Expression of angiopoietin-1 and -2, and its clinical significance in human bladder cancer

To investigate the relationship between angiopoietin-1 and -2 expression and the clinicopathological variables and clinical outcome in patients with bladder cancer treated by surgical resection, as both have been recently identified as antagonistic angiogenic factors which regulate tumour growth. The expression of angiopoietin-1 and -2 were assessed by immunohistochemistry in tissue sections from 52 transitional cell carcinomas of the bladder (33 grade 1, 15 grade 2, four grade 3, including two associated with carcinoma in situ; 22 were stage Ta, 19 T1 and 11 T2 tumours). Normal bladder specimens were also resected during each operation as controls. The expression angiopoietins were related to the clinicopathological variables of the tumours. Positive immunostaining was detected in 18 samples (35%) for angiopoietin-1 and in 23 (44) for angiopoietin-2. There was no significant difference in survival according to tumour angiopoietin-1 status in the patients, but in contrast the overall survival of patients with angiopoietin-2-positive tumours was significantly lower than for those with angiopoietin-2-negative tumours (P < 0.05). Positive angiopoietin-2 expression was significantly correlated with histological grade (P = 0.026), histological stage (P = 0.009) and poor prognosis (P < 0.05). On multivariate analysis, positive angiopoietin-2 expression was an independent negative predictor for survival (P = 0.042). These results suggest that angiopoietin-2 overexpression is associated with tumour progression, thereby indicating a poor prognosis for some patients treated by surgical resection for bladder carcinoma.


Robust Classification of Renal Cell Carcinoma Based on Gene Expression Data and Predicted Cytogenetic Profiles

Renal cell carcinoma (RCC) is a heterogeneous disease that includes several histologically distinct subtypes. The most common RCC subtypes are clear cell, papillary, and chromophobe, and recent gene expression profiling studies suggest that classification of RCC based on transcriptional signatures could be beneficial. Traditionally, however, patterns of chromosomal alterations have been used to assist in the molecular classification of RCC. The purpose of this study was to determine whether it was possible to develop a classification model for the three major RCC subtypes that utilizes gene expression profiles as the bases for both molecular genetic and cytogenetic classification. Gene expression profiles were first used to build an expression-based RCC classifier. The RCC gene expression profiles were then examined for the presence of regional gene expression biases. Regional expression biases are genetic intervals that contain a disproportionate number of genes that are coordinately up- or down-regulated. The presence of a regional gene expression bias often indicates the presence of a chromosomal abnormality. In this study, we demonstrate an expression-based classifier can distinguish between the three most common RCC subtypes in 99% of cases (n = 73). We also demonstrate that detection of regional expression biases accurately identifies cytogenetic features common to RCC. Additionally, the in silico-derived cytogenetic profiles could be used to classify 81% of cases. Taken together, these data demonstrate that it is possible to construct a robust classification model for RCC using both transcriptional and cytogenetic features derived from a gene expression profile.


Amiloride and Urinary Trypsin Inhibitor Inhibit Urothelial Cancer Invasion

To determine the contribution of urokinase-type plasminogen activator (uPA) and plasmin in the invasion of highly invasive urothelial cancer cells. We compared expression levels of mRNA and protease activity of uPA and plasmin formation in primary cultures of the noninvasive transitional cell carcinoma, UCT-1, and in the highly invasive type, UCT-2. By using in vitro cell invasion assay system, we evaluated the effects of amiloride and urinary trypsin inhibitor (UTI), which inhibit uPA and plasmin, respectively, on invasion by both cell lines. Expression levels of mRNA, protein, and activities of uPA were significantly higher (p<0.005) and resulted in more plasminogen activation in UCT-2 than in UCT-1. Amiloride and UTI significantly inhibited plasmin formation and the invasion of both cell lines (p<0.001). High expression levels of mRNA, activities of uPA and high plasmin formation significantly potentiated the invasiveness of urothelial cancer cells. Thus, inhibitors of uPA and plasmin, such as amiloride and UTI, respectively, could be useful therapeutic tools with which to treat urothelial cancer.


