Publications by authors named "Shinya Fukunishi"

117 Publications

Cancer Cachexia: Its Mechanism and Clinical Significance.

Int J Mol Sci 2021 Aug 6;22(16). Epub 2021 Aug 6.

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

The term "cachexia" is derived from the Greek words kakos (bad) and hexis (habit). Cachexia is a malnutrition associated with chronic diseases such as cancer, chronic heart failure, chronic renal failure, and autoimmune diseases, and is characterized by decreased skeletal muscle mass. Cancer cachexia is quite common in patients with advanced cancer. Weight loss is also a characteristic symptom of cancer cachexia, along with decreased skeletal muscle mass. As nutritional supplementation alone cannot improve cachexia, cytokines and tumor-derived substances have been attracting attention as its relevant factors. Cancer cachexia can be also associated with reduced chemotherapeutic effects, increased side effects and treatment interruptions, and even poorer survival. In 2011, a consensus definition of cachexia has been proposed, and the number of relevant research reports has increased significantly. However, the pathogenesis of cachexia is not fully understood, and there are currently few regulatory-approved standard treatments for cachexia. The main reason for this is that multiple etiologies are involved in the development of cachexia. In this review, we will outline the current status of cachexia, the mechanisms of which have been elucidated in recent years, especially from the perspective of advanced cancer.
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http://dx.doi.org/10.3390/ijms22168491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8395185PMC
August 2021

Efficacy of lenvatinib for unresectable hepatocellular carcinoma based on background liver disease etiology: multi-center retrospective study.

Sci Rep 2021 Aug 17;11(1):16663. Epub 2021 Aug 17.

Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan.

It was recently reported that hepatocellular carcinoma (HCC) patients with non-alcoholic steatohepatitis (NASH) are not responsive to immune-checkpoint inhibitor (ICI) treatment. The present study aimed to evaluate the therapeutic efficacy of lenvatinib in patients with non-alcoholic fatty liver disease (NAFLD)/NASH-related unresectable-HCC (u-HCC). Five hundred thirty u-HCC patients with Child-Pugh A were enrolled, and divided into the NAFLD/NASH (n = 103) and Viral/Alcohol (n = 427) groups. Clinical features were compared in a retrospective manner. Progression-free survival (PFS) was better in the NAFLD/NASH than the Viral/Alcohol group (median 9.3 vs. 7.5 months, P = 0.012), while there was no significant difference in overall survival (OS) (20.5 vs. 16.9 months, P = 0.057). In Cox-hazard analysis of prognostic factors for PFS, elevated ALT (≥ 30 U/L) (HR 1.247, P = 0.029), modified ALBI grade 2b (HR 1.236, P = 0.047), elevated AFP (≥ 400 ng/mL) (HR 1.294, P = 0.014), and NAFLD/NASH etiology (HR 0.763, P = 0.036) were significant prognostic factors. NAFLD/NASH etiology was not a significant prognostic factor in Cox-hazard analysis for OS (HR0.758, P = 0.092), whereas AFP (≥ 400 ng/mL) (HR 1.402, P = 0.009), BCLC C stage (HR 1.297, P = 0.035), later line use (HR 0.737, P = 0.014), and modified ALBI grade 2b (HR 1.875, P < 0.001) were significant. Lenvatinib can improve the prognosis of patients affected by u-HCC irrespective of HCC etiology or its line of treatment.
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http://dx.doi.org/10.1038/s41598-021-96089-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8370989PMC
August 2021

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

Impact of modified albumin-bilirubin grade on survival in patients with HCC who received lenvatinib.

Sci Rep 2021 Jul 14;11(1):14474. Epub 2021 Jul 14.

Hepato-Biliary Center, Matsuyama Red Cross Hospital, Matsuyama, Japan.

