Publications by authors named "Kyohei Yugawa"

28 Publications

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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

Prognostic Impact of Lymphocyte-C-Reactive Protein Ratio in Patients Who Underwent Surgical Resection for Hepatocellular Carcinoma.

J Gastrointest Surg 2021 Jul 13. Epub 2021 Jul 13.

Department of Surgery, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Hiroshima, 730-0052, Japan.

Background: Systemic inflammation-related factors, either independently or in combination, are recognized 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 the LCR in patients with hepatocellular carcinoma (HCC).

Methods: This was a single-center retrospective study of patients who underwent surgical resection for HCC between 2004 and 2017. Patients were divided into high- and low-LCR status groups, and the relationships between LCR status, prognosis, and other clinicopathological characteristics were analyzed.

Results: A total of 454 patients with HCC were enrolled and assigned to the high- (n=245) or low- (n=209) LCR groups. Compared with the high-LCR group, patients in the low-LCR group had a significantly lower serum albumin level (median 4.1 vs. 3.9 g/dL, P <0.0001), lower platelet count (median 14.0 vs. 12.0 ×10/μL, P=0.0468), lower prothrombin time (median 93.2 vs. 89.6 %, P=0.0006), and larger tumor size (median 2.3 vs. 2.5 cm, P=0.0056). Patients with low-LCR status had significantly worse outcomes of overall survival and disease-free survival than patients with high-LCR status (P=0.0003 and P=0.0069, respectively). Low-LCR status was significantly associated with worse overall survival in multivariate analysis (hazard ratio 1.57, 95% confidence interval 1.14-2.17, P=0.0058).

Conclusions: Low-LCR status may predict worse outcomes in patients with HCC. Measurement of LCR is routine and can easily be applied for risk stratification in the assessment of patients with HCC.
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http://dx.doi.org/10.1007/s11605-021-05085-zDOI Listing
July 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

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

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

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

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

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

Impact of Capicua on Pancreatic Cancer Progression.

Ann Surg Oncol 2021 Jun 20;28(6):3198-3207. Epub 2020 Nov 20.

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

Background: The transcription factor capicua (CIC) regulates mammalian development and homeostasis. Growing evidence shows that CIC suppresses various human cancers by directly repressing the downstream cancer-related target genes. This study investigated the clinical and biologic significance of CIC expression in pancreatic cancer (PC).

Methods: The study reviewed 132 patients with PC who underwent curative resection. The patients were divided into two groups according to CIC immunoreactivity score by immunohistochemistry, and the associations between CIC expression, clinicopathologic characteristics, and postoperative prognosis were investigated. Moreover, the influence of CIC expression on the malignant potential of PC cells was assessed with cell proliferation, motility assays, and use of quantitative real time-polymerase chain reaction and Western blot on the downstream target genes of CIC in knockdown experiments.

Results: The low-CIC expression group showed a higher proportion of lymphatic invasion (72.9% vs. 53.1%; p = 0.024), intrapancreatic neural invasion (94.1% vs. 81.3%; p = 0.021), and extrapancreatic plexus invasion (30.9% vs. 7.8%; p = 0.0006) than the high-CIC expression group as well as significantly worse overall survival (p = 0.0002) and recurrence-free survival (p = 0.0041) rates. Low CIC expression was an independent risk factor for poor prognosis (p = 0.038). Pancreatic cancer cells with knockdown CIC significantly enhanced cell motilities and cell cycle progression, promoted expression levels of ETV4 and MMP-9, and induced EMT.

Conclusions: The study elucidated the association of low CIC expression with a poor prognosis for patients with PC and suggested that the CIC-ETV4-MMP-9 axis might control PC progression.
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http://dx.doi.org/10.1245/s10434-020-09339-zDOI Listing
June 2021

Prognostic impact of tumor microvessels in intrahepatic cholangiocarcinoma: association with tumor-infiltrating lymphocytes.

Mod Pathol 2021 04 19;34(4):798-807. Epub 2020 Oct 19.

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

Tumor microvessel density (MVD) is a prognostic factor for patients with intrahepatic cholangiocarcinoma (ICC). Tumor-infiltrating lymphocytes (TILs) are also key components of the tumor microenvironment that play important roles in ICC progression. This study aimed to clarify the relationships between the MVD and immune status and prognosis in patients with ICC. Immunohistochemical staining for cluster of differentiation 34 (CD34), cluster of differentiation 8 (CD8), forkhead box protein P3 (Foxp3), and programmed death-ligand 1 (PD-L1) was performed. The relationships between the MVD and clinicopathological characteristics and outcomes were analyzed. Additionally, the correlations between the MVD, CD8+ and Foxp3+ TIL counts, and PD-L1 expression were evaluated. One hundred ICC patients were classified into high (n = 50) and low (n = 50) MVD groups. The serum platelet and carbohydrate antigen 19-9 levels were higher in the low MVD group than in the high MVD group (P = 0.017 and P = 0.008, respectively). The low MVD group showed a significantly larger tumor size (P = 0.016), more frequent microvascular invasion (P = 0.001), and a higher rate of intrahepatic (P = 0.023) and lymph node (P < 0.001) metastasis than the high MVD group. Moreover, the MVD showed a high positive correlation with CD8+ TILs (r = 0.754, P < 0.001) and a negative correlation with Foxp3+ TILs (r = -0.302, P = 0.003). In contrast, no significant correlation was observed between the MVD and PD-L1 expression in cancer cells (P = 0.817). Patients with low MVDs had a significantly worse prognosis than those with high MVDs. Furthermore, multivariable analyses revealed that a low MVD influenced recurrence-free survival. A decreased intratumoral MVD might predict ICC patient outcomes. Tumor microvessels might be associated with ICC progression, possibly by altering TIL recruitment.
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http://dx.doi.org/10.1038/s41379-020-00702-9DOI Listing
April 2021

