Hiroyuki Miyakawa

The revised Japanese clinical diagnostic criteria for chronic pancreatitis

In Japan, we are now using the clinical diagnostic criteria for chronic pancreatitis (CP) that were revised in 2001 to add the findings of magnetic resonance cholangiopancreatography to the criteria compiled by the Japan Pancreas Society (JPS) in 1995. Because the current criteria are set for diagnosing advanced CP, they are unlikely to improve patients’ prognoses. In addition, they seem unsuitable for current clinical practice because exocrine pancreatic function tests, which have become obsolete in Japan, are included in the diagnostic factors. For these reasons, the Research Committee on Intractable Pancreatic Diseases supported by the Ministry of Health, Labour and Welfare of Japan, the JPS and the Japanese Society of Gastroenterology have revised the criteria. The revised criteria are unique in that they contain an introduction to the concept of early CP. It is a challenge aimed at improvement of the long-term prognosis of CP patients by early diagnosis and therapeutic intervention in this disease. We need to determine and clarify the clinico-pathological outcome of early CP by a prospective long-term follow-up of the patients in this category.

Upregulation of BNIP3 by 5-aza-2′-deoxycytidine sensitizes pancreatic cancer cells to hypoxia-mediated cell death

BackgroundPancreatic cancer cells often show resistance to hypoxia-mediated apoptosis, but the molecular mechanism underlying that resistance remains unknown. The purpose of the present study, therefore, was to examine the role of epigenetic gene alteration in the resistance to hypoxia-mediated apoptosis among pancreatic cancer cells.MethodsReverse transcription-polymerase chain reaction (RT-PCR) was used to examine the expression of five genes associated with hypoxia-mediated apoptosis (PUMA, Caspase-8 [CASP8], APAF-1, BNIP3, and BNIP3L) in a panel of pancreatic cancer cell lines. Protein expression was examined by Western blot analysis, using lysates from cells incubated under normoxic or hypoxic conditions. The methylation status of the genes was determined using bisulfite-PCR and sequencing. The percentages of cells that were apoptotic were determined using flow cytometry.ResultsUnder normoxic conditions, the expression of the BNIP3 gene varied among the 12 pancreatic cancer cell lines tested, with 50% of them showing no BNIP3 expression at all, whereas expression of the other four genes was readily detected in all 12 cell lines. DNA methylation of BNIP3’s CpG island in the region around the transcription start site of the gene was closely associated with its silencing. The expression of BNIP3 was restored by the methyltransferase inhibitor 5-aza-deoxycytidine (5-aza-dC), as was the hypoxia-mediated pancreatic cancer cell death.ConclusionsBNIP3 expression is silenced in some pancreatic cancer cells by the methylation of its CpG island. Demethylation of BNIP3, using a methyltransferase inhibitor, restores the gene’s expression and induces hypoxia-mediated cell death. BNIP3 may thus be a useful target for new therapies aimed at treating pancreatic cancer.

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.

An Application of Endoscopic Color Doppler Ultrasonography (ECDUS) in the Diagnosis of Hemodynamics of Gastric Varices, and the Therapeutic Effect of Endoscopic Therapy

Abstract: We studied 14 patients using endoscopic color Doppler ultrasonography (ECDUS) to evaluate the hemodynamics of gastric varices, and evaluated the endoscopic therapeutic effects on gastric varices in 8 patients. Three patients had F3 type gastric varices and eleven had F2. The ECDUS was performed with a PENTAX FG‐32UA (7.5MHz, convex type) and a HITACHI EUB 565 was used as a display machine. The intramural blood flow in the gastric varices and inflows from the extra‐gastric wall were clearly observed with the ECDUS in all 14 patients. The extramural blood flow (gastro or spleno‐renal shunts) was detected in 9 of 14 patients. The velocity of the intramural flow in tumorous type varices (F3) was higher than in the nodular or flat elevated type (Fa). Next, we evaluated the therapeutic effects on gastric varices of the ECDUS. The successful disappearance of intramural blood flow was observed in 6 of 8 patients who had this endoscopic therapy. In two of the 8 patients, there was not enough therapeutic effect on the intramural blood flow. The extramural blood flow, however, did not change before or after endoscopic therapy with the ECDUS.

