Yasutaka Ishii

Statins induce apoptosis and inhibit proliferation in cholangiocarcinoma cells

Given the poor prognosis for cholangiocarcinoma, new and effective treatments are urgently needed. HMG-CoA reductase inhibitors (statins) reportedly exert anticancer effects in a variety of diseases, but there have been no reports of these effects in cholangiocarcinoma. In this study, we investigated the utility of statins for cholangiocarcinoma treatment. Proliferation suppression by pitavastatin and atorvastatin was investigated in the human cholangiocarcinoma cell lines HuCCT1 and YSCCC while changes in the cell cycle and intracellular signals were examined by FACS and Western blotting, respectively. Additive proliferation suppression by statins and pre-existing anticancer drugs was also investigated. HuCCT1 and YSCCC cell proliferation was dramatically suppressed by incubation with statins for 72 h or longer. Cell cycle analysis revealed a reduction in the G2M fraction and an increase in the sub-G1 fraction in statin-treated cells, while Western blotting showed increased levels of cleaved caspase-3 and a reduction in p-ERK. Furthermore, statins in combination with gemcitabine, cisplatin and 5-FU showed additive proliferation suppression. In this study, treatment of human cholangiocarcinoma cells with statins induced apoptosis via suppression of the classical MAPK pathway. Together, these results suggest that statins may be a new cholangiocarcinoma treatment option that could potentially enhance the anticancer effect of pre-existing anticancer drugs.

Cholestatic jaundice in two patients with primary amyloidosis : Ultrastructural findings of the liver

Two patients with primary amyloidosis (amyloid light chain case) and severe cholestatic jaundice are described. Liver biopsy in the preterminal stage demonstrated amyloid deposits in the perisinusoidal space and in portal tracts, and hepatocytes were atrophic because of compression by amyloid fibrils. Ultrastructural findings showed amyloid fibrils not only in Disses space but also in the sinusoids, and the hepatocyte microvilli facing the amyloid fibrils were spicular. There were aggregates of lysosomal granules in the vicinity of bile canaliculi and some bile canaliculi were dilated with loss of microvilli. Amyloid fibrils in the portal tract compressed bile ductules, causing wide intercellular space and separated basement membranes from their epitheliums. These findings suggested disturbance in transporting not only of essential materials from sinusoids to hepatocytes but also of secretory vesicles into bile canaliculi and leakage of bile juice from small bile ductules in preterminal stage of primary amyloidosis.

Elevated expression of cyclooxygenase-2 and microsomal prostaglandin E synthase-1 in primary sclerosing cholangitis : Implications for cholangiocarcinogenesis

Cholangiocarcinoma (CCA) occurs frequently in primary sclerosing cholangitis (PSC). Cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1) induced by inflammation are believed to mediate prostaglandin E2 (PGE2) production thereby promoting carcinogenesis. Their expression in PSC-associated CCA tissues and non-neoplastic bile duct epithelial cells (BDECs) in PSC was investigated. COX-2 and mPGES-1 levels in 15 PSC patients (7 with CCA) were scored using immunohistochemical staining. The results were compared with those obtained in CCA tissues and non-neoplastic BDECs (controls) of 15 sporadic CCA patients. Non-neoplastic BDECs from large and small bile ducts were investigated separately. The mRNA expression levels of COX-2 and mPGES-1 in CCA tissues were analyzed by quantitative polymerase chain reaction. Ki-67 immunostaining was performed to evaluate cell proliferation. COX-2 was strongly expressed in PSC-associated CCA tissues and non-neoplastic BDECs in PSC. This expression was significantly upregulated in both compared with sporadic CCA tissues and non-neoplastic BDECs in sporadic CCA (both P<0.01). mPGES-1 was expressed at moderate to strong levels in PSC. Compared with controls, the expression was significantly higher in non-neoplastic small BDECs (P<0.01). COX-2 mRNA levels were significantly higher in PSC-associated tissues than in sporadic CCA tissues (P<0.01). Conversely, no differences were observed in mPGES-1 mRNA levels. Ki-67 labeling indices were higher in PSC-associated CCA tissues and non-neoplastic BDECs in PSC than in controls. In conclusion, COX-2 and mPGES-1 were highly expressed in PSC-associated CCA tissues and non-neoplastic BDECs in PSC, suggesting the involvement of COX-2 and mPGES-1 in cholangiocarcinogenesis.

A comparative study of 4 Fr versus 6 Fr nasobiliary drainage catheters: a randomized, controlled trial

Despite the benefits of endoscopic nasobiliary drainage (NBD) in endoscopic retrograde cholangiopancreatography (ERCP), post‐ERCP pancreatitis (PEP) and nose/throat discomfort can result. We aimed to determine whether the use of a smaller catheter alleviates these complications.

