Yuichi Tachibana

Randomised controlled trial of long-term maintenance corticosteroid therapy in patients with autoimmune pancreatitis

Objective Corticosteroid has been established as the standard therapy for autoimmune pancreatitis (AIP), but the requirement for maintenance corticosteroid therapy is controversial. We conducted a randomised controlled trial to clarify the efficacy of maintenance corticosteroid therapy in patients with AIP. Design We conducted a multicentre, tertiary setting, randomised controlled trial. After the induction of remission with the initial oral prednisolone (PSL) treatment, maintenance therapy with PSL at 5–7.5 mg/day was continued for 3 years or withdrawn at 26 weeks. The primary endpoint was relapse-free survival over 3 years and the secondary endpoint was serious corticosteroid-related complications. All analyses were performed on an intention-to-treat basis. Results Between April 2009 and March 2012, 49 patients with AIP were randomly assigned to the maintenance therapy group (n=30) or the cessation group (n=19). Baseline characteristics were not different between the two groups. Relapses occurred within 3 years in 11 out of 19 (57.9%) patients assigned to the cessation group, and in 7 of 30 (23.3%) patients in the maintenance therapy group. The relapse rate over 3 years was significantly lower in the maintenance therapy group than that in the cessation group (p=0.011). The relapse-free survival was significantly longer in the maintenance therapy group than that in the cessation group (p=0.007). No serious corticosteroid-related complications requiring discontinuation of PSL were observed. Conclusions Maintenance corticosteroid therapy for 3 years may decrease relapses in patients with AIP compared with those who discontinued the therapy at 26 weeks. Trial registration number UMIN000001818; Results.

Evidence-based clinical practice guidelines for chronic pancreatitis 2015.

Chronic pancreatitis is considered to be an irreversible progressive chronic inflammatory disease. The etiology and pathology of chronic pancreatitis are complex; therefore, it is important to correctly understand the stage and pathology and provide appropriate treatment accordingly. The newly revised Clinical Practice Guidelines of Chronic Pancreatitis 2015 consist of four chapters, i.e., diagnosis, staging, treatment, and prognosis, and includes a total of 65 clinical questions. These guidelines have aimed at providing certain directions and clinically practical contents for the management of chronic pancreatitis, preferentially adopting clinically useful articles. These revised guidelines also refer to early chronic pancreatitis based on the Criteria for the Diagnosis of Chronic Pancreatitis 2009. They include such items as health insurance coverage of high-titer lipase preparations and extracorporeal shock wave lithotripsy, new antidiabetic drugs, and the definition of and treatment approach to pancreatic pseudocyst. The accuracy of these guidelines has been improved by examining and adopting new evidence obtained after the publication of the first edition.

Efficacy of endoscopic ultrasonography and endoscopic ultrasonography-guided fine-needle aspiration for the diagnosis and grading of pancreatic neuroendocrine tumors

Abstract Background and aim: Pancreatic neuroendocrine tumors (pNETs) are histologically categorized according to the WHO 2010 classification by their mitotic index or Ki-67 index as G1, G2, or G3. The present study examined the efficacy of endoscopic ultrasonography (EUS) and EUS-guided fine-needle aspiration (EUS-FNA) in the diagnosis and grading of pNET. Methods: We retrospectively reviewed 61 pNETs in 51 patients who underwent EUS between January 2007 and June 2014. All lesions were pathologically diagnosed by surgical resection or EUS-FNA. We evaluated the detection rates of EUS for pNET and sensitivity of EUS-FNA, and compared the Ki-67 index between EUS-FNA samples and surgical specimens. EUS findings were compared between G1 and G2/G3 tumors. Results: EUS showed significantly higher sensitivity (96.7%) for identifying pNET than CT (85.2%), MRI (70.2%), and ultrasonography (75.5%). The sensitivity of EUS-FNA for the diagnosis of pNET was 89.2%. The concordance rate of WHO classification between EUS-FNA and surgical specimens was 69.2% (9/13). The concordance rate was relatively high (87.5%, 5/6) in tumors <20 mm but lower (57.1%; 4/7) in tumors ≥20 mm. Regarding EUS findings, G2/G3 tumors were more likely to be large (>20 mm), heterogeneous, and have main pancreatic duct (MPD) obstruction than G1 tumors. Multivariate analysis showed large diameter and MPD obstruction were significantly associated with G2/G3 tumors. Conclusions: EUS and EUS-FNA are highly sensitive and accurate diagnostic methods for pNET. Characteristic EUS findings such as large tumor size and MPD obstruction are suggestive of G2/G3 tumors and would be helpful for grading pNETs.

