Patients with Chronic Liver Disease under Surveillance for Hepatocellular Carcinoma Have a Favorable Long-Term Outcome for Pancreatic Cancer Due to Early Diagnosis and High Resection Rate.

Patients with viral hepatitis-related chronic liver disease (CLD) under surveillance for hepatocellular carcinoma (HCC) are often diagnosed with pancreatic cancer (PC) at an early stage. However, the long-term outcomes of these patients are unclear. We aimed to clarify the long-term outcomes of patients with PC with viral hepatitis-related CLD using a chart review. Data collection included the Union for International Cancer Control (UICC) stage at PC diagnosis, hepatitis B virus and hepatitis C virus status, and long-term outcomes. The distribution of the entire cohort (N = 552) was as follows: early stage (UICC 0-IB; n = 52, 9.5%) and non-early stages (UICC IIA-IV; n = 500, 90.5%). At diagnosis, the HCC surveillance group (n = 18) had more patients in the early stages than the non-surveillance group (n = 534) (50% vs. 8.0%), leading to a higher indication rate for surgical resection (72.2% vs. 29.8%) and a longer median survival time (19.0 months vs. 9.9 months). We confirmed that patients with viral hepatitis-related CLD under HCC surveillance were diagnosed with PC at an early stage. Because of the higher indication rate for surgical resection in these patients, they had favorable long-term outcomes for PC.

Prospective observational study of zinc deficiency symptoms during first-line chemotherapy for gastric and colorectal cancer.

Background: Zinc deficiency during long-term chemotherapy and its related symptoms, including skin rash, taste disorders, and oral mucositis, have not been sufficiently investigated. Methods: This prospective observational study enrolled patients with gastric and colorectal cancer who underwent standard first-line chemotherapy. According to the Practice Guidelines for Zinc Deficiency, zinc deficiency is defined as a serum level of <60 µg/dL. Serum zinc levels were measured before and after (1, 3, and 6 months) chemotherapy, and symptoms were assessed using the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events version 1.0. Repeated measures were analyzed using a generalized linear mixed model. Results: Of the 61 enrolled patients, 48 who underwent standard first-line chemotherapy with fluoropyrimidine plus oxaliplatin were analyzed. Zinc deficiency was observed in 18 patients (38%) before chemotherapy. The least-squares means of serum zinc levels significantly decreased at 3 and 6 months of chemotherapy in 30 patients without zinc deficiency at the start of chemotherapy (both P<0.01) but not in 18 with zinc deficiency at the beginning. Changes in serum zinc levels during chemotherapy negatively correlated with changes in taste, rash, and itching (all P<0.04) in patients without zinc deficiency before treatment initiation. Conclusions: Serum zinc levels decreased during chemotherapy in zinc-non-deficient patients at the beginning of chemotherapy and correlated with taste changes, skin rash, and itching. Therefore, investigating whether zinc supplementation ameliorates these symptoms is necessary.

Endoscopic duodenal stent placement versus gastrojejunostomy for unresectable pancreatic cancer patients with duodenal stenosis before introduction of initial chemotherapy (GASPACHO study): a multicenter retrospective study.

BACKGROUND: Endoscopic duodenal stent placement is an alternative technique to gastrojejunostomy for gastric outlet obstruction due to pancreatic cancer. We compared the efficacy of endoscopic duodenal stent placement with that of gastrojejunostomy for treating patients with pancreatic cancer who are candidates for intensive combination chemotherapies as the first line of treatment. METHODS: This retrospective observational study included 100 patients from 18 institutions in Japan. Inclusion criteria were as follows: (1) cytologically or histologically confirmed adenocarcinoma of the pancreas, (2) good performance status, (3) gastric outlet obstruction scoring system score of 0-1 and (4) no history of treatment for pancreatic cancer. RESULTS: There was no significant difference in the background characteristics of patients in the endoscopic duodenal stent placement (n = 57) and gastrojejunostomy (n = 43) groups. The median overall survival in the endoscopic duodenal stent placement and gastrojejunostomy groups was 5.9 and 6.0 months, respectively. Clinical success was achieved in 93 cases; the median time to food intake resumption was significantly shorter in the endoscopic duodenal stent placement group (median: 3 days, n = 54) than in the gastrojejunostomy group (median: 5 days, n = 43). Chemotherapy was introduced in 63% of the patients in both groups after endoscopic duodenal stent placement or gastrojejunostomy. Chemotherapy was started earlier in the endoscopic duodenal stent placement group (median: 14 days) than in the gastrojejunostomy (median: 32 days) group. CONCLUSIONS: Endoscopic duodenal stent placement showed similar or better clinical outcomes than gastrojejunostomy. Thus, it might be a promising option in patients with good performance status.

