Publications by authors named "Shinji Itoh"

206 Publications

Less Carcinogenic Chlorinated Estrogens Applicable to Hormone Replacement Therapy.

Int J Mol Sci 2021 Jul 5;22(13). Epub 2021 Jul 5.

Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, NY 11794-8651, USA.

Human estrogens prescribed for hormone replacement therapy (HRT) are known to be potent carcinogens. To find safer estrogens, several chlorinated estrogens were synthesized and their carcinogenic potential were determined. A pellet containing either 2-chloro-17β-estradiol (2-ClE) or 4-chloro-17β-estradiol (4-ClE) was implanted subcutaneously for 52 weeks into August Copenhagen Irish (ACI) rats, a preferred animal model for human breast cancer. 17β-Estradiol (E) frequently induced mammary tumors while both 2-ClE and 4-ClE did not. Their 17α-ethinyl forms, thought to be orally active estrogens, were also synthesized. Neither 2-chloro-17α-ethinylestradiol (2-ClEE) nor 4-chloro-17α-ethinylestradiol (4-ClEE) induced tumors. The less carcinogenic effects were supported by histological examination of mammary glands of ACI rats treated with the chlorinated estrogens. A chlorine atom positioned at the 2- or 4-position of E may prevent the metabolic activation, resulting in reducing the carcinogenicity. 2-ClE and 4-ClE administered subcutaneously and 2-ClEE and 4-ClEE given orally to ovariectomized rats all showed uterotrophic potency, albeit slightly weaker than that of E. Our results indicate that less carcinogenic chlorinated estrogens retaining estrogenic potential could be safer alternatives to the carcinogenic estrogens now in use for HRT.
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http://dx.doi.org/10.3390/ijms22137222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268473PMC
July 2021

Impact of Metabolic Activity in Hepatocellular Carcinoma: Association With Immune Status and Vascular Formation.

Hepatol Commun 2021 Jul 26;5(7):1278-1289. Epub 2021 Mar 26.

Department of Surgery and Science Graduate School of Medical Sciences Kyushu University Fukuoka Japan.

We evaluated the prognostic value of fluorine-18 fluorodeoxyglucose (F-FDG) positron emission tomography/computed tomography (PET/CT) in hepatocellular carcinoma (HCC). Their association with programmed death ligand 1 (PD-L1) expression and vascular formation was further investigated. In this retrospective study, using a database of 418 patients who had undergone F-FDG PET/CT before hepatic resection for HCC, immunohistochemical staining of PD-L1, clusters of differentiation (CD) 8, CD68, and CD34 was performed. Patients with a high maximum standardized uptake value (SUVmax) on F-FDG PET/CT showed a significantly worse recurrence-free survival (RFS) (hazard ratio [HR]: 1.500; 95% confidence interval [CI]: 1.088-2.069;  = 0.0133) and overall survival (OS) (HR: 2.259; 95% CI: 1.276-4.000;  = 0.0052) than patients with a low SUVmax. Logistic regression analysis showed that a high SUVmax in HCC was significantly associated with PD-L1-positive expression (odds ratio: 4.407; 95% CI: 2.265-8.575;  < 0.0001). SUVmax values of HCC were associated with intratumoral CD8-positive T-cell counts ( = 0.0044) and CD68-positive macrophage counts ( = 0.0061). Stratification based on SUVmax, PD-L1 expression, and the vessels that encapsulate tumor clusters (VETC) status was also significantly associated with RFS and OS. SUVmax, VETC, and PDL1 expression were independently predictive of survival on multivariable analysis. Our large cohort study showed that a high SUVmax on F-FDG PET/CT is associated with a poor clinical outcome and PD-L1 expression in patients with HCC. Additionally, stratification of patients based on the combination of SUVmax, PD-L1 expression, and the VETC status predicts poor clinical outcome.
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http://dx.doi.org/10.1002/hep4.1715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279470PMC
July 2021

Impact and risk factors for skeletal muscle mass loss after hepatic resection in patients with hepatocellular carcinoma.

JGH Open 2021 Jul 10;5(7):785-792. Epub 2021 Jun 10.

Department of Surgery and Science, Graduate School of Medical Sciences Kyushu University Fukuoka Japan.

Background And Aim: The aims of this study were to determine whether a postoperative decrease in skeletal muscle mass (SMM) after hepatic resection can predict long-term outcomes in patients with hepatocellular carcinoma (HCC) and identify risk factors for SMM loss in patients who undergo hepatic resection.

Methods: This was a large retrospective study of 400 patients who underwent hepatic resection for HCC and pre- and postoperative computed tomography (CT) scans. SMM was measured at the third lumbar vertebrae, and the postoperative change in SMM compared with preoperative values was calculated as Δ SMM. The cutoff value for the post-/preoperative ratio was set at 0.9.

Results: Sixty patients (15.0%) developed SMM loss. These patients had a significantly prolonged prothrombin time ( = 0.0092), longer duration of surgery ( = 0.0021), more blood loss ( = 0.0040), and higher rate of postoperative complications ( = 0.0037) than those without SMM loss. Multivariate analysis revealed that prolonged prothrombin time and postoperative complications were independent risk factors for SMM loss after hepatic resection. Patients with SMM loss had significantly shorter overall survival ( = 0.0018) than the other patients had. SMM loss was an independent prognostic factor for overall survival (hazard ratio 1.551, 95% confidential interval 1.028-2.340,  = 0.0363).

Conclusions: We demonstrated an association of SMM loss with postoperative complications and long-term prognosis in patients with HCC. Patients with prolonged prothrombin time, or postoperative complications, may need to maintain their SMM. Further prospective studies are needed to investigate whether nutritional support can improve SMM loss.
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http://dx.doi.org/10.1002/jgh3.12588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264232PMC
July 2021

Lymphocyte-to-C-reactive protein ratio as a prognostic factor for hepatocellular carcinoma.

