Purpose:Data supporting neoadjuvant chemotherapy (NAC) in high-grade (HG) upper-tract urothelial carcinoma (UTUC) is scant. This multi-institution prospective phase II trial investigated pathologic...

Suprahepatic inferior vena caval tumor thrombus in renal cell carcinoma cases has historically portended a poor prognosis. With advances in perioperative treatment of patients with high level thrombus contemporary outcomes are hypothesized to be improved. We evaluated long-term oncologic outcomes of contemporary surgical treatment of patients with renal cell carcinoma in whom level III-IV inferior vena caval thrombus was managed at high volume centers. We examined clinical and pathological data on patients with renal cell carcinoma and level III-IV thrombus treated with surgery from January 2000 to June 2013 at 4 tertiary referral centers. Survival outcomes and associated prognostic variables were assessed by Kaplan-Meier and multivariate Cox regression analyses. We identified 166 patients, including 69 with level III and 97 with level IV thrombus. Median postoperative followup was 27.8 months. Patients with no evidence of nodal or distant metastasis (pN0/X, M0) had 5-year 49.0% cancer specific survival and 42.2% overall survival. There was no difference in survival based on tumor thrombus level or pathological tumor stage. Variables associated with an increased risk of death from kidney cancer on multivariate analysis were regional nodal metastases (HR 3.94, p <0.0001), systemic metastases (HR 2.39, p = 0.01), tumor grade 4 (HR 2.25, p = 0.02), histological tissue necrosis (HR 3.11, p = 0.004) and increased preoperative serum alkaline phosphatase (HR 2.30, p = 0.006). Contemporary surgical management achieves almost 50% 5-year survival in patients without metastasis who have renal cell carcinoma thrombus above the hepatic veins. Factors associated with increased mortality included nodal/distant metastases, advanced grade, histological necrosis and increased preoperative serum alkaline phosphatase. These findings support an aggressive surgical approach to the treatment of patients with renal cell carcinoma who have advanced tumor thrombus.

Renal cell carcinoma (RCC) is characterized by a particularly broad metastatic swath, and, enigmatically, when the pancreas is a destination, the disease is associated with improved survival. Intrigued by this observation, we sought to characterize the clinical behavior, therapeutic implications, and underlying biology. While pancreatic metastases (PM) are infrequent, we identified 31 patients across 2 institutional cohorts and show that improved survival is independent of established prognostic variables, that these tumors are exquisitely sensitive to antiangiogenic agents and resistant to immune checkpoint inhibitors (ICIs), and that they are characterized by a distinctive biology. Primary tumors of patients with PM exhibited frequent PBRM1 mutations, 3p loss, and 5q amplification, along with a lower frequency of aggressive features such as BAP1 mutations and loss of 9p, 14q, and 4q. Gene expression analyses revealed constrained evolution with remarkable uniformity, reduced effector T cell gene signatures, and increased angiogenesis. Similar findings were observed histopathologically. Thus, RCC metastatic to the pancreas is characterized by indolent biology, heightened angiogenesis, and an uninflamed stroma, likely underlying its good prognosis, sensitivity to antiangiogenic therapies, and refractoriness to ICI. These data suggest that metastatic organotropism may be an indicator of a particular biology with prognostic and treatment implications for patients.

Objective: To validate the impact of Ki67 expression on oncological outcomes of patients treated for clinically localized clear‐cell renal cell carcinoma ( ccRCC ). Patients and Methods: Immunohistochemistry for Ki67 was performed on tissue microarray constructs of patients treated with radical or partial nephrectomy for clinically localized ( M0 ) ccRCC and Ki67 expression >10% was considered abnormal. Clinical and pathological data elements were entered into an institutional review board‐approved database. The K aplan– M eier method and C ox regression models were used to analyse disease‐free survival ( DFS ) and cancer‐specific survival ( CSS ) probabilities. Results: Of 401 patients, 59.6% were males. The median (range) age was 58 (17–85) years, follow‐up was 22 (0–150) months and time to death was 27 (0–150) months. A total of 20.2% of patients had advanced stage ( pT3 – T4 ) and 31% had advanced grade (3–4) disease. Abnormal expression of Ki67 was seen in 6.5% of our cohort and was associated with adverse pathological features ( P < 0.05). Patients with high expression of Ki67 were found to have 5‐year DFS and CSS rates of 67 and 84%, respectively, vs 87 and 95%, respectively, in those with normal expression ( P < 0.001 and P < 0.05, respectively). In multivariable analyses, adjusting for stage and grade, abnormal Ki67 expression was an independent predictor of DFS (hazard ratio [ HR ] 3.77, P = 0.011, 95% confidence interval [ CI ] 1.35–10.52), but not of CSS ( HR 3.51 P = 0.137, 95% CI 0.671–18.35). Conclusions: Our findings support the role of Ki67 as a powerful independent predictor of inferior oncological outcomes in patients with ccRCC . Further prospective studies are needed to determine the clinical applicability of these findings.

Study Type – Therapy (multi‐insititutional cohort) Level of Evidence 2b What’s known on the subject? and What does the study add? Neoadjuvant chemotherapy offers survival benefits for patients with urothelial carcinoma of the bladder. However, it is still underutilized in the ‘biologically similar’ upper tract urothelial carcinoma. Systemic chemotherapy in a neoadjuvant setting is a more attractive option, as loss of renal function after nephrectomy can complicate the administration of adjuvant chemotherapy. We found that preoperative systemic therapy followed by aggressive surgical debulking is a promising treatment strategy for upper tract urothelial carcinoma patients with known or at risk of loco‐regional nodal metastasis. OBJECTIVE: • To describe a multicentre experience with preoperative platinum‐based chemotherapy before radical nephroureterectomy (RNU) in patients with upper tract urothelial carcinoma (UTUC) with loco‐regional nodal metastases. PATIENTS AND METHODS: • We identified 313 patients from the UTUC Collaboration (over 1200 patients), who underwent RNU with concomitant retroperitoneal lymph node dissection between 1990 and 2007 and met the inclusion criteria for one of three groups. • Group 1 comprised patients who received chemotherapy before RNU because of biopsy‐proven loco‐regional nodal metastases. • Group 2 consisted of patients who underwent primary RNU and were found to have metastatic nodal disease on final pathological review (node‐positive). • Group 3 comprised a comparative cohort of patients treated with primary RNU for invasive or locally advanced (pT2/pT4) node‐negative (N0) UTUC. RESULTS: • Groups 1, 2 and 3 included 18, 120 and 175 patients, respectively. The 5‐year disease‐free survival rates were 49%, 30% and 64%, whereas the 5‐year cancer‐specific survival rates were 44%, 36% and 69% in groups 1, 2 and 3, respectively. • In group 1, on final pathological evaluation, nine patients were pN0, six patients were pT0 and five patients had pT0N0 disease. Kaplan–Meier survival analyses showed similar recurrence and survival rates in group 1 compared with group 3 ( P = 0.14 and P = 0.06, respectively). • Meanwhile, group 2 had significantly lower disease‐free and cancer‐specific survival rates compared with group 3 ( P < 0.001 and P < 0.001, respectively) and compared with group 1 ( P = 0.04 and P = 0.06, respectively). CONCLUSIONS: • Preoperative chemotherapy followed by aggressive surgical consolidation may yield favourable oncological outcomes in patients with UTUC with loco‐regional nodal metastases. • These data support further evaluation of neoadjuvant systemic therapy in patients at risk for locally advanced UTUC.