Androgen deprivation therapy: past, present and future.

Since Huggins and Hodges demonstrated the responsiveness of prostate cancer to androgen deprivation therapy (ADT), androgen-suppressing strategies have formed the cornerstone of management of advanced prostate cancer. Approaches to ADT have included orchidectomy, oestrogens, luteinizing hormone-releasing hormone (LHRH) agonists, anti-androgens and more recently the gonadotrophin-releasing hormone antagonists. The most extensively studied antagonist, degarelix, avoids the testosterone surge and clinical flare associated with LHRH agonists, offering more rapid PSA and testosterone suppression, improved testosterone control and improved PSA progression-free survival compared with agonists. The clinical profile of degarelix appears to make it a particularly suitable therapeutic option for certain subgroups of patients, including those with metastatic disease, high baseline PSA (>20 ng/mL) and highly symptomatic disease. As well as forming the mainstay of treatment for advanced prostate cancer, ADT is increasingly used in earlier disease stages. While data from clinical trials support the use of ADT neoadjuvant/adjuvant to radiotherapy for locally advanced or high-risk localized prostate cancer, it remains to be established whether specific ADT classes/agents provide particular benefits in this clinical setting.

Autophagy is increased in prostate cancer cells overexpressing acid ceramidase and enhances resistance to C6 ceramide.

Acid ceramidase (AC) overexpression has been observed in prostate cancer cell lines and primary tumors, and contributes to resistance to chemotherapy and radiation. The consequence of AC overexpression is the ability to convert ceramide, which is often produced as a proapoptotic response to stress, to sphingosine, which can then be converted to the prosurvival molecule sphingosine-1-phosphate. In addition to their ability to metabolize ceramide produced in response to stress, we show here that prostate cancer cell lines overexpressing AC also have increased lysosomal density and increased levels of autophagy. Furthermore, pretreatment with 3-methyladenine restores sensitivity of these cells to treatment with C(6) ceramide. We also observed increased expression of the lysosomal stabilizing protein KIF5B and increased sensitivity to the lysosomotropic agent LCL385. Thus, we conclude that AC overexpression increases autophagy in prostate cancer cells, and that increased autophagy enhances resistance to ceramide.

Adjuvant androgen deprivation therapy augments cure and long-term cancer control in men with poor prognosis, nonmetastatic prostate cancer.

Historically, adjuvant androgen deprivation therapy has been viewed as a palliative treatment option for patients with poor-prognosis non-metastatic prostate cancer. In addition, guidelines from bodies such as the European Association of Urology and American Society for Clinical Oncology do not specifically categorize adjuvant hormonal therapy as being curative in intent. We propose that adjuvant androgen deprivation therapy should now be classified as a treatment of curative intent in patients with poor-prognosis, non-metastatic prostate cancer. By applying a carefully considered definition of cure (based on long-term (10- to 15-year) disease-free survival curves) to the findings from randomized controlled clinical trials that have studied adjuvant hormonal treatments in non-metastatic prostate cancer, we challenged whether this viewpoint should now be considered redundant. According to our review of relevant studies and our definition of cure, goserelin appears to augment cure in a sizeable proportion of men with poor-prognosis non-metastatic prostate cancer when given adjuvant to radical prostatectomy or radiotherapy. Across several trials, the relevant survival curves for the goserelin-treated population became indefinitely flat after long-term follow-up. This indicates that these patients have a mortality risk comparable to the general population without prostate cancer. On the basis of the evidence presented within this review, we believe that, given it can control disease for a long period of time, adjuvant goserelin should be reclassified as a treatment of curative intent for patients with poor-prognosis non-metastatic prostate cancer.

Gunshot wounds to the ureter: a 40-year experience at Grady Memorial Hospital.

