Association of the Low-density Lipoprotein Cholesterol/High-density Lipoprotein Cholesterol Ratio with Glecaprevir-pibrentasvir Treatment.

Objective The change in serum lipid levels by direct-acting antiviral (DAA) treatment for chronic hepatitis C varies depending on the type of DAA. How the lipid level changes induced by glecaprevir-pibrentasvir (G/P) treatment contribute to the clinical outcome remains unclear. We conducted a prospective observational study to evaluate the effectiveness of G/P treatment and the lipid level changes. Methods The primary endpoint was a sustained virologic response at 12 weeks (SVR12). The total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) levels and LDL-C/HDL-C (L/H) ratio were measured every two weeks. Patients This study included 101 patients. Seventeen cases of liver cirrhosis and nine cases of DAA retreatment were registered. The G/P treatment period was 8 weeks in 74 cases and 12 weeks in 27 cases. Results SVR12 was evaluated in 96 patients. The rate of achievement of SVR12 in the evaluable cases was 100%. We found significantly elevated TC and LDL-C levels over the observation period compared to baseline. The serum levels of HDL-C did not change during treatment but were significantly increased after treatment compared to baseline. The L/H ratio was significantly increased two weeks after the start of treatment but returned to the baseline after treatment. Conclusion The primary endpoint of the SVR12 achievement rate was 100%. G/P treatment changed the serum lipid levels. Specifically, the TC and LDL-C levels increased during and after treatment, and the HDL-C levels increased after treatment. G/P treatment may be associated with a reduced thrombotic risk. Therefore, validation in large trials is recommended.

The effect of forced expression of mutated K-RAS gene on gastrointestinal cancer cell lines and the IGF-1R targeting therapy.

Mutation in K-RAS (K-RAS-MT) plays important roles in both cancer progression and resistance to anti-epidermal growth factor receptor (EGFR) therapy in gastrointestinal tumors. Insulin-like growth factor-1 receptor (IGF-1R) signaling is required for carcinogenicity and progression of many tumors as well. We have previously shown successful therapy for gastrointestinal cancer cell lines bearing a K-RAS mutation using an anti-IGF-1R monoclonal antibody. In this study, we sought to evaluate effects of forced K-RAS-MT expression on gastrointestinal cancer cell lines representing a possible second resistance mechanism for anti-EGFR therapy and IGF-1R-targeted therapy for these transfectants. We made stable transfectants of K-RAS-MT in two gastrointestinal cancer cell lines, colorectal RKO and pancreatic BxPC-3. We assessed the effect of forced expression of K-RAS-MT on proliferation, apoptosis, migration, and invasion in gastrointestinal cancer cells. Then we assessed anti-tumor effects of dominant negative IGF-1R (IGF-1R/dn) and an IGF-1R inhibitor, picropodophyllin, on the K-RAS-MT transfectants. Overexpression of K-RAS-MT in gastrointestinal cancer cell lines led to more aggressive phenotypes, with increased proliferation, decreased apoptosis, and increased motility and invasion. IGF-1R blockade suppressed cell growth, colony formation, migration, and invasion, and up-regulated chemotherapy-induced apoptosis of gastrointestinal cancer cells, even when K-RAS-MT was over-expressed. IGF-1R blockade inhibited the Akt pathway more than the extracellular signal-regulated kinase (ERK) pathway in the K-RAS-MT transfectants. IGF-1R/dn, moreover, inhibited the growth of murine xenografts expressing K-RAS-MT. Thus, K-RAS-MT might be important for progressive phonotype observed in gastrointestinal cancers. IGF-1R decoy is a candidate molecular therapeutic approach for gastrointestinal cancers even if K-RAS is mutated. © 2016 Wiley Periodicals, Inc.

Mediastinal Yolk Sac Tumor Producing Protein Induced by Vitamin K Absence or Antagonist-II.

Extragonadal yolk sac tumors (YSTs) are rare. We herein report the case of a 66-year-old man with mediastinal, lung and liver tumors. The largest mass was located in the liver and contained a high concentration of protein induced by vitamin K absence or antagonist-II (PIVKA-II) and alpha-fetoprotein. Therefore, the lesion was difficult to distinguish from hepatocellular carcinoma. Finally, YST was diagnosed based on the results of a liver biopsy. Although chemotherapy was effective, the patient died of respiratory failure. The autopsy revealed primary mediastinal YST. In the current report, we describe this case of PIVKA-II-producing YST and review previous cases of PIVKA-II-producing tumors other than hepatoma.

