Strategy for repeat prostate biopsy: predictors of positive biopsy and additional biopsy location.

PURPOSE: We analyzed patterns of tumor distribution in radical prostatectomy specimens from patients with repeat biopsies to determine additional appropriate biopsy locations for repeat biopsy. METHODS: Between January 2000 and June 2005, a total of 382 patients underwent transrectal ultrasound-guided prostate biopsy. Of these, 47 patients underwent repeat biopsy. Radical prostatectomy was performed for 7 of 22 cancer-positive cases. The 7 specimens were superimposed to create an idealized prostate gland at 3 levels: apex, mid-prostate, and base. We compared these tumor maps with those from 35 initial biopsy positive patients. RESULTS: Prostate cancer was detected in 22 of 47 patients who underwent repeat biopsy. Tumor mapping showed that tumors detected on repeat biopsy in comparison with tumor maps of initial biopsy were dense at the periurethral area of the apex in prostate. CONCLUSIONS: Additional biopsy cores taken from periurethral area of the apex on repeat biopsy might further enhance the detection of cancers.

Bladder cancer cell invasion is enhanced by cross-talk with fibroblasts through hepatocyte growth factor.

OBJECTIVES: To examine the effects of fibroblast-derived humoral factors, especially hepatocyte growth factor (HGF), on the invasive potential of bladder cancer cells. Stromal cells in cancer tissue are thought to play an important role in the transformation and invasion of cancer cells. METHODS: The influence of fibroblast cells (TIG-1 cells) and HGF on the invasive potential of bladder cancer cells (5637, T24, J82, HT1376, and MGHU-1 cells) was evaluated by in vitro cell invasion assay. The expression of HGF and c-Met, which is the receptor of HGF, was examined by reverse transcriptase-polymerase chain reaction. To clarify the relationship between the serum HGF level and invasive bladder cancer, we measured the serum concentrations of HGF in patients with bladder cancer without metastatic disease and normal controls, using an enzyme-linked immunosorbent assay. RESULTS: The in vitro cell invasion assay showed that the number of invading bladder cancer cells was significantly increased by the conditioned medium (CM) of the fibroblast cells. HGF neutralization antibody partially inhibited the enhancement of invasiveness by fibroblast CM. The CM of fibroblasts cultured with bladder cancer CM stimulated cancer cell invasion more strongly (with increased HGF secretion) than did the CM of fibroblasts cultured without bladder cancer CM. The serum HGF levels were significantly greater in patients with muscle-invasive bladder cancer (regardless of tumor size) than in patients with non-muscle-invasive bladder cancer. CONCLUSIONS: The present results have suggested that bladder cancer cell invasion is enhanced by cross-talk with fibroblasts through humoral factors, including HGF. Elucidation of this mechanism could lead to novel therapeutic strategies for bladder cancer.

[A non-seminomatous extra-gonadal germ cell tumor responding to intensive treatment: a case report].

A 23-year-old man presented with lumbago as a chief complaint. Computed tomographic (CT) scan revealed multiple lung tumors, multiple liver tumors, bulky retroperitoneal tumors with marked elevation of serum lactic dehydrogenase (LDH), alpha-fetoprotein, and beta subunit of human chorionic gonadotropin (HCG-beta). The patient was referred to our hospital for treatment. Scrotal ultrasonography and physical examination revealed bilateral normal testes. Because of bulky retroperitoneal masses with elevated specific tumor markers as well as bilateral normal testes, our diagnosis led to extra-gonadal germ cell tumor. Because the pulmonary lesion had increased rapidly, chemotherapy was performed without the tumor biopsy. After multiple chemotherapy regimens including BEP (bleomycin, etoposide, cisplatin), high-dose chemotherapy, and TIN (paclitaxel, ifosfamide, nedaplatin), all tumor marker levels fell into within the normal range. The tumor size was decreased remarkably on CT. Then, retroperitoneal lymphadenectomy were performed to confirm whether they still contained viable tumor cells. They contained only necrotic tissues without viable cancer cells by pathological examination. Consequently, the patient has been free of recurrence for 18 months after intensive treatment.

