Prevalence,Disease-free,and Overall Survival of Contemporary Patients With Renal Cell Carcinoma Eligible for Adjuvant Checkpoint Inhibitor Trials

IntroductionDesigning adjuvant trials is challenging because of uncertainties of prevalence and outcome of high-risk renal cell cancer (RCC) despite use of validated risk scores. Our objective is to investigate how differences in eligibility criteria may impact on potential study results in RCC adjuvant trials.Patients and MethodsRECUR is a multicenter European database capturing patient and tumor characteristics, recurrence patterns, and survival of those curatively treated for non-metastatic RCC from 2006 to 2011 without any adjuvant therapy. We used RECUR to evaluate prevalence, disease-free survival (DFS), and overall survival (OS) according to eligibility criteria of immunotherapy-based adjuvant trials IMMotion 010 (NCT03024996), Checkmate 914 (NCT03138512), Keynote-564 (NCT03142334), RAMPART (NCT03288532), and PROSPER (NCT03055013).ResultsOf 3024 relevant patients in RECUR, 408 (13.5%), 725 (24%), 609 (20.1%), 1363 (45.1%), and 1071 (35.4%) met eligibility criteria for IMMotion-010, CheckMate-914, Keynote-564, RAMPART, and PROSPER, respectively. The median and 5-year DFS Kaplan-Meier estimates in RECUR corresponding to each trial eligibility criteria were: not reached and 69.6% for RAMPART; not reached and 64.5% for PROSPER; 109.3 months (95% confidence interval [CI], 83.9-134.6 months) and 57% for CheckMate-914; 75.8 months (95% CI, 52.7-98.8 months) and 54.3% for Keynote-564; and 43.6 months (95% CI, 30.8-56.4 months) and 45% for IMMotion-010. Our analysis may be limited by the retrospective design.ConclusionsRECUR provides estimated DFS and OS benchmarks for placebo arms of adjuvant checkpoint inhibitor studies and hence likely time to trial reporting. Well-documented contemporary registries rather than past risk models should be used to design future adjuvant trials.     

Cancer-specific mortality in patients with non-metastatic renal cell carcinoma who have undergone a nephrectomy and are eligible for adjuvant pembrolizumab

BackgroundData in patients with malignant melanoma, who have been previously treated with pembrolizumab as adjuvant therapy, show a reduction in pembrolizumab efficacy upon rechallenge. We examined this scenario in patients with non-metastatic renal cell carcinoma (RCC) eligible for adjuvant pembrolizumab after nephrectomy. We hypothesized that a proportion of such patients will either require re-treatment with pembrolizumab upon metastatic progression prior to cancer-specific mortality (CSM) or die from other cause mortality (OCM).Materials and methodsWe identified within the SEER database 10,635 patients, between 2004 and 2017, with a diagnosis of non-metastatic intermediate-high and high risk RCC, who had undergone nephrectomy and fulfilled criteria for enrollment in KEYNOTE-564. Kaplan-Meier analyses addressed overall survival (OS), CSM and OCM.Results9,825 (92.4%) of the 10,635 patients had intermediate-high risk RCC and 9,456 (88.9%) underwent radical nephrectomy. Additionally, 760 (7.1%) harbored sarcomatoid features. In Kaplan-Meier analyses, median OS was 9.8 (9.1–11.4) years. At 10-years of follow-up, CSM rate was 36% and OCM rate was 22%.ConclusionsBased on CSM, our observations indicate that by 10-years of follow-up 36% of patients treated with adjuvant pembrolizumab will require a rechallenge, in a setting where a checkpoint inhibitor may have reduced efficacy. Moreover, at 10-years of follow-up, 22% of patients with RCC, previously treated with adjuvant pembrolizumab, will die of other causes. These percentages should be strongly considered prior to routine use of adjuvant pembrolizumab, especially given an OS benefit has not been proven.     

