市川 智彦

A case of Sertoli cell tumor of the testicle is reported. A 33-year-old man visited the Chiba University Hospital with the chief complaint of a painless right testicular swelling on May 1990. The right testis was hard and swollen on palpation. Gynecomastia was not present. Serum levels of tumor markers and hormones including alphafetoprotein, human chorionic gonadotropin-beta, carcinoembryonic antigen, testosterone, prolactin, estradiol, luteinizing hormone, and follicle stimulating hormone were within normal limits. Ultrasonic examination showed a high echoic lesion in the right testis. Computerized tomography and magnetic resonance imaging showed no evidence of retroperitoneal lymph node enlargement. A high right orchiectomy was performed under a diagnosis of right testicular tumor. The right testis was elastic hard and measured 9 x 10 x 7 cm, weighing 450 g. The cut surface was light yellowish white and was completely displaced by the tumor. No normal tissue was seen. Histological examination showed a Sertoli cell tumor. No adjuvant therapy was performed. Neither recurrence nor evidence of metastasis has been detected for 8 years postoperatively.

Frequent allelic losses on chromosome arm 13q are observed in carcinomas of the head and neck, breast, ovary, and pituitary gland. We analyzed 59 primary prostate tumors (stage B, 18 patients; C, 12 patients; D1, 4 patients; and endocrine therapy-resistant cancer death, 25 patients), as well as 18 metastatic tissues from 14 of the 25 cancer death patients for loss of heterozygosity (LOH) using 35 microsatellite markers on chromosome arm 13q. Of the 59 primary tumors, 31 (53%) showed LOX involving at least one locus. Detailed deletion mapping identified a distinct commonly deleted region in the 1-cM interval flanked by D13S153 and D13S273 on 13q14 and this region overlapped a part of the RB1 gene. Paired DNAs were available from both primary and metastatic tumors in the 14 cases of cancer death; among those pairs, we detected LOH on 13q in seven (50%) primary tumors, and in all metastatic foci (P = 0.0029). Moreover, the regions lost in metastatic tissues were more extensive than those seen in the corresponding primary tumors. These results suggest that inactivation of a putative tumor suppressor gene(s) including the RB1 gene on 13q14 plays an important role in human prostate cancer. Genes Chromosomes Cancer 24: 183-190, 1999. (C) 1999 Wiley-Liss, Inc.

Allelotype analyses of human prostate cancer indicate that allelic losses on human chromosome arms 7q, 8p, 10q, 13q, 16q, 17q, and 18q are observed frequently. For the study of the possible biological significance of the frequently observed deletions on chromosome arm 7q in human prostate cancer, human chromosome 7 was introduced into highly metastatic rat prostate cancer cells by use of a microcell-mediated chromosome transfer technique. The introduction of human chromosome 7 resulted in the suppression of metastatic ability of the microcell hybrids, whereas no suppression of tumorigenicity was observed. To identify the portion of chromosome 7 containing the metastasis-suppressive function gene, the derivative chromosome 7 that was generated with the initial transfer was retransferred into rat prostate cancer cells. Human chromosome 7-containing rat prostate cancer cells could be used as the donor cells, because rodent cells produced a sufficient number of microcells with colchicine treatment. Cytogenetic and molecular analyses of these clones demonstrated that loss of segments on 7q was related to the reexpression of the metastatic phenotype. These results show that human 7q contains a metastasis suppressor gene or genes for rat prostate cancer. The findings also suggest that this gene may play an important role in the progression of human prostate cancer. Genes Chromosomes Cancer 24:1-8, 1999. (C) 1999 Wiley-Liss, Inc.

