Phytochemicals for the Prevention and Treatment of Renal Cell Carcinoma: Preclinical and Clinical Evidence and Molecular Mechanisms.

Renal cell carcinoma (RCC) is associated with about 90% of renal malignancies, and its incidence is increasing globally. Plant-derived compounds have gained significant attention in the scientific community for their preventative and therapeutic effects on cancer. To evaluate the anticancer potential of phytocompounds for RCC, we compiled a comprehensive and systematic review of the available literature. Our work was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria. The literature search was performed using scholarly databases such as PubMed, Scopus, and ScienceDirect and keywords such as renal cell carcinoma, phytochemicals, cancer, tumor, proliferation, apoptosis, prevention, treatment, in vitro, in vivo, and clinical studies. Based on in vitro results, various phytochemicals, such as phenolics, terpenoids, alkaloids, and sulfur-containing compounds, suppressed cell viability, proliferation and growth, showed cytotoxic activity, inhibited invasion and migration, and enhanced the efficacy of chemotherapeutic drugs in RCC. In various animal tumor models, phytochemicals suppressed renal tumor growth, reduced tumor size, and hindered angiogenesis and metastasis. The relevant antineoplastic mechanisms involved upregulation of caspases, reduction in cyclin activity, induction of cell cycle arrest and apoptosis via modulation of a plethora of cell signaling pathways. Clinical studies demonstrated a reduced risk for the development of kidney cancer and enhancement of the efficacy of chemotherapeutic drugs. Both preclinical and clinical studies displayed significant promise of utilizing phytochemicals for the prevention and treatment of RCC. Further research, confirming the mechanisms and regulatory pathways, along with randomized controlled trials, are needed to establish the use of phytochemicals in clinical practice.

Novel plasma glycoprotein biomarkers predict progression-free survival in surgically resected clear cell renal cell carcinoma.

INTRODUCTION: Limited data exists on utilization of protein post-translational modifications as biomarkers for clear cell renal cell carcinoma (ccRCC). We employed high-throughput glycoproteomics to evaluate differential expression of glycoprotein-isoforms as novel markers for ccRCC progression-free survival (PFS). METHODS: Plasma samples were obtained from 77 patients treated surgically for ccRCC. Glycoproteomic analyses were carried out after liquid chromatography tandem mass spectrometry. Age-adjusted Cox proportional hazard models were constructed to evaluate PFS. Optimized Harrell's C-index was employed to dichotomize the collective for the construction of Kaplan-Meier curves. RESULTS: The average length of follow-up was 3.4 (range: 0.04-9.83) years. Glycoproteomic analysis identified 39 glycopeptides and 14 non-glycosylated peptides that showed statistically significant (false discovery rate P ≤ 0.05) differential expression associated with PFS. Five of the glycosylated peptides conferred continuous hazard ratio (HR) of > 6 (range 6.3-11.6). These included prothrombin A2G2S glycan motif (HR = 6.47, P = 9.53E-05), immunoglobulin J chain FA2G2S2 motif (HR = 10.69, P = 0.001), clusterin A2G2 motif (HR = 7.38, P = 0.002), complement component C8A A2G2S2 motif (HR = 11.59, P = 0.002), and apolipoprotein M glycopeptide with non-fucosylated and non-sialylated hybrid-type glycan (HR = 6.30, P = 0.003). Kaplan-Meier curves based on dichotomous expression of these five glycopeptides resulted in hazard ratios of 3.9 to 10.7, all with P-value < 0.03. Kaplan-Meyer plot using the multivariable model comprising 3 of the markers yielded HR of 11.96 (P < 0.0001). CONCLUSION: Differential glyco-isoform abundance of plasma proteins may be a useful source of biomarkers for the clinical course and prognosis of ccRCC.

Statin Use and Association with Postoperative Estimated Glomerular Filtration Rates in Patients Undergoing Robot-Assisted Partial Nephrectomy.