Treatment outcome with mTOR inhibitors for metastatic renal cell carcinoma with nonclear and sarcomatoid histologies

BackgroundThe clinical trials that reported benefit of the rapalogs temsirolimus and everolimus in advanced renal cell carcinoma (RCC) were primarily conducted in patients with clear-cell histology (ccRCC). We assessed outcome with these mammalian target of rapamicin (mTOR) inhibitors in two subsets of kidney cancer: sarcomatoid variant ccRCC and nonclear-cell RCC.Patients and methodsBaseline clinical features, information on prior treatment, and histologic subtypes were collected for patients previously treated with rapalogs for metastatic RCC of either nonclear phenotype or ccRCC with sarcomatoid features. Outcome was assessed centrally by a dedicated research radiologist for determination of tumor response, progression-free survival (PFS), and overall survival (OS).ResultsEighty-five patients received temsirolimus (n = 59) or everolimus (n = 26). Nonclear-cell phenotypes included papillary (n = 14), chromophobe (n = 9), collecting duct (n = 4), translocation-associated (n = 3), and unclassified (n = 32) RCC. Twenty-three patients had clear-cell histology with sarcomatoid features. The response rate in assessable patients (n = 82) was 7% (all partial responses); 49% of patients achieved stable disease, and 44% had progressive disease as their best response. Tumor shrinkage was observed in 26 patients (32%). Median PFS and OS were 2.9 and 8.7 months, respectively. Nine patients (11%) were treated for ≥1 year, including cases of papillary (n = 3), chromophobe (n = 2), unclassified (n = 3) RCC, and ccRCC with sarcomatoid features (n = 1). No tumor shrinkages were observed for patients with collecting duct or translocation-associated RCC.ConclusionsA subset of patients with nonclear-cell and sarcomatoid variant ccRCC subtypes benefit from mTOR inhibitors, but most have poor outcome. Histologic subtype does not appear to be helpful in selecting patients for rapalog therapy. Future efforts should include the identification of predictive tissue biomarkers.     

Renal Function Impairment Below Safety Limits Correlates With Cancer-specific Mortality in Localized Renal Cell Carcinoma: Results From a Single-center Study

BackgroundA recent multi-center study showed how estimated glomerular filtration rate (eGFR) and cancer-specific mortality (CSM) are linearly and inversely related in organ-confined renal cell carcinoma (RCC) whenever the eGFR decreases below specific thresholds. We addressed our previous work limitations related to heterogeneity and missing data, and explored the relationship between eGFR and CSM also in locally advanced RCC.Materials and MethodsAll patients with RCC treated with either partial or radical nephrectomy from 1990 to 2018 at a single institution and with complete data on renal function were included. eGFR was managed as a time-dependent variable. The relationship between eGFR and CSM was analyzed using a Fine and Gray multivariable competing risks framework. Subdistribution hazard ratios (SHRs) were calculated accounting for deaths from other causes.ResultsMultivariable competing risks analysis showed a “piecewise” relationship between eGFR and CSM, with an inverse linear correlation for eGFR values below 85 mL/min. Below this breakpoint, a significant relationship existed between eGFR and CSM in both clinical (SHR, 1.27; P < .001) and pathologic (SHR, 1.27; P = .001) models in stage I to II RCC subgroup. Conversely, no significance was recorded in this subgroup when considering eGFR values above 85 mL/min. In the stage III to IV subgroup, no significant relationships were recorded, regardless of eGFR values. The retrospective design with inherent biases in data collection represents a limitation.ConclusionsIn patients undergoing surgery for stage I to II RCC, preservation of renal function over “safety limits” is protective from CSM.     

Systemic therapy for sarcomatoid renal cell carcinoma

Renal cell carcinoma (RCC) is the most common malignant neoplasm of the kidney, and sarcomatoid RCC is an aggressive and lethal variant. Sarcomatoid features can be seen in all types of RCC and do not constitute a separate histologic type. No cellular or genetic biomarker for the sarcomatoid variant has yet been discovered. Most systemic therapies developed for metastatic RCC are less effective in sarcomatoid RCC, although some of the cytotoxic drugs may actually be more effective for sarcomatoid RCC because of its rapid rate of proliferation. Several ongoing prospective clinical trials are investigating new drug combinations for this disease.     

Systemic therapy for sarcomatoid renal cell carcinoma

Renal cell carcinoma (RCC) is the most common malignant neoplasm of the kidney, and sarcomatoid RCC is an aggressive and lethal variant. Sarcomatoid features can be seen in all types of RCC and do not constitute a separate histologic type. No cellular or genetic biomarker for the sarcomatoid variant has yet been discovered. Most systemic therapies developed for metastatic RCC are less effective in sarcomatoid RCC, although some of the cytotoxic drugs may actually be more effective for sarcomatoid RCC because of its rapid rate of proliferation. Several ongoing prospective clinical trials are investigating new drug combinations for this disease.     

