Relapse rate and predictors of relapse after cessation of glucocorticoid maintenance therapy in type 1 autoimmune pancreatitis: a multicenter retrospective study.

BACKGROUND: Type 1 autoimmune pancreatitis responds well to glucocorticoid therapy with a high remission rate. Moreover, glucocorticoid maintenance therapy can help prevent relapse. However, the relapse rate following cessation of long-term glucocorticoid therapy is unknown. The aim of this study was to clarify the relapse rate and predictors of relapse following long-term glucocorticoid therapy cessation. METHODS: We analyzed 94 patients who achieved remission after undergoing glucocorticoid therapy, discontinued treatment after at least 6 months of maintenance therapy, and were subsequently followed up for at least 6 months. The patients were divided into three groups based on treatment duration (< 18, 18-36, and ≥ 36 months), and their relapse rates were compared. Univariate and multivariate analyses of clinical factors were conducted to identify relapse predictors. RESULTS: After discontinuing glucocorticoid therapy, relapse was observed in 43 (45.7%) patients, with cumulative relapse rates of 28.2% at 1 year, 42.1% at 3 years, 47.0% at 5 years, and a plateau of 77.6% at 9 years. Of the 43 patients who relapsed, 25 (58.1%) relapsed within 1 year after after cessation of glucocorticoid therapy. Relapse and cumulative relapse rates did not differ significantly according to treatment duration. In the multivariate analysis, an elevated serum IgG4 level at the time of glucocorticoid cessation was found to be an independent predictor of relapse (hazard ratio, 4.511; p < 0.001). CONCLUSIONS: A high relapse rate occurred after cessation of glucocorticoid maintenance therapy, regardless of the duration of maintenance therapy, especially within the first year after cessation. However, the normalization of long-term serum IgG4 levels may be a factor in considering cessation.

Impact of sclerosing dacryoadenitis/sialadenitis on relapse during steroid therapy in patients with type 1 autoimmune pancreatitis.

OBJECTIVES: Steroids are the first-line drugs for induction of remission in patients with type 1 autoimmune pancreatitis (AIP), and the usefulness of steroid maintenance therapy to prevent relapse has recently been reported. However, even during steroid therapy, a relatively large percentage of patients relapse and the predictive factors for relapse have not yet been elucidated. The aim of this study was to clarify the predictive factors for relapse of AIP patients during steroid therapy. MATERIALS AND METHODS: The medical records of 76 patients with type 1 AIP with continued steroid therapy after induction of remission were analyzed retrospectively. The relapse rate during steroid therapy was evaluated, and the risk factors for relapse were investigated by univariate and multivariate analysis of clinical factors. RESULTS: Relapse occurred in 28.9% (22/76) of the patients. The cumulative relapse rates were 10.5% at 1 year, 25.0% at 3 years, 34.9% at 5 years, and 43.0% at 10 years. In multivariate analysis, presence of sclerosing dacryoadenitis/sialadenitis at the time of initial diagnosis of AIP was an independent risk factor for relapse (HR 3.475, p = .009). The cumulative relapse rates of patients with sclerosing dacryoadenitis/sialadenitis reached 21.4% at 1 year, 56.0% at 3 years, and 78.0% at 5 years. CONCLUSIONS: Sclerosing dacryoadenitis/sialadenitis was a predictive factor for relapse in type 1 AIP during steroid therapy; in such cases, strict follow-up is necessary with relapse in mind.

Evaluation of antibiotic use to prevent post-endoscopic retrograde cholangiopancreatography pancreatitis and cholangitis.