Objective: To evaluate the association between preoperative statin use with changes in estimated glomerular filtration rate (eGFR) after robot-assisted partial nephrectomy (RAPN). Methods: Three hundred eighty-nine consecutive patients undergoing RAPN were evaluated. Associations of preoperative statin use with change in eGFR from pre-RAPN to postoperative day 1 (POD1), 1, 6, and 12 months after RAPN were evaluated using longitudinal mixed-effects regression models with random patient-specific intercepts and slopes while accounting for imbalance of preoperative patient and tumor characteristics between groups with stabilized inverse propensity score weighting. Postoperative eGFR change from baseline was measured as total change, maintaining eGFR within 10% of baseline, and as going from eGFR >60 mL/min/1.73 m2 to <60 mL/min/1.73 m2. Results: One hundred sixty-seven (43.0%) of 389 patients were on statin therapy preoperatively. Statin patients were older (66 vs 58 years) and had higher rates of comorbidities, including diabetes mellitus (31.7% vs 14.9%) and hypertension (82.6% vs 45%). Statin patients tended to have lower preoperative eGFR (mean ± standard deviation, 71.1 ± 17.6 vs 77.4 ± 19.4 mL/min/1.73 m2). There was no evidence of an association of preoperative statin use with changes in eGFR at any time point after RAPN (p = 0.66). Conclusion: Patients on preoperative statins undergoing RAPN had lower eGFR preoperatively compared with those not taking those medications. There was no evidence of an association between preoperative statin use and change in post-RAPN eGFR in the immediate postoperative period or at 1 year after surgery.

Evaluation of Peri-operative Outcomes Associated With Resident Involvement on Tumor Resection and Renorrhaphy During Robotic-assisted Partial Nephrectomy.

OBJECTIVE: To evaluate perioperative outcomes of resident trainee involvement in tumor resection and renorrhaphy during robotic assisted partial nephrectomy (RAPN). MATERIALS AND METHODS: We analyzed 500 consecutive RAPN in a single surgeon prospectively maintained database. Cases with resident performed tumor resection and renorrhaphy (N = 71) were case matched on R.E.N.A.L. score and RAPN year using a greedy matching algorithm. Perioperative variables were compared to attending cases. RESULTS: There were no statistically significant differences in high grade postoperative complications (resident: 3% vs attending: 6%, P = .68), positive margins (resident: 1% vs attending: 3%, P = .31), length of stay (resident: 2.0 vs attending: 2.0 days, P = .73), and 30 day readmission (resident: 7% vs attending: 11%, P = .56). However, residents had a statistically significant longer warm ischemia time (median 21 vs 15 minutes, P <.001), thus less likely to achieve trifecta (66% vs 85%, P = .02). Resident involvement had longer median operative time (197 vs 184 minutes, P = .03). No statistically significant difference in functional volume loss (P = .12) or surface intermediate base margin score (P = .66) between residents and attending was found. No difference in post-operative creatinine change was found at 1 day and 1 month (resident: 0.2 vs attending: 0.1 mg/dL, P = .4 and resident: 0.1 vs attending: 0.1 mg/dL, P = .6, respectively). CONCLUSION: Supervised resident console involvement in tumor resection and renorrhaphy during RAPN is safe and does not increase rates of complications. Residents have longer median warm ischemia time compared to attending only cases, but this does not appear to impact post-operative renal function.

Crizotinib-associated renal cyst development may be associated with prolonged progression-free survival in patients with ALK-positive non-small-cell lung cancer: Case report and review of the literature.

Non-small cell lung cancer patients with anaplastic lymphoma kinase or c-ros oncogene 1 mutations who are treated with the tyrosine kinase inhibitor crizotinib rarely develop crizotinib-associated renal cysts (CARCs). Here, we present a case report and review of the literature supporting the hypothesis that CARCs may correlate positively with progression-free survival.

Association of Ancillary Pathology Findings in Non-neoplastic Renal Parenchyma and Renal Outcomes of Robotic-Assisted Partial Nephrectomy.

