Induction of cancer, actinic keratosis, and specific p53 mutations by UVB light in human skin maintained in severe combined immunodeficient mice.

To study the mechanism and risk of human skin cancer from solar light, we exposed human skin transplanted to severe combined immunodeficient mice to daily doses of UVB for periods of approximately 2 years. We have succeeded for the first time in inducing cancer and solar (actinic) keratosis in human skin by UVB. Of 18 normal skins exposed to doses of 7.3 x 10(5) to 1.8 x 10(6) J/m2, 14 actinic keratoses (77.8%) and 3 squamous cell carcinomas (16.7%) developed, whereas neither actinic keratosis nor cancer was observed in 15 human skins not exposed to UVB. Each human skin showed a different susceptibility, and skins sensitive for actinic keratosis were also sensitive for cancer induction. Among p53 mutations at various sites, mutation at codon 242 (C TGC --> C CGC; Cys --> Arg) was specifically observed in both skin cancers and actinic keratoses. Furthermore, double or triple mutations were induced in all UVB-induced skin cancers and in three of eight actinic keratoses. Most of the mutations (17 of 20) occurred at dipyrimidine sites.

Differential induction of the androgen receptor transcriptional activity by selective androgen receptor coactivators.

Several new androgen receptor (AR) cofactors, associated to the ligand binding domain of AR, have been identified by our group and named AR associated protein (ARA)70, ARA55, and ARA54. Our previous reports have suggested that the cofactor ARA70 can confer the androgenic effect from 17 beta-estradiol (E2) and antiandrogen to AR. It is of interest for us to compare and determine if the specificity of sex hormones and antiandrogens could be modulated by different coactivators. Our results indicate that ARA70 is the best coactivator to confer the androgenic activity on E2. Only ARA70 and ARA55 could increase significantly the androgenic activity of hydroxyflutamide, a widely used antiandrogen for the treatment of prostate cancer. Furthermore, as compared to the relative specificity of these coactivators to AR in the prostate cancer DU145 cells, our results suggest that ARA70 has a relatively higher specificity. Together, our data suggest that the specificity of sex hormones and antiandrogens can be modulated by some selective AR coactivators. These findings may not only help us to better understand the specificity of the sex hormones and antiandrogens, but also to facilitate the development of better antiandrogens or androgens to fight the androgen-related diseases, such as prostate cancer.

Retroperitoneal schwannoma.

A case of retroperitoneal benign schwannoma is presented; in addition, 133 cases of retroperitoneal schwannoma reported in Japanese literature are studied. In our series 66 per cent of the cases were found to be cystic. Therefore, the cystic change may be one of the preoperative features of schwannomas, because other types of retroperitoneal tumor do not frequently form cysts. Furthermore, the necessity of postoperative electron microscopy for accurate histologic diagnosis is discussed.

Assignment of six patients with xeroderma pigmentosum in Hokkaido area to a variant form.

Six Japanese patients in Hokkaido area were diagnosed as xeroderma pigmentosum (XP) at two University Hospital; one patient, a 29 years old female (XP2AS) at Asahikawa Medical College, and five patients, namely, a 53 years old male (XP1SA), a 45 years old female (XP2SA), a 46 years old female (XP3SA), a 47 years old male (XP4SA) and a 34 years old male (XP5SA) at Hokkaido University School of Medicine. All these XP patients showed mild skin symptoms and had no apparent neurological abnormalities. To identify genetic complementation groups of these patients, DNA repair capacities in skin fibroblasts derived from the patients were analyzed by ultraviolet light (UV)-induced unscheduled DNA synthesis (UDS), and also by colony-forming abilities of UV-irradiated cells incubated with or without caffeine added in post-UV culture medium. The levels of UDS measured by autoradiography in these XP cells irradiated with 20 J/m2 of UV were 67 to 84% of those of normal human fibroblasts. Although one XP cell strain (XP2AS) showed about 2-fold greater sensitivity to killing by UV than normal cells, UV sensitivities of the rest of 5 XP strains were similar or only slightly higher than those of normal cells. However, UV sensitivities of all the 6 XP cell strains markedly increased by addition of 1 mM caffeine in the post-UV incubation medium, a phenomenon characteristic of XP variant cells. We also analyzed post-replication repair in XP1SA cells by sedimentation of newly-synthesized DNA in alkaline sucrose gradient, and found that this strain is defective in this repair system. From these results, we concluded that all the 6 XP strains studied here belong to XP variants.

