Clinicopathological characteristics of gastric cancer with carbohydrate antigen 19-9 expression occurring in elderly individuals: An autopsy study.

The clinicopathological significance of carbohydrate antigen 19-9 (CA19-9) in gastric cancer (GC) remains obscure. Therefore, the current study aimed to clarify the clinicopathological value of CA19-9 in GC utilizing autopsy cases. We examined the expression of CA19-9 and mucin core proteins in GC immunohistochemically, and analyzed serum CA19-9 levels and clinicopathological variables or complications. We also investigated whether fucosyltransferases 2 and 3 (FUT2/3) allelic variants influence CA19-9 expression in GC. Compared to GC cases with negative CA19-9 expression (tCA19-9-N), those with positive CA19-9 expression (tCA19-9-P) demonstrated significant differences in characteristic features such as lymph node and distant organ metastases, lymphatic and venous permeation, and higher Tumor, Node, Metastasis (TNM) stages. Moreover, compared to GC cases with low serum CA19-9 levels (sCA19-9-L), those with high serum CA19-9 levels (sCA19-9-H) were related to venous permeation, higher proportion of lymph node and distant organ metastases, and higher TNM stages. Both tCA19-9-P GC and sCA19-9-H GC cases were significantly associated with coagulation abnormalities. sCA19-9-H GC cases correlated significantly with MUC1 and MUC5AC expression. FUT2/3 genotypes were not associated with CA19-9 expression in GC. These results suggest that CA19-9 can predict the risk of lymph node and distant metastases as well as of coagulation abnormalities.

Characteristics of colonoscopic findings in the very elderly.

AIM: To determine the incidence and endoscopic types of colorectal lesions diagnosed with colonoscopy in elderly patients. METHODS: Consecutive Japanese patients who underwent colonic endoscopy between 1994 and 2007 (n = 5145; 2245 men and 2900 women, age 20-101 years) were examined retrospectively. Correlations between age, sex and number of lesions were analyzed. RESULTS: The incidence of advanced tumors was significantly correlated with increasing age in men (P = 0.02), and tumors were detected mainly in the sigmoid colon and rectum in both sexes. Right-sided colon cancer was significantly more common in women compared with men (P < 0.001). Polyps were detected throughout the colon, and their incidence was correlated significantly with increasing age in women (P = 0.01). Diverticula were frequently detected in the ascending and sigmoid colon in both sexes. Left-sided diverticula were significantly more common in women compared with men (P < 0.001). Lateral spreading tumors were detected mainly in the cecum in both sexes. Though the number of cases with angioectasia was small, angioectasia was slightly more common in the cecum and the ascending colon in women. CONCLUSIONS: In the present study, the incidence of advanced tumors correlated with increasing age in men, and right-sided cases were significantly more common in women than in men. The incidence of polyps correlated with increasing age in women. Left-sided diverticula were significantly more common in women than in men. Geriatr Gerontol Int 2016; 16: 1319-1323.

Association of aldehyde dehydrogenase 2 gene polymorphism with pancreatic cancer but not colon cancer.

AIMS: Most of the acetaldehyde, a recognized animal carcinogen, generated during alcohol metabolism is eliminated by liver mitochondrial aldehyde dehydrogenase 2 (ALDH2). More than 40% of Japanese people have the inactive form of ALDH2, and inactive ALDH2 is a risk factor for multiple cancer of the esophagus, as well as head and neck cancer. Possible associations between pancreatic cancer and ALDH2 gene polymorphism, as well as between colon cancer and ALDH2 gene polymorphism, in conjunction with smoking and/or drinking habits, were examined in a Japanese population. METHODS: Patients with pancreatic cancer (n = 187) and with colon cancer (n = 49) were examined. The drinking (5 g ethanol consumption/day) and/or smoking habits as well as ALDH2 gene polymorphism were examined. The age-matched control subjects were recruited in the NILS Longitudinal Study of Aging (LSA). RESULTS: Aging, smoking and inactive ALDH2, but not alcohol, are independent risk factors for pancreatic cancer. The frequency of smoking habits tended to be higher in patients with colon cancer compared with the patients without cancer. However, age, body mass index or the distribution of ALDH2 genotypes did not differ significantly among the patients with colon cancer, colon polyps and others. CONCLUSIONS: Inactive ALDH2 is an independent risk factor for pancreatic cancer, but inactive ALDH2 might not be a risk for colon cancer.