The t(1;3) breakpoint-spanning genes LSAMP and NORE1 are involved in clear cell renal cell carcinomas

By positional cloning, we identified two breakpoint-spanning genes in a familial clear cell renal cell carcinoma (CCRCC)-associated t(1;3)(q32.1;q13.3): LSAMP and NORE1 (RASSF1 homolog). Both genes are downregulated in 9 of 9 RCC cell lines. While the NORE1A promoter predominantly presents partial methylation in 6 of the cell lines and 17/53 (32%) primary tumors, the LSAMP promoter is completely methylated in 5 of 9 cell lines and in 14/53 (26%) sporadic and 4 familial CCRCCs. Expression of LSAMP and NORE1A proteins in CCRCC cell lines inhibited cell proliferation. These characteristics indicate that LSAMP and NORE1A may represent new candidate tumor suppressors for CCRCC.


Distinct roles of Rab3B and Rab13 in the polarized transport of apical, basolateral, and tight junctional membrane proteins to the plasma membrane

Regulated transport of proteins to distinct plasma membrane domains is essential for the establishment and maintenance of cell polarity in all eukaryotic cells. The Rab family small G proteins play a crucial role in determining the specificity of vesicular transport pathways. Rab3B and Rab13 localize to tight junction in polarized epithelial cells and cytoplasmic vesicular structures in non-polarized fibroblasts, but their functions are poorly understood. Here we examined their roles in regulating the cell-surface transport of apical p75 neurotrophin receptor (p75NTR), basolateral low-density lipoprotein receptor (LDLR), and tight junctional Claudin-1 using transport assay in non-polarized fibroblasts. Overexpression of Rab3B mutants inhibited the cell-surface transport of LDLR, but not p75NTR and Claudin-1. In contrast, overexpression of Rab13 mutants impaired the transport of Claudin-1, but not LDLR and p75NTR. These results suggest that Rab3B and Rab13 direct the cell-surface transport of LDLR and Claudin-1, respectively, and may contribute to epithelial polarization.

Biochemical and Biophysical Research Communications


Strategy for treating pediatreic urological disease in the department of urology

徳島大学泌尿器科における小児泌尿器科医療の取り組み


Functional evaluation of one-stage urethroplasty with parameatal foreskin flaps repair of hypospadias using uroflowmetry

Uroflowmetry is a simple, accurate and non-invasive test. In the present study, we aimed to determine the role of uroflowmetry in the evaluation of the functional results of one-stage urethroplasty with parameatal foreskin flaps (OUPF) technique. Twenty-one children who had undergone OUPF repair at our clinic were selected. Selection criteria were that patients were toilet trained and had no fistula. Uroflowmetry was performed using a rotating disk sensor. The maximum flow rate (Qmax) and average flow rate (Qave) were plotted against body surface related flow rate nomograms. The upper 95% tolerance limits for the 5th, 10th, 15th, 20th and 25th percentiles of the normal population were used for comparison. The flow pattern was classified as bell ring, plateau or intermittent. The median age at the first uroflowmetry was 4.7 years (range 2.5-8.6) and the mean postoperative follow-up period was 25 months (range 1-58). Twelve children had Qmax above the 25th, six between the 5th and 25th and three less than the 5th percentiles of the normal population. A normal bell-shaped flow curve was obtained in 17 (80.6%) of the children. Of the three children with Qmax below the 5th percentile, two children had a plateau flow pattern and were found to have a urethal stricture. Dilation was performed successfully, after which the Qmax returned to the normal range and the symptoms disappeared. The OUPF technique provided satisfactory functional results for hypospadias repair. We advocate the use of uroflowmetry for routine postoperative follow-up.