We investigated the impact on survival of modified albumin-bilirubin (mALBI) grade versus Child-Pugh classification in patients with hepatocellular carcinoma (HCC) who received lenvatinib. A total of 524 patients with HCC who received lenvatinib were included. Univariate analysis showed that mALBI grade 2b/3 and Child-Pugh class B/C were significantly associated with survival [hazard ratio (HR), 2.471; 95% confidence interval (CI), 1.944-3.141 and HR, 2.178; 95%CI, 1.591-2.982]. In patients with a Child-Pugh score of 5, multivariate analysis showed that mALBI grade 2b/3 was independently associated with survival (HR, 1.814; 95%CI, 1.083-3.037). Conversely, among patients with mALBI grade 1/2a, there was no difference in survival between those with a Child-Pugh class of 5 or 6 (p = 0.735). Time-dependent receiver operating characteristic analysis showed that the ALBI score predicted survival better than the Child-Pugh score. The optimal cut-off value of the ALBI score for predicting survival was nearly the same as the value separating mALBI grades 2a and 2b. In conclusion, the mALBI grade was a better predictor of survival than the Child-Pugh classification in patients with unresectable HCC who received lenvatinib therapy.
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http://dx.doi.org/10.1038/s41598-021-93794-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280227PMC
July 2021

Adverse events as potential predictive factors of activity in patients with advanced hepatocellular carcinoma treated with lenvatinib.

Liver Int 2021 Jul 12. Epub 2021 Jul 12.

Department of Gastroenterology, Tokushima Prefectural Central Hospital, Tokushima, Japan.

Background And Aim: Lenvatinib is a standard of care option in first-line therapy of advanced hepatocellular carcinoma (HCC). In the present study, we aim to identify, in patients with HCC treated with lenvatinib, a possible association between occurrence and grading of adverse events (AEs) and outcome.

Methods: We performed a retrospective analysis of 606 Japanese and Italian patients treated with lenvatinib in first-line setting and investigated the possible correlation between the onset of AEs, toxicity grade (G) and outcome measures such as overall survival (OS) and progression-free survival (PFS).

Results: The appearance of arterial hypertension G ≥ 2 independently predicted prolonged OS [hazard ratio (HR) 0.66, 95% confidence interval (CI) 0.46-0.93, P = .0188], whereas decreased appetite G ≥ 2 independently predicted decreased OS (HR 1.70, 95% CI 1.25-2.32, P = .0007) by multivariate analysis. Appearance of hand-foot skin reaction independently predicted prolonged PFS (HR 0.72, 95% CI 0.56-0.93, P = .0149), whereas decreased appetite G ≥ 2 predicted decreased PFS (HR 1.36, 95% CI 1.04-1.77, P = .0277).

Conclusions: Our main findings are that the occurrence of arterial hypertension G ≥ 2 is a predictor of longer survival, whereas decreased appetite G ≥ 2 predicts for a poor prognosis. A careful management of AEs under lenvatinib treatment for HCC is required, to improve patients' quality of life, minimize the need for treatment discontinuation and achieve optimal outcome.
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http://dx.doi.org/10.1111/liv.15014DOI Listing
July 2021

Ileal Bile Acid Transporter Inhibitor Improves Hepatic Steatosis by Ameliorating Gut Microbiota Dysbiosis in NAFLD Model Mice.

mBio 2021 Aug 6;12(4):e0115521. Epub 2021 Jul 6.

Second Department of Internal Medicine, Osaka Medical Collegegrid.444883.7, Takatsuki, Japan.

Nonalcoholic fatty liver disease (NAFLD), characterized by excessive fat deposition in the liver unrelated to alcohol consumption, is highly prevalent worldwide. However, effective therapeutic agents approved for NAFLD treatment are lacking. An ileal bile acid transporter inhibitor (IBATi), which represents a new mode of treatment of chronic idiopathic constipation, leads to increased delivery of bile acids to the colon. We investigated the effect of IBATi against NAFLD through modification of the gut microbiota in mice. IBATi treatment significantly suppressed body weight gain, liver dysfunction, and serum low-density lipoprotein levels and significantly decreased NAFLD activity scores in high-fat diet (HFD) mice. Treatment with IBATi ameliorated the decreased hepatic cholesterol 7-a-monooxygenase () and increased ileal fibroblast growth factor 15 () mRNA expression in HFD mice. Further, IBATi treatment changed the α-diversity in the gut microbiota reduced by HFD, which was analyzed in feces using 16S rRNA sequencing. To establish the mechanism underlying improvement in NAFLD induced by IBATi, we recolonized antibiotic solution-treated mice by fecal microbiome transplantation (FMT) using stool from HFD or HFD plus IBATi mice. This is the first report that fecally transplanted gut microbiota from HFD plus IBATi mice prevented hepatic steatosis caused by HFD. In conclusion, IBATi improved hepatic steatosis by ameliorating gut microbiota dysbiosis in NAFLD model mice, suggesting a potential therapeutic agent for NAFLD treatment. NAFLD is an increasingly recognized condition that may progress to liver cirrhosis and hepatocellular carcinoma, and community surveys have assessed that the prevalence is 14 to 32% worldwide. The first line of treatment for NAFLD is lifestyle modification to achieve weight reduction, particularly through diet and exercise. However, weight reduction is difficult to achieve and maintain, and pharmacological agents approved for the treatment of NAFLD are lacking. This study investigated the influence of the gut microbiota and the effect of an IBATi on NAFLD using a murine model. Treatment with IBATi significantly improved NAFLD in HFD mice. Further, fecal microbiome transplantation using stool from HFD plus IBATi mice prevented hepatic steatosis caused by HFD. Our study makes a significant contribution to the literature because the study findings suggest a potential treatment strategy for NAFLD patients by ameliorating gut microbiota dysbiosis.
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http://dx.doi.org/10.1128/mBio.01155-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406289PMC
August 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

