Development and Validation of a Risk-Adapted Scoring Model for Metachronous Upper Tract Urothelial Carcinoma following Radical Cystectomy.

PURPOSE: The incidence and risk factors for metachronous upper tract urothelial carcinoma (UTUC) following radical cystectomy (RC) remain incompletely defined, which has limited the ability to individualize postoperative surveillance. MATERIALS AND METHODS: A retrospective review of 2 institutional registries was performed to identify patients undergoing RC for urothelial carcinoma. Multivariable Cox proportional hazard models for metachronous post-RC UTUC were developed in one institutional data set and validated in the second institutional data set. A post-RC UTUC risk score was then developed from these models. RESULTS: A total of 3,170 RC patients were included from the training cohort and 959 RC patients from the validation cohort. At a median followup after RC of 4.6 years (IQR 2.1-8.7), 167 patients were diagnosed with UTUC. On multivariable analysis in the training cohort, risk factors for metachronous UTUC were the presence of positive urothelial margin (HR 2.60, p <0.01), history of bacillus Calmette-Guérin treatment prior to RC (HR 2.20, p <0.01), carcinoma in situ at RC (HR 2.01, p <0.01) and pre-RC hydronephrosis (HR 1.48, p=0.04). These factors had similar discriminative capacity in the training and validation cohorts (C-statistic 0.71 and 0.73, respectively). A UTUC risk score was developed with these variables which stratified patients into low (0 points), intermediate (1-3 points), and high risk (4+ points) for post-RC UTUC, with respective 5-year UTUC-free survivals of 99%, 96%, 89% in the training cohort and 98%, 96%, and 91% in the validation cohort. CONCLUSIONS: We developed and validated a risk score for post-RC UTUC that may optimize UTUC surveillance protocols after RC.

MicroRNA profiling in clear cell renal cell carcinoma tissues potentially links tumorigenesis and recurrence with obesity.

BACKGROUND: Twenty to 40% localised RCC patients may experience recurrence after curative surgery. Limited miRNA predictors have been identified for ccRCC recurrence. METHODS: Through a multi-phase study design, we analysed miRNAs in tissues obtained from 203 ccRCC patients. Paired t-test was used for tumour-normal comparisons and Cox regression model was performed to compute hazard ratios (HRs) and corresponding 95% CIs. RESULTS: A 17-miRNA signature was identified that can concordantly classify >95% of tumour/adjacent normal samples. Significant enrichment was found as 6 out of 17 miRNAs were associated with obesity (binomial probability=0.001). Decreased levels of miR-204-5p and miR-139-5p were each associated with an approximately three-fold increased risk of recurrence (P<0.01). Risk score was generated based on expressions of miR-204-5p and miR-139-5p, and the trend test was significant in both discovery and validation sets (Pfor trend<0.05). Striking MST reduction was observed for patients with a high-risk score (high vs low: discovery, 9.4 vs >97.7 months; validation, 20.8 vs >70.3 months). Expressions of miR-204-5p were also associated with body mass index (ß=5.64, P<0.001). Significant inverse correlations were observed and validated between miR-204-5p and 13 obesity-related genes (r<0, P<0.01). CONCLUSIONS: We identified 17 miRNAs dysregulated in ccRCC tissues and showed that low expressions of miR-204-5p and miR-139-5p were associated with the higher risk of recurrence. The link between miR-204-5p and ccRCC recurrence may be partially mediated by regulating the expression of targeted obesity-related genes.

Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma.

Antiangiogenic therapy resistance occurs frequently in patients with metastatic renal cell carcinoma (RCC). The purpose of this study was to understand the mechanism of resistance to sunitinib, an antiangiogenic small molecule, and to exploit this mechanism therapeutically. We hypothesized that sunitinib-induced upregulation of the prometastatic MET and AXL receptors is associated with resistance to sunitinib and with more aggressive tumor behavior. In the present study, tissue microarrays containing sunitinib-treated and untreated RCC tissues were stained with MET and AXL antibodies. The low malignant RCC cell line 786-O was chronically treated with sunitinib and assayed for AXL, MET, epithelial-mesenchymal transition (EMT) protein expression and activation. Co-culture experiments were used to examine the effect of sunitinib pretreatment on endothelial cell growth. The effects of AXL and MET were evaluated in various cell-based models by short hairpin RNA or inhibition by cabozantinib, the multi-tyrosine kinases inhibitor that targets vascular endothelial growth factor receptor, MET and AXL. Xenograft mouse models tested the ability of cabozantinib to rescue sunitinib resistance. We demonstrated that increased AXL and MET expression was associated with inferior clinical outcome in patients. Chronic sunitinib treatment of RCC cell lines activated both AXL and MET, induced EMT-associated gene expression changes, including upregulation of Snail and ß-catenin, and increased cell migration and invasion. Pretreatment with sunitinib enhanced angiogenesis in 786-0/human umbilical vein endothelial cell co-culture models. The suppression of AXL or MET expression and the inhibition of AXL and MET activation using cabozantinib both impaired chronic sunitinib treatment-induced prometastatic behavior in cell culture and rescued acquired resistance to sunitinib in xenograft models. In summary, chronic sunitinib treatment induces the activation of AXL and MET signaling and promotes prometastatic behavior and angiogenesis. The inhibition of AXL and MET activity may overcome resistance induced by prolonged sunitinib therapy in metastatic RCC.

