Yoshiaki Katano

Intraductal papillary mucinous neoplasms of the pancreas: differentiation of malignant and benign tumors by endoscopic ultrasound findings of mural nodules.

Background and Aim:Intraductal papillary mucinous neoplasms (IPMNs) have a wide pathologic spectrum and it is difficult to differentiate malignant from benign tumors. The aim of this study was to identify predictors of malignancy using contrast-enhanced endoscopic ultrasound (CE-EUS). Subjects and Methods:In our institute, main duct type and mixed type IPMNs, branch duct type IPMNs with mural nodules, and IPMNs with coexistent invasive ductal cancer were indications for surgery. Eighty-seven IPMNs (14 main duct, 25 mixed, and 48 branch duct type) were resected and CE-EUS findings were compared with pathologic findings. Twelve clinicopathological variables and CE-EUS morphologic findings were assessed. Mural nodules defined as blood flow supplied protrusions were classified into 4 types: type I: low papillary nodule, type II: polypoid nodule, type III: papillary nodule, and type IV: invasive nodule. Results:Forty-two, 26, 16, and 3 were pathologically diagnosed as adenoma, noninvasive carcinoma, invasive IPMNs, and coexistent invasive ductal cancer, respectively. Multivariable logistic regression analysis showed that types III/IV mural nodule (odds ratio = 10.8; 95% confidential intervals = 2.75–56.1) and symptomatic IPMNs (odds ratio = 4.31; 95% confidential intervals = 1.37–14.7) were significant for malignancy. For mural nodule diameter, invasive IPMNs were significantly larger, but types III and IV mural nodules were more frequently associated with malignancy, particularly invasive cancer, at 88.9% and 91.7%, respectively. The diagnosis of IPMNs with types III or IV mural nodule as malignant resulted in a sensitivity of 60%, specificity of 92.9%, and accuracy of 75.9%. Conclusions:In conclusion, new morphologic criteria were useful to identify the malignant potentials of IPMNs.

Efficacy of antiviral therapy with lamivudine after initial treatment for hepatitis B virus-related hepatocellular carcinoma

Aim:  The aim of this study was to determine whether antiviral therapy with lamivudine is beneficial in patients after initial treatment for hepatitis B virus (HBV)‐related hepatocellular carcinoma (HCC).

A combination therapy of gemcitabine with immunotherapy for patients with inoperable locally advanced pancreatic cancer.

Objectives: Dendritic cell (DC) therapy frequently induces a measurable immune response. However clinical responses are seen in a minority of patients, presumably due to insufficient expansion of antigen-specific cytotoxic T lymphocytes (CTLs) capable of eradicating tumor cells. To increase therapeutic efficacy of DC-based vaccination, we have undertaken the first clinical trial involving a combination therapy of gemcitabine (GEM) with immunotherapy for patients with inoperable locally advanced pancreatic cancer. Methods: Patients (n = 5) received the treatment course, which consisted of intravenous GEM administration at 1000 mg/m2 (day 1) and the endoscopic ultrasound-guided fine-needle injection of OK432-pulsed DCs into a tumor, followed by intravenous infusion of lymphokine-activated killer cells stimulated with anti-CD3 monoclonal antibody (CD3-LAKs) (day 4), at 2-week intervals. Results: No serious treatment-related adverse events were observed during the study period. Three of the 5 patients demonstrated effective responses to this clinical trial; 1 had partial remission and 2 had long stable disease more than 6 months. In the patient with partial remission, it has been shown that DC-based vaccination combined with GEM administration induces tumor antigen-specific CTLs. Conclusion: This combined therapy was considered to be synergistically effective and may have a role in the therapy of pancreatic cancer for inducing tumor antigen-specific CTLs.

Malignant transformation of branch duct-type intraductal papillary mucinous neoplasms of the pancreas based on contrast-enhanced endoscopic ultrasonography morphological changes: focus on malignant transformation of intraductal papillary mucinous neoplasm itself.

Objectives The natural history of branch duct–type intraductal papillary mucinous neoplasms (BD-IPMNs) of the pancreas remains unclear. We conducted a retrospective long-term follow-up study for malignant transformation (MT) of BD-IPMNs focusing on morphological changes. Methods The subjects consisted of 142 patients who underwent contrast-enhanced endoscopic ultrasonography for initial diagnosis from January 2001 with more than 12 months of follow-up. The MT rate, including the co-occurrence of invasive ductal cancer, was evaluated by univariate and multivariate analysis. In addition, on the basis of morphological changes in patients who underwent surgery, the predictive factors for malignant IPMNs were evaluated. Results Median follow-up term was 42.5 months (range, 12–105 months). Thirty patients who exhibited morphological changes underwent surgery. Malignant transformation occurred in 9 patients (6.3%), and 5-year MT rate was 10.7%. The co-occurrence of invasive ductal cancer was seen in 5 patients. Multivariate analysis showed that the existence of mural nodules at initial diagnosis and involvement of main pancreatic duct were significant predictors of MT of BD-IPMN. Conclusions Malignant transformation of BD-IPMN is not rare. The observation of morphological changes of main pancreatic duct and nodules, mainly on contrast-enhanced endoscopic ultrasonography, is practical and useful for predicting MT of BD-IPMN itself. Abbreviations IPMN - intraductal papillary mucinous neoplasm BD-IPMN - branch duct–type intraductal papillary mucinous neoplasm MT - malignant transformation IDC - invasive ductal cancer MPD - main pancreatic duct CE-EUS - contrast-enhanced endoscopic ultrasonography EUS-FNA - endoscopic ultrasonography–guided fine needle aspiration MD-IPMN - main duct–type intraductal papillary mucinous neoplasm MD-CT - multidetector row computed tomography HR - hazard ratio OR - odds ratio

Efficacy of peginterferon-α-2b plus ribavirin in patients aged 65 years and older with chronic hepatitis C.

