Is SARS-CoV-2-induced disease a decisive factor influencing testosterone in males? Findings from a case-control ex post facto study.

BACKGROUND: Whether the observed lower total testosterone (tT) levels in male patients with COVID-19 are caused by a direct impact of SARS-CoV-2 infection or are collateral phenomena shared by other systemic inflammatory conditions has not yet been clarified. OBJECTIVES: To investigate the independent role of COVID-19 in reducing circulating tT levels in men. MATERIALS AND METHODS: We compared demographic, clinical, and hormonal values of patients with laboratory confirmed COVID-19 admitted during the first wave of the pandemic with a cohort of consecutive male patients admitted to the intensive care unit (ICU) of the same academic center because of severe acute respiratory distress syndrome (ARDS) but without SARS-CoV-2 infection and no previous history of COVID-19. Linear regression model tested the independent impact of COVID-19 on circulating tT levels. Logistic regression model was used to test predictors of death in the entire cohort. RESULTS: Of 286 patients with COVID-19, 70 men had been admitted to the ICU ( = cases) and were compared to 79 patients equally admitted to ICU because of severe ARDS but negative for SARS-CoV-2 infection and without previous history of COVID-19 ( = controls). Controls were further grouped into noninfective (n = 49) and infective-ARDS (n = 30) patients. At baseline, controls were older (p = 0.01) and had more comorbidities (p < 0.0001). Overall, cases admitted to ICU had significantly lower circulating tT levels compared to controls (0.9 nmol/L vs. 2.1 nmol/L; vs. 1.2 nmol/L; p = 0.03). At linear regression, being negative for COVID-19 was associated with higher tT levels (Coeff: 2.13; 95% confidence interval - CI 0.71-3.56; p = 0.004) after adjusting for age, BMI, comorbidities and IL-6 levels. Only age and IL-6 levels emerged to be associated with higher risk of death regardless of COVID-19 status. CONCLUSIONS: This case-control ex post facto study showed lower tT levels in men with COVID-19 compared to those without COVID-19 despite both groups have been equally admitted to ICU for severe ARDS, thus suggesting a possible direct impact of SARS-CoV-2 infection toward circulating tT levels and a consequent more severe clinical outcome.

Testosterone in males with COVID-19: a 12-month cohort study.

BACKGROUND: Male patients with COVID-19 have been found with reduced serum total testosterone (tT) levels and with more severe clinical outcomes. OBJECTIVES: To assess total testosterone (tT) levels and the probability of recovering eugonadal tT levels during a minimum 12-month timespan in a cohort of men who have been followed over time after the recovery from laboratory-confirmed COVID-19. MATERIALS AND METHODS: Demographic, clinical and hormonal values were collected for the overall cohort. Hypogonadism was defined as tT ≤9.2 nmol/l. The Charlson Comorbidity Index was used to score health-significant comorbidities. Descriptive statistics was used to compare hormonal levels at baseline versus 7-month (FU1) versus 12-month (FU2) follow-up, respectively. Multivariate cox proportional hazards regression model was used to identify the potential predictors of eugonadism recovery over time among patients with hypogonadism at the time of infection. RESULTS: Of the original cohort of 286 patients, follow-up data were available for 121 (42.3%) at FU1 and 63 (22%) patients at FU2, respectively. Higher median interquartile range (IQR) tT levels were detected at FU2 (13.8 (12.3-15.3) nmol/L) versus FU1 (10.2 [9.3-10.9] nmol/L) and versus baseline (3.6 [3.02-4.02] nmol/L) (all p < 0.0001), whilst both LH and E2 levels significantly decreased over the same time frame (all p ≤ 0.01). Circulating IL-6 levels further decreased at FU2 compared to FU1 levels (19.3 vs. 72.8 pg/ml) (p = 0.02). At multivariable cox regression analyses, baseline tT level (HR 1.19; p = 0.03 [1.02-1.4]) was independently associated with the probability of tT level normalization over time, after adjusting for potential confounders. CONCLUSIONS: Circulating tT levels keep increasing over time in men after COVID-19. Still, almost 30% of men who recovered from COVID-19 had low circulating T levels suggestive for a condition of hypogonadism at a minimum 12-month follow-up.

