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Sunitinib is an oral multi-target tyrosine kinase inhibitor approved for treating metastatic renal cell carcinoma (RCC). It is metabolized mainly by CYP3A4 to the pharmacologically active N-desethyl metabolite SU12662 [1]. In a phase I clinical trial, the recommended dose of sunitinib with manageable toxicity was determined to be 50 mg day−1 (4 weeks on, 2 weeks off; 4/2 schedule) [1]. Although a single dose of up to 350 mg was well tolerated [1], a case of sunitinib overdose has never been reported. Here, we report the pharmacokinetic analysis of sunitinib and a life-threatening adverse event in a patient with metastatic RCC who took 450 mg of sunitinib as a single dose together with brotizolam.

群馬大学医学部附属病院泌尿器科において2007年4月より2009年3月までに, 腎腫瘍に対する体腔鏡下手術を41例に施行. そのうち70歳以上は18例, 80歳以上に限ると5例に対して体腔鏡下腎摘除術を施行した. 80歳以上と80歳未満の症例において, 手術時間, 出血量, 飲水開始時期, 食事開始時期, 術後退院までの日数について検討したところ, 飲水開始時期以外には明らかな差を認めなかった. 80歳以上の高齢者においても安全性, 侵襲の面で80歳未満症例と差がないと考えられた.

Bartter症候群では一般的に腎不全に進行することは少ない. 今回われわれは腎不全を呈した小児Bartter症候群type IV症例に対して生体腎移植を施行した1例を経験したので報告する. 患者は15歳男児で, 新生児期より哺乳不良, 体重増加不良であり, 10か月時多飲多尿が出現した. 1歳9か月時の精査にて血漿レニン活性の高値, 低カリウム血症, 難聴などを認めたことからBartter症候群type IVと診断されインドメタシン, スピロノラクトン, 塩化カリウムの投与が開始された. 腎機能に関しては, 乳児期より低下していたが思春期になりさらに低下し, 生体腎移植目的に2004年4月に当科紹介受診となった. 2004年11月中旬に移植予定であったが, 10月中旬にBUN 156mg/dL, Cr 17.2mg/dLと腎機能の悪化を認めたため, 腎移植前のコンディショニングとして血液透析を開始し, 11月中旬に40歳の母親をドナーとして生体腎移植を施行した. Bartter症候群の腎移植症例として, 術前にRAA系の亢進は認めていなかったがマレイン酸エナラプリルとロサルタンカリウムを移植前より投与した. 腎移植後, 腎機能は改善しRAA系の亢進も認めていない. Bartter症候群では一般的に腎不全に進行することはまれであり, 腎不全の因子としてはBartter症候群の病態だけでなく, Bartter症候群の治療に用いられるNSAIDsもその因子のうちの一つである. またこれまでの報告を含め, 腎不全を呈したBartter症候群に対しては, 腎移植後に腎不全だけでなくBartter症候群による内分泌学的異常も改善し, 腎移植が有用な治療であると考えられた.

1987年から慢性腎不全の臨床治療として腎移植治療を継続的に施行している. 2006年12月までの20年間で62回 (59名) の生体腎移植を施行した. 移植腎生着率は, 1年92％, 5年81％, 10年62％であり, 患者生存率は1年95％, 5年91％, 10年91％であった. 生体腎提供者は親が49名と最も多く, 姻族は4名であった. ABO血液型不適合移植を8名, 2次移植を3名に施行した. 急性拒絶反応出現率は後半の10年で激減した. 腎移植後の妊娠出産を3名に認め, 合計5名の挙児を得た. 移植腎機能喪失原因は, 慢性移植腎症が7例と最も多く, 次いで死亡が4例であった. 腎移植後に甲状腺癌1名, 精巣腫瘍1名を認めたが, 現在再発なく移植腎機能も良好である.

1987年から慢性腎不全の臨床治療として腎移植治療を継続的に施行している. 2006年までの20年間で19例の献腎移植を施行した. 移植腎生着率は, 1年95％, 5年76％, 10年44％であり, 患者生存率は1年100％, 5年87％, 10年73％であった. 移植腎機能喪失原因は, 死亡が4例と最も多く次いで慢性移植腎症が3例であった. 現在当科外来通院中の11名の血清クレアチニンは1mg/dl前後であり移植腎機能は非常に良好である. また, 合併症は腎移植後13年経過する1症例に循環器系の合併症を認め薬物療法中であるが, その他の症例には合併症をほとんど認めず, 外来通院の11名は非常に高いQOLを保持している.

