Hitoshi Kotanagi

Clinical application of monoclonal antibody-drug conjugates for immunotargeting chemotherapy of colorectal carcinoma

Monoclonal antibody—drug conjugates were applied as a clinical trial for patients who, based on the experimental study, had colorectal cancer. Monoclonal antibody A7, from a mouse splenocyte immunized against human colon cancer, was used as a drug carrier for colon cancer. The anti‐cancer drugs mitomycin C (MMC) and neocarzinostatin (NCS) were bound covalently to A7 to form the conjugates A7‐MMC and A7–NCS. The in vitro cytotoxic effects of the conjugates on SW1116 cells were stronger than those on free MMC or NCS. The conjugate A7–NCS, when administered to nude mice, brought about the highest NCS tumor concentration, whereas normal immunoglobulin G (IgG)—NCS distributed evenly in all tissues. The conjugates showed a strong antitumor effect on colon cancer transplanted into nude mice. Forty‐one patients with colorectal cancer, including ten patients with postoperative metastasis, were given A7–NCS. The immunoperoxidase and drug concentration studies of the resected specimens showed that NCS was localized specifically in cancer. Patients receiving the conjugate did not experience serious adverse effects. Of the eight patients with postoperative liver metastasis, three showed evidence of tumor reduction on computed tomography (CT) scan and three claimed pain relief. The conjugate did not benefit patients with multiple lung metastasis or peritoneal metastasis.

Inhibitory Effect of Dietary Perilla Oil Rich in the n-3 Polyunsaturated Fatty Acid α-Linolenic Acid on Colon Carcinogenesis in Rats

The inhibitory effect of dietary perilla oil rich in the n‐3 polyunsaturated fatty acid α‐linolenic acid against colon carcinogenesis was investigated in rats. Four groups of 26 F344 rats each received an intrarectal dose of 2 mg of N‐methyl‐N‐nitrosourea 3 times a week for 2 weeks, and received a diet containing 12% perilla oil, 6% or 12% safflower oil (rich in the n‐6 polyunsaturated fatty acid linoleic acid), or 12% palm oil (rich in saturated and monounsaturated fatty acids). At week 35, the incidence of colon cancer was significantly lower in perilla oil‐fed rats than in other dietary groups; 19% vs. 46%, 56% and 58%. When examined at week 10, the concentration of fecal bile acids, known to be tumor promoters, was not significantly different among the dietary groups, and the intrarectal deoxycholic acid‐induced colonic mucosal ornithine decarboxylase activity, a marker of tumor promotion, was significantly lower in perilla oil‐fed group than in other groups. The serum and colonic mucosal fatty acid compositions and the blood plasma prostaglandin E2 level directly reflected the fatty acid composition of each dietary fat. The results suggest that the anti‐tumor‐promoting effect of dietary perilla oil was a result of a decreased sensitivity of colonic mucosa to tumor promoters arising from the altered fatty acid composition in membrane phospholipid of colonic epithelial cells, and was not a consequence of a decrease of promoters such as bile acids.

Increased mucosal ornithine decarboxylase activity in large bowel with multiple tumors, adenocarcinoma, and adenoma.

The polyamine biosynthetase, ornithine decarboxylase (ODC), involved in tumor promotion, was investigated in grossly normal mucosa obtained from surgically resected large bowel; 48 cases with and six cases without large bowel cancer. The mucosal ODC activity was significantly higher in 17 multiple tumor cases bearing adenocarcinoma(s) plus adenoma(s) than in 31 solitary tumor cases bearing one adenocarcinoma alone. It was higher in the mucosa of the two groups of cases than in the mucosa of individuals without large bowel cancer. Furthermore, the enzyme activity in left‐sided cancer cases was significantly higher than that in right‐sided cancer cases. Carcinoma tissue showed a remarkable high level of enzyme activity, compared with the normal mucosa. The results indicate the larger the number of tumors the higher the level of the ODC activity in the normal mucosa, particularly in left‐sided cancer cases. It is concluded that the mucosal ODC may provide a good biological marker to detect individuals at higher risk for large bowel cancer due to exogenous or endogenous factors, and thus contribute to the prevention of mortality from large bowel cancer.

Small Bowel Perforation Caused by Metastasis from an Extra-Abdominal Malignancy: Report of Three Cases

Abstract Small bowel perforation is rarely caused by metastasis from an extra-abdominal malignancy. This report describes three cases of small bowel perforation that occurred secondary to a metastatic tumor. The first case involved a 72-year-old man with malignant lymphoma of the larynx that had been treated with chemo- and radiation therapy; the second involved a 70-year-old man with rhabdomyosarcoma of the mediastinum that had been treated with radiation therapy; and the third involved a 41-year-old man with lung carcinoma that had been treated with surgery 10 months prior to perforation. Each patient presented with acute abdominal pain, had X-ray findings of free air in the abdomen, and underwent limited emergency surgery. Wedge resection and closure of the ileum was performed for the first patient and partial bowel resection with the creation of an intestinal stoma was performed for the second and third patients. In each case, the histologic findings of the resected specimens were consistent with the extra-abdominal primary tumors. Although the patients recovered sufficiently to begin eating and moving about, all three died of cancer or cancer-related complications within 45 days of surgery. We conclude that surgeons should be aware of the poor prognosis of such patients and perform only the minimal surgery required.