Int J Clin Oncol 2021 Jul 12. Epub 2021 Jul 12.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Background: Systemic inflammation has been correlated with worse survival for some cancers. We evaluated prognostic values of various inflammatory factor combinations in patients who underwent resections for hepatocellular carcinoma (HCC).

Methods: We retrospectively analysed 306 consecutive patients with HCC who underwent curative liver resections. After assessing eight combinations of inflammatory markers for predictive value for recurrence, we focused on lymphocyte-to-C-reactive protein ratio (LCR) to elucidate its associations with recurrence-free survival (RFS) and overall survival (OS) in univariate and multivariate analyses (Cox proportional hazards model). We also used immunohistochemical CD34 and CD8 staining to investigate the mechanism of LCR elevation.

Results: LCR showed the highest association with RFS in HCC patients among the compared indices. High preoperative LCR correlated with a high serum albumin concentration, small tumour size, early Barcelona Clinic Liver Cancer stage and low rates of microscopic vascular invasion and microscopic intrahepatic metastasis. Higher preoperative LCR was an independent predictor of longer RFS and OS in this cohort. High LCR patients had fewer vessels encapsulating tumour clusters, and higher intratumoural CD8 T-cell counts than low LCR patients.

Conclusions: Preoperative LCR is a novel and convenient prognostic marker for patients with HCC, and is associated with the tumour microenvironment immune status.
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http://dx.doi.org/10.1007/s10147-021-01985-xDOI Listing
July 2021

ASO Visual Abstract: Prognostic Impact of Vessels that Encapsulate Tumor Cluster (VETC) in Patients who Underwent Liver Transplantation for Hepatocellular Carcinoma.

Ann Surg Oncol 2021 Jul 6. Epub 2021 Jul 6.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, 812-8582, Fukuoka, Japan.

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http://dx.doi.org/10.1245/s10434-021-10248-yDOI Listing
July 2021

Identification of SLC38A7 as a Prognostic Marker and Potential Therapeutic Target of Lung Squamous Cell Carcinoma.

Ann Surg 2021 Jun 18. Epub 2021 Jun 18.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, 811-1395, Japan Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan Department of Thoracic Surgery, National Hospital Organization Kyushu Medical Center, Fukuoka, 810-8563, Japan. Department of Biostatistics, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi, 755-8505, Japan Division of Bioinformatics, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. Division of Epigenomics and Development, Medical Institute of Bioregulation, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan.

Background: No effective molecular targeted therapy has been established for squamous cell lung cancer (SCC). We conducted a comprehensive study of SCC patients using RNA-sequencing and The Cancer Genome Atlas (TCGA) dataset in order to clarify the driver oncogene of SCC.

Method: Forty-six samples of 23 patients were totally analyzed with RNA-sequencing. We then searched for candidate-oncogenes of SCC using the TCGA database. To identify candidate oncogenes, we used the following two criteria: 1) the genes of interest were overexpressed in tumor tissues of SCC patients in comparison to normal tissues; and 2) using an integrated mRNA expression and DNA copy number profiling analysis using the TCGA dataset, the DNA copy number of the genes was positively correlated with the mRNA expression.

Result: We identified 188 candidate-oncogenes. Among those, the high expression of SLC38A7 was a strong prognostic marker that was significantly associated with a poor prognosis in terms of both overall survival (OS) and recurrence-free survival in the TCGA dataset (p < 0.05). Additionally, 202 resected SCC specimens were also subjected to an immunohistochemical analysis. Patients with the high expression of SLC38A7 (alternative name is SNAT7) protein showed significantly shorter OS in comparison to those with the low expression of SLC38A7 protein (median OS 3.9 years [95% CI, 2.4-6.4 years] vs. 2.2 years [95% CI, 1.9-4.1 years]; log rank test: p = 0.0021).

Conclusion: SLC38A7, which is the primary lysosomal glutamine transporter required for the extracellular protein-dependent growth of cancer cells, was identified as a candidate therapeutic target of SCC.
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http://dx.doi.org/10.1097/SLA.0000000000005001DOI Listing
June 2021

Lymphocyte-C-reactive protein ratio as a prognostic marker associated with the tumor immune microenvironment in intrahepatic cholangiocarcinoma.

Int J Clin Oncol 2021 Jun 12. Epub 2021 Jun 12.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.

Background: Changes in immune cell and inflammation-associated protein levels, either independently or in combination, are commonly used as prognostic factors for various cancers. The ratio of lymphocyte count to C-reactive protein concentration (lymphocyte-CRP ratio; LCR) is a recently identified prognostic marker for several cancers. Here, we examined the prognostic value of LCR and its relationship to various aspects of the tumor immune microenvironment in patients with intrahepatic cholangiocarcinoma (ICC).

Methods: This was a single-center, retrospective study of patients who underwent surgical resection for ICC between 1998 and 2018. Patients were dichotomized into high- and low-LCR status groups, and the relationships between LCR status, prognosis, and other clinicopathological characteristics were analyzed. Tumor-infiltrating CD8+ and FOXP3s+ lymphocytes and tumor expression of CD34 and programmed death-ligand 1 were evaluated by immunohistochemical staining of resected tumors.

Results: A total of 78 ICC patients were enrolled and assigned to the high (n = 44)- and low (n = 34)-LCR groups. Compared with the high-LCR group, patients in the low-LCR group had a significantly higher serum CA19-9 level (median 20.6 vs. 77.3 U/mL, P = 0.0017) and larger tumor size (median 3.5 vs. 5.5 cm, P = 0.0018). LCR correlated significantly with tumor microvessel density (r = 0.369, P = 0.0009) and CD8+ T lymphocyte infiltration (r = 0.377, P = 0.0007) but not with FOXP3+ T lymphocyte infiltration or tumor PD-L1 expression. Low-LCR status was significantly associated with worse overall survival by multivariate analysis (P = 0.0348).

