Tetsuhide Ito

Everolimus for Advanced Pancreatic Neuroendocrine Tumors

BACKGROUND Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), has shown antitumor activity in patients with advanced pancreatic neuroendocrine tumors, in two phase 2 studies. We evaluated the agent in a prospective, randomized, phase 3 study. METHODS We randomly assigned 410 patients who had advanced, low-grade or intermediate-grade pancreatic neuroendocrine tumors with radiologic progression within the previous 12 months to receive everolimus, at a dose of 10 mg once daily (207 patients), or placebo (203 patients), both in conjunction with best supportive care. The primary end point was progression-free survival in an intention-to-treat analysis. In the case of patients in whom radiologic progression occurred during the study, the treatment assignments could be revealed, and patients who had been randomly assigned to placebo were offered open-label everolimus. RESULTS The median progression-free survival was 11.0 months with everolimus as compared with 4.6 months with placebo (hazard ratio for disease progression or death from any cause with everolimus, 0.35; 95% confidence interval [CI], 0.27 to 0.45; P<0.001), representing a 65% reduction in the estimated risk of progression or death. Estimates of the proportion of patients who were alive and progression-free at 18 months were 34% (95% CI, 26 to 43) with everolimus as compared with 9% (95% CI, 4 to 16) with placebo. Drug-related adverse events were mostly grade 1 or 2 and included stomatitis (in 64% of patients in the everolimus group vs. 17% in the placebo group), rash (49% vs. 10%), diarrhea (34% vs. 10%), fatigue (31% vs. 14%), and infections (23% vs. 6%), which were primarily upper respiratory. Grade 3 or 4 events that were more frequent with everolimus than with placebo included anemia (6% vs. 0%) and hyperglycemia (5% vs. 2%). The median exposure to everolimus was longer than exposure to placebo by a factor of 2.3 (38 weeks vs. 16 weeks). CONCLUSIONS Everolimus, as compared with placebo, significantly prolonged progression-free survival among patients with progressive advanced pancreatic neuroendocrine tumors and was associated with a low rate of severe adverse events. (Funded by Novartis Oncology; RADIANT-3 ClinicalTrials.gov number, NCT00510068.).

Clinical diagnostic criteria of autoimmune pancreatitis: revised proposal.

In 1961, Sarles et al.1 asked the following question regarding the particular cases of pancreatitis with hypergammaglobulinemia: “Chronic inflammatory sclerosis of the pancreas—an autoimmune pancreatic disease?” As similar cases were rarely observed, a relationship between such pancreatitis and autoimmunity was viewed skeptically during the following several decades. In 1992, Toki et al.2 have reported 4 cases with unusual diffuse irregular narrowing of the main pancreatic duct and diffuse enlargement of the entire pancreas due to lymphocyte infiltration. In 1995, Japanese investigators3 firstly proposed a concept of “autoimmune pancreatitis (AIP)”, in which the patients showed diffusely enlarged pancreas, narrowing pancreatogram, increased serum IgG, presence of autoantibodies, fibrotic changes with lymphocytic infiltration and steroidal efficacy. Thereafter, many AIP cases have been reported from Japan, and AIP has been accepted as a new clinical entity.4,5 The histopathological findings of AIP show massive infiltration of lymphoplasmacytes with fibrosis, which is consistent with lymphoplasmacytic sclerosing pancreatitis (LPSP).6 Many Japanese investigators have paid great attention to AIP, especially with regard to its unique pancreatic images,2 IgG4,7 disease-associated autoantibodies,8 extrapancreatic lesions,6,9–14 and steroidal efficacy.14,15 Currently in Japan, diagnosis of AIP is based on the “diagnostic criteria 2002 of autoimmune pancreatitis”16 proposed by the Japan Pancreas Society. However, the accumulation of many AIP cases shows that the concept of AIP has changed slightly to include extrapancreatic lesions and associated disorders, which suggests that the current diagnostic criteria are becoming inadequate. In 2003, the Research Committee of Intractable Diseases of the Pancreas, supported by the Japanese Ministry of Health, Labour and Welfare (Chairman, M. Otsuki), began to review the current diagnostic criteria in light of recently acquired information and knowledge. The team organized a working group (WG), consisting of the team members and researchers specializing in autoimmune pancreatitis, to develop a proposal for the revision of the current diagnostic criteria. On 7 October 2005 and 22 April 2006, the Research Committee of Intractable Diseases of the Pancreas and the Japan Pancreas Society jointly held open forums to discuss the proposed amendments. This report describes the background of the proposed amendments and the final proposal for the revised version of the clinical diagnostic criteria of AIP.