Diagnostic Performance of 48-Hour Fasting Test and Insulin Surrogates in Patients With Suspected Insulinoma

Objectives This study aimed to evaluate the usefulness of the 48-hour fasting test and insulin surrogates followed by a glucagon stimulatory test (GST) for the diagnosis of insulinoma. Methods Thirty-five patients with suspected insulinoma who underwent 48-hour fasting test and GST were retrospectively included in our study: 15 patients with surgically proven insulinomas and 20 patients in whom insulinoma was clinically ruled out. We determined the duration of the fasting test, plasma glucose levels, serum levels of immunoreactive insulin and C-peptide, and insulin surrogates (serum levels of &bgr;-hydroxybutyrate, free fatty acid, and response of plasma glucose to intravenous glucagon [&Dgr;PG]) at the end of the fast. Results The sensitivity and specificity of the 48-hour fasting test were 100.0% and 80.0%, respectively, for the diagnosis of insulinoma. When the 48-hour fasting test and immunoreactive insulin, C-peptide, or insulin surrogates were combined, the combination with GST showed the best results. The sensitivity, specificity, and accuracy rate were 93.3%, 95.0%, and 94.3%, respectively, with 1 false-negative case and 1 false-positive case occurring. Conclusions A more accurate and less invasive diagnosis of insulinoma was possible by combining the 48-hour fasting test with the GST, compared with the existing method.

Serum levels of Wisteria floribunda agglutinin-positive Mac-2 binding protein reflect the severity of chronic pancreatitis

To evaluate the utility of serum Wisteria floribunda agglutinin‐positive Mac‐2 binding protein (WFA +‐M2BP) level as a marker for chronic pancreatitis (CP).

Should the Selective Arterial Secretagogue Injection Test for Insulinoma Localization Be Evaluated at 60 or 120 Seconds

Objective The selective arterial secretagogue injection (SASI) test is considered indispensable for the accurate localization of insulinoma. However, the optimum timing of the post-injection evaluation is controversial, as some studies recommend 60 seconds [SASI (60 seconds)] while others support 120 seconds [SASI (120 seconds)]. The aim of this study was to determine the optimum timing for the SASI test evaluation for insulinoma localization. Methods Thirteen patients with surgically proven insulinoma were studied retrospectively. For the SASI test, immunoreactive insulin (IRI) was determined at baseline and at 30, 60, 90, and 120 seconds after calcium gluconate injection. A two-fold or greater increase in IRI over the baseline value was considered positive. The localization abilities of SASI (60 seconds) and SASI (120 seconds) were then compared. Results In 13 patients, a secretagogue was injected into 40 arteries supplying the pancreas. In the SASI (60 seconds) and SASI (120 seconds), the respective findings were as follows: positive predictive value, 72.2% and 68.2%; false positive rate, 25.0% and 35.0%; and rate of positivity in the head and body/tail, 38.5% and 46.2%. When the artery with the largest change was taken as the dominant artery, the localization detection sensitivity was 76.9% for SASI (60 seconds) and 92.3% for SASI (120 seconds). The sensitivity of morphological imaging techniques for localization ranged from 61.5-91.7%. Conclusion Compared with SASI (60 seconds) or morphological imaging, the insulinoma localization ability of SASI (120 seconds) was superior. Given these findings, we believe that the IRI level should be measured at 120 seconds in the SASI test.

