Tomoaki Matsumori

Pathogenicity of IgG in patients with IgG4-related disease

Objective IgG4-related disease (IgG4-RD) is a systemic disease characterised by elevated serum IgG4 and IgG4-positive lymphoplasmacytic infiltration in the affected tissues. The pathogenic role of IgGs, including IgG4, in patients with IgG4-RD, however, is unknown. Design We examined the pathogenic activity of circulating IgGs in patients with IgG4-RD by injecting their IgGs into neonatal male Balb/c mice. Binding of patient IgGs to pancreatic tissue was also analysed in an ex vivo mouse organ culture model and in tissue samples from patients with autoimmune pancreatitis (AIP). Results Subcutaneous injection of patient IgG, but not control IgG, resulted in pancreatic and salivary gland injuries. Pancreatic injury was also induced by injecting patient IgG1 or IgG4, with more destructive changes induced by IgG1 than by IgG4. The potent pathogenic activity of patient IgG1 was significantly inhibited by simultaneous injection of patient IgG4. Binding of patient IgG, especially IgG1 and IgG4, to pancreatic tissue was confirmed in both the mouse model and AIP tissue samples. Conclusions IgG1 and IgG4 from patients with IgG4-RD have pathogenic activities through binding affected tissues in neonatal mice.

Resected tumor seeding in stomach wall due to endoscopic ultrasonography-guided fine needle aspiration of pancreatic adenocarcinoma.

Endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA) is a useful and relatively safe tool for the diagnosis and staging of pancreatic cancer. However, there have recently been several reports of tumor seeding after EUS-FNA of adenocarcinomas. A 78-year-old man was admitted to our hospital due to upper gastric pain. Examinations revealed a 20 mm mass in the pancreatic body, for which EUS-FNA was performed. The cytology of the lesion was adenocarcinoma, and the stage of the cancer was T3N0M0. The patient underwent surgery with curative intent, followed by adjuvant chemotherapy with S-1. An enlarging gastric submucosal tumor was found on gastroscopy at 28 mo after surgery accompanied by a rising level of CA19-9. Biopsy result was adenocarcinoma, consistent with a pancreatic primary tumor. Tumor seeding after EUS-FNA was strongly suspected. The patient underwent surgical resection of the gastric tumor with curative intent. The pathological result of the resected gastric specimen was adenocarcinoma with a perfectly matched mucin special stain result with the previously resected pancreatic cancer. This is the first case report of tumor seeding after EUS-FNA which was surgically resected and inspected pathologically.

Diagnostic ability of EUS-FNA for pancreatic solid lesions with conventional 22-gauge needle using the slow pull technique: a prospective study

Abstract Objective. Endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA) using the slow pull technique (SP-FNA) has recently attracted attention as an effective tissue acquisition technique. However, efficacy of SP-FNA with a 22-gauge conventional needle remains unclear. The aim of this study is to evaluate the diagnostic ability of SP-FNA with a 22-gauge needle. Material and methods. Patients with a pancreatic solid lesion were prospectively enrolled in this study. SP-FNA was performed at two needle passes with a 22-gauge needle. One dedicated pathologist evaluated the obtained samples in terms of quantity (Grade 0: scant; Grade 1: inadequate; Grade 2: adequate), quality (Grade 0: poor; Grade 1: moderate; Grade 2: good), and blood contamination (Grade 0: significant; Grade 1: moderate; Grade 2: low), and provided a pathological diagnosis. Additional EUS-FNA was performed by applying suction (SA-FNA). The evaluation points were as follows: diagnostic accuracy of SP-FNA compared with that of SA-FNA, and the quantity, quality, and blood contamination level of SP-FNA-obtained samples. Results. We enrolled 40 cases. The diagnostic accuracy of SP-FNA was 90% (36/40). There was no significant difference in the accuracy between SP-FNA and SA-FNA (90% vs. 90%, p = 1.000). The samples obtained using SP-FNA were assessed as Grade 2 for quantity in 29 cases (73%), quality in 31 (78%), and blood contamination in 25 (63%). Conclusions. Adequate, high-quality, and unsubstantially blood-contaminated samples could be obtained using SP-FNA. The diagnostic ability of SP-FNA was 90%, which appeared to be similar to that of SA-FNA.