Standard steroid treatment for autoimmune pancreatitis

Objective: To establish an appropriate steroid treatment regimen for autoimmune pancreatitis (AIP). Methods: A retrospective survey of AIP treatment was conducted in 17 centres in Japan. The main outcome measures were rate of remission and relapse. Results: Of 563 patients with AIP, 459 (82%) received steroid treatment. The remission rate of steroid-treated AIP was 98%, which was significantly higher than that of patients without steroid treatment (74%, 77/104; p<0.001). Steroid treatment was given for obstructive jaundice (60%), abdominal pain (11%), associated extrapancreatic lesions except the biliary duct (11%), and diffuse enlargement of the pancreas (10%). There was no relationship between the period necessary to achieve remission and the initial dose (30 mg/day vs 40 mg/day) of prednisolone. Maintenance steroid treatment was given in 377 (82%) of 459 steroid-treated patients, and steroid treatment was stopped in 104 patients. The relapse rate of patients with AIP on maintenance treatment was 23% (63/273), which was significantly lower than that of patients who stopped maintenance treatment (34%, 35/104; p = 0.048). From the start of steroid treatment, 56% (55/99) relapsed within 1 year and 92% (91/99) relapsed within 3 years. Of the 89 relapsed patients, 83 (93%) received steroid re-treatment, and steroid re-treatment was effective in 97% of them. Conclusions: The major indication for steroid treatment in AIP is the presence of symptoms. An initial prednisolone dose of 0.6 mg/kg/day, is recommend, which is then reduced to a maintenance dose over a period of 3–6 months. Maintenance treatment with low-dose steroid reduces but dose not eliminate relapses.

Asian diagnostic criteria for autoimmune pancreatitis: consensus of the Japan-Korea Symposium on Autoimmune Pancreatitis

In 2002, the Japan Pancreas Society (JPS) was the first in the world to propose diagnostic criteria for autoimmune pancreatitis (AIP). Since the concept of AIP has changed with the accumulation of AIP cases, the Research Committee of Intractable Pancreatic Diseases (RCIPD) provided by the Ministry of Health, Labour and Welfare of Japan and the JPS issued revised clinical diagnostic criteria of AIP in 2006. The Asan Medical Center of Korea also proposed diagnostic criteria for AIP in 2006. However, there are subtle but clinically challenging differences between the Japanese and Korean criteria. This inconsistency makes it difficult to compare data in studies from different centers and elucidate the characteristics of AIP. To reach a consensus on AIP, the RCIPD and the Korean Society of Pancreatobiliary Diseases established the following Asian criteria for the diagnosis of AIP: I-1. Imaging studies of pancreatic parenchyma show a diffuse/segmental/focally enlarged gland, occasionally with a mass and/or a hypoattenuation rim. I-2. Imaging studies of pancreaticobiliary ducts show diffuse/segmental/focal pancreatic ductal narrowing, often with stenosis of the bile duct. (Both I-1 and I-2 are required for diagnosis). II. Elevated level of serum IgG or IgG4, and detection of autoantibodies. III. Common lymphoplasmacytic infiltration and fibrosis, with abundant IgG4-positive cell infiltration. AIP should be diagnosed when criterion I and one of the other two criteria are satisfied, or when histology shows the presence of lymphoplasmacytic sclerosing pancreatitis in the resected pancreas. A diagnostic trial of steroid therapy can be applied carefully by expert pancreatologists only in patients fulfilling criterion I alone with negative diagnostic work-up results for pancreatobiliary cancer.