Conclusions: Low-LCR status may reflect a poor anti-tumor immune response and predict worse outcomes in ICC patients.
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http://dx.doi.org/10.1007/s10147-021-01962-4DOI Listing
June 2021

Which is better to use "body weight" or "standard liver weight", for predicting small-for-size graft syndrome after living donor liver transplantation?

Ann Gastroenterol Surg 2021 May 11;5(3):363-372. Epub 2020 Dec 11.

Department of Surgery and Science Graduate School of Medical Sciences Kyushu University Fukuoka Japan.

Aim: Little evidence about whether to apply graft-to-recipient body weight ratio (GRWR) or graft weight to standard liver weight (GW/SLW) for graft selection has been published. The aim of the present study was to clarify the importance of the correct use of GRWR and GW/SLW for selecting graft according to the recipients' physique in living donor liver transplantation (LDLT).

Methods: Data were collected for 694 recipients who underwent LDLT between 1997 and 2020.

Results: One of the marginal grafts meeting GW/SLW ≥ 35% but GRWR < 0.7% has been used in more recipients with men and higher body mass index (BMI), and the other meeting GRWR ≥ 0.7% but GW/SLW < 35% has been used in more recipients with women with lower BMI. In the cohort of BMI > 30 kg/m, the recipients with GRWR < 0.7% had a significantly higher incidence of small-for-size graft syndrome (SFSS) compared to those with GRWR ≥ 0.7% ( = 0.008, 46.2% vs 5.9%), and using the cutoff of GW/SLW < 35% could not differentiate. In contrast, in the cohort of BMI ≤ 30 kg/m, the recipients with GW/SLW < 35% also had a significantly higher incidence of SFSS ( = 0.013, 16.9% vs 9.4%). Multivariate analysis showed that GRWR < 0.7% [odds ratio (OR) 14.145,  = 0.048] was the independent risk factor for SFSS in obese recipients, and GW/SLW < 35% [OR 2.685,  = 0.002] was the independent risk factor in non-obese recipients.

Conclusion: Proper use of the formulas for calculating GRWR and GW/SLW in choosing graft according to recipient BMI is important, not only to meet metabolic demand for avoiding SFSS but also to ameliorate donor shortages.
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http://dx.doi.org/10.1002/ags3.12412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164458PMC
May 2021

Prognostic Impact of Vessels that Encapsulate Tumor Cluster (VETC) in Patients who Underwent Liver Transplantation for Hepatocellular Carcinoma.

Ann Surg Oncol 2021 Jun 5. Epub 2021 Jun 5.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: There is limited published information about prognostic value of vessels that encapsulate tumor cluster (VETC) based on their involvement with immune cells in hepatocellular carcinoma (HCC). Our goal was to evaluate prognostic impact of VETC in patients who underwent living-donor liver transplantation (LDLT) for HCC, focusing on the involvement of VETC with immune status in tumor microenvironment (TME).

Methods: Using a database of 150 patients who underwent LDLT for HCC, immunohistochemical staining of CD34 for VETC, angiopoietin-2 (Ang-2), CD3, and CD68, was reviewed with patients' clinicopathological factors.

Results: A strong correlation between VETC pattern and malignant potential in HCC was observed; larger tumor size (P < 0.001), more numbers of tumors (P = 0.003), higher α-fetoprotein levels (P = 0.001), higher des-γ-carboxy prothrombin levels (P = 0.022), microvascular invasion (P < 0.001), and poor differentiation (P = 0.010). Overall survival (OS) of patients with VETC was significantly lower than those with VETC (P = 0.021; 5-year OS rates, 72.0% vs. 87.1%). Furthermore, the ratio of CD3 cells was significantly lower in VETC group (P = 0.001), indicating that VETC activity may be strongly correlated with lymphocyte activity. Moreover, combination status of VETC/CD3 was an independent risk factor for mortality (hazard ratio 2.760, 95% confidence interval 1.183-6.439, P = 0.019). Additionally, the combination of VETC expression with immune status (low CD3 levels) enabled further classification of patients based on their clinical outcome.

Conclusions: Our results show the prognostic impact of VETC expression, tumor-infiltrating lymphocytes (TILs), and their combination in the setting of LDLT for HCC, which can be a novel prognostic biomarker for mortality after LDLT.
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http://dx.doi.org/10.1245/s10434-021-10209-5DOI Listing
June 2021

Efficacy of pembrolizumab in microsatellite instability-high locally advanced cholangiocarcinoma: a case report.

Clin J Gastroenterol 2021 Jun 3. Epub 2021 Jun 3.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Cholangiocarcinoma is a biliary malignant tumor which can arise at any point of biliary tree. Surgical resection is the only curative treatment and chemotherapy is used for unresectable cases, but its prognosis is poor compared with other types of cancer. Recently, pembrolizumab (PEM), an anti-programmed cell death protein 1 (PD-1) antibody, has become available for microsatellite instability (MSI)-high advanced cancers. Here, we report the use of PEM for MSI-high locally advanced cholangiocarcinoma. A 57-year-old man presented to our department with jaundice. Contrast-enhanced computed tomography showed a solitary 28-mm-diameter tumor deep in the anterior segment of the liver. Endoscopic retrograde cholangiopancreatography and intraductal ultrasonography showed narrowing of the common bile duct and absence of contrast in the right hepatic duct, and tumor invaded from hilar region of liver into left hepatic duct. We diagnosed this as double primary cancers, locally advanced intrahepatic and distal cholangiocarcinomas. The patient began gemcitabine in combination with cisplatin therapy as first-line treatment and gemcitabine in combination with S-1 therapy as second-line treatment. However, the tumor gradually grew (maximum 69 mm), intrahepatic metastasis appeared, and tumor marker increased. Because MSI-high was confirmed not only by biopsy specimens but also by liquid biopsy, the patient began PEM (200 mg per every 3 weeks). After 15 cycles of PEM were administered over about 10 months, size of tumor was reduced and tumor marker dramatically decreased. We experienced the rare case which PEM has been successfully used for MSI-high double primary cancers.
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http://dx.doi.org/10.1007/s12328-021-01458-8DOI Listing
June 2021

