Purpose: Hypoxia-inducible factor-1a (HIF-1a) plays an important role in tumoral adaptation to hypoxic conditions by serving as a transcription factor for several crucial proteins, including vascular endothelial growth factor and carbonic anhydrase IX (CAIX). Here, we evaluated the significance of HIF-1ain renal cell carcinoma (RCC). Experimental Design: Immunohistochemical analysis was done on a tissue microarray constructed from paraffin-embedded primary tumor specimens from 357 patients treated by nephrectomy for RCC. Nuclear expression was evaluated by a single pathologist who was blinded to outcome. The expression levels were associated with pathologic variables and survival. Results: HIF-1aexpression was greater in RCC than in benign tissue. Clear cell RCC showed the highest expression levels. In clear cell RCC, HIF-1a was significantly correlated with markers of apoptosis (p21, p53), the mammalian target of rapamycin pathway (pAkt, p27), CXCR3, and proteins of the vascular endothelial growth factor family. HIF-1a was correlated with CAIX and CAXII in localized, but not in metastatic RCC. HIF-1aexpression predicted outcome in metastatic patients: patients with high HIF-1a expression (>35%) had significantly worse survival than patients with low expression (V35%); median survival, 13.5 versus 24.4 months, respectively (P = 0.005). Multivariate analysis retained HIF-1aand CAIX expression as the strongest independent prognostic factors for patients with metastatic clear cell RCC. Conclusions: HIF-1ais an important independent prognostic factor for patients with metastatic clear cell RCC. Because HIF-1aand CAIX are independently and differentially regulated in metastatic clear cell RCC, both tumor markers can be complementary in predicting prognosis.

Eastern Cooperative Oncology Group performance status, metastatic status, sarcomatoid features and concomitant perinephric fat invasion are the most powerful prognostic factors of survival in renal cell carcinoma with tumor thrombus extension. Our data indicate that a redefinition of the current T3 classification may improve its predictive accuracy. We propose that T3 renal cell carcinoma with fat invasion or thrombus extension alone should be classified as T3a, while that with thrombus extension plus fat invasion should be classified as T3b.

Purpose: To identify the molecular signature of localized (N0M0) clear cell renal cell carcinoma (RCC) and assess its ability to predict outcome. Methods: Clinical characteristics and pathologic records of 170 patients with localized clear cell RCC who underwent nephrectomy were reviewed.

More than 85% of small solid renal tumors are renal cell carcinoma. The majority of localized small renal tumors can be cured with existing surgical approaches. However, there is a small but not insignificant risk of synchronous and metachronous metastatic disease and cancer associated death. Patients considering experimental therapies such as ablation and surveillance should be aware of this. Tumor size alone is not sufficient to distinguish renal cell carcinoma with benign behavior from aggressive small renal cell carcinoma. Survival of patients with small metastatic renal cell carcinoma is better then expected. The biology of these unique tumors should be further studied.

Several unique patients were identified who had a novel response to systemic therapy that altered the surgical strategy. RESULTSFour patients who had targeted therapy before surgery are described and in whom there were effects on tumour biology not seen previously with chemotherapy and cytokine therapy. The selected patients who had neoadjuvant targeted therapy had shrinkage of a tumour thrombus in the inferior vena cava, nodal involvement, renal fossa recurrence and tumour within a solitary kidney. CONCLUSIONSThe introduction of new molecular agents has revolutionized the treatment of patients with metastatic RCC. Responses to targeted therapy within the primary tumour, tumour thrombus, renal fossa recurrence, and lymph node metastases are novel findings not seen during treatment with immunotherapeuticbased strategies. This might be a signal for urological surgeons to re-evaluate the paradigm for the surgical management of advanced RCC. Potential applications are presented to encourage further investigations with targeted therapy in the neoadjuvant setting. OBJECTIVETo evaluate our early experience with neoadjuvant therapy (sunitinib or sorafenib) in advanced renal cell carcinoma (RCC), to explore the effect on both tumour biology and potential for downstaging advanced tumours, as systemic therapy for RCC has historically resulted in little if any primary tumour response, but recent experience with targeted therapy suggests otherwise. PATIENTS AND METHODSThe preliminary experience with neoadjuvant therapy for the surgical management of RCC was reviewed at two large referral centres.