Development of hypertension within 2 weeks of initiation of sorafenib for advanced hepatocellular carcinoma is a predictor of efficacy.

BACKGROUND: Sorafenib is an agent that inhibits vascular endothelial growth factor and is associated with onset or worsening of hypertension in some patients. We conducted a retrospective analysis of whether the development of hypertension during sorafenib treatment of advanced hepatocellular carcinoma could be a predictor of anti-cancer efficacy. METHODS: The study included 38 patients with advanced hepatocellular carcinoma who had received sorafenib for at least 1 month between January 2010 and December 2012. A retrospective analysis of the efficacy of sorafenib was conducted by dividing the patients into two groups-a hypertension group, presenting with grade 2 or higher hypertension according to the Common Terminology Criteria for Adverse Events (CTCTE) version 4.0; and a non-hypertension group, which included all other patients. This study evaluated the occurrence of hypertension within 2 weeks of initiation of therapy in order to avoid any treatment duration bias. Images were evaluated using the modified Response Evaluation Criteria in Solid Tumors. The response rate, time to progression, and overall survival were assessed. RESULTS: Twenty-two patients (58 %) developed grade 2 or higher hypertension within 2 weeks of initiation of therapy. The response rate was significantly higher in the hypertension group. Median time to progression was 153 days in the hypertension group versus 50.5 days in the non-hypertension group, which was significantly longer in the hypertension group. Moreover, median overall survival was 1,329 days in the hypertension group versus 302 days in the non-hypertension group, which was significantly longer in the hypertension group. CONCLUSIONS: Hypertension within 2 weeks of initiation of therapy may be a predictor of the anti-cancer efficacy of sorafenib when used for the treatment of advanced hepatocellular carcinoma.

Genome-wide analysis of DNA methylation identifies novel cancer-related genes in hepatocellular carcinoma.

Aberrant DNA methylation has been implicated in the development of hepatocellular carcinoma (HCC). Our aim was to clarify its molecular mechanism and to identify useful biomarkers by screening for DNA methylation in HCC. Methylated CpG island amplification coupled with CpG island microarray (MCAM) analysis was carried out to screen for methylated genes in primary HCC specimens [hepatitis B virus (HBV)-positive, n = 4; hepatitis C virus (HCV)-positive, n = 5; HBV/HCV-negative, n = 7]. Bisulfite pyrosequencing was used to analyze the methylation of selected genes and long interspersed nuclear element (LINE)-1 in HCC tissue (n = 57) and noncancerous liver tissue (n = 50) from HCC patients and in HCC cell lines (n = 10). MCAM analysis identified 332, 342, and 259 genes that were methylated in HBV-positive, HCV-positive, and HBV/HCV-negative HCC tissues, respectively. Among these genes, methylation of KLHL35, PAX5, PENK, and SPDYA was significantly higher in HCC tissue than in noncancerous liver tissue, irrespective of the hepatitis virus status. LINE-1 hypomethylation was also prevalent in HCC and correlated positively with KLHL35 and SPDYA methylation. Receiver operating characteristic curve analysis revealed that methylation of the four genes and LINE-1 strongly discriminated between HCC tissue and noncancerous liver tissue. Our data suggest that aberrant hyper- and hypomethylation may contribute to a common pathogenesis mechanism in HCC. Hypermethylation of KLHL35, PAX, PENK, and SDPYA and hypomethylation of LINE-1 could be useful biomarkers for the detection of HCC.

[A case of hepatocellular carcinoma diagnosed based on the result of a bone biopsy, in which the primary hepatocellular carcinoma was identified in the liver 14 months after the initial diagnosis].

A 64-year-old man complained of pain in his left humerus. A histopathological examination of biopsy specimens taken from the lesion revealed a hepatocellular carcinoma. No primary hepatic lesion was revealed in a subsequent examination performed at this time. Enhanced computed tomography examination of the abdomen 14 months later, showed a nodular lesion, approximately 15 mm in diameter, therefore a partial hepatectomy was performed. The lesion was histopathologically diagnosed as a moderately-poorly differentiated hepatocellular carcinoma. The inability to identify the primary hepatocellular carcinoma is quite rare, and the present case may be the first report of the discovery of the primary hepatocellular cancer after the diagnosis of a secondary lesion.

