Steven C. Campbell

ADVANCES IN ANGIOGENESIS RESEARCH: RELEVANCE TO UROLOGICAL ONCOLOGY

PURPOSE Important advances in angiogenesis research are reviewed along with recent data implicating angiogenesis in the pathogenesis of urological malignancies. MATERIALS AND METHODS The current understanding of angiogenesis and its importance in tumor biology is summarized. The rationale for anti-angiogenic therapy is reviewed and the clinical experience with these agents is discussed. An extensive literature search of angiogenesis in urological malignancies was performed. RESULTS Quantitative immunohistochemistry for endothelial antigens suggests that, as is the case with many other tumors, induction of angiogenesis contributes to the malignant phenotype of prostate and bladder carcinomas. Anti-angiogenic agents have demonstrated efficacy against urological tumors in experimental systems, and recent data suggest that these agents may also be useful for chemoprophylactic purposes. Putative angiogenesis inducers specific for each of the major urological malignancies have been identified. Quantitation of the expression of angiogenesis inducers and estimation of microvessel density have demonstrated prognostic value for urological malignancies. CONCLUSIONS The available data indicate that angiogenesis has an important role in the progression and metastasis of urological malignancies. Preclinical data coupled with experience in other cancers indicate that combining anti-angiogenic therapy with conventional treatment modalities has the potential to improve dramatically our management of these malignancies. Further research will be needed to define the mechanisms controlling angiogenesis in urological malignancies and to determine if any of the angiogenic correlates will be of genuine clinical use. The rapid pace of research in this field suggests that this aspect of tumor biology will soon have an increasingly important role in the evaluation and treatment of urological cancers.

Biochemical disease-free survival following adjuvant and salvage irradiation after radical prostatectomy

PURPOSE To present the biochemical cure rates (biochemically no evidence of disease) after external irradiation (RT) in patients with high-risk prostate cancer after radical prostatectomy. METHODS AND MATERIALS Seventy-six patients who underwent radical prostatectomy and subsequent RT were included in this analysis. No patient received hormonal therapy. Adjuvant RT was administered in 35 patients (46%), and 41 patients (54%) underwent salvage RT. After prostatectomy, the Gleason score was <7 in 87%, and 24% had seminal vesicle invasion. The median RT dose in the adjuvant RT and salvage RT groups was 60 Gy and 65 Gy, respectively. The biochemical cure rate was defined as a serum prostate-specific antigen of < or =0.2 ng/mL. RESULTS The overall 5-year Kaplan-Meier biochemical control rate from the end of RT was 70%. The 5-year biochemical cure rate for adjuvant RT was significantly superior to that after salvage RT (86% vs. 57%). The significant predictors of biochemical failure were seminal vesicle invasion in the adjuvant RT group and the presence of Gleason grade 4 or 5 in the salvage RT group. The clinical local control rate in the prostate bed was 100%. CONCLUSION This report demonstrates the efficacy of RT in achieving high biochemical cure rates after radical prostatectomy. Additional clinical studies are required to determine the optimal treatment of patients at high risk of biochemical failure after postprostatectomy RT.

p53 AND MICROVESSEL DENSITY IN PRIMARY RESECTION SPECIMENS OF SUPERFICIAL BLADDER CANCER

PURPOSE p53 Regulates angiogenesis in fibrosarcoma and correlative studies suggest a similar role for muscle invasive bladder cancer. We evaluated the associations of p53 status and microvessel density with pathological features and clinical outcomes in a large population of patients with superficial bladder cancer. In addition, we assessed the correlation of p53 status with microvessel density, which would suggest the regulation of angiogenesis by p53. MATERIALS AND METHODS We stained 84 primary bladder resection specimens, including 55 stage pTa, 29 stage pT1, 27 grade 1, 35 grade 2 and 22 grade 3 samples, for p53, CD31 and CD34. The relationships of p53 or microvessel density and tumor stage-grade or clinical recurrence-progression were analyzed by analysis of variance and pairwise comparison analysis for least significant difference, and Pearson correlation coefficients. Only patients with no previous biopsy were included in analysis to preclude interference by granulation tissue related neovascularization. The 4 samples with significant inflammation were also excluded from study. RESULTS At a mean followup of 33 months (range 1 to 93) 34 of 84 patients (40.4%) experienced 1 or more tumor recurrences and 10 (11.9%) had stage and/or grade progression. Statistically significant associations were observed of p53 immunostaining and microvessel density with tumor stage and grade (p <0.05). However, the association of p53 status with microvessel density was weak and not statistically significant. Similar results were observed for the CD31 and CD34 based estimates of microvessel density. Neither p53 status nor microvessel density correlated with recurrence or progression. CONCLUSIONS Our study confirms the strong association of p53 and microvessel density with the well established prognostic factors of grade and stage in superficial bladder cancer, supporting other evidence of an important role for p53 and angiogenesis in the tumor biology of this disease. However, our data argue against a primary role of p53 in the regulation of angiogenesis in superficial bladder cancer. This study, which to our knowledge is the first to focus on primary resection specimens, suggests that other genetic or environmental factors may contribute to the regulation of angiogenesis in superficial bladder cancer.