Feasibility, Efficacy, and Predictive Factors for the Technical Success of Endoscopic Nasogallbladder Drainage: A Prospective Study

Background/Aims Several studies have shown the usefulness of endoscopic nasogallbladder drainage (ENGBD) in patients with acute cholecystitis. However, the procedure is difficult, and factors that affect technical success have not yet been clarified. We conducted a prospective study to evaluate the technical feasibility, efficacy, and predictive factors for the technical success of ENGBD in patients with acute cholecystitis. Methods All patients with moderate or severe acute cholecystitis who were enrolled underwent ENGBD between April 2009 and April 2011. Patients with surgically altered anatomy or pancreatobiliary malignancies were excluded. The primary outcomes included technical success, clinical success, and complications. Factors that could affect the technical success were also examined. Results Of the 27 patients who underwent ENGBD during the study period, technical success was achieved in 21 (78%) and clinical improvement was achieved in 20 (95%). Early complications were encountered in four patients (15%). Gallbladder wall thickness (odds ratio [OR], 1.64; 95% confidence interval [CI], 1.08 to 2.47) and age (OR, 1.16; 95% CI, 1.00 to 1.35) were effective predictors of technical failure. Conclusions ENGBD was effective in resolving acute cholecystitis; however, this modality was technically challenging and had a limited success rate. Because of technical difficulties, ENGBD should be reserved for limited indications.

A novel dry model for practicable sphincterotomy and precut needle knife sphincterotomy.

Aim. We aimed to develop a simulation dry model for endoscopic sphincterotomy (ES) and needle knife precut sphincterotomy (NKP) and to evaluate its usefulness as a training simulator. Materials and Methods. An endoscopic retrograde cholangiopancreatography trainer was used as a duodenum, bile duct, and papilla simulator. A simulated papilla was created with a piece of rolled uncured ham, and ES and NKP were performed. Hands-on training was carried out using this model, and success and failure of the procedures were evaluated. A questionnaire survey was conducted among the participants to assess the performance and usefulness of the dry model for ES and NKP training. Results. Twenty-two endoscopists participated in the hands-on training using this dry model. ES was successful in 33 out of 34 attempts (97%) whereas NKP was successful in all 7 attempts (100%). Based on the results of the questionnaire survey, the median score for realism was 7 (range: 2–9) for ES and 8 for NKP on a scale of 1 to 10. Conclusions. The dry model using an uncured ham provides a condition closely similar to actual clinical practice and is useful as a training model for ES and NKP.

Performance of novel tissue harmonic echo imaging using endoscopic ultrasound for pancreatic diseases

Background and study aims: Recently, tissue harmonic echo (THE) imaging has advanced with the development of a new endoscopic ultrasound (EUS) monitor/processing unit. With this new technology, penetration (THE-P) and resolution (THE-R) images can be obtained. The aim of this study was to investigate the performance of this novel THE imaging using a new processing unit for pancreatic diseases. Patients and methods: Fifty patients with pancreatic lesions (38 cystic, 12 solid) were retrospectively analyzed. At each examination, 3 EUS images of the same pancreatic lesion were obtained using B-mode, THE-P mode, and THE-R mode imaging. Each set of EUS images was randomly arranged and evaluated independently by 4 physicians blinded to the imaging technique. Images were compared using a Likert scale 5-point grading system for each parameter. Results: For cystic lesions, THE-P mode images were significantly superior to conventional B-mode images for visualizing the boundary, septum, nodules, and total image quality (P < 0.05). THE-R mode images were significantly superior to conventional B-mode images for visualizing the boundary, septum, and total image quality (P < 0.05). However, for solid lesions, there was no significant difference in all the evaluation points between THE-P and conventional B-mode images. THE-R mode images were inferior to conventional B-mode images for visualizing the boundary, internal structure, and total image quality (P < 0.05). Conclusions: For pancreatic cystic lesions, THE mode images provided better lesion characterization than conventional B-mode images. Further research is required to determine if this improvement will result in improved EUS diagnostics.

