Complications of radical cystectomy.

Radical cystectomy has become a standard and arguably the best definitive form of therapy for high-grade, invasive bladder cancer. Lower urinary tract reconstruction, particularly orthotopic diversion, has been a major component in enhancing the quality of life of patients requiring cystectomy. As with any major surgery, however, complications do arise. It is important for all surgeons to be familiar with the presentation, prevention and treatment of the major causes of morbidity and mortality associated with radical cystectomy and lower urinary tract reconstruction. The complications discussed are among the most common of the complications seen with cystectomy and urinary-intestinal diversion. There are, in fact, many others that may be encountered, as the published literature testifies, and a thorough understanding as to their presentation, prevention and treatment is equally essential for a successful patient outcome. Adherence to proper surgical technique, familiarization with recent data regarding the most successful treatment methods, and attention to detail in the perioperative period are crucial for minimizing complications in any surgical undertaking. Radical cystectomy with orthotopic neobladder as well as total pelvic exenteration and its modifications need to be considered among the treatment options for patients with muscle invasive bladder cancer or advanced pelvic malignancies. Recent advances in patient selection, surgical technique, and perioperative care have led to decreased morbidity. Despite this, these procedure remain complex with the potential for both short and long-term complications. There is abundant evidence that radical cystectomy for bladder malignancies and pelvic exenteration for primary rectal cancer and cervical cancer can lead to meaningful long-term survival; however, the prognosis after pelvic exenteration for recurrent rectal cancer is not as good. The recent introduction of combined chemoradiotherapy is likely to improve local recurrence rates and may translate into more durable long-term survival. Pelvic exenteration continues to have an important role in the multimodality approach to patients with advanced pelvic malignancies. In conclusion, pelvic exenteration appears to be a safe and effective option for an experienced multi specialty surgical team in the treatment of complex locally advanced pelvic malignancy. The success of pelvic exenteration is highly dependent on good patient selection where an en bloc resection may result in prolonged disease-free survival and long term cure. In recent times the morbidity and mortality of this operation has decreased so that palliative exenteration has a role to help improve quality of life for this difficult group of patients.

EphB4 receptor tyrosine kinase is expressed in bladder cancer and provides signals for cell survival.

We sought to evaluate the biological function of the receptor tyrosine kinase EphB4 in bladder cancer. All of the nine bladder cancer cell lines examined express EphB4 and the receptor could be phosphorylated following stimulation with its cognate ligand, EphrinB2. Out of the 15 fresh bladder cancer specimens examined, 14 expressed EphB4 with a mean sevenfold higher level of expression compared to adjacent normal urothelium. EphB4 expression was regulated by several mechanisms: EPHB4 gene locus was amplified in 27% tumor specimens and 33% cell lines studied; inhibition of EGFR signaling downregulated EphB4 levels; and forced expression of wild-type p53 reduced EphB4 expression. EphB4 knockdown using specific siRNA and antisense oligodeoxynucleotides molecules led to a profound inhibition in cell viability associated with apoptosis via activation of caspase-8 pathway and downregulation of antiapoptotic factor, bcl-xl. Furthermore, EphB4 knockdown significantly inhibited tumor cell migration and invasion. EphB4 knockdown in an in vivo murine tumor xenograft model led to a nearly 80% reduction in tumor volume associated with reduced tumor proliferation, increased apoptosis and reduced tumor microvasculature. EphB4 is thus a potential candidate as a predictor of disease outcome in bladder cancer and as target for novel therapy.

Molecular prognostication in bladder cancer--a current perspective.

The optimal management of bladder cancer depends on the accurate assessment of the tumour's biological potential. Advances in molecular biology and cytogenetics have spurred intense research in identifying and characterising prognostic markers for patients with transitional cell carcinoma (TCC) of the bladder. The molecular changes that occur can be categorised into (1) chromosomal alterations leading to carcinogenesis, (2) cellular proliferation as a result of dysregulation of cell cycle control, and (3) growth control processes such as angiogenesis leading to metastasis. The accumulation of these changes ultimately determines a tumour's clinical behaviour and response to therapy. As the understanding of bladder cancer evolves, novel molecular markers for prognostication will make their way from the research laboratory to the clinical setting with the promise to improve patient care and outcomes.

Comparison of surgery alone with surgery and adjuvant radiotherapy for pT3N0 prostate cancer.

