The role of angiogenesis in prostate and other urologic cancers: a review.

Angiogenesis is a process critical to both tumour growth and metastasis. It is a dynamic integrated process involving basement membrane degradation, endothelial cell proliferation and migration, and capillary tubule formation. Under normal circumstances, the microvasculature is maintained in a quiescent state. The acquisition of the angiogenic phenotype depends on the outcome of stimulatory and inhibitory regulation by the tumour and its microenvironment. There are markers of angiogenesis that potentially could provide prognostic information in addition to that gained from conventional clinicopathologic data, and antiangiogenic therapy for urologic cancers has potential advantages over current therapeutic strategies. Promising preclinical studies have led to the initiation of phase I studies of antiangiogenic therapy in combination with chemotherapy, which may lead to novel treatments for urologic malignant tumours and may identify new intermediate markers for the response to therapy.

Local tumor control with salvage cryotherapy for locally recurrent prostate cancer after external beam radiotherapy.

PURPOSE: We identified variables associated with a positive prostate biopsy after salvage cryotherapy in patients in whom initial external beam radiotherapy for prostate cancer failed to improve our cryotherapy technique, optimize local control and improve our patient selection criteria for salvage cryotherapy. MATERIALS AND METHODS: Between July 1992 and January 1995, 145 patients underwent salvage cryotherapy. Post-cryotherapy sextant prostate biopsies were performed in 107 cases. We evaluated certain variables on univariate and multivariate analysis as predictors of a positive biopsy after cryotherapy, including the type of previous therapy, tumor stage and grade at initial diagnosis, prostate volume, pre-cryotherapy prostate specific antigen (PSA), number of positive biopsy cores before cryotherapy, PSA nadir after cryotherapy, stage and grade of local recurrence, number of cryoprobes, number of freeze-thaw cycles and use of a urethral warming catheter during cryotherapy. RESULTS: Biopsies were positive in 23 cases (21%) after salvage cryotherapy. Variables associated with a positive biopsy on univariate analysis were initial stage, precryotherapy PSA, PSA nadir after cryotherapy, number of cryoprobes, number of freeze-thaw cycles and a history of chemotherapy (p = 0.005, 0.027, 0.001, 0.009, 0.018 and 0.008, respectively). Variables that remained associated with a positive biopsy on multivariate analysis were the number of probes used and post-cryotherapy PSA nadir (p = 0.013 and 0.019, respectively). CONCLUSIONS: Patients with initial clinical stage T1-2N0M0 disease and PSA no more than 10 ng./ml. have a higher rate of negative biopsies after salvage cryotherapy. Therefore, they are better candidates for salvage cryotherapy for locally recurrent prostate adenocarcinoma after external beam radiotherapy. To optimize the potential for local control the technique of salvage cryotherapy should include 2 freeze-thaw cycles and a minimum of 5 cryoprobes. Detectable PSA after salvage cryotherapy is a strong predictor of local failure.

Differential expression of progression-related genes in the evolution of superficial to invasive transitional cell carcinoma of the bladder.

It is generally accepted that there are dichotomous biologic pathways that lead to the development of either: i) superficial papillary (Ta) transitional cell carcinoma (TCC) or ii) precursor lesions to muscle-invasive (CIS, T1) TCC and muscle-invasive (> or =T2) TCC. We investigated the expression of several progression-related genes to characterize the phenotype of these tumors within these divergent developmental pathways. Using a colorimetric in situ hybridization technique, we examined the expression of mRNAs of several progression-related genes in archival, pathologic specimens from 77 patients with bladder TCC. These genes included basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), interleukin (IL)-8, matrix metalloproteinase (MMP)-9, and epidermal growth factor receptor (EGFR). Relative gene expression was quantified using image analysis. Gene expression was normalized using poly (dT) and the expression of each factor in a panel of specimens of normal urothelium. Patients were stratified according to disease stage, and the level of gene expression among the stratified groups was compared. VEGF, bFGF, IL-8, and MMP-9 expression was increased in muscle-invasive compared with superficial papillary tumors, (p<0.05) and VEGF expression was increased in muscle-invasive tumors compared with CIS specimens (p<0. 05). bFGF, IL-8, and EGFR expression was increased in CIS specimens compared with superficial papillary tumors (p<0.05). The pattern of expression of bFGF, VEGF, IL-8, MMP-9, and EGFR represent the divergent developmental pathways in the pathogenesis of bladder TCC, which characterizes superficial or invasive bladder cancer. bFGF, IL-8, and EGFR appear to be upregulated in early precursor lesions (CIS), whereas VEGF appears to be upregulated at later stages in the development of muscle-invasive TCC.