Combined plasma levels of IL-10 and testosterone, but not soluble HLA-G5, predict the risk of death in COVID-19 patients.

BACKGROUND: The identification of biomarkers correlated with coronavirus disease 2019 (COVID-19) outcomes is a relevant need for clinical management. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is characterized by elevated interleukin (IL)-6, IL-10, HLA-G, and impaired testosterone production. OBJECTIVES: We aimed at defining the combined impact of sex hormones, interleukin-10, and HLA-G on COVID-19 pathophysiology and their relationship in male patients. MATERIALS AND METHODS: We measured by chemiluminescence immunoassay, electrochemiluminescent assays, and enzyme-linked immunosorbent assay circulating total testosterone, 17ß-estradiol (E2 ), IL-10, and -HLAG5 as well as SARS-CoV-2 S1/S2 Immunoglobulin G from 292 healthy controls and 111 COVID-19 patients with different disease severity at hospital admission, and in 53 COVID-19 patients at 7-month follow-up. RESULTS AND DISCUSSION: We found significantly higher levels of IL-10, HLA-G, and E2 in COVID-19 patients compared to healthy controls and an inverse correlation between IL-10 and testosterone, with IL-10, progressively increasing and testosterone progressively decreasing with disease severity. This correlation was lost at the 7-month follow-up. The risk of death in COVID-19 patients with low testosterone increased in the presence of high IL-10. A negative correlation between SARS-CoV-2 Immunoglobulin G and HLA-G or IL-10 at hospitalization was observed. At the 7-month follow-up, IL-10 and testosterone normalized, and  HLA-G decreased. CONCLUSION: Our findings indicate that combined evaluation of IL-10 and testosterone predicts the risk of death in men with COVID-19 and support the hypothesis that IL-10 fails to suppress excessive inflammation by promoting viral spreading.

Acute Kidney Injury at Hospital Admission for SARS-CoV-2 Infection as a Marker of Poor Prognosis: Clinical Implications for Triage Risk Stratification.

BACKGROUND/AIMS: The new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a wide spectrum of effects, including acute kidney injury (AKI) in up to 40% of hospitalized patients. Given the established relationship between AKI and poor prognosis, whether AKI might be a prognostic indicator for patients admitted to the hospital for SARS-CoV-2 infection would allow for a straightforward risk stratification of these patients. METHODS: We analyzed data of 623 patients admitted to San Raffaele Hospital (Milan, IT) between February 25 and April 19, 2020, for laboratory-confirmed SARS-CoV-2 infection. Incidence of AKI at hospital admission was calculated, with AKI defined according to the KDIGO criteria. Multivariable Cox regression models assessed the association between AKI and overall mortality and admission to the intensive care unit (ICU). RESULTS: Overall, 108 (17%) patients had AKI at hospital admission for SARS-CoV-2 infection. After a median follow-up for survivors of 14 days (interquartile range: 8, 23), 123 patients died, while 84 patients were admitted to the ICU. After adjusting for confounders, patients who had AKI at hospital admission were at increased risk of overall mortality compared to those who did not have AKI (hazards ratio [HR]: 2.00; p = 0.0004), whereas we did not find evidence of an association between AKI and ICU admission (HR: 0.95; p = 0.9). CONCLUSIONS: These data suggest that AKI might be an indicator of poor prognosis for patients with SARS-CoV-2 infection, and as such, given its readily availability, it might be used to improve risk stratification at hospital admission.

Testosterone in males with COVID-19: A 7-month cohort study.