Prediction of progression after radical nephrectomy for patients with clear cell renal cell carcinoma: a stratification tool for prospective clinical trials

BACKGROUND: The objective of the current study was to develop an algorithm to predict progression to metastases after radical nephrectomy for patients with clinically localized renal cell carcinoma (RCC) to allow stratification of patients for potential adjuvant therapy trials. METHODS: The authors identified 1671 sporadic patients with clinically localized, unilateral clear cell RCC who underwent radical nephrectomy between 1970 and 2000. The clinical features examined included age, gender, smoking history, recent onset hypertension, performance status, and presenting symptoms. The pathologic features examined included surgical margins, tumor stage, regional lymph node status, tumor size, nuclear grade, histologic tumor necrosis, sarcomatoid component, cystic architecture, and multifocality. Metastases free survival was estimated using the Kaplan-Meier method. A multivariate Cox proportional hazards regression model was fit to determine associations between the clinical and pathologic features and distant metastases. RESULTS: The median follow-up was 5.4 years (range, 0-31 years). Metastases occurred in 479 patients at a median of 1.3 years (range, 0-25 years) after nephrectomy. The estimated metastases free survival rates were 86.9% at 1 year, 77.8% at 3 years, 74.1% at 5 years, 70.8% at 7 years, and 67.1% at 10 years. Multivariate analysis showed that the following features were associated with progression to metastases: tumor stage, regional lymph node status, tumor size, nuclear grade, and histologic tumor necrosis (P < 0.001 for all). CONCLUSIONS: In patients with clear cell RCC, tumor stage, regional lymph node status, tumor size, nuclear grade, and histologic tumor necrosis showed statistically significant associations with progression to metastatic RCC. The authors present a scoring algorithm based on these features that can be used to predict disease progression after patients undergo radical nephrectomy for clinically localized clear cell RCC. Cancer 2003;97:1663-71.     

Overall Survival of Biopsy-confirmed T1B and T2A Kidney Cancers Managed With Observation: Prognostic Value of Tumor Histology

IntroductionThe natural history of T1b (4-7 cm) or T2a (> 7-10 cm) kidney cancers managed with observation is not well-understood. The aim of our study was to determine if the addition of histologic subtype to a predictive model of overall survival (OS) that includes covariates for competing risks in observed, biopsy-proven, T1b and T2a renal cell carcinomas (RCCs) improves the model’s performance.Materials and MethodsWe queried the National Cancer Database for patients with biopsy-proven stage T1b or T2a RCC and managed nonoperatively between 2004 and 2015. OS was estimated by Kaplan-Meier curves based on histologic subtype. The concordance index (c-index) from a Cox proportional hazards model was used to estimate the extent to which histologic subtypes predict survival for each stage when included in a model along with competing risks of age, gender, race/ethnicity, insurance status, area-level socioeconomic indicators, Charlson-Deyo index, and tumor grade.ResultsA total of 937 patients (754 with T1b and 185 with T2a) with biopsy-proven RCC were identified. Kaplan-Meier analysis suggested differences in OS by histologic subtype where sarcomatoid, followed by clear cell, papillary, and chromophobe, had the highest mortality risk at 1, 3, and 5 years. However, there was marginal improvement in the multivariable model of OS using competing risks and histology (c-index, 0.64 and 0.697) compared with competing risks alone (c-index, 0.631 and 0.671) for T1b and T2a RCCs, respectively.ConclusionsIn patients with T1b or T2a RCC managed with observation, incorporation of histologic subtype into a risk-stratification model to determine prognostic OS did not improve modeling of OS compared with variables representing competing risks. Histologic subtype of observed T1b and T2a RCC appears to have prognostic OS value when not considering competing risks. These findings may impact the usefulness of renal biopsy to inform decision-making when managing patients with T1b and T2a renal tumors with observation.     