Simple prognostic markers for optimal treatment of patients with unresectable pancreatic cancer.

ABSTRACT: Most patients with pancreatic cancer are ineligible for curative resection at diagnosis, resulting in poor prognosis. This study aimed to evaluate the prognostic factors in patients with unresectable pancreatic cancer.We retrospectively collected clinical data from 196 patients with unresectable pancreatic cancer who received palliative chemotherapy (N = 153) or palliative care alone (N = 43) from January 2011 to December 2013. Patients' background data and overall survival were analyzed using the Cox proportional hazard regression model.In patients receiving palliative chemotherapy (gemcitabine-based regimen, 88.2%) and palliative care alone, the median (range) ages were 68 (43-91) and 78 (53-90) years, and metastatic diseases were present in 80% (N = 123) and 86% (N = 37), respectively. Multivariate analysis in the palliative chemotherapy patients showed that liver metastasis (hazard ratio [HR] 2.25, 95% confidence interval [CI] 1.58-3.20, P < .001), neutrophil-to-lymphocyte ratio (>4.5 vs ≤4.5; HR 3.45, 95% CI 2.22-5.36, P < .001), and cancer antigen 19-9 (CA19-9) (≥900 vs <900 U/mL; HR 1.45, 95% CI 1.02-2.05, P = .036) were independent prognostic factors. In those receiving palliative care alone, lung (HR 3.27, 95% Cl 1.46-7.35, p = 0.004) and peritoneum (HR 2.50, 95% CI 1.20-5.18, P = .014) metastases and the C-reactive protein-to-albumin ratio (≥1.3 vs <1.3; HR 3.33, 95% Cl 1.51-7.35, P = .003) were independent prognostic factors. Furthermore, patients with multiple factors had worse prognosis in both groups. Median survival time of palliative chemotherapy patients with risk factors 0, 1, 2, and 3 were 13.1 (95% CI 8.0-16.9), 9.4 (95% CI 7.9-10.1), 6.6 (95% CI 4.9-7.8), and 2.5 (95% CI 1.7-4.0) months, respectively. Similarly, median survival time was 5.7 (95% CI 1.3 -8.0), 2.1 (95% CI 1.5-3.9), and 1.3 (95% CI 0.6-1.7) months, respectively, for palliative care alone patients with risk factor 0, 1, and 2 to 3.Prognostic markers for pancreatic cancer were neutrophil-to-lymphocyte ratio, liver metastasis, and CA19-9 in patients undergoing palliative chemotherapy and C-reactive protein-to-albumin ratio and lung/peritoneum metastases in patients undergoing palliative care alone. These simple markers should be considered when explaining the prognosis and therapeutic options to patients.

ABO Blood Type and the Long-term Outcomes of Pancreatic Cancer.

Objective The long-term effect of the ABO blood type on the clinical course of patients with pancreatic cancer (PC) is inconclusive. This study aimed to determine whether or not the ABO blood type influences the long-term outcomes of PC in Japanese patients. Methods The medical records of Japanese patients with PC were reviewed. Data, including the age, sex, and outcomes, from the Ehime Pancreato-Cholangiology Study Group were analyzed. Results The mean age of the 406 patients was 71.0±10.5 years, and 220 (54.2%) were men. A total of 44.6%, 20.7%, 22.4%, and 12.3% had blood type A, B, O, and AB, respectively. The median survival time (MST) of patients with A alleles was shorter than that of patients with non-A alleles (p=0.048), especially among those who underwent resection (p=0.031). In contrast, no marked difference in the MST was noted among those who underwent chemotherapy and palliative care. Finally, a multivariate analysis confirmed A alleles as an independent factor associated with the long-term outcome of PC (p<0.05 in 2 different models). Conclusion The ABO blood type influenced the long-term outcomes of Japanese patients with PC, presumably due to its impact on disease onset and tumor behavior.

Inference-assisted intelligent crystallography based on preliminary data.

