A novel molecular signature identifies mixed subtypes in renal cell carcinoma with poor prognosis and independent response to immunotherapy.

BACKGROUND: Renal cell carcinoma (RCC) is a heterogeneous disease comprising histologically defined subtypes. For therapy selection, precise subtype identification and individualized prognosis are mandatory, but currently limited. Our aim was to refine subtyping and outcome prediction across main subtypes, assuming that a tumor is composed of molecular features present in distinct pathological subtypes. METHODS: Individual RCC samples were modeled as linear combination of the main subtypes (clear cell (ccRCC), papillary (pRCC), chromophobe (chRCC)) using computational gene expression deconvolution. The new molecular subtyping was compared with histological classification of RCC using the Cancer Genome Atlas (TCGA) cohort (n = 864; ccRCC: 512; pRCC: 287; chRCC: 65) as well as 92 independent histopathologically well-characterized RCC. Predicted continuous subtypes were correlated to cancer-specific survival (CSS) in the TCGA cohort and validated in 242 independent RCC. Association with treatment-related progression-free survival (PFS) was studied in the JAVELIN Renal 101 (n = 726) and IMmotion151 trials (n = 823). CSS and PFS were analyzed using the Kaplan-Meier and Cox regression analysis. RESULTS: One hundred seventy-four signature genes enabled reference-free molecular classification of individual RCC. We unambiguously assign tumors to either ccRCC, pRCC, or chRCC and uncover molecularly heterogeneous tumors (e.g., with ccRCC and pRCC features), which are at risk of worse outcome. Assigned proportions of molecular subtype-features significantly correlated with CSS (ccRCC (P = 4.1E - 10), pRCC (P = 6.5E - 10), chRCC (P = 8.6E - 06)) in TCGA. Translation into a numerical RCC-R(isk) score enabled prognosis in TCGA (P = 9.5E - 11). Survival modeling based on the RCC-R score compared to pathological categories was significantly improved (P = 3.6E - 11). The RCC-R score was validated in univariate (P = 3.2E - 05; HR = 3.02, 95% CI: 1.8-5.08) and multivariate analyses including clinicopathological factors (P = 0.018; HR = 2.14, 95% CI: 1.14-4.04). Heterogeneous PD-L1-positive RCC determined by molecular subtyping showed increased PFS with checkpoint inhibition versus sunitinib in the JAVELIN Renal 101 (P = 3.3E - 04; HR = 0.52, 95% CI: 0.36 - 0.75) and IMmotion151 trials (P = 0.047; HR = 0.69, 95% CI: 0.48 - 1). The prediction of PFS significantly benefits from classification into heterogeneous and unambiguous subtypes in both cohorts (P = 0.013 and P = 0.032). CONCLUSION: Switching from categorical to continuous subtype classification across most frequent RCC subtypes enables outcome prediction and fosters personalized treatment strategies.

[Management of testosterone in advanced hormone-sensitive prostate cancer: still up to date?] / Ist das Testosteron-Management beim fortgeschrittenen hormonsensitiven Prostatakarzinom zeitgemäß?

Androgen-deprivation therapy (ADT) is the standard therapy used for advanced or metastatic prostate cancer, either alone or in association with additional procedures and substances. The optimum value of testosterone postulated more than 40 years ago was arbitrarily set to be < 50 ng/dL or < 1.7 nmol/L and, from today's perspective, was defined by more insensitive measurement methods. Since then, more and more data has been generated, suggesting that a value of < 20 ng/dL would be prognostically relevant. Yet no guideline has been changed so far despite the call for lowering the target value. Measuring testosterone to evaluate the response to androgen suppression is not yet established in clinical routine. There are no specific recommendations in national and international guidelines. Based on the evolving evidence, the question about testosterone management during ADT is gaining importance. The current data is summarised in this paper.

External validation of a postoperative nomogram for the prediction of disease-specific survival in patients with papillary renal cell carcinoma using a large multicenter database.