Survival After Partial Cystectomy for Variant Histology Bladder Cancer Compared With Urothelial Carcinoma: A Population-based Study

BackgroundThe present study tested cancer-specific (CSM) and overall mortality (OM) after partial cystectomy (PC) for variant histology bladder cancer (non–urothelial carcinoma of the urinary bladder UCUB), relative to UCUB and relative to radical cystectomy (RC).Materials and MethodsWithin the Surveillance, Epidemiology, and End Results registry (2001-2016), we identified patients with stage T1-T2N0M0 non-UCUB and UCUB who had undergone PC or RC. Non-UCUB included adenocarcinoma, squamous carcinoma, neuroendocrine carcinoma, and other histologic subtypes. First, CSM and OM after PC were compared between the non-UCUB and UCUB groups. Second, CSM and OM after PC were compared with RC in the non-UCUB group. Kaplan Meier plots and multivariable Cox regression models were used before and after inverse probability of treatment weighting.ResultsOverall, 248 patients (16.3%) treated with PC had had non-UCUB. Of the 248 cases, 115 (46.5%), 50 (20%), 34 (14%), and 49 (19.5%) were adenocarcinoma, squamous carcinoma, neuroendocrine carcinoma, and other histologic subtypes, respectively. The comparison between PC in the non-UCUB and PC in the UCUB group showed higher CSM (hazard ratio, 1.4; P = .03) but the same OM rates (hazard ratio, 1.1; P = .7) in the non-UCUB group. The comparison between PC and RC for the non-UCUB group showed no CSM or OM differences.ConclusionsPC for non-UCUB was associated with higher CSM compared with PC for UCUB. However, PC instead of RC for select patients with non-UCUB appears not to undermine cancer-control outcomes. Thus, the excess CSM is probably unrelated to cystectomy type but could originate from differences in the tumor biology. These results could act as hypothesis generating for the design of future trials.     

Contemporary Incidence and Mortality Rates in Patients With Testicular Germ Cell Tumors

BackgroundWe comprehensively tested contemporary incidence and mortality rates in patients with germ cell tumor of the testis (GCTT).Materials and MethodsWithin the Surveillance, Epidemiology, and End Results database (2004-2015), statistical analyses included estimated annual percentage changes, multivariable logistic regression (MLR) models, Kaplan–Meier curves, and multivariable Cox regression (MCR) models.ResultsOf 13,114 GCTT patients, 7954 (60.6%) harbored seminoma germ cell tumors of the testis (SGCTT) and 5160 (39.4%) non-SGCTT (NSGCTT). Relative to SGCTT, NSGCTT patients harbored more advanced stage (for stage III 824 [16.0%] vs. 279 patients [3.5%]; P < .001). In MLR, higher rates of stage II/III affected those with never-married status (odds ratio [OR], 1.6; P < .001) and African American ethnicity (OR, 1.5; P = .005) for SGCTT and never-married (OR, 1.3; P = .002) and Hispanic ethnicity (OR, 1.3; P < .001) for NSGCTT. Significant differences in 5-year cancer-specific mortality (CSM) distinguished SGCTT (stage I: 0.4; stage II: 3.4; stage III: 11.4%; P < .001) from NSGCTT (stage I: 1.6; stage II: 2.5; stage III: 22.2%; P < .001). In MCR, unmarried status independently predicted higher CSM for SGCTT (hazard ratio [HR], 2.1; P = .007) and NSGCTT (HR, 1.9; P < .001).ConclusionStage I and stage III NSGCTT survival is worse, than for SGCTT. Never-married, Hispanic, and African American individuals are at higher risk of more advanced stage and/or CSM in SGCTT and NSGCTT.     

Partial Cystectomy With Pelvic Lymph Node Dissection for Patients With Nonmetastatic Stage pT2-T3 Urothelial Carcinoma of Urinary Bladder: Temporal Trends and Survival Outcomes