Hepatic resection for recurrent hepatocellular carcinoma during pregnancy: a case report.

Surg Case Rep 2020 Sep 29;6(1):229. Epub 2020 Sep 29.

Department of Surgery, Hiroshima Red Cross Hospital and Atomic-Bomb Survivors Hospital, 1-9-6 Senda-machi, Naka-ku, Hiroshima, 730-8619, Japan.

Background: Hepatocellular carcinoma (HCC) during pregnancy is extremely rare. Treatment strategies for cancers detected during pregnancy have been controversial. We herein report a case of recurrent HCC detected at 20 weeks of pregnancy, which subsequently prompted hepatic resection after abortion.

Case Presentation: A 36-year-old woman underwent laparoscopic partial hepatectomy for HCC (20 mm in diameter) in segment 5 of the liver during follow-up after being determined as a hepatitis B virus carrier two and a half years ago. Post-surgery follow-up abdominal ultrasonography revealed a 36-mm tumor in segment 7 of the liver. Abdominal contrast-enhanced computed tomography revealed a well-enhanced tumor with a 40-mm diameter in segment 7 adjacent to the inferior vena cava and right hepatic vein, suggesting HCC recurrence. Laboratory data revealed total bilirubin (0.4 mg/dL), aspartate aminotransferase (28 IU/L), alanine aminotransferase (30 IU/L), glutamyltransferase (16 IU/L), prothrombin time (115.3%), and indocyanine green retention rate at 15 min (7.0%). α-Fetoprotein (AFP) (12,371.5 ng/mL; normal range < 10 ng/mL) and PIVKA-II (208 mAU/mL; normal range < 40 mAU/mL) were both significantly elevated. After discussions with a cancer board consisting of experts from the departments of gastroenterology, obstetrics and gynecology, and surgery, as well as obtaining appropriate informed consent from the patient and her family, we decided to perform a hepatic resection after abortion. Subsequently, abortion surgery was performed at 21 weeks and 2 days of pregnancy. After 6 days, subsegmentectomy of liver segment 7 was performed under general and epidural anesthesia, with a pathological diagnosis which was moderately differentiated HCC being established. Given the good postoperative course, without particular complications, the patient was subsequently discharged 10 days after the operation. Approximately 2 years after the surgery, the patient remains alive without recurrence, while both AFP and PIVKA-II were within normal limits.

Conclusions: Treatment strategies for HCC detected during pregnancy remain controversial. As such, decisions should be made based on HCC growth and fetal maturity after thorough multidisciplinary team discussions and obtaining appropriate informed consent from the patient and her family.
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http://dx.doi.org/10.1186/s40792-020-00985-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524929PMC
September 2020

Cancer-associated fibroblasts promote hepatocellular carcinoma progression through downregulation of exosomal miR-150-3p.

Eur J Surg Oncol 2021 02 19;47(2):384-393. Epub 2020 Aug 19.

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

Purpose: Hepatocellular carcinoma (HCC) is a common and deadly cancer. The prognosis of HCC is poor and is related to tumor progression. The malignant potential of HCC is regulated by the tumor microenvironment (TME). As cancer-associated fibroblasts (CAFs) help regulate tumor progression, understanding how they function in HCC could improve patient outcomes. The aim of this study was to determine whether specific microRNAs (miRNAs) in exosomes derived from CAFs might be involved in HCC progression.

Methods: MiRNA microarray assay was used to analyze miRNA profiles of exosomes derived from CAFs and normal fibroblasts (NFs) in HCC. Migration and invasion assays were performed to examine the effects of miR-150-3p on HCC in vitro. In addition, the relationships between prognosis of HCC patients and miR-150-3p expression in HCC tissues and plasma exosomes were retrospectively analyzed.

Results: MiR-150-3p was significantly reduced in CAFs-derived exosomes, and inhibited HCC migration and invasiveness. MiR-150-3p was transferred from CAFs transfected miR-150-3p to HCC cells through exosomes, and abrogated HCC migration and invasiveness. Furthermore, low miR-150-3p expression in HCC tissues was a significant risk factor for recurrence in HCC patients. More importantly, survival rate in patients with low miR-150-3p levels in plasma exosomes was significantly poor compared with that in patients with high miR-150-3p levels.

