Shozo Sasaki

Life-Threatening Gastrointestinal Mucosal Necrosis during Methotrexate Treatment for Rheumatoid Arthritis

Methotrexate (MTX), a folic acid antagonist, is widely used in the treatment of neoplasms, psoriasis and rheumatoid arthritis. Despite its efficacy, MTX sometimes finds limited application because of its adverse effects, including renal or liver impairment, bone marrow toxicity and gastrointestinal mucosal injury. Intestinal mucositis, bleeding and peptic ulcers are well-known gastrointestinal adverse effects of MTX, although cases of fatal mucosal necrosis induced by MTX are extremely rare. Here, we report the case of an 82-year-old Japanese woman who developed severe gastrointestinal mucosal necrosis after 8 years of treatment with low-dose MTX (8 mg/week). In the drug lymphocyte stimulation test, MTX showed a strong positive reaction, with a stimulation index of 443% against normal controls. Physicians must be aware of potential drug-induced adverse effects in patients with chronic diseases who are on long-term medication.

Impact of Inflammation-Metaplasia- Adenocarcinoma Sequence and Prevention in Surgical Rat Models

The incidence of esophageal cancer continues to rise in the Western world. Prior studies have suggested that gastroduodenal content reflux from gastroesophageal reflux disease induces the inflammation-mediated progression from hyperplasia to metaplasia, and to adenocarcinoma. We further investigated the sequential development of esophageal adenocarcinoma (EADC) with the use of an established surgical rat model. The present paper will describe the impact of the inflammation-metaplasia-adenocarcinoma sequence and chemoprevention in surgical rat models. A clinically relevant rat reflux model was used to investigate the cause of carcinogenesis, the sequential development of adenocarcinoma and chemoprevention with the use of a proton pump inhibitor. We found that duodenal reflux plays an important role in the inflammation-induced transformation of esophageal mucosa to adenocarcinoma. We were able to inhibit this transformation with rabeprazole, a proton pump inhibitor. Duodenal reflux promotes inflammation in the esophagus. The inflammation-metaplasia-adenocarcinoma sequence is important in the progression and development of EADC. Carcinogenesis can be prevented with chemoprevention agents such as rabeprazole. These results will need to be validated in clinical trials.

A selective cyclooxygenase‐2 inhibitor prevents inflammation‐related squamous cell carcinogenesis of the forestomach via duodenogastric reflux in rats

Duodenal reflux causes inflammation‐related squamous cell carcinogenesis in the forestomach of rats without any carcinogens. The aim of this study was to investigate the efficacy of a selective cyclooxygenase (COX)‐2 inhibitor, meloxicam, in preventing this carcinogenesis.

Barrett's esophagus and animal models

The following on Barretts esophagus (BE) and animal models contains commentaries on the factors of BE carcinogenesis; a duodenoesophageal reflux model; translation of targeted therapies for esophageal adenocarcinoma; and novel target regimens selected through a proteomics screen.

Chemoprevention of glandular stomach carcinogenesis through duodenogastric reflux in rats by a COX-2 inhibitor.

Duodenogastric reflux (DGR) causes glandular stomach carcinogenesis in rats without carcinogens. We aimed to investigate how this carcinogenesis might be prevented by a selective COX‐2 inhibitor, meloxicam. A series of 188 Fisher 344 rats underwent a surgical DGR procedure and were divided into 2 groups. One group was given commercial chow (control group), and the other an experimental chow containing meloxicam [0.3 mg/kg bw/day] (meloxicam group). The animals were sequentially sacrificed at weeks 20, 30, 40, 50 and 60 after surgery. The stomachs were removed and examined for the presence of carcinoma, incidence of reflux‐induced morphologic changes, COX‐2 expression and its activity. Adenocarcinoma in the glandular stomach developed in 7 of 21 animals (33%) in the control group at week 60, but none of 20 (0%) in the meloxicam group (p < 0.01). Moreover, reflux‐induced gastritis was definitely alleviated in the meloxicam group compared with the control group. COX‐2 immunoreactivity was predominantly detected in stromal cells such as macrophages and fibroblasts. Compared with nonsurgical rats, RNA expression of COX‐2 in the mucosa increased, reaching peak at an early phase of week 20 in both groups (p < 0.005). Expression of microsomal prostaglandin E synthase‐1 was lower in the meloxicam group than in the control group. PGE2 production was significantly suppressed throughout the experiment in the meloxicam group compared with the control group (p < 0.01). Gastric carcinogenesis via duodenal reflux was mediated by the COX‐2 pathway in rats. Administration of meloxicam prevented this carcinogenesis by suppressing the inflammatory process.

Inflammation-related carcinogenesis and prevention in esophageal adenocarcinoma using rat duodenoesophageal reflux models.

Development from chronic inflammation to Barretts adenocarcinoma is known as one of the inflammation-related carcinogenesis routes. Gastroesophageal reflux disease induces regurgitant esophagitis, and esophageal mucosa is usually regenerated by squamous epithelium, but sometimes and somewhere replaced with metaplastic columnar epithelium. Specialized columnar epithelium, so-called Barretts epithelium (BE), is a risk factor for dysplasia and adenocarcinoma in esophagus. Several experiments using rodent model inducing duodenogastroesophageal reflux or duodenoesophageal reflux revealed that columnar epithelium, first emerging at the proliferative zone, progresses to dysplasia and finally adenocarcinoma, and exogenous carcinogen is not necessary for cancer development. It is demonstrated that duodenal juice rather than gastric juice is essential to develop esophageal adenocarcinoma in not only rodent experiments, but also clinical studies. Antireflux surgery and chemoprevention by proton pump inhibitors, nonsteroidal anti-inflammatory drugs, selective cyclooxygenase-2 inhibitors, green tea, retinoic acid and thioproline showed preventive effects on the development of Barretts adenocarcinoma in rodent models, but it remains controversial whether antireflux surgery could regress BE and prevent esophageal cancer in clinical observation. The Chemoprevention for Barretts Esophagus Trial (CBET), a phase IIb, multicenter, randomized, double-masked study using celecoxib in patients with Barretts dysplasia failed to prove to prevent progression of dysplasia to cancer. The AspECT (Aspirin Esomeprazole Chemoprevention Trial), a large multicenter phase III randomized trial to evaluate the effects of esomeprazole and/or aspirin on the rate of progression to high-grade dysplasia or adenocarcinoma in patients with BE is now ongoing.