Anemia is a common complication in patients with chronic kidney diseases including posttransplant patients. Guidelines for the treatment of anemia in chronic kidney disease published by NHF-K/DOQI recommend the target hemoglobin and hematocrit (Hb and Ht) levels to be in the 11 to 12 g/dL and 33% to 36% ranges, respectively, which are somewhat higher than those recommended in Japan (Ht = 30%). However, these guidelines were established mainly from the data on hemodialysis patients with only limited information available as to the impact of anemia control in posttransplant patients. The aim of the present study was to evaluate cardiac function and quality of life (QOL) when the Ht was raised to about 36% by administration of recombinant-human-erythropoietin (rHuEPO) to patients with mild impairment of renal function (s-Cre2.0 mg/dL) after renal transplantation. Twenty-five patients were analyzed for cardiac function, blood data, and QOL in a prospective study encompassing 8 months of rHuEPO treatment. Using a once weekly subcutaneous dose of 6000 IU of Epoetin-beta, the Ht became 33% to 36% and Hb was 11 to 12 g/dL. Among the cardiac function tests, left ventricular end-diastolic diameter and left ventricular mass index decreased significantly. QOL did not show any significant changes after administration of rHuEPO. In conclusion, we demonstrated a potential benefit of using rHuEPO to maintain the Hb between 11 and 12 g/dL and the Ht between 33% and 36% in posttransplant patients with regard to the prevention of cardiovascular complications. Further study is required to establish the benefits of correcting anemia by rHuEPO on the outcome of posttransplant patients.

The 1997 fourth Banff meeting revised the consensus for describing transplant biopsies. We have conducted a retrospective analysis of biopsies correlated between the Banff 97 classification and clinical outcome. The patients ( n=149), who had a total of 404 biopsy-proven rejections, were assessed and the biopsies taken from these patients were re-examined and classified according to the Banff 97 classification. Morphological changes in the glomeruli (g), interstitium (i), tubules(t), and arterial vessels (v) were scored. Severity of acute rejection was statistically associated with unresponsiveness to anti-rejection treatment ( P0.0001) and predicted an increased risk of graft failure ( P0.05). Each quantitative criterion (g, i, t, and v) was also statistically associated with unresponsiveness to anti-rejection treatment. Mean serum creatinine levels were significantly higher in the groups graded Banff 97 type I-III after 1 and 2 years of follow-up. The Banff 97 classification correlated with reversibility of rejection episodes and long-term graft survival.

慢性腎不全を合併した血友病A患者に, 抗凝固薬や止血法を工夫し安全に維持血液透析を施行できた1例を経験したので報告する.症例は38歳男性. 生来出血傾向は軽度であったが15歳時に血友病Aを指摘されていた. 18歳時糖尿病 (I型) と診断された. 徐々に腎機能が悪化し2000年10月感染をきっかけに腎不全が増悪し緊急透析導入となり, 社会復帰を考慮しCAPD管理となった. 以後, 時に腹膜炎, 肺水腫を併発し臨時血液透析を施行しつつCAPD継続していたが, 2002年4月左前腕内シャントを作製し, 同年10月CAPDの継続が困難となり維持血液透析へ移行となった.維持血液透析時の抗凝固療法は, 当初はnafamostat mesilate (フサン®) を使用したが, 第VIII因子活性20%, APTT 53.5秒, 透析前ACT180秒以上であったため, 無抗凝固薬透析を試みた. しかし, 透析終了時に少量の残血を認めたため, 透析開始時に静脈側からのdalteparin sodium (フラグミン®) 1,000単位のワンショットの全身ヘパリン化を施行し, 現在, 凝固トラブル, 出血症状はなく施行できている. また, 抜針時は第VIII因子製剤 (リコネイト®) 500単位を透析終了時静注し10-15分で止血可能であった. 使用24時間後の第VIII因子活性は平均23%で, 現在のところ第VIII因子インヒビターは陰性である.

Background & Aims : To clarify whether aspirin-dialminate administration suppresses the serum phosphorus (P) level in hemodialysis patients. Methods : The subjects were 13 hemodialysis patients who required antiplatelet therapy with aspirin-dialminate. Serum P and calcium (Ca) levels and the Ca-P product were measured after aspirin-dialminate administration, and they were compared with the levels before treatment. Results : Serum P level decreased from 5.66±1.45 to 4.72 ± 0.92 mg/dL, and the Ca-P product decreased from 53.4± 16.0 to 44.3 ± 10.3 after one month of aspirin-dialminate intake (p < 0.05), however, these effects were not maintained after 2 and 3 months. Serum Ca levels showed no change through the period of the present study. Conclusions : Aspirin-dialminate has an intermittent and limited effect on suppressing the serum P level and the Ca-P product in hemodialysis patients.

