Toshiaki Nakano

Incidence of and risk factors for hepatocellular carcinoma in primary biliary cirrhosis: National data from Japan

Primary biliary cirrhosis (PBC) primarily affects females and is rarely complicated by hepatocellular carcinoma (HCC). Although the HCC incidence in PBC patients is low, several characteristics and risk factors associated with its development have been reported. In this study, national data concerning the current status of carcinogenesis in PBC patients in Japan are reviewed. Using data from two national questionnaire surveys, we investigated the clinicopathological findings associated with HCC in PBC patients. According to the data of all reviewed PBC patients, the HCC incidence was 2.4% (71/2946). The HCC incidence by gender was 5.1% (19/370) in males and 2.0% (52/2576) in females, and the proportion of males was 26.7%. Prognosis was significantly poorer in the PBC patients with HCC than in those without. Multivariate analysis of risk factors associated with HCC by gender revealed histological stage at the time of PBC diagnosis as an independent risk factor associated with the development of HCC in females, but not in males. Furthermore, data from another national survey of 178 PBC patients with HCC (male/female = 49/129; proportion of males 27.5%) revealed that the duration between the diagnosis of PBC and that of HCC was significantly shorter in males than in females. In addition, histological stage at the time of HCC diagnosis was an independent risk factor for HCC in females, whereas no risk factors were identified in males. Conclusion: these data indicate that males are at risk of developing HCC at any histological stage of PBC. Therefore, male PBC patients in particular should be carefully screened for HCC from the early stages of PBC. (HEPATOLOGY 2013)

Long-term prognosis of primary biliary cirrhosis (PBC) in Japan and analysis of the factors of stage progression in asymptomatic PBC (a-PBC)

Objective: Based on data from a national survey of primary biliary cirrhosis (PBC), the pathology and prognosis of PBC in Japan were clarified. In particular, we tried to perform multivariate analysis of factors useful in determining prognosis of asymptomatic PBC (a-PBC). Methods: The survey was performed 10 times. Responses from 3778 of 4361 registered patients (416 institutions) were investigated (survey period: January 1968-December 1998). At the time of diagnosis, patients were classified as a-PBC or symptomatic PBC (s1-PBC; pruritus only, s2-PBC; jaundice and serum bilirubin level above 2 mg/dl). The survival rate was obtained by the Kaplan-Meier method. Logistic regression analysis was used in multivariate analysis of prognostic factors of a-PBC. Results: There were no significant differences in clinical findings from those in previous reports. The 5-year survival rates of patients with a-PBC, s1-PBC, and s2-PBC at the time of diagnosis were 97, 88, and 53%, respectively. Patients with a-PBC at the time of diagnosis were divided into groups: those in whom the disease progressed to s2-PBC (8%) and did not progress to s2-PBC (92%) at the final examination, and the prognosis was compared between groups. The prognosis was significantly poorer in the s2-PBC progression group. As a result of multivariate analysis for prediction of prognosis, levels at diagnosis of total serum bilirubin (T-Bil), albumin (Alb), total cholesterol (T-Cho), histological stage, and presence or absence of ursodeoxycholic acid (UDCA) administration were selected as significant factors (P<0.00001). Conclusion: Serum T-Bil, Alb, T-Cho, and histological stage at the time of diagnosis and presence or absence of UDCA administration were considered useful early prognostic indicators in patients diagnosed as having a-PBC whose prognosis may deteriorate with progression to s2-PBC.

Cell proliferation kinetics in acetic acid-induced gastric ulcer evaluated by immunohistochemical staining of proliferating cell nuclear antigen.

A monoclonal antibody to proliferating cell nuclear antigen (PCNA) has been previously shown to be capable of identifying proliferating cells. We investigated proliferative activity in the healing process of acetic acid-induced gastric ulcer by immunohistochemical staining of PCNA and 5-bromo-2-deoxyuridine (BrdU), and the two methods were compared. Cell proliferative activity of regenerated mucosa around ulcers showed continuous acceleration for 42 days, and PCNA-labeled cells had stained nuclei as clearly discernible as those of BrdU-labeled cells. In addition, immunohistochemical staining of PCNA provided reproducible and quantifiable results without the requirement of pretreatment. We conclude that immunohistochemical staining of PCNA may represent a useful technique for analysis of proliferative activity during healing of gastric ulcers.

DIFFUSE CALCIFICATION IN GASTRIC CANCER

The progressive expansion of calcification into the wall of the stomach and peritoneal metastatic foci was observed in a 31-year-old female with Borrmann type 4 calcified advanced gastric cancer. Despite treatment with systemic lentinan, uracil tegaful and mitomycin C, together with intraperitoneal injections of mitomycin C, OK-432 and prednisolone, the patient died 27 months after first presentation. The case provided a useful means of studying the mechanism of calcification.