PURPOSE: Because of the morbidity associated with missed ureteral injuries, a high index of suspicion must be present to diagnose this type of injury. We reviewed our 40 years of trauma experience at Grady Memorial Hospital. MATERIALS AND METHODS: We retrospectively reviewed the records of 118 patients with ureteral injuries secondary to a gunshot wound to the ureter from 1960 to 1999. All cases were reviewed for the mechanism of injury, location, initial urinalysis, imaging modalities, associated injuries, operative procedures and complications. RESULTS: Our population consisted of patients 14 to 71 years old, of whom 66 had right ureteral, 51 had left ureteral and 1 had bilateral injury. Urinalysis revealed no evidence of blood in the urine in 15% of the patients in whom the test was performed. Excretory urography had a false-negative rate of 33%. The injury was located at the proximal, mid and distal ureter in 43, 38 and 37 cases, respectively. Multiple surgical approaches were used depending on the location and severity of the defect. Only 1 patient had an isolated ureteral injury, while the remainder had associated injuries. Complications were present in 24 cases. CONCLUSIONS: To our knowledge this series of ureteral injuries is the largest reported to date. Because preoperative urinalysis and imaging studies are unreliable for ruling out injury, a high index of suspicion must be present. Furthermore, a predefined trauma protocol, as defined in our algorithm, decreases the number of missed ureteral injuries that may potentially complicate the outcome of an already critical case.

Poor prognosis associated with thrombocytosis in patients with renal cell carcinoma.

OBJECTIVES: To better define the relationship between platelet count and survival using a retrospective analysis in patients with thrombocytosis and metastatic renal cell carcinoma (RCC), some of whom had a shorter life expectancy than those with a normal platelet count. PATIENTS AND METHODS: The records were reviewed of patients with stage IV RCC who had undergone a variety of adjuvant therapies after nephrectomy between 1972 and 1992. Entry criteria included a tissue diagnosis of RCC, at least one platelet count and a complete follow-up until the time of death. Of 350 patients available for review, 259 met the entry criteria. Patients were divided into two groups: group 1 included 112 patients whose platelet counts remained at < 4 x 105/microL between the time of nephrectomy and the time of death; group 2 included 147 patients with at least one platelet count of > 4 x 105/microL (mean age in each group 57 years). RESULTS: The mean (SD) survival for group 1 was 151 (34) months, compared with 92 (18) months for those in group 2. Using the log-rank chi-square test the difference in survival between the groups was significant (P = 0.005). Controlling for established prognostic indicators of pathological stage, nuclear grade and cell type, using Cox's regression technique, the difference in survival between the groups remained significant (P = 0.015). CONCLUSIONS: These results suggest that patients with metastatic RCC who receive adjuvant therapy and have a persistently normal platelet count have a 64% longer life expectancy than those with thrombocytosis. The difference is highly statistically significant when controlled for nuclear grade, cell type and pathological stage.

Embryology, anatomy, and surgical applications of the kidney and ureter.

This article discusses the embryology and anatomy of the kidney and ureter. Surgical approaches, such as the lumbar and thoracoabdominal, are provided. Operations for kidney (i.e., radical nephrectomy, nephroureterectomy, and partial nephrectomy) and ureteric tumors also are discussed.

pT1 urothelial carcinoma of the bladder: criteria for diagnosis, pitfalls, and clinical implications.

One of the challenging areas in genitourinary pathology is the recognition of early invasion in urothelial neoplasia. Not uncommon, the patterns of invasion into lamina propria are subtle because a desmoplastic response is absent. Tangential sectioning due to inability to orient transurethral resection of bladder tumor specimens, crush and cautery artifacts further compound this problem. This review is presented to familiarize surgical pathologists with the criteria and different patterns of lamina propria invasion by urothelial carcinoma. Problems and pitfalls associated with the recognition of invasion and the clinicopathologic significance of lamina propria invasive urothelial cancer are also discussed.

Relationship of cytokeratin 20 and CD44 protein expression with WHO/ISUP grade in pTa and pT1 papillary urothelial neoplasia.

The aim of this study was to assess the relationship of immunoreactivity of cytokeratin 20 (CK20) and CD44 across the spectrum of urothelial neoplasia using the WHO/ISUP consensus classification. A total of 120 papillary urothelial pTa and pT1 tumors (8 papillomas, 8 neoplasms of low malignant potential, and 42 low-grade and 62 high-grade carcinomas) were immunostained by using CK20 and CD44 antibodies. The relationships of tumor grade, pathologic stage, recurrences, and progression in stage with CK20 and CD44 immunoreactivity were assessed. WHO/ISUP grade correlated with tumor stage (P < 0.005), recurrence (P = 0.02), and progression in stage (P = 0.031). Normal urothelium showed CK20 immunoreactivity restricted to a few umbrella cells. Expression of CD44 in normal urothelium was restricted to the basal cell layer. Loss of CD44 immunoreactivity and increasing CK20 positivity were significantly associated with increasing tumor grade and stage (P < 0.005). An inverse relationship was observed in the staining patterns of CK20 and CD44 within individual cases, as well as in the aggregate data, with 79.2% of tumors with CD44 loss showing CK20 positivity (P < 0.001). In conclusion, CK20 and CD44 immunoreactivity are significantly related to the WHO/ISUP grade and to each other, and our data suggest their potential combined utility in predicting biologic behavior in patients with papillary urothelial pTa and pT1 neoplasms.

