IgG4-related Sclerosing Cholangitis Complicated with Cholangiocarcinoma and Detected by Forkhead Box P3 Immunohistochemical Staining.

An 80-year-old man was admitted due to biliary stricture with autoimmune pancreatitis. Although radiographical examinations suggested Immunoglobulin G4-related sclerosing cholangitis (IgG4-SC), punched biopsies from the bile duct revealed adenocarcinoma. In the resected specimen, abundant N-terminus of Forkhead box P3 (Foxp3)-positive cells were localized in cholangiocarcinoma (CCA) tissue, while IgG4-positive cells were spread around the entire bile duct. Therefore, the case was diagnosed with IgG4-SC accompanied by CCA, not sporadic CCA. We herein report an informative case wherein IgG4-positive cells were abundant in CCA tissue and Foxp3 immunohistochemical staining allowed us to determine that this case had two entities.

One-step versus two-step distal self-expandable metal stent placement: A multicenter prospective randomized trial.

BACKGROUND AND AIM: Two methods of transpapillary covered self-expandable metal stent (SEMS) placement are used for distal malignant biliary obstruction (MBO): after initial drainage by plastic stent (two-step method) and without previous drainage (one-step method). METHODS: In total, 90 patients with unresectable pancreatic cancer and distal MBO were enrolled in this prospective multicenter randomized study and allocated to one-step (n = 45) and two-step (n = 45) groups. The main outcome was the time to recurrent biliary obstruction (TRBO). Secondary outcomes were the rates of early and late adverse events, survival time, the time required for bilirubin level reduction, and cost-effectiveness. RESULTS: The median TRBO did not differ significantly between the one-step and two-step groups (not available vs 314 days, P = 0.134). SEMS migration occurred significantly more frequently in the two-step group (14.3% vs 0%, P = 0.026). No significant difference was observed between groups in early (7.3% vs 14.3%, P = 0.483) or late (12.2% and 11.9%, P = 1) adverse events other than RBO, survival time (P = 0.104), or the median number of days required to reach a bilirubin level considered to be acceptable for chemotherapy administration (<3 mg/dL; P = 0.881). The total costs of stent placement and reintervention were significantly lower in the one-step SEMS group (3347 vs 5465 US dollars, P < 0.001). CONCLUSIONS: The superiority of TRBO with two-step SEMS placement was not demonstrated. One-step SEMS placement might be a promising method from the viewpoints of cost-effectiveness and less invasiveness (UMIN-CTR clinical trial registration number: UMIN000016010).

Perivascular Epithelial Cell Tumor of the Pancreas Diagnosed Preoperatively by Endoscopic Ultrasound-guided Fine-needle Aspiration.

We herein report a 49-year-old woman with a perivascular epithelial cell tumor (PEComa) of the pancreas. Imaging studies demonstrated a relatively well-demarcated mass, measuring approximately 40 mm in diameter, located in the pancreatic tail. It was heterogeneously enhanced almost to the same degree as the surrounding pancreatic tissue in both the arterial and portal venous phases. We performed endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) using the Acquire® 22-gauge needle and preoperatively obtained a definitive diagnosis with a sufficient sample. Clinicians should consider pancreatic PEComa in their differential diagnosis of patients with a pancreatic mass.

The utility and efficacy of self-expandable metal stents for treating malignant gastric outlet obstructions in patients under best supportive care.

