Faculty Bibliography

BACKGROUND: Sonic hedgehog (Shh) signaling plays a pivotal role in stromal-epithelial interaction during normal development but its role in tumor-stromal interaction during carcinogenic progression is less well defined. Since hormone refractory prostate cancer with bone metastasis is difficult to treat, it is crucial to investigate how androgen independent (AI) human prostate cancer cells communicate with their associated stroma. METHODS: Shh and its target transcription factor, Gli1 mRNA, were assessed by RT-PCR and/or quantitative RT-PCR in co-cultured cell recombinants comprised of AI C4-2 either with NPF (prostate fibroblasts from normal/benign prostate gland) or CPF (cancer-associated stromal fibroblasts) under Shh/cyclopamine (a hedgehog signaling inhibitor) treatment. Human bone marrow stromal (HS27A) cells were used as controls. In vivo investigation was performed by checking serum PSA and immunohistochemical staining for the apoptosis-associated M30 gene in mice bearing chimeric C4-2/NPF tumors. RESULTS: We found that (1) Shh has minimal growth-stimulating effects on prostate cancer cells, but it stimulated the growth of NPF but not CPF; (2) active Shh signaling was found between AI C4-2 cells and NPF but not CPF; and (3) osteonectin (ON) is a Gli1 target gene in NPF and not in CPF, and ON up-regulation in NPF can be blocked by cyclopamine CONCLUSIONS: Based on co-culture and chimeric tumor models, active Shh-mediated signaling was demonstrated between AI prostate cancer and NPF in a paracrine- and tumor progression-dependent manner. Our study suggests that drugs like cyclopamine that interfere with Shh signaling could be beneficial in preventing AI progression in prostate cancer cells. Prostate (c) 2011 Wiley-Liss, Inc

Kidney cancer is a common genitourinary malignancy. The incidence of kidney cancer has progressively increased in the past few decades, with the greatest increase noted for incidentally discovered small renal masses. Along with the change in presentation and diagnosis of kidney cancer, surgical treatment of kidney cancer also has evolved dramatically during the past 5 decades, moving from universal use of radical extirpation to more frequent nephron-sparing and minimally invasive surgeries. This article reviews the contemporary management of localized kidney cancers and discusses the impact of surgery on oncologic and nononcologic outcomes

BACKGROUND: The prognostic significance of venous involvement and tumour thrombus level in renal cell carcinoma (RCC) remains highly controversial. In 2010, the American Joint Committee on Cancer (AJCC) and the Union International Centre le Cancer (UICC) revised the RCC staging system (7th edition) based on tumour thrombus level, differentiating the T stage of tumours limited to renal-vein-only involvement. OBJECTIVE: We aimed to evaluate the impact of tumour thrombus extension in a multi-institutional cohort of patients. DESIGN, SETTING, AND PARTICIPANTS: An international consortium of 11 institutions was established to retrospectively review a combined cohort of 1215 patients undergoing radical nephrectomy and tumour thrombectomy for RCC, including 585 patients with inferior vena cava (IVC) involvement or higher. MEASUREMENTS: Predictive factors of survival, including histology, tumour thrombus level, nodal status, Fuhrman grade, and tumour size, were analysed. RESULTS AND LIMITATIONS: A total of 1122 patients with complete data were reviewed. The median follow-up for all patients was 24.7 mo, with a median survival of 33.8 mo. The 5-yr survival was 43.2% (renal vein involvement), 37% (IVC below the diaphragm), and 22% with caval involvement above the diaphragm. On multivariate analysis, tumour size (hazard ratio [HR]: 1.64 [range: 1.03-2.59]; p=0.036), Fuhrman grade (HR: 2.26 [range: 1.65-3.1]; p=0.000), nodal metastasis (HR: 1.32 [range: 1.09-1.67]; p=0.005), and tumour thrombus level (HR: 2.10 [range: 1.53-3.0]; p=0.00) correlated independently with survival. CONCLUSIONS: Based on analysis of the largest known cohort of patients with RCC along with IVC and atrial thrombus involvement, tumour thrombus level is an independent predictor of survival. Our findings support the changes to the latest AJCC/UICC staging system