IntroductionWe investigated the effect of partial cystectomy (PC) on cancer-specific mortality (CSM) and other-cause mortality (OCM) and the effect of pelvic lymph node dissection (PLND) during PC on CSM.Materials and MethodsWithin the Surveillance, Epidemiology, and End Results database (2004-2015), 11,429 cases of nonmetastatic stage pT2-T3 urothelial carcinoma of the urinary bladder treated with either PC or radical cystectomy (RC) were identified. All comparisons between PC and RC relied on propensity score (PS; ratio, 1:1) adjusted univariable and multivariable logistic and competing risks regression models. In contrast, all comparisons between PLND and no PLND at PC relied on inverse probability of treatment weighting-adjusted univariable and multivariable Cox regression models.ResultsWithin the SEER database, PC had been performed in 979 patients (8.6%). The PC annual rates decreased from 11.0% to 6.8% during the study period (P < .001). In PS-adjusted multivariable analyses focusing on CSM and OCM, no statistically significant difference between the PC and RC groups (P = .2 and P = .3, respectively). The annual PLND rates with PC (50.3%) did not vary over time (P = .3). In the overall cohort and the PC subgroup, PLND was associated with a lower CSM rate (hazard ratio, 0.56; P < .001; and hazard ratio, 0.57; P < .001, respectively).ConclusionsA small proportion of patients with stage pT2-T3 urothelial carcinoma of the urinary bladder were candidates for PC. In the PS-adjusted multivariable analyses, no statistically significant differences were found in CSM or OCM between the PC and RC groups. Within the PC group, PLND had been omitted 50% of the time despite its association with lower CSM.     

Clinical Trials Eligibility of Patients With Malignant Pleural Mesothelioma: Use of Novel Therapies and Outcomes

IntroductionStudies of bevacizumab and pembrolizumab in the treatment of malignant pleural mesothelioma suggest anticancer efficacy; clinical trial populations are not reflective of real-world patients. We aimed to determine the proportion of real-world patients who would be eligible for trials, identify patients who participated in clinical trials, and examine treatment and outcome data.Patients and MethodsConsecutive patients with unresectable malignant pleural mesothelioma seen at our center from January 2012 to July 2018 were assessed with regards to their eligibility for Mesothelioma Avastin Cisplatin Study (MAPS) and KEYNOTE-028 clinical trials. Prognostic information, treatment use, and overall survival (OS) data were also collected.ResultsA total of 133 patients were included: 50% and 37%, respectively, did not meet trial eligibility for MAPS or KEYNOTE-028, most commonly owing to age ≥75 (23%), Eastern Cooperative Oncology Group performance status of ≥2 (21%), concomitant medication (21%), or comorbidity (12%). MAPS eligibility did not correlate with use of bevacizumab (P = .30) or improved OS (P = .87). Eligibility for KEYNOTE-028 correlated with pembrolizumab use (P < .001), but not improved OS (P = .21). Patients who received an investigational anticancer therapy on any clinical trial had improved OS: 32.4 (95% CI, 23.9-40.9) months versus 20.5 (95% CI, 15.8-25.3) months (P = .01).ConclusionOnly ≤63% of our patients were eligible for these trials, highlighting the differences between real-world patients and the highly select trial population. Our patients who participated in clinical trials had superior OS, further emphasizing the selection bias in the trial population.     

Epidemiologic trends in renal cell carcinoma in the cytokine and post-cytokine eras: a registry analysis of 28,252 patients

BackgroundBefore 2004, advanced renal cell cancer (RCC) therapy consisted primarily of cytokines such as interferon and/or interleukin-2. Subsequently, randomized trials of targeted therapies have shown a survival benefit, leading to the approval of several new agents since 2004. Whether the survival benefit seen in highly selected patients accrued to these trials has already translated to the general RCC patient population is unclear. To explore this, a large RCC patient registry was evaluated for changes in outcome between the cytokine (1998-2003) and post-cytokine (2004-2007) eras.MethodsData from the California Cancer Registry (CCR), a population-based cancer surveillance system, was used to retrospectively analyze 28,252 patients with RCC diagnosed between 1998 and 2007. Inter-era differences in clinical variables—including year of diagnosis, histologic characteristics, age, sex, race, stage, nephrectomy status, overall survival (OS), and cause-specific survival (CSS)—were assessed. Univariate and multivariate Cox models were used.ResultsCrude 3-year OS (68.2% vs. 74.6%; 2P < .001) and CSS (78.1% vs. 82.3%; 2P < .001) were significantly higher in the post–cytokine era. In multivariate analysis, the 3 strongest predictors for improved survival were localized disease (hazard ratio [HR], 18.1; 95% confidence interval [CI], 16.6-19.6), nephrectomy (HR, 2.87; 95% CI, 2.68-3.08), and clear cell histologic type (HR, 1.33; 95% CI, 1.22-1.44).ConclusionsIn this analysis of a large RCC registry, there was an apparent increase in crude OS and CSS in the post–cytokine era compared with the cytokine era. Insufficient follow-up time in the post–cytokine era and a higher proportion of localized disease in that era confound the possibility of benefit derived from targeted therapies. Longer follow-up for patients treated in the post–cytokine era is necessary for a more robust comparison of long-term OS.     