症例は, 31歳, 女性. 腎血管筋脂肪腫破裂による, 右腎摘出の既往がある. 2002年2月上旬, 左腎血管筋脂肪腫破裂による出血性ショック状態で当科緊急入院となった. 保存的治療で軽快せず, 左腎摘出術を施行し血液透析 (HD) に導入した. 手術前後で輸血量は約6,000mLに及んだ. 術直後のHD時の抗凝固剤はメシル酸ナファモスタットを使用し, 術後4回目より低分子ヘパリン2,500単位one shotに変更した. しかし, 返血時回路内に残血を認めたため6回目より2,700単位に増量したところ, 残血なくHDを施行できた. 血小板数は7.2万から19.3万の間を変動していた. その後ヘパリン透析に変更したところ, 全身倦怠感, 網膜剥離, 脈絡膜循環障害による視力障害, 血小板減少の増悪, 貧血などが出現した. この時の抗ヘパリン抗体は陰性であったが, 眼底所見, 臨床所見よりheparin-induced thrombocytopenia (HIT) を疑い, 輸血を併用しながら抗凝固剤をアルガトロバン, メシル酸ナファモスタットに変更してHDを施行した. アルガトロバンを使用して早期に治療したことにより, 約2か月で血小板数は15万まで回復し, 血栓症による視力障害も重篤な障害を残すことなく回復した.

Association between genetic polymorphisms of CYP1A1 and familial prostate cancer risk was examined by a case-control study of 185 individuals. Although the individual analysis of m1 or m2 genotype of CYP1A1 showed no significant association with prostate cancer risk, the presence of any mutated alleles significantly increased prostate cancer risk in comparison with wild-type genotypes by combination analysis (odds ratio [OR]=2.38; 95% confidence interval [CI]=1.72-3.29; P=0.0069). Furthermore, metastatic cancer had a significant association with mutated alleles of m1 and m2. These finding suggested that CYP1A1 polymorphisms has an association with prostate cancer risk, especially with progression of prostate cancer.

群馬大学医学部附属病院において1995年1月1日から2000年12月31日までの6年間にシャントと腹膜透析カテーテル関連手術以外の手術療法を受けた慢性維持透析患者延べ213名について, 手術内容, 基礎疾患などを検討し, 特に1999年と2000年の全身麻酔下手術症例に関しては手術前検査値, 手術後合併症なども検討した.各年ともに眼科系手術が約50%を占めていたが, 各科にわたりmajor surgeryが積極的に施行され, 心, 血管系手術は毎年施行されていた. 眼科系手術症例は糖尿病を基礎疾患として透析導入後比較的早い時期に手術が施行されていた.1999年 (16例) と2000年 (14例) の全身麻酔下手術症例の検討では, 2000年症例の方が手術時平均年齢の高齢化傾向や平均維持透析期間の長期化傾向を認めた. また, Hct, Hb, TP, BUN, 血清クレアチニン値などの手術前検査値が改善していた. 手術後合併症は感染症 (手術創移開, 肺炎) が最も多く, 次に出血 (消化管出血や脳出血) が続いた. 手術後合併症出現症例の基礎疾患は糖尿病と悪性腫瘍が多くを占めた.維持透析患者の周術期管理方法の改善により維持透析患者の手術適応は拡大し積極的に手術が施行されている. しかし, 基礎疾患に糖尿病と悪性腫瘍を持つ維持透析患者に関しては, 手術後合併症予防管理方法にまだ課題が残っている.

In renal transplantation, the long-term graft survival rate has not been improved. Until now, the differences between late graft loss and long-term graft survival have still not been estimated thoroughly. We have attempted to define clinical risk factors and parameters for late graft loss by comparing the differences in these two groups. Data from the Osaka University Database were assessed on 156 renal allografts during a 7-yr period. Thirty-six patients comprised the late graft loss group (patients in this group had graft function without need for dialysis for more than 3 yr post-transplantation, afterwards lost the allograft: loss group'). One hundred and twenty patients comprised the long-term graft survival group (patients in this group had graft function without need for dialysis until 31 December 1999: 'survival group'). Various immunological and non-immunological parameters were included in an univariate regression analysis. This analysis showed that donor age (P < 0.01), HLA mismatch number (P < 0.01) and a repeat of acute rejection (P < 0.01) were significant factors. Serum creatinine levels at 3 months (P = 0.01), proteinuria at 1 yr (P < 0.01) and antihypertensive treatment at 2 yr (P = 0.03) after transplantation were predictive of the risk of late graft loss. CsA trough concentration at 3-6 months (P < 0.05) and body mass index increase at 1 yr (P = 0.046) were elevated in the loss group. These results from a single centre suggest that immunological as well as non-immunological factors are associated with the pathogenesis of late graft loss.