There is a critical need for markers that can be used to predict accurately the malignant potential of histological prostate cancers (J. T. Isaacs, Am. J, Pathol,, 150: 1511-1521, 1997), Metastasis-suppressor genes are attractive candidates for marker development because, by definition, their loss should be associated with the acquisition of metastatic ability, In an effort to identify such genes, a single copy of human chromosome 12, tagged with the neomycin resistance gene, was introduced into highly metastatic Dunning AT6.1 prostate cancer cells by microcell-mediated chromosomal transfer. Thirty-two AT6.1-12 clonal cell lines were established and the region(s) of chromosome 12 retained was determined by sequence tagged site-based PCR analysis. Representative AT6.1-12 clones containing overlapping regions of chromosome 12 were characterized cytogenetically and were shown to have a normal complement of parental AT6.1 rat chromosomes. Fluorescence iis situ hybridization, performed on representative AT6.1-12 hybrids, demonstrated a single human chromosome 12-specific signal. The metastatic ability of six representative clones was tested in immunodeficient mice. All of the AT6.1-12 clones showed the same in vivo growth rates as the control AT6.1-neo cells. Clonal cell lines that contained a conserved similar to 70-cM portion of chromosome 12 (e.g., AT6.1-12-8, -8-1, and -8-3), showed a >30-fold suppression in the number of macroscopic surface lung metastases, Mice that received injections of these cells developed a mean number 4 lung metastases whereas mice that received injections of other AT6.1-12 hybrids (lacking the similar to 70-cM region) or AT6.1-neo control cells, developed a mean number of 140 metastases, Interestingly, histological examination of the lungs of the mice that received injections of AT6.1-12-8 cells showed essentially no microscopic metastases, These findings suggest that a gene(s) encoded by the similar to 70-cM portion of human chromosome 12 suppresses an early step in the metastatic cascade.

BACKGROUND. We recently isolated the KAI1 gene, a metastasis suppressor gene for prostate cancer, from human chromosome region 11p13-cen-containing rat prostate cancer cells. The present study was performed to further locate the region of the KAI1 gene on the short arm of chromosome 11, and to examine whether loss of this region is significant during progression of human prostate cancer. METHODS. The small portion of human chromosome 11 (i.e., 11p13-cen) was reintroduced into highly metastatic rat prostate cancer cells by using microcell-mediated chromosome transfer. Loss of heterozygosity (LOH) at polymorphic microsatellite loci on the human chromosome 11 was examined in human prostate cancer tissues. RESULTS. The minimum region of human chromosome 11 that contained the KAI1 gene was located on the proximal region of 11p11.2 divided by the D11S554 locus. The percentage of LOH or allelic imbalance at the D11S1344 locus, which is located on the same region as the KAI1 locus, in metastasis tissues from autopsy cases who died from metastatic prostate cancer was 70% (7 of 10 informative cases), whereas the percentages in primary tumors from the same cases and from cases with clinically localized prostate cancer were 33% (3 of 9 informative cases) and 8% (1 of 12 informative cases), respectively. CONCLUSIONS. These findings demonstrate a high frequency of LOH or allelic imbalance at the centromeric region of 11p, which contains the KAI1 gene in advanced prostate cancer. (C) 1997 Wiley-Liss, Inc.

BACKGROUND. Introduction of human chromosome 8 to a highly metastatic subline (AT6.2) from the Dunning R-3327 rat prostate cancer resulted in suppression of metastatic ability of the resultant microcell hybrids (AT6.2-8 clones) [12]. The present study has been performed to clarify which step of metastasis was suppressed in the microcell hybrids. METHODS. Northern blot analysis of E-cadherin and alpha-catenin, in vitro invasion assay, and intra-venous metastasis assay by injection of tumor cells into the lateral tail vein of nude mice were performed. RESULTS. No detectable expressions of either E-cadherin or alpha-catenin were found in either AT6.2 parental or AT6.2-8 microcell hybrid clones. In the invasion assay, invasiveness of AT6.2-8 hybrid clones was less than that of the AT6.2 parental clone. In the intravenous metastasis assay, no significant differences in the number of lung metastases were observed among these cell lines. CONCLUSIONS. Introduction of human chromosome 8 to AT6.2 cells shows suppression of invasiveness and no suppression of cell dissociation or process after entry into blood circulation. This suggests that human chromosome 8 contains suppressor gene(s) for the invasive ability of prostate cancer. (C) 1997 Wiley-Liss, Inc.