BACKGROUND: Circulating testosterone levels have been found to be reduced in men with severe acute respiratory syndrome coronavirus 2 infection, COVID-19, with lower levels being associated with more severe clinical outcomes. OBJECTIVES: We aimed to assess total testosterone levels and the prevalence of total testosterone still suggesting for hypogonadism at 7-month follow-up in a cohort of 121 men who recovered from laboratory-confirmed COVID-19. MATERIALS AND METHODS: Demographic, clinical, and hormonal values were collected for all patients. Hypogonadism was defined as total testosterone ≤9.2 nmol/L. The Charlson Comorbidity Index was used to score health-significant comorbidities. Descriptive statistics and multivariable linear and logistic regression models tested the association between clinical and laboratory variables and total testosterone levels at follow-up assessment. RESULTS: Circulating total testosterone levels increased at 7-month follow-up compared to hospital admittance (p < 0.0001), while luteinizing hormone and 17ß-estradiol levels significantly decreased (all p ≤ 0.02). Overall, total testosterone levels increased in 106 (87.6%) patients, but further decreased in 12 (9.9%) patients at follow-up, where a total testosterone level suggestive for hypogonadism was still observed in 66 (55%) patients. Baseline Charlson Comorbidity Index score (OR 0.36; p = 0.03 [0.14, 0.89]) was independently associated with total testosterone levels at 7-month follow-up, after adjusting for age, BMI, and IL-6 at hospital admittance. CONCLUSIONS: Although total testosterone levels increased over time after COVID-19, more than 50% of men who recovered from the disease still had circulating testosterone levels suggestive for a condition of hypogonadism at 7-month follow-up. In as many as 10% of cases, testosterone levels even further decreased. Of clinical relevance, the higher the burden of comorbid conditions at presentation, the lower the probability of testosterone levels recovery over time.

Severely low testosterone in males with COVID-19: A case-control study.

BACKGROUND: Circulating androgens could have a relevant pathobiological role in clinical outcomes in men with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (COVID-19). OBJECTIVES: We aimed to assess: (a) circulating sex steroids levels in a cohort of 286 symptomatic men with laboratory-confirmed COVID-19 at hospital admission compared to a cohort of 281 healthy men; and (b) the association between serum testosterone levels (tT), COVID-19, and clinical outcomes. MATERIALS AND METHODS: Demographic, clinical, and hormonal values were collected for all patients. Hypogonadism was defined as tT ≤9.2 nmol/l. The Charlson Comorbidity Index (CCI) was used to score health-significant comorbidities. Severe clinical outcomes were defined as patients either transferred to intensive care unit (ICU) or death. Descriptive statistics and multivariable linear and logistic regression models tested the association between clinical and laboratory variables and tT levels. Univariable and multivariable logistic regression models tested the association between tT and severe clinical outcomes. RESULTS: Overall, a significantly lower levels of LH and tT were found in patients with COVID-19 compared to healthy controls (all p < 0.0001); conversely, healthy controls depicted lower values of circulating E2 (p < 0.001). Testosterone levels suggestive for hypogonadism were observed in 257 (89.8%) patients at hospital admission. In as many as 243 (85%) cases, hypogonadism was secondary. SARS-CoV-2 infection status was independently associated with lower tT levels (p < 0.0001) and greater risk of hypogonadism (p < 0.0001), after accounting for age, BMI, CCI, and IL-6 values. Lower tT levels were associated with higher risk of ICU admission and death outcomes (all p ≤ 0.05), after accounting for clinical and laboratory parameters. CONCLUSIONS: We unveil an independent association between SARS-CoV-2 infection status and secondary hypogonadism already at hospital admission, with lower testosterone levels predicting the most severe clinical outcomes.

Perioperative and oncologic outcomes of open radical nephrectomy and inferior vena cava thrombectomy with liver mobilization and Pringle maneuver for Mayo III level tumor thrombus: single institution experience.