Hand-assisted vs. retroperitoneal laparoscopic nephrectomy.

PURPOSE We retrospectively compared our initial experience with the hand-assisted and retroperitoneal laparoscopic nephrectomy techniques to determine if there are important differences between these approaches. PATIENTS AND METHODS Twenty-four laparoscopic cases consisting of 12 hand-assisted and 12 retroperitoneal nephrectomies were compared. All cases but one were radical nephrectomies with intact specimen extraction performed for suspected stage T1 neoplasms. Data were collected from medical records and a postoperative questionnaire. To determine if significant learning curves existed, the first six nephrectomies in each group were compared with the second six nephrectomies on the basis of operative criteria. The two groups did not differ significantly in age, body mass index, ASA rating, or number of previous abdominal operations. RESULTS Although the mean tumor volume was greater in the hand-assisted group than the retroperitoneal group, the difference did not quite reach statistical significance (91.19 v 24.7 cc3; P = 0.06). The mean operative time, estimated blood loss, narcotic use (milligrams of intravenous morphine equivalent), hours to oral intake, hospital stay, and estimated percent activity at 2 weeks for the hand-assisted group (238.33 min, 293.75 mL, 35.7 mg, 17.56 hours, 4.4 days, 74.75%, respectively) were not significantly different from the values in the retroperitoneal group (255.83 min, 141.67 mL, 24.5 mg, 22.36 hours, 3.6 days, 76.91%). We found no significant difference in the mean operative times for the first and second six cases in either group. CONCLUSION In the initial experience and comparison of hand-assisted and retroperitoneal laparoscopic nephrectomy, we found no significant differences in operative time, estimated blood loss, narcotic usage, hours to oral intake, hospital stay, or activity level at 2 weeks postoperatively. A randomized trial is under way at our institution.

The role of hypoxia and p53 in the regulation of angiogenesis in bladder cancer.

PURPOSE Our previous studies defined thrombospondin-1 (TSP-1) and vascular endothelial growth factor (VEGF) as the primary mediators of angiogenesis in the bladder and the loss of inhibitory TSP-1 as a key event in the transition to an angiogenic phenotype during bladder cancer development. We evaluated the role of p53, which is commonly inactivated in bladder cancer, and hypoxia in the regulation of angiogenesis in the bladder. MATERIALS AND METHODS The p53 status was modulated in normal urothelial and bladder cancer cells, and conditioned media was collected under normal oxygen or hypoxic (0.5% O2) conditions. Angiogenic activity was evaluated with the endothelial cell migration assay, and the levels of secreted TSP-1 and VEGF were determined by Western blot analysis and enzyme-linked immunosorbent assay, respectively. RESULTS Retroviral mediated expression of the E6 oncoprotein reduced wild-type p53 levels in normal urothelial cells by greater than 90% but did not significantly alter TSP-1 or VEGF levels, while total inductive and inhibitory activities remained unchanged. Adenoviral mediated expression of wild-type p53 was confirmed in 4 bladder cancer cell lines by Western blot analysis for p53 and its downstream effector protein p21 (2.5 to 5.0-fold increase). TSP-1 levels remained unchanged but the levels of secreted VEGF in the high grade UMUC-3 and 253J cell lines were significantly decreased 5 to 50-fold and a corresponding decrease in net angiogenic activity was observed. However, (increased expression) of p53 had no effect on the angiogenic activity of the low grade RT4 or high grade HT1376 bladder cancer cells. Hypoxia converted normal urothelial cell derived conditioned media from anti-angiogenic to angiogenic and increased the angiogenic activity of bladder cancer cell derived conditioned media. This change was due to 2.5 to 6-fold hypoxic up-regulation of VEGF because the expression of inhibitory TSP-1 was not significantly altered. CONCLUSIONS Our results suggest that p53 does not regulate angiogenesis in the bladder in the setting of an otherwise normal genome and gene therapy with wild-type p53, which is currently being studied for this cancer, may have only limited effects on angiogenesis. In contrast, hypoxia regulates angiogenesis in this system, primarily through its effects on VEGF.

