[A case of alpha-fetoprotein-producing fetal gut-like small intestinal cancer].

A 72-year-old Japanese woman was admitted because of vomiting and abdominal pain. An enhanced computed tomography scan showed a small intestinal obstruction due to ileal wall thickening and multiple liver metastases. Her serum alpha-fetoprotein (AFP) level was high at 1671.9ng/ml. An ileocecal resection was performed. The histological diagnosis was AFP-producing small intestinal cancer resembling the primitive gut epithelium of a fetus. The present case suggested that even intestinal cancer could produce AFP.

Clinical utility of transarterial infusion chemotherapy using cisplatin-lipiodol emulsion for unresectable hepatocellular carcinoma.

BACKGROUND: We evaluated the clinical efficacy of transarterial infusion chemotherapy using a cisplatin-lipiodol emulsion for unresectable hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Fifty-seven patients with advanced HCC, with no indications for surgical resection or local ablative therapy, such as percutaneous ethanol injection and radiofrequency ablation, were enrolled in this retrospective study. RESULTS: Twelve patients were treated with cisplatin-alone at a dose of 65 mg/m(2) by infusion into the artery. Forty-two patients were treated with the same dose of cisplatin suspended in 1-10 ml of lipiodol (C/LPD). Cumulative survival rates in the cisplatin-treated group were 46.2% at one year, and 18.5% at two years, whereas these in the C/LPD group were 81.6% and 44.4%, respectively, with a significant difference between the two groups (p<0.01). In the cisplatin-treated group (n=13), no (0%) patients had a complete response (CR), two (15%) a partial response (PR), three (23%) no change (NC), and eight (62%) progressive disease (PD). In the C/LPD group (n=44), four (9%) patients had CR, 16 (35%) PR, 12 (26%) NC, and 12 (26%) PD. CR and PR were seen in 15% of the cisplatin-treated group and in 44% of the C/LPD group. C/LPD was significantly more effective than cisplatin-alone (p=0.039). Some patients showed tumor response to C/LPD after intra-arterial infusion of low-dose 5-fluorouracil. CONCLUSION: C/LPD produced superior effects compared to cisplatin-alone for unresectable HCC, causing no major side-effects, and increasing the survival rate.

Up-regulation of glypican-3 in human hepatocellular carcinoma.

AIM: To investigate the expression and significance of glypican-3 (GPC3) in human hepatocellular carcinoma (HCC). MATERIALS AND METHODS: DNA chips were used to measure the expression of mRNAs for members of the glypican and syndecan families of heparan sulfate proteoglycans (HSPGs) in normal liver tissue, non-tumor tissues and HCC. GPC3 protein expression was investigated by immunohistochemical staining in the tissues samples and Western blotting in human HCC cell lines. In addition, the levels of GPC3 protein in the blood were determined by ELISA. RESULTS: Only the expression of GPC3 was found to be markedly elevated in HCCs. In the human HCC cell lines, GPC3 expression was consistently observed, and was mainly located in the cell membrane and cytoplasm. Immunohistochemistry showed a tendency for overall staining of the cytoplasm of cells in the liver carcinoma tissues, but the cell membrane was preferentially stained in poorly differentiated HCC when compared with well-differentiated HCC. Moreover, the cell membrane was preferentially stained in metastatic lesions of HCC when compared with primary HCC lesions. Non-tumor tissues and cholangiocellular carcinoma tissues were not stained. In addition, using HepG2 cells, AG490 and piceatannol, which are signal transducer and activator of transcription 3 (STAT3) inhibitors, each increased the amount of GPC3 mRNA expressed. Assay of the circulating levels of GPC3 protein in chronic liver disease and HCC found that serum GPC3 protein levels were significantly elevated in the latter. CONCLUSION: GPC3 is highly expressed in HCC, and its expression pattern differs according to the degree of cell differentiation. In addition, the expression of GPC3 is regulated by Janus kinase-STAT signaling. GPC3 shows potential as a tumor biomarker for HCC that can be used for molecularly targeted therapy.

Functional cell surface expression of toll-like receptor 9 promotes cell proliferation and survival in human hepatocellular carcinomas.