BACKGROUND: Scarce data are available regarding the technique and outcomes for patients with RCC and Mayo III caval thrombi. The aim of this study was to report surgical and oncological outcomes of RCC patients with Mayo III thrombi treated with radical nephrectomy and thrombectomy after liver mobilization (LM) and Pringle maneuver (PM). METHODS: Retrospective analysis of surgical technique, outcomes and cancer control in 19 patients undergoing LM and PM in a single tertiary care institution were analyzed. RESULTS: Overall, 78% of the patients had performance status ECOG 1 and 58% had a Comorbidity Index >2. Median surgical time was 305 minutes (IQR 264-440). Intraoperative complications were reported for 39% of patients and postoperative complications for 58% (only grade 1 and 2). Intensive Care Unit support was necessary in 16% of the cases. Median length of hospital stay was 9 days (IQR: 7-11). Thirty- and 90-day mortality were 5% and 15%. Two-year overall survival and cancer-specific survival were 60% and 62%, respectively. CONCLUSIONS: We reported surgical techniques, intra- and perioperative complications and follow-up in the largest cohort of RCC patients requiring LM and PM.

Risk Factors for Upstaging, Recurrence, and Mortality in Clinical T1-2 Renal Cell Carcinoma Patients Upstaged to pT3a Disease: An International Analysis Utilizing the 8th Edition of the Tumor-Node-Metastasis Staging Criteria.

OBJECTIVE: To investigate risk factors for and outcomes in pathological T3a-upstaging in Renal Cell Carcinoma (RCC), as Tumor-Node-Metastasis staging for T3a RCC was recently revised. METHODS: Multicenter retrospective analysis of patients with clinical T1-T2 RCC, stratified by occurrence of pathologic T3a-upstaging. Primary outcome was recurrence-free survival (RFS). Multivariable analyses (MVA) were conducted for upstaging and recurrence. Kaplan-Meier analysis (KMA) was utilized for RFS and overall survival (OS). RESULTS: We analyzed 2573 patients (1223 RN/1350 PN). Upstaging occurred in 360 (14.0%). On MVA, higher clinical stage was associated with increasing risk of upstaging [cT1a (referent), odds ratio for cT1b, cT2a, and cT2b was 2.6, 6.5, and 14.1, P < .001]. Higher clinical stage at presentation correlated with increasing risk of recurrence in pT3a-upstaged RCC (cT1a upstaged-pT3a [referent], hazard ratio [HR] for cT1b, cT2a, and cT2b upstaged pT3a was 1.16 [P = .729], 3.02 [P = .013], and 4.5 [P = .003]). Perirenal fat (HR 1.6, P = .038) and renal vein (HR 2.2, P = .006) invasion were associated with increased risk of recurrence; type of surgery was not (P = .157). KMA for RFS and OS in pT3a-upstaged patients demonstrated differences based on initial clinical stage (5-year PFS for cT1a/b, and cT2 upstaged was 84.5%/72.8%, and 44.7%, P < .001; 5-year OS for cT1 and cT2 upstaged was 83.8% and 63.2%, P < .001). CONCLUSION: Risk of pT3a-upstaging and recurrence in pT3a-upstaged RCC correlates with clinical stage at presentation. Renal vein and perinephric fat invasion were associated with increased risk of recurrence. PN did not increase risk of recurrence and potential of pT3a-upstaging should not deter consideration of PN.

Should partial nephrectomy be considered "elective" in patients with stage 2 chronic kidney disease? A comparative analysis of functional and survival outcomes after radical and partial nephrectomy.

