377 Background: Current predictors of metastatic progression after radical nephrectomy for localized clear cell renal cell carcinoma (ccRCC) include clinicopathologic features such as tumor stage and grade. The addition of molecular tumor characteristics in a prognostic score may improve risk stratification and patient selection for enhanced follow up strategies or adjuvant therapies. Methods: We retrospectively identified consecutive patients with ccRCC who underwent radical nephrectomy (RNx) for localized disease. Those who developed metastasis were identified. Whole-transcriptome mRNA sequencing of primary tumors was performed followed by gene set enrichment analysis (GSEA) for the most significant cancer hallmark pathways enriched in patients who did or did not develop metastasis. For each patient, the 22-gene epithelial mesenchymal transition (EMT) score was calculated (high vs. low), using cut-offs from a prior study using TCGA data. The prognostic impact of the EMT score was evaluated by performing multivariable cox-proportional hazard testing and Kaplan-Meier (KM) survival analysis. Results: We analyzed 82 patients with median age 62 years and median tumor size 6 ±2.9 cm. The median time to metastasis after radical nephrectomy for patients who developed metastasis (n = 12) was 18.2 months and 31.1 months for patients who did not develop metastasis (n = 70). We observed a significant enrichment of EMT, myogenesis, inflammatory response and hypoxia hallmark pathways in patients with metastasis vs. those without metastasis. Multivariable analysis controlling for relevant clinicopathologic features such as age, sex, tumor size, tumor stage etc. revealed high EMT score to be significantly associated with development of metastasis [hazard ratio (HR) 7.2; 95% CI 1.15-44.8; ]. Conclusions: Here we validate a prognostic 22-gene epithelial mesenchymal transition (EMT) score in patients treated with radical nephrectomy for localized ccRCC. Pending further studies, the EMT score may improve risk stratification and select patients for adjuvant therapy.
Wnt signaling has been implicated as a driver of prostate cancer-related osteoblast differentiation, and previous studies have linked modifications in Wnt function with the induction of tumor metastasis. A unique aspect of prostate cancer bone metastases in mouse models is their relative predilection to the hindlimb (femur) compared to the forelimb (humerus). Comparative gene expression profiling was performed within the humerus and femur from non–tumor-bearing mice to evaluate differences in the microenvironments of these locations. This revealed the relative overexpression of the Wnt signaling inhibitors WIF1 and SOST in the humerus compared to the femur, with increased WNT5A expression in femur bone marrow, suggesting a coordinated upregulation of Wnt signals within the femur compared to the humerus. Conditioned medium (CM) from bone marrow stromal cells (HS-5 cells) was used to mimic the bone marrow microenvironment, which strongly promoted prostate cancer cell invasion (3.3-fold increase in PC3 cells, P < .05; 7-fold increase in LNCaP cells, P < .05). WNT5A shRNA knockdown within the CM-producing HS-5 cells significantly decreased PC3 (56%, P < .05) and LNCaP (60%, P < .05) cell invasion. Similarly, preincubation of CM with WIF1 significantly blocked LNCaP cell invasion (40%, P < .05). shRNA-mediated knockdown of the Wnt receptors FZD4 and FZD8 also strongly inhibited tumor cell invasion (60% inhibition shFZD4, P < .05; 63% shFZD8, P < .05). Furthermore, small molecule inhibition of JNK, which is an important component of the noncanonical Wnt signaling pathway, significantly inhibited CM-mediated tumor invasion. Overall, this study reveals a role for Wnt signaling as a driver of prostate cancer bone metastatic tropism and invasion.
The first three papers in this section relate to the use of radical cystectomy in bladder cancer, and each study describes issues which are uncommonly written about, but which are relevant and important to any urologist who manages such patients. There is also a paper from Cleveland describing the rare condition of neuroendocrine tumours in the kidney. This is a large series of cases, and the authors recommend awareness of the condition and the prudent use of immunohistochemical neuroendocrine markers. There are a further six papers on prostate cancer; two of them evaluate high‐grade prostatic intraepithelial neoplasia, taking different views on the subject. OBJECTIVE To examine the association between the interval from the last transurethral resection (TUR) to radical cystectomy (RC) and bladder cancer‐specific outcome, as the decision to proceed to RC for an individual patient is complex, and recent reports suggest an interval from diagnosis to RC of >3 months is associated with adverse outcomes. PATIENTS AND METHODS The records of 592 patients who had RC were reviewed; the interval from the last TUR was analysed as both a continuous and categorical variable (<3 vs ≥3 months). Logistic regression and survival analyses were used to evaluate the association between the interval to RC with pathological characteristics and clinical outcomes. RESULTS The mean ( sd ) actuarial cancer‐specific survival was 70.5 (2.3)% and 60.7 (3.2)% at 3 and 7 years, respectively. Overall, the median (range) time from TUR to RC was 1.8 (0.3–11.6) months. The interval to RC analysed as a continuous or categorical variable was not associated with extravesical or nodal disease, lymph node metastases, disease recurrence, overall or cancer‐specific survival. The results were similar in the subgroup of 320 patients (54%) with clinically muscle‐invasive disease. CONCLUSIONS These results suggest that a reasonable delay from the last TUR to RC is not independently associated with stage progression or with decreased recurrence‐free or disease‐specific survival. These findings might have important implications for trial design in the ongoing evaluation of neoadjuvant regimens. Nevertheless, we see no reason to advocate anything less than the timely consideration of definitive treatment for patients with high‐risk bladder cancer.