Interferon-α/ß and anti-fibroblast growth factor receptor 1 monoclonal antibody suppress hepatic cancer cells in vitro and in vivo.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most commonly occurring primary liver cancer and ranks as the fifth most frequently occurring cancer, overall, and the third leading cause of cancer deaths, worldwide. At present, effective therapeutic options available for HCC are limited; consequently, the prognosis for these patients is poor. Our aim in the present study was to identify a novel target for antibody therapy against HCC. METHODOLOGY/PRINCIPAL FINDINGS: We used Western blot and flow cytometric and immunocytochemical analyses to investigate the regulation of FGFR1 expression by interferon-α/ß in several human hepatic cancer cell lines. In addition, we tested the efficacy of combined treatment with anti-FGFR1 monoclonal antibody and interferon-α/ß in a murine xenograft model of human HCC. We found that interferon-α/ß induces expression of FGFR1 in human HCC cell lines, and that an anti-FGFR1 monoclonal antibody (mAb) targeting of the induced FGFR1 can effectively inhibit growth and survival of HCC cells in vitro and in vivo. Moreover, the combination of interferon-α, anti-FGFR1 mAb and peripheral blood mononuclear cells (PBMCs) exerted a significant antitumor effect in vitro. CONCLUSIONS: Our results suggest that the combined use of an anti-FGFR1 antibody and interferon-α/ß is a promising approach to the treatment of HCC.

[Hyperplastic hepatic nodules in a case of idiopathic portal hypertension: changes in imaging findings during a 6-year follow-up].

A 22-year-old man had been given a diagnosis of idiopathic portal hypertension in childhood. In June 2001, a hepatic nodule which gradually increased in size over the next 2 years, was detected in the left hepatic lobe. In February 2003, a left lateral segmentectomy was performed. Histological examination of the nodules suggested focal nodular hyperplasia (FNH)-like hyperplasia. Computerized tomography performed 2 years later showed other hepatic nodules, and a liver biopsy was performed. Histopathological examination conducted at this time also suggested FNH-like hyperplasia. Owing to the substantial enlargement of the nodules and frequent recurrence, it can be difficult to distinguish between benign and malignant lesions.

[Liver metastasis with portal vein tumor thrombosis as a late recurrence of chromophobe renal cell carcinoma].

We report a case of liver metastasis with portal vein tumor thrombosis from chromophobe renal cell carcinoma (RCC). A 62-year-old man was noted to have a wedge-shaped low density area in the liver by computed tomography thirteen years after radical nephrectomy. Hepatic arterioportal shunt was suspected because liver biopsy did not show malignancy. Several months later, the patient showed aggravation of liver function which did not improve regardless of anticoagulant therapy. Recurrent liver biopsy revealed metastatic RCC. Autopsy showed portal vein tumor thrombus from RCC in the liver.

[Hemorrhage from varices of an interposed jejunum after choledochojejunostomy successfully treated by transileocolic vein obliteration].

A 72-year-old man was admitted to our hospital with refractory gastrointestinal bleeding. He received extrahepatic bile duct resection, hepaticojejunostomy and pancreatojejunostomy for bile duct stenosis and pancreatic pseudocyst 6 approximately 8years ago. We revealed that the cause of shock state was bleeding from varices of an interposed jejunum and portal vein obstruction as a complication of these operations. He received transileocolic vein obliteration with coils. Refractory gastrointestinal bleeding stopped. We concluded that this obliteration was effective and useful treatment for this complication.

Frequent epigenetic inactivation of SFRP genes in hepatocellular carcinoma.

BACKGROUND: Activation of the Wnt signaling pathway is frequently observed in hepatocellular carcinoma (HCC), though mutation of three of its components, CTNNB1, AXIN1, and AXIN2, is observed substantially less often. METHODS: We examined the relationship between Wnt signaling and epigenetic alteration of secreted frizzled-related protein (SFRP) genes in HCC. RESULTS: We frequently detected the active form of beta-catenin and accumulation of nuclear beta-catenin in liver cancer cell lines. We detected methylation of SFRP family genes in liver cancer cell lines (SFRP1, 9/12, 75%; SFRP2, 7/12, 58%; SFRP4, 3/12, 25%; SFRP5, 7/12, 58%) and primary HCCs (SFRP1, 9/19, 47%; SFRP2, 12/19, 63%; SFRP5, 8/19, 42%), though methylation of SFRP4 was not found in primary HCCs. SFRP methylation also was detected in hepatitis B or C virus-associated chronic hepatitis (SFRP1, 6/37, 16%; SFRP2, 14/37, 38%; SFRP5, 5/37, 14%) and liver cirrhosis (SFRP1, 10/28, 36%; SFRP2, 9/28, 32%; SFRP5, 3/28, 11%), suggesting that methylation of these genes is an early event in liver carcinogenesis. Ectopic expression of SFRPs downregulated T-cell factor/lymphocyte enhancer factor (TCF/LEF) transcriptional activity in liver cancer cells, while overexpression of a beta-catenin mutant and depletion of SFRP1 using siRNA synergistically upregulated TCF/LEF transcriptional activity. CONCLUSIONS: Our results confirm the frequent methylation and silencing of Wnt antagonist genes in HCC, and suggest that their loss of function contributes to activation of Wnt signaling during hepatocarcinogenesis.