Laparoscopic nephroureterectomy for dysplastic kidney in children: an initial experience

Laparoscopic nephroureterectomy for dysplastic kidney is now becoming a widely accepted procedure. We report here our initial experience with laparoscopic nephroureterectomy in four girls. Between 1993 and 1999, laparoscopic nephroureterectomy was performed in four girls (mean age 5.3 years). Three patients had an ectopic dysplastic kidney with ectopic ureter, and one patient had hydronephrosis with megaureter due to distal ureteral atresia of the upper moiety in a duplicated dysplastic kidney. The transperitoneal approach was used in all cases. Mean operative time was 195 min (range 150-266). Blood loss was minimal. All operations were completed successfully and there were no intraoperative or postoperative complications except for subcutaneous emphysema in one patient (case 4). Postoperative analgesia was used in three patients and administered in the form of diclofenac sodium suppositories 12.5 mg (cases 1 and 2) or acetaminophen suppositories 50 mg (case 3) for 1-2 days. One patient did not require any analgesia (case 4). Oral fluid intake was resumed on the first postoperative day and ambulation began within 1-3 days (mean 1.6, cases 1, 2 and 3) and 6 days (case 4). All children returned to normal activity within 3-6 days of surgery. Mean postoperative hospital stay was 7.3 days. All cases had uneventful courses after discharge. Laparoscopic nephroureterectomy can be performed safely, with minimal postoperative pain, excellent cosmetic results and early ambulation. We advocate the use of laparoscopy for the diagnosis and treatment of dysplastic kidney with ectopic ureter.


Gene expression profiling of clear cell renal cell carcinoma: Gene identification and prognostic classification

To better understand the molecular mechanisms that underlie the tumorigenesis and progression of clear cell renal cell carcinoma (ccRCC), we studied the gene expression profiles of 29 ccRCC tumors obtained from patients with diverse clinical outcomes by using 21,632 cDNA microarrays. We identified gene expression alterations that were both common to most of the ccRCC studied and unique to clinical subsets. There was a significant distinction in gene expression profile between patients with a relatively nonaggressive form of the disease [100% survival after 5 years with the majority (15/17 or 88%) having no clinical evidence of metastasis] versus patients with a relatively aggressive form of the disease (average survival time 25.4 months with a 0% 5-year survival rate). Approximately 40 genes most accurately make this distinction, some of which have previously been implicated in tumorigenesis and metastasis. To test the robustness and potential clinical usefulness of this molecular distinction, we simulated its use as a prognostic tool in the clinical setting. In 96% of the ccRCC cases tested, the prediction was compatible with the clinical outcome, exceeding the accuracy of prediction by staging. These results suggest that two molecularly distinct forms of ccRCC exist and that the integration of expression profile data with clinical parameters could serve to enhance the diagnosis and prognosis of ccRCC. Moreover, the identified genes provide insight into the molecular mechanisms of aggressive ccRCC and suggest intervention strategies.

Proceedings of the National Academy of Sciences of the United States of America


Secondary amyloidosis of the bladder causing macroscopic hematuria

Bladder involvement in amyloidosis is unusual. The case of an 80-year-old man with macroscopic hematuria caused by secondary amyloidosis of the bladder is described. Cystoscopic examination revealed only a diffuse edematous area and bleeding. No tumor-like lesions were identified. Transurethral biopsy revealed amyloid deposits. Macroscopic hematuria disappeared spontaneously after cystoscopy and bladder biopsy. The patient has been followed up without treatment and is currently free of symptoms.