Contemporary management of renal cell carcinoma with coexistent renal artery disease : Update of the cleveland clinic experience

OBJECTIVES To treat concurrent renal cell carcinoma (RCC) and renal artery disease (RAD), which pose an unusual and challenging management dilemma. METHODS Before June 1998, 48 patients presented with localized RCC and RAD affecting all the functioning renal parenchyma. These patients were grouped into four distinct categories: group 1, a solitary kidney with RCC and RAD (n = 8); group 2, bilateral RCC and coexistent RAD (n = 9); group 3, unilateral RCC and contralateral RAD (n = 15); and group 4, unilateral RCC and bilateral RAD (n = 16). The most common cause of RAD was atherosclerosis (n = 40), followed by medial fibroplasia (n = 5), renal artery aneurysm (n = 2), and arteriovenous malformation (n = 1). RESULTS All patients underwent complete surgical excision of RCC. A nephron-sparing operation was performed preferentially (44 patients), and bilateral renal cancer operations were staged. Eleven patients underwent surgical renal vascular reconstruction in conjunction with either partial (n = 9) or radical (n = 2) nephrectomy. In 2 patients, renal revascularization was accomplished by percutaneous transluminal angioplasty before tumor excision. No perioperative deaths occurred. Postoperatively, preservation of renal function was achieved in 47 patients; 1 patient required chronic dialysis. The overall and cancer-specific 5-year patient survival rates in this series were 66% and 90%, respectively. At a mean follow-up of 58 months, 28 patients were alive with no evidence of malignancy. Six patients died of metastatic RCC, and 14 died of unrelated causes with no evidence of malignancy. CONCLUSIONS Nephron-sparing surgery combined with selective renal arterial reconstruction can yield gratifying results in this complex patient population.

Solitary fibrous tumor of the prostate a report of 2 cases and review of the literature.

We report 2 cases of solitary fibrous tumor of the prostate. Histologically, both tumors demonstrated a multipatterned architecture with varying degrees of collagenization and hemangiopericytoma-like foci, and both were composed of CD34-immunopositive spindled cells that insinuated themselves between strips of collagen. The tumor in case 1 was well circumscribed and showed minimal mitotic activity or pleomorphism, whereas the tumor in case 2 was more cellular, less collagenous, had a more diffuse growth pattern, and exhibited cytologic atypia and high mitotic activity. Prostatic solitary fibrous tumor must be distinguished from other spindle cell tumors reported to occur in the prostate. To our knowledge, these cases represent only the fifth and sixth reported cases of prostatic solitary fibrous tumor.

Evaluation of the Renal Mass

The detection and evaluation of renal masses have changed significantly in this era of ubiquitous abdominal imaging for myriad signs and symptom complexes. Currently, the extended use of ultrasonography (US), computed tomography (CT), and magnetic resonance imaging (MRI) has rendered incidental discovery by cross-sectional imaging the most common presentation of a renal mass. The assessment of renal masses is complex, because of the predominance of renal lesions, the vast majority of which are benign in nature. The ultimate goal of evaluation of the patient with a renal mass is accurate diagnosis and staging by clinical and radiographic means, leading to timely treatment and avoidance of unnecessary procedures.

Antiangiogenic Approaches to Renal Cell Carcinoma

Angiogenesis-the formation of new blood vessels from preexisting ones-is a complex process regulated by a number of soluble factors as well as important interactions between endothelial cells, extracellular matrix components, and adjacent cells (1-5). Activation of the endothelial cell, which occurs when the balance between proangiogenic and antiangiogenic signals within a given microenvironment tilts in a positive direction, leads initially to increased expression of proteases, allowing the endothelial cell to mobilize itself and release inducers sequestered within the matrix (1,6,7). This is followed by endothelial-cell proliferation and migration and culminates in reorganization of the endothelial cell plexus to form tubules and eventually capillary structures that can conduct blood. Most proangiogenic factors-such as VEGF and basic fibroblast growth factor (bFGF)-are peptide growth factors that bind to transmembrane-receptor tyrosine kinases on the surface of the endothelial cell, initiating intracellular transduction pathways resulting in cellular activation (8,9). Other important angiogenic factors-the angiopoietins-further modulate this process by stabilizing or destabilizing interactions between small blood vessels and adjacent pericytes (10 ). Expression of angiopoietin 2 results in dissociation of pericytes, which can lead to endothelial-cell activation or vascular regression, depending on whether angioinductive or angioinhibitory signals predominate (10,11). In contrast, angiopoietin 1 stabilizes interactions with pericytes and promotes vascular quiescence (10,12).

The Radiologic Evaluation of Renal Masses

The detection and evaluation of renal masses have changed significantly with improved radiographic techniques such as ultrasonography, CT, and magnetic resonance imaging (MRI). Historically, due to their retroperitoneal location, renal masses often remained clinically silent until large enough to cause local signs and symptoms, a frequent harbinger of advanced disease [1]. Currently, in an era of ubiquitous imaging with ultrasonography or CT for various complaints, incidental discovery by cross-sectional imaging with ultrasonography or CT has become the most common presentation of a renal mass [2–4]. Significantly, increased detection has led to diagnosis of renal cell carcinomas (RCCs) that are smaller and of a lower stage, with fewer patients presenting with metastatic disease [2,5–7]. Ultimately, serendipitous discovery of smaller lesions should correspond to improved cure rates and increased patient survival.