Seiichiro Shimizu

Targeted deletion of the H-ras gene decreases tumor formation in mouse skin carcinogenesis.

To clarify the role of the H-Ras in vivo, we generated H-ras null mutant mice by gene targeting. In spite of the importance of the Ras in cell proliferation and differentiation, H-ras null mutant mice grew normally and were fertile. The oldest H-ras mutant mice grew to be more than 30 months old. We used the H-ras deficient mice to study the importance of the H-ras and other ras genes in the development of skin tumors induced by initiation with 7,12-dimethylbenz(a)anthracene (DMBA) followed by promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA). We showed that H-ras null mutant mice develop approximately six times less papillomas compared with wild-type littermates after 20 weeks of TPA treatment. While all papillomas examined (17 out of 17) in wild-type mice have mutations of H-ras at codon 61, 13 (62%) out of 21 papillomas in H-ras null mutant mice have mutations of K-ras gene at codon 12, 13, or 61 and another eight (38%) papillomas have no mutations in these codons of K-ras or N-ras genes. This suggests that the activation of H-ras gene is critical in the wild-type mice, but the activation of K-ras gene can replace the H-ras activation in the initiation step of skin tumor development in the H-ras deficient mice.

Plexiform angiomyxoid myofibroblastic tumor of the stomach.

We report 2 cases of plexiform angiomyxoid myofibroblastic tumor of the stomach, a tumor entity that has not been described previously. The patients were a 50-year-old man (case 1) and a 68-year-old man (case 2). In case 1, the patient presented with acute abdominal pain. The tumor in case 2 was incidentally found at laparoscopic cholecystectomy. Grossly, the tumors were 4.0 cm (case 1) and 4.5 cm (case 2) in their greatest dimension, and they were recognized as submucosal tumors. The tumor caused gastric perforation in case 1. Histologically, the tumors extended from the serosa to the submucosa of the gastric wall, showing a plexiform growth pattern. Bland spindle tumor cells were observed, and they were separated by abundant intercellular myxoid matrix. The stroma was rich in small vessels. Immunohistochemically, the tumor cells were positive for α-smooth muscle actin and muscle actin, and negative for KIT, CD34, and S-100 protein. Electron microscopic findings were consistent with the myofibroblastic nature of the tumor cells. No mutations were found in the c-kit and platelet-derived growth factor receptor alpha genes. Although clinical follow-up data were insufficient, the histologic appearances suggested the benign nature of the tumors. However, the tumor in case 1 caused gastric perforation and necessitated an emergency operation.

Follicular dendritic cell sarcoma complicated by hyaline‐vascular type Castleman's disease in a schizophrenic patient

Follicular dendritic cell (FDC) sarcoma is an exceedingly rare neoplasm of unknown pathogenesis. A case of FDC sarcoma complicated by the hyaline‐vascular type Cattlemans disease occurring in a schizophrenic male is presented. Swelling of the left cervical lymph node appeared In a 44‐year‐old male schizophrenic who had been reeducated with major tranquilizers for 20 years. He had had a history of cervical lymphadenopathy 14 years before, for which a diagnosis of hyaline‐vascular type Castiemans disease had been made. The present specimen, obtained from the same site, was an enlarged lymph node heavily infiltrated with oval to spindie‐shaped atypical cells but was uninvolved at the periphery. The infiltrating cells showed nodular or sheet‐like growth, occasionally taking fascicular or storiform patterns. Follicular Involvement was also common. Peculiarly, varlous amounts of small lymphocytes were Intermingled with the neopiastic cells. The atypical cells expressed two FDC‐specific antigens, DRC‐1 and K1–M4 antigen, together with a few other markers that are shared by FDC, Including CD21 and HLA‐DR. These findings ciearly show the tumor to be FDC sarcoma. in addition, a peculiar fibro‐hyalinous change in the lymph follicle, which is compatible with hyallne‐vascular type Cattlemans disease, was noted at the periphery of the lymph node where neoplastic cells had not infiltrated. Surprisingly, similar hyaline‐vascular changes were observed in the previous biopsy taken 14 years ago. Meanwhlle, Kaposis sarcoma‐associated herpesvirus, which is often Identified from generalized Castiemans disease, was not identified in the present case by polymerase chain reaction study. Thus, this case is unique in two aspects: (I) the overlap of FDC sarcoma with hyaline‐vascular type follicular changes: and (II) Its Occurrence in a schirzophrenic patient.

Mutational Analysis of the p53 and K-ras Genes and Allelotype Study of the Rb-1 Gene for Investigating the Pathogenesis of Combined Hepatocellular-Cholangiocellular Carcinomas

Because combined hepatocellular‐cholangiocellular carcinoma is rare and its biological features and pathogenesis have not been well established, we investigated alterations of the p53, K‐ras and Rb‐1 genes, as well as expression patterns of carcinoembryonic antigen and keratin, in seven combined hepatocellular‐cholangiocarcinoinas out of 557 hepatocellular carcinomas autopsied at Tokyo University during 30 years. Mutations of the p53 gene were found in two cases, at codon 244 (GGC to TGC) in the cholangiocellular carcinoma component of case 1 (mixed type, showing an intimate intermingling of both elements) and at codon 234 (TAC to AAC) in both components of case 5 (combined type, consisting of contiguous but independent masses of both elements). Mutation of the K‐ras gene (codon 12, GGT to GAT) was seen only in the cholangiocellular carcinoma component of clinically apparent double cancer, case 6. Allelic alteration of the Rb‐1 gene was observed in two cases, deletion of both alleles in the hepatocellular carcinoma component of case 3 (combined type) and replication error of the same pattern in both components of case 4 (mixed type). Immunohistochemical analysis showed that the hepatocellular carcinoma components of five cases (cases 2, 3, 5, 6, 7) were immunoreactive for keratin, suggesting biliary epithelial transformation. In four of the five cases (cases 3 and 5 combined, case 7 mixed and case 6 double cancer), cholangiocellular carcinoma components were also positive for keratin. These results suggest that both components of combined hepatocellular‐cholangio‐carcinoma have the same genetic and phenotypic character and might have arisen from the same origin in some cases.