Sex-Related Differences Include Stage,Histology, and Survival in Urethral Cancer Patients

PurposeTo test the effect of sex on histologic subtype, stage at presentation, treatment, and cancer-specific mortality (CSM) in urethral cancer.Patients and MethodsWe identified urethral cancer patients within the Surveillance, Epidemiology, and End Results (SEER) registry (2004-2016). After matching for tumor and patient characteristics, cumulative incidence plots and multivariable competing risks regression models, adjusted for other-cause mortality, tested CSM according to sex.ResultsOf 1645 eligible urethral cancer patients, 1073 (65%) were male. Urothelial histologic subtype was most frequent in male (59%) but not female (27%) subjects. Adenocarcinoma, squamous cell carcinoma, and other histologies were more frequent in female patients. Most male subjects harbored T1N0M0 (32%) stage disease, whereas most female subjects harbored T3-4N0M0 (29%) stage disease. In urothelial and adenocarcinoma histologic subtypes, African American female subjects were most prevalent (31 and 78%) versus whites (16 and 52%) versus Hispanics (27 and 74%). In T1N0M0 stage, single-mode surgical treatment was more frequent in male than female patients (respectively, 73% vs 59%). In T3-4 and/or N1-2 stage disease, multimodal therapy was more frequent in female than male (42% vs 37%) patients. In nonmetastatic urethral cancer (T1-4N0-2M0), after propensity score matching for stage, race, treatment, and age, cumulative incidence plots showed 5-year CSM of 36% and 25% in female and male patients, respectively, and after further multivariable adjustment resulted in 1.3-fold higher CSM in female as opposed to male patients (P = .07).ConclusionFemale patients with urethral cancer present with higher disease stage. Despite higher rates of multimodal therapy, and despite matching for stage disadvantage, female subjects with urethral cancer exhibited higher CSM.     

Lymph Node Density as an Independent Prognostic Factor in Node-Positive Renal-Cell Carcinoma: Results From the Surveillance,Epidemiology, and End Results Program

BackgroundPrevious studies have revealed lymph node density (LND) to be an independent prognostic factor in cancer. However, data from 20 years ago failed to demonstrate the prognostic value of LND in node-positive renal-cell carcinoma (RCC). This study was undertaken to comprehensively investigate the prognostic value of LND in node-positive RCC.Patients and MethodsWithin the Surveillance, Epidemiology and End Results database, we accessed data on patients diagnosed with histologically confirmed node-positive RCC from 2004 to 2014. The cubic spline smoothing technique and Cox regression were used to evaluate the correlation between LND and cancer-specific mortality (CSM). The X-Tile program was used to identify the optimal cut point of LND in node-positive RCC. Robustness of the results in various subgroups was also explored. Univariable and multivariable analyses were performed to determine predictors of CSM. Sensitivity analyses were performed.ResultsA total of 1750 node-positive RCCs were identified. We found a nonlinear positive correlation between the likelihood of CSM and LND. X-Tile analysis identified best cut point of LND as 35% with a maximum chi-square of 18.58. Every 10% increase in LND increased CSM by 5% (hazard ratio = 1.05; 95% confidence interval, 1.02-1.07; P < .0001), and LND ≥ 35% was associated with 41% increase in CSM (hazard ratio = 1.41; 95% confidence interval, 1.20-1.65; P < .0001) in fully adjusted Cox regression. Results of sensitivity analyses were consistent with those of the primary analysis.ConclusionLND is an independent prognostic factor in node-positive RCC and should be incorporated into the cancer staging system.     