Crystal structure analysis is routinely used to determine atomically resolved molecular structures and structure-property relationships. The accumulation of reliable structural characteristics obtained by crystal structure analysis has forged a robust basis that is frequently used in molecular and materials sciences. However, experimental techniques remain hampered by time-consuming 'blind' measurement-analysis iterations, which are sometimes required to find appropriate crystals and experimental conditions. Herein, we present a method that uses a small preliminary data set to evaluate the to-be-observed structures and the to-be-collected data. Moreover, we demonstrate the practical utility of this method to improve the efficiency of crystal structure analysis. This method will help selecting suitable crystals and choosing favorable experimental conditions to generate results that satisfy the level of precision required for specific research objectives.

Early Detection of Pancreatic Cancer in Patients With Chronic Liver Disease Under Hepatocellular Carcinoma Surveillance.

OBJECTIVE: To evaluate whether patients with hepatitis B virus (HBV)- and hepatitis C virus (HCV)-related chronic liver disease were diagnosed as having pancreatic cancer (PC) at an early stage during abdominal imaging surveillance for hepatocellular carcinoma (HCC). PATIENTS AND METHODS: We retrospectively examined 447 patients with PC diagnosed at Ehime University Hospital and affiliated centers (2011-2013). Data were collected regarding HBV and HCV status, likelihood of PC diagnosis, and Union for International Cancer Control (UICC) stage. Intergroup comparisons were performed using the χ2 test. RESULTS: The UICC stage distribution in the HCC surveillance group (n=16) was stage 0 (n=2, 12.5%), stage IA (n=3, 18.8%), stage IB (n=2, 12.5%), stage IIA (n=2, 12.5%), stage IIB (n=2, 12.5%), stage III (n=1, 6.3%), and stage IV (n=4, 25%). The UICC stage distribution in the nonsurveillance group (n=431) was stage 0 (n=4, 0.9%), stage IA (n=28, 6.5%), stage IB (n=27, 6.3%), stage IIA (n=86, 20.0%), stage IIB (n=48, 11.1%), stage III (n=56, 13.0%), and stage IV (n=182, 42.2%). The HCC surveillance group had significantly more patients with stage 0 disease than with stages IA through IV (P=.02). Similar results were observed when including stages IA (P=.007) and IB (P=.004) as early stages but not stage IIA (P=.10). A dilated pancreatic duct led to a PC diagnosis in all 6 patients with stage 0 disease. CONCLUSION: Patients with HBV- and HCV-related chronic liver disease had an early PC diagnosis during HCC surveillance. Careful evaluation of the pancreas is warranted during HCC surveillance.

Usefulness of laparoscopy and intraductal ultrasonography in a patient with isolated immunoglobulin G4-related sclerosing cholangitis.

Immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) is often associated with type 1 autoimmune pancreatitis, and the frequency of isolated IgG4-SC seems to be quite low, making the diagnosis of isolated IgG4-SC challenging. A 63-year-old male was admitted to our hospital for frequent fever. Abdominal magnetic resonance cholangiopancreatography showed diffuse narrowing of the common bile duct and post-stenotic dilatation of the right posterior bile duct. Laboratory tests showed abnormalities in the levels of hepatobiliary enzymes and serum IgG4 levels. Endoscopic retrograde cholangiopancreatography showed diffuse narrowing of intrahepatic bile ducts and post-stenotic dilatation of the right posterior bile duct but no abnormalities in the pancreas. Intraductal ultrasonography showed symmetric circumferentially thickened walls of both narrowed and non-narrowed common bile ducts. Histologic examination of the common bile duct mucosa showed infiltration of IgG4-positive plasma cells. Laparoscopic observations showed discoloration with red lobular markings and multiple small depressed lesions. Liver histology showed mild cholangitis with infiltration of IgG4-positive plasma cells around the bile ducts. From these findings, the patient was diagnosed with isolated IgG4-SC. After treatment with a steroid, bile duct dilatations improved. Laparoscopy and intraductal ultrasonography were useful to diagnose isolated IgG4-SC.

Diagnostic Challenge in Pancreatic Sarcoidosis Using Endoscopic Ultrasonography.