Atezolizumab plus bevacizumab treatment for unresectable hepatocellular carcinoma: Early clinical experience.

Cancer Rep (Hoboken) 2021 Jun 11:e1464. Epub 2021 Jun 11.

Department of Internal Medicine, Himeji Red Cross Hospital, Hyogo, Japan.

Background: Although atezolizumab plus bevacizumab (Atez/bev) treatment has been developed for unresectable hepatocellular carcinoma (u-HCC), changes in hepatic function during therapy have yet to be reported.

Aim: This retrospective clinical study aimed to elucidate early responses to Atez/Bev.

Methods: From September 2020 to April 2021, 171 u-HCC patients undergoing Atez/Bev treatment were enrolled (BCLC stage A:B:C:D = 5:68:96:2). Of those, 75 had no prior history of systemic treatment. Relative changes in hepatic function and therapeutic response were assessed using albumin-bilirubin (ALBI) score and Response Evaluation Criteria in Solid Tumors (RECIST), ver. 1.1, respectively.

Results: In initial imaging examination findings, objective response rates for early tumor shrinkage and disease control after 6 weeks (ORR-6W/DCR-6W) were 10.6%/79.6%. Similar response results were observed in patients with and without a past history of systemic treatment (ORR-6W/DCR-6W = 9.7%/77.8% and 12.2%/82.9%), as well as patients in whom Atez/Bev was used as post-progression treatment following lenvatinib (ORR-6W/DCR-6W = 7.7%/79.5%), for which no known effective post-progression treatment has been established. In 111 patients who underwent a 6-week observation period, ALBI score was significantly worsened at 3 weeks after introducing Atez/Bev (-2.525 ± 0.419 vs -2.323 ± 0.445, p < .001), but then recovered at 6-weeks (-2.403 ± 0.452) as compared to 3-weeks (p = .001). During the observation period, the most common adverse events were appetite loss (all grades) (12.3%), general fatigue/hypertension (all grades) (11.1%, respectively), and urine protein (all grades) (10.5%).

Conclusion: Atez/Bev might have therapeutic potential not only as first but also later-line treatment of existing molecular target agents. In addition, this drug combination may have less influence on hepatic function during the early period, as the present patients showed a good initial therapeutic response.
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http://dx.doi.org/10.1002/cnr2.1464DOI Listing
June 2021

Clinical trial of autologous adipose tissue-derived regenerative (stem) cells therapy for exploration of its safety and efficacy.

Regen Ther 2021 Dec 21;18:97-101. Epub 2021 May 21.

Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan.

Introduction: Liver cirrhosis is the ultimate condition of chronic liver diseases. Non-alcoholic steatohepatitis and fatty liver diseases are emerging in association with metabolic syndrome largely due to excess nutrition. Stromal cells of adipose tissue are enriched mesenchymal stem cells which are pluripotent and immunomodulatory, which are expected to be applied for repairing/regenerative therapy of the impaired organs.

Methods: We conducted the multi-institutional clinical trial (Japanese UMIN Clinical Trial Registry: UMIN000022601) of cell therapy using freshly isolated autologous adipose tissue-derived regenerative (stem) cells (ADRCs), which are obtained by the investigational trial device, adipose tissue dissociation device, for liver cirrhosis patients due to non-alcoholic steatohepatitis or fatty liver disease, to exploratory assess efficacy as well as safety of this trial. We completed treatment and 24 weeks follow-up for 7 patients.