Conclusions: Overall, our findings suggest that the loss of antitumoral miR-150-3p in CAFs-derived exosomes greatly promotes HCC progression. Exosomal miR-150-3p is a potential prognostic biomarker, and transferring miR-150-3p-loaded exosomes to HCC cells might become a novel therapeutic option.
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http://dx.doi.org/10.1016/j.ejso.2020.08.002DOI Listing
February 2021

Mitochondrial expression of the DNA repair enzyme OGG1 improves the prognosis of pancreatic ductal adenocarcinoma.

Pancreatology 2020 Sep 25;20(6):1175-1182. Epub 2020 Jul 25.

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

Background/objectives: 8-Hydroxydeoxyguanosine (8-OHdG) is an indicator of oxidative stress and causes transversion mutations and carcinogenesis. 8-OHdG is excision repaired by 8-OHdG DNA glycosylase 1 (OGG1), which is classified as nuclear and mitochondrial subtypes. We aimed to clarify the role of OGG1 in pancreatic ductal adenocarcinoma (PDAC).

Methods: Ninety-two patients with PDAC who had undergone surgical resection at multiple institutions were immunohistochemically analyzed. The OGG1 and 8-OHdG expression levels were scored using the Germann Immunoreactive Score. The cutoff values of OGG1, as well as that of 8-OHdG, were determined.

Results: The low nuclear OGG1 expression group (n = 41) showed significantly higher carbohydrate antigen (CA)19-9 (p = 0.026), and higher s-pancreas antigen (SPAN)-1 (p = 0.017) than the high expression group (n = 51). Nuclear OGG1 expression has no effect on the prognosis. The low mitochondrial OGG1 expression group (n = 40) showed higher CA19-9 (p = 0.041), higher SPAN-1 (p = 0.032), and more histological perineural invasion (p = 0.037) than the high expression group (n = 52). The low mitochondrial OGG1 expression group had a significantly shorter recurrence-free survival (p = 0.0080) and overall survival (p = 0.0073) rates. The Cox proportional hazards model revealed that low mitochondrial OGG1 expression is an independent risk factor of the PDAC prognosis. OGG1 expression was negatively correlated with 8-OHdG expression (p = 0.0004), and high 8-OHdG expression shortened the recurrence-free survival of patients with PDAC.

Conclusions: Low mitochondrial OGG1 expression might aggravate the PDAC prognosis.
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http://dx.doi.org/10.1016/j.pan.2020.07.011DOI Listing
September 2020

Large surgically resected leiomyosarcoma of the liver: a case report.

Surg Case Rep 2020 Jul 9;6(1):168. Epub 2020 Jul 9.

Department of Surgery, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, 1-9-6 Senda-machi, Naka-ku, Hiroshima 730-8619, Japan.

Background: Primary hepatic leiomyosarcoma (PHL) is an extremely rare type of tumor. We herein report a case of a large surgically resected leiomyosarcoma of the liver.

Case Presentation: A 69-year-old man with a feeling of epigastric compression was referred for examination of an abdominal mass. He had no history of liver disease or alcohol abuse. Liver function tests indicated Child-Pugh class A. Tumor markers were negative. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed a relatively well-contrasted 12 × 11 × 8 cm tumor with well-defined boundary replacing the lateral segment of the liver alongside multiple intrahepatic metastases. Several nodules up to 12 mm were found in both lungs, suggestive of metastasis. SUVmax of the liver mass and lung tumor in positron emission tomography were 10.4 and 1.5, respectively. Hepatocellular carcinoma was primarily suspected. Lateral segmentectomy of the liver was performed to confirm diagnosis and prevent tumor rupture. Macroscopically, the lateral segment of the liver had been replaced by a lobular or multinodular tumor with a maximum diameter of 15 cm. In pathological findings, the tumor consisted of bundle-like proliferation of complicated banding spindle-like cells with clear cytoplasm, accompanied by storiform pattern and compressed blood vessels. Nuclear fission images were observed in 8/10 HPF. Partial necrosis was present, with associated venous invasion and intrahepatic metastasis. Immunohistochemical staining for tumor cells revealed desmin, α-smooth muscle actin (αSMA), and h-caldesmon were all positive, informing a final diagnosis of PHL. The postoperative course was uneventful, and he was discharged on the 12th postoperative day.

Conclusions: PHL is a rare malignant disease with relatively poor prognosis. To confirm a diagnosis of PHL, immunohistochemical analysis as well as histopathological findings is important. The preferred treatment is surgical resection, sometimes in combination with adjuvant chemotherapy and radiotherapy. Further studies are needed to elucidate and better understand this uncommon clinical entity.
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http://dx.doi.org/10.1186/s40792-020-00934-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347740PMC
July 2020

Mixed adenoneuroendocrine carcinoma of the distal bile duct: a case report.

