Reza Mehrazin

Comparison of rates and risk factors for developing chronic renal insufficiency, proteinuria and metabolic acidosis after radical or partial nephrectomy

To investigate the incidence of and risk factors for developing chronic renal insufficiency (CRI), proteinuria and metabolic acidosis (MA) in patients treated with radical nephrectomy (RN) or nephron‐sparing surgery (NSS).

Accelerated Methotrexate, Vinblastine, Doxorubicin, and Cisplatin Is Safe, Effective, and Efficient Neoadjuvant Treatment for Muscle-Invasive Bladder Cancer: Results of a Multicenter Phase II Study With Molecular Correlates of Response and Toxicity

PURPOSE Neoadjuvant cisplatin-based chemotherapy is standard of care for muscle-invasive bladder cancer (MIBC); however, it is infrequently adopted in practice because of concerns regarding toxicity and delay to cystectomy. We hypothesized that three cycles of neoadjuvant accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC) would be safe, shorten the time to surgery, and yield similar pathologic complete response (pT0) rates compared with historical controls. PATIENTS AND METHODS Patients with cT2-T4a and N0-N1 MIBC were eligible and received three cycles of AMVAC with pegfilgrastim followed by radical cystectomy with lymph node dissection. The primary end point was pT0 rate. Telomere length (TL) and p53 mutation status were correlated with response and toxicity. RESULTS Forty-four patients were accrued; 60% had stage III to IV disease; median age was 64 years. Forty patients were evaluable for response, with 15 (38%; 95% CI, 23% to 53%) showing pT0 at cystectomy, meeting the primary end point of the study. Another six patients (14%) were downstaged to non-muscle invasive disease. Most (82%) experienced only grade 1 to 2 treatment-related toxicities. There were no grade 3 or 4 renal toxicities and no treatment-related deaths. One patient developed metastases and thus did not undergo cystectomy; all others (n = 43) proceeded to cystectomy within 8 weeks after last chemotherapy administration. Median time from start of chemotherapy to cystectomy was 9.7 weeks. TL and p53 mutation did not predict response or toxicity. CONCLUSION AMVAC is well tolerated and results in similar pT0 rates with 6 weeks of treatment compared with standard 12-week regimens. Further analysis is ongoing to ascertain whether molecular alterations in tumor samples can predict response to chemotherapy.

Chemoresistance in Prostate Cancer Cells Is Regulated by miRNAs and Hedgehog Pathway

Many prostate cancers relapse due to the generation of chemoresistance rendering first-line treatment drugs like paclitaxel (PTX) ineffective. The present study aims to determine the role of miRNAs and Hedgehog (Hh) pathway in chemoresistant prostate cancer and to evaluate the combination therapy using Hh inhibitor cyclopamine (CYA). Studies were conducted on PTX resistant DU145-TXR and PC3-TXR cell lines and clinical prostate tissues. Drug sensitivity and apoptosis assays showed significantly improved cytotoxicity with combination of PTX and CYA. To distinguish the presence of cancer stem cell like side populations (SP), Hoechst 33342 flow cytometry method was used. PTX resistant DU145 and PC3 cells, as well as human prostate cancer tissue possess a distinct SP fraction. Nearly 75% of the SP cells are in the G0/G1 phase compared to 62% for non-SP cells and have higher expression of stem cell markers as well. SP cell fraction was increased following PTX monotherapy and treatment with CYA or CYA plus PTX effectively reduced their numbers suggesting the effectiveness of combination therapy. SP fraction cells were allowed to differentiate and reanalyzed by Hoechst staining and gene expression analysis. Post differentiation, SP cells constitute 15.8% of total viable cells which decreases to 0.6% on treatment with CYA. The expression levels of P-gp efflux protein were also significantly decreased on treatment with PTX and CYA combination. MicroRNA profiling of DU145-TXR and PC3-TXR cells and prostate cancer tissue from the patients showed decreased expression of tumor suppressor miRNAs such as miR34a and miR200c. Treatment with PTX and CYA combination restored the expression of miR200c and 34a, confirming their role in modulating chemoresistance. We have shown that supplementing mitotic stabilizer drugs such as PTX with Hh-inhibitor CYA can reverse PTX chemoresistance and eliminate SP fraction in androgen independent, metastatic prostate cancer cell lines.

Survival outcomes after radical and partial nephrectomy for clinical T2 renal tumours categorised by R.E.N.A.L. nephrometry score

We evaluated survival outcomes of partial nephrectomy (PN) and radical nephrectomy (RN) for clinical T2 renal masses (cT2RM) controlling for R.E.N.A.L. nephrometry score.