SCID (severe combined immunodeficiency) mice as a new system to investigate metastasis of human tumors.

In severe combined immunodeficiency (scid) mice which are deficient in T and B cell functions, human yolk sac tumor (YST-2) grew rapidly to enormous sizes in all of the animals after both subcutaneous and intraperitoneal transplantation, while only half of the subcutaneous and none of the intraperitoneal transplants were accepted in usual athymic nude mice. Furthermore, transplanted tumors metastasized spontaneously to distant organs such as lung, liver, kidney, pancreas, and spleen in scid mice, while metastases were not found in athymic nude mice. Similar results were observed in scid mice and scid-nude (streaker) double mutant mice with human classic (typical) seminoma which has been neither transplantable nor metastatic in athymic nude mice. Thus, scid mice provide an invaluable experimental system to investigate the mechanism of metastasis which is the most important and life-threatening problem in cancer patients.

Urinary nitrite in Japanese patients with urinary tract infections.

Urinary nitrite, a precursor of carcinogenic nitrosamines, and nitrate were measured in 73 Japanese patients with urinary tract infections (UTI) and in two control groups. Nitrite was detected in 12% of patients with uncomplicated UTI (226 +/- 161 mumol/l) and in 42% of those with complicated UTI (375 +/- 297 mumol/l). None of the subjects in the control groups excreted detectable amounts of nitrite. The excretion of nitrite in four out of five nitrite excretors continued for at least 14-55 days. The concentrations of urinary nitrite were significantly correlated with those of nitrate- plus nitrite-nitrogen, which reflect dietary nitrate ingestion. The results suggest the importance of close monitoring of nitrite excretor group in UTI patients, to clarify the mechanism of the association between UTI and bladder cancer.

[A case of small simple renal cyst associated with renal cell carcinoma].

A 61-year-old male was admitted to our clinic for the purpose of further examination of the small renal mass discovered incidentally by ultrasonography. Subtraction angiography disclosed a small renal cell carcinoma of the upper-lateral margin of the left kidney dramatically. Enucleating surgery of the tumor was performed successfully (about 2 cm in diameter). Histological examination revealed a small simple renal cyst associated with renal cell carcinoma. The patient is well without evident metastasis 1 year postoperatively. Since this is a very rare case in the literature, we report this case and discuss the preoperative diagnosis of small renal cell carcinoma. We believe that ultrasonography is a simple and very useful method for mass screening of small urological malignancies.

[Lymphangioma of the penis: a case report].

We report a case of lymphangioma of the penis. A 45-year-old man presented with a painless mass on the dorsal penis. A soft and movable mass was excised under local anesthesia. Pathological findings demonstrated vast amounts of fluid, which did not involve any blood cells and confirmed it to be cavernous lymphangioma. After 2 years postoperatively, no evidence of recurrence was present. We review 22 reports of penile lymphangioma in Japan.

Bilateral primary non-Hodgkin's lymphoma of the adrenal glands with adrenal insufficiency: a case report.

A 72-year-old woman with bilateral non-Hodgkin's lymphoma of the adrenal glands causing adrenal insufficiency is reported. The left-side lymphoma (diffuse large B-cell lymphoma) was removed surgically but the right-side lymphoma could not be removed. Complete response was obtained with subsequent combined chemotherapy and was maintained for 6 months with repeated chemotherapies. However, the patient died of liver recurrence 1 year after admission. In cases of malignant lymphoma forming a bulky mass, surgery with subsequent chemotherapy appears to reduce the cancer volume and improve the therapeutic outcome.

[Prostatic malacoplakia: a case report].

We report a case of prostatic malacoplakia in a 68-year-old man complaining of fever, residual urinary sensation and small urinary stream. Culture of the urine showed E. coli and Enterococcus faecalis. Digital examination and transrectal ultrasound of the prostate were most compatible with carcinoma. However, transrectal needle biopsy revealed the histopathological features of malacoplakia. The patient had been treated with trimethoprim-sulfamethoxazole, bethanechol and ascorbic acid for 5 months. Twenty-seven cases of prostatic malacoplakia in the Japanese literature are reviewed.