Our previous studies demonstrated that human chromosome 8 contains metastasis suppressor gene(s) for rat prostate cancer, However, it is still unknown which portion of human chromosome 8 is associated with suppression of metastatic ability, because all of the clones in which metastatic ability is suppressed contain at least one copy of intact human chromosome 8, In the present study, we used the irradiated microcell-mediated chromosome transfer technique to enrich for specific chromosomal arm deletions of selected chromosomes. The resultant series of human chromosomes 8 with a variety of chromosomal deletions was introduced into highly metastatic Dunning rat prostate cancer cells, All of the resultant microcell hybrids showed reduced metastatic ability. To obtain a smaller size of human chromosome 8 and to locate further the region of metastasis suppressor gene(s), the most reduced size of human chromosome 8 that was generated with the initial irradiated chromosome transfer was retransferred into the Dunning cancer cells without irradiation. The resultant microcell hybrids were analyzed to determine which portion of human chromosome 8 suppressed the metastatic ability of the recipient cells, This analysis demonstrates that the portion of human chromosome 8 containing metastasis suppressor gene(s) for rat prostate cancer cells lies on human chromosome segment 8p21-p12, where frequent allelic losses have been detected in allelotype analyses of human prostate cancer. This suggests that one of the metastasis suppressor genes for rat prostate cancer on human chromosome 8 may also play an important role in the progression of human prostate cancer. (C) 1996 Wiley-Liss, Inc.

The KAI1 gene, recently identified as a metastatic suppressor gene for prostate cancer, was cloned and tuns revealed to be identical to the C33/IA4/R2/4R9 gene, The expression of KAI1 protein was examined immunohistochemically in the tissues from 14 cases of benign prostatic hyperplasia and 46 cases of prostate cancer using mouse monoclonal anti-human C33 antibody. In benign prostatic hypertensin tissues, KAI1 protein was uniformly expressed in the glandular cell membrane at cell-to-cell borders, The KAI1 protein in the tissues of untreated prostate cancer teas also located at similar sites to those of benign prostatic hyperplasia, but the percentage of strongly, positive cancer cells was correlated inversely to the Gleason pattern (P < 0.0001, one-way analysis of variance). There was also a statistically inverse correlation between the percentage of KAI1-positive cancer cells and the clinical stage (chi(2) = 9.6; P = 0.0081). In 4 cancer death cases relapsed from endocrine therapy, KAI1 protein was not stained in either primary or metastatic foci. These results indicate that the expression of KAI1 protein correlates to tumor characteristics in prostate cancer.

To examine the role of human chromosomes in the development of metastatic prostate cancer, we introduced a copy of human chromosomes into highly metastatic Dunning R-3327 rat prostatic cancer cells by microcell-mediated chromosome transfer. Each microcell hybrid clones containing human chromosomes 8, 10, 11, and 17, respectively, showed decreased ability to metastasize to the lung, without any loss of tumorigenicity. This finding demonstrates that these human chromosomes contain metastasis suppressor genes for prostate cancer. Spontaneous deletion of portions of human chromosomes was observed in human chromosome 10, 11, and 17 studies. In the human chromosome 8 study, irradiated microcell-mediated chromosome transfer was performed to enrich chromosomal arm deletions of human chromosome 8. Relationships between the size of human chromosomes introduced into microcell hybrid clones and the number of lung metastases produced by the clones were analyzed to determine which part of human chromosomes contained metastasis suppressor gene(s) for prostate cancer. Molecular and cytogenetic analyses of microcell hybrid clones demonstrated that metastasis suppressor genes on human chromosomes 8, 10, and 11 were located on 8p23-q12, 10q, 11p13-11.2, respectively. Further analyses are proposed to confirm the potentially useful advantage of this assay system to identify metastasis suppressor gene(s) for prostate cancer. (C) 1996 Wiley-Liss, Inc.