PURPOSE: Based on data retrieved from a comprehensive multicenter database, we externally validated a published postoperative nomogram for the prediction of disease-specific survival (DSS) in patients with papillary renal cell carcinoma (papRCC). METHODS: A multicenter database containing data of 2325 patients with surgically treated papRCC was used as validation cohort. After exclusion of patients with missing data and patients included in the development cohort, 1372 patients were included in the final analysis. DSS-probabilities according to the nomogram were calculated and compared to actual DSS-probabilities. Subsequently, calibration plots and decision curve analyses were applied. RESULTS: The median follow-up was 38 months (IQR 11.8-80.7). Median DSS was not reached. The c-index of the nomogram was 0.71 (95% CI 0.60-0.83). A sensitivity analysis including only patients operated after 1998 delivered a c-index of 0.84 (95% CI 0.77-0.92). Calibration plots showed slight underestimation of nomogram-predicted DSS in probability ranges below 90%: median nomogram-predicted 5-year DSS in the range below 90% was 55% (IQR 20-80), but the median actual 5-year DSS in the same group was 58% (95% CI 52-65). Decision-curve analysis showed a positive net-benefit for probability ranges between a DSS probability of 5% and 85%. CONCLUSIONS: The nomogram performance was satisfactory for almost all DSS probabilities; hence it can be recommended for application in clinical routine and for counseling of patients with papRCC.

Serum Levels of MicroRNA-371a-3p (M371 Test) as a New Biomarker of Testicular Germ Cell Tumors: Results of a Prospective Multicentric Study.

PURPOSE: Previous studies suggested that serum levels of microRNA (miR)-371a-3p (so-called M371 test) have a much higher sensitivity and specificity than the classic markers of testicular germ cell tumors (GCTs) and are applicable toward both seminoma and nonseminoma. We sought to confirm the usefulness of this test as a novel biomarker for GCT. PATIENTS AND METHODS: In a prospective, multicentric study, serum samples of 616 patients with testicular GCTs and 258 male controls were examined for serum levels of miRNA-371a-3p (miR levels) by quantitative polymerase chain reaction. The GCT population encompassed 359 patients with seminoma and 257 with nonseminoma; 371 had clinical stage I disease, 201 had systemic disease, and 46 had relapses. Paired measurements before and after orchiectomy were performed in 424 patients; 118 with systemic disease had serial measurements during treatment. miR levels were compared with those of ß-human chorionic gonadotropin, α-fetoprotein, and lactate dehydrogenase. RESULTS: For the primary diagnosis of GCT, the M371 test showed a sensitivity of 90.1%, a specificity of 94.0%, an area under the curve of 0.966 upon receiver operating characteristic analysis, and a positive predictive value of 97.2%. α-Fetoprotein, ß-human chorionic gonadotropin, and lactate dehydrogenase had sensitivities of less than 50% in seminoma and slightly higher sensitivities in nonseminomas. miR levels were significantly associated with clinical stage, primary tumor size, and response to treatment. Relapses had elevated miR levels that subsequently dropped to normal upon remission. Teratoma did not express miR-371a-3p. CONCLUSION: The M371 test outperforms the classic markers of GCT with both a sensitivity and a specificity greater than 90%. All histologic subgroups, except teratoma, express this marker. The test could be considered for clinical implementation after further validation.

Evaluation of Transperineal Magnetic Resonance Imaging/Ultrasound-Fusion Biopsy Compared to Transrectal Systematic Biopsy in the Prediction of Tumour Aggressiveness in Patients with Previously Negative Biopsy.

OBJECTIVES: We compared the transperineal MRI/ultrasound-fusion biopsy (fusPbx) to transrectal systematic biopsy (sysPbx) in patients with previously negative biopsy and investigated the prediction of tumour aggressiveness with regard to radical prostatectomy (RP) specimen. MATERIAL AND METHODS: A total of 710 patients underwent multiparametric magnetic resonance imaging (mpMRI), which was evaluated in accordance with Prostate Imaging Reporting and Data System (PI-RADS). The maximum PI-RADS (maxPI-RADS) was defined as the highest PI-RADS of all lesions detected in mpMRI. In case of proven prostate cancer (PCa) and performed RP, tumour grading of the biopsy specimen was compared to that of the RP. Significant PCa (csPCa) was defined according to Epstein criteria. RESULTS: Overall, scPCa was detected in 40% of patients. The detection rate of scPCa was 33% for fusPbx and 25% for sysPbx alone (p < 0.005). Patients with a maxPI-RADS ≥3 and a prostate specific antigen (PSA)-density ≥0.2 ng/mL2 harboured more csPCa than those with a PSA-density < 0.2 ng/mL2 (41% [33/81] vs. 20% [48/248]; p < 0.001). Compared to the RP specimen (n = 140), the concordance of tumour grading was 48% (γ = 0.57), 36% (γ = 0.31) and 54% (γ = 0.6) in fusPbx, sysPbx and comPbx, respectively. CONCLUSIONS: The combination of fusPbx and sysPbx outperforms both biopsy modalities in patients with re-biopsy. Additionally, the PSA-density may represent a predictor for csPCa in patients with maxPI-RADS ≥3.