Inflammation-Induced Tumorigenesis and Metastasis.

Int J Mol Sci 2021 May 21;22(11). Epub 2021 May 21.

Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan.

Inflammation, especially chronic inflammation, plays a pivotal role in tumorigenesis and metastasis through various mechanisms and is now recognized as a hallmark of cancer and an attractive therapeutic target in cancer. In this review, we discuss recent advances in molecular mechanisms of how inflammation promotes tumorigenesis and metastasis and suppresses anti-tumor immunity in various types of solid tumors, including esophageal, gastric, colorectal, liver, and pancreatic cancer as well as hematopoietic malignancies.
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http://dx.doi.org/10.3390/ijms22115421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196678PMC
May 2021

Feasibility of hepatic resection for liver metastasis of head-and-neck carcinoma or esophageal carcinoma: a multi-center experience.

Surg Today 2021 May 25. Epub 2021 May 25.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Purpose: Patients with liver metastasis of head-and-neck carcinoma and esophageal carcinoma are generally not treated with hepatic resection, but there are no established standard treatment methods. We report 11 cases of hepatic resection for liver metastasis of head-and-neck carcinoma or esophageal carcinoma performed at 5 Japanese institutions.

Methods: The subjects of this retrospective analysis were 11 patients who underwent hepatic resection for metastatic liver tumors, originating from head-and-neck carcinoma in 5 and from esophageal cancer in 6, between January, 2010 and March, 2020 RESULTS: There were nine men and two women (median age, 64 years; range 40-72 years). The primary disease was esophageal carcinoma in six patients and pharyngeal carcinoma in five patients. All cancers were squamous cell carcinoma. The time from the initial treatment to the diagnosis of liver metastasis was 15.3 months and the 1-year and 3-year overall survival rates after hepatic resection were 72% and 32%, respectively. The overall and disease-free survival rates after hepatic resection were significantly higher for patients who underwent hepatic resection more than 12 months after the initial treatment than for those who underwent hepatic resection within 12 months after the initial treatment (p = 0.0172 and p = 0.0120, respectively).

Conclusions: Liver resection may prolong the survival of patients with liver metastases controlled for more than 12 months after the initial treatment of head and neck or esophageal carcinoma.
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http://dx.doi.org/10.1007/s00595-021-02305-6DOI Listing
May 2021

Immunosuppression Free Protocol for Liver Transplant from an Identical Twin Mimicking Positive Donor-Specific Antibodies: A Case Report.

Transplant Proc 2021 May 14. Epub 2021 May 14.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

There are some reported cases of liver transplant between identical twins with no immunosuppressants because of their matched HLA. However, there is no mention of donor-specific antibodies (DSA). Here, we report a rare case of living donor liver transplant (LDLT) between identical twins, mimicking DSA positivity, on a low-dose immunosuppression protocol. A 57-year-old man with acute liver failure underwent LDLT using the right lobe from his identical twin. Their blood types were identical on HLA matching. However, the preoperative DSA test results were positive for class II antibodies. This was supposed to be due to the relatively large amount of blood transfusion before testing: a total of 580 units of fresh frozen plasma for plasma exchange. The presence of class II antibodies for DSA positivity was the result of the passive immunity from transfusion, and this result could not be ignored, given the risk of rejection. Therefore, we arranged low-dose postoperative immunosuppressants using tacrolimus at a quarter dose and no mycophenolate mofetil. The postoperative course was uneventful. A few months after LDLT, the patient's DSA level was negative for class II antibodies, thus confirming our preoperative hypothesis of DSA as the result of transfusion. Currently, 6 months after LDLT, he is free from immunosuppressive medication with good liver function. When administering relatively large doses of fresh frozen plasma by repeated plasma exchange before LDLT, even between identical twins, it is important to consider that the DSA test could be positive and that immunosuppressive treatment should be performed carefully.
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http://dx.doi.org/10.1016/j.transproceed.2021.04.008DOI Listing
May 2021

Myostatin as a fibroblast-activating factor impacts on postoperative outcome in patients with hepatocellular carcinoma.

Hepatol Res 2021 Jul 25;51(7):803-812. Epub 2021 May 25.

Department of Liver Disease, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan.

Aim: In patients with liver cirrhosis, high levels of serum myostatin are associated with poor prognosis. We aimed to clarify the influence of myostatin on the prognosis of patients with non-alcoholic fatty liver disease-hepatocellular carcinoma (NAFLD-HCC) without cirrhosis and on the progression of liver fibrosis.

Methods: Serum myostatin levels were evaluated in 234 patients who underwent primary surgical resection for single HCC. To clarify the impact of myostatin on liver fibrosis, we established human primary liver fibroblasts from resected livers, and cultured them in the presence of myostatin.

