Cristina Carenzi

Effect of number and location of distant metastases on renal cell carcinoma mortality in candidates for cytoreductive nephrectomy: Implications for multimodal therapy

To test whether the combination of number and location of distant metastases affects cancer‐specific survival in patients with metastatic renal cell carcinoma.

The extent of lymphadenectomy does affect cancer specific survival in pathologically confirmed T4 renal cell carcinoma

Background Controversies exist regarding the effect of lymphadenectomy (LND) in renal cell carcinoma (RCC). We hypothesized that patients with locally advanced cancer invading beyond Gerotas fascia (pT4 Nany Many RCC) might benefit from an extended LND not only for staging but also for survival purposes. Materials and Methods Clinical and pathologic data were prospectively gathered in 1.847 patients treated at a single Academic Center, between 1987 and 2011. Only patients with pT4 RCC (TNM 2009, n=44, 2.4%) were included. Univariable (UVA) and multivariable (MVA) Cox regression analyses targeted the association between the number of lymph nodes removed and cancer specific mortality (CSM). Analyses were adjusted for age, Fuhrman grade, symptoms at presentation, metastases at diagnosis, ECOG performance status, tumor size, number of positive nodes, and presence of necrosis or sarcomatoid features. Results Mean number of nodes removed was 11.8 (median 8, range 1–37). Mean number of positive nodes was 4.8 (median 2, range 0–36). Cancer-specific survival rates at 1, 2 and 3 years of follow-up were 39.3%, 25.0% and 8.6%, respectively. When stratified for nodal status, cancer-specific survival rates at 1, 2 and 3 years of follow-up were 65.0, 36.1, and 9.0% vs. 13.3, 13.0, and 6.7%, for pN0 vs. pN+ cases, respectively (p=0.004). At MVA, after adjusting for all the possible confounders, the number of positive nodes resulted independently associated with CSM (HR 1.25, p=0.001). Interestingly, at MVA, the number of nodes removed achieved the independent predictor status, as well (HR 0.84, p=0.007) showing a protective effect on survival. The risk of dying increased of 16% every positive node found (p<0.001), and decreased of 8% every node removed (p=0.02) (Table II). Conclusions A more extended retroperitoneal lymphadenectomy at the time of nephrectomy statistically significantly decreased CSM in pT4 cases.

Staging lymphadenectomy in renal cell carcinoma must be extended: a sensitivity curve analysis

In renal cell carcinoma the role of lymphadenectomy (LND) is still controversial. Moreover, no firm consensus exists regarding the minimum number of lymph nodes that should be removed to obtain a satisfactory staging LND at the time of surgery. Our findings demonstrate that, when clinically indicated, staging LND in renal cell carcinoma should be extended. The removal of 15 lymph nodes might represent the lowest threshold to define a staging LND as adequate. More extended LND should be pursued if unfavourable clinical and pathological characteristics are evident at diagnosis and/or during surgery.

The key role of time in predicting progression-free survival in patients with renal cell carcinoma treated with partial or radical nephrectomy: Conditional survival analysis

INTRODUCTION In surgically treated patients with renal cell carcinoma (RCC), the progression-free survival (PFS) rate may significantly change according to the progression-free postoperative period. To test this hypothesis, we set to evaluate the conditional PFS rate in surgically treated patients with RCC. METHODS We evaluated 1,454 patients with RCC, surgically treated between 1987 and 2010, at a single institution. Cumulative survival estimates were used to generate conditional PFS rates. Separate Cox regression models were fitted to predict clinical-progression risk in patients who were progression free from 1 to 10 years after surgery. RESULTS During the immediate postoperative period, the 5-year PFS rate was 88%, and it increased to 92%, 94%, and 97% in patients who remained progression free at, respectively, 1, 5, and 10 years after surgery. At multivariable analyses, where patients with stage I disease were considered as a reference, the highest clinical-progression risk was observed at the eighth postoperative year in patients with stage II disease (hazard ratio [HR]: 2.9) and during the immediate postoperative period in patients with stage III to IV disease (HR: 5.5). In comparison with patients with grade I disease, the highest clinical-progression risk was observed at the fourth (as well as eighth) postoperative year in patients with grade II disease (HR: 5.7), sixth postoperative year in patients with grade III disease (HR: 7.2), and during the immediate postoperative period in patients with grade IV disease (HR: 8.5). CONCLUSIONS The postoperative progression-free period has an important effect on the subsequent clinical-progression risk. This aspect should be considered along with tumor characteristics to plan the most cost-effective follow-up scheme for surgically treated patients with RCC.

