Nobuo Satake

Biallelic mutations of the Tsc2 gene in chemically induced rat renal cell carcinoma

A number of cancer genes have been identified by the study of hereditary human cancers and shown to be involved in sporadic genesis of the same tumors. We have identified a germline mutation in the rat homologue of the human tuberous sclerosis (TSC2) predisposing gene in the Eker rat model. In this study, we searched for mutations of the Tsc2 gene in chemically induced non‐Eker rat renal cell carcinomas (RCs). N‐ethyl‐N‐hydroxyethylnitrosamine (EHEN)‐ and diethylnitrosamine (DEN)‐induced non‐Eker rat primary RCs were subjected to polymerase chain reaction‐single strand conformational polymorphism (PCR‐SSCP) analysis using specific primers covering all exons of the Tsc2 gene (41 coding exons and 1 non‐coding exon). We simultaneously searched for mutations in the Vhl gene, a rat homologue of von Hippel‐Lindau disease (VHL) gene, as well as the Tsc2 gene. Mutations in the Vhl gene were not detected in any rat RCs (0/8). In contrast, Tsc2 gene mutations were detected at a high frequency in EHEN‐induced RCs (2/3) and DEN‐induced RCs (3/5) (total 5/8) (p < 0.05). By a direct cloning approach utilizing PCR analysis in 2 applicable cases, we could demonstrate the presence of intragenic somatic mutations in both alleles of the Tsc2 gene. Our results suggest that Tsc2 gene inactivation plays an important role in EHEN‐ and DEN‐induced RCs as well as in Eker rat RCs. Int. J. Cancer 77:895–900, 1998.© 1998 Wiley‐Liss, Inc.

Complicated paraneoplastic neurological syndromes: a report of two patients with small cell or non-small cell lung cancer

Paraneoplastic neurological syndromes are frequently associated in patients with small cell lung cancer (SCLC) and antineuronal antibodies are involved in the autoimmune mechanism. Multiple syndromes are sometimes complicated in a single patient with SCLC. However, little is known about non-SCLC-associated neurological manifestations. We report two patients with complicated paraneoplastic neurological syndromes. Patient 1 showed paraneoplastic limbic encephalitis (PLE), paraneoplastic sensory neuropathy (PSN) and Lambert-Eaton myasthenic syndrome (LEMS) associated with SCLC. Patient 2 developed opsoclonus-ataxia and probable PLE associated with non-SCLC. Analysis of various antineuronal antibodies revealed that anti-Hu and P/Q-type voltage-gated calcium channel (VGCC) antibodies were positive in Patient 1 but any antibodies were not in Patient 2. Brain MRI demonstrated high intensity signals in temporal lobes particularly on fluid-attenuated inversion recovery (FLAIR) or diffusion-weighted images. These findings suggest that complicated paraneoplastic neurological syndromes occur in non-SCLC as well as SCLC and that unidentified antineuronal autoantibodies may underlie the pathophysiology.

Role of Copper Accumulation in Spontaneous Renal Carcinogenesis in Long-Evans Cinnamon Rats

Spontaneous renal cell tumors in totals of 223 male and female Long‐Evans Cinnamon (LEC) rats of 51–120 weeks old, 157 male F344 rats of 51–120 weeks old, and 14 male Long‐Evans Agouti (LEA) rats of 51–70 weeks old were examined histologically. The incidences of renal cell tumors increased with age in male and female LEC rats, but no tumors developed in F344 or LEA rats. Dilated atypical tubules of the kidneys were observed at high incidence in aged LEC rats. Copper staining of LEC rat kidneys showed a positive reaction in proximal tubules of the cortex and the outer stripe of the medulla. The renal copper concentration of LEC rats reached a peak in the period of necrotizing hepatitis with renal tubular necrosis, and was higher than that in F344 rats for up to 106 weeks. In contrast, the renal iron concentration of LEC rats was lower than that in F344 rats except in the period of necrotizing hepatitis. Long‐term treatment of LEC rats with d‐penicillamine, a copper‐chelating agent, inhibited accumulation of copper, but not iron, in the kidneys, and inhibited the development of karyomegaly of proximal tubules and dilated atypical tubules. These results suggest that persistent copper accumulation after toxic necrosis of tubules is the major cause of spontaneous renal carcinogenesis in LEC rats.

So-called mesothelial/monocytic incidental cardiac excrescences obtained during valve replacement surgery: report of three cases and literature review.

Abstract We present three cases of so-called mesothelial/monocytic incidental cardiac excrescences (MICE) of the heart and a brief review of related literature. Case 1 was a 51-year-old woman who underwent mitral- and aortic-valve replacement. A tissue sample was submitted as a thrombus attached to the left atrial endocardium. Case 2 was a 69-year-old woman who underwent mitral-valve replacement. The sample was incidentally obtained as whitish clot-like fragments, but its exact origin was not known. Case 3 was a 68-year-old woman who underwent mitral-valve replacement for suspected infective endocarditis. The sample adherent to the pericardium was removed after valvular surgery. Histologically, these lesions were composed of a mixture of plump histiocytoid cells, a papillary arrangement of cuboidal cells, various sized vacuoles, and fibrin. The nests of cuboidal cells resembled cancer cells but showed features of mesothelial cells and no proliferative activity, immunohistochemically or ultrastructurally. In all cases, a suction tube placed in the left atrium was occasionally used to remove overflowing intrapericardial fluid during the surgery. The tip of the suction tube was covered with spiral wire, which is likely to transfer the stripped pericardial mesothelial cells to the left atrium. The significance of MICE is their possibility of being misdiagnosed as metastatic carcinoma by pathologists and a risk of arterial embolization by mesothelial debris clinically.