OBJECTIVE: To compare the outcome between patients with pT3N0 adenocarcinoma of the prostate treated with radical prostatectomy (RP) and those receiving RP followed by a planned course of postoperative radiation therapy (RT). PATIENTS AND METHODS: During a period of 22 years 622 patients with pT3N0 prostate cancer were treated in one medical centre by RP. Of these, 199 (32%) were treated with surgery alone while 423 (68%) received planned postoperative pelvic RT (median 48 Gy). Patients were selected for RT by having a higher incidence of adverse prognostic factors than those undergoing RP alone. These prognostic factors included pathological stage (P = 0.001) preoperative prostate specific antigen (PSA) level (P < 0.001) and Gleason score (P = 0.18). The patients' median age was 66 years; the median follow-up was 6.1 years for all patients, 7 years for RP + RT and 5 years for the RP-alone. RESULTS: The 5- and 10-year actuarial survival was 92% and 73%, respectively, for RP + RT patients, and nearly identical for those in the RP-alone group (P = 0.73). The 5- and 10-year disease-free survival (DFS; PSA < 0.05 ng/mL) was 69% and 51%, respectively, for the former, and 71% and 60%, respectively, for the latter group. There was no significant difference in DFS between the treatment groups by pathological stage and Gleason score (P = 0.77). Likewise, there was no significant difference in mean and median time to relapse. A preoperative PSA level of < 10 vs 10-25 vs > 25 ng/mL did not influence overall survival but a PSA of > 25 ng/mL was predictive of DFS (P = 0.02). In a multivariate analysis the Gleason score was the most important predictor for overall survival and DFS (P < 0.001), while pathological stage was predictive of clinical recurrence and DFS (P < 0.001). After controlling for pathological stage and Gleason score, RP + RT patients were predicted to recur at 92% of the rate of RP-alone patients (P = 0.65). In all, 43 (10%) patients developed a clinical recurrence in the RP + RT group, including 30 (7%) patients with distant metastases alone, 13 (3%) with local recurrence, with an additional 88 (21%) who had PSA recurrence (PSA > 0.05 ng/mL). This compared with 13 (6.5%) patients with clinical recurrence, including seven (3.5%) with local recurrence and 23 (11.6%) with PSA > 0.05 ng/mL in the RP-alone group. Postoperative RT was well tolerated and did not add to the incidence of surgical complications. CONCLUSION: We propose that postoperative RT, as described here, helped to reduce the incidence of local recurrence and improved DFS to equal that of a lower-risk group of patients treated with RP alone. A randomized comparison is needed to define the role of adjuvant RT in patients with pT3N0 disease.

Enhanced apoptosis and radiosensitization by combined 13-cis-retinoic acid and interferon-alpha2a; role of RAR-beta gene.

PURPOSE: Combined use of 13-cis-retinoic acid (cRA) and interferon-alpha2a (IFNalpha) induced significant radiosensitization in human cervical cancer ME-180 cell line, whereas it failed to achieve similar radiation enhancement in HeLa cells. The differential radiosensitization could be from the difference of retinoic acid receptor (RAR) expression because RAR-beta was highly expressed in ME-180 cells in contrast to the HeLa cells where RAR-beta was not detectable. We examined the role of this gene in mediating radiosensitization by cRA and IFNalpha, and explored the mechanism of radiation-induced cell killing. METHODS AND MATERIALS: Human cervical cancer cell lines, ME-180 and HeLa, were treated with cRA and IFNalpha followed by radiation. Apoptosis and radiosensitization were quantitated by TUNEL assay (in situ DNA nick end labeling) and colony-forming ability of surviving cells. The cells were transfected with bcl-2 gene and RAR-beta gene to test the role of these genes in mediating radiosensitization and apoptosis. RESULTS: Synergistic radiosensitization and apoptosis was observed by combined use of cRA and IFNalpha with radiation in ME-180 cells which express high level of RAR-beta mRNA, whereas these were not seen in HeLa cells where RAR-beta mRNA is not detectable. Both radiosensitization and apoptosis were abolished by bcl-2 gene in ME-180 cells. RAR-beta gene transfection induced similar radiation enhancement and apoptosis in HeLa cells. CONCLUSION: Apoptosis and radiation response were enhanced in the cells with high level of RAR-beta mRNA expression. The RAR-beta gene appears to mediate the radiation-induced apoptosis by cRA and IFNalpha. These findings indicate that presence of RAR-beta in the cancer cells could be exploited for patient selection in using these drugs for apoptosis and radiosensitization.