MicroRNA 193b-3p as a predictive biomarker of chronic kidney disease in patients undergoing radical nephrectomy for renal cell carcinoma

Background:A significant proportion of patients undergoing radical nephrectomy (RN) for clear-cell renal cell carcinoma (RCC) develop chronic kidney disease (CKD) within a few years following surgery. Chronic kidney disease has important health, social and economic impact and no predictive biomarkers are currently available. MicroRNAs (miRs) are small non-coding RNAs implicated in several pathological processes.Methods:Primary objective of our study was to define miRs whose deregulation is predictive of CKD in patients treated with RN. Ribonucleic acid from formalin-fixed paraffin embedded renal parenchyma (cortex and medulla isolated separately) situated >3 cm from the matching RCC was tested for miR expression using nCounter NanoString technology in 71 consecutive patients treated with RN for RCC. Validation was performed by RT–PCR and in situ hybridisation. End point was post-RN CKD measured 12 months post-operatively. Multivariable logistic regression and decision curve analysis were used to test the statistical and clinical impact of predictors of CKD.Results:The overexpression of miR-193b-3p was associated with high risk of developing CKD in patients undergoing RN for RCC and emerged as an independent predictor of CKD. The addition of miR-193b-3p to a predictive model based on clinical variables (including sex and estimated glomerular filtration rate) increased the sensitivity of the predictive model from 81 to 88%. In situ hybridisation showed that miR-193b-3p overexpression was associated with tubule-interstitial inflammation and fibrosis in patients with no clinical or biochemical evidence of pre-RN nephropathy.Conclusions:miR-193b-3p might represent a useful biomarker to tailor and implement surveillance strategies for patients at high risk of developing CKD following RN.

Minimally Invasive Partial Nephrectomy Versus Laparoscopic Cryoablation for Patients Newly Diagnosed with a Single Small Renal Mass

BACKGROUND Minimally invasive partial nephrectomy (MIPN) and laparoscopic renal cryoablation (LRC) are two treatment options increasingly used for small renal masses. OBJECTIVE To compare perioperative, oncologic, and functional outcomes after MIPN and LRC. DESIGN, SETTING, AND PARTICIPANTS We included 372 consecutive patients newly diagnosed with a single small renal mass and treated with either MIPN or LRC at a single institution. INTERVENTION MIPN and LRC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Regression models were used to evaluate the impact of surgical treatment (MIPN vs LRC) on perioperative, oncologic, and functional outcomes. RESULTS AND LIMITATIONS Overall, 206 patients (55%) underwent MIPN and 166 (45%) were treated with LRC. In multivariate analysis, the rate of postoperative complications was significantly lower in the MIPN compared to the LRC group (20% vs 28%; adjusted difference -11%; p=0.02) after adjusting for age at surgery, American Society of Anesthesiologists score (1 vs 2 vs 3), and tumor size. The median follow-up was similar in the two groups (43 and 39 mo for MIPN and LRC, respectively). In univariate Cox regression analysis, treatment type was not significantly associated with disease-free survival (hazard ratio 1.06, 95% confidence interval [CI] 0.45-2.52; p=0.9). The disease-free survival rate at 5 yr was 92% in MIPN and 93% in LRC patients. In multivariate linear regression analysis, LRC was significantly associated with a higher estimated glomerular filtration rate (eGFR) at 6 mo compared to MIPN (coefficient 4.68, 95% CI 0.06-9.30; p=0.047) after adjusting for age at surgery, tumor size, and preoperative eGFR. There was no significant association between surgical treatment and postoperative eGFR at 3 yr after surgery (coefficient -2.36, 95% CI -7.55 to 2.83; p=0.4). Limitations include the retrospective study design and selection bias. CONCLUSIONS MIPN and LRC provided similar cancer control and comparable renal function at intermediate-term follow-up. Both surgical techniques emerged as viable treatment options for patient newly diagnosed with a single small renal mass. Further multi-institutional studies with longer follow-up and nephrometry scores are needed to corroborate our findings. PATIENT SUMMARY In patients newly diagnosed with a single small renal mass, minimally invasive partial nephrectomy and laparoscopic renal cryoablation provided similar cancer control and comparable renal function at intermediate-term follow-up.

Radical Nephrectomy with or without Lymph Node Dissection for High Risk Nonmetastatic Renal Cell Carcinoma: A Multi-Institutional Analysis

Purpose: Lymph node dissection may benefit patients at increased risk for lymph node metastases from renal cell carcinoma. Therefore, we evaluated the association of lymph node dissection with survival in patients at high risk undergoing radical nephrectomy for renal cell carcinoma. Materials and Methods: We identified 2,722 patients with M0 renal cell carcinoma who underwent radical nephrectomy with or without lymph node dissection at 2 international centers from 1990 to 2010. The associations of lymph node dissection with the development of distant metastases, and cancer specific and all cause mortality were evaluated using propensity score techniques and traditional multivariable Cox regression. Subset analyses were done to examine patients at increased risk of lymph node metastases. Results: Overall 171 patients (6.3%) had pN1 disease. Median followup was 9.6 years. Clinicopathological features were well balanced after propensity score adjustment. Lymph node dissection was not significantly associated with a reduced risk of distant metastases, or cancer specific or all cause mortality in the overall cohort, among patients with preoperative radiographic lymphadenopathy (cN1), or across an increasing probability of pN1 disease from 0.10 or greater to 0.50 or greater. Neither extended lymph node dissection nor the extent of lymph node dissection was associated with improved oncologic outcomes. Conclusions: The current analysis of a large, international cohort indicates that lymph node dissection is not associated with improved oncologic outcomes among patients at high risk who undergo radical nephrectomy for M0 renal cell carcinoma. This includes patients with radiographic lymphadenopathy (cN1) and across increasing probability thresholds of pN1 disease.

