Toxicologic Pathology Forum: Current Status on the Use of Animal Models of Human Disease in the Pharmaceutical Industry in Japan in Nonclinical Safety Assessment-Opinion Paper.

In nonclinical safety studies for new drug development, healthy animals have been commonly used. However, in some cases, the use of animal models of human disease is considered to be more favorable in evaluating risks in patients. To elucidate the current status of the use of animal models for nonclinical safety assessment, an internal questionnaire from the Japan Pharmaceutical Manufacturers Association and surveys (questionnaire period: August 27 to September 30, 2015) of both common technical documents and review reports of approved drugs (approval period: May 1999 to May 2017) disclosed by the Pharmaceutical and Medical Devices Agency were conducted. Although there were some concerns and limitations raised, the survey results revealed that animal models have been used in nonclinical safety assessment on a case-by-case basis and that nonclinical safety studies using animal models were included in the data packages of several approved drugs in Japan. The survey results also revealed that nonclinical safety studies using animal models have become more frequent in the past few years. In almost all cases, useful information, such as signs of toxicity under disease conditions and mechanisms of toxic change, was obtained from the results of nonclinical studies using animal models. Note: This is an opinion article submitted to the Toxicologic Pathology Forum. It represents the views of the author(s). It does not constitute an official position of the Society of Toxicologic Pathology, British Society of Toxicological Pathology, or European Society of Toxicologic Pathology, and the views expressed might not reflect the best practices recommended by these Societies. This article should not be construed to represent the policies, positions, or opinions of their respective organizations, employers, or regulatory agencies.

Efficacy of video capsule endoscopy with flexible spectral imaging color enhancement at setting 3 for differential diagnosis of red spots in the small bowel.

BACKGROUND: Red spots on the small bowel mucosa are observed in patients with angioectasia and enteritis. The present study investigated the effectiveness of capsule endoscopy (CE)-flexible spectral imaging color enhancement (FICE) as a method for differential diagnosis of the two conditions. PATIENTS AND METHODS: The subjects were 30 patients who underwent CE and double-balloon endoscopy at Dokkyo Medical University Hospital between February 2007 and January 2013. Of these 30 patients, those diagnosed with angioectasia were assigned to Group A (n = 13) and those diagnosed with enteritis were assigned to Group E (n = 17). RESULTS: Using FICE at setting 3 and comparing the color intensity of the red spots on a four-step scale (0-3), no statistically significant (P = 0.712) difference was found between the twogroups (Group A: 2.69 ± 0.48, Group E: 2.76 ± 0.56). Subjects were considered to show a positive blue sign when areas of blue were observed against the yellow-green background and surrounding the red spots. A comparison of the ratio of positive blue sign for both groups (Group A: 15.4% ± 37.6%, Group E: 94.1% ± 24.2%) showed a statistically significant increase in the ratio in Group E (P < 0.001). CONCLUSION: The results of the present study suggest that blue sign may be effective in the differential diagnosis of angioectasia and enteritis in patients with red spots.

[¹8F-fluorodeoxyglucose PET/CT and small bowel endoscopy in a patient with small bowel leiomyoma].

A 49-year-old man was admitted to our hospital because of recurrent gastrointestinal bleeding of unknown origin, after repeated negative endoscopic and radiographic evaluation, including colonoscopy, esophago-gastro-duodenoscopy, CT and angiography. His condition had not been diagnosed for the past 18 years. ¹8F-fluorodeoxyglucose (FDG) on positron emission tomography (PET/CT) showed mild FDG uptake by a tumor of the small bowel (SUVmax 2.83), and capsule endoscopy (CE) and double balloon endoscopy (DBE) revealed a well-defined smooth submucosal tumor in the jejunum. The patient underwent a laparotomy and small bowel resection. The pathologic diagnosis was a small intestinal leiomyoma. Our report suggests the significance of combination of CE, DBE and PET/CT in the diagnosis of small bowel leiomyoma.

Frequency of nonsteroidal anti-inflammatory drug-associated ulcers.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for treatment of orthopedic diseases, inflammatory diseases, etc., and low-dose aspirin is a common antiplatelet therapy given mainly for secondary prevention of atherothrombosis (e.g., myocardial infarction and cerebral infarction). As to the history of NSAID-induced gastric mucosal injury in Japan, the first case of an aspirin-induced gastric ulcer was reported as early as 1934. Based on a meta-analysis of risk factors for peptic ulcers, Helicobacter pylori infection and NSAIDs are the main etiologies of peptic ulcers. NSAIDs alone increase the odds ratio for ulcer development to 19.4 and that for ulcer bleeding to 4.85. In fact, the Japan Rheumatism Foundation reported in 1991 that active gastric ulcers and active duodenal ulcers were detected in 15.5 and 1.9 % of 1008 patients, respectively, taking oral NSAIDs for 3 months or longer. In Japan, which is becoming an increasingly aged society, the numbers of patients taking NSAIDs and low-dose aspirin are expected to increase dramatically in the future. It is hoped that accumulation of evidence on gastrointestinal risk will allow many patients to rationally avoid gastrointestinal complications while receiving the benefits of NSAIDs and low-dose aspirin.

[Strategy to manage low dose aspirin-induced gastrointestinal injury].