PURPOSE: Self-expandable metallic stents (SEMSs) may be used to effectively palliate malignant gastric outlet obstructions (GOOs), but their utility and efficacy in patients under best supportive care (BSC) have not been explored. METHOD: In this multicenter retrospective study, we reviewed data on patients under BSC who underwent endoscopic SEMS placement to treat malignant GOO without chemotherapy. We evaluated the safety and efficacy of the procedure. RESULTS: We enrolled a total of 208 patients. SEMS placement was technically successful in 207 (99.5%) and clinically successful in 164 (78.8%). The mean procedure time was 25.6 ± 2.8 min. Stent dysfunction later developed in 30 (14.4%) patients, of whom 90% (27/30) underwent reintervention. The procedure-related mortality rate was 1.44%; all deaths were due to pneumonia. Subgroup analysis by Karnofsky performance status (KPS) revealed that neither technical success, stent dysfunction, reintervention rate, procedure-related pneumonia or death, nor death within 14 days differed between patients with good and poor KPS. However, the clinical success rate and the median survival time were significantly lower and shorter, respectively, in those with poor KPS (p < 0.001). CONCLUSIONS: Duodenal SEMS placement is an effective palliative treatment for malignant GOO in BSC patients. Although the GOO score did not dramatically improve in patients with poor KPS, the procedure was safe and palliatively feasible. Procedure-related pneumonia was fatal; thus, it is essential to proceed with great caution. TRIAL REGISTRATION: Clinical trial registration number: UMIN000028367.

The absence of class III ß-tubulin is predictive of a favorable response to nab-paclitaxel and gemcitabine in patients with unresectable pancreatic ductal adenocarcinoma.

The combined administration of nab-paclitaxel and gemcitabine (nab-P + Gem) is a standard chemotherapy for unresectable pancreatic ductal adenocarcinoma (UR-PDAC); thus, a predictive biomarker to identify patients best suited for nab-P + Gem therapy would be useful. Class III ß-tubulin (TUBB3) has been reported to be a predictive marker for taxane resistance in various tumors. However, the correlation between TUBB3 expression and the response to nab-P + Gem in patients with UR-PDAC has not been evaluated. We retrospectively reviewed 75 patients with UR-PDAC who received nab-P + Gem. TUBB3 expression was examined immunohistochemically in specimens obtained by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). From 67 analyzable specimens that were available for TUBB3 staining, 14 (21%) were negative for TUBB3 immunostaining and 53 (79%) were positive. Patients with negative TUBB3 expression showed a significantly higher disease control rate (100% vs. 64.2%; P = .008) and longer progression-free survival (PFS); (7.1 months vs. 3.7 months; log-rank test, P = .036) than those of patients with positive. Furthermore, negative TUBB3 expression was an independent predictive marker of a prolonged PFS on multivariate analysis (hazard ratio, 2.41; 95% confidence interval, 1.11-5.24; P = .026). Our data indicate that an absence of TUBB3 expression in specimens obtained by EUS-FNA may be a favorable predictive marker of the response to nab-P + Gem in patients with UR-PDAC, highlighting its use as a potential new biomarker for treatment optimization.

Covered duodenal self-expandable metal stents prolong biliary stent patency in double stenting: The largest series of bilioduodenal obstruction.

BACKGROUND AND AIM: Endoscopic biliary and duodenal stenting (DS; double stenting) is widely accepted as a palliation therapy for malignant bilioduodenal obstruction. The aim of the current study was to investigate the patency and adverse events of duodenal and biliary stents in patients with DS. METHODS: Patients who underwent DS from April 2004 to March 2017 were analyzed retrospectively with regard to clinical outcomes and predictive factors of recurrent biliary and duodenal obstruction (recurrent biliary obstruction [RBO] and recurrent duodenal obstruction [RDO]). RESULTS: A total of 109 consecutive patients was enrolled. Technical success of DS was achieved in 108 patients (99.1%). Symptoms due to biliary and duodenal obstruction were improved in 89 patients (81.7%). RBO occurred in 25 patients (22.9%) and RDO in 13 (11.9%). The median times to RBO and RDO from DS were 87 and 76 days, respectively. Placement of a duodenal uncovered self-expandable metal stent (U-SEMS) was significantly associated with RBO in the multivariable analysis (P = 0.007). Time to RBO was significantly longer in the duodenal covered self-expandable metal stent group than in the U-SEMS group (P = 0.003). No predictive factors of RDO were detected, and duodenal stent type was not associated with the time to RDO (P = 0.724). CONCLUSIONS: Double stenting was safe and effective for malignant bilioduodenal obstruction. Duodenal U-SEMS is a risk factor for RBO. The covered self-expandable metal stent is the preferred type of duodenal SEMS in patients with DS (Clinical trial registration number: UMIN000027606).

