Ramy F. Youssef

Preoperative multivariable prognostic model for prediction of nonorgan confined urothelial carcinoma of the upper urinary tract

PURPOSE We created a prognostic tool for the accurate preoperative prediction of nonorgan confined upper tract urothelial carcinoma. MATERIALS AND METHODS A computerized data bank containing comprehensive information on 1,453 patients who underwent radical nephroureterectomy at 13 academic institutions was generated and continuously updated. This study comprised a subset of 659 patients in whom all appropriate preoperative prognostic variables (age, gender, race, symptoms, Eastern Cooperative Oncology Group performance status, primary tumor location, tumor architecture, tumor grade and history of previous bladder cancer) were available for statistical analysis. A multivariable logistic regression model containing relevant clinicopathological variables addressed the prediction of nonorgan confined stage disease (T3-4 and/or N+) at radical nephroureterectomy. A backward step-down selection process was applied to achieve the most informative and parsimonious model. Internal validation was performed using 200 bootstrap resamples. RESULTS Pathological nonorgan confined urothelial carcinoma was found in 40% of patients. Grade, architecture and location of the tumor were independently associated with nonorgan confined disease. A nomogram including these 3 variables achieved 76.6% accuracy in predicting nonorgan confined upper tract urothelial cancer. CONCLUSIONS We developed a simple and accurate prognostic tool for the prediction of locally advanced upper tract urothelial cancer. This preoperative prediction model can be used for designing clinical trials, selecting patients for preoperative systemic therapy and guiding the extent of concomitant lymph node dissection at nephroureterectomy.

The Impact of Targeted Molecular Therapies on the Level of Renal Cell Carcinoma Vena Caval Tumor Thrombus

BACKGROUND Targeted molecular therapies (TMTs) previously have demonstrated oncologic activity in renal cell carcinoma (RCC) by reducing the size of primary tumors and metastases. OBJECTIVE To assess the cytoreductive effect of TMTs on inferior vena cava tumor thrombi. DESIGN, SETTING, AND PARTICIPANTS A multi-institutional database of patients treated with TMTs for RCC was reviewed. The subset with in situ level II or higher caval thrombi (above renal vein) was assessed for radiographic response in thrombus size and level. Pre- and posttreatment characteristics of this population were assessed for predictors of response in height, diameter, and level of the tumor thrombi. MEASUREMENTS The main outcome measured was a change in the clinical level of tumor thrombus following TMT. We also measured radiographic responses in thrombus size and location before and after TMT. RESULTS AND LIMITATIONS Twenty-five patients met the inclusion criteria. Before TMT, thrombus level was II in 18 patients (72%), III in 5 patients (20%), and IV in 2 patients (8%). The first-line therapy was sunitinib in 12 cases; alternative TMTs were administered in 13. The median duration of therapy was two cycles (range: one to six cycles). Following TMT, 7 patients (28%) had a measurable increase in thrombus height, 7 (28%) had no change, and 11 (44%) had a decrease. One patient (4%) had an increase in thrombus-level classification, 21 (84%) had stable thrombi, and in 3 (12%) the thrombus level decreased. There was only one case (4%) where the surgical approach was potentially affected by tumor thrombus regression (level IV to III). No statistically significant predictors of tumor thrombus response to TMTs were found. Limitations include the descriptive and retrospective study design. Because TMTs were initiated according to physician and/or patient preferences, and not all patients were treated in anticipation of surgery, no conclusions could be drawn regarding selection and duration of therapy. Thus it may not be appropriate to extrapolate our experience to all patients with locally advanced RCC. Although this is the largest reported experience with in situ caval tumor thrombi treated with TMT, this series lacks sufficient statistical power to assess the usefulness of TMTs adequately in tumor thrombus cytoreduction. CONCLUSIONS TMT had a minimal clinical effect on RCC tumor thrombi. Only patients treated with sunitinib had clinical thrombus regression; however, the clinical magnitude and relevance of this effect is not clear and should be investigated prospectively.