1)測定検出感度は,0.2ng/mlであった。2) 46歳以上の男子成人の平均値+2SDは1.41ng/mlであったので,男子成人の正常上限値は1.5ng/mlとした。3)前立腺癌および前立腺肥大症より,診断効率,ROC曲線をえて,両者の鑑別が最も良好な2.5ng/mlを本キットのcut offとした。この結果,男子成人,前立腺癌,前立腺肥大症および前立腺癌以外の泌尿器科癌での異常値出現率は,それぞれ0.7%,65%,20%および10%であった。4)前立腺癌の病期別の検出率は,病期A2, B2, C, D1+D2それぞれ0%,0%,64%および83%であった。5)マーキットMPAキット(R)によるPSAと本PAPにて,前立腺癌および前立腺肥大症を測定した。Delfia PAPキット(R)およびマーキットMPAキット(R)の診断効率は前者が52%,後者が71%と,後者が約20%高かった。正診率でも,前者が69%,後者が84%と,後者が優れていたFundamental and clinical studies of serum prostatic acid phosphatase (PAP) detected by a Delfia PAP kit were performed. The system is a time-resolved fluoroimmunoassay using europium as a tracer. The lower limit of detection was 0.2 ng/ml. Sera from 54 patients with prostate cancer, 20 with benign prostatic hypertrophy, 20 with urological malignancies other than prostate cancer and 140 adult males over 46 years old were determined. From the mean + 2 S.D. of serum PAP values obtained on the adult males, 1.5 ng/ml was considered as the upper normal level of adult males. By calculating the efficiency and ROC curve using the PAP values of prostate cancer and benign prostatic cancer, 2.5 ng/ml was decided as a cut-off value of this kit. The positive rates of adult males, prostate cancer, benign prostatic cancer and urological malignancies other than prostate cancer were 0.7%, 65%, 20% and 10%, respectively. The sensitivity of stage A2, B2, C and D1 + D2 was, 0%, 0%, 64% and 83%, respectively. The efficiency of the Delfia PAP kit was 52% and that of the Markit M PA kit was 71%. The correlation between the values assayed with the Delfia PAP kit and the Dinabot PAP kit was very high; the value obtained with the Delfia PAP kit was about 80% of that obtained with the Dinabot PAP kit.

In previous allelotype analyses of human prostatic cancer specimens, allelic loss on the short arm of chromosome 8 is frequently observed. However, it is still unclear whether this allelic loss is an initial event or a later one in development of prostatic cancer. Our previous studies demonstrate that introduction of human chromosome 11 into highly metastatic rat prostatic cancer cells results in suppression of metastatic ability without suppression of the in vivo growth rate or tumorigenicity of the hybrid cells (T. Ichikawa et al. Cancer Res., 52: 3486-3490, 1992). To clarify the role of human chromosome 8 in prostatic cancer, this chromosome was introduced into highly metastatic rat prostatic cancer cells using microcell-mediated chromosome transfer. Introduction of human chromosome 8 resulted in suppression of metastatic ability of the microcell hybrids, whereas no suppression of the in vivo growth rate or tumorigenicity was observed. These results demonstrate that human chromosome 8 contains metastasis suppressor gene(s) for prostatic cancer derived from a rat. These also suggest that human chromosome 8 has an important role in development of prostatic cancer.

精索捻転症の手術において,患側精巣の固定術および摘除術の比較を行った。1)造精機能は固定群では正常化したが,摘除群では術後2年以上経過してもその一部に20×106/ml未満の乏精子症および無精子症を認めた。2)FSHは固定群は術後経過とともに値が低下し正常化したが,摘除群ではこのような傾向はみられず一部は高値のままであった。3)発症後早期の患側精巣固定術が造精機能の回復にとって重要であると思われた4)摘除群においても,手術時思春期前であれば術後造精機能の障害は少ないと思われたSemen quality and endocrine parameters after spermatic cord torsion were investigated. Of 24 patients evaluated following spermatic cord torsion 12 were treated with bilateral orchiopexy (orchiopexy group), and 12 were treated with ipsilateral orchiectomy and contralateral orchiopexy (orchiectomy group). The average sperm density and the average total sperm count in the orchiectomy group were significantly lower than those in the orchiopexy group (p < 0.05, p < 0.05, respectively). The mean serum follicle stimulating hormone level in the orchiectomy group was significantly higher than that in the orchiopexy group (p < 0.05). These findings suggest a significant decrease in testicular function in the orchiectomy group. All the patients in the orchiopexy group demonstrated a normal semen quality and endocrine parameters during followup. Four of the 8 patients in the orchiectomy group whose duration of followup was more than two years still demonstrated oligozoospermia (< 20 x 10(6)/ml, one of 4 was azoospermia). The average age at operation of these four patients with abnormal semen quality was significantly higher than that of the other 4 patients with normal semen quality (p < 0.05), whereas no significant difference in duration of torsion preceding surgical therapy was observed between these two groups. These findings suggest that subsequent semen quality is likely to remain within normal limits with early surgical treatment by bilateral orchiopexy. Ipsilateral orchiectomy in the younger generation seems to result in less damage of the contralateral testis than in the older generation.