Only <10% of Patients Selected for Radical Prostatectomy Reach the Competing Mortality Rate of the Prostate Cancer Intervention Versus Observation Trial (PIVOT).

In the Prostate Cancer Intervention Versus Observation Trial (PIVOT), surgery was not associated with lower mortality compared with observation. However, the high competing mortality rate of approximately 33% after 10 yr among the PIVOT study population has raised concerns on the generalizability of these results. We investigated 4282 patients who underwent radical prostatectomy at our institution between 1992 and 2010 to determine which subgroups harbored a competing (non-prostate cancer) mortality risk comparable to that of PIVOT and tested several combinations of higher age and comorbidities ("worst case scenarios") to identify subgroups reaching or even superseding the competing mortality rate of the PIVOT population. The competing mortality rate of PIVOT was not reached till an age-adjusted Charlson score of 5 or higher (corresponding to an age of 70-79 yr with diabetes with end-organ damage). Only 8.9% of patients belonged to this high-risk subgroup, and only small subgroups comprising 1-5% patients superseded the competing mortality rate among the PIVOT study population. This data underline that the results of PIVOT should be used with great caution to exclude candidates for radical prostatectomy with comorbidities from curative treatment. PATIENT SUMMARY: Only <10% of patients selected for radical prostatectomy reached the competing mortality rate of approximately 33% observed in the Prostate Cancer Intervention Versus Observation Trial (PIVOT). The results of PIVOT should be used with great caution to exclude patients with concomitant diseases who seem otherwise fit for radical prostatectomy from curative treatment.

Validation of the Preoperative Score to Predict Postoperative Mortality in Patients Undergoing Radical Cystectomy.

Standardized prediction of perioperative mortality risk is of major clinical concern in the radical cystectomy setting. We validated the recently developed Preoperative Score to Predict Postoperative Mortality (POSPOM) in a sample of 1083 consecutive cystectomy patients treated between 1993 and 2014. POSPOM was calculated as originally described based on age and 13 further parameters; three parameters which were not available in our database were ignored. Thirty-day and 90-d mortality were 1.0% and 4.1%, respectively. The areas under the receiver operator characteristic curves were 0.86 for 30-d mortality and 0.78 for 90-d mortality. Below the median of 27 POSPOM risk points, 30-d mortality was 0% and 90-d mortality was 0.5%. Above this level, the corresponding figures were 1.7% and 6.5%, respectively. The 30-d (p<0.0001) and even the 90-d mortality rates (p=0.004) were lower than the POSPOM-predicted in-hospital mortality rate for this sample (5.8%). Nevertheless, with its good discriminative accuracy, POSPOM might standardize the prediction of postoperative mortality after radical cystectomy. The absolute mortality figures in a high volume academic center were, however, lower than predicted based on nationwide collected data. PATIENT SUMMARY: With a good discriminative accuracy, Preoperative Score to Predict Postoperative Mortality might standardize the prediction of postoperative mortality after radical cystectomy. The absolute mortality figures in a high volume academic center were, however, lower than predicted based on nationwide collected data.

Predicting 90-day and long-term mortality in octogenarians undergoing radical cystectomy.