Acute Acalculous Cholecystitis Caused by Giardia lamblia.

We report a case of a 70-year-old man with acute acalculous cholecystitis caused by Giardia lamblia. Contrast-enhanced computed tomography (CT) showed distention of the gallbladder due to a pericholecystic abscess without gallstones. Magnetic resonance cholangiopancreatography and drip infusion cholecystocholangiography-CT demonstrated a stricture of the hilar bile duct and cystic duct obstruction. We conducted transpapillary bile duct brush cytology and a biopsy of the hilar bile duct stricture; numerous active trophozoites of Giardia lamblia were observed without malignant findings. We considered this bile duct lesion to be biliary giardiasis. Biliary giardiasis should be taken into consideration when diagnosing acute acalculous cholecystitis.

IgG4-Related Sclerosing Cholangitis.

More men than women develop immunoglobulin G4-related sclerosing cholangitis (IgG4-SC). Age at clinical onset is significantly older in patients with IgG4-SC. Patients with IgG4-SC appear similar to those with cholangiocarcinoma and primary sclerosing cholangitis (PSC). The association between IgG4-SC and autoimmune pancreatitis (AIP) is useful for the diagnosis of IgG4-SC. However, some IgG4-SC cases are isolated from AIP and are difficult to diagnose. The authors focus on three distinct features of IgG4-SC. First, diffuse inflammation induces a longer stenosis on cholangiography in contrast to the short stenosis of patients with PSC. Second, fibroinflammatory involvement is observed mainly in the stroma of the bile duct wall, whereas the bile duct epithelium is intact. Third, steroid therapy results in remarkable improvement. Although the prognosis of patients with IgG4-SC is good, some cases have developed portal hypertension and liver cirrhosis during their clinical course. Further study is needed to elucidate the long-term outcomes and mechanism of IgG4-SC.

IgG4-related Sclerosing Cholangitis with No Biliary Stricture but Severe Thickening of the Bile Duct Wall.

We herein report a case of a 56-year-old man with IgG4-related sclerosing cholangitis (IgG4-SC) with no biliary stricture, but with a severely thickened bile duct wall. Contrast-enhanced computed tomography showed diffuse swelling of the pancreas and thickening of the common bile duct (CBD) wall with delayed enhancement. Obvious diffuse wall thickening of the CBD was observed on endoscopic ultrasonography. However, endoscopic retrograde cholangiography showed no biliary stricture in the CBD that had thickened. Although IgG4-SC has been classified by a stenotic lesion on cholangiography, we should be aware of some IgG4-SC cases showing only bile duct wall thickness without any biliary stricture.

Clinical features of acute obstructive suppurative pancreatic ductitis: A retrospective review of 20 cases.

BACKGROUND AND AIMS: The clinical features of acute obstructive suppurative pancreatic ductitis (AOSPD) have not been elucidated. We aimed to clarify the clinical features of AOSPD. METHODS: We retrospectively reviewed the clinical features of 20 patients with AOSPD at two tertiary referral centers between 1993 and 2012. We compared 17 AOSPD patients with chronic pancreatitis (CP) and 42 patients with acute-on-CP in terms of clinical characteristics, presentation, and laboratory and imaging findings. RESULTS: The etiology of AOSPD involved CP in 17 (85%) patients, pancreatic ductal adenocarcinoma in 2 (10%), and intraductal papillary mucinous neoplasm in 1 (5%). Endoscopic pancreatic drainage was effective in 19 (95%) patients. Body temperature was significantly higher in AOSPD with CP than acute-on-CP patients (median: 38.2 vs 36.9 °C; P < 0.001). Serum amylase levels at onset were significantly lower (median: 133 vs 364.5 U/L; P = 0.009), and C-reactive protein was significantly higher (median: 9.42 vs 1.06 mg/dL; P < 0.001) in AOSPD with CP patients. Enlargement of the pancreatic parenchyma (18 vs 93%; P < 0.001) and stranding of the surrounding fat (12 vs 93%; P < 0.001) on computed tomography were observed less frequently in patients with AOSPD with CP patients. The diameter of the main pancreatic duct was significantly greater in AOSPD with CP than acute-on-CP patients (median: 7 vs 5 mm; P = 0.006). CONCLUSIONS: The major etiology of AOSPD involved CP, and endoscopic pancreatic drainage was effective. The clinical features differ between AOSPD with CP and acute-on-CP.