群馬大学医学部附属病院における1999年の外来初診患者の臨床統計を報告した.総数729名であり, 男性529名, 女性200名で男女比は2.65:1であった.紹介患者は61.5%(448名)で院外の紹介が48.0%(350名)を占めていた.悪性新生物は96例で, 前立腺癌38例, 腎癌18例, 膀胱腫瘍17例, 精巣腫瘍10例であった.良性新生物では前立腺肥大症が205例と大部分を占めていた.その他, 多い疾患として尿路結石59例, 血液透析51例, 膀胱炎46例と続いた.市中病院の報告に比し, 悪性腫瘍, 男性不妊, 透析関係は多く, 包茎, 外傷, STDは少ない傾向だった.

日本では, 1999年末には透析患者が約20万人に達した. 男性透析患者は約11万人であり, このうち80%が50歳以上であり, 平均年齢59.9歳と男性透析患者は高齢化している. 透析患者の癌発生率は正常人に比し高いといわれ消化器系癌や尿路系癌の報告が多かった. 最近, 透析患者の前立腺癌症例の報告が散見される. そこで, 尿量が少なく排尿症状の訴えが少ない男性透析患者に対して, 前立腺癌の早期発見のために血清PSAスクリーニング検査を施行した.男性透析患者66名を対象とした. 平均年齢60.1歳 (37-83歳) で, 平均透析期間は5.6年 (0.3-16.4年) であった. 血清PSA値は, Tosoh II PAキットを使用して測定した. 血清PSA値が4ng/ml以上の患者には, 直腸診や経直腸式前立腺超音波検査を施行し, 同意が得られれば経直腸式超音波ガイド下の前立腺6分割6箇所生検法を施行した.全症例の血清PSA値は, 0.1-40.4ng/ml (平均1.9ng/ml) であった. 血清PSA値が4ng/ml以上の症例は3例であり, 全3症例に前立腺生検を施行した. その結果, 3例中2例に前立腺癌が発見されたが, 2例ともにリンパ節転移や遠隔転移を認めなかった. この2例は尿量がほとんどなく排尿に関する自覚症状がなかったので, 血清PSAスクリーニング検査は前立腺癌の早期発見に非常に有効であった. 今回の前立腺癌発見率は3% (2/66例) であり, 群馬県の前立腺検診の癌発見率1.8% (119/6744名) より高値であり, 男性透析患者に前立腺癌も発生しやすいことが示唆された. 症例数は少ないが, 前立腺癌症例を除いた64名の透析期間と血清PSA値, 年齢と血清PSA値には相関関係を認めなかったが, 男性透析患者の血清PSA値は透析療法に影響を受けず正常腎機能症例と同様に考えて良いことが示唆された.

1993年1月から1999年4月までの約6年間に群馬大学医学部附属病院泌尿器科において加療を行った精巣腫瘍77例に対して臨床的検討を行った.胚細胞性腫瘍が71例を占め, セミノーマが34例, 非セミノーマが37例であった.非胚細胞性腫瘍は悪性リンパ腫5例, Leydig cell tumorが1例であった.年齢は0歳から75歳に分布し, 30歳代が最も多かった.病理組織型別, 臨床病期別の生存率の比較を行ったが, それぞれセミノーマ, 早期症例で良好であったが有意差を認めなかった.再発症例は4例あり, そのうち2例が癌死した, また, 初回化学療法が奏功せずに進行症例2例が治療開始後1年以内に癌死した.治療上の課題として, 進行症例における化学療法の選択基準早期症例におけるsurveillance policy導入の是非などがあげられ, 今後なお検討を要すると考えられた.

Objectives: Several clinical features, such as the spontaneous regression of some renal cell carcinoma (RCC) metastases after nephrectomy, suggest immune involvement in tumor destruction. Patients and Methods: We investigated the role of genetic variation at the HLA class II loci in RCC by analyzing the HLA-DR antigen and HLA-DRB1, DRB3, DRB4 and DRB5 alleles in 55 patients using the polymerase chain rection. Results: No statistically significant differences were observed in the frequency of the HLA-DR antigen or HLA-DRB3, DRB4, or DRB5 genes between the patients and a healthy control group. On the other hand, the HLA-DRB1*0403 and *1202 alleles were significantly more frequent in the patients than in the controls (p < 0.001 and p < 0.01, respectively). Conclusion: RCC might be linked to these two alleles in Japanese patients.