BACKGROUND: Radical cystectomy bears a considerable perioperative mortality risk particularly in elderly patients. In this study, we searched for predictors of perioperative and long-term competing (non-bladder cancer) mortality in elderly patients selected for radical cystectomy. METHODS: We stratified 1184 consecutive patients who underwent radical cystectomy for high risk superficial or muscle-invasive urothelial or undifferentiated carcinoma of bladder into two groups (age < 80 years versus 80 years or older). Multivariable and cox proportional hazards models were used for data analysis. RESULTS: Whereas Charlson score and the American Society of Anesthesiologists (ASA) physical status classification (but not age) were independent predictors of 90-day mortality in younger patients, only age predicted 90-day mortality in patients aged 80 years or older (odds ratio per year 1.24, p = 0.0422). Unlike in their younger counterparts, neither age nor Charlson score or ASA classification were predictors of long-term competing mortality in patients aged 80 years or older (hazard ratios 1.07-1.10, p values 0.21-0.77). CONCLUSIONS: This data suggest that extrapolations of perioperative mortality or long-term mortality risks of younger patients to octogenarians selected for radical cystectomy should be used with caution. Concerning 90-day mortality, chronological age provided prognostic information whereas comorbidity did not.

Evaluation of Magnetic Resonance Imaging/Ultrasound-Fusion Biopsy in Patients with Low-Risk Prostate Cancer Under Active Surveillance Undergoing Surveillance Biopsy.

INTRODUCTION: Targeted biopsy of tumour-suspicious lesions detected in multiparametric magnetic resonance imaging (mpMRI) plays an increasing role in the active surveillance (AS) of patients with low-risk prostate cancer (PCa). The aim of this study was to compare MRI/ultrasound-fusion biopsy (fusPbx) with systematic biopsy (sysPbx) in patients undergoing biopsy for AS. METHODS: Patients undergoing mpMRI and transperineal fusPbx combined with transrectal sysPbx (comPbx) as surveillance biopsy were investigated. The detection of Gleason score upgrading and reclassification according to Prostate Cancer Research International Active Surveillance criteria were evaluated. RESULTS: Eighty-three patients were enrolled. PCa upgrading was detected in 39% by fusPbx and in 37% by sysPbx (p = 1.0). The percentage of patients who were reclassified in fusPbx and sysPbx (p = 0.45) were 64 and 59% respectively. ComPbx detected more frequently tumour upgrading than fusPbx (71 vs. 64%, p = 0.016) and sysPbx (71 vs. 59%, p < 0.001) and more patients had to be reclassified after comPbx than after fusPbx or sysPbx alone. CONCLUSIONS: The combination of fusPbx and sysPbx outperforms both modalities alone with regard to the detection of upgrading and reclassification in patients under AS. Because a high missing rate of significant PCa still exists in both biopsy modalities, a combination of fusPbx and sysPbx should be recommended in these patients.

Selection Effects May Explain Smoking-related Outcome Differences After Radical Cystectomy.

The impact of smoking on mortality among patients with bladder cancer is subject to controversy. We investigated 1000 patients who consecutively underwent radical cystectomy between 1993 and 2013. Proportional hazards models for competing risks were used to study the combined effects of variables on mortality. Compared to nonsmokers, current smokers were more frequently male (35.7% vs 12.0%, p<0.0001), younger (63.5 vs 70.5 yr, p<0.0001), had a lower body mass index (26.2 vs 27.1kg/m2, p<0.0001), and suffered less frequently from cardiac insufficiency (12.7% vs 19.3%, p=0.0129). Among current smokers there was a trend towards lower bladder cancer mortality and higher competing mortality in comparison to nonsmokers. On multivariable analysis, current smoking was not a predictor of bladder cancer mortality (hazard ratio [HR] in the full model 0.76; p=0.0687) but was a predictor of competing mortality (HR in the optimal model 1.62; p=0.0044). In conclusion, this study did not confirm adverse bladder cancer-related outcome among current smokers after radical cystectomy. With a younger mean age and a male predominance, there was a trend towards lower bladder cancer mortality current smokers that was eventually neutralized by higher competing mortality, illustrating that selection effects may explain some smoking-related outcome differences after radical cystectomy. The single-center design is a study limitation. PATIENT SUMMARY: Current smokers are not at higher risk of bladder cancer after radical cystectomy but have a higher risk of competing mortality.

Prospective comparison of transperineal magnetic resonance imaging/ultrasonography fusion biopsy and transrectal systematic biopsy in biopsy-naïve patients.