Clinical research of renal vein control using Hem-o-lok clips in laparoscopic nephrectomy.

Control of the renal vein represents a crucial step in laparoscopic nephrectomy. Although endovascular gastrointestinal anastomosis (GIA) staplers have generally been used for renal vein control because of the large diameter of the vessel, Hem-o-lok clips have recently been used for renal artery control. GIA staplers are expensive and can malfunction on rare occasions, resulting in severe complications. We evaluated renal vein control using Hem-o-lok clips (adaptive vascular width 7-16 mm) in laparoscopic nephrectomy. Since April 2004, we have ligated renal arteries using Hem-o-lok clips. From June 2004, this method was applied for renal vein control in 40 laparoscopic nephrectomies. After renal pedicle dissection, renal pedicle ligation was accomplished using extra large (XL) Hem-o-lok clips on both the renal arteries and veins by placing two clips on the patient side and one clip on the specimen side. Ligation times for obtaining renal vein control were compared between XL Hem-o-lok clips and GIA staplers in 40 cases before June 2004. Vascular control using XL Hem-o-lok clips was successful in all 40 cases, without any slipping of clips or uncontrolled bleeding. After renal pedicle dissection, ligation time for achieving renal vein control was 167.0 +/- 48 s (range: 122-295 s) using XL Hem-o-lok clips (mean, three clips) and 68 +/- 24.0 s (range: 54-150 s) using a GIA stapler. XL Hem-o-lok clips allow safe and reliable control of renal veins in laparoscopic nephrectomy. Ligation time is only 100 s longer than using a GIA stapler. In addition, costs are reduced by more than 90% compared to GIA stapling.

Indications for laparoscopic adrenalectomy for non-functional adrenal tumor with hypertension: usefulness of adrenocortical scintigraphy.

AIM: Laparoscopic adrenalectomy is currently indicated for biochemically and clinically functional adrenal tumors and potentially malignant tumors of the adrenal glands. Non-functional adenomas greater than 5 cm in diameter of the adrenal gland are generally considered to represent potentially malignant tumors. The present study shows indications of laparoscopic adrenalectomy for non-functional adrenal tumors with hypertension in a retrospective fashion. METHODS: Between 1994 and 2004, 110 laparoscopic adrenalectomies were performed at Tokushima University Hospital. All 110 patients underwent detailed endocrinological examination before surgery. Medical and operative records of these 110 patients (57 men, 53 women), including operative parameters, histopathological findings and pre- and postoperative hypertension, were reviewed. Forty-five patients underwent laparoscopic adrenalectomy for non-functional adrenal tumors, and [(131)I]6beta-iodomethyl-19-norcholest-5(10)-en-3beta-ol (NP-59) scintigraphy was performed for patients with preoperative hypertension. RESULTS: Mean patient age was 55.0 years (range, 22-77 years). Mean maximum tumor diameter was 42 mm (range, 20-105 mm). All adrenal tumors were removed successfully by laparoscopic surgery. Hypertension was postoperatively improved in seven of the 11 patients with preoperative hypertension, without subclinical Cushing syndrome. Importantly, all patients who improved hypertension after adrenalectomy displayed strong accumulation in adrenal tumors with visualization of the contralateral gland on NP-59 scintigraphy. Conversely, blood pressure did not improve in four patients for whom scintigraphy yielded negative results. CONCLUSIONS: The indication of laparoscopic adrenalectomy for non-functional adrenal tumors is generally considered for lesions more than 5 cm diameter. However, the present study suggests that laparoscopic surgery should be considered even in patients with tumors less than 5 cm in diameter, if both hypertension and accumulation in tumors on NP-59 scintigraphy are present.

Prostate stem cell antigen predicts tumour recurrence in superficial transitional cell carcinoma of the urinary bladder.