Autoimmune pancreatitis as a new clinical entity : Three cases of autoimmune pancreatitis with effective steroid therapy

The most common forms of chronic pancreatitisare related to alcohol ingestion, whereas the entity ofnon-alcohol-associated (idiopathic) pancreatitis ispoorly understood. Autoimmunity has been suggested as a possible etiologic factor of idiopathicchronic pancreatitis. A total of 362 Japanese patientsunderwent endoscopic retrograde pancreatography (ERP)for suspected pancreatic disease, and 161 were diagnosed with chronic pancreatitis. Among them, we foundthree cases (1.86% incidence) of unique chronicpancreatitis, in which ERP revealed diffuse narrowing ofthe main pancreatic duct with an irregular wall. We diagnosed these three patients as havingpancreatitis associated with an autoimmune mechanismmorphologically and biochemically and started them onsteroid therapy. The characteristics of the these three patients were as follows:hypergammaglobulinemia, eosinophilia, ultrasonographyshowing hypoehoic diffuse swelling in the pancreas(sausage-like appearance), ERP showing diffuse narrowingof the main pancreatic duct with irregular like thumbprintlike marks,reversible exocrine insufficiency, and positiveanti-carbonic anhydrase II antibody. After one month ofthe treatment with steroids, pancreatitis dramatically improved morphologically and enzymatically.Here we describe these cases of the suspected autoimmunechronic pancreatitis. We must recognize the concept andthe features of autoimmune pancreatitis in order to avoid unnecessary surgery as pancreaticcancer.

Japanese clinical guidelines for autoimmune pancreatitis.

Objectives: As the patients with autoimmune pancreatitis (AIP) are increasing in Japan, the practical guideline for managing AIP is required to be established. Methods: Three committees (the professional committee for making clinical questions [CQs] and statements by Japanese specialists, the expert panelist committee for rating statements by the modified Delphi method, and the evaluating committee by moderators) were organized. Fifteen specialists for AIP extracted the specific clinical statements from a total of 871 literatures by PubMed search (∼1963-2008) and from a secondary database and made the CQs and statements. 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 13, 6, 6, and 11 CQs and statements for the concept and diagnosis, extrapancreatic lesions, differential 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 guideline for AIP has been established. Further studies for the international guideline are needed after international consensus for diagnosis and treatment.

Bombesin-Related Peptides and their receptors: recent advances in their role in physiology and disease states

Purpose of reviewMammalian bombesin-related peptides, gastrin-releasing peptide and neuromedin B actions are mediated by two receptors (BB1-receptor, BB2-receptor), which are closely related to the orphan receptor BRS-3 (BB3-receptor). The purpose of this review is to highlight advances in the understanding of these peptides in physiology/disease states. Recent findingsPharmacologic/receptor-knockout studies show involvement of these receptors in a number of new processes/diseases. Neuromedin B/BB1-receptor is an important physiological regulator of pituitary–thyroid function; in mediating behavior, especially feas/anxiety; in mediating satiety through different cascades than gastrin-releasing peptide/BB2 receptors and for its autocrine tumor-growth effects. Gastrin-releasing peptide/BB2-receptor plays important roles in mediating signals for pruritus, lung development/injury, small intestinal mucosal defense, and central nervous system processes such as learning/memory. The signaling mechanisms of its potent growth effects are being elucidated and their possible therapeutic targets identified. BB3-receptor knockout mice provided insights for their obesity/glucose intolerance and demonstrated that this receptor may be important in the lung response to injury, tumor growth and gastrointestinal motility. Each receptor is frequently overexpressed in human tumors and has potent growth effects. This effect is being explored to develop new antitumor treatments, such as bombesin-receptor ligands conjugated to cytotoxic agents. SummaryThis receptor family is involved in an increasing number of central nervous system/peripheral processes physiologically and in disease states, and increased understanding of its role may lead to novel treatments.