PURPOSE: To compare renal function and survival outcomes in patients with baseline chronic kidney disease (CKD) stage 2 undergoing partial (PN) or radical nephrectomy (RN), as nephron-sparing surgery is considered to be elective in this group. METHODS: Retrospective analysis of patients with CKD stage 2 and T1/T2 renal mass undergoing PN or RN from 2001 to 2015. Patients were stratified into substage CKD 2a or CKD 2b and analyzed between types of surgery. Primary outcome was overall survival (OS), eGFR < 45 at last follow-up was the secondary outcome. Multivariable analysis (MVA) was conducted for predictors of eGFR < 45 and OS. Kaplan-Meier analyses were conducted for freedom from eGFR < 45 and OS. RESULTS: 1213 patients analyzed (CKD 2a 609/CKD 2b 604) on MVA, RN (OR 3.68, p = 0.001) and CKD 2b (OR 3.3, p = 0.002) were independently associated with development of eGFR < 45 at last follow-up and RN (OR 3.76, p = 0.005) and eGFR < 45 (OR 2.51, p = 0.029) were associated with decreased OS. Kaplan-Meier analyses revealed that patients with CKD 2a/PN had the highest 5-year freedom from eGFR < 45 (94.3%) compared to CKD 2a/RN patients (91.5%), CKD2b/PN patients (87.6%) and CKD 2b/RN patients 82.0% (p < 0.001). Kaplan-Meier analyses for OS demonstrated that patients with CKD 2a/PN had significantly greater 5-year OS (97.6%) compared to CKD 2a/RN patients (95.2%), CKD 2b/PN patients (93.2%), and CKD 2b/RN patients (92.4%, p = 0.043). CONCLUSIONS: Patients with baseline CKD stage 2, particularly CKD 2b and undergoing RN, are at increased risk of GFR < 45, which was associated with decreased OS. In patients with CKD 2b, a nephron-sparing strategy is indicated and should be prioritized when feasible.

The Association of Uromodulin Genotype with Renal Cancer Aggressiveness.

The aim of the study was to investigate the association of the uromodulin (UMOD) genotype with patient health status and with renal cell carcinoma (RCC) aggressiveness. The UMOD genotype at the top single nucleotide variant rs4293393 was determined in a cohort of 211 patients diagnosed with a renal mass and treated with surgery. Clinical data were prospectively collected. Due to the higher frequency of allele T relative to the lower frequency of allele C, recessive homozygous (CC), and heterozygous (TC) patients were grouped together and compared with homozygous (TT) patients. Mann-Whitney and chi-square tests were used to compare clinical characteristics after stratification for the UMOD genotype. UMOD genotype frequencies resulted TT and TC-CC in 67% (n=141) and 33% (n=70) of the population, respectively. The rate of cM1 RCC at clinical staging was higher in patients with genotype TT relative to patients with genotype TC-CC (18% vs 1%, p=0.001). Similarly, the rate of pT3-pT4 (41% vs 25%, p=0.047) and lymphovascular invasion (29% vs 13%, p=0.02) RCC at final pathology were higher in patients with genotype TT relative to patients with genotype TC-CC. PATIENT SUMMARY: In patients diagnosed with renal cell carcinoma and treated with surgery, uromodulin homozygous genotype is associated with more aggressive renal cell carcinoma clinical and pathological characteristics.

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.

Perioperative and Oncologic Outcomes of Nephrectomy and Caval Thrombectomy Using Extracorporeal Circulation and Deep Hypothermic Circulatory Arrest for Renal Cell Carcinoma Invading the Supradiaphragmatic Inferior Vena Cava and/or Right Atrium.

BACKGROUND: Radical nephrectomy (RN) and caval thrombectomy (CT) for renal cell carcinoma, with extracorporeal circulation (ECC) and deep hypothermic circulatory arrest (DHCA) is a challenging surgical approach. OBJECTIVE: To assess peri-operative and oncologic outcomes of renal cell carcinoma patients treated with RN and CT, using ECC and DHCA. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively evaluated 46 patients who underwent RN and CT using ECC and DHCA. SURGICAL PROCEDURE: After retroperitoneal nodal dissection and RN, a cardiopulmonary bypass was placed and DHCA achieved. A combined approach through the abdomen and the thorax was described. MEASUREMENTS: Perioperative and long-term survival outcomes were reported. RESULTS AND LIMITATIONS: Median operative time and length of hospital stay were 545min and 22 d. Overall, 33 patients (72%) did not require any additional interventional or surgical treatment. Thirty-day and 90-d mortality were 11% (5/46) and 15% (7/46). The 1-yr, 2-yr, and 3-yr cancer specific mortality (CSM)-free survival rates were 77%, 62%, and 56%, respectively. After stratification, according to metastatic status at diagnosis, CSM-free survival rates were significantly lower for cM1 patients compared with cM0 patients (1-yr 46% vs 93%, 2-yr 23% vs 81%, 3-yr 23% vs 73%, p<0.01). Our study is limited by its retrospective and uncomparative nature. CONCLUSIONS: RN with CT using ECC and DHCA is a challenging procedure which requires a dedicated multidisciplinary working team to minimise complications and maximise patients' outcomes. PATIENT SUMMARY: Patients with kidney cancer and a thrombus within the inferior vena cava, which reaches above the diaphragm, can be treated with surgery. However, this kind of surgical treatment is challenging and requires a dedicated multidisciplinary team in order to accomplish the task.