Major surgery to manage definitively severe complications of salvage cryotherapy for prostate cancer.

PURPOSE: Severe complications of salvage cryotherapy may be debilitating and chronic but these complications may be managed by definitive extirpative surgical procedures. We evaluated the effectiveness of the major surgical procedures performed to manage these complications, and assessed patient survival and complications after extirpative surgery. MATERIALS AND METHODS: Between 1992 and 1995 salvage cryotherapy was performed in 150 men with biopsy proved, locally recurrent prostate cancer after radiotherapy and/or systemic therapy. We retrospectively reviewed patient charts to assess the complications managed by extirpative surgery. RESULTS: Extirpative surgery was performed in 6 of the 150 patients for serious complications, including uncontrollable hematuria, osteitis pubis, rectourethral fistula, refractory perineal pain, bladder outlet obstruction and complete urinary incontinence. Cystoprostatectomy was done in 4 patients, of whom 3 also underwent en bloc pubic symphysectomy. In the remaining 2 men salvage prostatectomy was performed with bladder neck closure and continent catheterizable stomal creation. Surgery successfully managed severe cryotherapy complications in all 6 cases. The complications of extirpative surgery included superficial wound infection in 1 patient and 3 incisional hernias in another. Prostate specific antigen was undetectable in 4 of the 6 men at 36, 38, 39 and 42 months, and detectable in 2 at 31 and 41 months, respectively. CONCLUSIONS: Extirpative surgery may successfully alleviate severe salvage cryotherapy complications without major additive morbidity. Long survival duration justifies extirpative surgery in select patients with severe complications of salvage cryotherapy.

PSP94 expression after androgen deprivation therapy: a comparative study with prostate specific antigen in benign prostate and prostate cancer.

PURPOSE: To examine the clinical use of PSP94 (prostate secretory protein of 94 amino acids) as an androgen independent marker, we conducted a comparative study of prostate samples including benign tissue and cancers which did and did not have androgen deprivation. MATERIALS AND METHODS: Among 163 radical prostatectomy cases 75 had androgen deprivation before operation, while surgery was performed in the remainder without prior hormone treatment. Considering the pathological up grading following hormone therapy, contiguous sections from radical prostatectomy samples were stained for PSP94 and prostate specific antigen (PSA) by immunohistochemistry, and equivalent tumor foci were evaluated by assessing the intensity and extent of the staining. RESULTS: In untreated benign prostate tissue PSP94 and PSA staining was positive and identical in all sections in the no pretreatment group. However, PSP94 expression in the androgen deprivation group was significantly higher than PSA in intensity (p = 0.0005) and extent (p = 0.034). In untreated cancer cases PSP94 intensity and extent demonstrated strong inverse association with Gleason grade (p <0.0001). In contrast, PSA expression was high in every grade, resulting in no statistical association with tumor grade. In the androgen deprivation group PSA staining was decreased in every grade compared to the no pretreatment group. On the other hand, PSP94 expression was decreased in grade 3 tumor foci but increased in grades 4 and 5 tumor foci compared with samples of the corresponding grade in the no pretreatment group (p = 0.0034). CONCLUSIONS: PSP94 expression in benign prostate persists under androgen deprivation compared to PSA. PSP94 synthesis in high grade tumor appears to be activated in the absence of androgen stimulation, indicating the possible alternative pathways in the regulation of PSP94.

Localized bladder cancer.