A 66-year-old female was admitted to Chiba University Hospital for the evaluation of a left adrenal mass which was incidentally discovered by computerized tomography. The patient had no clinical signs of Cushing's syndrome. Although the plasma ACTH level was suppressed, serum cortisol and urinary 17-OHCS levels were normal. Serum cortisol was not suppressed by dexamethasone and loss of diurnal rhythm of cortisol was observed. Uptake of 131I-aldosterone in the left adrenal gland was noted, but no accumulation was observed in the right one. Left adrenalectomy was performed. The tumor resected was 20 x 22 x 26 mm in size. Pathological diagnosis was adreno-cortical adenoma. Whether slight abnormality of adrenocortical function without clinical symptoms observed in the present case would develop into a clinically typical Cushing's syndrome remains to be solved.

Previous studies using somatic cell hybridization of highly metastatic and nonmetastatic rat prostatic cancer cells demonstrated that the resultant hybrids were nonmetastatic if all of the parental chromosomes were retained. Somatic hybrid segregants which underwent nonrandom chromosomal losses reexpressed high metastatic ability. These results demonstrated that there are gene(s) the expression of which can suppress metastatic ability of prostatic cancer cells. To identify the location of homologous gene(s) in the human, specific human chromosomes were introduced into highly metastatic rat prostatic cancer cells using the microcell-mediated chromosome transfer. Introduction of human chromosome 11 into highly metastatic rat prostate cancer cells results in suppression of metastatic ability without suppression of the in vivo growth rate or tumorigenicity of the hybrid cells. Spontaneous deletion of portions of human chromosome 11 in some of the clones delineated the minimal portion of human chromosome 11 capable of suppressing prostatic cancer metastases as the region between 11p11.2-13 but not including the Wilms' tumor-1 locus.

17例の膀胱腫瘍患者について,0.256テスラー超電導MRIを用いて撮像を行ない,深達度を判定した.撮像は横断,矢状断,冠状断の3平面について行ない,パルス系列はスピンエコー法を用い,繰返し時間,エコー時間を変化させて撮像した.MRIは軟部組織の描出に優れているので,膀胱腫瘍の描出は容易であった.膀胱壁はT2強調画像において低信号の帯として描出されるので,腫瘍の壁内深達度の判定が可能であった.手術により確認された膀胱腫瘍の深達度の正診率は70.6%であり,筋層浸潤についての正診率は76.5%であった.

[原著］Suyama T, Furuya M, Nishiyama M, Kasuya Y, Kimura S, Ichikawa T, Ueda T, Nikaido T, Ito H, Ishikura H.：Up-regulation of the interferon gamma (IFN-gamma)-inducible chemokines IFN-inducible T-cell alpha chemoattractant and monokine induced by IFN-gamma and of their receptor CXC receptor 3 in human renal cell carcinoma.

[原著］Uchida T, Baba S, Irie A, Soh S, Masumori N, Tsukamoto T, Nakatsu H, Fujimoto H, Kakizoe T, Ueda T, Ichikawa T, Ohta N, Kitamura T, Sumitomo M, Hayakawa M, Aoyagi T, Tachibana M, Ikeda R, Suzuki K, Tsuru N, Suzuki K, Ozono S, Fujimoto K, Hirao Y, Monden K, Nasu Y, Kumon H, Nishi K, Ueda S, Koga H, Naitoh S.：Transrectal high-intensity focused ultrasound in the treatment of localized prostate cancer: a multicenter study.

[原著］Shimbo M, Suzuki H, Kamiya N, Imamoto T, Komiya A, Ueda T, Watanabe M, Shiraishi T, Ichikawa T.：CAG Polymorphic Repeat Length in Androgen Receptor Gene Combined with Pretreatment Serum Testosterone Level as Prognostic Factor in Patients with Metastatic Prostate Cancer.