Flexible ureterorenoscopy versus extracorporeal shock wave lithotripsy for treatment of lower pole stones of 10–20 mm

Study Type – Therapy (case series)

Association of Angiogenesis Related Markers With Bladder Cancer Outcomes and Other Molecular Markers

PURPOSE We tested whether the altered immunohistochemical expression of angiogenesis related markers is associated with outcomes of patients with urothelial carcinoma of the bladder, and assessed the correlation of angiogenesis related markers with molecular markers commonly altered in urothelial bladder carcinoma. MATERIALS AND METHODS Vascular endothelial growth factor, basic fibroblast growth factor and thrombospondin 1 expression data were collected, as were microvessel density data. Immunohistochemical staining was performed on specimens from 204 patients treated with radical cystectomy for urothelial carcinoma of the bladder. We also stained serial sections of the specimens for cyclin E1, cyclin D1, p53, p21, p27, pRB, Ki-67, Bcl-2, caspase-3, survivin and cyclooxygenase-2. We measured time to disease recurrence and cancer specific mortality, as well as the association with clinical and pathological features and other molecular markers. RESULTS The altered expression of vascular endothelial growth factor (over expression), basic fibroblast growth factor (over expression) and thrombospondin 1 (decreased expression) was 86%, 79% and 63%, respectively. Median microvessel density was 20. All 4 markers were associated with established clinicopathological features of aggressive urothelial carcinoma of the bladder (such as stage, lymphovascular invasion and lymph node metastasis) and other molecular markers. On multivariable analyses that adjusted for standard pathological features basic fibroblast growth factor and thrombospondin 1 were independent predictors of disease recurrence (HR 3.6, p = 0.002 and HR 2.2, p = 0.001, respectively) and cancer specific mortality (HR 2.8, p = 0.02 and HR 2.3, p = 0.003, respectively). When all 4 markers were included in 1 model basic fibroblast growth factor and thrombospondin 1 retained their independent association with disease recurrence (HR 2.9, p = 0.014 and HR 1.8, p = 0.022, respectively) and only thrombospondin 1 was independently associated with cancer specific mortality (HR 1.9, p = 0.031). CONCLUSIONS Angiogenesis related molecular markers are commonly altered in urothelial carcinoma of the bladder, making them a target for therapy. Down-regulation of thrombospondin 1 and up-regulation of basic fibroblast growth factor are independent predictors of clinical outcomes of patients with urothelial carcinoma of the bladder.

Semirigid Ureteroscopy for Ureteral Stones: A Multivariate Analysis of Unfavorable Results

PURPOSE We determined the factors predicting unfavorable results of semirigid ureteroscopy for ureteral calculi. MATERIALS AND METHODS We reviewed the computerized files of 841 patients who underwent a total of 908 ureteroscopic procedures for ureteral stones from January 2003 through December 2006. A semirigid 6/7.5Fr ureteroscope was used in pediatric patients and an 8/10Fr or 8.5/11.5Fr ureteroscope was used in adults. Patients with favorable results were those who became stone-free after a single ureteroscopic procedure without any complications. They were compared with patients who had unfavorable results using univariate (chi-square and t tests) and multivariate (logistic regression) statistical tests to identify risk factors for unfavorable results. RESULTS The study included 567 males and 274 females with a mean age of 48.5 years (range 2 to 81). The complication rate was 6.7% (61 procedures). The stone-free rate after a single ureteroscopic intervention was 87% (791 procedures). Favorable results were documented in 751 procedures (82.7%). Significant factors for unfavorable results were proximal ureteral stones, ureteroscopy done by surgeons other than experienced endourologists, stone impaction and stone width (relative risk 4, 2.5, 1.8 and 1.2, respectively). CONCLUSIONS Semirigid ureteroscopy is a safe and highly effective treatment modality for ureteral stones.