Surg Case Rep 2020 Jul 6;6(1):160. Epub 2020 Jul 6.

Department of Surgery, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, 1-9-6 Senda-machi, Naka-ku, Hiroshima, 730-8619, Japan.

Background: Mixed adenoneuroendocrine carcinoma (MANEC) of the common bile duct (CBD) is very rare, with only 10 reported cases. Here, we report a case of MANEC of the distal bile duct (DBD) that was surgically resected under a diagnosis of cholangiocarcinoma (CCA).

Case Presentation: A 60-year-old male had epigastric pain and was admitted to our hospital for the treatment of a suspected CBD stone. Upon admission, laboratory findings revealed elevated hepatobiliary enzymes including serum aspartate aminotransferase, serum alanine aminotransferase, serum glutamyltransferase, and serum alkaline phosphatase. Both carcinoembryonic antigen and carbohydrate antigen 19-9 were negative. Computed tomography (CT) showed dilation of the CBD. Endoscopic retrograde cholangiopancreatography (ERCP) showed circumferential stenosis and a 5-mm elevated lesion in the DBD. Brush cytology showed atypical ductal cells, indicating adenocarcinoma (AC) of the DBD. Under a diagnosis of CCA of the DBD, a subtotal stomach-preserving pancreaticoduodenectomy was performed. Neither peritoneal dissemination nor lymph node metastasis was found. Microscopically, the lesion was seen to be composed of predominantly well-differentiated tubular AC in the superficial layer of the tumor, admixed with neuroendocrine carcinoma (NEC) in the deeper portion, indicating a diagnosis of MANEC of the DBD. After immunohistochemical staining, NEC components were positive for synaptophysin and CD56 and were for SSTR2, SSTR5, and mammalian target of rapamycin (mTOR). Three months postsurgery, postoperative adjuvant chemotherapy with S-1 was started. More than 3 years postsurgery, he is alive without recurrence.

Conclusions: MANEC is highly malignant, progresses rapidly, and has a poor prognosis. Preoperative diagnosis is difficult; therefore, identifying NEC components by immunohistochemical staining using resected specimens is important.
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http://dx.doi.org/10.1186/s40792-020-00921-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338298PMC
July 2020

Prognostic impact of 8-hydroxy-deoxyguanosine and its repair enzyme 8-hydroxy-deoxyguanosine DNA glycosylase in hepatocellular carcinoma.

Pathol Int 2020 Aug 17;70(8):533-541. Epub 2020 May 17.

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

Hepatocellular carcinoma (HCC) has a poor prognosis in the setting of chronic inflammation and fibrosis, both of which promote nuclear DNA oxidative damage. 8-hydroxy-deoxyguanosine (8-OHdG) DNA glycosylase (OGG1) enhances the repair of 8-OHdG, which is the primary oxidative stress-induced mutation that leads to malignant alterations. This study aims to clarify the relationships between oxidative stress-induced factors and HCC progression. The clinicopathological factors were compared with immunohistochemistry OGG1 and 8-OHdG expressions in 86 resected HCC specimens. High 8-OHdG expression was associated with high serum aspartate transaminase and total bilirubin levels, as well as a low platelet count, compared with low 8-OHdG expression. Histological liver cirrhosis and poor differentiation were more frequent in patients with high 8-OHdG expression than in those with low 8-OHdG expression. The 8-OHdG was negatively correlated with OGG1 expression in HCC patients. Therefore, we classified the patients into two groups, low OGG1/high 8-OHdG group and the other group. The patients with low OGG1/high 8-OHdG expressions had worse prognosis than those with the other expressions. Our results showed that low OGG1/high 8-OHdG expressions in nuclei influence HCC patient outcomes. Evaluating the patterns of OGG1 and 8-OHdG expressions might provide pivotal prognostic biomarkers in patients with HCC.
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http://dx.doi.org/10.1111/pin.12952DOI Listing
August 2020

Surgical Indications for Hepatocellular Carcinoma with Non-hypervascular Hypointense Nodules Detected by Gd-EOB-DTPA-Enhanced MRI.

Ann Surg Oncol 2020 Sep 3;27(9):3344-3353. Epub 2020 Apr 3.

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

Background: The surgical indication for non-hypervascular hypointense nodules (NHVN) detected incidentally on gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (Gd-EOB-MRI) for classical hepatocellular carcinoma (HCC) is unknown. Our aim is to clarify the long-term outcomes in patients with this finding.

Methods: We reviewed the cases of 290 HCC patients, including 66 patients with NHVN, who underwent Gd-EOB-MRI prior to hepatectomy, between October 2008 and December 2017 at our center. We divided the patients into three groups: a no-NHVN group, a treated NHVN group, and an untreated NHVN group.