OBJECTIVES: To evaluate the value of multiparametric magnetic resonance imaging (mpMRI) in the detection of significant prostate cancer (PCa) and to compare transperineal MRI/ultrasonography fusion biopsy (fusPbx) with conventional transrectal systematic biopsy (sysPbx) in biopsy-naïve patients. PATIENTS AND METHODS: This multicentre, prospective trial investigated biopsy-naïve patients with suspicion of PCa undergoing transperineal fusPbx in combination with transrectal sysPbx (comPbx). The primary outcome was the detection of significant PCa, defined as Gleason pattern 4 or 5. We analysed the results after a study period of 2 years. RESULTS: The study included 214 patients. The median (range) number of targeted and systematic cores was 6 (2-15) and 12 (6-18), respectively. The overall PCa detection rate of comPbx was 52%. FusPbx detected more PCa than sysPbx (47% vs 43%; P = 0.15). The detection rate of significant PCa was 38% for fusPbx and 35% for sysPbx (P = 0.296). The rate of missed significant PCa was 14% in fusPbx and 21% in sysPbx. ComPbx detected significantly more significant PCa than fusPbx and sysPbx alone (44% vs 38% vs 35%; P < 0.005). In patients presenting with Prostate Imaging Reporting and Data System (PI-RADS) 4 and 5 lesions there was a higher detection rate of significant PCa than in patients presenting with PI-RADS ≤3 lesions in comPbx (61% vs 14%; P < 0.005). CONCLUSIONS: For biopsy-naïve men with tumour-suspicious lesions in mpMRI, the combined approach outperformed both fusPbx and sysPbx in the detection of overall PCa and significant PCa. Thus, biopsy-naïve patients may benefit from sysPbx in combination with mpMRI targeted fusPbx.

Surgical resection of locally recurrent renal cell carcinoma after nephrectomy: Oncological outcome and predictors of survival.

OBJECTIVE: To describe the course of disease of patients surgically treated for locally recurrent renal cell carcinoma (LRRCC) after nephrectomy and to identify potential predictive factors for long-term survival. PATIENTS AND METHODS: We, retrospectively, identified 54 patients who underwent surgical resection of LRRCC after open nephrectomy for localized kidney cancer. The median age at time of surgery for LRRCC was 65 years. Survival rates were determined with the Kaplan-Meier method. Mantel-Haenszel hazard ratios were calculated. Comparisons were made with the log-rank test. Cox proportional hazard models were used to analyze combined effects of variables. RESULTS: Median time to local recurrence after nephrectomy was 36 months (5-242 months). Median follow-up after surgery for LRRCC was 39 months. At time of analysis 18 patients (33%) were alive without any evidence of disease, 8 patients (15%) were alive with disease, 20 patients (37%) died of renal cell carcinoma, and 8 patients (15%) died of other causes. A 5-year overall survival (OS) was 60% (95% CI: 0.44-0.73) and 10-year OS was 32% (95% CI: 0.15-0.51). The median survival after surgery for LRRCC was 79 months. In univariate analysis OS differed significantly by the time period between primary surgery and occurrence of LRRCC (<2 years vs. ≥2 years: 10-year OS rate 31% (95% CI: 10.2-55.0) vs. 45% (95% CI: 21.5-65.8; hazard ratio = 0.26; P = 0.0034). In multivariate analysis sarcomatoid features in the primary nephrectomy specimen, positive surgical margins of the LRRCC specimen and a Charlson score of ≥2 were associated with a significantly worse prognosis in this cohort. CONCLUSION: In patients with a disease-free interval of more than 2 years after surgery for the primary tumor, surgical removal of LRRCC may achieve long-term survival in most patients. In those with a shorter disease-free interval, long-term survival is unlikely.

Organ Preservation Is Less Frequently Performed in Women Surgically Treated for Papillary Renal Cell Carcinoma-Results of a Comprehensive Multicenter Study.

