Kenichiro Seki

Primary Hepatic Neuroendocrine Carcinoma Coexisting with Hepatocellular Carcinoma in Hepatitis C Liver Cirrhosis: Report of a Case

Abstract.Primary hepatic neuroendocrine carcinoma is an extremely rare tumor of the liver. We herein describe a case of primary hepatic neuroendocrine carcinoma with lymph node metastases, coexisting with hepatocellular carcinoma, on a background of hepatitis C cirrrhosis, in a 72-year-old man. Abdominal ultrasonography and computed tomography (CT) showed a tumor (3 cm in diameter) in Couinauds hepatic segment 8 (S8) with regional lymph node metastases. Whole-body CT, magnetic resonance imaging (MRI), and endoscopy did not reveal primary lesions outside the liver. Feridex MRI and [18F]fluorodeoxyglucose positron emission tomography were strongly suspicious of malignancy. A limited hepatectomy with regional lymph node dissection was performed. Histopathology, immunohistochemistry, and electron microscopy confirmed a diagnosis of primary neuroendocrine carcinoma on a background of liver cirrhosis. A tumor (1.5 cm in diameter) found in hepatic S5 at operation was also simultaneously resected, and histologically diagnosed to be hepatocellular carcinoma. We also review previous reports of hepatic neuroendocrine carcinoma and discuss hypotheses for the histogenesis of these tumors as well as prognostic implications. Given the background cirrhosis and coexisting hepatocellular carcinoma, we speculate that one of the hepatocellular carcinomas underwent neuroendocrine differentiation.

Intraductal mucinous tumors occurring simultaneously in the liver and pancreas

A case of simultaneous intraductal mucinous tumors of the liver and pancreas in a 67-year-old man is described. Abdominal ultrasonography and computed tomography (CT) revealed the presence of cystic lesions with intraluminal septae both in the caudate lobe of the liver and in the uncinate process of the pancreas; these cystic lesions communicated with the hepatic duct and pancreatic duct, respectively. Mucin retention was observed in the cysts, and cholestasis was induced by mucin secretion into the common bile duct. The lesions were resected by left hepatic lobectomy with caudate lobectomy, and segmental pancreatectomy. Both lesions were multilocular cystic tumors with no papillary projections or focal mass effect in their walls. Histologically, both cystic lesions were a mixture of hyperplasia and adenoma lined by low papillary columnar epithelium. There were no cellular or histological features to suggest malignant change. The fibrous intratumor interstitium lacked any mesenchymal or ovarian-like stroma. The hepatic lesion was considered to be of a similar nature to intraductal papillary mucinous tumor (IPMT) of the pancreas. However, the two lesions occurred simultaneously in the liver and pancreas. This case is of interest in regard to the diagnosis and management of mucinous hepatopancreatobiliary lesions.

Clinical Significance of Combined Immunohistochemical Detection of CD44v and Sialyl Lex Expression for Colorectal Cancer Patients Undergoing Curative Resection

To evaluate their prognostic value, the expressions of CD44v and sialyl LeX (SLX) in colorectal cancers were studied immunohistochemically. Tissue specimens were reacted with monoclonal antibodies (mAb) CD44-1V and CSLEX-1. Of the 145 colorectal cancer patients undergoing curative resection, 59 (40.7%) were positive for mAb CD44-1V, and 40 (27.6%) were positive for mAb CSLEX-1. There was a significant correlation between the combined expression of SLX and CD44v8–10 and lymph node metastasis. The patients with tumors negative for CD44v8–10 and SLX had the most favorable prognoses. Conversely, the patients with tumors positive for both CD44v8–10 and SLX had a high recurrence rate and the poorest prognoses. In a multivariate analysis using the Cox regression model, the combined expression of SLX and CD44v8–10 emerged as an independent prognostic indicator. These results suggested that the combined expression of CD44v8–10 and SLX may be a biologic marker of prognostic significance.

Predictive parameter of tolvaptan effectiveness in cirrhotic ascites

The efficacy of the vasopressin V2 receptor antagonist tolvaptan for difficult‐to‐treat cirrhotic ascites has recently been reported. However, its effect is variable among patients. This study aimed to clarify the predictive factors for obtaining a good response to tolvaptan in patients with difficult‐to‐treat ascites.

