steatosis was observed in teneligliptin group 1. Mice in teneligliptin group 1 fed the diet containing teneligliptin had lower hepatic triglyceride (TG) and free fatty acid (FFA) levels. Mice in teneligliptin group 1 exhibited improvement of insulin resistance; however, those in teneligliptin group 2 did not show any improvement of insulin resistance. Our results thus suggest that teneligliptin may be used as a preventative, but not as a treatment drug for the development of NAFLD.
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http://dx.doi.org/10.3892/ijmm.2017.2899DOI Listing
April 2017

Rosuvastatin as a potential preventive drug for the development of hepatocellular carcinoma associated with non-alcoholic fatty liver disease in mice.

Int J Mol Med 2016 Nov 3;38(5):1499-1506. Epub 2016 Oct 3.

Second Department of Internal Medicine, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan.

Hepatocellular carcinoma (HCC) represents approximately 85% of all primary liver cancer cases. Non-alcoholic fatty liver disease (NAFLD) is one of the risk factors for HCC. NAFLD occurs in patients with components of metabolic syndrome, such as type 2 diabetes mellitus, obesity, hypertension and hyperlipidemia. Therefore, hyperlipidemia also represents a patient population at risk for HCC that can readily be identified. Rosuvastatin, a 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitor, has exhibited a more potent affinity for the active site of HMG-CoA reductase than other statins. In addition, the hepatic uptake of rosuvastatin in rats has been found to be more selective and efficient than that with other drugs. Furthermore, the cytoprotective effects of rosuvastatin against ischemic injury have been clearly reported. Thus, in this study, we aimed to determine the role of rosuvastatin as a preventive drug in HCC associated with NAFLD. STAM mice, which developed HCC from NAFLD by being fed a high-fat diet (HFD), were divided into a group in which a HFD was given to the mice for 15 weeks (n=8) and another in which a HFD supplemented with 0.00125% rosuvastatin was given to the mice for 15 weeks (n=8). Rosuvastatin inhibited the development of hepatic tumors in the mice with NAFLD induced by a specific diet both macroscopically and histologically. Rosuvastatin significantly decreased the expression levels of pro-inflammatry cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-6 and transforming growth factor (TGF)-β1. Tumor aggressiveness is mediated by angiogenic factors. Therefore, we examined the hepatic mRNA expression of vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR) and platelet-derived growth factor (PDGF). The hepatic expression of these factors significantly decreased in the rousvastin-fed mice. Our results thus suggest rosuvastatin that prevents carcinogenesis and improves the hepatic background. Our data suggest that rosuvastatin has potential for use as a preventive drug for the development of HCC associated with NAFLD in mice.
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http://dx.doi.org/10.3892/ijmm.2016.2766DOI Listing
November 2016

Co-Administration of Saireito Enabled the Withdrawal of Corticosteroids in an Elderly Woman with Autoimmune Hepatitis.

Intern Med 2016 1;55(1):43-7. Epub 2016 Jan 1.

2nd Department of Internal Medicine, Osaka Medical College, Japan.

An 82-year-old woman with autoimmune hepatitis had been treated with 5 mg prednisolone (PSL) orally to maintain normal transaminase levels. The subsequent transaminase levels were elevated and remained unchanged despite increasing the dose of PSL to 20 mg and introducing ursodeoxycholic acid (UDCA) at a dose of 900 mg. This combined treatment with UDCA was, however, ineffective. Treatment with Saireito at a dose of 9.0 g in conjunction with PSL was then initiated, which led to the subsequent normalization of her transaminase levels. Oral administration of PSL was discontinued eight weeks after the co-administration of Saireito. The patient had a significant response to this treatment.
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http://dx.doi.org/10.2169/internalmedicine.55.5128DOI Listing
July 2016

Effects of Oral L-Carnitine on Liver Functions after Transarterial Chemoembolization in Intermediate-Stage HCC Patients.

Mediators Inflamm 2015 19;2015:608216. Epub 2015 Nov 19.

Second Department of Internal Medicine, Osaka Medical College, 2-7 Daigakumachi, Takatsuki, Osaka 569-8686, Japan.

Transarterial chemoembolization (TACE) is usually followed by hepatic dysfunction. We evaluated the effects of L-carnitine on post-TACE impaired liver functions. Methods. 53 cirrhotic hepatocellular carcinoma patients at Osaka Medical College were enrolled in this study and assigned into either L-carnitine group receiving 600 mg oral L-carnitine daily or control group. Liver functions were evaluated at pre-TACE and 1, 4, and 12 weeks after TACE. Results. The L-carnitine group maintained Child-Pugh (CP) score at 1 week after TACE and exhibited significant improvement at 4 weeks after TACE (P < 0.01). Conversely, the control group reported a significant CP score deterioration at 1 week (P < 0.05) and 12 weeks after TACE (P < 0.05). L-carnitine suppressed serum albumin deterioration at 1 week after TACE. There were significant differences between L-carnitine and control groups regarding mean serum albumin changes from baseline to 1 week (P < 0.05) and 4 weeks after TACE (P < 0.05). L-carnitine caused prothrombin time improvement from baseline to 1, 4 (P < 0.05), and 12 weeks after TACE. Total bilirubin mean changes from baseline to 1 week after TACE exhibited significant differences between L-carnitine and control groups (P < 0.05). The hepatoprotective effects of L-carnitine were enhanced by branched chain amino acids combination. Conclusion. L-carnitine maintained and improved liver functions after TACE.
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http://dx.doi.org/10.1155/2015/608216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4668308PMC
September 2016

Sitagliptin can inhibit the development of hepatic steatosis in high-fructose diet-fed ob/ob mice.

J Clin Biochem Nutr 2015 Nov 1;57(3):244-53. Epub 2015 Nov 1.

2nd Department of Internal Medicine, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan.

The beneficial effect of dipeptidyl peptidase-4 inhibition on diet-induced extra-pancreatic effects, especially on liver tissue remains poorly understood. Thus, we made the experimental designs as follows; five-week-old male ob/ob mice, which develop type 2 diabetic mellitus and nonalcoholic fatty liver disease by taking a high-carbohydrate diet (HCD), were divided into a group in which a HCD was given for 8 weeks as control, and another in which a HCD added with 0.0018% sitagliptin was given for 8 weeks. Hepatic steatosis was seen in all mice, but the mean grade of steatosis in the sitagliptin-administrated mice was significantly decreased. The acetyl-CoA concentrations were lower in sitagliptin-administrated mice, although the differences were not significant. However, the malonyl-CoA concentrations were significantly lower in sitagliptin-administrated mice. The expression of acetyl-CoA carboxylase 1 was inhibited in sitagliptin-administrated mice, irrespective of expressions of carbohydrate responsive element-binding protein (ChREBP) or sterol regulatory element-binding protein (SREBP)-1c. In conclusion, sitagliptin may affect the development of nonalcoholic fatty liver disease by inhibiting the production of malonyl-CoA and thus synthesis of fatty acids in the liver.
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http://dx.doi.org/10.3164/jcbn.15-84DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4639593PMC
November 2015
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