New concept of traction force applied to biliary self-expandable metallic stents.

BACKGROUND AND STUDY AIMS: Various mechanical properties of self-expandable metallic stents (SEMSs) have been reported. They can be classified into the device behavior during and after deployment. While there have been several reports on the latter, information on the former is insufficient. During deployment, the position is maintained by retracting the delivery catheter. We propose that this pulling force be called the traction force and that the magnitude of traction force is termed the traction momentum. The aim of this study was to measure these parameters in order to clarify the properties of SEMSs in terms of their deployment. MATERIAL AND METHODS: The traction force, traction momentum, and shortening rate of 10 different SEMSs were measured. Traction force was measured using in-house equipment, and the shortening rate was determined by measuring the stents. RESULTS: The shortening rate was closely related to the stent structure. The traction force varied between 1.5 N and 9.4 N, and the traction momentum was significantly elevated in covered and braided stents. A high traction force did not imply a high traction momentum. CONCLUSIONS: A low or constant traction force and a minimal shortening rate significantly facilitated SEMS deployment to optimal positions. Traction force could be an important element for new ideal SEMS design.

Predictive factors for positive diagnosis of malignant biliary strictures by transpapillary brush cytology and forceps biopsy.

OBJECTIVE: The diagnostic yields of endoscopic transpapillary brush cytology and forceps biopsies for malignant biliary strictures (MBS) remain unclear and predictive factors for diagnosis have not been established. We aimed to clarify the diagnostic yields of both methods and the predictive factors METHODS: We reviewed 241 patients with biliary strictures who underwent transpapillary brush cytology (n = 202) or forceps biopsy (n= 208) between 2004 and 2014 at a single academic center. RESULTS: The sensitivity of forceps biopsy for MBS was significantly higher than that of brush cytology [60.6% (97/160) vs 36.1% (57/158), P < 0.01). The sensitivity of forceps biopsy was significantly higher in diagnosing bile duct cancer than pancreatic cancer [78.8% (52/66) vs 42.4% (28/66), P < 0.01). Multivariate analysis revealed that serum total bilirubin (TB) level (T-Bil) ≥ 4 mg/dL [odds ratio (OR) 2.506, 95% confidence interval (CI): 1.139-5.495, P = 0.022) was an independent predictor for positive diagnosis by brush cytology, while bile duct cancer (OR 4.926, 95% CI 2.183-11.111, P < 0.001), stricture length ≥ 30 mm (OR 2.941, 95% CI 1.119-7.752, P = 0.029) and TB ≥ 4 mg/dL (OR 2.252, 95% CI 1.052-4.831, P = 0.037) were significant indicators of a positive diagnosis by forceps biopsy. CONCLUSIONS: Endoscopic transpapillary forceps biopsy shows higher sensitivity than that of brush cytology for MBS. Bile duct cancer, stricture length ≥ 30 mm and TB ≥ 4 mg/dL are good indicators of forceps biopsy.