Background: To evaluate robotic-assisted partial nephrectomy (RAPN) renal outcomes associated with ancillary pathology findings in non-neoplastic renal parenchymal tissue. Methods: Tissue samples from 378 RAPNs were analyzed for glomerular disease (GD), vascular disease (VD), and tubulointerstitial disease (TD). One hundred and fifty-two patients were excluded due to insufficient non-neoplastic tissue for analysis and 4 patients were excluded due to calyceal diverticulum. Non-neoplastic tissue was evaluated for GD (negative, moderate, or global), VD (absent, mild, moderate, or severe), and TD (present or absent). Associations of ancillary pathology factors with patient characteristics were explored using the non-parametric Kendall tau-test and propensity score adjusted longitudinal mixed effects regression models were used to evaluate associations of these pathology factors with changes in estimated glomerular filtration rate (eGFR) following RAPN. Results: One hundred and fifty-three (68.9%) patients had hypertension and 50 (22.5%) patients had diabetes. The majority of patients did not have any GD (N = 158, 71.2%) or TD (N = 186, 83.8%) while 129 (58.1%) had VD. VD was categorized as absent (N = 93, 41.9%), mild (N = 45, 20.3%), moderate (N = 76, 34.2%), and severe (N = 8, 6.8%). Older age (P = 0.018), hypertension (P < 0.001), and high grade MAP score (P = 0.047) were associated with a higher number of ancillary pathology factors. High grade MAP score (P = 0.03, P = 0.002) and hypertension (P = 0.02, P < 0.001) were individually associated with GD severity and VD severity, respectively. Older age was also individually associated with VD severity (P = 0.002) and hypertension was associated with TD (P = 0.04). Moderate-to-severe VD was associated with a worse change in eGFR from pre-RAPN to 1-month post-RAPN compared to those with mild or no VD (difference in mean change, -3.4 ml/kg/1.73m2; 95% CI, -6.6 to -0.2 ml/kg/1.73m2; P = 0.036). Conclusions: Moderate-to-severe VD in non-neoplastic renal parenchyma is associated with post-operative changes in eGFR. Older age, hypertension, and high grade MAP scores are associated with the number of ancillary pathologies observed in RAPN specimens.

Validation of the Mayo Adhesive Probability score as a predictor of adherent perinephric fat and outcomes in open partial nephrectomy.

BACKGROUND: Adherent perinephric fat (APF) contributes to surgical complexity and can be associated with adverse perioperative outcomes for partial nephrectomy (PN). The Mayo Adhesive Probability (MAP) score accurately predicts the presence of APF during robotic-assisted partial nephrectomy (RAPN). Our primary aim is to validate MAP score as a predictor of APF in open partial nephrectomy (OPNx). METHODS: We reviewed 105 consecutive OPNx (100 patients) performed by a single surgeon with intraoperative determination of APF. We evaluated the ability of the MAP score to discriminate between those with APF and those without APF by estimating the area under the receiver operating characteristic curve (AUROCC). The association of perioperative outcomes with APF was evaluated as well. RESULTS: Forty-three patients [49%; 95% confidence interval (CI), 39-59%] had intraoperative identification of APF. The MAP score had excellent ability to predict APF in OPNx (AUROCC, 0.82; 95% CI, 0.74-0.92). APF was observed in 6% of patients with a MAP score of 0-1, 27% with score 2, 52% with score 3, 75% with score 4, and 90% with score 5. The presence of APF was associated with longer operative times (P=0.004) and higher estimated blood loss (EBL) (P=0.003). Although not statistically significant, our study did suggest that APF may be associated with postoperative complications and prolonged length of stay (LOS) (>3 days). CONCLUSIONS: MAP score accurately predicts the presence of APF in patients undergoing OPNx. APF is associated with longer operative time and higher blood loss in OPNx.

Perioperative Outcomes of Laparoscopic Radical Nephrectomy for Renal Mass in Patients on Dialysis or with Renal Transplant in Place Compared to Normal Controls.

Background: The risk of renal cell carcinoma (RCC) development in the native kidney of patients on dialysis or with a renal transplant is increased compared to the general population. This study examines perioperative outcomes of laparoscopic radical nephrectomy (LN) in dialysis patients or renal transplant patients compared to normal controls. Methods: Four hundred twelve consecutive LN were evaluated (July 2007 to October 2018). Patients were divided into three groups (control, dialysis, and transplant). Perioperative outcomes, including operating room time (OT), postoperative complications, hospital length of stay, and 90-day readmission rates, were evaluated for the three groups. Results: There were 62 patients in the dialysis group, 20 renal transplants, and 330 normal controls. Dialysis patients were younger (median: 58 years versus 67 years; P = .002) and predominantly male (73% versus 59%, P = .047). Dialysis patients compared to controls had shorter total OT (median: 133 versus 149; P = .022), more papillary RCC (27% versus 10%; P < .001), and fewer high grade tumors (73% [8/11] versus 94% [100/106]; P = .038). Renal transplant patients had a higher rate of 90-day readmission (20% versus 6%; P = .034) and more papillary RCC (30% versus 10%; P = .016) compared to controls. Conclusion: LN on dialysis patients does not alter expected perioperative outcomes compared to a large cohort of control LN. LN on renal transplant patients carries a higher 90-day readmission rate than control LN.