Role of partial nephrectomy as cytoreduction in the management of metastatic renal cell carcinoma.

In this review, we describe the role, feasibility and safety of partial nephrectomy in the setting of metastatic renal cell carcinoma. Partial nephrectomy is currently the preferred therapeutic modality in patients with localized renal tumors, while radical cytoreductive nephrectomy is the standard of care for appropriately selected patients with metastatic disease. Several studies have shown the prognostic value of percentage tumor removed when cytoreductive nephrectomy is done. This concept of percentage tumor removal and the associated benefit should also be applied when considering patients for cytoreductive partial nephrectomy; however, the potential adverse events after partial nephrectomy should be kept in mind, as these, when they occur, could delay time to starting systemic therapy. Several small retrospective studies have shown the feasibility of this approach in carefully selected patient groups. In well-selected patients with metastatic disease and primary tumors that are amenable to nephron sparing approaches, partial nephrectomy could offer an alternative to radical nephrectomy, with manageable adverse events, and good renal functional outcomes. Preserving renal function in this population could allow these patients to participate in clinical trial that they otherwise might not qualify for.

Pilot trial of sunitinib therapy in patients with von Hippel-Lindau disease.

BACKGROUND: Von Hippel-Lindau (VHL) disease induces vascular neoplasms in multiple organs. We evaluated the safety and efficacy of sunitinib in VHL patients and examined the expression of candidate receptors in archived tissue. METHODS: Patients with VHL were given four cycles of 50 mg sunitinib daily for 28 days, followed by 14 days off. Primary end point was toxicity. Modified RECIST were used for efficacy assessment. We evaluated 20 archival renal cell carcinomas (RCCs) and 20 hemangioblastomas (HBs) for biomarker expression levels using laser-scanning cytometry (LSC). RESULTS: Fifteen patients were treated. Grade 3 toxicity included fatigue in five patients. Dose reductions were needed in 10 patients. Eighteen RCC and 21 HB lesions were evaluable. Six of the RCCs (33%) responded partially, versus none of the HBs (P = 0.014). LSC revealed that mean levels of phosphorylated vascular endothelial growth factor receptor-2 were lower in HB than in RCC endothelium (P = 0.003) and mean phosphorylated fibroblast growth factor receptor substrate-2 (pFRS2) levels were higher in HB (P = 0.003). CONCLUSIONS: Sunitinib treatment in VHL patients showed acceptable toxicity. Significant response was observed in RCC but not in HB. Greater expression of pFRS2 in HB tissue than in RCC raises the hypothesis that treatment with fibroblast growth factor pathway-blocking agents may benefit patients with HB.

Ablative therapies in renal cell carcinoma.

We reviewed the use of ablative therapies in the management of renal cell carcinoma. We performed a PubMed search of the English language literature using the keywords "ablation" and "renal carcinoma." Pertinent articles specific to the technologic advancement of ablative therapy and clinical outcomes were selected for review. Intermediate-term oncologic outcomes of cryoablation and radiofrequency ablation are acceptable but are not quite as good as for surgical excision based nearly all on retrospective studies. No randomized studies have been performed comparing excisional and ablative therapies. Careful selection of patients and tumor characteristics results in improved outcomes. Diagnostic biopsy for tissue confirmation is mandatory and should even be considered post therapy after 6-12 months in patients with a concern about recurrence. Ablative therapies are associated with decreased morbidity, less severe complication rates, and excellent preservation of renal function in comparison with surgical excision. The majority of recurrences occur early, but long-term surveillance is required as delayed recurrences are also possible and the long-term oncologic efficacy is not yet established. Ablation can be delivered percutaneously or laparoscopically, and the superiority of one over the other remains controversial. The percutaneous approach is more cost effective and causes less perinephric desmoplasia. Nearly all data on ablation are retrospective and, with few exceptions, from single institutions. Ablative therapy is an appealing option for the management of small renal tumors shown to be renal cell carcinoma on biopsy in patients who are unsuitable candidates for surgical extirpation.

Outcome of patients with metastatic renal cell carcinoma treated with targeted therapy without cytoreductive nephrectomy.