Frequent epigenetic inactivation of DICKKOPF family genes in human gastrointestinal tumors.

Activation of Wnt signaling has been implicated in tumorigenesis, and epigenetic silencing of Wnt antagonist genes has been detected in various cancers. In the present study, we examined the expression and methylation of DICKKOPF (DKK) family genes in gastrointestinal cancer cell lines. We found that all known DKK genes were frequently silenced in colorectal cancer (CRC) cells (DKK1, 3/9, 33%; DKK2, 8/9, 89%; DKK3, 5/9, 56% and DKK4, 5/9, 56%), but not in normal colon mucosa. DKK1, -2 and -3 have 5' CpG islands, and show an inverse relation between expression and methylation. DKK methylation also was frequently observed in gastric cancer (GC) cell lines (DKK1, 6/16, 38%; DKK2, 15/16, 94% and DKK3, 10/16, 63%), but was seen less frequently in hepatocellular carcinoma and pancreatic cancer cell lines. DKKs also were frequently methylated in primary CRCs (DKK1, 7/58, 12%; DKK2, 45/58, 78% and DKK3, 12/58, 21%) and GCs (DKK1, 15/31, 48%; DKK2, 26/31, 84% and DKK3, 12/31, 39%). Against a background of CTNNB1 or APC mutations, Dickkopfs (Dkks) were less effective inhibitors of Wnt signaling than secreted frizzled-related proteins, though over-expression of Dkks suppressed colony formation of CRC cells with such mutations. Our results demonstrate that DKKs are frequent targets of epigenetic silencing in gastrointestinal tumors, and that loss of DKKs may facilitate tumorigenesis through beta-catenin/T-cell factor-independent mechanisms.

Differential roles of alterations of p53, p16, and SMAD4 expression in the progression of intraductal papillary-mucinous tumors of the pancreas.

Intraductal papillary-mucinous tumors (IPMTs) of the pancreas are characterized by dilated pancreatic ducts and ductules that are lined by tall columnar mucin-producing neoplastic epithelial cells. IPMTs have been suggested to be distinct neoplasms with a less aggressive phenotype than that of conventional ductal adenocarcinomas of the pancreas. Molecular mechanisms underlying tumorigenesis of IPMTs are beginning to be characterized. Allelic losses have frequently been detected at 9p, 17p, and 18q, suggesting that inactivation of tumor suppressor genes at these loci play a role in tumorigenesis of IPMTs. Using immunohistochemistry, we analyzed 38 IPMTs, including 9 hyperplasia, 16 adenoma, and 13 carcinoma tissues, for expression of p53, Ki-67, p16, and SMAD4. Nuclear p53 expression was observed in 5 (38%) of 13 carcinoma tissues but not in hyperplasia or adenoma tissues. Partial loss of p16 expression was observed in 9 (56%) and 12 (92%) of the 16 adenoma and 13 carcinoma tissues, respectively. Partial loss of p16 expression was observed even in adenomas with mild atypia. Partial loss of SMAD4 expression was observed in 6 (38%) and 12 (92%) of the 16 adenoma and 13 carcinoma tissues, respectively. The SMAD4 negative index was significantly higher in invasive carcinomas than in non-invasive carcinomas. Our results suggest that loss of p16 is an early event and p53 alteration is a late event during the progression of IPMTs. SMAD4 inactivation appears to be an early event but also involved in invasive tumor growth. Our results suggest that these alterations accumulate during the progression of IPMTs, reflecting results of analysis of allelic losses that showed a stepwise accumulation of genetic changes during progression.