Evaluation of staging lymphadenectomy in prostate cancer.

OBJECTIVES: To prospectively evaluate a clinical algorithm that predicts nodal status in patients with prostate cancer and to assess the impact on the outcome. METHODS: Between September 1988 and December 1994, 192 patients with organ-confined prostate cancer and considered surgical candidates for radical perineal prostatectomy (RPP) were stratified using the algorithm: prostate-specific antigen (PSA) 20 ng/mL or less, Gleason score 7 or lower, and clinical Stage T2a or lower. Patients failing any of these criteria were placed in the high-risk group and underwent a pelvic lymphadenectomy. Patients who satisfied all the criteria were placed in the low-risk group and underwent RPP without evaluation of the pelvic lymph nodes. Another contemporaneous cohort of patients (n = 65) underwent pelvic lymphadenectomy and radical retropubic prostatectomy (RRP) without use of the algorithm and were used as a control group. Patients were monitored for at least 24 months. RESULTS: In the RPP group, 177 patients were considered low risk according to the algorithm and were not offered staging lymphadenectomy before surgery, whereas 15 patients were categorized as high risk for metastasis and underwent staging lymphadenectomy. In the RRP and lymphadenectomy group, 41 patients were considered at low risk and 24 at high risk of disease spread according to the algorithm. In the RPP group, low-risk patients (no lymphadenectomy) had a PSA recurrence rate (27%) similar to that of low-risk patients in the RRP group with negative lymph nodes (29%), P = 0.8. Similarly, high-risk patients with negative lymph nodes in both groups had a similar recurrence rate (53% for RPP and 50% for RRP). Univariate logistic regression analysis showed that PSA was the most significant predictor for disease recurrence (P = 0.0004) followed by preoperative Gleason scores (P = 0.02) and clinical stages (P = 0.03). Multivariate stepwise analysis demonstrated that Gleason score and clinical stage did not add to the prediction of recurrence over PSA alone. CONCLUSIONS: Staging lymphadenectomy can be omitted in low-risk patients without deleterious effects on the outcome as measured by PSA recurrence.

Two cases of vasculitis of the urinary bladder: diagnostic and pathogenetic considerations.

BACKGROUND: Vasculitis involving the urinary bladder is rare and difficult to diagnose. Organ-isolated vasculitis challenges pathogenetic theories. METHODS AND RESULTS: A human immunodeficiency virus- and hepatitis B virus-infected man with hematuria and a mass lesion was initially given a clinicopathologic diagnosis of bladder hamartoma. Over 11 months, without immunosuppressive therapy, there were multiple "recurrences" of the tumor with progressive distal ureteral obstruction, but no evidence of systemic vasculitis. Polyarteritis nodosa-like vasculitis with positive immunostaining for hepatitis B surface antigen in urothelium and vessels was found on review. A second patient, presenting with signs and symptoms suggesting transitional cell carcinoma in situ, was found to have small vessel vasculitis. CONCLUSIONS: Bladder vasculitis should be considered in the differential diagnosis of neoplasia. Extrahepatic hepatitis B virus infection may be related to the organ specificity in some cases of vasculitis.

Camptothecin analogues/cisplatin: an effective treatment of advanced bladder cancer in a preclinical in vivo model system.

OBJECTIVE: To evaluate the impact of the camptothecin analogs on human TCC xenograft, both as monotherapy and in combination with cisplatin (CDDP). MATERIALS AND METHODS: Human transitional cell carcinoma (TCC) xenograft tumor line (DU4184) tested by subrenal capsule assay in 112 nude mice(NM-SRCA). CDDP and the camptothecin analogs irinotecan (CPT-11) and 9-aminocamptothecin(9-AC) were evaluated. RESULTS: Both of the camptothecin analogs showed significant short term tumor inhibition which translated into enhanced survival. Maximal tumor inhibition (>95%) was achieved when either of the camptothecin analogs was combined with CDDP with minimal host toxicity. This translated into 400% increase in median survival. While all controls were dead 39 days following tumor implantation, none of the combination treated animals had died. CONCLUSION: The combination of CDDP with these camptothecin analogs is an effective therapy against this model of advanced TCC. These observations suggest potential clinical value.