Risk Based Surveillance after Surgical Treatment of Renal Cell Carcinoma

Purpose: We assessed the accuracy of the UISS (UCLA Integrated Staging System) to predict the postoperative recurrence of renal cell carcinoma. We also evaluated whether including patient age and tumor histology would improve clinical decision making. Materials and Methods: We analyzed the records of 1,630 patients treated with nephrectomy at a single academic center. The accuracy of the UISS model to predict early (12 months or less) and late (more than 60 months) recurrence after surgery was compared with a new model including patient age and disease histology. Results: The new model and the UISS model showed high accuracy to predict early recurrence after surgery (AUC 0.84, 95% CI 0.81–0.88 and 0.83, 95% CI 0.80–0.87, respectively). In patients diagnosed with low risk tumor types (eg papillary type 1 and chromophobe lesions) the average risk of early recurrence significantly decreased in each UISS risk category when tumor histology was added to the predictive model (low risk 1.6% vs 0.6%, intermediate risk 5.5% vs 1.9% and high risk 45% vs 22%). Kaplan‐Meier analysis showed no difference in the risk of late recurrence among the UISS risk categories. Conclusions: The UISS model should be applied to tailor the early followup protocol after nephrectomy. Patients with low risk histology deserve less stringent followup regardless of the UISS risk category. Our results do not support a risk stratification model to design a surveillance protocol after 5 years postoperatively.

When to Perform Preoperative Bone Scintigraphy for Kidney Cancer Staging: Indications for Preoperative Bone Scintigraphy

OBJECTIVE To identify an objective and reproducible strategy for preoperative staging bone scintigraphy (BS) in patients diagnosed with renal cell carcinoma (RCC), because in the absence of objective criteria, the decision to perform preoperative BS remains a subjective practice. PATIENTS AND METHODS The study included a total of 2008 patients with RCC treated with surgery and prospectively included into an institutional database. The study outcome was the presence of 1 or more bone lesions suspicious for metastases at staging BS. A multivariable logistic regression model predicting a positive BS was fitted. The predictors consisted of the preoperative clinical tumor (cT) and clinical nodal (cN) stages, the presence of systemic symptoms, and the platelet-to-hemoglobin (PLT/Hb) ratio. RESULTS The rate of positive BS was 4% (n = 81). At the multivariable logistic regression analysis, cT2, cN1, the presence of systemic symptoms, and the PLT/Hb ratio were all associated with am increased risk of positive BS (P <.05). Following the 2000-sample bootstrap validation, the concordance index was 0.77 (proposed model) vs 0.63 (decision making based on symptoms only). At the decision curve analysis, the proposed strategy was associated with a higher net benefit. If BS is performed when the risk of positive result is >5%, a negative BS is spared in 80% and a positive BS is missed in 2% of the population only. CONCLUSION Using preoperative variables, it is possible to accurately estimate the risk of positive BS at RCC staging using preoperative characteristics. Compared with the strategy supported by available guidelines, the proposed model was more objective, statistically more accurate, and clinically associated with higher net benefit.

Lymph node dissection should not be dismissed in case of localized renal cell carcinoma in the presence of larger diseases

OBJECTIVE To assess whether even in the group of localized renal cell carcinoma (RCC), some patients might harbor a disease with a predilection for lymph node invasion (LNI) and/or lymph node (LN) progression and might deserve lymph node dissection (LND) at the time of surgery. MATERIALS AND METHODS Between 1990 and 2014, 2,010 patients with clinically defined T1-T2N0M0 RCC were treated with nephrectomy and standardized LND at a single tertiary care referral center. The endpoint consists of the presence of LNI and/or nodal progression, defined as the onset of a new clinically detected lymphadenopathy (>10mm) in the retroperitoneal lymphatic area with associated systemic progression or histological confirmation or both. We tested the association between clinical characteristics and the endpoint of interest. Predictors consisted of age at surgery, clinical tumor size, preoperative hemoglobin, and platelets levels. Multivariable logistic regression model and smoothed Lowess method were used. RESULTS LNI was recorded in 14 cases (2.2%). The median follow-up after surgery was 68 months. During the study period, 23 patients (1.1%) experienced LN progression; 91% of those patients experienced LN progression within 3 years after surgery. Combining the 2 endpoints, 36 patients (1.8%) had LNI and/or LN progression. Clinical tumor size was the only independent predictors of LNI and/or LN progression (OR = 1.25). A significant increase of the risk of LNI and/or LN progression was observed in RCC larger than 7cm (cT2a or higher). CONCLUSIONS LNI and/or LN progression is a rare entity in patients with localized RCC. Nonetheless, patients with larger tumors might still benefit from LND because of a non-negligible risk of LNI and/or LN progression.