[A case of Caroli's disease associated with intrahepatic cholangiocarcinoma].

A 65-year-old male with Caroli's disease had a fast rise in serum CA19-9 level during follow-up. Contrast-enhanced computed tomography (CT) revealed an irregular mass with a 3cm diameter, showing ring-like and delayed improvement in segment 8 of the liver. Gadolinium ethoxybenzyl diethylenetriamine penta-acetic acid-enhanced magnetic resonance imaging (MRI) demonstrated a mass with the hypointense signal on T1-weighted images, mildly hyperintense signal on T2-weighted images, and hypointense signal in the hepatobiliary phase. Positron emission tomography/CT revealed the absorption of (18) F-fluorodeoxyglucose in the hepatic mass and a nodule in the anterior mediastinum. The patient was diagnosed with intrahepatic cholangiocarcinoma and supraclavicular lymph node metastasis and had partial hepatectomy and lymph node dissection. Caroli's disease is an uncommon congenital condition with myriad small cystic dilatations of the peripheral intrahepatic bile duct as the primary lesion. The disease is not only often associated with recurrent cholangitis and hepatolithiasis but is also a high-risk group of intrahepatic cholangiocarcinoma. Caroli's disease requires regular screening for intrahepatic cholangiocarcinoma utilizing suitable imaging modalities, such as CT and MRI, as well as tumor marker testing.

Optimal indication of endoscopic retrograde pancreatography-based cytology in the preoperative pathological diagnosis of pancreatic ductal adenocarcinoma.

BACKGROUND: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is extremely useful for pathological diagnosis of pancreatic ductal adenocarcinoma (PDAC); however, puncturing is difficult in some cases, and there is a risk of needle tract seeding. This study evaluated the indications for endoscopic retrograde pancreatography-based (ERP)-based cytology for the preoperative diagnosis of PDAC. METHODS: This study included 267 patients with PDAC who underwent preoperative ERP. The diagnostic performance of ERP-based cytology for PDAC was evaluated based on the sample collection method (pancreatic juice cytology [PJC] during ERP, brush cytology, PJC via endoscopic nasopancreatic drainage [ENPD] catheter), lesion site (pancreatic head, body/tail), and lesion size (≤10 mm, 10-20 mm, >20 mm), and compared with the diagnostic performance of EUS-FNA. RESULTS: The overall sensitivity of ERP-based cytology was 54.9%; sensitivity by the sampling method was 34.7% for PJC during ERP, 65.8% for brush cytology, and 30.8% for PJC via an ENPD catheter. The sensitivity of EUS-FNA was 85.3%. Brush cytology and PJC via an ENPD catheter were performed more often in pancreatic body/tail lesions than in head lesions (P = 0.016 and P < 0.001, respectively), and the overall sensitivity of ERP-based cytology was better for body/tail lesions (63.2% vs. 49.0%, P = 0.025). The sensitivities of ERP-based cytology and EUS-FNA in diagnosing PDAC ≤10 mm were 92.3% and 33.3%, respectively. Post-ERP pancreatitis was observed in 22 patients (8.2%) and significantly less common with ENPD catheters (P = 0.002). CONCLUSIONS: ERP-based cytology may be considered the first choice for pathological diagnosis of PDAC ≤10 mm and in the pancreatic body/tail.

Pembrolizumab-induced Focal Pancreatitis Diagnosed by Endoscopic Ultrasound-guided Fine-needle Aspiration.

A 69-year-old man with advanced non-small-cell lung cancer was treated with pembrolizumab for 4 months. Three months after pembrolizumab was discontinued, computed tomography showed enlargement of the pancreatic head, with hypoattenuating areas in the pancreatic head to body. On endoscopic ultrasonography, the entire pancreatic parenchyma was hypoechoic. Endoscopic retrograde cholangiopancreatography showed narrowing of the main pancreatic duct at the pancreatic head. Endoscopic ultrasound-guided fine-needle aspiration showed inflammatory cell infiltration in the stroma but no neoplastic lesions. CD8-positve T cells were dominant over CD4-positive T cells in the infiltrating lymphocytes, and the patient was diagnosed with pembrolizumab-induced pancreatitis.