BACKGROUND/AIMS: The purpose of this study was to evaluate the relationship between prophylactic antibiotic use and complications following endoscopic retrograde cholangiopancreatography (ERCP). METHODOLOGY: We retrospectively evaluated 605 consecutive patients who underwent ERCP in our hospital between September 2009 and November 2011. The antibiotic group included patients who underwent their procedure before October 2010, while the control group included patients after October 1, 2010, who did not receive antibiotics. We compared the incidence of postoperative pancreatitis and cholangitis between the groups. RESULTS: There were no significant differences in the backgrounds of the 304 control and the 301 antibiotic-treated patients. The incidence of post-ERCP pancreatitis was 4.9% in the control group and 4.3% in the antibiotic group (p = 0.72). The incidence of postoperative cholangitis was 2.0% in the control group and 1.7% in the antibiotic group (p = 0.99). Choledocholithiasis, pancreatic duct injection, and female gender were detected as significant risk factors for postoperative pancreatitis by multivariate analysis; sclerosing cholangitis and incomplete biliary drainage were significant risk factors for postoperative cholangitis. Even in cases with these risk factors, prophylactic antibiotic use did not influence the incidence of pancreatitis or cholangitis. CONCLUSION: Prophylactic antibiotics do not reduce the incidence of either pancreatitis or cholangitis following ERCP.

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

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.

Comparative study of 4 Fr versus 6 Fr nasobiliary drainage catheters: a randomized, controlled trial.

BACKGROUND AND AIM: 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. METHOD: A randomized, controlled trial at a tertiary care center compared 4 Fr and 6 Fr NBD catheters; 165 ERCP patients with naïve papillae were randomly assigned to a catheter-size group. RESULTS: The prevalence of PEP was significantly lower in the 4 Fr group (3.7%; 3/82) than in the 6 Fr group (15.7%; 13/83; P = 0.019). No spontaneous catheter displacement occurred within 24 h. Discomfort visual analog scores were 2.6 and 4.3 in the 4 Fr and 6 Fr groups, respectively (P = 0.0048) on procedure day; on the following day, the scores were 2.3 and 3.6 (P = 0.028). Bile output was 16.3 mL/h and 21.4 mL/h in the 4 Fr and 6 Fr groups (P = 0.051). On obstructive jaundice subgroup analysis, bile drainage was 19.2 mL/h and 22.1 mL/h in the 4 Fr and 6 Fr groups (P = 0.40). The 4 Fr group required 5.6 days to reduce bilirubin levels versus 6.1 days in the 6 Fr group (P = 0.51). CONCLUSIONS: In patients with naïve papillae, lower rates of PEP and less nose/throat discomfort are associated with the use of 4 Fr NBD catheters. In patients with obstructive jaundice, 4 Fr and 6 Fr catheters are comparable with regard to bile output and bilirubin level reduction.

Characteristic Features of Cholangiocarcinoma Complicating Primary Sclerosing Cholangitis.

BACKGROUND/AIMS: Primary sclerosing cholangitis (PSC) is often complicated by cholangiocarcinoma (CCA); thus, early detection of CCA is an important way to improve PSC prognosis. METHODOLOGY: In a retrospective study, 23 cases of PSC were included. Seven cases were complicated by CCA (CCA group) and 16 cases were not (control group). Blood examinations, bile duct imagings from direct cholangiography, intraductal ultrasonography (IDUS) findings and pathological diagnosis results (bile juice cytology, brush cytology, and forceps biopsy) were referenced. RESULTS: Blood examinations showed that serum carbohydrate antigen 19-9 (CA19-9), total bilirubin, and aspartate aminotransferase were significantly higher in the CCA group, whereas cholangiography showed that the dominant stricture was significantly longer in the CCA group. No significant difference in the IDUS findings was observed between the 2 groups. Cholangioscopy enabled CCA diagnosis via identification of the papillary mucosa in sites other than the stricture. Forceps biopsy was the most useful pathological diagnostic technique, with a sensitivity of 86% and a specificity of 100%. CONCLUSIONS: The CA19-9 level and bile duct stricture morphology were useful for diagnosing CCA complicating PSC. Aggressive performance of cholangioscopy and pathological diagnostic techniques, such as brush cytology and forceps biopsy, are essential for identification.

The effect of respiratory-gated positron emission tomography/computed tomography in patients with pancreatic cancer.