BACKGROUND: Cytoreductive nephrectomy (CN) became a standard procedure in metastatic renal cell carcinoma (mRCC) in the immunotherapy era. Historically, median overall survival (OS) of patients treated with interferon alpha (IFN-α) without CN was 7.8 months. Median OS in patients treated with targeted therapy (TT) without CN is unknown. PATIENTS AND METHODS: We retrospectively reviewed records of patients with mRCC who received TT without CN. Kaplan-Meier methods and Cox regression analysis were used to estimate median OS and identify poor prognostic factors. RESULTS: One hundred and eighty-eight patients were identified. Most patients had intermediate-risk (54.8%) or poor-risk (44.1%) disease. Median OS for all patients was 10.4 months [95% confidence interval (CI) 8.1-12.5]. By multivariable analysis, elevated baseline lactate dehydrogenase and corrected calcium, performance status of two or more, retroperitoneal nodal metastasis, thrombocytosis, current smoking, two or more metastatic sites, and lymphopenia were independent risk factors for inferior OS. Patients with four or more factors had increased risk of death (hazard ratio 8.83, 95% CI 5.02-15.5, P < 0.001) and 5.5-month median OS. Nineteen patients (10.0%) survived for 2+ years. CONCLUSIONS: These data highlight the improved OS of patients with mRCC treated with TT without CN, compared with historical IFN-α treatment, and may guide the design of trials investigating the role of CN in the TT era.

Laparoscopic ultrasonography.

The use of laparoscopic ultrasonography (LUS) allows visualization of tissues beyond the two-dimensional laparoscopic picture, enhancing the amount and quality of information available to the surgeon. Linear-array transducers with frequencies of 7.5 to 10 MHz are typically used for LUS, employing B-mode scanning and color Doppler capability on probes with articulating tips. In general surgery, LUS has become a common adjunct to the intraoperative staging of upper gastrointestinal malignancy to determine resectability, avoiding unnecessary laparotomy. In urology, LUS appears to be a promising adjunct for four current procedures: difficult pelvic lymphocele marsupialization, renal cyst decortication, nephrolithotomy and other renal stone surgery, and cryotherapy of renal masses. The role of LUS during varicocelectomy is limited, and enthusiasm for this procedure is waning. Laparoscopic ultrasonography is a critical adjunct to renal cryoablation, a developmental procedure that currently lacks long-term data but is promising as therapy for small, incidentally detected renal masses. It appears that as laparoscopic urologic procedures continue to expand, so will the application of this promising operative imaging modality.

Impaired alpha-interferon signaling in transitional cell carcinoma: lack of p48 expression in 5637 cells.

The limited success of IFN-alpha therapy for clinical treatment of transitional cell carcinoma (TCC) has prompted us to investigate the responsiveness of TCC lines to IFN-alpha. The response to IFN-alpha in terms of 561 gene induction, an IFN-stimulated response element-containing IFN-alpha/beta-inducible gene, and IFN-stimulated gene factor 3 (ISGF3) formation was normal in primary human urothelial cells. We tested the antiproliferative effects of IFN-alpha in three TCC lines as a measure of IFN-alpha responsiveness, and variable patterns of growth inhibition were observed in three TCC lines. More than 90% growth inhibition was noted in TCCSUP cells, whereas only 40% and 10% inhibition by IFN-alpha was observed in 5637 and HT1197 cells, respectively. IFN-alpha treatment formed extremely low levels of ISGF3 in electrophoretic mobility shift assays in these later two relatively insensitive cells. In addition, expression of the 561 gene was significantly reduced in these two TCC lines by Northern blots. We have further identified a low expression level of Tyk2 in HT1197 cells compared with two other TCCs. This suggests that an extremely low ISGF3 level after IFN-alpha treatment may be due to low Tyk2 expression or other unidentified defects. In 5637 cells, p48 protein expression was undetectable. This undetectable p48 expression is not due to a deletion in the coding region because the correct size protein is detected following IFN-gamma treatment. Consequently, the ISGF3 complex formation and 561 gene induction were restored by IFN-gamma pretreatment plus IFN-alpha treatment. Introduction of p48 expressing plasmid into 5637 cells was sufficient to form the ISGF3 complex by IFN-alpha treatment, suggesting the defect lies in the expression of p48 protein in 5637 cells. Detailed mechanistic understanding of the action of IFNs in bladder cancer cell lines may explain the abrogated therapeutic response of IFN-alpha in the clinical treatment of TCCs.

Laparoscopic marsupialization of the difficult lymphocele using internalized peritoneal dialysis catheter.

PURPOSE: Definitive treatment of the recurrent or anatomically difficult lymphocele without a common wall between the lymphocele and peritoneal cavities requires open surgery. We present a novel technique of laparoscopic marsupialization of such lymphoceles with placement of a cable of 2 internalized peritoneal dialysis catheters for maintaining permanent lymphoperitoneal drainage. MATERIALS AND METHODS: Two patients with a symptomatic, post-renal transplant pelvic lymphocele underwent the procedure. Laparoscopic marsupialization was performed with ultrasound guidance and in each case a cable of 2 internalized peritoneal dialysis catheters was anchored through the limited peritoneal window to maintain lymphoperitoneal drainage. RESULTS: Both procedures were successful. During a followup of 20 and 21 months, respectively, no recurrence or infectious complications were noted in these immunocompromised patients. CONCLUSIONS: Laparoscopic marsupialization with internalization of peritoneal dialysis catheters is a feasible, alternative measure available for select cases with a difficult or recurrent lymphocele.