Using CRISPR/Cas9 to Knock out Amylase in Acinar Cells Decreases Pancreatitis-Induced Autophagy

Pancreatic cancer is a malignant neoplasm that originates from acinar cells. Acinar cells get reprogrammed to become duct cells, resulting in pancreatic cancer. Pancreatitis is an acinar cell inflammation, leading to “impaired autophagy flux”. Pancreatitis promotes acinar-to-ductal transdifferentiation. Expression of amylase gets eliminated during the progression of pancreatic cancer. Amylase is considered as an acinar cell marker; however, its function in cells is not known. Thus, we investigated whether amylase affects the acinar cell autophagy and whether it plays any role in development of pancreatitis. Here, we knocked out ATG12 in a pancreatic cancer cells and acinar cells using CRISPR/Cas9. Autophagy inhibition led to an increase in the expression of duct cell markers and a simultaneous decrease in that of acinar cell markers. It also caused an increase in cell viability and changes in mitochondrial morphology. Next, we knocked out amylase in acinar cells. Amylase deficiency decreased autophagy induced by pancreatitis. Our results suggest that amylase controls pancreatitis-induced autophagy. We found that eliminating amylase expression contributes to pancreatic cancer etiology by decreasing autophagy. Furthermore, our results indicate that amylase plays a role in selective pancreatitis-induced autophagy of pancreatic enzyme vesicles.

Utility of chromogranin B compared with chromogranin A as a biomarker in Japanese patients with pancreatic neuroendocrine tumors

Objective Currently, serum chromogranin A is a well-established biomarker for pancreatic neuroendocrine tumors; however, other pancreatic diseases, oral use of a proton pump inhibitor and renal impairment can affect chromogranin A. Meanwhile, chromogranin B, belonging to the same granin family as chromogranin A, is not fully examined in these conditions. The present study aimed to evaluate the utility of chromogranin B as a pancreatic neuroendocrine tumor biomarker. Methods Serum chromogranin B levels were determined by radioimmunoassay and serum chromogranin A levels by enzyme-linked immunosorbent assay in pancreatic neuroendocrine tumor (n = 91) and other pancreatic conditions, and in healthy people (n = 104), to assess the relationships with clinical features. Results The diagnostic ability of chromogranin B was as good as chromogranin A. The area under the curve was 0.79 for chromogranin B (sensitivity/specificity: 72%/77%), and 0.78 for chromogranin A (sensitivity/specificity: 79%/64%). Chromogranin B was not affected by proton pump inhibitor use and age, which affected chromogranin A. The number of cases without liver metastases was larger in pancreatic neuroendocrine tumor patients with positive chromogranin B and negative chromogranin A. Though chromogranin A significantly elevated cases with proton pump inhibitor treatment and had positive correlation with age, chromogranin B did not have the tendencies. However, both chromogranin B and chromogranin A elevated in the case with renal impairment. In addition, the logistic regression analysis showed that chromogranin B was superior to chromogranin A in differentiation of pancreatic neuroendocrine tumor from other pancreatic diseases. Conclusions Compared with chromogranin A, chromogranin B may be more useful during proton pump inhibitor treatment and can detect tumors without liver metastases. In addition, chromogranin B may be an excellent biomarker when differentiation of pancreatic neuroendocrine tumor from other pancreatic diseases is required.

Effectiveness of endoscopic duodenal stenting for the management of patients with unresectable pancreatic cancer

Background and aims: This study evaluated the effectiveness of endoscopic duodenal stenting (EDuS) for the treatment of unresectable pancreatic cancer. Methods: The medical records of twenty patients with unresectable pancreatic cancer who underwent EDuS in a single institution were analyzed retrospectively. Results: Both the technical and clinical success rates were 100%. The median times of survival and stent patency were 113 and 109 days, respectively. In all patients, obstructive symptoms disappeared immediately after stenting. The mean time to resume oral intake after stenting was 1.8 days. The Gastric Outlet Obstruction Scoring System score was improved significantly after stenting. Fewer complications occurred in patients with obstruction in the horizontal part than in those with obstruction in other parts of the duodenum. Five patients lived >6 months after stenting without surgical treatment. Four of these patients had obstruction in the horizontal part, and they did not develop any complications after stenting. Conclusion: EDuS for duodenal obstruction in patients with unresectable pancreatic cancer is an effective method. In particular, in patients with obstruction in the horizontal part, EDuS might contribute to long-term survival because of its association with fewer complications. Further studies are needed to clarify the indications for EDuS. Correspondence to: Dr. Tetsuhide Ito, MD, PhD, Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; Tel: +81-92-642-5285, Fax: +81-92-642-5287; E-mail: itopapa@intmed3.med.kyushu-u.ac.jp