We herein report a 55-year-old woman who presented with erythema and bilateral hilar lymphadenopathy 4 months prior to the detection of pancreatic lesions on an ultrasound. A skin biopsy showed evidence of sarcoidosis. The largest lesion in the tail of the pancreas was hypoechoic on endoscopic ultrasonography (EUS). The lesion was initially iso-enhanced on contrast enhanced-EUS (CE-EUS) but subsequently became hypoenhanced. The lesion revealed heterogeneous components of both soft and hard tissue on EUS elastography. She was ultimately diagnosed with pancreatic sarcoidosis based on the presence of noncaseating granulomas seen on pancreatic tissue retrieved through an EUS-guided fine needle aspiration biopsy.

Bayesian inference of metal oxide ultrathin film structure based on crystal truncation rod measurements.

Monte Carlo (MC)-based refinement software to analyze the atomic arrangements of perovskite oxide ultrathin films from the crystal truncation rod intensity is developed on the basis of Bayesian inference. The advantages of the MC approach are (i) it is applicable to multi-domain structures, (ii) it provides the posterior probability of structures through Bayes' theorem, which allows one to evaluate the uncertainty of estimated structural parameters, and (iii) one can involve any information provided by other experiments and theories. The simulated annealing procedure efficiently searches for the optimum model owing to its stochastic updates, regardless of the initial values, without being trapped by local optima. The performance of the software is examined with a five-unit-cell-thick LaAlO3 film fabricated on top of SrTiO3. The software successfully found the global optima from an initial model prepared by a small grid search calculation. The standard deviations of the atomic positions derived from a dataset taken at a second-generation synchrotron are ±0.02 Šfor metal sites and ±0.03 Šfor oxygen sites.

Efficacy of chemotherapy in elderly patients with unresectable pancreatic cancer: a multicenter review of 895 patients.

BACKGROUND: The efficacy of chemotherapy for unresectable pancreatic cancer has improved. However, it is occasionally difficult to make treatment decisions for elderly patients. We reviewed the outcomes of elderly patients with unresectable pancreatic cancer by using a large cohort and evaluated whether they had received chemotherapy and the reason why. METHODS: Data for 895 pancreatic cancer patients who were treated using chemotherapy or best supportive care were analyzed considering demographics, clinical stage, treatment, and outcome. Data were analyzed using the chi-square test, Student t-test, or Mann-Whitney U-test, as appropriate. Outcomes were analyzed using the Kaplan-Meier method. Differences in survival were analyzed using the log-rank test. RESULTS: The median survival time was significantly shorter in elderly patients (≥65 years) than in younger patients (<65 years) (181 vs. 263 days, P = 0.0001). The median survival time of patients treated with chemotherapy was not significantly different between the elderly and the younger group (274 days vs. 333 days, P = 0.09), and nor was that of patients choosing best supportive care (84 days vs. 78 days, P = 0.83). These results held true even when the age cut-off between younger and elder patients was increased to 70, 75, and 80 years. Elderly patients treated with chemotherapy had a significantly longer median survival time than those choosing best supportive care (274 vs. 86 days, P < 0.0001); a significantly greater proportion of elderly patients chose best supportive care compared to younger patients (47.8 vs. 25.8%, P < 0.0001). The reason for choosing best supportive care was established in 261 elderly patients (82.9%); 133 (51.0%) met the eligibility criteria for chemotherapy, but of these, 78 (58.6%) were not informed about their disease. The treatment preferences of elderly patients were not always considered; they often received only best supportive care per family members preference (N = 65, 48.8%) or because the physician based their treatment decision only on the patient's age (N = 68, 51.1%). CONCLUSIONS: Chemotherapy appears effective for elderly pancreatic cancer patients with unresectable disease, but treatment needs to be optimized to improve prognosis.

Downregulation of ANP32B exerts anti-apoptotic effects in hepatocellular carcinoma.

