Contrast-enhanced transrectal color doppler ultrasonography (TRCDUS) for assessment of angiogenesis in prostate cancer.

BACKGROUND: The clinical relevance of tumor angiogenesis has been investigated in several human tumors, including prostate carcinoma (PC). Previously, we found angiogenesis, measured as microvessel density (MVD), to be an independent prognostic factor in PC. Therefore, we evaluated contrast-enhanced Transrectal Color Doppler Ultrasonography (TRCDUS) for assessment of angiogenesis in PC. MATERIALS AND METHODS: We investigated 15 patients with PC before radical prostatectomy (RP) and 3 control patients before radical cystoprostatectomy. TRCDUS was performed using a micro-bubble-based ultrasound enhancer Levovist for identifying hypervascularized areas within the prostate. Computer-assisted quantification of color pixel intensity (PI) was used to evaluate objectively the hypervascularized areas; resistive index (RI) measurements were also obtained in these areas. After histopathological examination of the entire prostate gland for tumor confirmation, immunohistochemical evaluation of MVD using a polyclonal antibody against factor VIII was performed as described by Weidner et al. (N Engl J Med 324: 1-8, 1991). TRCDUS findings were correlated with the immunohistochemical data. RESULTS: All patients showed hypervascularized areas (range: 1-9) on contrast-enhanced TRCDUS. Hypervascularized areas showed a sensitivity of 50.8% and a specificity of 95.2% for detecting PC. Analysis of TRCDUS data and immunohistochemistry revealed a significant correlation between PI and MVD in PC specimens, demonstrating a correlation coefficient of r2 = 0.977 (p<0.001). RI did not correlate with MVD. CONCLUSION: Contrast-enhanced TRCDUS showed a high specificity in identifying PC. PI correlated significantly with MVD. Therefore, quantification of color Doppler signals seems to be helpful for assessment of angiogenesis in PC.

Predictive value of total and percent free prostate specific antigen in high grade prostatic intraepithelial neoplasia lesions: results of the Tyrol Prostate Specific Antigen Screening Project.

PURPOSE: We evaluate the predictive values of total and percent free prostate specific antigen (PSA) in regard to high grade intraepithelial lesions in volunteers who participated in the Tyrol PSA Screening Project. MATERIALS AND METHODS: Between June 1995 and December 1998, 1,474 patients undergoing transrectal biopsy of the prostate were evaluated. The primary detection rates of prostate cancer and high grade intraepithelial lesions were evaluated. In addition, the rate of prostate cancer detected on biopsy in patients diagnosed with high grade prostatic intraepithelial neoplasia on the previous biopsy was assessed. Mean total PSA values and mean percent free PSA levels were determined for each study group and compared using the Mann-Whitney U test. RESULTS: A total of 1,077 (73.1%) volunteers had benign prostatic hyperplasia or prostatitis, and 327 (22.2%) had prostate cancer. The primary detection rate for high grade intraepithelial lesions was 4.7% (70 patients) and on repeat biopsy was 38.6% (27). Mean total PSA for the benign prostatic hyperplasia, prostate cancer, high grade and intraepithelial cancer groups were 6.0, 8.7, 5.9 and 5.2 ng./ml., respectively. Mean percent free PSA values for the various groups were 21.9, 12.1, 15.0 and 12.0, respectively. In regard to total PSA there was a statistically significant difference between the prostate cancer and high grade prostatic intraepithelial neoplasia groups (p = 0.016), as well as the prostate cancer and intraepithelial cancer groups (p = 0.028). However, the high grade and intraepithelial cancer groups did not differ significantly. In regard to percent free PSA there were statistically significant differences between the prostate cancer and high grade prostatic intraepithelial neoplasia groups (p = 0.0001), and the high grade and intraepithelial cancer groups (p = 0.013). CONCLUSIONS: In regard to percent free PSA our data indicate a significant difference between high grade intraepithelial lesion and intraepithelial cancer. Due to a substantial overlap in percent free prostate specific antigen between the 2 groups, a clinically useful cutoff point could not be established. Therefore, we recommend repeat biopsy in all patients with high grade intraepithelial lesions regardless of the percent free PSA.

Vascular endothelial growth factor and its correlation with angiogenesis and p53 expression in prostate cancer.