Toll-like receptor 9 (TLR9) is a pattern-recognition receptor that is involved in immune signaling and plays a crucial role in cell survival through recognition of various bacterial and viral components including unmethylated CpG-DNA. TLR9 expression and function in cancer cells are not well understood. We investigated the expression of TLR9, and the function of TLR9 signaling, in hepatocellular carcinoma (HCC) cells following stimulation with CpG-oligodeoxynucleotides (ODNs). Positive immunohistochemical staining for TLR9 was observed in 85.7% of HCC tissues. Western blot analysis revealed that TLR9 was expressed both on the cell membrane and in the cytoplasm of HCC cell lines. Full-length TLR9 was predominantly expressed on the membrane rather than in the cytoplasm, whereas multiple cleaved forms of TLR9 were predominantly expressed in the cytoplasm rather than on the membrane. Cell surface stimulation of TLR9 promoted cell proliferation, and, furthermore, the TLR9 agonists, CpG-ODNs, reduced the cytotoxicity of the anti-cancer drug adriamycin (ADM) via up-regulation of apoptosis inhibitors such as survivin, Bcl-xL, XIAP and cFLIP, in HCC cell lines. Although cell surface stimulation of TLR9 did not activate either the NF-kappaB signaling pathway or the type-I IFN secretion pathway, gene chip microarray analysis indicated that TLR9 agonists closely regulated multiple oncology-related genes and transcription factors involved in tumorigenesis and cancer progression. In conclusion, our results indicate that functional cell surface expression of TLR9 in human HCC may play an important role in tumorigenesis and cancer progression.

Clinical significance of tumor markers in detection of recurrent hepatocellular carcinoma after radiofrequency ablation.

The aim of this study was to elucidate the importance of three tumor markers, alpha-fetoprotein (AFP), Lens culinaris agglutinin A-reactive fraction of AFP (AFP-L3), and des-gamma-carboxy prothrombin (DCP), for detecting and predicting the recurrence of hepatocellular carcinomas (HCCs). A total of 108 patients with initial non-advanced HCC who underwent curative radiofrequency ablation (RFA) in our hospital were enrolled in this study. The effectiveness of the three tumor markers for detecting recurrence and recurrence-free survival was analyzed. Positivity of these three makers was not markedly increased at the first or second recurrence. In addition, there was no significant correlation between the initial and recurrent levels of each tumor marker. The tumor marker that was positive at the time of initial HCC was not necessarily positive at recurrence. The tumor marker levels at recurrence were not correlated with pre-ablation levels. No significant correlation was found in the tumor marker values between pre-ablation and the time of recurrence. On multivariate analysis, high AFP-L3 levels (>/=10%) were significantly predictive of recurrence-free survival. All three tumor markers should be routinely measured to detect recurrence during follow-up after RFA. Especially high AFP-L3 levels should be followed closely.

Classification of hypocholesterolemia lipid patterns using Chol/Trig Combination System.

Patterns of hypocholesterolemic lipid fractions in 295 patients with liver diseases, malignant tumors, arteriosclerotic and renal diseases with cholesterol (Chol) levels of <30 mg/dl were classified using a simultaneous analytical method for the Chol and triglyceride (TG) fractions (Chol/Trig Combo System). Hypocholesterolemia was classified as follows: IV, Type IV on WHO hyperlipidemia phenotype classification; intermediate density lipoprotein (IDL), cases with appearance of IDL, including appearance of Lp(a); high + low density lipoproteins (HDL+LDL), lipids mostly consisting of HDL and LDL fractions; HDL abnormality, cases with slow alphaHDL or fast HDL; abnormal LDL, both Chol and TG fractions mostly consisting of LDL fraction; normal type, ratios of HDL, very low density lipoproteins (VLD) and LDL fractions were almost normal; and low HDL, HDL-C was <30 mg/dl. Many patients with liver diseases had HDL+LDL (45%), and abnormal LDL was noted in 13% of the cases. In malignant tumors, the frequencies of low HDL, normal type, and HDL+LDL cases were similar (22-30%). In arteriosclerosis, normal type accounted for 46% of the cases, and the frequency of normal type was higher (60%) in renal diseases. Mortality rate (within 1 year after measurement) was then compared among lipid patterns. In liver diseases, mortality rate increased in the following order: abnormal LDL (55%); low HDL (31%); HDL abnormality (25%); and HDL+LDL (21%). No deaths were seen among patients with normal type. In malignant tumors, mortality rate was very high (88%) in patients with HDL+LDL, but low in patients with normal type (22%) and low HDL (9%). Mortality rate was low in patients with arteriosclerosis and renal diseases in the short-term follow-up period (1 year). In the comparisons of distribution, mean, and appearance rate of charge modification frequency (CMF) among lipid patterns, parameters were high in all patterns other than HDL+LDL. Classification of hypocholesterolemia lipid patterns and evaluation of CMF may therefore be clinically useful.

Development of hepatocellular carcinoma in patients with chronic hepatitis C more than 10 years after sustained virological response to interferon therapy.