The acidic (leucine-rich) nuclear phosphoprotein 32 family member B (ANP32B), a highly conserved member of the acidic nuclear phosphoprotein 32 (ANP32) family, is critical for the development of normal tissue. However, its role in the development of hepatocellular carcinoma (HCC) is controversial. In this study, we elucidated the role of ANP32B in HCC cell lines and tissues. ANP32B expression in HCC cell lines was modulated using siRNA and ANP32B expression plasmids and lentiviruses. The levels of apoptosis-related proteins were analyzed by real-time RT-PCR and Western blotting. The expression of ANP32B in tissues from patients with HCC was investigated using real-time RT-PCR and immunohistochemistry. ANP32B knockdown by siRNA altered the expression of apoptosis-related proteins in HCC cell lines and reduced the expression of cleaved forms of caspase 3 and caspase 9, but not that of caspase 8, in HCC cells cultured with the pro-apoptotic agent staurosporine. Phosphorylated Bad was upregulated, whereas Bak was downregulated. Moreover, ABT-737, which binds to and inhibits anti-apoptotic proteins of the Bcl-2 family, rendered HCC cells resistant to apoptosis induced by ANP32B silencing. Conversely, ANP32B overexpression decreased Bad phosphorylation and upregulated Bak, but did not induce apoptosis because Bax expression was downregulated. In tissues from patients with HCC, a low tumor/non-tumor ratio of ANP32B mRNA expression was related to advanced UICC stage (p = 0.032). TUNEL-positive cells were observed in parallel with ANP32B expression in HCC tissues. ANP32B modulates Bad phosphorylation as well as Bak and Bax expression, resulting in regulation of apoptosis in HCC. These findings indicate the potential value of ANP32B as a therapeutic target for HCC.

Role of Geminin in cell fate determination of hematopoietic stem cells (HSCs).

Geminin exerts two distinct molecular roles. Geminin negatively regulates DNA replication licensing through the direct interaction with Cdt1 to prevent re-replication in proliferating cells. Geminin also regulates chromatin remodeling through the direct interaction with Brahma/Brg1 to maintain undifferentiated states of stem cells. We previously uncovered that Polycomb-group complex 1 and Hoxb4/Hoxa9, well-known intrinsic factors that are essential for maintaining the hematopoietic stem cell (HSC) activity, alternatively act as ubiquitin-proteasome systems for Geminin protein to reduce the protein expression level, and sustain the HSC activity. Thus, Geminin is presumed to play an important role in determining cell fate, i.e., turning on and off cellular quiescence and proliferation/differentiation, in HSCs. We recently generated recombinant cell-penetrating Geminin (CP-Geminin), enabling rapid incorporation and withdraw of Geminin protein in cells. CP-Geminin may be useful in regulating the cell cycle and chromatin configuration. In this article, we summarize current information on the molecular functions of Geminin and the regulatory system for Geminin protein expression, and argue for the molecular role of Geminin in cell fate determination of HSCs, and future perspective of a new technology for manipulating the activities of HSCs and cancer stem cells (CSCs).

Early pancreatic volume reduction on CT predicts relapse in patients with type 1 autoimmune pancreatitis treated with steroids.

BACKGROUND: Type 1 autoimmune pancreatitis (AIP) is clinically characterized by a response to steroid therapy. Despite having a favorable prognosis, AIP has a high relapse rate and factors predicting relapse in AIP patients treated with steroids have not yet been established. METHODS: A retrospective chart review was conducted of 32 newly diagnosed type 1 AIP patients who had undergone enhanced computed tomography (CT) pre- and post-steroid therapy. RESULTS: Ten patients experienced relapse. Pancreatic volume was reduced significantly in all patients (pre-treatment volume, 88.5 ± 32.9 cm(3) vs. post-treatment volume, 45.4 ± 21.1 cm(3); P < 0.001), although the pre-treatment pancreatic volume did not differ between the relapse and non-relapse groups (92.6 ± 10.5 cm(3) vs. 86.6 ± 7.1 cm(3), P = 0.401). However, the post-treatment pancreatic volume was significantly greater in the relapse group than that in the non-relapse group (56.9 ± 6.3 cm(3) vs. 40.2 ± 4.2 cm(3), P = 0.008). Similarly, the percent reduction in pancreatic volume was significantly smaller in the relapse group than that in the non-relapse group (36.6 ± 4.7 % vs. 52.1 ± 3.2 %, P = 0.002). Multivariate analysis identified post-treatment pancreatic volume (HR, 1.04, 95 % CI: 1.01-1.08, P = 0.010) and percent reduction in pancreatic volume (HR, 0.87, 95 % CI: 0.79-0.94, P < 0.001) as predictive factors for relapse of type 1 AIP. A post-treatment pancreatic volume of 50 cm(3) < (P = 0.009) and a percent reduction in the pancreatic volume of <35 % (P = 0.004) had a significantly high relapse rate. These data suggest that early pancreatic volume changes after steroid therapy may be a useful prognostic value, because type 1 AIP patients with a high post-treatment pancreatic volume or low pancreatic volume reduction showed significant relapse. CONCLUSIONS: Early pancreatic volume reduction on CT after steroid therapy indicates the therapeutic effects of steroids, and a low decrease in the pancreatic volume may be associated with a limited response that predicts future relapse in patients with type 1 AIP. Reduction of steroids in these cases must be observed carefully with consideration of immunomodulator use.