[A case of invasive squamous carcinoma of the urinary bladder perforated intraperitoneally after intra-arterial chemotherapy].

We report a case of invasive squamous cell carcinoma of the urinary bladder, which was perforated intraperitoneally after intra-arterial chemotherapy. The patient was a 67-year-old woman complaining of macrohematuria and body weight loss. After thorough examination, the diagnosis of clinical stage C of squamous cell carcinoma of urinary bladder was made. At first, balloon occluded intra-arterial infusion with 80 mg, cis-dichlorodiamine platinum 10 mg mitomycin C and 1 mg vincristine was performed, followed by radiotherapy and 15 mg bleomycin injection. On the 5th day, the patient fell into shock with abdominal expansion, and bladder perforation into peritoneal cavity was confirmed by rapid cystography. Emergency cystohysterectomy and drainage were performed. Resected bladder had a large defect on its posterior wall, and tumor had fallen into severe necrosis. Since January, 1986 we performed balloon occluded intra-arterial infusion of antineoplastic drugs for 3 other cases. We obtained a partial response for 2 of these cases. The outcome of intra-arterial chemotherapy in our hospital is also reported.

[Bellini duct carcinoma treated with partial nephrectomy: a case report].

We report a rare case of collecting duct carcinoma of the kidney (Bellini's duct carcinoma). A 37-year-old woman visited our hospital with a chief complaint of asymptomatic hematuria. We suspected right renal pelvic tumor from the detection of round filling defects in the upper calyces of the right kidney by image diagnoses. A ureteroscopic biopsy revealed a low grade renal cell carcinoma. Therefore, she received right partial nephrectomy immediately. Histological examination of the surgical specimen showed a highly differentiated adenocarcinoma with papillary proliferation besides the collecting duct epithelium. With the results of the strongly positive patterns of immunohistochemical staining with high molecular cytokeratin and peanut aggulutinin, the tumor corresponded to the distal nephrons. Therefore we made the diagnosis of Bellini's duct carcinoma. She had been alive without evidence of metastases for one year after surgery.

[Leiomyosarcoma of the prostate accompanied by multiple hepatocellular carcinoma: report of a case].

A case of leiomyosarcoma of the prostate accompanied by multiple hepatocellular carcinoma in a 51-year-old man is presented. He visited our hospital with the complaints of feeling of residual urine and pain of the coccygeal bone in November, 1990. A histopathological study of the transrectal needle biopsy specimens revealed leiomyosarcoma of the prostate. Since multiple liver tumors were pointed out, the patient was given combined chemotherapy (CYVADIC: cyclophosphamide, vincristine, adriamycin and DTIC). He died 1 year and 2 months after the initial diagnosis due to hepatic failure. The autopsy findings revealed that the histology of the liver tumors was hepatocellular carcinoma, and that the leiomyosarcoma of the prostate had directly invaded the wall of the urinary bladder and the rectum, but there was no obvious distant metastasis.

[Growth fractions of bladder cancer determined by proliferating cell nuclear antigen immunostaining].

Immunohistochemical staining of proliferating cell nuclear antigen (PCNA) can be performed on conventionally fixed and processed tissue. We applied anti-PCNA monoclonal antibodies to transurethrally resected bladder cancer specimens. The labelling index (LI) of PCNA increased with tumor grade and that of the invasive tumor group was higher than that of the non-invasive tumor group. Especially in large tumors, there was intratumoral variation of labelled cell distribution, which may represent tumor heterogeneity. These findings suggest that PCNA might be a useful marker for bladder cancer proliferation.

[Primary squamous cell carcinoma of the ureter: report of a case].

A case of squamous cell carcinoma of the ureter in a 63-year-old female is reported. Right hydronephrosis was found by examination of duodenal ulcer. Ureteroscopy and biopsy revealed squamous cell carcinoma (SCC) of the lower ureter. Total nephroureterectomy with a bladder cuff was performed. Pathological diagnosis was SCC pT3 G2 INF beta pL1 pV0 pR0. Three cycles of chemotherapy were performed postoperatively with bleomycin, methotrexate and cisplatin. Fifty-three cases of primary ureteral squamous cell carcinoma from the Japanese literature are reviewed and characteristic clinical figures of the tumor are discussed.

[A case of verrucous carcinoma of the penis with detection of human papillomavirus using the in situ hybridization method].