Results: There was no significant difference in (RFS) or overall survival (OS) between the no-NHVN and untreated NHVN groups (p = 0.103 and 0.103, respectively). There was no significant difference between these two groups after propensity score matching. Multivariate analyses showed that microscopic intrahepatic metastases and the size of the main classical HCC, the target tumor, were independent prognostic factors of overall survival, but the presence of non-hypervascular hypointense nodules was not. There was no significant difference in RFS or OS between the treated NHVN and untreated NHVN groups (p = 0.158 and 0.109, respectively).

Conclusions: Non-hypervascular hypointense nodules detected incidentally on Gd-EOB-MRI associated with targeted hypervascular HCC did not reflect prognosis of HCC after hepatectomy. Surgical procedures for classical enhancing HCC may be performed even if non-hypervascular hypointense nodules adjacent to the targeted HCC cannot be removed completely.
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http://dx.doi.org/10.1245/s10434-020-08419-4DOI Listing
September 2020

Combined hepatocellular-cholangiocarcinoma after tetralogy of Fallot repair: a case report and review of literature.

Pathol Res Pract 2020 May 29;216(5):152908. Epub 2020 Feb 29.

Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashiku, Fukuoka, 812-8582, Japan. Electronic address:

Background: Liver fibrosis and cancer are serious hepatic complications for patients with congenital heart diseases. We present a rare case of combined hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) (cHCC-CCA) after the repair of tetralogy of Fallot (TOF).

Case Presentation: A 54-year-old Japanese woman had undergone biventricular repair for TOF at 7 years old. She presented with abdominal distension. Abdominal CT revealed ascites and a 90-mm tumor involving the liver's left lobe. Tumor marker values were: alpha-fetoprotein, 16,208 ng/mL and des-gamma-carboxy prothrombin, 33,920 mAU/mL. The preoperative diagnosis was malignant tumor of the liver (e.g., HCC or intrahepatic CCA). We performed a left lobectomy of the liver. Histopathologically, the tumor was composed of two components growing in trabecular and irregular tubular patterns accompanied by a transitional area; the tumor was diagnosed as cHCC-CCA. The non-cancerous area showed fibrous change mainly surrounding a central vein and sinusoid, expanding toward the portal area without inflammation.

Conclusions: We provide the details of our patient's cHCC-CCA that developed from fibrous congestive liver associated with right-sided heart failure after TOF repair, diagnosed based on histopathological features. We discuss liver fibrosis as a hepatic complication and a careful follow-up maneuver for improving the outcomes of patients with chronic hepatic congestion.
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http://dx.doi.org/10.1016/j.prp.2020.152908DOI Listing
May 2020

Living-Donor Liver Transplantation for Patients With Extrahepatic Malignancy: A Series of 14 Patients in a Single Institution.

Transplant Proc 2020 Apr 3;52(3):889-893. Epub 2020 Mar 3.

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

Extrahepatic malignancy is a relative contraindication for liver transplant in many countries. Nevertheless, the indications for living-donor liver transplantation (LDLT) for such patients vary by institution. Our aim was to reevaluate the indications for LDLT in patients with extrahepatic malignancy. We retrospectively reviewed data for 609 patients who underwent adult LDLT from May 1997 to January 2018 and analyzed patients with a history of extrahepatic malignancies or concurrent malignancies. Fourteen patients had extrahepatic malignancies concurrent with or before LDLT. Malignancies in 9 patients were detected during their systematic screening for LDLT. The mean duration between surgeries was 70 days (range, 20-209 days). Five patients had a history of extrahepatic malignancies before considering LDLT. The estimated 5-year survival rate was 100%. Although the risk and long-term prognosis of patients with extrahepatic malignancy are not well known, such patients can be candidates for LDLT if they undergo curative surgery for the malignancy, and if the prognosis of the malignancy is the same or superior to that of LDLT.
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http://dx.doi.org/10.1016/j.transproceed.2019.12.041DOI Listing
April 2020

Impact of Immune Response on Outcomes in Hepatocellular Carcinoma: Association With Vascular Formation.

Hepatology 2020 12 20;72(6):1987-1999. Epub 2020 Oct 20.

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

Background And Aims: We investigated the prognostic value of programmed death ligand 1 (PD-L1) expression, tumor-infiltrating CD8-positive T-cell status, and their combination in hepatocellular carcinoma (HCC). Their association with PD-L1 expression and vascular formation was further explored.

Approach And Results: Using a database of 387 patients who underwent hepatic resection for HCC, immunohistochemical staining of PD-L1, CD8, and CD34 was performed. Additionally, we undertook an enzyme-linked immunosorbent assay for soluble PD-L1. Compared with patients with HCC and PD-L1-negative expression (n = 311), patients with HCC and PD-L1-positive expression (n = 76) showed significantly worse overall survival (OS; multivariate hazard ratio, 2.502; 95% confidence interval [CI], 1.716-3.649; P < 0.0001). The presence of tumor-infiltrating CD8-positive T cells was significantly correlated with longer OS (multivariate hazard ratio, 0.383; 95% CI, 0.274-0.537; P < 0.0001). Stratification based on PD-L1 expression in cancer cells and tumor-infiltrating CD8-positive T-cell status was also significantly associated with OS (log-rank, P < 0.0001). HCC with PD-L1-positive expression was significantly correlated with positivity for vessels that encapsulated tumor clusters. Serum PD-L1 levels were significantly higher in the group of patients who had PD-L1-positive expression than in the group of patients who had PD-L1-negative expression (P = 0.0158).