Utility of the inside stent as a preoperative biliary drainage method for patients with malignant perihilar biliary stricture.

BACKGROUND/PURPOSE: Appropriate preoperative biliary drainage (PBD) is extremely important in patients with operable malignant perihilar biliary strictures. The aim of this study was to clarify the utility of inside stents in PBD. METHODS: Eighty-one patients with malignant perihilar biliary stricture who underwent endoscopic nasobiliary drainage (ENBD) as the first PBD method were enrolled. Biliary stenting was performed in 61 patients during the study course (41 patients-inside stent implanted in the bile duct; 20 patients-conventional stent placed across the papilla of Vater). Twenty patients continued ENBD until surgery. Treatment outcomes were compared among the three groups. RESULTS: The re-intervention rate was significantly lower in the inside stent group than in the conventional stent group and ENBD group (9.8% vs 40% and 35%, P = .013 and .030, respectively), and the time to re-intervention was also significantly longer (log-rank: P = .004 and .041, respectively). Of the five patients in the inside stent group who underwent neoadjuvant chemotherapy, only one required re-intervention. There was no significant difference in the incidence of postoperative complications among the three groups. CONCLUSIONS: The inside stent may be a useful PBD method for patients with malignant perihilar biliary stricture.

Role of Endoscopic Ultrasonography and Endoscopic Retrograde Cholangiopancreatography in the Diagnosis of Pancreatic Cancer.

Pancreatic cancer has the poorest prognosis among all cancers, and early diagnosis is essential for improving the prognosis. Along with radiologic modalities, such as computed tomography (CT) and magnetic resonance imaging (MRI), endoscopic modalities play an important role in the diagnosis of pancreatic cancer. This review evaluates the roles of two of those modalities, endoscopic ultrasonography (EUS) and endoscopic retrograde cholangiopancreatography (ERCP), in the diagnosis of pancreatic cancer. EUS can detect pancreatic cancer with higher sensitivity and has excellent sensitivity for the diagnosis of small pancreatic cancer that cannot be detected by other imaging modalities. EUS may be useful for the surveillance of pancreatic cancer in high-risk individuals. Contrast-enhanced EUS and EUS elastography are also useful for differentiating solid pancreatic tumors. In addition, EUS-guided fine needle aspiration shows excellent sensitivity and specificity, even for small pancreatic cancer, and is an essential examination method for the definitive pathological diagnosis and treatment decision strategy. On the other hand, ERCP is invasive and performed less frequently for the purpose of diagnosing pancreatic cancer. However, ERCP is essential in cases that require evaluation of pancreatic duct stricture that may be early pancreatic cancer or those that require differentiation from focal autoimmune pancreatitis.

The role of apparent diffusion coefficient value in the diagnosis of localized type 1 autoimmune pancreatitis: differentiation from pancreatic ductal adenocarcinoma and evaluation of response to steroids.

PURPOSE: The aim of this study was to clarify the usefulness of the apparent diffusion coefficient (ADC) value in the differential diagnosis of localized autoimmune pancreatitis (AIP) and pancreatic ductal adenocarcinoma (PDAC) and the evaluation of response to steroids. METHODS: This study retrospectively analyzed 40 patients with localized AIP and 71 patients with PDAC who underwent abdominal MRI with DWI (b = 0 and 1000 s/mm2). Their ADC values at the lesion sites and five MRI findings useful for diagnosing AIP were evaluated. In addition, ADC values before and after steroid therapy were compared in 28 patients with localized AIP. RESULTS: The median ADC value was significantly lower for localized AIP than for PDAC (1.057 × 10-3 vs 1.376 × 10-3 mm2/s, P < 0.001). In the ROC curve analysis, the area under the curve was 0.957 and optimal cut-off value of ADC for differentiating localized AIP from PDAC was 1.188 × 10-3 mm2/s. ADC value ≤ 1.188 × 10-3 mm2/s showed the highest sensitivity and accuracy among the MRI findings (92.6% and 90.7%, respectively), and when combined with one or more other MRI findings, showed 96.3% specificity. The median ADC values before and after steroid therapy (mean 7.9 days) were 1.061 × 10-3 and 1.340 × 10-3 mm2/s, respectively, and ADC values were significantly elevated after steroid induction (P < 0.001). CONCLUSION: The measurement of ADC values was useful for the differential diagnosis of localized AIP and PDAC and for the early determination of the effect of steroid therapy.