Upper urinary tract urothelial carcinoma with loco-regional nodal metastases: Insights from the Upper Tract Urothelial Carcinoma Collaboration

Study Type – Therapy (multi‐insititutional cohort)

Predictors of outcome of non-muscle-invasive and muscle-invasive bladder cancer

Bladder cancer is a major cause of morbidity and mortality. At initial diagnosis, 75% of patients present with non—muscle-invasive disease and 25% of patients have muscle-invasive or metastatic disease.Patients with noninvasive disease suffer from a high rate of recurrence and 10–30% will have disease progression. Patients with muscle-invasive disease are primarily treated with radical cystectomy, but frequently succumb to their disease despite improvements in surgical technique. In non–muscle-invasive disease, multiplicity, tumor size, and prior recurrence rates are the most important predictors for recurrence, while tumor grade, stage, and carcinoma in situ are the most important predictors for progression. The most common tool that clinicians use to predict outcomes after radical cystectomy is still the tumor-node-metastasis (TNM) staging system, with lymph node involvement representing the most important prognostic factor. However, the predictive accuracy of staging and grading systems are limited, and nomograms incorporating clinical and pathologic factors can improve prediction of bladder cancer outcomes. One limitation of current staging is the fact that tumors of a similar stage and grade can have significantly different biology. The integration of molecular markers, especially in a panel approach, has the potential to further improve the accuracy of predictive models and may also identify targets for therapeutic intervention or patients who will respond to systemic therapies.

Molecular targets and targeted therapies in bladder cancer management

Bladder cancer remains a significant health problem. Currently, conventional histopathologic evaluation criteria (tumor grade and stage) are limited in their ability to accurately predict tumor behavior. A significant number of patients with muscle-invasive or extravesical disease treated by radical cystectomy alone die of metastasis. Intense research efforts are being made to better identify and categorize tumors by their molecular alterations and biological characteristics. A majority of the aggressive, invasive bladder carcinomas have alterations in the p53 and retinoblastoma pathways that regulate the cell cycle by interacting with signal transduction pathways. Angiogenesis further contributes to the neoplastic growth by providing a constant supply of oxygen and nutrients. It is becoming apparent that the accumulation of genetic and molecular changes ultimately determines a tumor’s phenotype and subsequent clinical behavior. We provide a contemporary outline of our current understanding of the molecular and genetic events associated with tumorigenesis and progression. We emphasize the ways by which molecular biology is likely to affect the development of future therapies that will be able to target molecular alterations in individual tumors based on their respective profiles. The current status of targeted therapies for bladder cancer is also presented as well as the ongoing clinical trials.

Oncological outcomes after radical nephroureterectomy for upper tract urothelial carcinoma: Comparison over the three decades

Objective:  To evaluate temporal trends in clinicopathological features and oncological outcomes after radical nephroureterectomy for upper tract urothelial carcinoma.

Shock Wave Lithotripsy Versus Semirigid Ureteroscopy for Proximal Ureteral Calculi (<20 mm): A Comparative Matched-pair Study

OBJECTIVES To use a matched-pair analysis design to compare the safety and efficacy of shock wave lithotripsy (SWL) and ureteroscopy (URS). Controversy still exists regarding whether SWL or URS is the best management of upper ureteral calculi. METHODS We reviewed the records of patients with a single radiopaque upper ureteral stone treated by URS or SWL from January 2003 to December 2005. SWL was performed as an outpatient procedure using the electromagnetic lithotripter (Dornier Lithotripter S). URS was performed using an 8F or 8.5F semirigid ureteroscope. Intracorporeal lithotripsy with pneumatic or holmium laser energy was used when needed. A matched-pair analysis was performed using 3 parameters (sex, stone size, and degree of hydronephrosis). The success rates, retreatment rates, auxiliary procedures, and complications were compared in each group. RESULTS A total of 427 patients were treated for upper ureteral stones. Forty-three matched pairs were identified and compared. The success rate was 83.7% for SWL vs 88.4% for URS (P = .8). The retreatment rate was significantly greater in the SWL group than in the URS group (65% vs 2.3%, respectively; P < .001). The need for auxiliary procedures was equal in both groups (16.3%). The complication rate was 14% in the URS group and 4.7% in the SWL group (P = .1). CONCLUSIONS SWL and semirigid URS are highly effective in the treatment of proximal ureteral stones <20 mm. The results of our study showed that SWL was safer and less invasive, but that URS was more effective and resulted in a lower retreatment rate.