Conclusions: PD-L1 expression in cancer cells was associated with a poor clinical outcome and vascular formation in patients with HCC. Additionally, the combination of PD-L1 expression with tumor-infiltrating CD8-positive T-cell status enabled further classification of patients based on their clinical outcome. Thus, PD-L1 expression in cancer cells and tumor-infiltrating CD8-positive T-cell status might serve as predictive tissue biomarkers.
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http://dx.doi.org/10.1002/hep.31206DOI Listing
December 2020

Modulation of Nqo1 activity intercepts anoikis resistance and reduces metastatic potential of hepatocellular carcinoma.

Cancer Sci 2020 Apr 3;111(4):1228-1240. Epub 2020 Mar 3.

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

The processing of intracellular reactive oxygen species (ROS) by nuclear factor erythroid-derived 2-like 2 (Nrf2) and NADPH quinone oxidoreductase 1 (Nqo1) is important for tumor metastasis. However, the clinical and biological significance of Nrf2/Nqo1 expression in hepatocellular carcinoma (HCC) remains unclear. We aimed to clarify the clinical importance of Nrf2/Nqo1 expression in HCC and evaluate the association of Nrf2/Nqo1 expression with HCC metastasis. We also evaluated the impact of Nqo1 modulation on HCC metastatic potential. We used spheroids derived from HCC cell lines. In anchorage-independent culture, HCC cells showed increased ROS, leading to the upregulation of Nrf2/Nqo1. Futile stimulation of Nqo1 by β-lapachone induces excessive oxidative stress and dramatically increased anoikis sensitivity, finally diminishing the spheroid formation ability, which was far stronger than depletion of Nqo1. We analyzed 117 cases of primary HCC who underwent curative resection. Overexpression of Nrf2/Nqo1 in primary HCC was associated with tumor size, high α-fetoprotein, and des-γ-carboxy-prothrombin levels. Overexpression of Nrf2/Nqo1 was also associated with multiple intrahepatic recurrences (P = .0073) and was an independent risk factor for poor prognosis (P = .0031). NADPH quinone oxidoreductase 1 plays an important role in anchorage-independent survival, which is essential for survival for circulation and distant metastasis of HCC cells. These results suggest that targeting Nqo1 activity could be a potential strategy for HCC adjuvant therapy.
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http://dx.doi.org/10.1111/cas.14320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156873PMC
April 2020

Association of inflammatory biomarkers with long-term outcomes after curative surgery for mass-forming intrahepatic cholangiocarcinoma.

Surg Today 2020 Apr 30;50(4):379-388. Epub 2019 Oct 30.

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

Purpose: Inflammatory biomarkers such as the neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and platelet-to-lymphocyte ratio (PLR) are reportedly predictive of the long-term outcomes of several cancers. We evaluated their correlations with the post-surgical long-term outcomes of patients with mass-forming (MF) intrahepatic cholangiocarcinoma (ICC).

Methods: The subjects of this study were 52 patients who underwent hepatic resection for MF-ICC at our hospital. We measured the cutoff values of NLR, LMR and PLR, using receiver operating characteristic curves, and compared the survival rates of patients with high vs. those with low values. We also evaluated a prognostic scoring system based on significant inflammatory biomarkers.

Results: The cutoff values for NLR, LMR, and PLR were 1.93, 4.78, and 98, respectively. The high-NLR and low-LMR groups had significantly worse prognoses than the low-NLR and high-LMR groups. We designed a scoring system using the inflammation score (IS) based on NLR and LMR values, stratifying patients into three groups with scores of 0, 1, or 2. The IS was significantly correlated with overall survival (OS), with 5-year survival rates by the IS score of 100% for 0, 61% for 1, and 32% for 2 (P = 0.011). The IS was found to be an independent predictor of OS in multivariate analysis.

Conclusions: Our IS scoring system may predict long-term outcomes after surgery for MF-ICC.
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http://dx.doi.org/10.1007/s00595-019-01905-7DOI Listing
April 2020

Solitary fibrous tumor in the liver: case report and literature review.

Surg Case Rep 2019 Apr 24;5(1):68. Epub 2019 Apr 24.

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

Background: Solitary fibrous tumors (SFTs) are uncommon mesenchymal neoplasms that present most commonly at intrathoracic sites. SFTs of the liver are rare, with only a few having been reported in the English-language literature. We report a rare case of a hepatic SFT and literature review.