Usefulness of peroral cholangioscopy in the differential diagnosis of IgG4-related sclerosing cholangitis and extrahepatic cholangiocarcinoma: a single-center retrospective study.

BACKGROUND: In the diagnosis of IgG4-related sclerosing cholangitis (IgG4-SC), differentiation from extrahepatic cholangiocarcinoma (ECC) is extremely important but is still a clinical challenge. This study aimed to elucidate the usefulness of peroral cholangioscopy (POCS) for the differential diagnosis between IgG4-SC and ECC. METHODS: POCS findings for bile duct stricture were retrospectively evaluated in 17 patients with IgG4-SC diagnosed at the Hiroshima University Hospital and 53 patients with surgically resected infiltrating ECC. Mucosal surface, dilated vessels (tortuosity, caliber alteration, and disruption), and easily bleeding were compared between the groups. RESULTS: The stricture sites of IgG4-SC evaluated by POCS were 10 extrapancreatic bile ducts and 9 intrapancreatic bile ducts. In patients with IgG4-SC, smooth mucosal surface was observed in 89% (17/19), dilated vessels in 58% (11/19) [tortuosity 82% (9/11), caliber alteration 18% (2/11), and disruption 9% (1/11)], and easily bleeding in 0%. Irregular mucosal surface and easily bleeding were observed significantly more frequently in ECC (both P <  0.001). The frequency of caliber alteration and disruption of dilated vessels was significantly less in IgG4-SC (P <  0.001 and 0.005, respectively). The sensitivity and specificity of POCS in the diagnosis of ECC were 96 and 89%, respectively. Dilated vessels in IgG4-SC were observed significantly more frequently in the extrapancreatic bile duct, especially the hilar bile duct (P = 0.006). Concerning image evaluation, the interobserver agreement was κ = 0.719, and the intraobserver agreement was κ = 0.768 and 0.754. CONCLUSIONS: Characteristic POCS findings of the stricture sites in IgG4-SC were smooth mucosal surface, dilated vessels without caliber alteration and disruption, and lack of easily bleeding. These POCS findings are extremely useful for distinguishing between IgG4-SC and ECC.

Signal Activation of Hepatitis B Virus-Related Hepatocarcinogenesis by Up-regulation of SUV39h1.

BACKGROUND: Hepatitis B virus (HBV) X (HBx) protein is associated with hepatocellular carcinogenesis via the induction of malignant transformation and mitochondrial dysfunction. However, the association between HBx and histone methyltransferase in carcinogenesis has not been fully clarified. In the current study, we analyzed the association between HBx and the histone methyltransferase suppressor of variegation 3-9 homolog 1 (SUV39h1) using HBV replication models. METHODS: We constructed several HBx and SUV39h1 expression plasmids and analyzed the association between HBx and SUV39h1 with respect to HBV replication and hepatocarcinogenesis. RESULTS: SUV39h1 up-regulation was observed in HBV-infected humanized mouse livers and clinical HBV-related hepatocellular carcinoma tissues, indicating that SUV39h1 expression might be regulated by HBV infection. Through in vitro analysis, we determined that the coactivator domain of HBx interacts with the PSET (PostSET) and SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domains of SUV39h1. The expression levels of 4 genes, activating transcription factor 6, α-fetoprotein, growth arrest and DNA damage-inducible 45a, and dual-specificity phosphatase 1, known to induce carcinogenesis via HBx expression, were up-regulated by HBx and further up-regulated in the presence of both HBx and SUV39h1. Furthermore, histone methyltransferase activity, the main function of SUV39h1, was enhanced in the presence of HBx. CONCLUSIONS: We demonstrated that SUV39h1 and HBx enhance each other's activity, leading to HBx-mediated hepatocarcinogenesis. We propose that regulation of this interaction could help suppress development of hepatocellular carcinoma.