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.

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.

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.

Lymphadenopathies in patients with renal cell carcinoma: clinical and pathological predictors of pathologically confirmed lymph node invasion.

INTRODUCTION: In renal cell carcinoma (RCC), lymph node status at preoperative imaging is affected by a non-negligible false-positive rate. We aimed to investigate which factors are related to a concordance between clinical suspicion and pathological confirmation of lymph node invasion (LNI). METHODS: At a single tertiary care institution, 2954 RCC patients underwent either partial or radical nephrectomy. For the aim of the study, only clinically positive lymph node cases were included (cN1). Statistical analyses assessed the concordance between preoperative and pathological nodal status. RESULTS: Preoperative axial CT scans revealed 424 (14.4 %) patients showing at least one enlarged lymph node suspected for LNI (cN1). All lymphadenopathies were removed at surgery, and LNI was pathologically confirmed (pN1) in 122 patients (28.8 %). When focusing the analyses on clinical characteristics (variables known before surgery), metastases at diagnosis [OR 3.0 (95 %1.9-4.8), p < 0.001] and tumor size [OR 1.1 (95 % 1.1-1.2), p < 0.001] were the two most informative predictors of concordance between clinical and pathological nodal status. Concordance was also more likely in patients with papillary type II tumors (55.6 %) relative to papillary type I (38.1 %), clear cell (27.7 %) and chromophobe (8.3 %) tumors. At multivariable analyses, none of the considered blood markers resulted to be independently associated with LNI. CONCLUSIONS: Roughly 70 % of patients showing a suspected lymph node preoperatively do not show LNI at the final pathological report. Among patients with clinically positive nodes, clinical tumor size and metastases at diagnosis represent the most informative and independent predictors of confirmed LNI at final pathology.

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.

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.

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

OBJECTIVE: To test whether the combination of number and location of distant metastases affects cancer-specific survival in patients with metastatic renal cell carcinoma. METHODS: Overall, 242 metastatic renal cell carcinoma patients with synchronous metastases at diagnosis underwent cytoreductive nephrectomy at a single institution. Combinations of number and location of distant metastases were coded as: single metastasis and single organ affected, multiple metastases and single organ affected, single metastasis for each of the multiple organs affected, and multiple metastases for each of the multiple organs affected. Covariates included age, symptoms, performance status, American Society of Anesthesiologists score, hemoglobin, lactate dehydrogenase, tumor size, Fuhrman grade, T stage, lymph node status, necrosis, sarcomatoid features and metastasectomy at the time of nephrectomy. RESULTS: The median survival was 34.7 versus 32.3 versus 29.6 versus 8.5 months for single metastasis and single organ affected, multiple metastases and single organ affected single metastasis for each of the multiple organs affected, and multiple metastases for each of the multiple organs affected patients, respectively. At multivariable analyses, the combination of number and location of distant metastases resulted in one of the most informative and independent predictors of cancer-specific survival in metastatic renal cell carcinoma patients. The lung was the location with the highest rate of single organ affected (50.3% vs 35.1% in other sites; P < 0.001). Considering only patients with a single metastasis, no statistically significantly different cancer-specific survival rates were recorded (P > 0.3) among different metastatic organs. CONCLUSIONS: Among metastatic renal cell carcinoma patients undergoing cytoreductive nephrectomy, the combination of the number and location of distant metastases is a major independent predictor of cancer-specific survival. Patients with multiple organs affected by multifocal disease are more likely to have poorer survival.