Results: We observed that 6 out of 7 patients' serum albumin concentration was improved. As for prothrombin activity, 5 out of 7 patients showed improvement. No trial-related adverse events, which were serious or non-serious, was observed. Besides, no malfunction of the investigational trial device was encountered.

Conclusion: Thus, treatment with autologous ADRCs obtained with the investigational trial device in steatohepatitis-related cirrhosis was confirmed to be safely conductible and potentially promising for the retaining or improving the impaired hepatic reserve.
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http://dx.doi.org/10.1016/j.reth.2021.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165289PMC
December 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

Therapeutic efficacy of ramucirumab after lenvatinib for post-progression treatment of unresectable hepatocellular carcinoma.

Gastroenterol Rep (Oxf) 2021 Apr 10;9(2):133-138. Epub 2020 Oct 10.

Gastroenterology Center, Ehime Prefectural Central Hospital, Ehime, Japan.

Background: Lenvatinib is used for unresectable hepatocellular carcinoma (u-HCC) as first-line, as well as second- and third-line therapy in Japan. We evaluated the therapeutic efficacy of newly developed ramucirumab when given after lenvatinib for post-progression treatment.

Methods: Of 385 patients with u-HCC and treated with lenvatinib at 16 different institutions in Japan between May 2018 and January 2020, 28 who received ramucirumab as the next treatment were enrolled and therapeutic responses were evaluated in a retrospective manner.

Results: The median age of the 28 patients given ramucirumab was 70 years and the median albumin-bilirubin score was -2.19. Of the 28 patients, 23 were male, 21 were classified as Child-Pugh A and 7 as Child-Pugh B, and 25 were Barcelona Clinic Liver Cancer Stage C. Ramucirumab was given as second-line therapy in 14, third-line in 9, and fourth-line in 5. Therapeutic response was obtained in only 26 patients; the objective response rate was 3.8% (1/26) and the disease-control rate was 42.3% (11/26), with a median period to progression of 2.0 months. The reasons for discontinuation of ramucirumab were progression of disease in 16 and Grade 3 adverse events (gastrointestinal bleeding, ascites) in 2.

Conclusions: The anticipated therapeutic efficacy of ramucirumab for post-progression treatment following lenvatinib was not seen in our early experience.
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http://dx.doi.org/10.1093/gastro/goaa042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128005PMC
April 2021

Exacerbation of liver dysfunction in non-alcoholic steatohepatitis patients during the coronavirus disease 2019 (COVID-19) pandemic.

J Clin Biochem Nutr 2021 May 3;68(3):243-245. Epub 2020 Dec 3.

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

Many people were forced to stay at home, including non-alcoholic steatohepatitis (NASH) patients, however it is unclear how this home-life has affected the prognosis of NASH. In this study, we examined the influences of living at home during the coronavirus disease 2019 (COVID-19) pandemic NASH patients. In this study, we compared the clinical parameters of NASH patients without COVID-19 infection 3 months before with those 3 months after the declaration of a state of emergency. In the results, the changes of aspartate transaminase and alanine aminotransferase in the 3 months before (aspartate transaminase, -3.6 ± 13.8 U/L; alanine aminotransferase, -6.8 ± 19.5 U/L) was significantly exacerbated in the 3 months after (aspartate transaminase, 2.3 ± 7.5 U/L; alanine aminotransferase, 1.7 ± 10.4 U/L). Furthermore, the changes of the fibrosis-4 index in the 3 months before (-0.27 ± 0.84) was also significantly exacerbated in the 3 months after (0.38 ± 0.96). In conclusion, liver dysfunctions in NASH patients were exacerbated due to the emergency declaration and outing restriction which accompanied COVID-19.
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http://dx.doi.org/10.3164/jcbn.20-136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129973PMC
May 2021

What Can Be Done to Solve the Unmet Clinical Need of Hepatocellular Carcinoma Patients following Lenvatinib Failure?

Liver Cancer 2021 Apr 25;10(2):115-125. Epub 2021 Feb 25.

Hepato-biliary Center, Matsuyama Red Cross Hospital, Matsuyama, Japan.

Background/aim: An effective postprogression treatment of lenvatinib (LEN) against unresectable hepatocellular carcinoma (u-HCC) has not been established. We aimed to elucidate the clinical role of continuing LEN beyond progression of disease (PD).