Occupational Radiation Exposure during Endoscopic Retrograde Cholangiopancreatography and Usefulness of Radiation Protective Curtains

Objective. To evaluate the effectiveness of radiation protective curtains in reducing the occupational radiation exposure of medical personnel. Methods. We studied medical staff members who had assisted in 80 consecutive therapeutic endoscopic retrograde cholangiopancreatography (ERCP) procedures. Use of radiation protective curtains mounted to the X-ray tube was determined randomly for each procedure, and radiation doses were measured with electronic pocket dosimeters placed outside the protective apron. Results. When protective curtains were not used, the mean radiation doses to endoscopists, first assistants, second assistants, and nurses were 340.9, 27.5, 45.3, and 33.1 µSv, respectively; doses decreased to 42.6, 4.2, 13.1, and 10.6 µSv, respectively, when protective curtains were used (P < 0.01). When the patient had to be restrained during ERCP (n = 8), the radiation dose to second assistants without protective curtains increased by a factor of 9.95 (P < 0.01) relative to cases in which restraint was not required. Conclusions. During ERCP, not only endoscopists, but also assistants and nurses were exposed to high doses of radiation. Radiation exposure to staff members during ERCP was reduced with the use of protective curtains.

Timing of radiological improvement after steroid therapy in patients with autoimmune pancreatitis.

Abstract Objective. We retrospectively studied the timing of radiological improvement after steroid therapy in patients with autoimmune pancreatitis (AIP). Material and methods. Patients with AIP (n = 31) received steroids followed by diagnostic imaging within 1 month. Pancreatic swelling, pancreatic and bile duct features, and apparent diffusion coefficient (ADC) were compared before and after treatment. The period from treatment initiation to evaluation was divided into five phases: early phase (days 3–5), week 1 (days 6 and 7), week 2 (days 8–14), week 3 (days 15–21), and week 4 (days 22–28). Five gastroenterologists evaluated pancreatic swelling and duct features (good/intermediate/no response), and the “good response” rate (response rate) was calculated for each phase. In addition, pancreatic volumes were measured with a 3D workstation before and after treatment, and the percentage change in volume was calculated. ADC values were calculated in 14 patients. Results. The median ratio of pancreatic volume after relative to before treatment was 0.89, 0.79, 0.67, 0.59, and 0.47 for early phase, week 1, week 2, week 3, and week 4, respectively. The response rate of the pancreatic swelling was 37.5%, 57.1%, 83.3%, 100%, and 100%; response rate of the pancreatic duct was 0%, 20%, 75%, 75% and 100%; and response rate of the bile duct was 0%, 66.7%, 83.3%, 100%, and 80%. The ADC increased after treatment in all 14 patients, including the 7 patients evaluated in the early phase. Conclusions. Evaluation of pancreatic swelling and duct features is recommended in week 2 and thereafter. The ADC increased soon after treatment initiation, suggesting its usefulness for evaluating early treatment responses.

Effects of colchicine on the synthesis and transport of albumin: A combined electron cytochemical and autoradiographic study

We investigated the intracellular transport of albumin in the livers of rats treated with colchicine using immunoperoxidase study as well as combined immunoelectron microscopy and autoradiography with [3H]‐leucine. Immunoreaction of albumin was observed in all hepatocytes. Its subcellular location was in the rough endoplasmic reticulum, Golgi apparatus and lysosomes. After the injection of [3H]‐leucine through the portal vein, a combined technique revealed accumulated grains on the albumin‐positive Golgi apparatus or the albumin‐positive vesicles in the vicinity of the Golgi apparatus. These findings suggest that albumin transport from the Golgi apparatus to sinusoids is disturbed by colchicine. Enzyme histochemistry showed many acid phosphatase‐positive lysosomes in hepatocytes of the liver treated with colchicine. Albumin retained in the vicinity of the Golgi apparatus may be digested by lysosomes.

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.

Use of 4-Fr versus 6-Fr Nasobiliary Catheter for Biliary Drainage: A Prospective, Multicenter, Randomized, Controlled Study

Background and Aim. Endoscopic nasobiliary drainage (NBD) effects according to diameter remain unclear. We aimed to assess the drainage effects of the 4-Fr and 6-Fr NBD catheters. Methods. This prospective, multicenter, randomized, controlled study was conducted at Hiroshima University Hospital and related facilities within Hiroshima Prefecture. Endoscopic retrograde cholangiopancreatography (ERCP) in 246 patients revealed acute cholangitis, obstructive jaundice, and/or extrahepatic cholestasis; 4-Fr or 6-Fr NBD catheters were randomly allocated and placed in these patients. The primary endpoint was the efficacy of NBD based on the technical success rate and clinical success (rates of change in blood test and amount of bile output). Secondary endpoints included the spontaneous catheter displacement rate and nasal discomfort. Results. The technical success rate and clinical success did not differ significantly between groups. No spontaneous catheter displacement was noted in either group. Nasal discomfort due to catheter placement was significantly lower in the 4-Fr group versus the 6-Fr group (24 h after ERCP: 2.4 versus 3.5 cm, P = 0.005; 48 h after ERCP: 2.2 versus 3.1 cm, P = 0.01). Conclusion. The 4-Fr NBD catheter was not inferior to 6-Fr NBD catheter in terms of clinical success; the 4-Fr NBD catheter was useful to reduce nasal discomfort.

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

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.