Prevalence of ischemic enterocolitis in patients with acute pancreatitis

BackgroundA considerable number of acute pancreatitis cases have been reported to be complicated by nonocclusive mesenteric ischemia. However, no reports have ever referred to the incidence of ischemic enterocolitis in patients with acute pancreatitis, using a series of autopsy cases. Here, we report our review of autopsy cases of patients with acute pancreatitis to examine the incidence of associated ischemic enterocolitis.MethodsThe intestinal and pancreatic slides of 48 autopsy cases of patients with acute pancreatitis were reviewed and the incidence of ischemic enterocolitis was determined. Clinical case records were also reviewed.ResultsThirteen (27%) of 48 autopsy cases of patients with acute pancreatitis were complicated by ischemic enterocolitis. The frequency of shock was significantly higher in patients with ischemic enterocolitis than in those without ischemic enterocolitis. The intestinal lesion was diffuse in many cases and gangrene was not an unusual finding.ConclusionsThe incidence of ischemic enterocolitis in patients with acute pancreatitis was much higher than that in the previous reports. Clinicians who treat patients with acute pancreatitis should consider ischemic enterocolitis as one of the frequent and severe complications of this condition.

Detection of ultraviolet photoproducts in mouse skin exposed to natural sunlight.

In the present study, we for the first time investigated the formation of ultraviolet (UV) photoproducts, cyclobutane pyrimidine dimers (CPDs), pyrimidine‐pyrimidone (6–4) photoproducts (64PPs) and Dewar isomers, in vivo in shaved and depilated C3H/HeN mouse skin exposed to natural sunlight (NSL) at noon for 5 min to 1 h in mid‐summer, using a highly sensitive immunohistochemical method. This method permits the quantitative analysis of UV‐photoproducts in formalin‐fixed, paraffin‐embedded sections with specific antibodies against CPDs, 64PPs and Dewar isomers. We demonstrated that the induction of CPDs in vivo in mouse skin by NSL was exposure time‐dependent, but the accumulation of 64PPs or Dewar isomers was comparatively low in the skin sections from mice exposed to NSL in vivo. The results indicate that CPDs are the main photoproducts in vivo induced by sunlight and that their formation and repair may be important in connection with carcinogenesis in sun‐exposed areas of human skin.

Protection against malignant progression of spontaneously developing liver tumors in transgenic mice expressing O6-methylguanine-DNA methyltransferase

To study the effect of O6‐methylguanine‐DNA methyltransferase (MGMT) on carcinogenesis, we have previously generated MGMT transgenic mice overexpressing the bacterial MGMT gene, ada, and demonstrated that high MGMT levels in the liver suppress induction of liver tumors after treatment with an alkylating hepatocarcinogen. To examine the effects of life‐long elevation of MGMT activity on mouse spontaneous liver tumor development, ada‐transgenic and control nontransgenic mice were compared. We also examined mutations at codon 61 of the H‐ras oncogene, reported as a hot spot in mouse liver tumors, using a direct DNA sequencing method. The results revealed no significant difference in tumor incidence or mutation spectrum, but interestingly, ada‐transgenic mice were found to have fewer malignant tumors and survived longer, indicating a possible protective role of MGMT against malignant conversion.

Primary malignant melanoma of the anterior mediastinum: CT and MR findings.

Malignant melanoma presenting in the mediastinum without an extrathoracic primary is extremely rare. To our knowledge, its imaging findings have not been described in the radiologic literature. We report a case of primary malignant melanoma of the anterior mediastinum and discuss its imaging findings on computed tomography and magnetic resonance imaging.

Pathological Study of a Goat That Survived for 532 Days with a Total Artificial Heart Using the 1/R Control Method

A goat survived for 532 days with a pneumatically driven total artificial heart (TAH) that was controlled by the 1/R (reciprocal of peripheral resistance) method. Pathological observations were compared with those of long-surviving goats which had been fitted with TAHs that were operated with fixed driving parameters. The most striking pathological differences were observed in the liver. In the goat under study, congestion of the liver was not as severe as in the past cases in which the central venous pressure (CVP) was high, although fibrosis was prominent around the hepatic veins in many areas of the liver. In both kidneys, severe infarctions were prominent (as in the past cases), but a characteristic of this case was the existence of marked hemosiderosis at proximal tubules; however, this was not prominent in the spleen and liver. This suggested that the hemosiderosis was due to hemolysis in the blood pump rather than due to an increased destruction of erythrocytes in the spleen and liver. The pathological improvements in the liver are believed to have been due to a comparatively low CVP (approximately 5–10 mmHg) which was achieved by the use of the 1/R control method, even though the existence of pathological abnormalities in the kidneys and liver suggested that such long-term driving of the TAH may still cause hemolysis and some damage to the liver. This point requires further investigation.