Exploring the length of the common channel of pancreaticobiliary maljunction on magnetic resonance cholangiopancreatography

In the revised diagnostic criteria for pancreaticobiliary maljunction (PBM), PBM can be diagnosed from a long common channel by magnetic resonance cholangiopancreatography (MRCP). However, it is necessary to differentiate from high confluence of pancreaticobiliary ducts (HCPBD) with a relatively long common channel (≥6 mm) and effect of the sphincter in the pancreaticobiliary junction. This multicenter study aimed to explore definite value of the length of an abnormally long common channel, which enables to distinguish PBM from HCPBD on MRCP.

Cell Proliferation Kinetics in the Marginal Mucosa of Gastric Ulcer Evaluated by Immunostaining of DNA Polymerase α

We studied the proliferative ability of the marginal mucosal cells surrounding the ulcer in the healing processes of gastric ulcers. We obtained a labeling index (LI) at the neck and generative zone of gastric pit using a monoclonal antibody against DNA polymerase alpha for tractable and intractable gastric ulcers located at the fundic mucosa during each endoscopic stage. The LI during the healing stage was higher than that during the active stage in both the tractable and intractable cases. However, in each stage, the LI of the tractable gastric ulcers was higher than that of their intractable counterparts. Finally, we analyzed the LI in tractable gastric ulcers after setting two groups: one treated with anti-ulcer drugs and the other untreated. There were no significant differences between these two groups. We believe that investigation of proliferative abilities in the marginal mucosa of gastric ulcers is important to understand the nature of gastric ulcers and to assess therapeutic efficacy.

Effect of deferred or no treatment with ursodeoxycholic acid in patients with early primary biliary cholangitis: Deferred/no UDCA treatment for early PBC patients

As primary biliary cholangitis (PBC) is a heterogeneous disease, we hypothesized that there is a population of patients with early PBC who do not require prompt treatment with ursodeoxycholic acid (UDCA). In this study, we analyzed data from a large‐scale PBC cohort in Japan, and retrospectively investigated whether outcomes of early PBC patients were affected with prompt or deferred/no UDCA treatment.

Epidemiology and Natural History in Japan

Multicenter national surveys of PBC have been carried out 15 times since 1980 in Japan by the members of the Intractable Hepato-Biliary Disease Study Group in Japan supported by the Health Labour Sciences Research Grant. The subjects were 8,509 patients with PBC diagnosed and followed up between January 1, 1968 and December 31, 2011 at 520 hospitals and institutions throughout the country. We investigated the epidemiological trends and long-term prognosis of PBC in Japan based on national surveys. The annual incidence expressed as number of PBC patients has almost leveled off after 1989, and almost 70 % of patients with PBC were diagnosed in the asymptomatic stage. The prevalence of PBC gradually increased throughout the observation period. There were no major differences in clinical findings of PBC in Japan from those in the previous reports. Recently, the annual number of deaths caused by liver disease has decreased. The 5-year survival rates were 97.9 and 80.3 %, the 10-year survival rate 93.7 and 66.7 %, and the 20-year survival rate 84.2 and 52.1 %, respectively, showing significant differences among the groups (p < 0.0001). As results of examining changes in survival rate of PBC patients at each clinical stage, there was significant difference between the 1980s, 1990s, and 2000s for a-PBC and s-PBC. The results of the national surveys support the view that increased a-PBC with excellent prognosis and improvement in prognosis of all clinical stages of PBC may be important for increased prevalence in Japan.

Acute Gastric Lesions Induced by Transcatheter Arterial Embolization and Intra-arterial Infusion Chemotherapy for Hepatocellular Carcinoma

We performed an endoscopic study of the acute gastric lesions induced by transcatheter arterial embolization (TAE) and infusion chemotherapy (one shot infusion: OSI). Forty‐eight patients with primary hepatocellular carcinoma were investigated, and of them, 25 received TAE and 23 were treated with OSI. Endoscopy was performed within 1 week both before and after therapy and any gastric mucosal changes were noted. Before treatment, all patients had gastric lesions such as redness, erosion, hemorrhage and ulcer. These lesions were exacerbated or new lesions appeared after both TAE and OSI in about 50% of the subjects, and no significant difference in the incidence of lesions was observed between these two treatments. Moreover, there was no significant correlation between the exacerbation or new appearance of gastric lesions and the Childs classification, the catheter position, or the presence or absence of A‐P shunt or portal thrombus.