Combination treatment of dipeptidyl peptidase IV inhibitor (sitagliptin) and angiotensin-II type 1 receptor blocker (losartan) suppresses progression in a nondiabetic rat model of steatohepatitis

Dipeptidyl peptidase‐4 (DPP4) inhibitors (DPP4‐I) are oral glucose‐lowering drugs for type 2 diabetes mellitus. Previously, we reported that DPP4‐I (sitagliptin) exerted suppressive effects on experimental liver fibrosis in rats. Blockade of the renin–angiotensin system by angiotensin‐II type 1 receptor blocker (losartan), commonly used in the management of hypertension, has been shown to significantly alleviate hepatic fibrogenesis and carcinogenesis. We aimed to elucidate the effects and possible mechanisms of a sitagliptin + losartan combination on the progression of non‐diabetic non‐alcoholic steatohepatitis (NASH) in a rat model.

Clinical significance of serum levels of CD44 variant exons 8-10 protein in colorectal cancer

Abstract: We examined serum levels of a CD44 splice variant that contained variant exons 8–10 (CD44v8–10) as a tumor marker in colorectal cancer patients. We performed enzyme-linked immunosorbent assays in 81 sera obtained from 71 colorectal cancer patients and 10 healthy controls. Serum CD44v8–10 levels were significantly higher in the colorectal cancer patients than in the healthy controls (0.209 ± 0.098 versus 0.114 ± 0.019 OD; P < 0.01). There was a close correlation between immunohistochemical expression and serum CD44v8–10 levels. Surgical resection of the tumors resulted in a reduction of serum CD44v8–10 levels. There was no significant correlation between serum CD44v8–10 level and serosal invasion or histologic type. However, a significant correlation was observed between serum CD44v8–10 level and lymphatic or venous invasion. In addition, serum CD44v8–10 levels were significantly higher in carcinomas associated with lymph node or liver metastasis than in those without metastasis. These findings suggest the usefulness of serum CD44v8–10 level in the prediction of colorectal cancer metastasis.

Sodium glucose cotransporter 2 inhibitor canagliflozin attenuates liver cancer cell growth and angiogenic activity by inhibiting glucose uptake

Sodium‐glucose cotransporter 2 inhibitors (SGLT2‐Is) comprise a new class of antidiabetic agents that inhibit glucose reabsorption in the renal proximal tubules. Although a recent report demonstrated the potential ability of SGLT2‐Is to attenuate cancer growth of SGLT2‐expressing cancer cells, little is known about the effects of SGLT2‐Is on hepatocellular carcinoma (HCC). Here, we investigate the anti‐cancer properties of a SGLT2‐I, canagliflozin, against human liver cancer cells. SGTL2 mRNA and protein expression were detected in Huh7 and HepG2 cells, although not in HLE as well as primary human hepatocytes and hepatic stellate cells. Canagliflozin exerted antiproliferative effects on SGLT2‐expressing Huh7 and HepG2 cells in a dose‐dependent manner by inhibiting glycolytic metabolism including glucose uptake, lactate and intracellular ATP production. This agent also induced G2/M arrest and apoptosis with inhibited phosphorylation of ERK, p38 and AKT and cleavage of caspase3. Xenograft tumor growth assay showed that oral administration of canagliflozin (10 mg/kg/day) significantly reduced subcutaneous tumor burdens in a glycemic status‐independent manner, and attenuated intratumor vascularization in Huh7‐ and HepG2‐derived xenograft tumors in BALB/c nude mice. In vitro, canagliflozin suppressed the increased human umbilical vein endothelial cell (HUVEC) proliferation and tubular formation which were observed in Huh7 or HepG2 co‐cultures. By contrast, canagliflozin had no effect on tumor growth and intratumor angiogenesis in SGLT2‐null HLE‐derived xenograft models. These results indicate that SGLT2‐I therapy is a potential new strategy for the treatment of HCC.