Association of a novel constitutional translocation t(1q;3q) with familial renal cell carcinoma

Four cases of late onset clear cell renal cell carcinoma (RCC), a case of gastric cancer, and a case of exocrine pancreatic cancer were identified in a Japanese family. In order to elucidate the underlying mechanism for tumorigenesis in this family, extensive genetic studies were performed including routine and spectral karyotyping (SKY), fluorescence in situ hybridisation (FISH), comparative genomic hybridisation (CGH), loss of heterozygosity studies (LOH), and VHL mutation analysis. A germline translocation t(1;3)(q32-q41;q13-q21) was identified by karyotyping in five members of the family including all three RCC cases tested. The translocation was refined to t(1;3)(q32;q13.3) by FISH analysis using locus specific genomic clones, and the two breakpoints were mapped to a 5 cM region in 3q13.3 and a 3.6 cM region in 1q32. Both CGH and allelotyping using microsatellite markers showed loss of the derivative chromosome 3 carrying a 1q segment in the three familial RCCs analysed. Additional chromosomal imbalances were identified by CGH, including amplifications of chromosomes 5 and 7 and loss of 8p and 9. No germline VHL mutation was found but two different somatic mutations, a splice (IVS1-2A>C) and a frameshift (726delG), were identified in two RCCs from the same patient confirming their distinct origin. Taken together, these results firmly support a three step model for tumorigenesis in this family. A constitutional translocation t(1q;3q) increased the susceptibility to loss of the derivative chromosome 3 which is then followed by somatic mutations of the RCC related tumour suppressor gene VHL located in the remaining copy of chromosome 3.


De-epithelialized flap for closure of urethrocutaneous fistula after hypospadias repair

尿道下裂形成手術後の尿道皮膚瘻に対するde-epithelialized flapを用いた瘻孔閉鎖術の検討

日本小児泌尿器科学会雑誌


Analysis of serum soluble interferon α/β receptor levels in patients with urological diseases

泌尿器科疾患における血清中可溶性インターフェロンα/βレセプターの意義

(Purpose)In order to define the clinical significance of serum soluble Interferon α/βreceptor(sIFN/α/βR)levels, we determined sIFNα/βR concentrations in serum of patients with urological benign and malignant diseases. (Materials and Methods)Serum sIFNα/βR levels were measured in normal control(n=22), patients with benign diseases(n=50)included urolithiasis(n=16), prostatic hypertrophy(n=13), and malignant diseases included bladder cancer(n=49), renal cell carcinoma(n=30)and prostate cancer(n=36)by the enzyme linked immunosolbent assay(ELISA)using monoclonal and pliyclonal antibodies. The levels of serum sIFNα/βR was correlated with the results of other hematoserological examinations, and clinical or pathological characters of each urological malignancies. (Results)The serum sIFNα/βR levels(pg/ml)of patients with urolithiasis(2,370.6±640.6, p=0.0002), benign prostatic hypertrophy(2,121.1±55.06, p=0.0103), bladder cancer(2,512.3±1,012.3,p=0.0006), renal cell carcinoma(2,686.4±1,510.9, p=0.0046), prostate cancer(3,188.7±1,788.0, P=0.0003)showed significantly higher values than those of controls(1,790.5±346.7). Moreover, we found statistically significant correlations among serum creatinine(Cr)levels and sIFNα/βR levels. However, there were no correlations between the sIFNα/βR levels and clinical stage, or histological grade in the patients with bladder cancer or prostate cancer, whenever the levels of sIFNα/βR were corrected by serum Cr levels. On the other hand, high level of corrected serum sIFNα/βR was observed in patients with high stage or high grade renal cell carcinoma, but not significant statistically. (Conclusion)Elevated serum sIFNα/βR was observed in patients with urological decease. Further examinations should be necessary to determine the clinical usefulness of serum sIFNα/βR.