Gastric cancer with choriocarcinoma and yolk sac tumor components: Case report

Choriocarcinoma‐ and yolk sac tumor‐like differentiation have rarely been reported in gastric cancers. We report a case of gastric adenocarcinoma, concurrently possessing choriocarcinoma and yolk sac tumor components, of a 74‐year‐old man. A hemorrhagic, 11 × 8 × 3 cm, tumor with ulceration was located in the body and pre‐pylorus of the stomach. Histological examination of the resected specimens demonstrated intermingled proliferation of three different components, namely, adenocarcinoma, choriocarcinoma and yolk sac tumor, which were immunoreactive for carcinoembryonic antigen (CEA), beta‐subunit of human chorionic gonadotropin (HCG) and alpha‐fetoprotein (AFP), respectively. Gastric cancers with germ cell tumor components are uncommon and this is the second reported case of gastric cancer with choriocarcinoma and yolk sac tumor components.

The role of mast cells in acute tubulo-interstitial nephritis with uveitis

We describe the clinicopathological characteristics of two patients with acute tubulo-interstitial nephritis with uveitis (TINU) with mast cells infiltrating the interstitium. The pathogenesis of TINU remains unknown, but a T-cell-mediated immune response was suggested to be involved. Recent studies have shown that infiltrating mast cells are closely associated with the development of renal interstitial fibrosis in glomerulonephritis. To address the role of mast cells in the renal interstitial injury in TINU, immunohistochemical studies were performed in renal biopsy sections using anti-human mast cell tryptase antibody specific for mast cells. In addition, we tried to detect CD68-positive macrophages to compare with the localisation of mast cells within the renal interstitium. Mast cells and macrophages could be detected in renal interstitial lesions of both patients. Massive infiltration of macrophages into interstitial lesions was observed, whereas mast cells were detected in a sporadic rather than a clustered manner, and associated with fibrotic lesions. Repeat renal biopsy findings suggested the involvement of these cells in the renal interstitial injury because the number of infiltrating mast cells and macrophages in the interstitium decreased with the improvements in clinical symptoms and pathological lesions. Conclusion:the present study showed that mast cells might play an important role in the development of renal interstitial injury in tubulo-interstitial nephritis with uveitis.

Lethal encephalopathy in a patient with isolated nervous system vasculitis

Vasculitic neuropathy can occur in patients with connective tissue diseases. On the other hand, non-systemic vasculitic neuropathy has been established as an independent clinical entity, and the risks for systemic spread and death are small.1 In patients with this disorder, vasculitis is limited to the peripheral nervous system (PNS), and histological evaluation is essential for the definitive diagnosis. We encountered a patient with isolated nervous system vasculitis who developed lethal encephalopathy. He had a persistently high titre of anti-GM1 IgG antibody, which is occasionally detected in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). A 67 year old man had been under treatment for type 2 diabetes for 10 years. In September 1998, he was referred to our hospital because of weight loss and numbness of the lower limbs. He was mentally alert and had exophthalmos. Muscle weakness was prominent in the distal muscles of all four limbs. Sensation was disturbed with a “stocking and glove” distribution. Deep tendon reflexes were diminished in all four extremities. Results of laboratory examination indicated diabetes mellitus and hyperthyroidism (haemoglobin A1c 6.8% (normal range 4.3–5.8); thyroid stimulating hormone <0.03 μIU/ml (normal range 0.2–3.2); free triiodothyronine 13.2 pg/ml (normal range 2.9–6.0); free thyroxine 7.65 ng/dl (normal range 0.78–2.10); antithyroglobulin antibody 3200 (normal <100); antithyroid microsomal antibody 26 800 (normal <100); antithyrotropin receptor antibody 16.1% (normal <10); thyroid stimulating antibody 207% (normal <150)). Serological examination for antiganglioside antibodies revealed anti-GM1 IgG, and the titre was 25 900 (normal <800) by enzyme linked immunosorbent assay. No other …

N-Ethyl-N-hydroxyethylnitrosamine (EHEN)-induced renal and hepatocarcinogenesis in the tumor suppressor Tsc2 transgenic rat

Hereditary renal carcinomas (RCs) develop in Tsc2 gene mutant (Eker) rats around the age of 1 year. We previously reported that Tsc2 mutations were detected in chemically (N-ethyl-N-hydroxyethylnitrosamine (EHEN) and diethylnitrosamine)-induced non-Eker rat RCs, suggesting an involvement of Tsc2 alteration in rat RC development. In this study, we evaluated the effect of extra copies of the Tsc2 gene on renal and hepatocarcinogenesis that was induced by EHEN in vivo. The incidence of RCs in non-transgenic rats (2/17) is slightly higher than in transgenic rats (0/32), although it is statistically not significant. These results suggest the presence of other target RC gene(s) in chemically (EHEN)-induced renal carcinogenesis. We observed no difference in the numbers and areas of the hepatic glutathione S-transferase placental type positive foci.