BACKGROUND: Previously it was demonstrated that in prostate tumors, angiogenesis measured as microvessel density (MVD) is associated with tumor stage as well as WHO grade and is an independent predictor of clinical outcome. Vascular endothelial growth factor (VEGF) is a major inducer of angiogenesis. There is some evidence that P53 mutations cause overexpression of VEGF. We studied VEGF expression, p53 overexpression, and P53 mutations in prostate cancer (PCA) to investigate the role of VEGF as an angiogenic marker and the possible deregulation of VEGF as a result of P53 mutations in PCA. METHODS: Immunohistochemical staining with a polyclonal VEGF antibody was performed in 55 paraffin-embedded PCA, in which MVD had previously been determined, as well as in 5 prostatic adenomas (PA) and 20 adjacent normal prostate tissues. In addition, 37 PCA and 5 PAs were examined for p53 expression by immunohistochemistry. Temperature gradient gel electrophoresis (TGGE) was performed in 13 of these PCA to screen for P53 mutations. VEGF expression, p53 expression, and mutations were then correlated with tumor stage, grade, MVD, and clinical outcome. RESULTS: While PA and normal prostate tissue generally showed no or only low VEGF expression, there was a significant increase in VEGF expression with tumor stage, grade, and MVD in PCA. During clinical follow-up (mean, 31.9 months), 9 of 55 patients had tumor progression. Significant differences in VEGF expression were found between patients with tumor progression and those without (P = 0.0004). Of the 37 PCA evaluated for p53 expression, 12 exhibited p53 overexpression. TGGE revealed P53 mutations in 3 of 13 PCA. However, there was no correlation between VEGF expression, p53 overexpression, and P53 mutation, respectively. CONCLUSIONS: VEGF seems to be an important, clinically relevant inducer of angiogenesis in PCA. VEGF expression was shown to correlate positively with tumor stage, grade, MVD, and clinical outcome. However, regulation of VEGF in PCA appears to be independent of p53 expression.

Laparoscopic surgery for stage T1 renal cell carcinoma: radical nephrectomy and wedge resection.

OBJECTIVES: Renal cell carcinoma (RCC) is likely to become one of the most important indications for laparoscopic surgery. We herein report our experience. METHODS: From April 1994 until April 1999, 98 patients presenting with RCC were treated laparoscopically by either radical nephrectomy (RN; n = 73) or wedge resection (WR; n = 25). The mean age was 62.3 years. The mean tumour diameters were 3.8 cm (RN) and 1.9 cm (WR). All tumours were clinical stage T1 lesions. The transperitoneal approach was used for RN in all patients. For WR either the transperitoneal or the retroperitoneal approach was used. In 15 patients, the adrenal gland was removed simultaneously. The specimen was entrapped in an organ bag and removed intact through a small muscle-splitting incision in the lower abdominal wall. RESULTS: RN: The mean operating time was 142 (range 86-230) min, the mean blood loss was 170 (range 0-1,500) ml, and the mean postoperative hospital stay was 7.4 (range 3-32) days. Minor complications occurred in 4.0% of the patients, while major complications were seen in 8.0% of them. WR: The mean operating time was 163.5 (range 90-300) min, the mean blood loss was 287 (range 20-800) ml, and the postoperative hospital stay was 8.0 (range 3-8) days. Minor complications: 4%, major complications: 8%. Histology revealed RCC stage T1 in 77 patients, stage T3a in 7, and stage T3b in 3 patients, oncocytoma in 2 patients, angiomyolipoma in 2, renal adenoma in 1, renal metastasis in 1, multilocular cysts in 4, and renal abscess in 1 patient. Over mean follow-up periods of 13.3 and 22.2 months for RN and WR, respectively, neither local recurrences nor metastases have been observed among patients with histologically confirmed RCC. CONCLUSIONS: Laparoscopic surgery for clinical stage T1 RCC is safe and efficient. Excellent tumour control can be achieved. However, longer follow-up periods will be necessary to confirm these results.

Tumor angiogenesis is associated with progression after radical prostatectomy in pT2/pT3 prostate cancer.

BACKGROUND: The clinical relevance of tumor angiogenesis has been investigated in several human tumor types. Angiogenesis (measured as microvessel density; MVD) was recently correlated with tumor stage, grade, and clinical course in prostate cancer (PC). However, considerable controversy remains concerning the prognostic value of angiogenesis in PC. METHODS: We examined MVD in primary PCs to further establish the prognostic relevance of angiogenesis in this tumor entity. In 98 paraffin-embedded PCs of various stages, 5 prostate adenomas, and 20 normal prostate tissues, MVD was determined immunohistochemically using a polyclonal antibody against factor VIII. The findings were correlated with the clinical data of the patients. RESULTS: Normal prostate tissue and prostate adenomas had a low MVD. In PC, MVD increased significantly with tumor stage and grade (P < 0.001). The Wilcoxon rank statistics showed significant differences for MVD (P < 0.0001), tumor stage (P < 0. 0027), and grade (P < 0.0001), but not for preoperative prostate-specific antigen values in PC patients with and without tumor progression subsequent to treatment, respectively. Importantly, multivariate survival analysis revealed that MVD and tumor grade were the only independent markers for progression in prostate carcinoma. CONCLUSIONS: In this study, tumor angiogenesis measured by MVD was associated with a dismal pathologic appearance and a negative clinical prognosis in PC after radical prostatectomy.