Outcomes and Indications of Segmental Pancreatectomy

Background/Aim: To preserve pancreatic function, segmental pancreatectomy has been proposed for benign or low-malignancy tumors in the pancreatic body. Indications for the procedure, however, are still controversial. Methods: In this study, we investigated the advantages and disadvantages of segmental pancreatectomy compared with distal pancreatectomy and subsequently determined indications for segmental pancreatectomy. Results: The distal pancreatectomy patients had shorter operation times, lower incidence of operative complications, and shorter hospital stays compared to segmental pancreatectomy patients. Endocrine function in distal pancreatectomy patients deteriorated compared to that of segmental pancreatectomy patients. The postoperative 75-gram oral glucose tolerance test showed a diabetic pattern in 3 of 7 distal pancreatectomy patients, whereas none of the segmental pancreatectomy patients became diabetic after surgery. The relation between the length of the removed pancreas and plasma glucose at 2 h after the 75-gram glucose intake showed a significant correlation. Conclusion: According to our results, if the length of removed pancreas is longer than 12 cm, the patients will have a risk of acquiring diabetes. In those cases, the segmental pancreatectomy should be considered.

Disseminated intra-abdominal cystic lymphangiomatosis with severe intestinal bleeding. A case report.

We describe cystic lymphangiomatosis with intestinal bleeding developing multiple lymphangiomas in the small intestine, mesentery, mesocolon, omentum, retroperitoneum, and spleen. Small intestinal fluorography showed multiple polypoid lesions, mainly in the jejunum. Ultrasonography, computed tomography, and magnetic resonance imaging showed diffuse cystic tumors in the mesentery and spleen. Cystic lymphangiomatosis was proved by histologic findings of the biopsied specimen at laparotomy.

Case Report: Intestinal Infarction After an Aneurysmal Occlusion of Superior Mesenteric Artery in a Patient With Behçet’s Disease

A patient with Behçets disease, accompanied by a large aneurysm of superior mesenteric artery, developed an ischemic enteritis with multiple perforated ulcers. The ischemic necrosis of the intestine preceded by recurrent abdominal pain was due to an aneurysmal occlusion of superior mesenteric artery, but not entero-Behçets disease. This is the first case report of intestinal infarction that occurred in a patient with vasculo-Behçets disease involving the superior mesenteric artery. Vasculo-Behçets disease should be included in a differential diagnosis of acute mesenteric artery thrombosis.

Homotypic Adhesion through Carcinoembryonic Antigen Plays a Role in Hepatic Metastasis Development

We established a cell line with high metastatic potential to the liver (LS‐LM4) after four successive repetitions of splenic injection of liver‐metastatic cells in SCID mice. This cell line strongly expressed CEA and showed increased homotypic adhesion as compared with the parent cell line (LS174T). To examine the role of CEA in the increased homotypic adhesion, LS‐LM4 cells were treated with anti‐CEA antibody and subjected to an in vitro adhesion and aggregation assay. Further, to study the role of CEA in the hepatic metastasis of cells with high metastatic potential, LS‐LM4 cells were treated with anti‐CEA antibody, and the inhibition of hepatic metastasis after splenic injection in vivo was examined. There was a 62% decrease in the homotypic adhesion of anti‐CEA antibody‐treated (100 μg/ml) LS‐LM4 cells under a Ca2+‐free condition as compared with the control (P<0.01). Anti‐CEA antibody (100 μg/ml) inhibited cell aggregation under a Ca2+‐free condition (P<0.05). Treatment with anti‐E‐cadherin antibody (60 μ/ml) plus anti‐CEA antibody (100 μg/ml) inhibited cell aggregation more potently than anti‐E‐cadherin antibody treatment alone in the presence of Ca2+. In vivo, there was a 75% decrease in the number of hepatic metastatic nodules in the G125 anti‐CEA antibody‐treated group as compared with the control group (P<0.01). Similarly, there was a 40% decrease in the diameter of metastatic nodules and there was a 90% decrease in total tumor volume of hepatic metastasis in the G125 anti‐CEA antibody‐treated group as compared with the control (P<0.01). These results suggest that increased metastatic potential to the liver is at least partly due to increased homotypic binding mediated by CEA.

Resection of metastatic thyroid carcinomas to the liver and the kidney: Report of a case

Differentiated thyroid cancer is considered to have a quite favorable prognosis. However, some patients die as a result of distant metastasis, which mainly consists of pulmonary, mediastinal, or osteal metastases. The biological features of the tumor, such as a slow growth gradient, indicate the possibility of achieving comparatively satisfactory results in the treatment of such distant metastases. A complete surgical excision of the distant metastases in differentiated thyroid carcinoma has been reported to offer the best chance for prolonged survival. A case of unusual metastasis sites on the caudate lobe of the liver and right kidney occurring in a 72-year-old woman is herein presented. The location of the surgically treated distant metastases of the papillary thyroid carcinoma make this case unique.

A case of toxic megacolon in ulcerative colitis associated with cytomegalovirus infection.

Cytomegalovirus (CMV) infection, which has been shown to complicate the course of ulcerative colitis (UC), has been implicated as a possible etiologic factor in the exacerbation of UC, especially in toxic megacolon. However, CMV infection in patients with UC accompanied by toxic megacolon has rarely been reported. Here we report a case of CMV infection of the colon accompanied by toxic megacolon occurring in UC. A 38-year-old woman had been treated with intravenous hydrocortisone, rectal steroid, and central venous alimentation for 6 weeks under the diagnosis of UC. She was transferred to Akita University Hospital because of increasing bloody diarrhea and abdominal pain. Toxic megacolon was identified by examinations on admission, and she underwent a total colectomy. Examination of the surgical specimen showed severe inflammation of the colon. Microscopically, cytomegalic inclusions were observed in and around the endothelial cells in the inflamed submucosal layer. It can be assumed that CMV infection was a secondary, opportunistic invader superimposed on UC, and that it played an important role in altering the clinical course of the patient.