Independent external validation of a nomogram to define risk categories for a significant decline in estimated glomerular filtration rate after robotic-assisted partial nephrectomy.

OBJECTIVE: To validate the Martini nomogram predicting the decline in estimated glomerular filtration rate after robotic-assisted partial nephrectomy. METHODS: Estimated glomerular filtration rate of 406 patients from a single surgeon series was calculated before robotic-assisted partial nephrectomy and at postoperative intervals. To determine the risk group, we calculated the total score and corresponding risk of significant estimated glomerular filtration rate reduction at 15 months using the Martini nomogram. The primary outcome was a reduction in estimated glomerular filtration rate of ≥25% from preoperative levels between 1 and 12 months after surgery. RESULTS: The median length of follow up for this study was 12 months (interquartile range 6-12 months). Overall, 134 (33%) patients were in the low-, 143 (35%) in the intermediate-, 119 (29%) in the high- and 10 (2%) in the very high-risk groups. The Kaplan-Meier estimates for the probability of significant estimated glomerular filtration rate reduction by 12 months after robotic-assisted partial nephrectomy was 12.9% in the low-risk group, 24.0% in the intermediate-risk group, 49.7% in the high-risk group and 40.0% in the very high-risk group. Harrell's C-index for discriminating between those with and without a significant reduction in estimated glomerular filtration rate 1-12 months after robotic-assisted partial nephrectomy was 0.73 (95% confidence interval 0.68-0.78). CONCLUSIONS: The risk groups proposed by the Martini nomogram are accurate in predicting those at higher risk for a >25% decline in postoperative estimated glomerular filtration rate after robotic-assisted partial nephrectomy at 12 months.

Retrospective Evaluation of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers on Postoperative Estimated Glomerular Filtration Rates Following Robotic-Assisted Partial Nephrectomy.

Objective: To evaluate the association between the use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) preoperatively with changes in estimated glomerular filtration rate (eGFR) after robotic-assisted partial nephrectomy (RAPN). Methods: Patients undergoing RAPN at our institution from February 2008 through April 2019 were evaluated. ACEIs/ARBs were held on the morning of the surgery and resumed on postoperative day number one in all patients. Associations of ACEIs/ARBs use with postoperative eGFR were explored by using a linear mixed-effects regression model with random patient-specific intercepts. We included eGFR measurements at the following time points: preoperatively, postoperative day 1 (POD1), 1 month postoperative, 6 months postoperative, and 12 months postoperative. p-Values <0.05 were considered statistically significant. Results: One hundred and seventy-one (44.0%) of 389 patients were on ACEIs/ARBs therapy preoperatively. The ACEIs/ARBs patients were older and had higher rates of comorbidities, including diabetes mellitus. The ACEIs/ARBs patients tended to have lower preoperative eGFR (mean ± standard deviation, 70.4 ± 17.5 vs 78.0 ± 19.2 mL/minute/1.73 m2; p < 0.001). However, this was not significant after adjustment for potentially confounding variables (mean difference, -1.7 mL/minute/1.73 m2; 95% confidence interval, -6.4 to 3.1 mL/minute/1.73 m2; p = 0.48). There was no evidence of an association of ACEIs/ARBs use with postoperative renal function after adjustment for potentially confounding variables (adjusted mean difference in change in eGFR from baseline was -1.1, -1.2, -0.3, and -1.2 mL/minute/1.73 m2 at POD1, 1, 6, and 12 months, respectively; all p ≥ 0.51). Conclusion: Continuation of ACEIs and ARBs throughout the perioperative period is not associated with change in post-RAPN eGFR.

Determinants and Implications of Excised Parenchymal Mass on Robotic-Assisted Partial Nephrectomy Outcomes.