A case of penile verrucous carcinoma is reported. The patient had a previous history of condyloma acuminatum of the penis. No signs of squamous cell carcinomas were observed in the histopathological findings. We also detected the histologic evidence of human papilloma virus (HPV) infection in the result of the study by in situ hybridization. The local positive reaction of HPV infection for type 6/11 was seen, and was related to the koliocytosis. However other types of HPV (16/18, 31/33, 51) were negative.

[Renal oncocytoma associated with tuberous sclerosis: report of a case].

A case of a renal oncocytoma associated with tuberous sclerosis in a 31-year-old woman is reported. She displayed many characteristic skin features of tuberous sclerosis but no central nervous symptoms. Although she complained of dysmenorrhea and hypermenorrhea, she had no complaints related to the kidney. A left renal tumor was discovered incidentally during preoperative examination for gynecologic disease and left nephrectomy was performed. Histologically, the tumor was shown to be a typical renal oncocytoma. This is supposed to be the first case of renal oncocytoma associated with tuberous sclerosis in Japan.

[Retroperitoneal giant malignant fibrous histiocytoma: report of a case].

A case of histiocytoma in a 63-year-old woman with general fatigue is described. Ultrasonography and radiological examination revealed a large mass at the retroperitoneum displacing the right kidney to medial anterior abdomen. Exploration of the tumor with right kidney was done via a transperitoneal approach because the tumor had invaded the hilar fat tissue of the right kidney. The total resected weight was 3,200 g. Histological study showed malignant fibrous histiocytoma, storiform-pleomorphic type. Post-operative chemotherapy consisting of cyclophosphamide, vincristine, adriamycin, dimethyl triazeno-imidazole carboxamide (CYVADIC) was performed and the patient is doing well without any evidence of recurrence or metastasis.

[HLA antigens in patients with testicular germ cell tumors].

The role of HLA antigens in the etiology of testicular germ cell tumor has been suggested previously. Several attempts have been made to establish associations of HLA antigens in patients with testicular cancers, but have yielded inconsistent results. We studied the frequencies of HLA antigens by serological typing and DNA typing and examined the association between testicular germ cell tumors and HLA antigens. The serological expression of HLA-A, -B, -C, -DR and -DQ antigens was analyzed in 23 patients with germ cell cancers of the testis. The findings indicated a trend towards an increase in the antigen DQ4 (p < 0.05). The 13 patients were typed for HLA DRB1 and DQB1 allele by PCR-RFLP analysis. The findings revealed an increased frequency of DRB1 0405 (p < 0.01) and DQB1 0401 (p < 0.01).

[Immunological study of the postoperative adjuvant treatment with interferon gamma in patients with renal cell cancer--measurement of peripheral blood lymphocyte subsets with three color flow cytometry].

The antitumoral effects of interferon (IFN) against renal cell carcinomas (RCC) are considered to consist of a direct tumoricidal activity and an indirect action related to the host immune system. Monitoring to T lymphocytes is an immunological parameter to evaluate the antitumoral effects of IFN. To examine in detail the change of CD8 positive cells reported previously, we analyzed the change of the peripheral blood T lymphocyte subsets using three color flowcytometry during the period of IFN-gamma administration. We administered recombinant interferon gamma (rIFN-gamma) to the patients with renal cell cancer. Eighteen patients received a prophylactic injection of rIFN-gamma (300 x 10(4) units per week) after nephrectomy. Among them three patients developed distant metastases and one had local recurrence after the start of rIF-gamma therapy. We evaluated the immunological change by measurement of the peripheral blood lymphocyte subsets consisting of activated cytotoxic T lymphocytes (ACTL), activated suppressor T lymphocytes (ASTL), activated suppressor-inducer T lymphocytes (AITL), cytotoxic T lymphocytes (CTL), helper T lymphocytes (HTL), and suppressor-inducer T lymphocytes (SITL), from the start of rIFN-gamma injection. We also estimated the natural killer (NK) activity by a cytolytic test at the same points. NK activity consecutively increased throughout the period of administration of rIFN-gamma. We found significant enhancement of ACTL at the sixth month (P < 0.05), ASTL at the third month (P < 0.01) and NK activity at the second week, the first month, the third month and the sixth month (P < 0.01) after the start of rIFN-gamma injection.(ABSTRACT TRUNCATED AT 250 WORDS)