Endoscopic retrograde cholangiopancreatography-related adverse events in patients with type 1 autoimmune pancreatitis.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is frequently performed for the diagnosis and treatment of type 1 autoimmune pancreatitis (AIP). However, the prevalence of ERCP-related adverse events in patients with type 1 AIP has not been evaluated. We aimed to clarify the feasibility of ERCP in patients with type 1 AIP. METHODS: We retrospectively reviewed 82 consecutive ERCP procedures performed in patients with type 1 AIP from 2004 to 2014 in one university hospital and three tertiary-care referral centers. One hundred four ERCP procedures in chronic pancreatitis and 1123 in non-AIP cohort were enrolled as control groups. We compared the incidence of post-ERCP pancreatitis (PEP) between type 1 AIP and control groups. We evaluated the incidence of ERCP-related adverse events and various predictive factors for hyperamylasemia after ERCP. RESULTS: Pancreatography and cholangiography by ERCP were obtained in 78 (95.1%) and 76 (92.7%) patients, respectively. The incidence of PEP, cholangitis, and bleeding was 1.2% (1/82), 0%, and 1.2%, respectively. PEP occurred in type 1 AIP patient with diffuse parenchymal imaging, and the severity was mild. The incidences of PEP were 2.9% (3/104) and 5.4% (61/1123) in chronic pancreatitis and normal cohort, respectively. The incidence of PEP was slightly lower in type 1 AIP than non-AIP cohort (1.2% vs 5.8%, p = 0.119). There were no significant predictive factors for hyperamylasemia after ERCP in type 1 AIP. CONCLUSIONS: The incidence of ERCP-related adverse events is low in patients with type 1 AIP. ERCP-related procedures are feasible in the diagnosis and treatment of AIP.

Chemopreventive effect of resveratrol and apocynin on pancreatic carcinogenesis via modulation of nuclear phosphorylated GSK3ß and ERK1/2.

Despite progress in clinical cancer medicine in multiple fields, the prognosis of pancreatic cancer has remained dismal. Recently, chemopreventive strategies using phytochemicals have gained considerable attention as an alternative in the management of cancer. The present study aimed to evaluate the chemopreventive effects of resveratrol (RV) and apocynin (AC) in N-Nitrosobis(2-oxopropyl)amine-induced pancreatic carcinogenesis in hamster. RV- and AC-treated hamsters showed significant reduction in the incidence of pancreatic cancer with a decrease in Ki-67 labeling index in dysplastic lesions. RV and AC suppressed cell proliferation of human and hamster pancreatic cancer cells by inhibiting the G1 phase of the cell cycle with cyclin D1 downregulation and inactivation of AKT-GSK3ß and ERK1/2 signaling. Further, decreased levels of GSK3ß(Ser9) and ERK1/2 phosphorylation and cyclin D1 expression in the nuclear fraction were observed in cells treated with RV or AC. Nuclear expression of phosphorylated GSK3ß(Ser9) was also decreased in dysplastic lesions and adenocarcinomas of hamsters treated with RV or AC in vivo. These results suggest that RV and AC reduce phosphorylated GSK3ß(Ser9) and ERK1/2 in the nucleus, resulting in inhibition of the AKT-GSK3ß and ERK1/2 signaling pathways and cell cycle arrest in vitro and in vivo. Taken together, the present study indicates that RV and AC have potential as chemopreventive agents for pancreatic cancer.

Photodynamic Therapy using Talaporfin Sodium for the Recurrence of Cholangiocarcinoma after Surgical Resection.

We herein report the case of a 72-year-old man who underwent photodynamic therapy (PDT) with talaporfin sodium for recurrent cholangiocarcinoma after surgical resection. Endoscopic retrograde cholangiography (ERC) showed severe stenosis with an irregular surface measuring approximately 1 cm in length from the anastomotic site, and a recurrent nodular lesion was observed at the anastomotic site of the right anterior intrahepatic bile duct on gastrointestinal endoscopy. ERC after PDT revealed a dramatic improvement in the bile duct stenosis, and the nodular lesion had disappeared. No adverse events from the PDT were detected. PDT using talaporfin sodium may be a safe alternative treatment for cholangiocarcinoma.

Correlation between long-term outcome and steroid therapy in type 1 autoimmune pancreatitis: relapse, malignancy and side effect of steroid.