OBJECTIVES: To evaluate the relationship between prostate stem cell antigen (PSCA) expression level in transitional cell carcinoma (TCC) of the urinary bladder and various clinicopathological features, including stage and grade; and to determine whether PSCA mRNA expression predicts disease recurrence in superficial (not muscle-invasive) TCC of the bladder. PATIENTS AND METHODS: Real-time reverse transcriptase-polymerase chain reaction (RT-PCR) was performed on 97 TCC tissue samples and in 36 samples of normal bladder urothelium; the findings were analysed in relation to clinicopathological factors. Immunohistochemical expression was examined using light and confocal immunofluorescence microscopy to validate the RT-PCR data. RESULTS: Twenty-seven patients developed disease recurrence, while the remaining 22 had no evidence of recurrence of superficial TCC of the bladder. There was significantly higher PSCA mRNA expression in TCC than in normal urothelium samples (P = 0.008). Superficial (TaT1) tumours had significantly higher PSCA expression than muscle-invasive (> or = pT2) tumours (P < 0.001). There was no significant difference between patients with G1-2 tumours and those with G3 tumours (P = 0.109). Immunohistochemical analysis showed markedly greater PSCA expression in superficial than invasive TCC. Notably, from a multivariate analysis, the expression level of PSCA was an independent predictor of disease recurrence in superficial TCC (P = 0.012). CONCLUSIONS: These findings suggest that the PSCA expression level measured by real-time RT-PCR could be a valuable prognostic marker for tumour recurrence in superficial TCC of the bladder.

[A case of renal capsular hemangiosarcoma].

We report herein a case of renal capsular hemangiosarcoma. A 68-year-old man was admitted to our hospital for treatment of a retroperitoneal tumor identified incidentally on abdominal computed tomography (CT) for follow-up of superficial bladder tumor. The tumor was about 7cm in diameter, positioned between the right kidney and the liver. Right nephrectomy was performed under a diagnosis of renal capsular tumor. Pathological diagnosis was hemangiosarcoma and positive surgical margins were suspected. Radiotherapy was performed postoperatively to a total dose of 50 Gy. Hemangiosarcoma frequently occurs in the skin, but is rare in the retroperitoneal cavity. Neither metastasis nor recurrence has been seen as of 19 months postoperatively.

Differences in gene expression between noninvasive and invasive transitional cell carcinoma of the human bladder using complementary deoxyribonucleic acid microarray: preliminary results.

This study was performed to identify differences in gene expression between superficial noninvasive and invasive transitional cell carcinoma (TCC) of the bladder in human beings. We used complementary deoxyribonucleic acid microarrays containing 14,551 different genes to analyze gene expression among 6 cases of superficial and 6 cases of invasive TCC of the bladder to identify differences in gene expression, which might explain differences in the biology and clinical outcomes of these histologic subtypes of TCC. Quantitative real-time polymerase chain reaction was performed for selected genes to validate the microarray data. Significant up-regulation of 40 genes was associated with cases of superficial noninvasive, but not in invasive, TCC of the urinary bladder. This effect included genes involved in epithelial cell dedifferentiation and keratinization, as well as genes related to cell cycle, cell adhesion, transcription, and apoptosis. Conversely, significant up-regulation of 34 genes was associated with cases of invasive TCC, but not in superficial TCC, including genes related to extracellular matrix degradation, immune responses, cell cycling, and angiogenesis. This study shows the usefulness of complementary deoxyribonucleic acid microarray technology for identifying differences in gene expression among different histotypes of bladder cancer.

Prognostic significance of matrix metalloproteinases-2 activation ratio in renal cell carcinoma.