Simeprevir with peginterferon/ribavirin for patients with hepatitis C virus genotype 1: high frequency of viral relapse in elderly patients.

PURPOSE: The tolerability and efficacy of simeprevir in combination with peginterferon and ribavirin in patients infected with hepatitis C virus (HCV) genotype 1 under actual clinical conditions were investigated. METHODS: A total of 176 patients with chronic HCV genotype 1 infection were treated with simeprevir for 12 weeks plus Peg-IFN/RBV for 24 weeks. Overall, 107 (60.7 %) patients were aged 60 years or more, and 16 (9 %) patients were aged 70 years or more. Treatment discontinuation, sustained virological response 12 (SVR12), and viral relapse were evaluated and compared between younger patients and elderly patients. RESULTS: The rates of undetectable HCV RNA at the end of treatment were 95.8, 100 and 93.1 % in treatment-naïve, prior relapse, and prior non-responders, respectively. However, the rates of SVR12 were 82.4, 88.2 and 69.2 %, respectively. Especially in prior non-responders, viral relapse was relatively frequent. Treatment discontinuation and SVR12 were not different between patients aged <70 and ≥70 years, but viral relapse after completing treatment was significantly more frequent in patients aged ≥70 years (p = 0.012). CONCLUSIONS: In simeprevir with peginterferon and ribavirin therapy, viral relapse was relatively frequent. Especially in elderly patients, the relapse rate was high after completing treatment, instead of low frequency of discontinuation by the adverse events.

Manipulation of Cell Cycle and Chromatin Configuration by Means of Cell-Penetrating Geminin.

Geminin regulates chromatin remodeling and DNA replication licensing which play an important role in regulating cellular proliferation and differentiation. Transcription of the Geminin gene is regulated via an E2F-responsive region, while the protein is being closely regulated by the ubiquitin-proteasome system. Our objective was to directly transduce Geminin protein into cells. Recombinant cell-penetrating Geminin (CP-Geminin) was generated by fusing Geminin with a membrane translocating motif from FGF4 and was efficiently incorporated into NIH 3T3 cells and mouse embryonic fibroblasts. The withdrawal study indicated that incorporated CP-Geminin was quickly reduced after removal from medium. We confirmed CP-Geminin was imported into the nucleus after incorporation and also that the incorporated CP-Geminin directly interacted with Cdt1 or Brahma/Brg1 as the same manner as Geminin. We further demonstrated that incorporated CP-Geminin suppressed S-phase progression of the cell cycle and reduced nuclease accessibility in the chromatin, probably through suppression of chromatin remodeling, indicating that CP-Geminin constitutes a novel tool for controlling chromatin configuration and the cell cycle. Since Geminin has been shown to be involved in regulation of stem cells and cancer cells, CP-Geminin is expected to be useful for elucidating the role of Geminin in stem cells and cancer cells, and for manipulating their activity.

Difficulty in management of intraductal papillary mucinous neoplasm-associated pancreatobiliary fistulas and the role of "pig-nose" appearance and intraductal ultrasonography in diagnosis.

Pancreatobiliary fistulas associated with intraductal papillary mucinous neoplasms (IPMN) often develop obstructive jaundice and cholangitis; thus, early diagnosis is important. However, computed tomography and cholangiography, the current methods for detecting pancreatobiliary fistulas, are not always effective. We previously reported a case of IPMN-associated pancreatobiliary fistula and proposed a potential new diagnostic marker: the "pig-nose" appearance of the duodenal papilla, which results from dilated pancreatic and bile ducts and can be visualized via endoscopy. In this study, we report another three cases of IPMN-associated pancreatobiliary fistulas detected by a different technology, intraductal ultrasonography (IDUS). As with our previously reported case, we confirmed the utility of the "pig-nose" appearance and IDUS in the diagnosis of IPMN-associated pancreatobiliary fistulas. In addition, we found it difficult to manage biliary obstruction that resulted from the flow of mucinous material through pancreatobiliary fistulas. The obstruction was treated with endoscopic nasal biliary drainage (ENBD), but this was not always successful. In two of our cases, additional treatment with a large diameter fully covered metal stent failed to improve jaundice. Therefore, we conclude that standard endoscopic stenting may not be effective, and that alternative endoscopic methods or surgery may be necessary.