OBJECTIVE: To analyze the impact of gender on the clinicopathologic features and survival of patients with surgically treated papillary renal cell carcinoma (papRCC) using a comprehensive international multicenter database. MATERIALS AND METHODS: Data of 2325 patients undergoing surgery for unilateral papRCC between 1984 and 2015 in 17 European and North American centers were retrospectively collated. The impact of clinicopathologic features on the likelihood of nephron-sparing surgery (NSS) was evaluated using a multivariable logistic regression model. The influence on cancer-specific mortality (CSM) and other-cause mortality was analyzed by multivariable competing-risk regression models. Finally, subgroup analyses were conducted for organ-confined (n = 2075) and non-organ-confined tumors (n = 250). The median follow-up was 47 months. RESULTS: The study cohort included 1782 (77%) male patients (male-to-female ratio 3.3:1.0). Considering age, symptoms at presentation, performance status, pathologic tumor size, stage, and grade, we observed that there were no significant gender-specific differences. In contrast, female patients underwent NSS significantly less frequently (P <.001). On multivariable analysis, the likelihood of NSS was 72% higher in male patients after adjusting for all relevant cofactors (P <.001). No significant gender-specific differences in terms of CSM and other-cause mortality were demonstrated, but CSM was 59% lower in female patients in the subgroup of organ-confined tumors (P = .001). CONCLUSION: No impact of gender on survival was found analyzing this large cohort of patients undergoing surgery for papRCC. However, CSM appears to be lower in female patients with organ-confined disease. In this context, it is interesting that the likelihood of NSS seems to be significantly higher in male patients.

Evaluation of Prostate Imaging Reporting and Data System Classification in the Prediction of Tumor Aggressiveness in Targeted Magnetic Resonance Imaging/Ultrasound-Fusion Biopsy.

OBJECTIVES: The study aimed to evaluate the prediction of Prostate Imaging Reporting and Data System (PI-RADS) with respect to the prostate cancer (PCa) detection rate and tumor aggressiveness in magnetic resonance imaging (MRI)/ultrasound-fusion-biopsy (fusPbx) and in systematic biopsy (sysPbx). MATERIALS AND METHODS: Six hundred and twenty five patients undergoing multiparametric MRI were investigated. MRI findings were classified using PI-RADS v1 or v2. All patients underwent fusPbx combined with sysPbx (comPbx). The lesion with the highest PI-RADS was defined as maximum PI-RADS (maxPI-RADS). Gleason Score ≥7 (3 + 4) was defined as significant PCa. RESULTS: The overall PCa detection rate was 51% (n = 321; 39% significant PCa). The detection rate was 43% in fusPbx (n = 267; 34% significant PCa) and 36% in sysPbx (n = 223; 27% significant PCa). Nine percentage of significant PCa were detected by sysPbx alone. A total of 1,162 lesions were investigated. The detection rate of significant PCa in lesions with PI-RADS 2, 3, 4, and 5 were 9% (18/206), 12% (56/450), 27% (98/358), and 61% (90/148) respectively. maxPI-RADS ≥4 was the strongest predictor for the detection of significant PCa in comPbx (OR 2.77; 95% CI 1.81-4.24; p < 0.005). CONCLUSIONS: maxPI-RADS is the strongest predictor for the detection of significant PCa in comPbx. Due to a high detection rate of additional significant PCa in sysPbx, fusPbx should still be combined with sysPbx.

Prognostic and discriminative power of the 7th TNM classification for patients with surgically treated papillary renal cell carcinoma: results of a multi-institutional validation study (CORONA subtype project).

OBJECTIVE: Studies on the prognostic reliability of the Union for International Cancer Control tumor, node, metastasis (TNM) staging system for renal cell carcinoma (RCC) predominantly focus on clear-cell RCC. Therefore, the aim of this study was to investigate whether the oncological prognosis of surgically treated papillary RCC (papRCC) patients is reliably given by the current TNM system, by analyzing the largest database reported to date. MATERIALS AND METHODS: Data on 2325 papRCC patients who underwent surgical treatment in 1984- 2015 were collated from 17 international centers (median follow-up 47 months). Tumor stage was adapted to the 7th edition of the TNM system. Multivariable, bootstrap-corrected Cox regression models were applied to assess the independent impact of the TNM system on cancer-specific mortality (CSM) and all-cause mortality (ACM). RESULTS: The median age at diagnosis was 63 years (interquartile range 54-70 years) and 77% of patients were male. Nephron-sparing surgery was performed in 42%, and 82% were with symptom free at diagnosis. In 6.7% (n = 156), organ metastasis (stage M1) was present at the time of surgery. On multivariable analysis, the TNM system and Fuhrman grade had an independent impact on both CSM and ACM, while patient age affected ACM only. The discriminative ability of the pT classification was significant for both endpoints: 5 year CSM rates were 5%, 17%, 36% and 56% for stages pT1, pT2, pT3 and pT4, respectively (each p < 0.001). The pT classification contributed significantly to the predictive accuracy of the CSM and ACM models by 6.3% and 2.5%, respectively (each p < 0.001). CONCLUSIONS: The 2010 TNM staging system can be reliably applied to papRCC patients and allows certain prognostic discrimination.