Comparison of intracellular responses between HBV genotype A and C infection in human hepatocyte chimeric mice.

BACKGROUND AND AIMS: The clinical course and responsiveness to antiviral treatments differs among hepatitis B virus (HBV) genotypes. However, the cause of these differences is unclear. In the present study, we compared mRNA expression profiles in human hepatocyte chimeric mice infected with HBV genotypes A and C. METHODS: Fifteen chimeric mice were prepared and divided into the following three groups: uninfected control mice, HBV genotype A-infected mice, and HBV genotype C-infected mice. Human hepatocytes were collected from these mouse livers and gene expression analyses were performed using next-generation RNA sequencing. RESULTS: Although similar pathways were influenced by HBV infection, including inflammation mediated by chemokine and cytokine signaling, p53, and integrin signaling pathways, expression levels of up-regulated genes by HBV genotype A or C infection were quite different. In HBV genotype A-infected hepatocytes, 172 genes, including KRT23 and C10orf54, were significantly more highly expressed than in HBV genotype C-infected cells, whereas 10 genes, including SPX and IER3, were expressed at significantly lower levels. Genes associated with the p53 pathway and the inflammation mediated by chemokine and cytokine signaling pathway were more highly expressed in cells with HBV genotype A infection, whereas genes associated with CCKR signaling map and oxidative stress response were more highly expressed in cells with HBV genotype C infection. CONCLUSION: Several differences in gene expression with respect to HBV genotype A and C infection were detected in human hepatocytes. These differences might be associated with genotypic difference in the clinical course or responsiveness to treatment.

Endoplasmic reticulum-mediated induction of interleukin-8 occurs by hepatitis B virus infection and contributes to suppression of interferon responsiveness in human hepatocytes.

The events in the immune response to hepatitis B virus (HBV) remain unclear. We analyzed the direct influence of HBV on gene expression in human hepatocytes under immunodeficient conditions using a human hepatocyte chimeric mouse model. HBV-infected or non-infected chimeric mouse livers were collected, and gene expression profiles were compared. Since IL-8 was the most significantly up-regulated gene at 8 weeks after HBV infection, we focused on IL-8 and found that HBx and the large HBs (L-HBs) protein induce transcription of IL-8 via endoplasmic reticulum stress. This stress induces IL-8 transcription via NFAT activation and contributes to suppression of interferon responsiveness in HBV-infected human hepatocytes. In the present study, we identified a novel regulatory mechanism in which the L-HBs protein activates IL-8 via endoplasmic reticulum stress, suggesting a key role for IL-8 in the immune response to HBV and a potential new target for antiviral treatments of HBV infection.

CTL-associated and NK cell-associated immune responses induce different HBV DNA reduction patterns in chronic hepatitis B patients.

The activation of hepatitis B virus (HBV)-related hepatitis is associated with both natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). We analyzed the association between the immune response and changes in the proportion of Pre-S deletion variants. We quantified Pre-S deleted HBV (HBV-del) and wild-type HBV (HBV-wt) DNA levels in sera obtained from HBV-infected mice and chronic hepatitis B patients. In chronic hepatitis B patients, the HBV-del proportion usually increased during or after ALT elevation but did not occur during all ALT elevations. To clarify this difference in the immunological responses, we performed in vivo analyses using HBV-infected human hepatocyte chimeric mice. Although HBV-del proportions did not change in mice with NK cell-associated hepatitis or in mice treated with entecavir, the proportions sharply increased in mice with CTL-associated hepatitis. Furthermore, the number of patients in which HBV-del proportions were greater than 5% was significantly higher in chronic hepatitis B patients than in asymptomatic carriers (P = 0.023). We identified associations between virological response in chronic hepatitis B patients and two different immune responses. The proportion of HBV-del variants could be a useful biomarker for distinguishing between chronic hepatitis and asymptomatic carriers.

Reduction of hepatitis B surface antigen in sequential versus add-on pegylated interferon to nucleoside/nucleotide analogue therapy in HBe-antigen-negative chronic hepatitis B patients: a pilot study.