Normal range prostate-specific antigen versus age-specific prostate-specific antigen in screening prostate adenocarcinoma.

OBJECTIVES: Prostate-specific antigen (PSA) has become the most useful serum tumor marker in the diagnosis and screening of prostate adenocarcinoma. The currently cited reference range of normal (0 to 4.0 ng/mL monoclonal) lacks both the sensitivity and specificity to be universally accepted as a screening test, and alternatives to serum PSA have been proposed, such as PSA density, PSA velocity, and age-adjusted PSA. Age-adjusted PSA takes into account the facts that as men grow older the prostate enlarges and that screening should have maximum sensitivity in younger men and maximum specificity in older men. METHODS: A population of 4,710 men with no known history of prostate adenocarcinoma underwent 5,629 examinations by transrectal ultrasound of the prostate (TRUS) from 1987 to 1994. This population consists of Mobile Urology Group, Mobile, Alabama, and Emory University, Atlanta, Georgia, patient databases. We have examined our data to determine the sensitivity, specificity, and positive predictive values for normal range PSA (0 to 4 ng/mL) versus age-specific PSA values. RESULTS: A total of 2040 patients had an abnormal digital rectal examination (DRE) and 3581 procedures were performed for an elevated PSA and a normal DRE. Biopsies were performed in 2,657 patients with 945 (35.6%) positive for cancer. Criteria for biopsy included elevated PSA (more than 4 mg/mL), PSA density more than 0.15 abnormal DRE, or suspicious TRUS. Patients were grouped according to decade: group 1 (ages 40 to 49 years, n = 183), group 2 (ages 50 to 59 years, n = 1018), group 3 (ages 60 to 69 years, n = 2358), and group 4 (ages 70 to 79 years, n = 1687). CONCLUSIONS: Use of the age-specific range for PSA increases the sensitivity in younger men more likely to benefit from treatment, and decreases the biopsy rate in older patients who may not be candidates for aggressive treatment. Age-adjusted PSA is the most valuable for patients over the age of 70 years of whom 22% would be spared TRUS with biopsy.

Conservative renal surgery. Has it a role in renal cell carcinoma?

Conservative renal surgery is a viable alternative for patients in whom preservation of renal function is important. The long-term survival is similar to that of radical nephrectomy, especially in low-grade malignancies. The technique is unproven in patients with a normally functioning contralateral renal unit, although it may be an option in small, peripheral, low-grade lesions.

Intravesical suramin in the prevention of transitional cell carcinoma.

OBJECTIVES: To examine the effects of intravesical suramin on N-methyl-N-nitrosurea (MNU)-induced bladder tumors in Fischer 344 rats. METHODS: Multiple cohorts of female rats received four biweekly intravesical instillations of MNU. A control group received no other treatment, the experimental group received 25 mg/kg intravesical suramin twice a week beginning at week 6. RESULTS: After 18 weeks from the first instillation of MNU, 60% to 65% of control animals developed papillary transitional cell carcinoma, compared with only 0% to 10% of the suramin-treated animals (P = 0.01 to P = 0.0007). There was no local or systemic toxicity observed. CONCLUSIONS: Intravesical suramin is an effective chemopreventative therapy for transitional cell carcinoma in vivo with minimal toxicity.

Impotence following pelvic fracture urethral injury: incidence, aetiology and management.

OBJECTIVE: To evaluate the potency status of patients undergoing delayed perineal repair following a pelvic fracture urethral injury to determine the incidence and aetiology of impotence. PATIENTS AND METHODS: Long-term potency (> 6 months post-operatively) was subjectively evaluated in 92 patients and correlated with their pre-operative and intra-operative findings. The management of their impotence was aso reviewed. Thirty original pelvic radiographs were assessed independently to determine if the pattern of bony injury was associated with the development of impotence. RESULTS: Fifty-seven patients (62%) remained impotent in the long term with a median follow-up of 48 months (range 12-128) and the operation did not render any potent patient impotent. Self-injection with vasoactive agents was successful in 24 of 27 (89%), suggesting a neurogenic aetiology in the majority. Bilateral pubic rami fracture was also associated with a high incidence of impotence. CONCLUSION: Disruption of the cavernosal nerves lateral to the prostatomembranous urethra behind the symphysis pubis is the most likely cause of impotence in this injury.