Methods: From March 2018 to October 2020, 99 u-HCC patients, in whom PD was confirmed (male:female = 78:21, median age 72 years, Child-Pugh A = 99, Barcelona Clinic Liver Cancer stage A:B:C = 2:43:54, LEN as first-line = 55), were enrolled (stopped LEN at PD [A group], = 26; continued LEN beyond PD [B group], = 73). Radiological response was evaluated with RECIST 1.1. Clinical features and prognostic factors for overall survival (OS) were retrospectively investigated using inverse probability weighting (IPW) calculated by propensity score.

Results: Median time to progression, best response, and modified albumin-bilirubin grade (mALBI) at both baseline and PD did not show significant difference between the groups. Postprogression treatment in the A group was best supportive care in 17, sorafenib in 4, regorafenib in 3, ramucirumab in 1, and hepatic arterial infusion chemotherapy in 1. After adjusting with IPW, the B group showed better prognosis in regard to OS after PD and OS after introducing LEN than the A group (10.8/19.6 vs. 5.8/11.2 months, < 0.001, respectively). In IPW-adjusted Cox hazard multivariate analysis, significant prognostic factors for OS after PD were mALBI 2b/3 at PD (HR 1.983, = 0.021), decline of Eastern Cooperative Oncology Group performance status (ECOG PS) from baseline at PD (HR 3.180, < 0.001), elevated alpha-fetoprotein (≥100 ng/mL) at introducing LEN (HR 2.511, = 0.004), appearance of new extrahepatic metastasis (HR 2.396, = 0.006), positive for hand-foot skin reaction (HFSR) before PD (any grade) (HR 0.292, < 0.001), and continuing LEN beyond PD (HR 0.297, < 0.001).

Conclusion: When ECOG PS and hepatic reserve function permit, continuing LEN treatment beyond PD, especially in u-HCC patients showed HFSR during LEN treatment, might be a good therapeutic option, at least until a more effective drug as a postprogression treatment after LEN failure is developed.
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http://dx.doi.org/10.1159/000513355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077500PMC
April 2021

Obesity and Liver Cancer in Japan: A Comprehensive Review.

Anticancer Res 2021 May;41(5):2227-2237

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

Lifestyle-related factors play a major role in the development of cancer. In recent years, obesity has become widespread in the world and has attracted attention not only as a cause of diabetes mellitus and atherosclerotic diseases but also as a factor in carcinogenesis. In Japan, the number of obesity-related malignancies has been increasing with the westernization of lifestyle. On the other hand, it is estimated that there are more than 10 million nonalcoholic fatty liver disease (NAFLD) patients in Japan. NAFLD is classified into simple fatty liver and nonalcoholic steatohepatitis (NASH), and 10-20% of NASH patients will progress to liver cirrhosis and 2-3% of them will develop hepatocellular carcinoma (HCC) per year. Research interest in metabolism-associated liver cancer has been increasing in recent years. Here in this review, we will comprehensively summarize the current knowledge with regard to the relationship between obesity and HCC in Japan.
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http://dx.doi.org/10.21873/anticanres.14999DOI Listing
May 2021

Sarcopenia and Frailty in Liver Cirrhosis.

Life (Basel) 2021 Apr 27;11(5). Epub 2021 Apr 27.

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

Skeletal muscle is the largest organ in the body, and skeletal muscle atrophy results from a shift in the balance of protein synthesis and degradation toward protein breakdown. Primary sarcopenia is defined as a loss of skeletal muscle mass and strength or physical function due to aging, and secondary sarcopenia is defined as a loss of skeletal muscle mass and strength or physical function due to underlying diseases. Liver cirrhosis (LC) is one of the representative diseases which can be complicated with secondary sarcopenia. Muscle mass loss becomes more pronounced with worsening liver reserve in LC patients. While frailty encompasses a state of increased vulnerability to environmental factors, there is also the reversibility of returning to a healthy state with appropriate intervention. Several assessment criteria for sarcopenia and frailty were proposed in recent years. In 2016, the Japan Society of Hepatology created assessment criteria for sarcopenia in liver disease. In Japan, health checkups for frailty in the elderly aged 75 years or more started in April 2020. Both sarcopenia and frailty can be adverse predictors for cirrhotic patients. In this review article, we will summarize the current knowledge of sarcopenia and frailty in LC patients.
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http://dx.doi.org/10.3390/life11050399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146021PMC
April 2021

Impact of Early Lenvatinib Administration on Survival in Patients with Intermediate-Stage Hepatocellular Carcinoma: A Multicenter, Inverse Probability Weighting Analysis.