Results: The median age was 67.4 years, the median L3 skeletal muscle mass index was 44.4 cm /m , and the median body mass index was 23.4 kg/m . Eighty-two (35.0%) patients had sarcopenia (L3 skeletal muscle mass index: men <42, women <38 cm /m ). The etiologies of liver disease were hepatitis B virus (n = 61), hepatitis C virus (n = 86), and non-B non-C hepatitis (n = 87) including NAFLD (n = 74). High preoperative serum myostatin and vascular invasion were independent predictors of poor overall survival (OS). High serum myostatin was associated with poor OS in patients with no sarcopenia (n = 152). In patients without advanced liver fibrosis (Fibrosis stage, 0-2; n = 58), high levels of serum myostatin were also associated with poor OS, regardless of sarcopenia. Serum myostatin levels were increased with the progression of liver fibrosis. Liver fibroblasts were activated and produced collagen following stimulation with myostatin.

Conclusions: In patients with NAFLD-HCC without advanced liver fibrosis, high levels of serum myostatin were associated with poor OS. Myostatin activated primary fibroblasts and stimulated collagen production.
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http://dx.doi.org/10.1111/hepr.13667DOI Listing
July 2021

Intractable Biliary Strictures After Living Donor Liver Transplantation: A Case Series.

Transplant Proc 2021 Jun 12;53(5):1726-1730. Epub 2021 May 12.

Department of Surgery, Kyushu Central Hospital of the Mutual Aid Association of Public School Teachers, Fukuoka, Japan.

Background: Biliary stricture (BS) is a severe complication after liver transplantation. It is difficult to treat, especially after living donor liver transplantation (LDLT). We successfully treated 4 patients for intractable BS after LDLT. All patients had developed cholangitis with stenosis of bile ducts anastomosis. CASE 1: . A 65-year-old woman underwent LDLT with right lobe graft and duct-to-duct biliary reconstruction. Internal plastic stents inserted by endoscopic retrograde cholangiography (ERC) were changed quarterly for the next 2 years. CASE 2: A 55-year-old man underwent LDLT with right lobe graft and duct-to-duct biliary reconstruction. Insertion of internal plastic stents by ERC was attempted; however, the posterior bile duct branch showed complete obstruction. After percutaneous transhepatic biliary drainage (PTCD), the stents were inserted using the rendezvous technique of ERC and were changed by ERC quarterly for the next 3 years. CASE 3: A 22-year-old man underwent LDLT with left lobe graft and hepaticojejunostomy. An external drainage tube was inserted by PTCD, and stents were changed quarterly for the next 2 years. CASE 4: A 60-year-old man underwent LDLT with right lobe graft and hepaticojejunostomy. An external drainage tube was inserted by PTCD, and changed to a metallic stent after 1 year. Three months later the stent was extracted using the rendezvous technique of double balloon enteroscopy.

Conclusion: BS of complete obstruction type after LDLT is difficult to treat. Appropriate procedures should be chosen based on the types of strictures and biliary reconstruction methods.
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http://dx.doi.org/10.1016/j.transproceed.2021.04.015DOI Listing
June 2021

Acute death caused by invasive aspergillosis after living-donor liver transplantation despite good graft function: a case report.

Surg Case Rep 2021 May 12;7(1):118. Epub 2021 May 12.

Department of Surgery and Sciences, Graduate School of Medical Sciences, Kyushu University Hospital, Kyushu University, 3 Chome-1-1 Maidashi, Higashiku, Fukuoka, Fukuoka, 812-8582, Japan.

Background: Invasive aspergillosis (IA) is one of the most serious causes of death after liver transplantation (LT). IA is the second most common fungal infection, and its mortality rate exceeds 80%.

Case Presentation: A 67-year-old man presented to our hospital because of fulminant hepatitis caused by hepatitis B virus. Candidiasis was detected in his sputum, and micafungin had already been administered. Living-donor LT was performed using a right lobe graft donated from his daughter with no intraoperative complications. Although he appeared to have good graft function, his oxygenation was inadequate, and a chest radiograph showed many invasive shadows on postoperative day 1. A computed tomography scan also showed many invasive shadows with the halo sign. A blood examination revealed positivity for Aspergillus antigen, and Aspergillus species were detected in his sputum. IA was diagnosed. The antifungal therapy was soon modified to amphotericin B combined with caspofungin. Despite good graft blood flow through the portal vein and hepatic artery and good graft function, the patient died of IA on postoperative day 3. The median time from LT to IA among reports published to date ranges from 18 to 25 days.

Conclusions: The present report describes the first case of very early onset of IA after LT.
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http://dx.doi.org/10.1186/s40792-021-01203-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116460PMC
May 2021

The Significant Prognostic Factors in Prolonged Intensive/High Care Unit Stay After Living Donor Liver Transplantation.

Transplant Proc 2021 Jun 30;53(5):1630-1638. Epub 2021 Apr 30.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: Prolonged stay in an intensive/high care unit (ICU/HCU) after living donor liver transplantation (LDLT) is a significant event with possible mortality.

Methods: Adult-to-adult LDLTs (n = 283) were included in this study. Univariate and multivariate analyses were performed for the factors attributed to the prolonged ICU/HCU stay after LDLT.

Results: Recipients who stayed in the ICU/HCU 9 days or longer were defined as the prolonged group. The prolonged group was older (P = .0010), had a higher model for end-stage liver disease scores (P < .0001), and had higher proportions of patients with preoperative hospitalization (P < .0001). Delirium (P < .0001), pulmonary complications (P < .0001), sepsis (P < .0001), reintubation or tracheostomy (P < .0001), relaparotomy due to bleeding (P = .0015) or other causes (P < .0001), and graft dysfunction (P < .0001) were associated with prolonged ICU/HCU stay. Only sepsis (P = .015) and graft dysfunction (P = .019) were associated with in-hospital mortality among patients with prolonged ICU/HCU stay or graft loss within 9 days of surgery. Among these patients, grafts from donors aged <42 years and with a graft-to-recipient weight ratio of >0.76% had significantly higher graft survival than grafts from others (P = .0013 and P < .0001, respectively).