Methoxypsoralen phototherapy of transitional cell carcinoma.

OBJECTIVES: The goal of this research was to assess whether methoxypsoralen compounds in combination with ultraviolet light were effective in preventing cellular proliferation in an in vitro model of human transitional cell carcinoma. METHODS: Three methoxypsoralen compounds, 5-methoxypsoralen (5-MOP), 8-methoxypsoralen (8-MOP), and 4'-aminomethyl 4,5'-8'-trimethylpsoralen (AMT), were added in vitro to T-24 transitional cell carcinoma cells. Psoralens directly bind to DNA, cross-linking the strands when exposed to ultraviolet light and thereby prevent cellular division. RESULTS: In vitro activity was demonstrated utilizing AMT and ultraviolet radiation at 320 to 340 nm, preventing cellular proliferation in T-24 transitional cell carcinoma. CONCLUSIONS: Methoxypsoralen compounds in combination with ultraviolet light are effective in preventing proliferation of bladder carcinoma cells in vitro. This therapy may prove to be effective in clinical early stage transitional cell carcinoma and warrants further assessment.

Combination versus single agent therapy in effecting complete therapeutic response in human bladder cancer: analysis of cisplatin and/or 5-fluorouracil in an in vivo survival model.

An in vivo study of cisplatin (CDDP) and 5-fluorouracil (5FU) cytotoxicity was performed using a multidose matrix with a human bladder transitional cell carcinoma xenograft tumor line (DU4284) tested by subrenal capsule assay in 154 nude mice (NM-SRCA). Statistical analysis of initial growth inhibition at 20 days and host survival demonstrates therapeutic, cooperative interaction. Toxic doses of either CDDP or 5FU alone as well as low-dose combinations provided modest or no survival benefit. The single dose of CDDP (7 mg/kg) and of 5FU (100 mg/kg) was best (by analysis of efficacy and toxicity) of those tested and caused > 97% initial regression. While 94% of controls incurred tumor deaths by 225 days, 75% treated at this dose were tumor free and likely cured. Our conclusions were: (a) NM-SRCA human xenograft testing is excellent for rapid in vivo screening of promising treatment strategies to evaluate for efficacy at acceptable toxicity, but confirmation of true therapeutic impact should be sought by correlating initial growth inhibition with host survival; (b) enhanced survival seen only when CDDP/5FU are used together (versus either single agent) supports the value of pursuing histiotype-specific screening of potentially synergistic drug combinations; and (c) of clinical relevance, human transitional cell carcinoma is now identified as a histiotype in which a therapeutic, cooperative interaction between CDDP/5FU has been demonstrated in vivo.

Gastric cancer: the case for a more selective policy in surgical management.

Over a 5-year period 114 patients with gastric cancer were evaluated. Seventy-seven (68%) of these underwent laparotomy, of which 5A (47%) had a resection performed though only 22 (19%) of these were considered curative. Thirty-seven patients (32%) were not offered surgery because they were aged, had poor cardiorespiratory function, or were thought to have advanced disease based on a combination of clinical (fixed epigastric mass, hepatomegaly, jaundice or ascites), radiological and endoscopic features. Overall 5-year survival was 10.9%, with the patients who had curative and palliative resections having 5-year survivals of 24.4% and 18.2% respectively. Eight of the 12 patients who had palliative gastroenterostomy were not satisfactorily palliated, and 9 patients who had 'open and close' laparotomy fared badly with an operative mortality of 44%; mean survival in these two groups was 3.8 and 3 months respectively. Mean survival in patients treated without operation was 5 months. Unit policy in the management of patients with carcinoma of the stomach has been to resect for cure and palliation whenever possible. However, because so many patients present with advanced disease, the avoidance of inappropriate surgery has been an equal priority. In this context, the wider use of ultrasonography, laparoscopy and perhaps computed tomography (CT) may be of help. In this paper, the experience of these 114 patients is reviewed.