Association of Long-Term Proton Pump Inhibitor Therapy with Bone Fractures and Effects on Absorption of Calcium, Vitamin B12, Iron, and Magnesium

Proton pump inhibitors (PPI) are one of the most widely used classes of drugs. PPIs have a very favorable safety profile, and it is unusual for a patient to stop them because of side effects. However, with increasing numbers of patients chronically taking PPIs for gastroesophageal reflux disease and other common, persistent conditions, the long-term potential adverse effects are receiving increasing attention. An insufficiently studied area receiving much attention is the long-term effect of chronic acid suppression on the absorption of vitamins and nutrients. This increased attention results from the reported potential adverse effect of chronic PPI treatment leading to an increased occurrence of bone fractures. Interest in this area has led to examination of the effects of PPIs on calcium absorption/metabolism and numerous cohort, case-control, and prospective studies of their ability to affect bone density and cause bone fractures. In this article, these studies are systematically examined, as are studies of the effects of chronic PPI use on absorption of VB12, iron, and magnesium. Studies in each area have led to differing conclusions, but when examined systematically, consistent results of several studies support the conclusion that long-term adverse effects on these processes can have important clinical implications.

Malignant tumors in choledochal cysts.

Between 1960 and 1975, 17 patients with congenital cystic dilatation of the common bile duct (choledochal cyst) were treated and three were associated with malignant tumors in the cysts and one was with carcinoma of the gallbladder. Preoperative diagnosis of adenocarcinoma in the choledochal cyst was established in one patient by cytologic examination of the bile which was obtained during the procedure of endoscopic pancreaticocholangraphy (EPCG) and percutaneous transhepatic cholangiography (PTC). Definitive treatment of the choledochal cysts associated with malignant tumors in the biliary tract was accomplished by excision of the cysts with tumor and choledochojejunostomy in two patients, by cystoduodenostomy following external drainage in one and by cholecystectomy with resection of invaded transverse colon in one with cancer of the gallbladder. Successful excision of choledochal cysts in 11 patients including three cases associated with malignant tumors in the biliary tract during the last 15 year period is the basis of this report.

A Prospective Study of Gastric Carcinoids and Enterochromaffin-Like Cell Changes in Multiple Endocrine Neoplasia Type 1 and Zollinger-Ellison Syndrome: Identification of Risk Factors

CONTEXT Multiple endocrine neoplasia type 1 (MEN1) patients frequently develop Zollinger-Ellison syndrome (ZES). These patients can develop proliferative changes of gastric enterochromaffin-like (ECL) cells and gastric carcinoids (ECL-cell tumors). ECL-cell changes have been extensively studied in sporadic ZES patients and can be precursor lesions of gastric carcinoids, but little is known about factors influencing their severity or development of carcinoids in MEN1/ZES patients. OBJECTIVES Our objective was to prospectively analyze ECL-cell changes and gastric carcinoids (ECL-cell tumors) in a large series of MEN1/ZES patients to detect risk factors and deduct clinical guidelines. SETTING AND PATIENTS Fifty-seven consecutive MEN1/ZES patients participated in this prospective study at two tertiary-care research centers. INTERVENTIONS AND OUTCOME MEASURES Assessment of MEN1, gastric hypersecretion, and gastroscopy with multiple biopsies was done according to a fixed protocol and tumor status. ECL-cell changes and alpha-human chorionic gonadotropin staining were assessed in each biopsy and correlated with clinical, laboratory, and MEN1 features. RESULTS ECL-cell proliferative changes were universally present, advanced changes in 53% and carcinoids in 23%. Gastric nodules are common and are frequently associated with carcinoids. Patients with high fasting serum gastrin levels, long disease duration, or a strong alpha-human chorionic gonadotropin staining in a biopsy are at higher risk for an advanced ECL-cell lesion and/or gastric carcinoid. CONCLUSIONS Gastric carcinoids and/or advanced ECL-cell changes are frequent in MEN1/ZES patients, and therefore, regular surveillance gastroscopy with multiple routine biopsies and biopsies of all mucosal lesions are essential. Clinical/laboratory data and biopsy results can be used to identify a subgroup of MEN1/ZES patients with a significantly increased risk for developing gastric carcinoids, allowing development of better surveillance strategies.