PURPOSE: We performed a multi-institutional retrospective cohort study to evaluate baseline renal function of patients who underwent partial nephrectomy for renal tumors, and determined rates of progression to higher stages of chronic kidney disease. MATERIALS AND METHODS: The Modification of Diet in Renal Disease study equation was used to estimate glomerular filtration rate. Preoperative and postoperative serum creatinine values were obtained from patients who underwent partial nephrectomy at 6 institutions with a normal contralateral kidney, and had baseline chronic kidney disease stage I (estimated glomerular filtration rate greater than 90 ml/minute/1.73 m(2)), II (estimated glomerular filtration rate 60 to 89 ml/minute/1.73 m(2)) or III (estimated glomerular filtration rate 30 to 59 ml/minute/1.73 m(2)). The end point was change in chronic kidney disease stage at long-term followup (3 to 18 months). Multivariate logistic and Cox regression models tested the association of newly acquired chronic kidney disease stage III or greater with pertinent demographic, tumor and surgical factors. RESULTS: For 1,228 patients with followup creatinine data at least 3 months after partial nephrectomy median baseline glomerular filtration rate was 74 ml/minute/1.73 m(2). At baseline 19%, 59% and 22% of patients had chronic kidney disease stage I, II and III, respectively. At long-term followup for patients with baseline chronic kidney disease stage I or II median postoperative glomerular filtration rate was 67 ml/minute/1.73 m(2) with 29% having progression to chronic kidney disease stage III or greater. Increasing age, female gender, increasing tumor size, clamping of the renal artery and vein, and lower preoperative estimated glomerular filtration rate were independently associated with newly acquired chronic kidney disease stage III or greater. The presence of comorbid conditions such as coronary artery disease, diabetes mellitus or hypertension did not independently predict an increased risk of higher chronic kidney disease stage. CONCLUSIONS: Chronic kidney disease stage III or greater will develop postoperatively in approximately a third of patients with an estimated glomerular filtration rate greater than 60 ml/minute/1.73 m(2), and this progression is associated with definable demographic, tumor and surgical factors

Introduction & Objectives: The prognostic significance of venous involvement and tumour thrombus level in renal cell carcinoma (RCC) remains highly controversial. Patients with Level III (above hepatic veins below diaphragm) and Level IV (Above diaphragm-atrium) can be managed with or without using of by-pass. Investigations have suggested differences in morbidity between the two approaches but there is a lack of data regarding the potential impact on oncological outcomes. We aimed to evaluate the impact of cardiopulmonary by-pass in Level III-IV thrombus in Cancer- Specific Mortality (CSM). Materials & Methods: An International Consortium of 11 institutions was established to retrospectively review a combined cohort of 1215 patients undergoing radical nephrectomy and tumour thrombectomy for RCC, including 271 (22%) patients with Level III (170-62%) or IV (101-38%%) involvement. Predictive factors of survival including age, cardiopulmonary by-pass, nodal status, Fuhrman grade, node status, preoperative embolisation and presence of metastasis at time or surgery were analysed. The Chi-square tests was used to compare discrete factors, t-tests for continuous factors and actuarial methods for the survival endpoints. (Graph presented) Results: The mean follow-up for uncensored patients were 39.8 (0-258) months with a median survival of 30 months. Finally we analyzed 170 Level III (113 withby- pass and 57 without-by-pass) and 101 Level IV (98 with-by-pass and 3 withoutby- pass). The 5-yr CSM was 31% (Level III with by-pass), 31% (Level III-without by-pass), 28% (Level IV-with by-pass) and on the Level IV without by-pass did not reach the minimum time to calculate. On multivariate analysis, only Fuhrman grade ( p=0.022) and existence of metastasis at the time of surgery (p=0,012) correlated independently with survival; age (p=0.39), N+ (p=0.50), by-pass (0.11), embolisation (p=0.21) were not associated with CSM. Conclusions: Based on analysis of the largest known cohort of patients with RCC along with Level III and IV thrombus involvement, Fuhrman grade and existence of preoperative metastasis were independent predictors of survival. Our findings support that based on oncological outcomes both approaches (with or without bypass using) are safe

Traditionally, the patient with a new diagnosis of localized prostate cancer faces either radical therapy, in the form of surgery or radiation, or active surveillance. A growing subset of these men may not be willing to accept the psychological burden of active surveillance nor the side effects of extirpative or radiation therapy. Local ablative therapies including cryotherapy, high-intensity focused ultrasound, and vascular-targeted photodynamic therapy have emerged as a means for minimally invasive definitive treatment. These treatments are well tolerated with decreased morbidity in association with improvements in technology; however, long-term oncologic efficacy remains to be determined