Systemic therapy in metastatic renal cell carcinoma.

PURPOSE: Current systemic treatment of targeted therapies, namely the vascular endothelial growth factor-antibody (VEGF-AB), VEGF receptor tyrosine kinase inhibitor (TKI) and mammalian target of rapamycin (mTOR) inhibitors, have improved progression-free survival and replaced non-specific immunotherapy with cytokines in metastatic renal cell carcinoma (mRCC). METHODS: A panel of experts convened to review currently available phase 3 data for mRCC treatment of approved agents, in addition to available EAU guideline data for a collaborative review as the plurality of substances offers different options of first-, second- and third-line treatment with potential sequencing. RESULTS: Sunitinib and pazopanib are approved treatments in first-line therapy for patients with favorable- or intermediate-risk clear cell RCC (ccRCC). Temsirolimus has proven benefit over interferon-alfa (IFN-α) in patients with non-clear cell RCC (non-ccRCC). In the second-line treatment TKIs or mTOR inhibitors are treatment choices. Therapy options after TKI failure consist of everolimus and axitinib. Available third-line options consist of everolimus and sorafenib. Recently, nivolumab, a programmed death-1 (PD1) checkpoint inhibitor, improved overall survival benefit compared to everolimus after failure of one or two VEGFR-targeted therapies, which is likely to become the first established checkpoint inhibitor in mRCC. Data for the sequencing of agents remain limited. CONCLUSIONS: Despite the high level of evidence for first and second-line treatment in mRCC, data for third-line therapy are limited. Possible sequences include TKI-mTOR-TKI or TKI-TKI-mTOR with the upcoming checkpoint inhibitors in perspective, which might settle a new standard of care after previous TKI therapy.

Predicting Competing Mortality in Patients Undergoing Radical Prostatectomy Aged 70 yr or Older.

Estimating the risk of competing mortality is of importance in tailoring optimal individual management strategies in patients with early prostate cancer. Using proportional hazard models for competing risks, we determined which parameters predict competing mortality in patients selected for radical prostatectomy aged 70 yr or older and compared the prognostic impact of individual parameters with that of their younger counterparts. Three common diseases (diabetes mellitus, chronic lung disease, and other cancer) that predicted competing mortality in younger men were not predictors of competing mortality in men selected for radical prostatectomy aged 70 yr or older (hazard ratio [HR]:<1). Besides age (HR/yr: 1.08, p=0.0255), peripheral vascular disease (HR: 2.33, p=0.0195), cerebrovascular disease (HR: 2.23, p=0.0242), American Society of Anesthesiologists physical status class 3 (HR: 2.19, p<0.0001), current smoking (HR: 2.18, p=0.0098), and lower or unknown level of education (HR: 2.07, p=0.0002) were independent predictors of competing mortality in patients aged 70 yr or older. Combining these five conditions in a score might provide a superior comorbidity measure in this particular population. PATIENT SUMMARY: Stricter selection may diminish the prognostic significance of several common diseases in men selected for radical prostatectomy aged 70 yr or older whereas other parameters (peripheral vascular disease, cerebrovascular disease, American Society of Anesthesiologists physical status class 3, current smoking, and level of education) sustained their meaningfulness and should be taken into consideration when the risk of competing mortality is estimated.

Direct comparison of multiparametric magnetic resonance imaging (MRI) results with final histopathology in patients with proven prostate cancer in MRI/ultrasonography-fusion biopsy.