Background: Familial prostate cancer has been studied in Europe and the United States. This study was conducted toclarify the clinical features and incidenceof the human leukocyte antigen (HLA) in familial prostate cancer in patients seen at hospitals in Japan. Methods: The age at diagnosis, clinical stage, histologic differentiation, prognosis, cause of death and family history were compiled from 43 patients from 20 families with familial prostate cancer (group F) and compared in patients with sporadic prostate cancer (group S). In addition, HLA class II gene typing was performed in 17 patients from 11 families with familial prostate cancer (group F') and their healthy family members (15 males and 25 females). Results: The age at diagnosis was significantly lower in group F patients (P < 0.001), but neither clinical stage nor prognosis differed between group F and group S, yet the incidence of moderately differentiated adenocarcinoma was significantly higher in group F (P& 0.01). There were no historical factors that were specific for group F patients. The frequency of HLA-DRB1 *0901 and *1201 alleles was significantly higher in group F' patients than in group J (the frequency of alleles in 1216 Japanese people attending the 11th Japan HLA Workshop), but not between group F' and their healthy male family members. Conclusion: There were no significant differences in clinical parameters between group F and group S, except that the age at diagnosis was lower in group F patients, and that the frequency of several HLA class II alleles was significantly higher in patients with prostate cancer. In men with a family history of prostate cancer, examinations for early detection of prostate cancer should begin at a young age.

Background Chronic expanding hematoma is a rare condition that develops after surgery, trauma, or injury. It can also develop at any location in the body in the absence of trauma. Clinical findings and various diagnostic imaging modalities can aid in the differential diagnosis of this condition. In general, hematomas are naturally reabsorbed and rarely cause serious problems. However, hematomas that develop slowly without a history of trauma, surgery, or bleeding disorders could be difficult to differentiate from soft tissue neoplasms. In the present case, we describe a patient, without any history or physical evidence of trauma, who exhibited a large chronic expanding hematoma in the retroperitoneal space that resulted in hydronephrosis because of the pressure exerted on the left ureter. Case presentation A 69-year-old man presented to our hospital with a swollen lesion in the left flank. A mass, 19 cm in diameter, was detected in the retroperitoneal space by computed tomography. We suspected the presence of a chronic expanding hematoma, soft tissue tumor, or left renal artery aneurysm. Surgical treatment was performed. However, postoperative histopathological examination indicated that the mass was a nonmalignant chronic expanding hematoma. No recurrence was observed during a 2-year follow-up period. Conclusion In patients without a history of trauma who present slowly growing masses, the differential diagnosis should include chronic expanding hematoma in addition to cysts and soft tissue tumors. Moreover, the use of magnetic resonance imaging and computed tomography is essential to differentiate between chronic expanding hematoma and soft tissue tumors.

For 7 cases of bladder stones, we carried out transurethral lithotripsy by using an ultrasonic lithotripter (UL), an electrohydraulic lithotripter (EHL) or a ballistic lithotripter (BL), and evaluated the safety, usefulness and therapeutic indication for each lithotripter.With the UL, though the power was weakest, there was little stone movement at irradiation and the view was good owing to continuous irrigation, and there was no mucosal injury due to misdirected irradiation. With the EHL, though the power was strongest, stone movement at irradiation was greatest, and mucosal injury occurred due to misdirected irradiation, and the probe was exhausted rapidly. BL was similar to EHL, but BL is more useful than EHL when safety and running cost are considered.From our consideration, small stones less than 2 cm can be treated by UL only. In case of larger stones, we recommend that the stone be divided into small pieces by BL at first and that the small fragments be disintegrated by UL.

CAPD療法の継続に重大な影響を及ぼす腹膜炎の原因として, 近年, バッグ交換時の手技的ミスよりも難治性の出口部感染 (ESI) やトンネル感染 (TI) が注目されている. その治療法は抗生物質投与, unroofing, cuff shavingなどが一般的で, その効果はある程度は認められているが, 最終的にカテーテルロスになる症例も多い. 今回我々は, これらに代わり新たな外科的治療法 (以下本法) を考え, 難治性ESIや外部カフより遠位に限局する難治性TIの4症例に施行した. 本法の手技は, 術野を十分消毒した後, 局所麻酔下で外部カフと一緒に感染部周囲を十分余裕をとり紡錐形に摘除する. その後残存カテーテル断端にチタニウムエクステンダー (Accurate Surgical社) をコネクターとして挿入し, カフ付きの新しいカテーテルを接合する. 摘除した感染巣の跡を十分消毒した後に, 接合部が直線になるように逆U字形に新皮下トンネルを作製して, 基本的に新出口部は旧出口部のやや下方になるようにカテーテルを留置する, というものである. 本法の利点は, 1) unroofingやcuff shavingでは摘除しきれない感染巣が完全に摘除できる, 2) unroofingやcuff shaving施行後は外部カフ欠如のため出口部付近でのカテーテル固定力が低下しESI易再発の可能性, またESIやTIが再発した場合感染が容易に内部カフまで波及し腹膜炎を併発し易い可能性があるが, 本法では新外部カフが存在するためこれらが予防できる, 3) カテーテル再挿入術に比べて手術侵襲が少なく, また患者の心理的負担もかなり軽い, 4) 出口部からチタニウムアダプターまでの間のカテーテルトラブルにも応用できる, である. 本法施行後20から56か月の観察期間中, 透析液の漏れ, カテーテル接合部の離開, 接合部カテーテルの屈曲, 皮下チタニウムエクステンダーの違和感やESIまたはTIの再発などは全例に認めず順調に経過している.