OBJECTIVES: To evaluate the association between excised parenchymal mass (EPM) and postoperative renal function (eGFR) following robotic-assisted partial nephrectomy (RAPN). EPM is the amount of healthy renal parenchyma excised during partial nephrectomy in order to achieve safe surgical margins. METHODS: We evaluated 406 consecutive RAPN performed by a single surgeon to eliminate variations in technique as a factor in EPM. EPM (mL) = (specimen volume * π/6) - (tumor volume * π/6). RENAL score was categorized as easy (4-6), moderate (7-9), or hard (10-12). EPM was grouped into four categories: ≤ 3.9 mL, 4.0-9.9 mL, 10.0-17.7 mL, and >17.7 mL. eGFR was evaluated preoperatively, postoperative day 1 (POD1), 1 month, and 6 months postoperatively. RESULTS: Median age was 63 years (22-84 years), 252 (62.1%) were male, and median EPM was 9.9 mL (interquartile range 3.9 to 17.7 mL). The median EPM and interquartile range for each RENAL category was 3.7 mL (2.0, 7.9), 12 mL (5.7, 19.4), and 16.2 mL (7.9, 24.3), respectively. Higher EPM was associated with worse changes in eGFR at POD1 (P = 0.005) and 1 month after RAPN (P = 0.002) but was not statistically significant at the 6-month time period (P = 0.35) CONCLUSION: Increased tumor complexity is associated with an increase in EPM during RAPN. Increased EPM is associated with eGFR decline at POD1 and 1 month post RAPN but not at 6 months postoperatively.

Utility of the Aortic-Lesion-Attenuation-Difference (ALAD) and Peak Early-Phase Enhancement Ratio (PEER) to differentiate benign from malignant renal masses.

INTRODUCTION: To evaluate the utility of the Aorta-Lesion-Attenuation-Difference (ALAD) and Peak Early-phase Enhancement Ratio (PEER) on contrast-enhanced computed tomography (CT) to differentiate between the appearances of chromophobe renal cell carcinoma, clear cell renal cell carcinoma, and oncocytoma. MATERIAL AND METHODS: ALAD and PEER values were retrospectively measured by a reviewer from 119 patients with surgically resected renal masses (chromophobe renal cell carcinoma n = 29, clear cell renal cell carcinoma n = 28, and oncocytoma n = 62). The ALAD value is expressed as: ALAD = Hounsfield Units aorta - Hounsfield Units mass. PEER is expressed as (Hounsfield Units contrast tumor - Hounsfield Units non-contrast tumor):( Hounsfield Units contrast cortex - Hounsfield Units non-contrast cortex). RESULTS: The ALAD median was 27.6 for oncocytomas, 68.5 for chromophobe renal cell carcinoma, and 55.4 for clear cell renal cell carcinoma. A significant difference between ALAD values of oncocytoma and chromophobe renal cell carcinoma was observed in the nephrographic (area under the ROC curve 0.92) and excretory phases (area under the ROC curve 0.95). The PEER median was 0.74 for oncocytomas and 0.37 for chromophobe renal cell carcinoma. The PEER values significantly differed while comparing oncocytomas and chromophobe renal cell carcinoma in the nephrographic and excretory phases. CONCLUSIONS: Preoperative contrast-enhanced CT ALAD and PEER values both significantly differentiate between chromophobe renal cell carcinoma and oncocytoma. PEER may be more effective in contrast-enhanced CT scans lacking distinct phases.

Assessment of Advanced Perioperative Outcomes to Identify the True Learning Curve of Robotic-assisted Partial Nephrectomy.

OBJECTIVES: To evaluate the learning curve of robotic-assisted partial nephrectomy as it pertains to operative time (OT) and advanced perioperative variables such as achievement of trifecta, postoperative complications, 30-day readmission rates (RR), warm ischemia time (WIT), and functional volume loss (FVL). METHODS: We evaluated 418 consecutive robotic-assisted partial nephrectomy performed by a single surgeon between February 2008 and April 2019. Multivariable log-log regression models were used to evaluate the associations between case number and continuous outcomes (OT, WIT, and FVL). Multivariable logistic regression models were used to evaluate the association of case number with dichotomous outcomes (trifecta, postoperative complications, RR). RESULTS: Among the 406 eligible patients included in the study, 252 (62.1%) were male, median age was 63 years (range, 22-84), and median body mass index was 29 kg/m2 (interquartile range 26-33). Surgeon experience was associated with shorter OT (-2.5% per 50% increase in case number; 95% confidence interval; P <.001) and plateaus around 77 cases performed. There was slight improvement with trifecta (odds ratio [per 50% increase in cases] = 1.08; 95% confidence interval) and the plateau was also at 77 cases, however, this was not statistically significant (P = .086). We did not find statistically significant associations of surgeon experience with FVL (P = .77), postoperative complications (P = .74), WIT (P = .73), or 30-day RR (P = .33). CONCLUSION: There does not appear to be a relationship between surgical experience and grade 3 or higher postoperative complications, 30-day RR, WIT, or FVL. Trifecta outcomes and maximum OT performance appear to be optimized at approximately 77 cases.