T-mechanism applied to urinary diversion: the orthotopic T-pouch ileal neobladder and cutaneous double-T-pouch ileal reservoir.

PURPOSE: As the evolution of lower urinary tract reconstruction continues, newer and improved forms of urinary diversion have developed. Critical components of continent urinary reservoirs included an antireflux and continent mechanism that is effective, durable, easily constructed, and associated with little morbidity. MATERIALS AND METHODS: We describe the flap valve known as the T-mechanism as it applies to an afferent antireflux mechanism in an orthotopic ileal reservoir (T-pouch) and as an antireflux and efferent continence mechanism in the continent cutaneous ileal reservoir (double T-pouch). CONCLUSIONS: We believe the T-mechanism is an extremely effective and versatile flap-valve technique that can be easily learned and applied to the construction of continent urinary diversions.

Surgical approaches to venous tumor thrombus.

The extension of tumor thrombus into the vena cava by renal cell carcinoma remains a technically challenging surgical condition. Attention to surgical detail and perioperative care can provide long-term survival in the appropriately selected patient. In reviewing our experience of 99 patients with venous tumor extension: renal vein only (n = 31), infrahepatic vena cava (n = 22), intrahepatic vena cava (n = 34), and intra-atrial extension (n = 12), we have demonstrated overall 2- and 5-year survival rates of 54% and 33%, respectively. Level of tumor thrombus appears to be correlated with overall survival. We continue to advocate an aggressive, optimistic approach for those patients with clinically confined tumors with isolated venous tumor thrombus extension.

Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients.

PURPOSE: To evaluate our long-term experience with patients treated uniformly with radical cystectomy and pelvic lymph node dissection for invasive bladder cancer and to describe the association of the primary bladder tumor stage and regional lymph node status with clinical outcomes. PATIENTS AND METHODS: All patients undergoing radical cystectomy with bilateral pelvic iliac lymphadenectomy, with the intent to cure, for transitional-cell carcinoma of the bladder between July 1971 and December 1997, with or without adjuvant radiation or chemotherapy, were evaluated. The clinical course, pathologic characteristics, and long-term clinical outcomes were evaluated in this group of patients. RESULTS: A total of 1,054 patients (843 men [80%] and 211 women) with a median age of 66 years (range, 22 to 93 years) were uniformly treated. Median follow-up was 10.2 years (range, 0 to 28 years). There were 27 (2.5%) perioperative deaths, with a total of 292 (28%) early complications. Overall recurrence-free survival at 5 and 10 years for the entire cohort was 68% and 66%, respectively. The 5- and 10-year recurrence-free survival for patients with organ-confined, lymph node-negative tumors was 92% and 86% for P0 disease, 91% and 89% for Pis, 79% and 74% for Pa, and 83% and 78% for P1 tumors, respectively. Patients with muscle invasive (P2 and P3a), lymph node-negative tumors had 89% and 87% and 78% and 76% 5- and 10-year recurrence-free survival, respectively. Patients with nonorgan-confined (P3b, P4), lymph node-negative tumors demonstrated a significantly higher probability of recurrence compared with those with organ-confined bladder cancers (P <.001). The 5- and 10-year recurrence-free survival for P3b tumors was 62% and 61%, and for P4 tumors was 50% and 45%, respectively. A total of 246 patients (24%) had lymph node tumor involvement. The 5- and 10-year recurrence-free survival for these patients was 35%, and 34%, respectively, which was significantly lower than for patients without lymph node involvement (P <.001). Patients could also be stratified by the number of lymph nodes involved and by the extent of the primary bladder tumor (p stage). Patients with fewer than five positive lymph nodes, and whose p stage was organ-confined had significantly improved survival rates. Bladder cancer recurred in 311 patients (30%). The median time to recurrence among those patients in whom the cancer recurred was 12 months (range, 0.04 to 11.1 years). In 234 patients (22%) there was a distant recurrence, and in 77 patients (7%) there was a local (pelvic) recurrence. CONCLUSION: These data from a large group of patients support the aggressive surgical management of invasive bladder cancer. Excellent long-term survival can be achieved with a low incidence of pelvic recurrence.

Molecular markers for diagnosis, staging, and prognosis of bladder cancer.