A 8-year-old boy with acute lymphocytic leukemia (ALL) had received chemotherapy and a complete bone marrow remission was obtained. Then he underwent bone marrow transplantation. After 6 months, he suddenly got left flank-low abdominal pain. Sequentially, he had swelling and redness of left scrotum, left testicular swelling and tenderness. Incision was done and enlarged and hard testis was diagnosed as testicular tumor, left orchiectomy was performed. Histological diagnosis was involvement of ALL, so he received radiotherapy. He remains free of disease by the present after 7 months.

We report a 60-year old male hemodialysis patient with intermittent deep coma due to liver cirrhosis. The patient had a clinical history of hemodialysis (HD) due to hepatonephric syndrome resulting from chronic hepatitis C and alcoholic cirrhosis for 5 years. Serum ammonia level gradually increased, despite the alteration from HD to hemodiafiltration (HDF) and administration of lactulose orally and Aminoleban™ intravenously. The rate of ablation in serum ammonia was about 30% and satisfactory. However, the patient was admitted to the hospital 6 times in 8 months for deep coma and died due to respiratory disturbance at home. Advanced alkalosis was more closely correlated with the onset of deep coma than was ammonia level in this case.

Histopathological findings in renal allograft with stable function remain unclear. We therefore performed non-episode biopsy in the long-surviving renal allograft to investigate the histopathological changes. Our data show that, although arteriolopathy is characteristic of drug-induced nephropathy, it is unrelated to dosage and concentration of cyclosporine or tacrolimus in non-episode biopsy. We evaluated therefore the clinicopathological findings of arteriolopathy in this study. Non-episode biopsy was defined as follows: as serum creatinine level lower than, 2.0 mg/dl and a urinary protein level lower than 500 mg/day. A total of 65 biopsy specimens were enrolled in this study as non-episode biopsy. Twenty-nine specimens revealed arteriolopathy. There were no statistically significant differences between arteriolopathy and dosage or concentration of cyclosporine or tacrolimus. Arteriolopathy in non-episode biopsy was related to time of biopsy, kidney age, hypertension, and hyperlipidemia, suggesting that it is important for graft survival to strictly control blood pressure and blood lipid level.

The significance of prostatic specific antigen (PSA) was investigated in the subjects examined by the mass screening for prostate cancer from 1985 to 1990. All subjects was examined by digital rectal examination (DRE) and with prostatic acid phosphatase (PAP) and the subjects in whom prostate cancer (Pca) was suspected from abnormal DRE and/or elevated PAP were recommended to receive the secondary screening to confirm the presence of Pca. PSA was measured by radioimmunoassay using Ball-Elsa-PSA-kit. 1,600 serum samples were obtained from our serum bank. The relationship among PSA, prostate size estimated by DRE and age was investigated. PSA was increased with age and the prostate size, PSA being more closely related with the latter. Therefore, we estimated that PSA has an ability to detect benign prostatic hypertrophy (BPH) in the mass screening. This estimation should be confirmed by using an ultrasound tomography because the prostate size obtained by DRE is inaccurate as compared with that obtained by ultrasound tomography. The cut off level of PSA was determined by control which was composed from the subjects with normal size prostate and one with BPH. When the cut off level was 8.6 ng/ml, the sensitivity, specificity and efficiency as Pca marker was 73.9%, 97.4% and 97.1%, respectively. PSA was more than 8.6 ng/ml in all of Pca with elevated PAP. PSA was expected to improve the Pca detection rate in our mass screening system.

Background: Many studies have shown the relationship between pretreatment serum testosterone levels and the clinical stage or histological grade, but the clinical significance of pretreatment testosterone levels is controversial. We studied the association of pretreatment total testosterone levels with the clinical stage and histological grade of prostate cancer. Methods: We evaluated 2914 patients whose pretreatment testosterone levels were recorded from 1982 to 2002. Serum testosterone levels were measured by radioimmunoassay. Results: There was a trend toward decreasing testosterone values with worsening clinical staging. There was a trend toward decreasing testosterone values with worsening histological grading, too. Patients with poorly differentiated adenocarcinoma had significantly lower testosterone levels than those with the others (versus well; p p Conclusions: Newly diagnosed patients with poorly differentiated adenocarcinoma of prostate have lower testosterone levels than the others.