BACKGROUND: Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases. MMP-2 and MMP-9 have been reported to be closely associated with tumor invasion and metastasis in various human carcinomas. METHODS: Tissue samples were obtained from 57 patients with renal cell carcinoma (RCC) who underwent radical nephrectomy in our hospital. We examined the expression of MMPs by gelatin zymography and assessed correlations with clinico-pathological parameters and clinical outcomes. RESULTS: We detected bands corresponding to MMP-9, proMMP-2 and active MMP-2. The expression of active MMP-2 and MMP-2 activation ratio (active MMP-2/[proMMP-2 and active MMP-2]) were higher in T3 tumors than in T1 and T2 tumors. There were no significant differences in the expression of proMMP-2, active MMP-2 or MMP-9 for any of the clinico-pathological parameters. Patients with high MMP-2 activation ratio or high MMP-9 had significantly worse cause-specific survival. Interestingly, among patients with stage III RCC, those with high MMP-2 activation ratio or high active MMP-2 had significantly worse cause-specific survival. Univariate analysis showed that histological grade (P = 0.0001), histologic type (P = 0.0005), MMP-2 activation ratio (P = 0.0159), stage (P = 0.0001), MMP-9 (P = 0.0316), and T (primary tumor) category of TNM (primary tumor, lymph node, metastasis) classification (P = 0.0021) were significant predictors of clinical outcome. Multivariate analysis showed that only histological grade (P = 0.002) and stage (P = 0.0099) were independently significant predictors of clinical outcome. CONCLUSION: Activation of MMP-2 appears to play important roles in initiating metastasis, as shown by results obtained with stage III RCC patients. However, further study is needed to confirm this.

Expression of angiostatin cDNA in a murine renal cell carcinoma suppresses tumor growth in vivo.

OBJECTIVES: To investigate the effectiveness of angiostatin gene therapy for renal cancer using a mouse model. The generally poor prognosis of advanced renal cancer indicates the need for new therapeutic modalities. The dependency of solid tumor growth on angiogenesis suggests that antiangiogenic therapy would be effective against renal cell carcinoma, which is generally a hypervascular tumor. METHODS: Murine renal cancer cells (Renca) transfected with murine angiostatin cDNA (AST-Renca) were subcutaneously implanted in BALB/c mice. Subsequently, the macroscopic appearance and volume of tumors were evaluated once per week. Renca cells transfected with empty plasmid DNA (mock-Renca) were used as a control. In addition, histologic sections of tumor were analyzed for neovascularization on the basis of an immunohistochemical analysis for CD31. The antitumor effect of AST-Renca on a parental Renca tumor at a distant site was also evaluated. RESULTS: The mean volume of AST-Renca tumors was significantly less than that of the control vector-transfected tumors 3 weeks after implantation. In the cell proliferation assay, the expression of angiostatin did not inhibit the proliferation of Renca cells in vitro. Immunohistochemical analysis of neovascularization by staining with anti-CD31 antibody revealed that angiostatin suppressed tumor vessel formation. Moreover, implantation of AST-Renca inhibited the growth of parental Renca implanted simultaneously at a distant site. CONCLUSIONS: Expression of an angiostatin transgene can suppress the growth of murine renal cancer through the inhibition of tumor-induced angiogenesis. Angiostatin gene therapy may be effective against renal cancer.

A convenient cancer vaccine therapy with in vivo transfer of interleukin 12 expression plasmid using gene gun technology after priming with irradiated carcinoma cells.

We studied interleukin (IL)-12 gene therapy using a gene gun as a new autologous vaccination strategy for cancer. In the first experiment, BALB/c mice were inoculated with syngeneic murine renal cancer cells (Renca) intradermally in the abdomen. This was followed by an injection of IL-12 expression plasmid using the gene gun. About 40% of the mice exhibited rejection of the tumor after the treatment and these mice also acquired immunological resistance against a secondary challenge with Renca cells. Based on these results, we examined whether antitumor activity can be potentiated when mice undergo combination treatment with intradermal inoculation of irradiated Renca cells and transfection with IL-12 gene. Inoculation of irradiated Renca cells alone was partially effective in inducing antitumor immunity, whereas the combined treatment remarkably intensified this effect. Moreover, this combined treatment inhibited tumor establishment and enhanced survival of the mice with tumor infiltration by CD4(+) and CD8(+) T cells, even when the treatment was started after tumor-implantation at a distant site. This antitumor effect was antigen specific and we confirmed the induction of antitumor cytotoxic T cells by this treatment. These results show that local cutaneous transfer of IL-12 expression plasmid using gene gun technology enhances systemic and specific antitumor immunity primed by irradiated tumor cells.