Endoscopic management of benign biliary stricture: should we treat more aggressively?

BENIGN BILIARY STRICTURES (BBS) have various etiologies, including intraoperative injury, postoperative stenosis, chronic pancreatitis, and primary and secondary cholangitis. Stasis of the bile juice causes abdominal pain, fever, and jaundice. At present, endoscopic biliary stenting or balloon dilatation is considered to be the first-line treatment for BBS. Recent advances in endoscopic techniques and various accessories have allowed successful treatment of most BBS cases. However, a consensus regarding the adequate management of BBS has not yet been reached. Moreover, various etiologies of BBS may confuse the choice of adequate treatment. Weber et al. reported interesting long-term follow-up results after endoscopic stent therapy for BBS depending on the various causes of the stricture. Intraoperative injury-induced stricture and postoperative stricture showed good follow-up results, whereas chronic pancreatitis-induced stricture revealed poor follow-up results. In terms of pathological findings, chronic pancreatitis was accompanied by not only fibrosis but also by swelling of the pancreas and calcification of the pancreatic parenchyma. These pathological conditions induce the formation of a difficult-to-resolve stricture. Single plastic stent placement is mainly used for the management of BBS. However, the single plastic stent does not usually achieve effective bile duct stricture resolution, and good long-term follow-up results. In addition, single plastic stents have short-term patency rates only, limited stent diameter, and a requirement for multiple endoscopic sessions. Moreover, most of the previous studies on single plastic stents are retrospective and have different patient selection criteria, dilatation methods, stent diameters, follow-up periods, and definitions of success. For these reasons, more aggressive treatments such as multiple plastic stent and covered metal stent insertions have been carried out. The concept of these treatments is to achieve larger dilatation of the stricture site. Costamagna et al. used multiple plastic stent insertion to obtain stricture resolution. They reported no recurrence of symptoms caused by a relapsing biliary stricture in 89 patients during a mean follow-up period of 48.8 months (range: 2–11.3 years). Catalano et al. treated symptomatic distal common bile duct stenosis and reported their prospective series compared with historical controls, together with a comparison of single versus multiple simultaneous plastic stents. Twelve consecutive patients with chronic pancreatitis and common bile duct stricture underwent endoscopic placement of multiple simultaneous plastic stents and were followed prospectively. Results were compared with a group of 34 patients in whom a single stent was placed. In the 12 patients with multiple stent placements, the diameter of the distal common bile duct stenosis increased from a mean of 1.0 mm to 3.0 mm post-treatment; no change in diameter was noted in the patients treated with a single stent. Theoretically, multiple stents have a larger boogie effect for stricture resolution than a single plastic stent. However, multiple plastic stent placement requires a longer procedure time and, in cases of tight strictures, it is difficult to pass and place multiple stents across the stricture. Another option for treating BBS is the placement of a metallic stent, which was first done in 1990. Unfortunately, an uncovered metallic stent was used which produced unsatisfactory results as the stent was difficult to remove because of endoluminal hyperplasia. To address this problem, covered self-expandable metallic stents (CSEMS) were used for BBS. CSEMS, particularly fully covered metallic stents (FCSEMS) can be reliably removed. Kahaleh et al. used CSEMS in 79 patients with BBS and confirmed stricture resolution in 90% of the patients. Although the dilating and stenting method has achieved successful resolution in most cases, 10–40% of BBS do not respond well. Moreover, stricture relapse may occur in 10–30% of cases after the initial resolution. Currently, the management of refractory BBS remains uncertain. In this issue of Digestive Endoscopy, Bing et al. report the most aggressive therapy for BBS using intraductal bipolar radiofrequency ablation (RFA). The treatment concept is aimed at using ablation power and treating the stricture rather than using the boogie effect. Endoscopic retrograde cholangiopancreatography and RFA therapy were carried out in nine patients. Among these patients, the causes of BBS included post-cholecystectomy injury in four patients, anastomotic stricture after liver transplantation in three, chronic inflammation in one and chronic pancreatitis in one. After RFA and balloon dilatation, stenosis of all the patients significantly improved and five patients (55%) met stricture resolution. Of the nine patients, three required no