(目的)泌尿器科疾患における可溶性インターフェロンα/βレセプター(soluble Interferon-α/βreceptor:sIFNα/βR)に関する検討はまだ十分なされていない．今回,ポリクローナル抗体およびモノクローナル抗体を用いたサンドイッチEnzyme Linked Immunosolbent Assay(ELISA)法による細胞膜外部分のsIFNα/βRの測定系が確立されたので,各種泌尿器科良性疾患,膀胱癌,腎細胞癌,前立腺癌の血清中sIFNα/βRを測定し臨床的意義について検討を行った．(対象と方法)健常コントロール22例,良性疾患50例(尿路結石症16例,前立腺肥大症13例,その他21例),膀胱癌49例,腎細胞癌30例,前立腺癌36例を対象として,血清中sIFNα/βR値をELISA法により測定した．臨床検査値との相関,各疾患群における血清中sIFNα/βR値の比較,さらには悪性腫瘍患者における臨床病理像との比較解析を行った．(結果)各疾患における血清中sIFNα/βR値(pg/ml)は,健常コントロール(1,709.5±346.7)に比し,尿路結石症(2,370.6±640.6,p=0.0002),前立腺肥大症(2,121.1±550.6,p=0.0103),膀胱癌(2,512.3±1,012.3,p=0.0006),腎細胞癌(2,636.4±1,510.9,p=0.0046),前立腺癌(3,188.7±1,788.0,p=0.0003)ともに,有意に高値を示した．各種血液学的検査結果との比較では,血清中クレアチニン値との相関が認められたが,その他の検査結果との相関は認めなかった．また,血清中sIFNα/βR値と膀胱癌および前立腺癌における臨床病理像との比較では,実測値および血清中クレアチニン値による補正値(Cr補正値)ともに有意な相関は認めなかった．一方,腎細胞癌では,進行例および異型度の強い症例においてCr補正値が高値を示したが,統計学的に有意ではなかった．(結論)血清中sIFNα/βR値は各種泌尿器科疾患において高値を示した．血清中sIFNα/βR値の臨床応用の可能性を評価するためには,今後さらに多数例における詳細な検討が必要と思われた．


The role of the activated form of matrix metalloproteinase-2 in urothelial cancer

To investigate the expression of matrix metalloproteinase-2 (MMP-2, reportedly associated with cancer cell invasion and metastasis in many human cancers) in urothelial tumours and thus define its role in this disease. Materials and methods The expression of both the activated form of MMP-2 and total MMP-2 (activated + latent form) was measured using gelatine zymography in tissue obtained surgically from 61 patients with urothelial cancer. The correlation between the level of the activated form of MMP-2 and clinical and histological variables was assessed. The expression of activated and total MMP-2 were significantly higher in invasive tumour tissue and both levels were correlated with histological grade. In particular, the level of activated MMP-2 was more closely correlated than that of total MMP-2 in invasive tumour tissue. Moreover, high levels of activated MMP-2 were strongly associated with shorter disease-specific survival (P = 0.0016). These findings suggest that activated MMP-2 plays a significant role in invasion of urothelial cancer and that the level of activated MMP-2 expression is a useful prognostic indicator.


The role of expression of vascular endothelial growth factor isoforms and platelet-derived endothelial cell growth factor in bladder cancer.


Injury of spleen, pancreas, and bowel during laparoscopic adrenalectomy or nephrectomy

術中合併症を回避するための方法と対処法 臓器損傷を回避するための注意点 副腎・腎摘除術における脾臓・膵臓・腸管損傷


徳島大学泌尿器科におけるBCG膀胱内注入療法の臨床検討

徳島大学泌尿器科におけるBCG膀胱内注入療法の臨床検討


後期研修医がおさえておきたい泌尿器疾患TOP30 尿路造影

後期研修医がおさえておきたい泌尿器疾患TOP30 尿路造影


子宮頸癌副腎転移との識別が困難であった18F-FDG PET/CT陽性副腎皮質線種の1例


限局性前立腺癌に対する密封小線源療法のリスク分類別治療成績

限局性前立腺癌に対する密封小線源療法のリスク分類別治療成績


射精障害を契機に発見されたトルコ鞍空洞症を伴う汎下垂体機能低下症の1例

射精障害を契機に発見されたトルコ鞍空洞症を伴う汎下垂体機能低下症の1例


Symposium: Next generation surgical treatment

シンポジウム1 次世代の外科治療


BCG膀胱内注入療法後に生じたReiter症候群の1例

BCG膀胱内注入療法後に生じたReiter症候群の1例


Late recurrence of renal cell carcinoma: retrospective and collaborative study of the Japanese Society of Renal Cancer.