Vitamin D receptor polymorphisms are associated with increased susceptibility to primary biliary cirrhosis in Japanese and Italian populations.

BACKGROUND/AIMS: Vitamin D receptor (VDR) agonists have recently been identified as potent immunomodulators capable of inhibiting Th1-mediated immune response, leading us to consider the hypothesis that functional VDR polymorphisms might contribute to enhanced risk for developing primary biliary cirrhosis (PBC), a Th1-mediated autoimmune disease. In the current study, we aimed at elucidating the genetic association of VDR polymorphisms with susceptibility to PBC in Japanese and Italian populations. METHODS: We enrolled 334 PBC patients (195 Japanese and 139 Italians), as well as 334 age- and sex-matched controls (179 Japanese and 156 Italians). VDR genotyping was performed by PCR-RFLP, using BsmI, ApaI and TaqI endonucleases. RESULTS: The genotype BB of BsmI polymorphism was significantly associated with PBC (OR = 1.80 [95% CI; 1.19-2.73], p = 0.005). The association of the genotype BB was observed in Japanese (OR = 13.77, p = 0.001), and Italians (OR = 1.83, p = 0.019), respectively, although not significant in Italians after Bonferroni correction. The frequency of the B allele at the BsmI polymorphism was significantly higher in PBC patients (OR = 1.27 [95% CI; 1.02-1.59], p = 0.040). CONCLUSIONS: The genotype 'BB' as well as 'B' allele at BsmI polymorphism of the VDR gene contribute to the risk of PBC development.

Successful treatment with colestimide for a bout of cholestasis in a Japanese patient with benign recurrent intrahepatic cholestasis caused by ATP8B1 mutation.

Benign recurrent intrahepatic cholestasis (BRIC) is an autosomal recessive disorder characterized by bouts of cholestasis that resolve spontaneously without leaving considerable liver damage. Most of BRIC patients have mutations in ATP8B1 gene coding FIC1 protein. It has been suggested that an imbalance between the gut absorption of bile acids and the liver excretion possibly causes the development of cholestasis. We encountered a Japanese woman patient with familial intrahepatic cholestasis type 1 (FIC1) deficiency manifesting BRIC, in whom a rapid and gross elevation of serum total bile acid (TBA) level preceded that of serum total bilirubin level. Interestingly, the early administration of colestimide prevented the development of hyperbilirubinemia along with the additional elevation of serum TBA level. This case suggests that FIC1 deficiency causes an imbalance between the gut absorption of bile acids and the liver excretion leading to cholestasis, and raised the possibility that colestimide may be used as an optional treatment for BRIC.

Gene expression profiling in whole liver of bile duct ligated rats: VEGF-A expression is up-regulated in hepatocytes adjacent to the portal tracts.

BACKGROUND AND AIM: It would be of clinical importance to clarify molecular mechanisms of cholangiocytes proliferation for the treatment of intractable cholestatic diseases. The aim of this study was to elucidate gene expression profiling in the whole liver of bile duct ligated (BDL) rats using microarray analysis. In addition, the localization and time course of up-regulated expression of vascular endothelial growth factor (VEGF) was investigated. METHODS: Male Sprague-Dawley rats were used. The whole liver was removed from BDL and sham-operated rats at day 2 after the procedure, and microarray analysis was performed using an array on which 3757 rat cDNA clones spotted. The up-regulation of VEGF expression was investigated by RT-PCR using livers at day 1, 2, 4 and 7, and immunoblotting and immunohistochemistry at day 2. RESULTS: Marked proliferation of bile ducts was observed in livers of BDL rats. By microarray analysis, 38 up-regulated and 17 down-regulated transcripts were detected in whole liver of the BDL rat. The expression of VEGF-A was significantly elevated in the BDL rats at day 2; the VEGF-A/GAPDH ratio was 4.030 +/- 2.493 in BDL rats and 1.159 +/- 0.125 in sham-operated rats (P = 0.0330). The up-regulation of VEGF-A expression was maximal at day 2. Immunoblotting also demonstrated up-regulated expression of VEGF-A at the protein level. Immunostaining of VEGF revealed that the expression was evident in hepatocytes adjacent to the portal tracts, and scarcely observed in hepatocytes at the centrilobular area or cholangiocytes. CONCLUSION: Gene expression profiling in the whole liver of the BDL rats revealed 38 up-regulated and 17 down-regulated transcripts. In addition, the up-regulated expression of VEGF was mainly observed in hepatocytes surrounding to the portal tracts.