Transitional cell carcinoma (TCC) of the bladder makes up 90% of bladder cancers. The approach to the management of localized TCC includes accurate clinical and histologic diagnosis and staging with pathologic material obtained through endoscopy. Once the diagnosis of superficial TCC has been established, histologically based prognostic factors guide which therapy or combination of therapies is indicated in the management of individual patients. Surgery alone (transurethral resection) is appropriate initial therapy for noninvasive papillary TCC. For lamina propria invasive tumors and carcinoma in situ, intravesical immunotherapy with bacille Calmette-Guérin (BCG) is often the first line of treatment to decrease tumor recurrence and to possibly decrease progression and improve survival. Intravesical chemotherapy and interferon are alternative therapies that can also decrease recurrence rates. For BCG-refractory TCC, durable response rates with alternative intravesical therapies are low. For superficial TCC that is refractory to endoscopic procedures and intravesical agents or for disease progression, radical cystectomy with neobladder formation or other forms of urinary diversion is the treatment of choice.

Serum bound forms of PSP94 (prostate secretory protein of 94 amino acids) in prostate cancer patients.

PSP94 (prostate secretory protein of 94 amino acids) was regarded as a possible prostate cancer marker, however, it has been controversial. All prior studies were designed to test the free form in serum using antibodies to PSP94. Results presented here demonstrate that PSP94 exists in prostate cancer patients in two forms, free and bound, and that the majority is present as serum bound complexes. This result was demonstrated by using both native and SDS-PAGE analyses of serum proteins from prostate cancer patients. Chromatographic separation of serum total proteins by a molecular sieve column generated two peaks (peak I and II), which were reactive with rabbit antiserum to human PSP94 in Western blot experiments. Peak I was eluted before the IgG fraction at a molecular weight larger than 150 kDa, and peak II appeared after serum albumin ( approximately 67 kDa) was eluted. By using a biotinylated PSP94 as an indicator of the free form of PSP94, we demonstrate that peak I contains serum PSP94-bound complexes and peak II is likely the free form of serum PSP94. Since the molecular weight of serum PSP94-bound complexes is close to IgG during molecular sieve separation, serum PSP94 complexes were further purified through two rounds of protein A column separation, followed by DEAE-ion exchange column chromatography. In vitro dissociation tests of the purified PSP94-bound complexes showed that the binding of serum PSP94-complexes is probably via disulfide bonds and is chemically stable. The results presented here indicate that serum PSP94-bound complexes must be considered in evaluating the clinical utility of PSP94 as a prostate cancer marker.

Metallothionein expression in renal cancer.

OBJECTIVES: To assess metallothionein (MT) expression with immunohistochemical localization in human renal cell carcinoma and to determine whether a possible relationship with the histopathologic findings, tumor grade, or pathologic tumor stage is demonstrable, because MT may have a role in carcinogenesis. METHODS: Archival pathologic specimens and medical records were reviewed for 28 patients with renal cell carcinoma. Immunohistochemical localization of MT was performed with a polyclonal-antibody-to-rat-liver MT, an anti-rabbit IgG linking antibody, and an avidin-biotin horseradish peroxidase complex. Correlation was sought between immunohistochemical data (MT staining intensity, extension, and subcellular site) and clinical data (histologic cell type, tumor grade, and pathologic stage). RESULTS: The mean patient age was 61.7 years (range 42 to 86). The predominant histologic cell type was the clear cell variant. Three, sixteen, and nine tumors were pathologically staged as 1, 2, and 3, respectively. There were 1, 13, 10, and 4 tumors with grades 1, 2, 3, and 4, respectively. Among the independent variables, greater immunoreactivity was observed in Stage 2 tumors (P = 0.028). A significant inverse relationship between tumor grade and MT staining intensity was also observed (P = 0.007). CONCLUSIONS: The inverse relationship in renal cell carcinoma between MT immunoreactivity and tumor grade may indicate a role for MT in tumor growth and dedifferentiation. Increased MT immunoreactivity in lower stage tumors may be related to rapid tumor growth during their growth cycle. Further study is required to elucidate the role of MT in renal cell carcinoma oncogenesis and its possible use as a clinical prognostic parameter.