Feasibility and efficacy of neoadjuvant sunitinib before nephron-sparing surgery.

Study type – Therapy (case series)
Level of Evidence 4

Assessing the burden of complications after surgery for clinically localized kidney cancer by age and comorbidity status.

OBJECTIVE To examine the association between high-risk patient status (age >75 years or Charlson comorbidity index count >2) and postoperative complications in patients undergoing surgical management for clinically localized renal tumors. MATERIALS AND METHODS Patients undergoing radical nephrectomy (RN) or partial nephrectomy (PN) (2005-2012) for localized renal cell carcinoma were analyzed. Multivariate logistic regressions were used to test the association between high-risk status and postoperative complications adjusting for patient, tumor, and operative characteristics. RESULTS Of 1092 patients undergoing PN (71.9%) or RN (28.1%) for clinically localized renal tumors, 255 (23.4%) were classified as high risk, and 175 patients (16%) developed at least 1 complication (mean 1.6 ± 1.0). Of note, 22.4% and 14.1% of high- and low-risk patients developed a complication, respectively (P = .002). Comparing high- and low-risk patients, significant differences in Clavien I-II (20.4% vs 11.1%; P <.001) and medical (16.1% vs 8.1%, P <.001) complications were observed, whereas no differences were seen in Clavien III-V or surgical complications. No differences in complications were observed comparing patients treated with RN and PN, albeit high-risk patients were more likely to undergo RN (35.3% vs 25.9%, P = .04). After adjustment, the odds of incurring any complication were 1.9 times higher in high- compared with low-risk patients (odds ratio 1.9 [confidence interval 1.3-2.8]). CONCLUSION Regardless of surgical type, patients deemed high risk by age and comorbidity criteria were more likely to incur a postoperative complication after renal mass resection. Improved understanding of surgical risks in the elderly and infirmed will help better inform patients deciding between active surveillance and resection of renal tumors.

Piperlongumine promotes autophagy via inhibition of Akt/mTOR signalling and mediates cancer cell death

Background:The Akt/mammalian target of rapamycin (mTOR) signalling pathway serves as a critical regulator of cellular growth, proliferation and survival. Akt aberrant activation has been implicated in carcinogenesis and anticancer therapy resistance. Piperlongumine (PL), a natural alkaloid present in the fruit of the Long pepper, is known to exhibit notable anticancer effects. Here we investigate the impact of PL on Akt/mTOR signalling.Methods:We examined Akt/mTOR signalling in cancer cells of various origins including prostate, kidney and breast after PL treatment. Furthermore, cell viability after concomitant treatment with PL and the autophagy inhibitor, Chloroquine (CQ) was assessed. We then examined the efficacy of in vivo combination treatment using a mouse xenograft tumour model.Results:We demonstrate for the first time that PL effectively inhibits phosphorylation of Akt target proteins in all tested cells. Furthermore, the downregulation of Akt downstream signalling resulted in decrease of mTORC1 activity and autophagy stimulation. Using the autophagy inhibitor, CQ, the level of PL-induced cellular death was significantly increased. Moreover, concomitant treatment with PL and CQ demonstrated notable antitumour effect in a xenograft mouse model.Conclusions:Our data provide novel therapeutic opportunities to mediate cancer cellular death using PL. As such, PL may afford a novel paradigm for both prevention and treatment of malignancy.

RENAL Nephrometry Score is Associated With Operative Approach for Partial Nephrectomy and Urine Leak