The prognostic value of erythrocyte polyamines in the preoperative evaluation of patients with renal cell carcinoma

IntroductionPolyamines, spermine and spermidine, are ubiquitous polycationic structures, which are essential for cell proliferation and differentiation. We tested whether spermine and spermidine could improve the prognostic ability of six established preoperative predictors of cancer-specific mortality (CSM) after partial or radical nephrectomy for renal cell carcinoma (RCC).Materials and methodsOverall, 385 patients with clinical stages T_1–3, M_0–1 RCC were treated with radical or partial nephrectomy at a single institution between 1990 and 2007. Kaplan–Meier plots depicted CSM after stratification according to spermine and spermidine levels (dichotomised to above and below the median value). Univariable and multivariable Cox regression models tested the prognostic ability of continuously coded spermine and spermidine levels in preoperative CSM predictions. Covariates consisted of pre-treatment T stage, M stage, age, gender and symptom classification.ResultsThe 5-year CSM-free survival of patients with spermine levels ?4.5 and >4.5 nmol/8 × 10⁹ erythrocytes were, respectively, 79.5% and 65.0%. Similarly, the 5-year CSM-free survival of patients with spermidine levels ?9.0 and > 9.0 nmol/8 × 10⁹ erythrocytes were, respectively, 81.1% and 63.7%. In multivariable analyses addressing CSM after surgery, both spermine (p ? 0.002) and spermidine (p ? 0.001) achieved independent predictor status and improved the accuracy of established preoperative CSM predictors by 2.1% (p < 0.001).ConclusionsCirculating polyamine levels may significantly improve the prognostic value of established determinants of CSM in patients with RCC of all stages prior to nephrectomy. External validation of our findings is required prior to implementation in clinical practice.     

Prognostic utility of the recently recommended histologic classification and revised TNM staging system of renal cell carcinoma: a Swiss experience with 588 tumors

BACKGROUND: A new, internationally accepted histologic classification of renal cell carcinoma (RCC) and a new edition of the TNM staging system were introduced in 1997. In the latter, there was a dramatic change in the pT classification of organ-confined renal cancer in which the break point between category pT1 and pT2 was increased from 2.5 cm to 7 cm. METHODS: To study the significance of the new pT classification and the new recommendations for histologic classification, 588 nephrectomy specimens were reevaluated to define morphologic prognostic parameters in RCC. pT classification (TNM 1997), histologic subtype, histologic tumor grade, presence of necrosis, and sarcomatoid differentiation were assessed. RESULTS: The histopathologic review according to the new classification revealed 487 conventional (clear cell) (83%), 64 papillary (11%), 31 chromophobe (5%), and 6 collecting duct (1%) RCCs. Clinical follow-up was available for 470 RCCs. The new pT classification (1997) was strongly correlated with patient survival (P < 0.0001). Histologic grade, presence of necrosis, and sarcomatoid differentiation provided independent prognostic information on the clear cell subtype of renal cancer. Sarcomatoid differentiation, but not tumor necrosis, portended a dismal prognosis for patients with papillary RCC. Chromophobe RCC was associated with a significantly better prognosis than clear cell RCC (P = 0.05). Papillary RCC with scanty cytoplasm and small cells (type 1) behaved less aggressively than papillary tumors with eosinophilic cytoplasm and large cells (type 2; P < 0.001). CONCLUSIONS: Accurate histologic classification according to the new recommendations has implications because the prognostic importance of other histologic features that are of independent significance varies with tumor subtype. The data suggest that the new pT classification allows good separation of prognostic groups of patients with renal cancer.     

c-Met is a prognostic marker and potential therapeutic target in clear cell renal cell carcinoma

BackgroundActivation of the c-Met pathway occurs in a range of malignancies, including papillary renal cell carcinoma (RCC). Its activity in clear cell RCC is less clear. We investigated c-Met expression and inhibition in a large cohort of RCC tumors and cell lines.Methodsc-Met protein expression was determined by automated quantitative analysis (AQUA) on a tissue microarray (TMA) constructed from 330 RCC tumors paired with adjacent normal renal tissue. c-Met expression and selective inhibition with SU11274 and ARQ 197 were studied in clear cell RCC cell lines.ResultsHigher c-Met expression was detected in all RCC subtypes than in the adjacent normal renal tissue (P < 0.0001). Expression was highest in papillary and sarcomatoid subtypes, and high-grade and stage tumors. Higher c-Met expression correlated with worse disease-specific survival [risk ratio = 1.36; 95% confidence interval (CI) 1.08–1.74; P = 0.0091] and was an independent predictor of survival, maintained in clear cell subset analyses. c-Met protein was activated in all cell lines, and proliferation (and colony formation) was blocked by SU11274 and ARQ 197.Conclusionsc-Met is associated with poor pathologic features and prognosis in RCC. c-Met inhibition demonstrates in vitro activity against clear cell RCC. Further study of ARQ 197 with appropriate biomarker studies in RCC is warranted.     