Management for pancreatolithiasis: a Japanese multicenter study.

Objectives A Japanese multicenter study of pancreatolithiasis was performed to investigate its clinical features and determine treatment strategies for pancreatolithiasis. Methods A retrospective study was performed on 916 patients managed in 34 institutions for a period of more than 5 years. Results The treatment methods were extracorporeal shock wave lithotripsy (ESWL) in 479 patients, surgery in 133, and endoscopy alone in 68. Fragmentation of stones after ESWL was achieved in 92.4% of the patients. However, complete stone clearance was achieved in 49.4% of the patients after ESWL alone. The complete stone clearance rate was lower after ESWL than after endoscopy (87.9%). The incidence of early complications was significantly higher after surgery (13.3%) than after ESWL (6.1%). The frequencies of total stone recurrence after ESWL (22.5%) and endoscopy (12.0%) were significantly higher than that after surgery (1.5%). After ESWL (17.6%), abdominal pain recurred significantly more frequently than after surgery (2.2%). Stones and abdominal pain most often recurred within 3 years after ESWL and endoscopy. Conclusions First-line treatment of pancreatic stones should be ESWL alone or with endoscopy because of its minimal invasiveness and low incidence of early complications. Surgery should be performed on patients in whom ESWL and endoscopy failed.

Clinical Features of Patients with Pancreas Divisum

Abstract: Between 1972 and 1992, 18, 128 ERCPs were performed. Pancreas divisum (PD) was diagnosed in 184 of these patients (1.02%). The clinical features of 108 cases were investigated (M53, F55, average age 54) who were encountered during the last 8 years.

Peroral Micro‐Pancreatoscopy (PMPS) for the Diagnosis of Pancreatic Diseases

In order to observe the inside of the main pancreatic duct endoscopically, we have performed pancreatoscopy using a microfiberscope with an external diameter of 0.75 mm which was inserted even into the undilated duct via a canula for ERCP without papillotomy. The peroral micro‐pancreatoscopy (PMPS) was carried out on 38 patients (16 cases of tumor, 21 of chronic pancreatitis and 1 of a cyst) and was successful in 33 patients (87%). In patients with cancer, rough elevation, redness, bleeding, or ulceration were recognized on the mucosa of the stenotic and the obstructed duct. In chronic pancreatitis, protein plugs were most frequently observed floating in the juice or attached to the ductal wall; some stones were also found in two patients.

The Usefulness of Endoscopic Color Doppler Ultrasonography (ECDUS) for Endoscopic Injection Sclerotherapy (EIS)

Abstract: We studied 12 patients using endoscopic injection sclerotherapy (EIS) guided by endoscopic color Doppler ultrasonography (ECDUS). The ECDUS was performed with a PENTAX FG‐32UA (7.5MH2, convex type) and a HlTACHl EUB 565 as a display machine.

Japanese Clinical Guidelines for Endoscopic Treatment of Pancreatolithiasis.

Objectives In addition to surgery, procedures for patients with pancreatolithiasis are developing; therefore, establishing practical guidelines for the management of pancreatolithiasis is required. Methods Three committees (the professional committee for asking clinical questions (CQs) and statements by Japanese endoscopists, the expert panel committee for rating statements by the modified Delphi method, and the evaluating committee by moderators) were organized. Eight endoscopists and a surgeon for pancreatolithiasis made the CQs and statements from a total of 694 reports of published literature by PubMed search (from 1983 to 2012). The expert panelists individually rated these clinical statements using a modified Delphi approach, in which a clinical statement receiving a median score greater than 7 on a 9-point scale from the panel was regarded as valid. Results The professional committee made 3, 7, and 10 CQs and statements for the concept and pathogenesis, diagnosis, and treatment, respectively. The expert panelists regarded them as valid after a 2-round modified Delphi approach. Conclusions After evaluation by the moderators, the Japanese clinical guidelines for pancreatolithiasis were established. Further discussions and studies for international guidelines are needed.