BACKGROUND: Although pegylated interferon (PEG-IFN) and nucleotide/nucleoside analogue (NA) combination therapy is considered to be optimal for accelerating serum hepatitis B surface antigen (HBsAg) reduction, the effect is limited, and the best approach to PEG-IFN treatment for chronic hepatitis B patients during long-term NA therapy has yet to be determined. METHODS: A total of 21 hepatitis B e antigen-negative chronic hepatitis B patients whose HBV DNA levels were suppressed to undetectable levels by NA therapy were administrated PEG-IFN-α2a for 48 weeks (sequential therapy: 10, add-on therapy: 11). Factors associated with HBsAg reduction by PEG-IFN therapy were analysed. RESULTS: During PEG-IFN treatment, HBsAg levels were reduced by 0.48 log IU/ml. More than 1 log IU/ml of HBsAg reduction was observed in eight patients (sequential therapy: six, add-on therapy: two), and one patient with sequential therapy achieved HBsAg loss. By univariate analysis, sequential therapy was marginally associated with more than 1 log IU/ml HBsAg reduction during PEG-IFN treatment (P=0.060). After PEG-IFN treatment, only five patients, including the patient with HBsAg loss, achieved more than 0.5 log IU/ml of HBsAg reduction by 1 year after PEG-IFN treatment. By univariate analysis, sequential therapy was significantly associated with HBsAg reduction after PEG-IFN treatment (P=0.012). In addition, alanine aminotransferase elevation during PEG-IFN therapy and lower serum interleukin-8 level at the end of PEG-IFN treatment were also significantly associated with HBsAg reduction by 1 year after PEG-IFN treatment (P=0.038, P=0.044, respectively). CONCLUSIONS: Sequential therapy may be superior to add-on therapy in reducing HBsAg levels during long-term NA therapy in chronic hepatitis B patients.

Indication and Usefulness of Bile Juice Cytology for Diagnosis of Gallbladder Cancer.

AIM: We examined the effectiveness of bile juice cytology for distinguishing between benign and malignant gallbladder lesions of the protruding type with various sampling points, sampling methods, and macroscopic forms in order to discuss the effectiveness of the endoscopic transpapillary gallbladder drainage (ETGD) cytology. METHODS: We studied 162 cases of patients with a lesion localized within the gallbladder. At first, we examined the effectiveness for diagnosis of ETBD cytology using ERC and then that of the first ETGD cytology after placing the ETGD. Next, we examined the diagnostic effectiveness of the washed ETGD cytology by using the ETGD. Finally, we examined complications. RESULTS: In the final diagnoses, we identified 33 cases of adenocarcinoma, 10 cases of adenoma, 63 cases of ADM, 35 cases of nonneoplastic polyp, and 21 cases of chronic cholecystitis. It was found that the sensitivity of ETBD cytology was 3.6% and that of ETGD cytology was 59.1%. In the comparison of diagnostic effectiveness of cytologic diagnosis using samples of bile juice from the gallbladder collected by different methods, the sensitivities were 38.9% and 73.3% for the first and washed ETGD cytologies, respectively. In the comparison of the diagnostic effectiveness of gallbladder bile juice cytology using samples collected for different forms of lesion and by different methods, the sensitivities were 38.9% and 73.3%, respectively, for the first and washed ETGD cytologies for flat gallbladder wall thickening, while it was impossible to diagnose for lesions of GB polyp. CONCLUSION: For diagnosis of gallbladder cancer, we consider that the ETGD cytology should be taken into consideration for lesions of flat gallbladder wall thickening, for which it is difficult to distinguish between benign and malignant lesions.

Impaired Processing of Prohormones in Secretogranin III-Null Mice Causes Maladaptation to an Inadequate Diet and Stress.