Upper Urinary Tract Tumors: Variant Histology Versus Urothelial Carcinoma

PurposeTo evaluate stage at presentation and cancer-specific mortality (CSM) in upper urinary tract tumors according to histologic subtype.MethodsWithin the Surveillance, Epidemiology, and End Results registry (SEER, 2004-2016), we identified patients with upper urinary tract tumors with pure variant histology (UTVH) and pure upper urinary tract urothelial carcinoma (UTUC). Cumulative incidence plots, after propensity score matching for tumor and patient characteristics, addressed CSM. Subgroup analyses addressed efficacy of radical nephroureterectomy (RNU) in stage T1-2 and of chemotherapy in metastatic UTVH patients.ResultsOf all 11,809 upper urinary tract tumor patients, 154 (1.3%) harbored squamous cell carcinoma (SCC), 86 (0.7%) adenocarcinoma, 39 (0.3%) neuroendocrine carcinoma, 38 (0.3%) other UTVH, and 11,492 (97.3%) UTUC. UTVH patients were more likely to exhibit metastatic stage disease at diagnosis than UTUC (odds ratio, 1.9; 95% confidence interval, 1.3-2.8; P < .01). After detailed matching for performance status, only SCC showed significantly higher CSM than UTUC (multivariate HR = 1.71; P < .01). Subgroup analyses in stage T1-2 RNU patients showed, relative to UTUC patients, no CSM differences for SCC or adenocarcinoma patients. No significant survival benefit for chemotherapy administration was identified in patients with metastatic SCC or metastatic adenocarcinoma. This study is limited by its sample size and the missing centralized pathologic review.ConclusionsDisease stage at diagnosis is more advanced in UTVH patients than UTUC. Across all stages, CSM is higher for SCC than for UTUC. However, in T1-2 stage disease, RNU results in similar survival in SCC or adenocarcinoma versus UTUC.     

Breast-Conserving Surgeries With and Without Cavity Shave Margins Have Different Re-excision Rates and Associated Overall Cost: Institutional and Patient-Driven Decisions for Its Utilization

BackgroundReducing the rate of margin positivity and reoperations remains a paramount goal in breast-conserving surgery (BCS). This study assesses the effectiveness of standard partial mastectomy with cavity shave margins (CSM) compared with partial mastectomy with selective margin resection (SPM), with regard to outcomes of the initial surgeries, re-excisions, and overall costs.Patients and MethodsThis is a retrospective review of 122 eligible breast cancer patients who underwent BCS at one institution. The CSM and SPM groups each included 61 patients, matched for presurgical diagnoses and clinical stage. Data including margin status, rates and reason for re-excision, associated operation times, and costs were analyzed.ResultsPatients undergoing CSM had less than half the rate of positive margins (PMs) (10% vs. 23%; P = .03) and re-excisions (8% vs. 23%; P = .02) compared with SPM. In the former group, the margin involvement was focal, and re-excisions were performed almost exclusively for PMs. For SPM, the majority (92%) of PMs were on the main lumpectomy specimen rather than the selective margins, and re-excisions included, in addition to PMs, extensive or multifocal negative but close margins. Reduced breast tissue volumes were removed with CSM, particularly for patients undergoing a single surgery (47 vs. 165 cm³; P < .001). The initial surgery with CSM is on average 27% more costly than that for SPM (P < .001), due to the increased pathology costs which are partially offset by the increased re-excision rates in SPM.ConclusionCircumferential cavity shaving, associated with consistent lower PMs, tissue volumes excised, and re-excision rates, is appropriate for routine implementation as a method offering superior surgical outcomes.