Pathophysiology of tumor angiogenesis and its relevance in renal cell cancer.

In many cases, solid tumors exhibit numerous and highly permeable blood vessels. For a long time, this observation drew little attention. In the early 70's, however, Folkman proposed for the first time the potential relevance of tumor angiogenesis (formation of new vessels) for tumor growth and metastasis (6). He realized that tumors up to a diameter of 1-2 mm could be nurtured with oxygen and energy simply by diffusion (prevascular phase). Further growth, however, would require newly formed blood vessels. He hypothesized that (assuming the formation of new vessels was essential for tumor growth) pharmacological inhibition of angiogenesis could be developed as a new, more specific form of tumor treatment. In recent years, several groups have investigated the pathophysiology of tumor angiogenesis. Folkman's hypothesis that tumor growth is dependent on the formation of new vessels was supported by several experiments: Implants of different tumors into an avascular cornea initially have a slow growth rate that increases exponentially after infiltration of new vessels into the tumors (9). Inversely, the growth rate of solid tumors decreases with increasing distance to the supplying capillaries (27). The onset of neovascularization at the bases of human melanomas is directly associated with tumor growth and metastasis (25). Experiments with transgenic mice have demonstrated that the transition from hyperplastic to malignant cell growth occurs parallel to the onset of angiogenesis (7). Tumor vessel density has been shown to be associated with tumor progression and the clinical course in many human tumors (e.g. of the breast, lung, colon, cervix, prostate and bladder). Aside from the basic research on the formation of new (tumor) vessels, it is the therapeutic potential of various inhibitors of angiogenesis, some of which are currently tested in clinical (phase I/II) studies, that deserves special scientific attention. This review gives an overview of the relevance of angiogenesis for tumor growth, especially for renal cancers. It also discusses the potential advantages and disadvantages of different anti-angiogenic therapeutic approaches.

Analysis of the DCC tumor suppressor gene in testicular germ cell tumors: mutations and loss of expression.

Inactivation of the DCC (Deleted in Colon Carcinoma) tumor suppressor gene by allelic loss and/or reduced expression is associated with the development of colon cancer, gliomas, gastric and prostatic malignancies. In a total cohort of 51 testicular germ cell tumors (GCT) of different histologies we analyzed restriction fragment length polymorphism (RFLP) for DCC at two specific DNA sites in 37 GCT and DCC mRNA expression compared to that of the adjacent normal testicular tissue in 41 GCT, one Leydig cell tumor and one testicular metastasis of a non-small cell lung cancer (NSCLC). Two of 17 tumors (11.7%) informative for the Msp I polymorphic site of the DCC gene and 6/25 tumors (24.0%) informative for variable number of tandem repeat (VNTR) showed loss of heterozygosity (LOH). DCC expression was analyzed by semi-quantitative polymerase chain reaction after initial reverse transcription (RT-PCR). Thirty of 41 GCT (73.1%) and both, the Leydig cell tumor and the testicular metastasis of NSCLC, had a nearly complete or total loss of DCC mRNA expression. Six of 11 (54.5%) seminomas and 24/30 (80.0%) nonseminomas had this loss of expression. Twelve of 17 (70.5%) localized tumors, 9/13 (69.2%) tumors with lymph node involvement and 9/11 (82.2%) tumors with distant metastases showed decreased or absent DCC expression. This data suggests that inactivation of the DCC gene, especially the loss of DCC expression, is associated with the development and progression of human GCT.

[Angiogenesis--principles and significance in urologic tumors]. / Angiogenese--Grundlagen und Bedeutung bei urologischen Tumoren.

Physiologically, angiogenesis in adults is a controlled process which plays a role, for example, in wound healing. Pathological angiogenesis is observed in tumor formation and represents a multifactorial process, in which specific angiogenic factors, as well as growth factors, extracellular matrix proteins and cell adhesion molecules are involved. Tumor growth is characterized by an imbalance in favor of angiogenic over angiogenesis-inhibiting factors. Some of the most frequently examined angiogenic factors are vascular endothelial growth factor, acidic/basic fibroblast growth factors and the platelet-derived endothelial cell growth factor. The most important angiogenesis inhibitors are angiostatin and thrombospondin. To date, the clinical relevance of tumor angiogenesis has been shown for several human tumors. For most urological tumors, the grade of tumor vessel formation, measured as microvessel density, has been associated with metastases, tumor growth and clinical course. The prognostic value of this feature of malignant growth seems to be higher than that of most of the classical and newer prognostic factors. Systematic investigations of tumor angiogenesis are becoming increasingly relevant for diagnostic and therapeutic strategies and offer opportunities for the development of new specific therapeutic approaches in clinical oncology.