A 8-year-old boy with acute lymphocytic leukemia (ALL) had received chemotherapy and a complete bone marrow remission was obtained. Then he underwent bone marrow transplantation. After 6 months, he suddenly got left flank-low abdominal pain. Sequentially, he had swelling and redness of left scrotum, left testicular swelling and tenderness. Incision was done and enlarged and hard testis was diagnosed as testicular tumor, left orchiectomy was performed. Histological diagnosis was involvement of ALL, so he received radiotherapy. He remains free of disease by the present after 7 months.

Hepatocyte growth factor (HGF) has been reported to be a renal regeneration factor. We previously reported that HGF acts as a renotropic factor, inducing cell recovery from ischemic injury or drug toxicity. Gene transfer by electroporation, which uses plasmid DNA as the vector, has several advantages over the conventional gene transfer method using viral vectors, inducing the ability to perform repeated transfers without apparent immunologic responses to the DNA vector. We recently demonstrated that electroporation of the HGF gene into skeletal muscle was an effective treatment for liver injury in an animal model. We presently investigated prevention of development of chronic renal disease by repetitive HGF gene transfer in rats with 5/6 nephrectomy. Hepatocyte growth factor gene transfer-treated rats showed better growth in body weight than untreated rats. Histologic changes such as glomerulosclerosis and interstitial fibrosis were significantly ameliorated by HGF gene transfer compared with untreated rats. Hepatocyte growth factor gene transfer by electroporation into skeletal muscle is feasible and effective against morphologic injury in subtotally nephrectomized rats.

Background: Fosfestrol drip infusion therapy is an available endocrinotherapy for prostate cancer. But since there have been few reports of its use in chronic dialysis patients, the pharmacokinetics of fosfestrol in these patients remains unclear. We conducted fosfestrol drip infusion therapy as an induction therapy in chronic hemodialysis patients with prostate cancer. Methods: Two male patients were included in this study. One was a 68-year-old man who had been in hemodialysis for 15.7 years and had stage B2 prostate cancer. The other was a 74-year-old man who had been in hemodialysis for 4.4 years and had stage C prostate cancer. A total of 250 mg of fosfestrol was dissolved in 250 mL of 5% glucose solution and administered by drip infusion. The drug was given subcutaneously during 14 consecutive days and a luteinizing hormone-releasing hormone agonist was injected on day 15. Results: Serum fosfestrol levels increased rapidly after the drip infusion was started and remained at high levels during infusion, but fell quickly after the treatment ended. Diethylstilbestrol (DES) was also detected in blood after the infusion was started and its levels peaked when infusion ended. But on the next day, neither fosfestrol nor DES were detected in the blood of the patients. Moreover, neither fosfestrol nor DES was detected in the blood of the two patients before administering fosfestrol on day 15. Fosfestrol was quickly eliminated from the blood after hemodialysis was started, while DES remained in the blood during hemodialysis. The adverse reactions were mild hepatic dysfunction and gynecomastia. Conclusions: Fosfestrol drip infusion therapy appeared to be safe as an endocrinotherapy for prostate cancer in chronic hemodialysis patients.

Hyperlipidemia is frequently developed following renal transplantation and results in worsening of the patient's prognosis. In study 1, the effects of immunosuppressants, cyclosporine (CsA) and tacrolimus on serum lipids were compared in-patients undergoing renal transplantation. The study included 32 cases of renal transplantation recipients who randomized to the CsA treatment group (15 patients) and the tacrolimus group (17 patients). Before and 1 month after the transplantation, we assessed the serum lipid levels, apolipoprotein levels, the concentrations of cholesterol in the respective lipoprotein fractions and the enzyme activities related to lipid-metabolism. The serum lipid levels in both groups were significantly increased at 1 month after renal transplantation. In the CsA group, there were significant increases in cholesterol contents in very-low-density lipoprotein (VLDL), LDL2 and HDL2 fractions, whereas, in the tacrolimus group, cholesterol content was increased in VLDL and HDL2 fractions. In study 2, 1 month after renal transplantation, 19 patients with hypercholesterolemia (total cholesterol (TC) >200 mg/dl) and hypertriglyceridemia (triglyceride (TG) >150 mg/dl) were treated with simvastatin 5-10 mg/day for 6 months. Simvastatin treatment significantly decreased serum TC (240+/-29-200+/-22 mg/dl, P