Secretogranin III (SgIII), a member of the granin family, binds both to another granin, chromogranin A (CgA), and to a cholesterol-rich membrane that is destined for secretory granules (SGs). The knockdown of SgIII in adrenocorticotropic hormone (ACTH)-producing AtT-20 cells largely impairs the regulated secretion of CgA and ACTH. To clarify the physiological roles of SgIII in vivo, we analyzed hormone secretion and SG biogenesis in newly established SgIII-knockout (KO) mice. Although the SgIII-KO mice were viable and fertile and exhibited no overt abnormalities under ordinary rearing conditions, a high-fat/high-sucrose diet caused pronounced obesity in the mice. Furthermore, in the SgIII-KO mice compared with wild-type (WT) mice, the stimulated secretion of active insulin decreased substantially, whereas the storage of proinsulin increased in the islets. The plasma ACTH was also less elevated in the SgIII-KO mice than in the WT mice after chronic restraint stress, whereas the storage level of the precursor proopiomelanocortin in the pituitary gland was somewhat increased. These findings suggest that the lack of SgIII causes maladaptation of endocrine cells to an inadequate diet and stress by impairing the proteolytic conversion of prohormones in SGs, whereas SG biogenesis and the basal secretion of peptide hormones under ordinary conditions are ensured by the compensatory upregulation of other residual granins or factors.

A comparison of 4-Fr with 5-Fr endoscopic nasopancreatic drainage catheters: A randomized, controlled trial.

BACKGROUND AND AIM: Although endoscopic nasopancreatic drainage (ENPD) is useful for collecting samples for pancreatic juice cytology and for treating leakage of pancreatic juice and occlusive pancreatitis, placement of the ENPD catheter is associated with complications such as post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP). We investigated whether an ENPD catheter with a smaller diameter could reduce the incidence of complications. METHODS: Patients requiring placement of an ENPD catheter (n = 254) were enrolled and randomly assigned to one of two catheter-size groups: the 4-Fr group or the 5-Fr group. The incidence of PEP, cholangitis, and spontaneous catheter displacement and the suitability of pancreatic juice cytology samples were compared between groups. In addition, univariate and multivariate analyses were conducted on factors associated with PEP. RESULTS: The incidence of PEP was significantly lower in the 4-Fr group compared with the 5-Fr group (4.1% vs 12.4%, respectively; P = 0.021). The rate of cholangitis and spontaneous catheter displacement and the suitability of pancreatic juice cytology samples did not differ between groups. Multivariate analysis revealed that the risk of PEP was 3.7 times higher when using a 5-Fr catheter than when using a 4-Fr catheter (P = 0.019). In addition, the risk of PEP was 4.1 times higher in patients with an intraductal papillary mucinous neoplasm than in those without (P = 0.0049) and 4.6 times higher in patients aged <65 than in those aged ≥65 (P = 0.0033). CONCLUSIONS: A 4-Fr catheter is as useful as a 5-Fr catheter and is associated with a significantly lower incidence of PEP.

Preoperative Biliary Drainage in Cases of Borderline Resectable Pancreatic Cancer Treated with Neoadjuvant Chemotherapy and Surgery.

Objective. To elucidate the optimum preoperative biliary drainage method for patients with pancreatic cancer treated with neoadjuvant chemotherapy (NAC). Material and Methods. From January 2010 through December 2014, 20 patients with borderline resectable pancreatic cancer underwent preoperative biliary drainage and NAC with a plastic or metallic stent and received NAC at Hiroshima University Hospital. We retrospectively analyzed delayed NAC and complication rates due to biliary drainage, effect of stent type on perioperative factors, and hospitalization costs from diagnosis to surgery. Results. There were 11 cases of preoperative biliary drainage with plastic stents and nine metallic stents. The median age was 64.5 years; delayed NAC occurred in 9 cases with plastic stent and 1 case with metallic stent (p = 0.01). The complication rates due to biliary drainage were 0% (0/9) with metallic stents and 72.7% (8/11) with plastic stents (p = 0.01). Cumulative rates of complications determined with the Kaplan-Meier method on day 90 were 60% with plastic stents and 0% with metallic stents (log-rank test, p = 0.012). There were no significant differences between group in perioperative factors or hospitalization costs from diagnosis to surgery. Conclusions. Metallic stent implantation may be effective for preoperative biliary drainage for pancreatic cancer treated with NAC.