Conclusion: Prolonged ICU/HCU stay after LDLT was associated with worse short-term outcomes. The use of grafts of sufficient volume from younger donors might improve graft survival.
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http://dx.doi.org/10.1016/j.transproceed.2021.02.020DOI Listing
June 2021

ARID1A Deficiency Is Associated With High Programmed Death Ligand 1 Expression in Hepatocellular Carcinoma.

Hepatol Commun 2021 Apr 30;5(4):675-688. Epub 2020 Dec 30.

Department of Surgery and Science Graduate School of Medical Sciences Kyushu University Fukuoka Japan.

The clinicopathological features of carcinomas expressing AT-rich interaction domain 1a (ARID1A) and programmed death ligand 1 (PD-L1) in HCC are poorly understood. Here, we examined ARID1A and PD-L1 expression in surgically resected primary hepatocellular carcinoma (HCC) and the association of ARID1A and PD-L1 expression with clinicopathological features and patient outcomes. Their association with ARID1A expression and tumor-associated CD68-positive macrophage was further explored. Using a database of 255 patients who underwent hepatic resection for HCC, immunohistochemical staining of ARID1A, PD-L1, and CD68 was performed. We also analyzed the expression PD-L1 after ARID1A knockdown in HCC cell lines. Samples from 81 patients (31.7%) were negative for ARID1A. Negative ARID1A expression was significantly associated with male sex, high alpha-fetoprotein, high des-gamma-carboxyprothrombin, large tumor size, high rate of poor differentiation, microscopic intrahepatic metastasis, and PD-L1 expression. In addition, negative ARID1A expression was an independent predictor for recurrence-free survival, overall survival, and positive PD-L1 expression. Stratification based on ARID1A and PD-L1 expression in cancer cells was also significantly associated with unfavorable outcomes. PD-L1 protein expression levels were increased through phosphoinositide 3-kinase/AKT signaling after ARID1A knockdown in HCC cells. HCC with ARID1A-low expression was significantly correlated with high levels of tumor-associated CD68-positive macrophage. Our large cohort study showed that ARID1A expression in cancer cells was associated with a poor clinical outcome in patients with HCC, PD-L1 expression in cancer cells, and tumor microenvironment. Therefore, ARID1A may be a potential molecular biomarker for the selection of patients with HCC for anti-programmed death 1/PD-L1 antibody therapy.
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http://dx.doi.org/10.1002/hep4.1659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034578PMC
April 2021

A no-ligation technique to prevent intraoperative hepatic artery dissection in living-donor liver transplantation.

Surg Today 2021 Apr 1. Epub 2021 Apr 1.

Departments of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Intrahepatic recipient hepatic artery dissection caused by hepatic artery thrombosis is a lethal complication of living-liver donor liver transplantation (LDLT). We herein report a new surgical technique that avoids the ligation of the recipient hepatic arteries in LDLT. Patients undergoing LDLT between 2009 and 2019 were evaluated. In the second half of this period, a technique involving no ligation of the recipient hepatic artery was initiated and its impact on the incidence of intrahepatic recipient hepatic artery dissection was determined. The middle and left hepatic arteries were ligated in 195 cases (53.4%), and the no-ligation technique was used in 170 (46.6%). The incidence of intraoperative hepatic artery dissection was significantly lower in the no-ligation group (n = 0, 0.0%) than in the ligation group (n = 10, 5.1%) (p = 0.0021). After propensity score matching to evaluate the patient characteristics, the incidence of intraoperative hepatic artery dissection was also significantly lower in the no-ligation group (n = 0, 0.0%) than in the ligation group (n = 6, 4.5%) (p = 0.0295). As a result, this new surgical technique is highly recommended to avoid recipient hepatic artery ligation in LDLT.
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http://dx.doi.org/10.1007/s00595-021-02276-8DOI Listing
April 2021

Obesity is a risk factor for intrahepatic cholangiocarcinoma progression associated with alterations of metabolic activity and immune status.

Sci Rep 2021 Mar 12;11(1):5845. Epub 2021 Mar 12.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.

Body mass index (BMI) is well known to be associated with poor prognosis in several cancers. The relationship between BMI and the long-term outcomes of patients with intrahepatic cholangiocarcinoma (ICC) is incompletely understood. This study investigated the relationships of BMI with clinicopathological characteristics and patient outcomes, focusing on metabolic activity and immune status. The relationship between BMI and the maximum standardized uptake value (SUVmax) on fluorine-18 fluorodeoxyglucose (F-FDG) positron emission tomography/computed tomography (PET/CT) was analyzed. In addition, immunohistochemistry was performed for programmed cell death-ligand 1 (PD-L1), cluster of differentiation 8 (CD8), and forkhead box protein P3 (Foxp3). Seventy-four patients with ICC were classified into normal weight (BMI < 25.0 kg/m, n = 48) and obesity groups (BMI ≥ 25.0 kg/m, n = 26), respectively. Serum carbohydrate antigen 19-9 levels were higher in the obesity group than in the normal weight group. Tumor size and the intrahepatic metastasis rate were significantly larger in the obesity group. Patients in the obesity group had significantly worse prognoses than those in the normal weight group. Moreover, BMI displayed a positive correlation with SUVmax on F-FDG PET/CT (n = 46, r = 0.5152). Patients with high F-FDG uptake had a significantly higher rate of PD-L1 expression, lower CD8 + tumor-infiltrating lymphocyte (TIL) counts, and higher Foxp3 + TIL counts. The elevated BMI might predict the outcomes of patients with ICC. Obesity might be associated with ICC progression, possibly through alterations in metabolic activity and the immune status.
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http://dx.doi.org/10.1038/s41598-021-85186-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955092PMC
March 2021

Metabolic Alteration in Hepatocellular Carcinoma: Mechanism of Lipid Accumulation in Well-Differentiated Hepatocellular Carcinoma.