Periostin cross‑reacts with the renin‑angiotensin system during liver fibrosis development

Periostin is a 90-kDa extracellular matrix protein, which is secreted primarily from fibroblasts and is expressed in the lungs, kidneys and heart valves. Angiotensin II (AT-II) serves pivotal roles in the pathogenesis of several diseases with accompanying fibrosis, including chronic liver diseases. AT-II induces periostin expression by regulating transforming growth factor-β1 (TGF-β1)/Smad signaling during cardiac fibrosis. The aim of the present study was to investigate the interaction between AT-II and periostin during liver fibrosis development. Fischer 344 rats were fed a choline-deficient L-amino-acid (CDAA)-defined diet for 12 weeks to simulate the development of steatohepatitis with liver fibrosis. Losartan, an AT-II type I receptor blocker, was administered to inhibit the effect of AT-II. The therapeutic effect of losartan on hepatic fibrosis development and on periostin expression was then evaluated. Several in vitro experiments were performed to examine the mechanisms underlying the interaction between AT-II and periostin in activated hepatic stellate cells (Ac-HSCs). Treatment with losartan suppressed the development of liver fibrosis induced by the CDAA diet, and reduced hepatic periostin expression. In addition, losartan treatment suppressed hepatic Ac-HSC expansion and hepatic TGF-β1 expression. In vitro analysis using LX2 HSC cells indicated that AT-II can augment TGF-β1 and collagen type I α1 mRNA expression via periostin expression, suggesting that the interaction between AT-II and periostin may serve a role in liver fibrosis development. In conclusion, blockade of AT-II-induced periostin may suppress the progression of liver fibrosis development.

Clinical significance of the Scheuer histological staging system for primary biliary cholangitis in Japanese patients.

Background Inadequate response to ursodeoxycholic acid (UDCA) is associated with unfavorable outcomes in patients with primary biliary cholangitis (PBC). We aimed to identify surrogate markers for predicting long-term prognosis and biochemical response to UDCA in patients with PBC. Patients and methods In this single-center, retrospective study, 99 patients with PBC were classified into responders (n=53) and nonresponders (n=46) based on reductions in the &ggr;-glutamyl transpeptidase levels at 1 year after initiating UDCA therapy (Nara criteria). We assessed whether the criteria for patentability by different countries are useful in predicting the prognosis of PBC. The accuracy of Scheuer and Nakanuma staging systems in predicting prognosis and treatment response was compared. Results Nara definition had comparable utility to the Paris-II definition for selecting patients in whom UDCA monotherapy can be safely continued. Patients at Scheuer stage 1 had a significantly better prognosis than those at Scheuer stages 3 or 4 (P<0.05 and 0.0001, respectively). Patients at Nakanuma stage 4 had decreased survival compared with those at stage 1 (P<0.05). The proportion of responders to nonresponders was significantly higher in stages 1–3 PBC than in stage 4 PBC, according to both staging systems (P<0.05 for both). All patients with Scheuer stage 4 PBC were nonresponders, whereas only 28.6% (2/7) of those with Nakanuma stage 4 PBC were responders. Conclusion The Scheuer staging system had greater utility in predicting long-term prognosis and UDCA response than the Nakanuma staging system.

Angiotensin receptor blockade attenuates cholangiocarcinoma cell growth by inhibiting the oncogenic activity of Yes-associated protein

Cholangiocarcinoma (CCA) is a destructive malignancy with limited responsiveness to conventional chemotherapy. Although angiotensin receptor blockers (ARBs) have gained attention for their potential anticancer activity, little is known about their effects on CCA. The transcriptional co-activator, Yes-associated protein (YAP) is a critical oncogene in several cancers, including CCA. Following recent evidence showing that YAP is regulated by angiotensin II (AT-II), we investigated the effects of an ARB, losartan, on two human CCA cell lines (KKU-M213 and HuCCT-1) with regards to YAP oncogenic regulation. Losartan suppressed AT-II-induced CCA cell proliferation in a dose-dependent manner, induced apoptosis, decreased YAP (Ser127), and downregulated the YAP target genes CTGF, CYR61, ANKRD1, and MFAP5. However, losartan did not affect epithelial-mesenchymal transition, differentiation, or stemness in the CCA cells. Xenograft tumor growth assay showed that oral administration of a low clinical dose of losartan considerably reduced subcutaneous tumor burden and attenuated intratumor vascularization in CCA cell-derived xenograft tumors in BALB/c nude mice. These results indicate that ARB therapy could serve as a potential novel strategy for CCA treatment.