Our aim of this study was to evaluate prospectively in patients with pancreatic cancer the effects of respiratory- gating during PET/CT acquisition on the determination of lesion volume and to measure tracer uptake. Our research included 36 patients diagnosed with pancreatic cancer. They underwent conventional whole-body PET/CT and subsequently respiratory-gated PET/CT of the upper abdomen. Based on list-mode PET acquisition data, respiratory-gated and non-gated images were created. Maximum standardized uptake values (SUVmax) and lesion volumes were compared between gated and non-gated images and also the rate of increase in SUVmax based on lesion size. Results showed that respiratory gating was successful in 34/36 patients. The median non-gated SUVmax was 6.2±2.1 and was 8.1±2.5 for respiratory- gated (P<0.01). Lesion volumes could be calculated in 27/34 patients. The median non-gated lesion volume was 5.82±5.57cm(3) and 4.31±4.56cm(3) for respiratory-gated (P<0.01). Furthermore, small lesions of ≤2cm had a significantly higher proportion of increased SUVmax compared to large lesions of >2cm (P=0.016). In conclusion, respiratory-gated PET/CT for patients with pancreatic cancer reduced respiratory motion artifacts and allowed significantly higher SUVmax to be obtained. In addition, the rate of increase in SUVmax tended to be higher in patients with pancreatic cancers of less or equal to 2cm diameter.

Favorable Management of Repeated Serous Retinal Detachment with Continued Tumor Response in a Patient with Intrahepatic Cholangiocarcinoma during Treatment with Pemigatinib.

Pemigatinib is a fibroblast growth factor receptor inhibitor (FGFRi) approved for the treatment of patients with previously treated biliary tract cancer with FGFR2 fusion. Although infrequent, ocular toxicity manifested as serous retinal detachment (SRD) has been observed and is regarded as a serious side effect. We herein report the case of a 54-year-old woman with unresectable cholangiocarcinoma-initiated pemigatinib after failure of gemcitabine plus S-1 (GS). Although the patient experienced repeated SRD after pemigatinib, dose interruption and dose reduction of pemigatinib from 13.5 mg to 9 mg, and from 9 mg to 4.5 mg led to complete recovery of SRD, and continued tumor shrinkage.

Diagnostic Ability and Safety of Repeated Pancreatic Juice Cytology Using an Endoscopic Nasopancreatic Drainage Catheter for Pancreatic Ductal Adenocarcinoma: A Multicenter Prospective Study.

Pathological examination is essential for the diagnosis and treatment of pancreatic ductal adenocarcinoma (PDAC). Moreover, a reliable pathological diagnosis is extremely important for improving prognosis, especially in early-stage PDAC. This study prospectively evaluated the usefulness of repeated pancreatic juice cytology (PJC) using an endoscopic nasopancreatic drainage (ENPD) catheter for the diagnosis of PDAC. We enrolled 82 patients suspected of having resectable PDAC, based on imaging studies, and judged the necessity for cytology. The diagnostic yield of up to six repeated PJCs and the incidence of complications, such as pancreatitis, was evaluated. A total of 60 patients were diagnosed with PDAC. The overall sensitivity and specificity were 46.7% and 95.5%, respectively. The cumulative positivity rate increased with the number of sampling sessions, reaching 58.3% in the sixth session. The sensitivity was significantly higher in the pancreatic head than in the pancreatic tail (p = 0.043). Additionally, it was 100% in four patients with a tumor size ≤10 mm. Pancreatitis occurred in six patients (7.3%), all of whom were treated conservatively. In the diagnosis of PDAC, repeated PJC using an ENPD catheter revealed a cumulative effect of sensitivity up to six times and an excellent diagnostic yield for small PDAC.

[Malignant phyllodes tumor metastatic to the pancreas: a case report].

A woman in her 50s was admitted with obstructive jaundice due to a pancreatic mass. She had a history of a right breast phyllodes tumor treated with mastectomy 3 years previously. Diagnostic imaging (endoscopic ultrasonography (EUS), CT, and MRI) demonstrated a well-demarcated mass in the pancreatic head. EUS-FNA showed spindle shaped tumor cells. The pancreaticoduodenectomy specimen showed a malignant spindle cell tumor consistent with a metastatic malignant phyllodes tumor. In addition, immunohistochemical staining demonstrated that the staining pattern of pancreatic tumor was similar to that of the breast phyllodes tumor. Pancreatic metastases from breast phyllodes tumors have rarely been reported in the literature.