Can J Gastroenterol Hepatol 2021 18;2021:8813410. Epub 2021 Feb 18.

Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.

Objective: Metabolic alteration is widely considered as one of the hallmarks of cancer. Hepatocellular carcinoma (HCC) presents a unique pathological feature in which lipid accumulation is common in well-differentiated HCC and rare in poorly differentiated HCC; however, the underlying mechanism remains unclear.

Methods: Tissue samples were obtained from 103 HCC patients who had undergone hepatic resection and 12 living donors of liver transplantation. We evaluated metabolic gene expressions in cancer tissues as well as background noncancer tissues and compared the expressions by the degree of cancer differentiation and by liver disease states. Besides, the metabolomics was evaluated and integrated to gene expressions in nonalcoholic steatohepatitis (NASH)-HCC model mice.

Results: In cancer tissues, the expression levels of enzymes related to glycolysis, pentose phosphate pathway (PPP), and fatty acid (FA) synthesis were increased and that of tricarboxylic acid (TCA) cycle and -oxidation were suppressed. Same metabolic alterations were observed in noncancer tissue as the liver disease progresses from healthy liver to chronic hepatitis, cirrhosis, and HCC. Similar alterations of metabolic genes were detected in NASH-HCC mice, which were consistent with the results of metabolomics. As the degree of cancer differentiation decreased, glycolysis and PPP were accelerated; however, FA synthesis and uptake were diminished.

Conclusions: The metabolic alterations including glycolysis, PPP, TCA cycle, and -oxidation became more prominent as liver disease progresses from normal, chronic hepatitis, cirrhosis, well-, moderately, and poorly differentiated HCC. FA synthesis and uptake were highest in well-differentiated HCC, which could explain the lipid accumulation.
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http://dx.doi.org/10.1155/2021/8813410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910064PMC
February 2021

Suppression of optineurin impairs the progression of hepatocellular carcinoma through regulating mitophagy.

Cancer Med 2021 03 18;10(5):1501-1514. Epub 2021 Feb 18.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Autophagy removes damaged organelles to inhibit malignant transformation during tumor initiation. Once a cancer matures, it uses the autophagic pathway as an energy source. Optineurin (OPTN) is an autophagy adaptor protein that recruits microtubule-associated protein 1 light chain 3, an autophagosome marker, to the autophagosome. Despite studies of the relation between cancer progression and autophagy adaptor proteins, there are no reports to our knowledge of a correlation between hepatocellular carcinoma (HCC) and OPTN. We aimed here to investigate the effects of OPTN expression on HCC progression through autophagy. Immunohistochemistry was used to measure the OPTN expression in the tissues of 141 Japanese patients with HCC. The effects of OPTN expression on HCC progression and mitophagy were assessed using an OPTN knockout (KO) cell line in vitro. We used this KO cell line to establish and exploit a mouse model of HCC to determine the effects of OPTN expression on tumor progression. Immunohistochemical analysis showed that patients with elevated expression of OPTN experienced shorter overall survival (OS) and recurrence-free survival (RFS). OPTN KO cells proliferated relatively slower versus wild-type (WT) cells in vitro. Western blot analysis showed that mitophagy was suppressed in OPTN KO cells, and ATP synthesis and beta-oxidation were reduced. The mouse model of HCC showed that OPTN KO cells formed smaller tumors versus WT cells less 10 weeks after implantation. Overall, the present findings suggest that OPTN is a key mediator of mitophagy that contributes to HCC progression through mitochondrial energy production.
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http://dx.doi.org/10.1002/cam4.3519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940236PMC
March 2021

Prognostic significance of systemic inflammation score in patients who undergo hepatic resection for hepatocellular carcinoma.

Langenbecks Arch Surg 2021 May 17;406(3):773-779. Epub 2021 Feb 17.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Purpose: Systemic inflammation score (SIS) is a novel prognostic score (0, 1, or 2) for various cancers, based on preoperative serum albumin level and lymphocyte-to-monocyte ratio (LMR); modified SIS (mSIS) uses a different LMR cutoff value and was thought to be a more accurate predictor for cancer prognosis. Here, we assessed the prognostic value of SIS and mSIS in patients who receive hepatic resection for hepatocellular carcinoma (HCC).

Methods: We retrospectively evaluated SIS and mSIS of 314 patients after hepatic resection for HCC, against their clinicopathological factors and outcomes, using receiver operating characteristics (ROC) analysis over time.

Results: Among patients with preoperative SIS 2, significantly more HCC specimens were poorly differentiated (P = 0.0281), larger (P = 0.0006), and had more microscopic vascular invasion (P = 0.0136) than the SIS 0-1 group; the mSIS 2 group also had significantly larger tumors (P = 0.0039) than the mSIS 0-1 group. In ROC analysis, SIS was a better predictor of overall survival (OS) and recurrence-free survival (RFS) than mSIS. The SIS 2 group had shorter OS (P = 0.0015) and RFS (P = 0.0065) than other patients. In multivariate analysis, SIS 2 was an independent risk factor for shorter OS (hazard ratio (HR) 1.53, P = 0.0497) and RFS (HR 1.58, P = 0.0053).