Low dose aspirin, as an anti-platelet medication, has been increasingly prescribed to elderly patients for primary and secondary prevention of cardio- and cerebro-vascular events. Nonetheless, aspirin's effectiveness in such disease prevention is limited by the risk of upper and lower gastrointestinal (GI) complications such as ulceration, hemorrhage and perforation. Aspirin administration is associated with 2-fold increase in the GI risk in middle-aged users without prior history of peptic ulcer and without concomitant medications. However, such GI risk increases dramatically in patients with a prior history of peptic ulcer disease, advanced age, and concomitant use of NSAIDs, corticosteroids, clopidogrel, or anticoagulants. Mechanisms of aspirin-induced GI injury are believed to be through local effects within the GI mucosa that cause topical injury and through systemic inhibition of cyclo-oxygenase (COX) resulting in depletion of mucosal protective prostaglandins. Herein, we focus on the strategy to manage aspirin-induced peptic ulcerations and their complications, based on the scientific evidence.

Management of obscure gastrointestinal bleeding based on the classification of capsule endoscopic bleeding findings.

BACKGROUND: Double-balloon endoscopy (DBE) and capsule endoscopy (CE) have been useful in managing obscure gastrointestinal bleeding (OGIB). However, DBE is invasive, complex and time-consuming, therefore indications should probably be selective. The aim of this study was to evaluate the usefulness of the classification of the CE bleeding findings for determining the indications and timing of DBE in patients with OGIB. METHODS: From February 2003 to January 2009, 123 patients with OGIB who underwent CE were included in this study. These CE findings were classified based on the bleeding source. Type CE-I, II, III, IV and 0 indicate active bleeding, previous bleeding, lesions without active bleeding, a lesion outside of the small bowel, and no findings, respectively. We compared diagnostic yield and outcome between the classification and the findings of DBE or enteroclysis. RESULTS: Comparisons of the positive findings rate with DBE or enteroclysis, the treatment rate and the rebleeding rate with the classification showed: CE-Ia, 100% (6/6), 50% (3/6), 33.3% (2/6); Ib, 66.7% (4/6), 0% (0/6), 16.7% (1/6); IIa, 33.3% (1/3), 33.3% (1/3), 33.3% (1/3); IIb, 53.8% (7/13),15.4% (2/13), 30.8% (4/13); III, 100% (84/84), 9.5% (8/84), 8.3% (7/84); IV, 100% (2/2), 50% (1/2), 0% (0/2); and 0, 0% (0/9), 0% (0/9), 0% (0/9), respectively. CONCLUSIONS: The proportion of patients requiring treatment, the positive findings rate with DBE or enteroclysis and the rebleeding rates tended to be higher in the higher ranked classification types (CE-I>II>III>IV>0). These findings suggest that the classification can provide useful information on determining the indications and timing of DBE.

Endoscopic submucosal dissection in 100 lesions with early gastric carcinoma.

BACKGROUND/AIMS: ESD is a new diagnostic and treatment technique for early gastric cancer. This study aimed to evaluate the therapeutic effects observed at our department. METHODOLOGY: The subject group included 95 patients with 100 early-stage gastric cancers. According to the Gastric Cancer Treatment Guidelines published by the Japanease Gastric Cancer Association (JGCA) in 2001. Sixty-seven lesions presented a tumor measuring less than 20 mm and were concave (if not flat) without ulceration (specified indication of the guidelines of the Japanese Gastric Cancer Association), and 33 lesions were expanded indications. We then compared one-piece resection rates, en-bloc resection rates (one-piece resection that is lateral- and vertical-stump negative), curative en-bloc resection rates (en-bloc resection that fulfills the following three criteria: 1. differentiated adenocarcinoma; 2. no lymphtic or venous invasion, 3a. intramucosal cancer regardless of tumor size without ulceration, 3b. intramucosal cancer 30 mm in size with ulceration, 3c. minute submucosal cancer 30 mm in size). RESULTS: Among the specified indications and expanded indications, one-piece resection rates accounted for 97.0% and 75.8%, en-bloc resection rates for 83.6% and 60.6%, and curative en-bloc resection rates for 83.6% and 57.6%. The numbers of accident cases were three (postoperative hemorrhage; n = 1 perforation; n = 2) and four (postoperative hemorrhage; n = 1, perforation; n = 3), respectively. CONCLUSIONS: These studies indicated higher one-piece resection rates, en-bloc resection rates and curative en-bloc resection rates for lesions based on the guidelines than those based on the expanded guidelines.

Abdominal aortic aneurysm associated with crossed renal ectopia without fusion: case report and literature review.

Genitourinary anomalies can present a formidable challenge to the vascular surgeon at abdominal aortic reconstruction. We saw a case of crossed renal ectopia without fusion, a rare anomaly, associated with abdominal aortic aneurysm. Because of risk for injury to the kidney during surgery, preoperative evaluation of this anomaly must include computed tomography, angiography, and intravenous pyelography. Preoperative placement of a ureteral catheter may prevent injury to the anomalous ureter. Renal failure of the ectopic kidney during aortic reconstruction can be a serious problem. We used in situ hypothermic perfusion with cold (4 degrees C) Ringer solution for renal protection, and reimplanted the aberrant renal artery. The postoperative course was good, without major complications. The procedure for renal preservation must be selected on the basis of anatomic findings. We review the literature and present the first case of crossed renal ectopia.