Case Presentation: A 49-year-old woman underwent surgery for a cranial hemangiopericytoma two decades previously. She currently presented with malaise. Abdominal computed tomography (CT) showed a huge, sharply demarcated mass in the anterior segment of the liver. Tumor marker levels were within the normal range. Following central bisegmentectomy of the liver, histological examination of the specimen revealed that the tumor was composed of spindle and fibroblast-like cells with collagenous stroma. Immunohistochemically, the spindle cells were negative for CD34 but positive for STAT6. The NAB2-STAT6 fusion gene was detected by the reverse transcription polymerase chain reaction. A diagnosis of SFT was thus confirmed histopathologically and genetically.

Conclusions: The SFT of the liver is an uncommon finding. Because there are no specific imaging features, it is difficult to diagnose the hepatic SFT preoperatively. We consider that careful surgical resection and postoperative follow-up are necessary for hepatic SFTs.
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http://dx.doi.org/10.1186/s40792-019-0625-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6482201PMC
April 2019

Bone morphogenetic protein 4 provides cancer-supportive phenotypes to liver fibroblasts in patients with hepatocellular carcinoma.

J Gastroenterol 2019 Nov 2;54(11):1007-1018. Epub 2019 Apr 2.

The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1, Kohnodai, Ichikawa, Chiba, 272-8516, Japan.

Background: Cancer-associated fibroblasts (CAFs) are essential constituents of cancer-supportive microenvironments. The high incidence of hepatocellular carcinoma (HCC) in advanced fibrosis patients implies that fibroblasts have a promoting effect on HCC development. We aimed to explore the regulators of phenotypes and function of CAFs in the liver.

Methods: We established primary cancer-associated fibroblasts (CAFs) and non-cancerous liver fibroblasts (NFs) from 15 patients who underwent HCC resection. We compared phenotypes, capacity of cytokine/chemokine production and gene expression profiles between pairs of CAFs and NFs from the same donors. We examined resected tissue from additional 50 patients with HCC for immunohistochemical analyses.

Results: The CAFs expressed more ACTA2 and COL1A1 than the NFs, suggesting that CAFs are more activated phenotype. The CAFs produced larger amounts of IL-6, IL-8 and CCL2 than the NFs, which led to invasiveness of HuH7 in vitro. We found that Bone Morphogenetic Protein-4 (BMP4) is up-regulated in CAFs compared to NFs. The CAF phenotype and function were gained by BMP4 over-expression or recombinant BMP4 given to fibroblasts, all of which decreased with BMP4 knockdown. In tissues obtained from the patients, BMP4-positive cells are mainly observed in encapsulated fibrous lesions and HCC. Positive expression of BMP4 in HCC in resected tissues, not in fibroblasts, was associated with poorer postoperative overall survival in patients with HCC.

Conclusion: Endogenous and exogenous BMP4 activate liver fibroblasts to gain capacity of secreting cytokines and enhancing invasiveness of cancer cells in the liver. BMP4 is one of the regulatory factors of CAFs functioning in the microenvironment of HCC.
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http://dx.doi.org/10.1007/s00535-019-01579-5DOI Listing
November 2019

Skeletal muscle mass predicts the prognosis of patients with intrahepatic cholangiocarcinoma.

Am J Surg 2019 11 14;218(5):952-958. Epub 2019 Mar 14.

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

Background: We studied the prognostic impact of sarcopenia after hepatic resection for intrahepatic cholangiocarcinoma (ICC).

Methods: Sixty-one patients who underwent surgery for ICC during 2000-2017 were analyzed retrospectively. Psoas muscle areas were measured on CT scans at the third lumbar vertebra. Areas less than the sex-specific median were deemed low skeletal muscle masses (SMMs).

Results: Low-SMM patients were significantly more often older (p = 0.002) than high-SMM patients, had lower serum albumin (p = 0.004), higher serum C-reactive protein (CRP) (p = 0.002), and higher carbohydrate antigen 19-9 (p < 0.001). Five-year overall survival rates were 72.5% and 17.6% and 5-year recurrence-free survival rates were 58.6% and 21.1%, respectively, in high- and low-SMM patients. Multivariable analysis revealed that low SMM predicted unfavorable prognoses. SMM was associated with immune nutritional status (e.g., prognostic nutritional index, Glasgow prognostic score, CRP/albumin ratio).

Conclusion: Low SMM was related to worse surgical outcomes in patients with ICC following hepatic resection.
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http://dx.doi.org/10.1016/j.amjsurg.2019.03.010DOI Listing
November 2019

Primary intrahepatic cholangiocarcinoma with sarcomatous stroma: case report and review of the literature.

Surg Case Rep 2018 Nov 26;4(1):138. Epub 2018 Nov 26.

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

Background: Hepatic carcinosarcomas, which include both carcinomatous and sarcomatous elements, are uncommon in adults. Although carcinosarcoma in hepatocellular carcinoma is occasionally reported, carcinosarcoma in intrahepatic cholangiocarcinoma (ICC) is an extremely rare ICC variant. Few such cases have been reported in English and no large study of its clinicopathological features exists.