To evaluate in collaboration the clinical features of late recurrence of renal cell carcinoma (RCC). Late recurrence is one of the specific biologic behaviors of RCC; however, the clinical and pathologic features of the late recurrence of RCC are not fully understood.


Phase III trial of everolimus in metastatic renal cell carcinoma: subgroup analysis of Japanese patients from RECORD-1.

To assess the efficacy and safety of everolimus in Japanese patients with metastatic renal cell carcinoma.


Three-dimensional CT cavernosography: reconsidering venous ligation surgery on the basis of the modern technology.

To examine the feasibility of three-dimensional (3D) CT cavernosography in the diagnosis of corporal veno-occlusive dysfunction.


Training system of laparoscopic surgery for young urologists in the university of Tokushima

効果的効率的な泌尿器腹腔鏡手術医の育成 徳島大学における泌尿器腹腔鏡技術認定医の育成に対する試み


Clinical significance of Galectin-3 in clear cell renal cell carcinoma.

Overexpression of galectin-3 in a variety of cancer cell lines has been shown to correlate with tumor progression and metastasis. In this study, we investigated the expression of galectin-3 in clear cell renal cell carcinoma (CC-RCC) and evaluated the relationship between galectin-3 expression levels and the clinicopathological features of CC-RCC. Expression of galectin-3 in the kidney cancer cell lines Caki-1, Caki-2, A704, ACHN and KPK-1 were evaluated using western blot analysis, while galectin-3 expression in CC-RCC tissues and normal parenchyma were measured by real-time PCR and immunohistochemistry. We found that galectin-3 was overexpressed in the Caki-1, Caki-2, A704, ACHN and KPK-1 cell lines and that the expression level in CC-RCC was also significantly higher than that in renal parenchyma obtained from the same patient samples (p=0.039). Galectin-3 expression in CC-RCC with distant metastasis was also significantly higher than that in CC-RCC without distant metastasis (p=0.045). In conclusion, we revealed that galectin-3 is highly expressed in CC-RCC, especially in CC-RCC with distant metastasis, suggesting that galectin-3 may serve as a novel target molecule for predicting CC-RCC metastasis.

The Journal of Medical Investigation : JMI


Long-term recurrence-free survivor after laparoscopic removal of solitary adrenal metastasis from endometrial adenocarcinoma.

Solitary adrenal metastasis from endometrial adenocarcinoma is extremely rare. We report herein the case of a laparoscopically resected solitary adrenal metastasis originating from endometrial adenocarcinoma. The patient was a 55-year-old woman who had undergone total abdominal hysterectomy for stage IIIc endometrial carcinoma, followed by 7 courses of adjuvant chemotherapy comprising carboplatin and paclitaxel. However, the patient developed an isolated right adrenal metastasis 15 months postoperatively. The solitary adrenal metastasis (diameter, 5.7 cm) was removed laparoscopically. The patient has now been in good health without recurrence for 5 years and 7 months after laparoscopic surgery. To the best of our knowledge, this is the first case of solitary adrenal metastasis originating from endometrial adenocarcinoma that is controlled for the long term by successful laparoscopic resection.


The role of actinin-4 in bladder cancer invasion.

To examine actinin-4 expression levels in bladder cancer, in particular its levels during cellular growth and invasion. Actinin-4 is an actin-binding protein that is associated with cell motility and cancer metastasis.


Mass screening for prostate cancer in Tokushima city - Analysis of the 3 year results from 2001 to 2003 -

徳島市前立腺がん検診―平成13∼15年度3年間の比較検討―