Metastatic gastric carcinoma from breast cancer mimicking primary linitis plastica: A case report

Metastases to the gastrointestinal tract rarely occur in breast cancer except in invasive lobular carcinoma. The present study reports a rare case of metastatic gastric cancer from invasive ductal carcinoma (IDC) of the breast mimicking primary gastric linitis plastica. A 51-year-old premenopausal female, who had a history of partial mastectomy for right breast cancer at the age of 40, was referred to Toyama City Hospital (Toyoma, Japan) for an endoscopic diagnosis of gastric linitis plastica. Abdominal computed tomography (CT) revealed left hydronephrosis, while peritoneal metastasis and malignant ascites were not detected. Chest CT detected a left lung tumor, which had invaded the left upper bronchus. Biopsy specimens were obtained and the histopathological findings on both the gastric tumor and lung tumor demonstrated poorly differentiated adenocarcinoma, whereas the histology of the original breast cancer was IDC with a solid-tubular type. Immunohistochemistry revealed that the biopsied specimens of the gastric and lung tumors were positive for estrogen receptor (ER), progesterone receptor (PgR) and negative for human epithelial growth factor receptor-2 (HER2). These molecular characteristics indicated the case was metastatic gastric carcinoma from the breast cancer with lung metastasis, since the statuses of ER, PgR and HER2 were concordant with those of the original breast cancer. However, the possibility of primary gastric cancer could not be completely ruled out. Therefore, a total gastrectomy was performed for the purpose of both diagnosis and treatment. Pathological examination of the resected specimen provided a definite diagnosis of multiple metastatic gastric carcinomas from the breast. To the best of our knowledge, metastatic gastric cancer derived from the breast presenting as linitis plastica 11 years following the surgical removal of IDC has not been described previously.

Massive pneumoretroperitoneum arising from emphysematous cholecystitis: a case report and the literature review.

BackgroundEmphysematous cholecystitis is a severe variant of acute cholecystitis caused by anaerobic bacteria. Although intraperitoneal air as a complication has been described in association with emphysematous cholecystitis, pneumoretroperitoneum arising from emphysematous cholecystitis is extremely rare. Herein, we describe a rare case of pneumoretroperitoneum arising from emphysematous cholecystitis that was successfully treated with emergency surgery.Case presentationAn 84-year-old male was transported to the Emergency Department of our hospital for acute abdomen. Computed tomography revealed acute cholecystitis accompanied by emphysematous change. Computed tomography also revealed massive pneumoretroperitoneum complicated with pneumobilia and gas in the hepatoduodenal ligament. Clinical findings fulfilled the diagnostic criteria for systemic inflammatory response syndrome and sepsis. Emergency surgery was carried out with a diagnosis of both emphysematous cholecystitis and gastrointestinal perforation. Intraoperative findings revealed acute gangrenous cholecystitis and pneumoretroperitoneum presenting with an odor-free foamy abscess along the loose connective tissue behind the ascending colon and mesocolon. No evidence of gastrointestinal perforation was found during surgery. Therefore, cholecystectomy and lavage drainage were performed. Bacterial culture examination isolated a single species of anaerobe, Klebsiella pneumoniae, which was considered to be the cause of emphysematous cholecystitis, pneumobilia, and pneumoretroperitoneum.ConclusionsEmphysematous cholecystitis should be considered as a possible cause of pneumoretroperitoneum. The present case is the first report of massive pneumoretroperitoneum extending to the dorsal side of the ascending mesocolon as a complication of emphysematous cholecystitis.

Sigmoid colon cancer arising in a diverticulum of the colon with involvement of the urinary bladder: a case report and review of the literature

BackgroundColon cancer can arise from the mucosa in a colonic diverticulum. Although colon diverticulum is a common disease, few cases have been previously reported on colon cancer associated with a diverticulum. We report a rare case of sigmoid colon cancer arising in a diverticulum with involvement of the urinary bladder, which presented characteristic radiographic images.Case presentationA 73-year-old man was admitted to our hospital for macroscopic hematuria. Computed tomography and magnetic resonance imaging revealed a sigmoid colon tumor that protruded into the urinary bladder lumen. The radiographs showed a tumor with a characteristic dumbbell-shaped appearance. Colonoscopy showed a type 1 cancer and multiple diverticula in the sigmoid colon. A diagnosis of sigmoid colon cancer with involvement of the urinary bladder was made based on the pathological findings of the biopsied specimens. We performed sigmoidectomy and total resection of the urinary bladder with colostomy and urinary tract diversion. Histopathological findings showed the presence of a colovesical fistula due to extramurally growing colon cancer. Around the colon cancer, the normal colon mucosa was depressed sharply with lack of the muscular layer, suggesting that the colon cancer was arising from a colon diverticulum.ConclusionThe present case is the first report of sigmoid colon cancer arising in a diverticulum with involvement of the urinary bladder. Due to an accurate preoperative radiological diagnosis, we were able to successfully perform a curative resection for sigmoid colon cancer arising in a diverticulum with involvement of the urinary bladder.

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