Case Presentation: Here, we report a 60-year-old man with an asymptomatic hepatic B infection who developed hepatic carcinosarcoma from an otherwise normal liver. The 6.0-cm tumor was accidentally discovered by PET-CT in a cancer examination. Serum examinations showed no elevation of tumor markers. He underwent left and caudate lobectomy of the liver. The diagnosis of intrahepatic cholangiocarcinoma with sarcomatous stroma was based on thorough pathologic examination and immunohistochemical staining. The tumor exhibited adenocarcinomatous and sarcomatous components; the adenocarcinomatous element was positive for epithelial markers, the sarcomatous element was positive for mesenchymal markers, but negative for epithelial markers. The patient made an uneventful recovery after surgery. At present, 14 months after surgery, he remains well with no evidence of tumor recurrence.

Conclusions: We report an unusual case of hepatic carcinosarcoma (intrahepatic cholangiocarcinoma with sarcomatous stroma) and discuss the etiology and prognosis of this rare disease.
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http://dx.doi.org/10.1186/s40792-018-0543-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6261094PMC
November 2018

Multiple hepatic sclerosing hemangiomas: a case report and review of the literature.

Surg Case Rep 2018 Jun 19;4(1):60. Epub 2018 Jun 19.

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

Background: Hepatic sclerosing hemangioma, a very rare benign tumor, is characterized by fibrosis and hyalinization occurring in association with degeneration of a hepatic cavernous hemangioma. Such atypical hemangiomas can be diagnosed incorrectly as primary or metastatic malignancies based on imaging characteristics. We present herein a rare case of giant and multiple hepatic sclerosing hemangiomas that are difficult to differentiate from hepatic malignancies and review the relevant literature.

Case Presentation: The patient was a 48-year-old male who was found to have multiple hepatic tumors and a giant tumor (67 × 53 mm) superior to the inferior vena cave by an abdominal ultrasonography during a routine medical examination. The patient was referred to our hospital for further evaluations and diagnosis of the multiple hepatic tumors. Dynamic CT showed low-density tumors in the delayed phase suggestive of membrane-covered lesions. EOB-MRI demonstrated a mass with low-signal intensity mass on T1-weighted images and areas of high-signal intensity on T2-weighted images and a hypointense mass in the hepatobiliary phase, which showed high intensity on DWI-based ADC map. FDG-PET showed no accumulation of [F]-FDG. A provisional diagnosis of multiple scirrhous hepatocellular carcinomas was made on the basis of these imaging studies, and caudate lobectomy of the liver and partial hepatectomy of S2 and S6 were performed. Histopathological examination showed that the tumors were composed of various sized irregularly dilated vessels with some blood thrombi, inflammatory cell infiltration, fibrous and hyalinized sclerotic or myxomatous stroma, resulting in a diagnosis of multiple hepatic sclerosing hemangiomas.

Conclusions: Differentiation of multiple sclerosing hemangiomas from other hepatic malignant tumors, such as intrahepatic cholangiocarcinoma, metastatic liver cancer, and scirrhous hepatocellular carcinoma characterized by abundant fibrous stroma, is difficult because the radiological findings are very similar. Inclusion of hepatic sclerosing hemangioma in the differential diagnosis of multiple liver tumors could enable optimal management; this possibility is important to consider before planning invasive therapies.
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http://dx.doi.org/10.1186/s40792-018-0468-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006004PMC
June 2018

Lymphocyte-to-Monocyte Ratio Is a Predictor of Survival After Liver Transplantation for Hepatocellular Carcinoma.

Liver Transpl 2018 11;24(11):1603-1611

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

Recent studies revealed that systemic inflammation was correlated with poorer prognosis in various cancers. We investigated the prognostic value of the lymphocyte-to-monocyte ratio (LMR) in patients who underwent living donor liver transplantation (LDLT) for hepatocellular carcinoma (HCC). We retrospectively analyzed the records of 216 patients who underwent LDLT for HCC. Patients were divided into high (n = 126) and low (n = 90) LMR groups. Their clinicopathological parameters and survival times were compared. To determine the mechanisms of the change in the LMR, we performed immunohistochemical analyses of CD3 and CD68 expression. A low LMR was significantly associated with a high Model for End-Stage Liver Disease score; a high Child-Pugh score; elevation of alpha-fetoprotein, des-gamma-carboxyprothrombin, and neutrophil-to-lymphocyte ratio; larger tumor size; more tumors; and poorer prognosis. A low LMR was associated with poor prognosis and represented an independent prognostic factor, particularly among patients beyond the Milan criteria. The ratio of CD3-positive to CD68-positive cells was significantly lower in the low-LMR group. In conclusion, our results show that the LMR was an independent predictor of survival of patients with HCC beyond the Milan criteria who underwent LDLT. The LMR reflected the immune status of the tumor microenvironment.
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http://dx.doi.org/10.1002/lt.25204DOI Listing
November 2018
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