Objectives: The aim of this study was to evaluate the efficacy and indication of combination therapy with ribavirin plus peginterferon‐α‐2b in chronic hepatitis C virus (HCV) patients aged 65 years and older.

Dynamic quantitative evaluation of contrast-enhanced endoscopic ultrasonography in the diagnosis of pancreatic diseases

Objectives: This study aimed to investigate the usefulness of contrast-enhanced endoscopic ultrasonography (EUS) with time-intensity curve (TIC) in differentiating pancreatic diseases. Methods: Patients who underwent contrast-enhanced EUS between January 2007 and June 2009 were analyzed retrospectively, including 48 with pancreatic ductal cancer (PC), 14 with autoimmune pancreatitis (AIP), 13 with mass-forming pancreatitis (MFP), and 16 with pancreatic endocrine tumor (PET). After intravenous injection of contrast agent, contrast imaging pattern, TIC-based quantitative evaluation, and diagnostic ability of EUS in combination with TIC to diagnose benignancy or malignancy were assessed. Results: Hypovascular and heterogeneous pattern (42/48) in PC, isovascular and homogenous (21/27) in AIP and MFP, and hypervascular and rapid stained (16/16) in PET were observed. The echo intensity reduction rate from the peak at 1 minute was the greatest in PC followed by MFP, AIP, and PET (P < 0.05). The diagnostic accuracies based on contrast imaging pattern (84.0%) and TIC (88.0%) were higher than those based on B-mode imaging (82.6%) and dynamic computed tomography (81.3%). In EUS in combination with TIC, sensitivity, specificity, and accuracy rose up to 95.8%, 92.6%, and 94.7%, respectively. Conclusions: Contrast-enhanced EUS with the dynamic quantitative analysis preparing TIC increased the diagnostic accuracy for pancreatic diseases.

Efficacy and safety of entecavir in lamivudine-refractory patients with chronic hepatitis B: randomized controlled trial in Japanese patients.

Background and Aim:  Entecavir is a potent inhibitor of both wild‐type and lamivudine‐resistant hepatitis B virus (HBV) with proven clinical efficacy. We conducted a randomized, double‐blind, multicenter study in Japan (ETV‐052) evaluating the efficacy and safety of two doses of entecavir in adult patients with lamivudine‐refractory chronic hepatitis B infection.

Regulation of branched-chain amino acid catabolism in rat models for spontaneous type 2 diabetes mellitus

The branched-chain alpha-keto acid dehydrogenase (BCKDH) complex is the most important regulatory enzyme in branched-chain amino acid (BCAA) catabolism. We examined the regulation of hepatic BCKDH complex activity in spontaneous type 2 diabetes Otsuka Long-Evans Tokushima Fatty (OLETF) rats and Zucker diabetic fatty rats. Hepatic BCKDH complex activity in these rats was significantly lower than in corresponding control rats. The amount of BCKDH complex in OLETF rats corresponded to the total activity of the complex. Activity and abundance of the bound form of BCKDH kinase, which is responsible for inactivation of the complex, showed an inverse correlation to BCKDH complex activity in OLETF rats. Dietary supplementation of 5% BCAAs for 10 weeks markedly increased BCKDH complex activity, and decreased the activity and bound form of BCKDH kinase in the rats. These results suggest that BCAA catabolism in type 2 diabetes is downregulated and enhanced by BCAA supplementation.

Elevation of serum cystatin C concentrations in patients with chronic liver disease.

Objective We examined serum cystatin C concentrations in patients to explore the possible clinical application of cystatin C as a marker of disease severity in cases of chronic liver diseases. Methods Serum cystatin C concentrations were determined by an enzyme-linked immunosorbent assay kit in 103 patients with various chronic liver diseases and compared with concentrations in healthy control volunteers. Results The mean cystatin C concentration was 0.68 ± 0.03 mg/l in chronic hepatitis patients, 1.13 ± 0.09 mg/l in liver cirrhosis patients and 1.16 ± 0.10 mg/l in hepatocellular carcinoma patients, all significantly higher than concentrations in the control volunteers (P < 0.0001). Significant correlations were observed between cystatin C concentrations and total bilirubin levels, albumin levels, platelet levels, type IV collagen levels and hyaluronic acid levels. Serum cystatin C concentrations correlated well with histological stages despite the lack of correlation with histological grades. Conclusion Our results show that serum cystatin C increases with the progression of chronic liver disease and that it is a potential marker for liver fibrosis.

Diagnosis of Pancreatic Disorders Using Contrast-Enhanced Endoscopic Ultrasonography and Endoscopic Elastography

Contrast-enhanced endoscopic ultrasonography (CE-EUS) and EUS-elastography are cutting-edge diagnostic modalities for pancreatic disorders. Each pancreatic disorder has characteristic hemodynamics. CE-EUS uses color Doppler flow imaging to classify pancreatic lesions into a spectrum of solid and cystic patterns. Although there is overlap in the patterns generated by specific types of tumors, some types of tumors tend to produce distinct flow images. EUS-elastography can assess tissue hardness by measuring its elasticity. This parameter appears to correlate with the malignant potential of the lesions. Tissue elasticity studies can provide information on both its pattern and distribution. The former is the conventional method of morphologic diagnosis, but it is restricted to observations made in a region of interest. The latter is an unbiased analysis that can be performed by image analysis software and is theoretically constant, regardless of regions of interest. The evolving modalities of CE-EUS and EUS-elastography might provide clinical utility in the diagnosis of pancreatic disorders.