OBJECTIVE To identify whether RENAL nephrometry score is associated with partial nephrectomy (PN) technique. RENAL nephrometry score quantifies anatomic characteristics of renal tumors. Data are limited regarding clinical utility for surgical planning. METHODS Multicenter analysis of patients undergoing PN for renal masses from March 2003 to May 2011. Cohort was stratified by surgical modality: open partial nephrectomy (OPN), laparoscopic partial nephrectomy (LPN), and robotic-assisted laparoscopic partial nephrectomy (RALPN). Demographic and clinicopathological variables were compared between groups; RENAL score was calculated from preoperative imaging. Factors associated with choice of treatment modality and urine leak were entered into multivariable models. RESULTS One hundred fifty-three patients who underwent OPN, 100 patients who underwent LPN, and 31 patients who underwent RALPN were evaluated, the median tumor size (cm) was significantly larger for OPN (OPN 4.2 vs LPN 2.4 vs RALPN 2.0; P < .001); median operative time (minutes) and ischemia time (minutes) were shorter in OPN (OPN 190 and 25 vs LPN 200 and 29 vs RALPN 195 and 30; P = .042 and P < .001). Mean RENAL score was highest in OPN (OPN 8 vs LPN 6.3 vs RALPN 6.4; P < .001). No significant differences were noted in overall/high-grade complication rates (Clavien, P = .441/.985). On multivariate analysis, there was a 55% increased odds of undergoing OPN for each increase in RENAL score (P < .001). Higher RENAL score was associated with increased odds of urine leak (odds ratios [OR], 1.56; P = .002). CONCLUSION RENAL nephrometry score was associated with type of surgical approach (open vs laparoscopic/robotic) and urine leak. RENAL score may be useful as a decision-making tool in evaluation of patients for nephron-sparing surgery (NSS). Further investigation is requisite.

Nonoperative management of blunt renal trauma: is routine early follow-up imaging necessary?

BackgroundThere is no consensus on the role of routine follow-up imaging during nonoperative management of blunt renal trauma. We reviewed our experience with nonoperative management of blunt renal injuries in order to evaluate the utility of routine early follow-up imaging.MethodsWe reviewed all cases of blunt renal injury admitted for nonoperative management at our institution between 1/2002 and 1/2006. Data were compiled from chart review, and clinical outcomes were correlated with CT imaging results.Results207 patients were identified (210 renal units). American Association for the Surgery of Trauma (AAST) grades I, II, III, IV, and V were assigned to 35 (16%), 66 (31%), 81 (39%), 26 (13%), and 2 (1%) renal units, respectively. 177 (84%) renal units underwent routine follow-up imaging 24–48 hours after admission. In three cases of grade IV renal injury, a ureteral stent was placed after serial imaging demonstrated persistent extravasation. In no other cases did follow-up imaging independently alter clinical management. There were no urologic complications among cases for which follow-up imaging was not obtained.ConclusionRoutine follow-up imaging is unnecessary for blunt renal injuries of grades I-III. Grade IV renovascular injuries can be followed clinically without routine early follow-up imaging, but urine extravasation necessitates serial imaging to guide management decisions. The volume of grade V renal injuries in this study is not sufficient to support or contest the need for routine follow-up imaging.

Factors Affecting Renal Function After Open Partial Nephrectomy—A Comparison of Clampless and Clamped Warm Ischemic Technique

OBJECTIVE To analyze factors impacting postoperative renal function after open partial nephrectomy using both the clampless and clamped warm-ischemic technique. METHODS We studied a cohort of patients who underwent clamped partial nephrectomy (n = 164) and clampless partial nephrectomy (n = 64) from March 2002 to March 2009 with ≥ 12-months follow-up. Clamped partial nephrectomy used hilar occlusion before resection. Clampless partial nephrectomy used focal radio frequency coagulation to facilitate hemostasis before resection, nonischemic dissection/resection with hydro-dissection, or sharp resection after local compression. Demographics, tumor characteristics/RENAL nephrometry scores, perioperative variables, and complications were compared between the two methods. Multivariable analysis was performed to identify factors predicting de novo estimated glomerular filtration rate <60. RESULTS Patient characteristics were similar between groups. Mean RENAL score was greater in clamped (6.9) vs clampless (6.4, P = .026); complications (P = .430) and urine leaks (clampless partial nephrectomy 3.1% vs clamped-PN 7.3%, P = .360) were similar. Mean warm ischemia time (min) was 24.5 for clamped partial nephrectomy. De novo estimated glomerular filtration rate <60(%) at last follow up was 13.5 (clamped) vs 3.1 (clampless) (P = .071). Multivariable analysis of the entire cohort revealed increasing body mass index (OR 1.1, P = .042) and RENAL score (OR 1.71, P = .002) as being independently associated with development of postoperative de novo estimated glomerular filtration rate <60. Multivariable analysis of the clamped subgroup demonstrated increasing body mass index (OR 1.12, P = .028), RENAL score (OR 1.56, P = .010), and ischemia time (OR 1.15, P = .042) as independent factors associated with de novo estimated glomerular filtration rate <60. CONCLUSION Body mass index and RENAL score were factors predictive of development of de novo estimated glomerular filtration rate <60 after partial nephrectomy, with increasing warm ischemia time also being predictive in clamped partial nephrectomy patients. Further investigation and long-term functional data are requisite.