Oncology 2021 27;99(8):518-527. Epub 2021 Apr 27.

Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Matsuyama, Japan.

Aim/background: Transarterial chemoembolization (TACE) is recommended for patients with intermediate-stage hepatocellular carcinoma (HCC). In this study, we investigated the impact of early lenvatinib administration in patients with intermediate-stage HCC, especially those with tumors beyond the up-to-7 criteria.

Materials/methods: A total of 208 patients with intermediate-stage HCC whose initial treatment was early lenvatinib administration or TACE were enrolled. Multivariate overall survival analysis was performed in this cohort. In addition, the impact of early lenvatinib administration on survival in patients with HCC beyond the up-to-7 criteria was clarified using inverse probability weighting (IPW) analysis.

Results: The overall cumulative survival rates at 6, 12, 18, and 24 months were 94.4, 79.9, 65.8, and 50.1%, respectively. Multivariate analysis with Cox proportional hazards modeling showed that HCC treatment with lenvatinib (hazard ratio [HR], 0.199; 95% confidence interval [CI], 0.077-0.517; p < 0.001), α-fetoprotein ≥100 ng/mL (HR, 1.687), Child-Pugh class B disease (HR, 1.825), and beyond the up-to-7 criteria (HR, 2.016) were independently associated with overall survival. The 6-, 12-, 18-, and 24-month cumulative survival rates were 96.0, 90.4, 65.7, and 65.7%, respectively, in patients treated with lenvatinib, and 94.1, 78.5, 65.3, and 48.4%, respectively, in patients who received TACE (p < 0.001). In addition, univariate analysis with Cox proportional hazards modeling adjusted by IPW showed that lenvatinib therapy was significantly associated with overall survival in patients with HCC beyond the up-to-7 criteria (HR, 0.230; 95% CI, 0.059-0.904; p = 0.035).

Conclusions: Lenvatinib may be a suitable first-line treatment for patients with intermediate-stage HCC beyond the up-to-7 criteria.
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http://dx.doi.org/10.1159/000515896DOI Listing
August 2021

Hepatic F4/80 CD11b CD68 cells influence the antibacterial response in irradiated mice with sepsis by Enterococcus faecalis.

J Leukoc Biol 2021 05;109(5):943-952

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

Gut-associated sepsis is a major problem in patients undergoing abdominal radiation therapy; the majority of pathogens causing this type of sepsis are translocated from the gut microbiota. While treating sepsis, bacterial clearance must be achieved to ensure patient survival, and the hepatic immune response is responsible for this process. In particular, Kupffer cells play a crucial role in the hepatic immune response against infectious agents. Recently, two populations of Kupffer cells have been described: liver-resident macrophages (Mϕ) (F4/80 CD11b CD68 cells) and hepatic Mϕ derived from circulating monocytes (F4/80 CD11b CD68 cells). We examined the properties of both types of hepatic Mϕ obtained from irradiated and normal mice and their role in sepsis. Hepatic F4/80 CD11b CD68 cells from both normal and irradiated mice did not show any antibacterial activity. However, F4/80 CD11b CD68 cells from normal mice behaved as effector cells against sepsis by Enterococcus faecalis, although those from irradiated mice lost this ability. Moreover, hepatic F4/80 CD11b CD68 cells from normal infected mice were shown to be IL-12 IL-10 CD206 CCL1 (considered M1Mϕ), and hepatic F4/80 CD11b CD68 cells from the same mice were shown to be IL-12 IL-10 CD206 CCL1 (considered M2aMϕ). When normal mice were exposed to radiation, hepatic F4/80 CD11b CD68 cells altered their phenotype to IL-12 IL-10 CD206 CCL1 (considered M2bMϕ), independent of infection, but hepatic F4/80 CD11b CD68 cells remained IL-12 IL-10 CD206 CCL1 (M2aMϕ). In addition, hepatic F4/80 CD11b CD68 cells from irradiated mice acquired antibacterial activity upon treatment with CCL1 antisense oligodeoxynucleotides. Therefore, the characteristics of hepatic F4/80 CD11b CD68 cells play a key role in the antibacterial response against gut-associated sepsis.
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http://dx.doi.org/10.1002/JLB.4A0820-550RRDOI Listing
May 2021

Therapeutic efficacy of lenvatinib as third-line treatment after regorafenib for unresectable hepatocellular carcinoma progression.