Hepatic steatosis as a possible risk factor for the development of hepatocellular carcinoma after eradication of hepatitis C virus with antiviral therapy in patients with chronic hepatitis C.

AIM: To elucidate risk factors contributing to the development of hepatocellular carcinoma (HCC) among patients with sustained viral response (SVR) after interferon (IFN) treatment and to examine whether HCV-RNA still remained in the liver of SVR patients who developed HCC. METHODS: Two-hundred and sixty-six patients, who achieved SVR, were enrolled in this study. We retrospectively reviewed clinical, viral and histological features of the patients, and examined whether the development of HCC depends on several clinical variables using Kaplan-Meier Method. RT-PCR was used to seek HCV-RNA in 3 out of 7 patients in whom liver tissue was available for molecular analysis. RESULTS: Among the enrolled 266 patients with SVR, HCC developed in 7 patients (7/266; 2.6%). We failed to detect HCV-RNA both in cancer and non-cancerous liver tissue in all three patients. The cumulative incidence for HCC was significantly different depending on hepatic fibrosis (F3-4) (P = 0.0028), hepatic steatosis (Grade 2-3) (P = 0.0002) and age (> or = 55) (P = 0.021) at the pre-interferon treatment. CONCLUSION: The current study demonstrated that age, hepatic fibrosis, and hepatic steatosis at pre-interferon treatment might be risk factors for developing HCC after SVR.

The clinical significance of IgA antimitochondrial antibodies in sera and saliva in primary biliary cirrhosis.

It still remains unclear how antimitochondrial autoantibodies (AMA) are involved with immunopathogenesis of primary biliary cirrhosis (PBC). We have suggested the potential role of IgA-AMA in damage to epithelial cells in PBC. In the current study, we investigated whether IgA-AMA were detectable in sera and saliva of PBC patients, to examine the association between detectable IgA-type autoantibodies in sera or saliva and progression of liver diseases. Fifty-three patients with PBC were enrolled, and IgA-AMA in sera and saliva were sought by immunoblotting using pork heart mitochondria as antigens. The progression of PBC was determined as Scheuer's classification consisting of four histological stages. We found IgA-AMA, IgA-anti-PDC-E2, and IgA-anti-E3BP in 43/53 (81%), 37/53 (70%), and 35/53 (66%) sera of patients with PBC, but none of controls. The progression of PBC was statistically associated with presence of IgA-anti-PDC-E2 (P = 0.0124), but neither with IgA-AMA (P = 0.1296) nor anti-IgA-E3BP (P = 0.5973). In saliva, detectable IgA-AMA, IgA-anti-PDC-E2, and IgA-anti-E3BP were noted in 12/26 (46%), 6/26 (23%), and 11/26 (42%), respectively. Detection of IgA-anti-PDC-E2 was strongly associated with progression of PBC (P = 0.0002), whereas detection of IgA-AMA and IgA-anti-E3BP were not associated (P = 0.2145 and P = 0.5118). The current findings suggest that the presence of IgA-anti-PDC-E2 in sera or saliva might be associated with progression of PBC, although a prospective study with PBC patients with detectable IgA-anti-PDC-E2 at early stages will be required to conclude the contribution of IgA-anti-PDC-E2 to the progression of PBC.

Liver injury induced by levothyroxine in a patient with primary hypothyroidism.

We report a patient with primary hypothyroidism, who developed hepatocellular injury due to levothyroxine, synthetic thyroxine. A 63-year-old male was admitted to our hospital due to elevation of liver enzymes. The patient was diagnosed as having hypothyroidism and had been treated with levothyroxine for almost two months until admission. Drug-induced liver injury induced due to levothyroxine was suspected and liver enzymes were rapidly decreased after discontinuation of levothyroxine and dried thyroid powder, also containing thyroxine. Synthetic triiodothyronine, the deiodinated form of levothyroxine was administered instead, and was well tolerated by the patient. The drug-induced lymphocyte stimulation test (DLST) using levothyroxine was negative. Since triiodothyronine which structurally resembles levothyroxine did not cause liver injury, and DLST using levothyroxine was negative, it is unlikely that levothyroxine itself was targeted by the immune system. Rather, we assume that the complex of levothyroxine as the hapten and liver-related macromolecules in the body as the carrier might have acquired antigenicity in this patient and subsequently resulted in liver injury.