The risk factors for the development of hepatocellular carcinoma (HCC) in patients who have achieved a long-term sustained viral response (SVR) to interferon (IFN) are not fully understood. This study aimed to investigate the characteristics of patients who developed HCC after 10 years of achieving SVR. We retrospectively studied 5 patients with HCC which developed more than 10 years after the termination of IFN therapy. The clinical characteristics at the induction of IFN therapy were male gender, a mean age of 51.6±9.1 years, while 2 patients were moderate alcohol consumers. None of the 5 patients were positive for either HBs Ag or anti-HBc Ab. A histological examination at the initial IFN therapy showed the activity scores to be A2 in all cases, and the fibrosis scores at least F2. The clinical parameters at the diagnosis of HCC included fluctuating transaminase levels in all cases. These levels scarcely fell below the upper limits even after SVR was achieved. In 3 patients, liver tissues were obtained at the treatment of HCC. These tissues showed marked improvement in both activities and fibroses, but severe steatosis in 1 patient. To conclude, chronic hepatitis C patients who respond to IFN therapy should undergo long-term follow-up, even after the eradication of HCV, with special attention particularly to patients who had elevated transaminase levels and steatosis.

Dual topology of functional Toll-like receptor 3 expression in human hepatocellular carcinoma: differential signaling mechanisms of TLR3-induced NF-kappaB activation and apoptosis.

Toll-like receptor 3 (TLR3) is a pattern-recognizing receptor that is involved in immune signaling and plays a crucial role in survival by being able to recognize various viral components including double-stranded RNA (dsRNA). TLR3 expression and function in cancer cells are not well understood. We investigated the expression of TLR3 in hepatocellular carcinoma (HCC) cells and the function of TLR3 signaling by stimulation and transfection with polyinosinic-polycytidylic acid (Poly I:C), a synthetic form of dsRNA. TLR3 mRNA was expressed in HCC tissues as well as in non-tumor tissues. Positive immunohistochemical staining for TLR3 was observed in 52.7% of HCC tissues, and in HCC cells we found both membranous and cytoplasmic expression of TLR3. While cell surface stimulation of TLR3 with Poly I:C did not affect cell viability, it did activate NF-kappaB levels. In contrast, cytoplasmic stimulation with transfected Poly I:C significantly induced apoptosis accompanied by the down-regulation of anti-apoptotic protein. Transfected Poly I:C also synergistically augmented TRAIL-induced apoptosis, but only with low levels of transfected Poly I:C was IFN-beta production not observed. In conclusion, our results indicate that TLR3 expression in HCC plays an important role with regard to cell survival and proapoptotic activity. Endogenously expressed TLR3 may provide new clinical prospects for TLR3 agonists as cytotoxic agents in HCC.

Type 1 diabetes mellitus provoked by peginterferon alpha-2b plus ribavirin treatment for chronic hepatitis C.

A 51-year-old man developed type 1 diabetes mellitus following 24 weeks of treatment with recombinant alpha-2b peginterferon plus ribavirin for chronic hepatitis C. Pancreatic autoantibody tests were negative before the start of therapy, but a significant increase in glutamic acid decarboxylase (GAD) antibody titer was seen after 24 weeks of treatment. Six months after the onset of type 1 diabetes mellitus, the patient continues to receive 40 units of insulin daily. The clinical course suggested that recombinant alpha-2b peginterferon plus ribavirin provoked type 1 diabetes mellitus, therefore, in patients who are candidates for interferon therapy the presence of pancreatic autoantibodies and the fasting plasma glucose level should be investigated before and during treatment.

Primary biliary cirrhosis following chemotherapy for Hodgkin's lymphoma.

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease primarily affecting middle-aged women. Although little is known about the etiology of PBC, it may be induced by an autoimmune response. Here, we describe a rare case of appearance of PBC following chemotherapy for Hodgkin's lymphoma.

Cervical mycotic aneurysm in a patient with alcoholic cirrhosis.

We report a case of 65-year-old man with alcoholic cirrhosis and diabetes mellitus, in whom a cervical mycotic aneurysm suddenly developed after sepsis with methicillin-resistant staphylococcus aureus. Severe infection associated with alcoholic cirrhosis may cause a typical mycotic aneurysm.

Jak inhibitor induces S phase cell-cycle arrest and augments TRAIL-induced apoptosis in human hepatocellular carcinoma cells.

Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in various cancers and plays a crucial role in oncogensis, including the activation of genes encoding apoptosis inhibitors and cell-cycle regulators. We investigated the biological significance of the Janus kinase (Jak)-STAT pathway in human hepatocellular carcinoma (HCC). Constitutive activation of STAT3 was seen in 49.4% of human HCC specimens and in HCC cell lines. Jak inhibitor AG490 inhibited activation of STAT3 and markedly reduced cell viability without significant apoptosis. AG490 also induced S phase cell-cycle arrest with down-regulation of cyclin D1, A, E and up-regulation of p21, p27, phospho-Chk2. AG490 also inhibited caspase inhibitory proteins, such as XIAP and survivin, and augmented TRAIL-induced apoptosis. Our study suggests that the Jak-STAT pathway plays an important role in cell-cycle progression and resistance to apoptosis. Inhibition of the Jak-STAT pathway may thus be a therapeutic target for HCC.