Chemokine CXCL16 mediates acinar cell necrosis in cerulein induced acute pancreatitis in mice

Severe acute pancreatitis is a lethal inflammatory disease frequently accompanied by pancreatic necrosis. We aimed to identify a key regulator in the development of pancreatic necrosis. A cytokine/chemokine array using sera from patients with acute pancreatitis (AP) revealed that serum CXCL16 levels were elevated according to the severity of pancreatitis. In a mouse model of AP, Cxcl16 expression was induced in pancreatic acini in the late phase with the development of pancreatic necrosis. Cxcl16−/− mice revealed similar sensitivity as wild-type (WT) mice to the onset of pancreatitis, but better resisted development of acinar cell necrosis with attenuated neutrophil infiltration. A cytokine array and immunohistochemistry revealed lower expression of Ccl9, a neutrophil chemoattractant, in the pancreatic acini of Cxcl16−/− mice than WT mice. Ccl9 mRNA expression was induced by stimulation with Cxcl16 protein in pancreatic acinar cells in vitro, suggesting a Cxcl16/Ccl9 cascade. Neutralizing antibody against Cxcl16 ameliorated pancreatic injury in the mouse AP model with decreased Ccl9 expression and less neutrophil accumulation. In conclusion, Cxcl16 expressed in pancreatic acini contributes to the development of acinar cell necrosis through the induction of Ccl9 and subsequent neutrophil infiltration. CXCL16 could be a new therapeutic target in AP.

Laminin 511 is a target antigen in autoimmune pancreatitis

The extracellular matrix protein laminin 511 is an autoantigen involved in the pathophysiology of autoimmune pancreatitis. Pancreatic perturbation Autoimmune pancreatitis (AIP) is difficult to diagnose and can sometimes be confused with pancreatic cancer, which presents with similar symptoms. AIP is an inflammatory disease involving elevated IgG4, but the target autoantigen(s) is unidentified. This group’s previous work pointed to the extracellular matrix, and now, Shiokawa et al. show that a truncated form of laminin 511 may be a major autoantigen in AIP. They observed that half of AIP patients they analyzed had anti–laminin 511 antibodies, which were absent in healthy controls. Patient pancreatic tissues were positive for laminin 511, and immunization of mice with this protein induced AIP-like symptoms. These results reveal an autoimmune target in this disease and one day may aid AIP diagnosis. Autoimmune pancreatitis (AIP), a major manifestation of immunoglobulin G4–related disease (IgG4-RD), is an immune-mediated disorder, but the target autoantigens are still unknown. We previously reported that IgG in patients with AIP induces pancreatic injuries in mice by binding the extracellular matrix (ECM). In the current study, we identified an autoantibody against laminin 511-E8, a truncated laminin 511, one of the ECM proteins, in patients with AIP. Anti–laminin 511-E8 IgG was present in 26 of 51 AIP patients (51.0%), but only in 2 of 122 controls (1.6%), by enzyme-linked immunosorbent assay. Because truncated forms of other laminin family members in other organs have been reported, we confirmed that truncated forms of laminin 511 also exist in human and mouse pancreas. Histologic studies with patient pancreatic tissues showed colocalization of patient IgG and laminin 511. Immunization of mice with human laminin 511-E8 induced antibodies and pancreatic injury, fulfilling the pathologic criteria for human AIP. Four of 25 AIP patients without laminin 511-E8 antibodies had antibodies against integrin α6β1, a laminin 511 ligand. AIP patients with laminin 511-E8 antibodies exhibited distinctive clinical features, as the frequencies of malignancies or allergic diseases were significantly lower in patients with laminin 511-E8 antibodies than in those without. The discovery of these autoantibodies should aid in the understanding of AIP pathophysiology and possibly improve the diagnosis of AIP.