Significance of ACADM mutations identified through newborn screening of MCAD deficiency in Japan.

BACKGROUND: Since the first case was detected in 2000, there has been a remarkable increase in Japanese patients diagnosed with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. Genetic analysis has revealed a spectrum of mutations that is quite different from those observed in Caucasian populations. In 2014, Japan initiated nationwide newborn screening (NBS) for MCAD using tandem mass spectrometry (MS/MS). It is an urgent issue to assess the risk of acute metabolic decompensation from the respective novel mutations found thus far. METHODS: To evaluate the pathogenic effect of each mutation, we established a eukaryotic cell expression system and prepared 11 mutant proteins identified in five symptomatic patients and eight MS/MS-NBS-positive newborns, as well as two common Caucasian mutations, p.K329E (c.985G>A) and p.Y67H (c.157C>T) for comparison. RESULTS: The expression of four mutant proteins (p.Q45R, p.P92L, p.P128X and p.Y397N) were severely impaired, whereas the others expressed normally, as did p.K329E and p.Y67H. Based on their dehydrogenase activities toward n-octanoyl-CoA, we determined three mutations (p.R53C, p.R281S and p.G362E) to be disease-causing, two mutations having (p.R17H and p.M274V) to be of marginal risk, and two mutations (p.K271E and p.I416T) as benign. Their allele-specific activities were as a whole in accordance with those estimated from the results of measurement in peripheral blood mononuclear cells. CONCLUSION: As most of the mutations detected in the Japanese population are unique, prudent genetic and enzymatic analysis is essential to precisely evaluate the latent risk of clinical onset for screening-positive newborns.

A case of hepatocellular carcinoma treated by radiofrequency ablation confirming the adjacent major bile duct under hybrid contrast mode through a biliary drainage catheter.

Bile duct injury is a potential complication of radiofrequency ablation (RFA). Bipolar RFA devices have recently become available. Because visibility of the bipolar RFA electrodes is not good on ultrasonography, more careful usage of the electrodes to avoid bile ducts is needed. We present a case with hepatocellular carcinoma (HCC) located near the B5 intrahepatic bile duct. To view the bile duct, we used contrast medium for ultrasonography, administered through a biliary drainage catheter for endoscopic nasobiliary drainage (ENBD). Infusing the contrast medium allowed clear visualization of the HCC adjacent to the major bile duct during RFA. We also used a navigation system for bipolar RFA to confirm positions of the electrodes and HCC. We confirmed complete ablation of the HCC while avoiding bile duct injury and late bile duct stenosis. Administration of contrast medium for ultrasonography through an ENBD tube appears useful to avoid bile duct injury during RFA.

Utility of Contrast-Enhanced Transabdominal Ultrasonography to Diagnose Early Chronic Pancreatitis.

Purpose. The purpose of this study was to establish the relationship between the grade of chronic pancreatitis (CP) and pancreatic blood flow as measured by contrast-enhanced transabdominal ultrasonography (CEUS) and to diagnose early CP easily. Methods. This pilot study was conducted in 8 patients with CP, 7 patients with early CP, and 6 control participants. After injecting 0.015 mL/kg of perflubutane by manual bolus, values in one region of interest (ROI) in pancreatic parenchyma and one ROI including the superior mesenteric artery (SMA) were measured. Results. The ratio of blood flow in the SMA and pancreatic parenchyma increased with grade of CP and was significantly higher in patients with CP (5.41; 2.10-11.02) than in patients with early CP (2.46; 1.41-5.05) and control participants (2.32; 1.25-3.04) (P = 0.0279, P = 0.0142, resp.). The ratio of blood flow in the SMA and pancreatic parenchyma correlated with grade of CP (rs = 0.5904, P = 0.0048). Conclusion. The ratio of blood flow correlates with grade of CP on CEUS. This safe and convenient method may be useful to diagnose early CP.