Background: We clinically and pathologically analyzed renal allografts from 19 renal transplant patients treated with tacrolimus (FK506) for more than 1 year. Methods: Twenty-six renal allograft biopsy specimens from 19 renal transplant patients who underwent transplantations between 1991 and 1 993 were evaluated. Thirteen biopsies were performed from stable functioning renal allografts with informed consent (nonepisode biopsy) and the other 13 were from dysfunctional renal allografts with a clinical indication for biopsy (episode biopsy). Results: The main pathologic diagnoses (some overlap) were acute rejection (AR; n = 4), chronic rejection (CR;n = 5), AR + CR(n=4), recurrent IgA nephropathy (n = 5), normal findings (n = 2), minimal-type chronic FK506 nephropathy (n = 9), and mild-type FK506 nephropathy (n = 11). Of the nonepisode biopsies, 7 and 4 biopsies showed minimal-type and mild-type chronic FK506 nephropathy, respectively. Chronic FK506 nephropathy consisted of rough and foamy tubular vacuolization (5 biopsies), arteriolopathy (angio-degeneration of the arteriolar wall; 20 biopsies), focal segmental glomerulosclerosis (4 biopsies) and the striped form of interstitial fibrosis (11 biopsies). The serum creatinine levels of patients in the mild-type chronic FK506 nephropathy group, which included 7 episode biopsies, were statistically higher than those in the minimum-type chronic FK506-nephropathy group (P < 0.001). Conclusions: This study demonstrates that chronic FK506 nephropathy consists primarily of arteriolopathy manifesting as insudative hyalinosis of the arteriolar wall, and suggests that mild-type chronic FK506 nephropathy is a condition which may lead to deterioration of renal allograft function.

We conducted an analysis of biopsy specimens of non-episode renal allografts from patients treated with tacrolimus (FK506) or cyclosporine (CsA) to evaluate chronic drug-induced nephropathy in stable allografts. A total of 38 biopsy specimens from stable functioning renal allografts were examined. The patients had been treated with FK506 (n = 16) or CsA (n = 18) as main immunosuppressant for 0.3 to 7.4 years. Of the 38 biopsy specimens, 15 showed mild drug-induced arteriolopathy (hyalinosis or insudative change of arterioles and small arteries) with striped-form interstitial fibrosis, 10 showed minimum interstitial cellular infiltration (borderline rejection), 2 showed IgA nephropathy, 4 showed evidence of chronic rejection (transplant nephropathy) and 12 showed no abnormal findings. Of 34 renal allograft biopsy specimens with stable function, 22 (65 %) showed pathological evidence of drug-induced nephropathy. There were no significant qualitative or quantitative differences between FK506- and CsA-associated nephropathy.

The Fas system-based rejection mechanism has not been studied well in terms of cytotoxic T cell activity in graft rejection. We investigated the Fas and Fas ligand level in renal grafts with acute and chronic rejection in a rat model using semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). Fas ligand in renal allografts was detected as early as 1 day after transplantation in an acute rejection model. It was highly expressed at day 4 and began to decline at day 6 after transplantation. In contrast, Fas ligand in normal kidneys was almost undetectable. Fas ligand in isografts was increased, but the expression level was much lower than in allografts. Interestingly, when Fas ligand expression began to decline in renal allografts, it increased in the spleens of recipients. Fas ligand expression in chronically rejecting allografts was slightly increased, but it was stronger than in isografts. In contrast to Fas ligand gene expression, Fas was constitutively expressed in isografts, allografts, and normal kidneys. However, the Fas level in renal allografts was higher than in normal kidneys. Our data demonstrated that the Fas system might play an important role in acute and chronic rejection by causing apoptosis, and the spleen may eliminate the lymphocytes strongly expressing Fas ligand after completion of the acute rejection.

Nine renal transplant recipients in stable systemic condition on FK506 capsules were converted to FK506 granules in order to investigate the safety, efficacy, and pharmacokinetics of the granular formulation of FK506. The study period for the administration of FK506 granules was 4 weeks, and in principle, the oral dose was the same as that of the FK506 capsules. Renal graft function remained stable and no rejection signs were noticed while the patients were taking the granules. The area under the blood concentration-time curve (AUC), the maximum blood level (Cmax), and the time to reach Cmax (Tmax) after FK506 capsules and FK506 granules were, respectively, 93.1 +/- 66.4 and 97.0 +/- 89.1 ng.h/ml (P = 0.81), 12.7 +/- 7.1 and 15.2 +/- 11.7 ng/ml (P = 0.39), and 2.0 +/- 1.7 and 1.3 +/- 0.6 h (P = 0.29). The mean trough blood level during FK506 medication was 4.25 +/- 3.42 and 4.02 +/- 3.83 ng/ml, respectively, for the capsules and the granules. FK506 granules, a new formulation, showed an efficacy comparable to that of the FK506 capsular formulation.