OBJECTIVES: Autoimmune pancreatitis (AIP) responds well to corticosteroid therapy (CST), and CST is essential to induce remission. However, the correlation between long-term outcome and CST has not been evaluated. We aimed to clarify the correlation between long-term outcome of AIP and CST. MATERIAL AND METHODS: We retrospectively evaluated relapse, risk of malignancy and side effects of CST by focusing on the correlation with CST in 84 patients with type 1 AIP. RESULTS: The incidence of relapse was 23.8%. The frequency of relapse after CST administration was significantly lower in patients taking CST for >6 months than in those who did not (22% versus 67%; p = 0.036). The incidence of malignancy was 10.7%. The standardized incidence ratio of malignancy was 2.14 [95% confidence interval 0.74-3.54]. There were no significant correlations between development of malignancy and CST. The incidences of total and serious side effects due to CST were 75% and 19.1%, respectively. Relapse was the only significant independent predictive risk factor for serious side effects in a multivariate analysis (odds ratio 4.065; 95% confidence interval 1.125-14.706; p = 0.032). The cumulative dose of corticosteroid was significantly higher in patients with serious side effects than in those without (12,645 mg versus 7322 mg; p = 0.041). CONCLUSIONS: CST reduces relapse of AIP. However, CST causes serious side effects, particularly in relapsing patients. Alternative maintenance therapy to prevent relapse is needed.

Case of arterial hemorrhage after endoscopic papillary large balloon dilation for choledocholithiases using a covered self-expandable metallic stent.

A 78-year-old male was admitted to our hospital because of choledocholithiasis. ERC demonstrated choledocholithiases with a maximum diameter of 13 mm, and we performed endoscopic papillary large balloon dilation (EPLBD) with a size of 15 mm. Immediately following the balloon deflation, spurting hemorrhage occurred from the orifice of the duodenal papilla. Although we performed endoscopic hemostasis by compressing the bleeding point with the large balloon catheter, we could not achieve hemostasis. Therefore, we placed a 10 mm fully covered self-expandable metallic stent (SEMS) across the duodenal papilla, and the hemorrhage stopped immediately. After 1 wk of SEMS placement, duodenal endoscopy revealed ulcerative lesions in both the orifice of the duodenal papilla and the lower bile duct. A direct peroral cholangioscopy using an ultra-slim upper endoscope revealed a visible vessel with a longitudinal mucosal tear in the ulceration of the lower bile duct. We believe that the mucosal tear and subsequent ruptured vessel were caused by the EPLBD procedure.

Impact of TP53 codon 72 and MDM2 SNP 309 polymorphisms in pancreatic ductal adenocarcinoma.

Single-nucleotide polymorphisms (SNPs) of TP53 (codon 72, rs1042522) and MDM2 promoter (SNP 309, rs2279744) have been associated with risk for various human cancers. However, studies analyzing these polymorphisms in pancreatic ductal adenocarcinoma (PDAC) are lacking. We investigated TP53 codon 72 and MDM2 SNP 309 polymorphisms in 32 patients with PDAC, 16 patients with chronic pancreatitis (CP), and 32 normal controls, using formalin-fixed paraffin-embedded tissue. We also examined TP53 and MDM2 protein immunohistochemistry (IHC) to assess the involvement of these differences in malignant transformation and disease progression. TP53 Pro/Pro genotype was significantly more frequent in PDAC patients than in controls (65.6 vs. 15.6%, p < 0.001) and no significant difference was found between CP patients (37.5%) and controls. In MDM2 SNP 309, there were no significant differences among the three groups. Based on the Kaplan-Meier analysis, overall survival was significantly shorter in MDM2 G/G genotypes compared with other genotypes (G/T and T/T) (359 vs. 911 days, p = 0.016) whereas no significant differences in TP53 genotypes were observed (638 vs. 752 days, p = 0.471). Although TP53 IHC was frequent in PDAC patients (53.1%), TP53 and MDM2 protein expression was not correlated with polymorphisms. Our study demonstrated TP53 codon 72 polymorphism is potentially a genetic predisposing factor while MDM2 SNP 309 polymorphism might be useful in predicting survival outcome.