Pancreatic duct rupture associated with high-grade pancreatic intraepithelial neoplasia treated by radical resection: a case report.

We here report a case of pancreatic duct rupture associated with high-grade pancreatic intraepithelial neoplasia treated by radical resection. A 71-year-old man presented to our hospital because of abdominal bloating. Diagnoses of early-stage pancreatic body cancer with pancreatic duct rupture, pancreatic ascites, and formation of a pseudocyst were made on the basis of blood tests, multidetector dynamic computed tomography, endoscopic ultrasonography, magnetic resonance cholangiopancreatography, and endoscopic retrograde cholangiopancreatography. After achieving control of the ascites by placement of a pancreatic duct stent and aspiration of the pseudocyst, distal pancreatectomy with D2 lymph node dissection was performed. Intraoperative cytologic examination of the ascites was negative. The pathological diagnosis was high-grade pancreatic intraepithelial neoplasia in the pancreatic body. The branched pancreatic duct was occluded and dilated by acute inflammation around the pancreatic neoplasm, the inflammation being in the region of the dilated branched pancreatic duct and having caused its rupture. To the best of our knowledge, this is the first published report of pancreatic duct rupture associated with high-grade pancreatic intraepithelial neoplasia.

A Rare Case of Delayed Perigastric Abscess after Curative Resection of Early Gastric Cancer by Uncomplicated Endoscopic Submucosal Dissection: Successful Treatment with Endoscopic Ultrasound-guided Drainage.

A 72-year-old man had undergone uncomplicated endoscopic submucosal dissection (ESD) with en bloc resection of a localized 20-mm IIc lesion in the anterior wall of the gastric angle. Twenty-eight days later, he was re-admitted with epigastric pain of one-week duration. Contrast-enhanced computed tomography (CT) revealed a 60-mm mass bordered by viscera; repeat endoscopy confirmed a smooth elevated submucosal tumor at the greater curvature on the oral side of the post-ESD ulcer. We diagnosed him with a perigastric abscess as a complication of ESD and performed endoscopic ultrasound-guided drainage. Subsequently, the symptoms and blood inflammatory parameters improved, and follow-up CT showed the disappearance of the abscess.

Clinical Analysis of Early-Stage Pancreatic Cancer and Proposal for a New Diagnostic Algorithm: A Multicenter Observational Study.

Early diagnosis of pancreatic ductal adenocarcinoma (PDAC) is challenging but essential for improving its poor prognosis. We established a multicenter study to clarify the clinicopathological features, and to propose new algorithm for early diagnosis of PDAC. Ninety-six patients with stage 0 and IA PDAC were enrolled from 13 high-volume centers. Overall, 70% of the patients were asymptomatic. The serum pancreatic enzyme levels were abnormal in half of the patients. The sensitivity of endoscopic ultrasonography (EUS) for detecting small PDAC was superior to computed tomography and magnetic resonance imaging (MRI) (82%, 58%, and 38%, respectively). Indirect imaging findings were useful to detect early-stage PDAC; especially, main pancreatic duct stenosis on MRI had the highest positive rate of 86% in stage 0 patients. For preoperative pathological diagnosis, the sensitivity of endoscopic retrograde cholangiopancreatography (ERCP)-associated pancreatic juice cytology was 84%. Among the stage IA patients, EUS-guided fine-needle aspiration revealed adenocarcinoma in 93% patients. For early diagnosis of PDAC, it is essential to identify asymptomatic patients and ensure close examinations of indirect imaging findings and standardization of preoperative pathological diagnosis. Therefore, a new diagnostic algorithm based on tumor size and imaging findings should be developed.

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.

Elevated expression of cyclooxygenase-2 and microsomal prostaglandin E synthase-1 in primary sclerosing cholangitis: ιmplications 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.

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.