OBJECTIVE: To compare multiparametric magnetic resonance imaging (mpMRI) of the prostate and histological findings of both targeted MRI/ultrasonography-fusion prostate biopsy (PBx) and systematic PBx with final histology of the radical prostatectomy (RP) specimen. PATIENTS AND METHODS: A total of 105 patients with prostate cancer (PCa) histopathologically proven using a combination of fusion Pbx and systematic PBx, who underwent RP, were investigated. All patients had been examined using mpMRI, applying the European Society of Urogenital Radiology criteria. Histological findings from the RP specimen were compared with those from the PBx. Whole-mount RP specimen and mpMRI results were directly compared by a uro-pathologist and a uro-radiologist in step-section analysis. RESULTS: In the 105 patients with histopathologically proven PCa by combination of fusion PBx and systematic PBx, the detection rate of PCa was 90% (94/105) in fusion PBx alone and 68% (72/105) in systematic PBx alone (P = 0.001). The combination PBx detected 23 (22%) Gleason score (GS) 6, 69 (66%) GS 7 and 13 (12%) GS ≥8 tumours. Fusion PBx alone detected 25 (26%) GS 6, 57 (61%) GS 7 and 12 (13%) GS ≥8 tumours. Systematic PBx alone detected 17 (24%) GS 6, 49 (68%) GS 7 and 6 (8%) GS ≥8 tumours. Fusion PBx alone would have missed 11 tumours (4% [4/105] of GS 6, 6% [6/105] of GS 7 and 1% [1/105] of GS ≥8 tumours). Systematic PBx alone would have missed 33 tumours (10% [10/105] of GS 6, 20% [21/105] of GS 7 and 2% [2/105] of GS ≥8 tumours). The rates of concordance with regard to GS between the PBx and RP specimen were 63% (n = 65), 54% (n = 56) and 75% (n = 78) in fusion, systematic and combination PBx (fusion and systematic PBx combined), respectively. Upgrading of the GS between PBx and RP specimen occurred in 33% (n = 34), 44% (n = 46) and 18% (n = 19) in fusion, systematic and combination PBx, respectively. γ-correlation for detection of any cancer was 0.76 for combination PBx, 0.68 for fusion PBx alone and 0.23 for systematic PBx alone. In all, 84% (n = 88) of index tumours were identified by mpMRI; 86% (n = 91) of index lesions on the mpMRI were proven in the RP specimen. CONCLUSIONS: Fusion PBx of tumour-suspicious lesions on mpMRI was associated with a higher detection rate of more aggressive PCa and a better tumour prediction in final histopathology than systematic PBx alone; however, combination PBx had the best concordance for the prediction of GS. Furthermore, the additional findings of systematic PBx reflect the multifocality of PCa, therefore, the combination of both biopsy methods would still represent the best approach for the prediction of the final tumour grading in PCa.

Evaluation of polymorphisms in angiogenesis-related genes as predictive and prognostic markers for sunitinib-treated metastatic renal cell carcinoma patients.

PURPOSE: Single nucleotide polymorphisms (SNPs) in angiogenesis-associated genes might play an important role in activity of the tyrosine kinase inhibitor sunitinib and could affect survival of cancer patients treated with this drug. The aim of this retrospective study was to elucidate the role of 10 known SNPs in VEGFA, VEGFR1, VEGFR2 and VEGFR3 as potential prognostic and predictive markers in an independent cohort of patients with metastatic renal cell carcinoma (mRCC). METHODS: DNA from 121 mRCC patients treated with sunitinib was used to analyze SNPs by TaqMan genotyping assays. Disease control rate was evaluated according to RECIST. Adverse effects of sunitinib were registered from medical records. The results of Cox and logistic regression were verified by correction for multiple testing. RESULTS: Kaplan-Meier analysis revealed a reduced progression-free survival in patients with the wild-type (WT) allele of the VEGFA SNP rs699947 compared to variant alleles. Patients with the AA/AC-alleles of the VEGFR1 SNP rs9582036 had an improved median overall survival compared to those with the CC-WT allele what could be confirmed by multivariable Cox proportional hazard regression analyses. No statistically significant associations between the analyzed SNPs and higher risk for adverse effects were observed. CONCLUSIONS: The results of this study suggest that most of the selected SNPs in angiogenesis-related genes are not associated with survival of mRCC patients after sunitinib therapy or with adverse effects. Only the VEGFR1 SNP rs9582036 showed a statistically significant association with overall survival. The potential of SNPs as prognostic and predictive markers for sunitinib-treated mRCC patients should be finally assessed by prospective studies.

Growth of a Level III Vena Cava Tumor Thrombus Within 1 Month.

We describe a patient with rapid growth of a vena cava tumor thrombus from level I-II to level III within 1 month. This case illustrates that once the diagnosis of vena cava involvement is established in renal cell carcinoma, surgery should not be delayed without urgent reasons.