Conventional histopathologic evaluation of bladder cancer, encompassing tumor grade and stage, is inadequate to accurately predict the behavior of most bladder tumors. Intense research efforts are under way to identify and characterize various bladder cancers and their true biological potential more effectively. The need to predict which superficial tumors will recur or progress--and which invasive tumors will metastasize--has led to the identification of a variety of potential prognostic markers for patients with bladder cancer. The molecular changes that occur in transitional cell carcinoma of the bladder are numerous and can be categorized into (1) chromosomal alterations, leading to carcinogenesis; (2) loss of cell-cycle regulation, accounting for cellular proliferation; and (3) growth control events such as angiogenesis, resulting in metastasis. It is becoming apparent that the accumulation of genetic and molecular changes ultimately determines a tumor's phenotype and subsequent clinical behavior. The potential clinical application of new diagnostic techniques (ie, loss-of-heterozygosity analysis to identify tumor suppressor genes) and older, well-established, techniques (ie, immunohistochemistry) combined with improvements in the use of automated and standardized systems are areas of active investigation.

Indications for early cystectomy.

Treatment goals for superficial bladder cancer are two-fold: (1) reducing tumor recurrence and the subsequent need for additional therapies (cystoscopy, transurethral resection, intravesical therapy) and the morbidity associated with these treatments; and (2) preventing tumor progression and the subsequent need for more aggressive therapy. The administration of intravesical therapy has become an important component in these treatment goals; however, there remains a group of patients with superficial bladder cancer that are at risk of disease progression, metastases, and death from their disease. The treating urologist must be extremely active and diligent when treating patients with superficial bladder cancer. An understanding of tumor biology and current intravesical therapies is important. Furthermore, and perhaps most important, the timely decision to abandon conservative therapy and proceed with radical cystectomy and urinary diversion should be kept in mind to prevent the potentially lethal sequelae of invasive bladder cancer. In view of the potential for recurrence, stage progression, and significant clinical understaging of patients with superficial bladder cancer, and the fact that radical cystectomy provides excellent results with regard to prevention of local recurrence and overall survival, radical cystectomy should be considered in patients with high-risk factors. Radical cystectomy may also provide important prognostic information and influence the decision for adjuvant therapy based on pathologic criteria. Finally, definite improvements in lower urinary tract reconstruction and nerve-sparing techniques have decreased the social implications of cystectomy for both men and women.

Carcinoma of the kidney, testis, and rare urologic malignancies.

The purpose of this symposium was to provide a forum for discussion on current information on the etiology and diagnosis of, and therapy for, tumors of the kidney, testis, and several uncommon malignancies of the genitourinary tract. The most recent contributions in epidemiology and molecular genetics were discussed with specific reference to their importance for clinical practice. Contemporary treatment approaches with the emphasis on multidisciplinary patient management of tumors commonly seen in the clinic as well as those that are only rarely diagnosed by urooncologists were presented. Major stress was given to the management optimization as it pertains to short- and long-term quality of life issues of patients treated for these tumors. Methods to reduce treatment toxicity including carcinogenic potential of chemotherapy, radiotherapy, or their combination were found to be of nearly equal importance to patient survival. Symposium participants reached consensus on a number of important points: 1) The management of patients with several malignancies discussed requires the presence of a multidisciplinary team of specialist who are interested in diagnosis and treatment of genitourinary tumors; 2) Patients managed in such an environment are expected to have optimal survival and the best possible quality of life; 3) Real advances in the management of patients can be best obtained through well-designed prospective clinical trials; and 4) There is a need for timely introduction of relevant advances in epidemiology and molecular genetics to clinics.

Tube gastrostomy after radical cystectomy and urinary diversion: surgical technique and experience in 709 patients.

We describe our surgical technique of tube gastrostomy and report our experience with 709 patients who underwent cystectomy and urinary diversion with gastrostomy tube placement from January 1988 to December 1997. This modified Stamm technique provides an effective means of gastric decompression without the discomfort associated with nasogastric decompression, is associated with a low complication rate (0.05%), and may be considered as the procedure of choice when gastric drainage is required after radical cystectomy and lower urinary tract reconstruction.

Right intrathoracic renal ectopia: a case report and review of the literature.

We report a case of right intrathoracic renal ectopia associated with a previously unreported congenital anomaly (trisomy 21) and review of the literature.