Conclusion: SIS is superior to mSIS in predicting prognosis of patients with HCC. mSIS is not a great predictor of prognosis in resected HCC.
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http://dx.doi.org/10.1007/s00423-021-02103-1DOI Listing
May 2021

CMTM6 Stabilizes PD-L1 Expression and Is a New Prognostic Impact Factor in Hepatocellular Carcinoma.

Hepatol Commun 2021 Feb 24;5(2):334-348. Epub 2020 Nov 24.

Department of Surgery and Science Graduate School of Medical Sciences Kyushu University Fukuoka Japan.

CKLF-like MARVEL transmembrane domain containing 6 (CMTM6) was identified as a regulator of programmed death ligand 1 (PD-L1), which induces antitumor immunity in several cancers. This study aimed to clarify the relationship between CMTM6 and PD-L1 expression and clinical outcomes in patients with hepatocellular carcinoma (HCC). In total, 259 patients with HCC who had undergone hepatic resection were enrolled. Immunohistochemical staining for CMTM6 and PD-L1 was performed. The relationships between CMTM6 expression and the clinicopathological characteristics and outcomes were analyzed. Additionally, the stabilization of PD-L1 expression and regulation of malignant activities by CMTM6 were examined . Our patients were divided into high (n = 65, 25.1%) and low (n = 194, 74.9%) CMTM6 expression groups. High CMTM6 expression was significantly associated with malignant aggregates, including poor differentiation ( < 0.0001), microscopic intrahepatic metastasis ( = 0.0369), and multiple intrahepatic recurrences ( = 0.0211). CMTM6 expression was significantly correlated with PD-L1 expression in HCC tissues ( < 0.0001). The patients were classified into three groups: high CMTM6/PD-L1 positive (n = 21), high CMTM6/ PD-L1 negative (n = 44), and low CMTM6 (n = 194) expression pattern groups. Overall survival was significantly different among the three groups ( < 0.0001). Additionally, immunohistochemical double staining revealed that CMTM6 and PD-L1 were co-expressed on HCC cells. , PD-L1 expression was enhanced at late time points in the presence of CMTM6 expression. CMTM6 also regulated epithelial-to-mesenchymal transition and stemness phenotypes in HCC cells. Our large cohort study found that CMTM6 co-expressed with PD-L1 was strongly associated with the clinical outcome in patients with HCC. The evaluation of CMTM6 combined with PD-L1 in HCC might be useful for patient selection in immune checkpoint therapy.
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http://dx.doi.org/10.1002/hep4.1643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850307PMC
February 2021

Surgically resected hepatic mass caused by fascioliasis.

Clin J Gastroenterol 2021 Apr 20;14(2):662-667. Epub 2021 Jan 20.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan.

Fascioliasis is a parasitic infestation caused by the digenetic trematodes Fasciola hepatica and F. gigantica. It is not commonly seen in developed countries, so diagnosis there is always difficult as a result of confusion with other hepatic or biliary disorders. A 56-year-old man presented at our hospital with a hepatic mass that had been inadvertently discovered by ultrasonography. Abdominal computed tomography revealed a multi-cystic lesion distributed along the branch of the right bile duct. Endoscopic retrograde cholangiopancreatography showed serrated changes ranging from the upper level of the common bile duct to the right hepatic bile duct. Eosinophilia was not observed and tumor marker levels were within normal ranges. Following right lobectomy combined with bile duct reconstruction, a histological examination revealed cholangitis with inflammatory cell infiltration accompanied by parasite egg-like structures and Charcot-Leyden crystals. An additional serologic test was positive for F. hepatica antibodies. A diagnosis of fascioliasis was thus confirmed by histopathology and serology. Fascioliasis should be suspected if imaging findings such as multiple small hypodense lesions in the liver are observed, and serologic tests can be useful for differential diagnosis.
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http://dx.doi.org/10.1007/s12328-021-01339-0DOI Listing
April 2021

Late recurrence of cancer stem cell-positive colorectal cancer liver metastases after 15 years.

Clin J Gastroenterol 2021 Apr 9;14(2):613-616. Epub 2021 Jan 9.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan.

No cases of late recurrence of colorectal cancer liver metastasis (CRLM) over 10 years have been reported in the literature. A 72-year-old woman had a surgical history of sigmoid colectomy and partial hepatic resections for sigmoid colon cancer and multiple liver metastases 15 years previously. The patient had been postoperatively treated with chemotherapy for 6 months and was observed regularly with no recurrence. Computed tomography (CT) performed due to high carcinoembryonic antigen (CEA) revealed a tumor of 70 mm in diameter at the anterior segment of the liver and a 6-mm nodule at the left lateral segment. There was no other malignant finding. We performed central bisegmentectomy and partial resection of the liver. Pathological findings showed the tumors to be well to moderately differentiated adenocarcinoma, and positive cytokeratin 20 (CK20) and caudal-type homeobox transcription factor 2 (CDX2) expression with negative expression of cytokeratin 7 (CK7). In addition, the tumors showed cluster of differentiation 44 (CD44) and 133 (CD133) positive signified cancer stem cell immunohistochemically. The postoperative diagnosis was recurrence of hepatic metastasis of sigmoid colon cancer. We report a rare case of late recurrence of CRLM more than 15 years after the primary diagnosis.
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http://dx.doi.org/10.1007/s12328-020-01330-1DOI Listing
April 2021

Immune microenvironment in primary and metastatic liver cancers.

Hepatol Res 2021 Jan;51(1):3-4

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

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http://dx.doi.org/10.1111/hepr.13607DOI Listing
January 2021

ASO Author Reflections: A New Prognostic Factor for Pancreatic Cancer.

Ann Surg Oncol 2021 Jun 23;28(6):3208. Epub 2020 Nov 23.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

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http://dx.doi.org/10.1245/s10434-020-09386-6DOI Listing
June 2021
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