Hepatol Res 2021 Aug 5;51(8):880-889. Epub 2021 May 5.

Department of Gastroenterology, Okayama City Hospital, Okayama, Japan.

Aim: Multiple molecular agents have been developed for treating unresectable hepatocellular carcinoma. This study aimed to elucidate the clinical efficacy of sequential treatment with lenvatinib after regorafenib failure.

Methods: From June 2017 to October 2020, 63 patients with Child-Pugh A and treated with regorafenib followed by sorafenib were enrolled (median age 71 years, 52 men, Barcelona Clinic Liver Cancer B:C = 23:40). They were divided into two groups, those treated with lenvatinib after regorafenib treatment (R-L group, n = 47) and those who did not receive lenvatinib after regorafenib (non-R-L group, n = 16). Prognostic factors were retrospectively analyzed after adjustment with inverse probability weighting.

Results: Serum albumin level at the start of regorafenib and reasons for discontinuation of regorafenib were significantly different between the R-L and non-R-L groups, whereas the albumin-bilirubin score, Child-Pugh class, and tumor burden were not. Progression-free survival was also not significantly different (median 4.1 vs. 3.8 months, p = 0.586). As for overall survival, the R-L group showed better prognosis after introducing regorafenib and after introducing sorafenib, following inverse probability weighting adjustment (MST 19.7 vs. 10.3 months, 33.8 vs. 15.3 months, p < 0.001 and p = 0.022, respectively). Modified albumin-bilirubin grade 2b (score >-2.27) at the start of regorafenib (HR 2.074, p = 0.041) and the presence of lenvatinib treatment after regorafenib failure (HR 0.355, p = 0.004) were found to be significant prognostic factors in Cox proportional hazards multivariate analysis, after inverse probability weighting adjustment.

Conclusion: These results show that lenvatinib is a good sequential treatment option after progression under regorafenib therapy in unresectable hepatocellular carcinoma patients with better hepatic reserve function.
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http://dx.doi.org/10.1111/hepr.13644DOI Listing
August 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

Lenvatinib versus sorafenib in first-line treatment of unresectable hepatocellular carcinoma: An inverse probability of treatment weighting analysis.

Liver Int 2021 06 20;41(6):1389-1397. Epub 2021 Feb 20.

Division of Internal Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.

Purpose: Data from common clinical practice were used to generate balanced cohorts of patients receiving either sorafenib or lenvatinib, for unresectable hepatocellular carcinoma, with the final aim to investigate their declared equivalence.

Methods: Clinical features of lenvatinib and sorafenib patients were balanced through inverse probability of treatment weighting (IPTW) methodology, which weights patients' characteristics and measured outcomes of each patient in both treatment arms. Overall survival was the primary endpoint and occurrence of adverse events was the secondary.

Results: The analysis included 385 patients who received lenvatinib, and 555 patients who received sorafenib. In the unadjusted cohort, lenvatinib did not show a survival advantage over sorafenib (HR: 0.85, 95% CI 0.70-1.02). After IPTW adjustment, lenvatinib still not returned a survival advantage over sorafenib (HR: 0.82, 95% CI: 0.62-1.07) even in presence of balanced baseline characteristics. Lenvatinib provided longer survival than sorafenib in patients previously submitted to TACE (HR: 0.69), with PS of 0 (HR: 0.73) or without extrahepatic disease (HR: 0.69).

Conclusion: Present results confirmed randomized controlled trial in the real-life setting, but also suggests that in earlier stages some benefit can be expected.
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http://dx.doi.org/10.1111/liv.14817DOI Listing
June 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

Analysis of efficacy of lenvatinib treatment in highly advanced hepatocellular carcinoma with tumor thrombus in the main trunk of the portal vein or tumor with more than 50% liver occupation: A multicenter analysis.

Hepatol Res 2021 Feb 5;51(2):201-215. Epub 2021 Jan 5.

Department of Gastroenterology, Saiseikai Niigata Hospital, Niigata, Japan.

Aims: To assess the safety, efficacy, and prognostic impact of clinical factors associated with lenvatinib treatment in highly advanced hepatocellular carcinoma (HCC) with tumor thrombus in the main portal vein trunk (VP4) or tumor with more than 50% liver occupation (tm50%LO).

Methods: A total of 61 highly advanced HCC patients (41 patients with tm50%LO and 20 patients with VP4) who were treated with lenvatinib at multicenter were enrolled and retrospectively analyzed for treatment outcomes according to their clinical status, including tumor morphology.

Results: The most frequent grade ≥3 adverse event in tm50%LO HCC was elevated aspartate aminotransferase (17.1%). Objective response rates were 37.5% and 0% in tm50%LO HCC patients with Child-Pugh grade (CP)-A and CP-B, respectively, and 26.7% and 0% in VP4 HCC patients with CP-A and CP-B, respectively. Estimated median progression-free survival and overall survival were 132 days and 229 days, and 101 days and 201 days in patients with tm50%LO and VP4, respectively. In multivariate analysis, modified albumin-bilirubin grade (hazard ratio 0.372, 95% CI 0.157-0.887; p = 0.0241) and tumor morphology (hazard ratio 0.322, 95% CI 0.116-0.889; p = 0.0287) were independently associated with progression-free survival in patients with tm50%LO HCC. In VP4 HCC, median progression-free survival was worse in CP-B (57 days) than in CP-A patients (137 days, p = 0.0462).

Conclusions: Lenvatinib treatment offers a benefit in highly advanced HCC (tm50%LO or VP4) patients with good liver function or nodular-type tumor. The various characteristics identified in this study might be useful as indicators of lenvatinib treatment in highly advanced HCC with tm50%LO or VP4, which are considered very refractory cancers.
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http://dx.doi.org/10.1111/hepr.13592DOI Listing
February 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

Clinical importance of muscle volume in lenvatinib treatment for hepatocellular carcinoma: Analysis adjusted with inverse probability weighting.

J Gastroenterol Hepatol 2021 Jul 29;36(7):1812-1819. Epub 2020 Nov 29.

Hepato-biliary Center, Matsuyama Red Cross Hospital, Matsuyama, Japan.

Background And Aim: This study aimed to elucidate the clinical importance of muscle volume loss (pre-sarcopenia) in patients receiving lenvatinib as treatment for unresectable hepatocellular carcinoma (u-HCC).

Methods: Of 437 u-HCC patients treated with lenvatinib at specific institutions in Japan between March 2018 and May 2020, 151 with available computed tomography imaging data from the time of lenvatinib introduction were enrolled. Pre-sarcopenia was diagnosed based on a previously reported cut-off value calculation formula [psoas muscle area at level of middle of third lumbar vertebra (cm )/height (m) ]. Clinical features and prognostic factors for overall survival (OS) with inverse probability weighting were investigated retrospectively for their relationship with pre-sarcopenia.

Results: Cox hazard multivariate analysis showed alpha-fetoprotein (≥400 ng/mL) (hazard ratio [HR] 2.271, P < 0.001), Barcelona Clinic Liver Cancer stage (C and D) (HR 1.625, P = 0.018), and positive for pre-sarcopenia (HR 1.652, P = 0.042) to be significant prognostic factors. OS rates for the pre-sarcopenia group (n = 41) were worse than those for the non-pre-sarcopenia group (n = 110) (0.5-, 1-, and 1.5-year OS: 72.5%, 27.9%, and 7.0% vs 80.7%, 56.7%, and 46.1%, respectively; P < 0.001), as was progression-free survival (P = 0.025). Time to stopping lenvatinib or disease progression was better in the non-pre-sarcopenia group (0.5-, 1-, and 1.5-year OS: 48.0%, 24.5%, and 8.4% vs 20.0%, 10.3%, and 4.2%, respectively; P < 0.001). Also, the frequency of the adverse event appetite loss (any grade) was greater in the pre-sarcopenia group (43.9% vs 18.2%, P = 0.003).

Conclusion: Pre-sarcopenia was shown to be a significant prognostic factor in patients treated with lenvatinib for u-HCC.
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http://dx.doi.org/10.1111/jgh.15336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8359359PMC
July 2021

Effects of Chronic Kidney Disease on Outcomes of Hepatic Resection.

J Gastrointest Surg 2021 05 27;25(5):1323-1326. Epub 2020 Oct 27.

Department of General and Gastroenterological Surgery, Osaka Medical College Hospital, 2-7 Daigaku-machi, Takatsuki City, Osaka, 569-8686, Japan.

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http://dx.doi.org/10.1007/s11605-020-04835-9DOI Listing
May 2021

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
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