Maria Carmen Mir

Parenchymal Volume Preservation and Ischemia During Partial Nephrectomy: Functional and Volumetric Analysis

OBJECTIVE To determine the relative effect of type and duration of ischemia and parenchymal volume preservation on renal function after partial nephrectomy (PN). MATERIALS AND METHODS Ninety-two patients with localized renal tumors (2007-2012) managed with PN at our center with necessary studies for analysis were included. This comprised 37 patients with a solitary kidney and 55 with a contralateral kidney. Thirty-five patients were managed with hypothermia and 57 with limited warm ischemia. Volumetric computed tomography was used to measure the volume of functional parenchyma before and after PN in the operated and contralateral kidneys. Glomerular filtration rate (GFR) was determined by the modification of diet in renal disease 2 equation, along with renal scan data for patients with a contralateral kidney. Regression analysis assessed the relationships between %GFR preserved in the operated kidney and potential predictive factors. All postoperative analyses were performed 4-12 months after surgery. RESULTS Median age was 61 years, median tumor size 3.5 cm, and median RENAL nephrometry score 8. Median cold ischemia time was 28 minutes and median warm ischemia time 21 minutes. Median %GFR preserved in the operated kidney was 79%. Median %parenchymal volume saved was 83%. Function in the contralateral kidney only increased marginally (median increase 6%). On regression analysis, %GFR preserved associated most strongly with %parenchymal volume saved (P <.0001), but also with lower RENAL scores (P = .0457) and the use of hypothermia (P = .0209). In contrast, ischemia time did not correlate with %GFR preserved (P = .5051). CONCLUSION Ultimate function after PN primarily correlated with parenchymal volume preservation, whereas ischemia played a secondary role. Thus, maximal parenchymal preservation with a precise PN should be a priority during PN.

Renal Ischemia and Function After Partial Nephrectomy: A Collaborative Review of the Literature

CONTEXT Partial nephrectomy (PN) is the current gold standard treatment for small localized renal tumors.; however, the impact of duration and type of intraoperative ischemia on renal function (RF) after PN is a subject of significant debate. OBJECTIVE To review the current evidence on the relationship of intraoperative ischemia and RF after PN. EVIDENCE ACQUISITION A review of English-language publications on renal ischemia and RF after PN was performed from 2005 to 2014 using the Medline, Embase, and Web of Science databases. Ninety-one articles were selected with the consensus of all authors and analyzed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria. EVIDENCE SYNTHESIS The vast majority of reviewed studies were retrospective, nonrandomized observations. Based on the current literature, RF recovery after PN is strongly associated with preoperative RF and the amount of healthy kidney parenchyma preserved. Warm ischemia time (WIT) is modifiable and prolonged warm ischemia is significantly associated with adverse postoperative RF. Available data suggest a benefit of keeping WIT <25min, although the level of evidence to support this threshold is limited. Cold ischemia safely facilitates longer durations of ischemia. Surgical techniques that minimize or avoid global ischemia may be associated with improved RF outcomes. CONCLUSIONS Although RF recovery after PN is strongly associated with quality and quantity of preserved kidney, efforts should be made to limit prolonged WIT. Cold ischemia should be preferred when longer ischemia is expected, especially in presence of imperative indications for PN. Additional research with higher levels of evidence is needed to clarify the optimal use of renal ischemia during PN. PATIENT SUMMARY In this review of the literature, we looked at predictors of renal function after surgical resection of renal tumors. There is a strong association between the quality and quantity of renal tissue that is preserved after surgery and long-term renal function. The time of interruption of renal blood flow during surgery is an important, modifiable predictor of postoperative renal function.

Decline in Renal Function after Partial Nephrectomy: Etiology and Prevention

PURPOSE Partial nephrectomy is the reference standard for the management of small renal tumors and is commonly used for localized kidney cancer. A primary goal of partial nephrectomy is to preserve as much renal function as possible. New baseline glomerular filtration rate after partial nephrectomy can have prognostic significance with respect to long-term outcomes. Recent studies provide an increased understanding of the factors that determine functional outcomes after partial nephrectomy as well as preventive measures to minimize functional decline. We review these advances, highlight ongoing controversies and stimulate further research. MATERIALS AND METHODS A comprehensive literature review consistent with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) criteria was performed from January 2006 to April 2014 using PubMed®, Cochrane and Ovid Medline. Key words included partial nephrectomy, renal function, warm ischemia, hypothermia, nephron mass, parenchymal volume, surgical approaches to partial nephrectomy, preoperative and intraoperative imaging, enucleation, hemostatic agents and energy based resection. Relevant reviews were also examined as well as their cited references. An additional Google Scholar search was conducted to broaden the scope of the review. Only English language articles were included in the analysis. The primary outcomes of interest were the new baseline level of function after early postoperative recovery, percent decline in function, potential etiologies and preventive measures. RESULTS Decline in function after partial nephrectomy averages approximately 20% in the operated kidney, and can be due to incomplete recovery from the ischemic insult or loss of nephron mass related to parenchymal excision or collateral damage during reconstruction. Compensatory hypertrophy in the contralateral kidney after partial nephrectomy in adults is marginal and decline in global renal function for patients with 2 kidneys averages about 10%, although there is some variance based on tumor size and location. Irreversible ischemic injury can be minimized by pharmacological intervention or surgical approaches such as hypothermia, limited warm ischemia, or zero or segmental ischemia. Excessive loss of nephron mass can be minimized by improved preoperative or intraoperative imaging, use of a bloodless field, enucleation and vascular microdissection. Hemostatic agents or energy based resection that minimizes the need for parenchymal and capsular suturing can also optimize preservation of the vascularized nephron mass. CONCLUSIONS Our understanding of the decline in renal function after partial nephrectomy has advanced considerably, including better appreciation of its magnitude and impact in various settings, possible etiologies and potential preventive measures. Many controversies persist and this remains an important area of investigation.

Multicenter Assessment of Neoadjuvant Chemotherapy for Muscle-invasive Bladder Cancer

BACKGROUND The efficacy of neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (BCa) was established primarily with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC), with complete response rates (pT0) as high as 38%. However, because of the comparable efficacy with better tolerability of gemcitabine and cisplatin (GC) in patients with metastatic disease, GC has become the most commonly used regimen in the neoadjuvant setting. OBJECTIVE We aimed to assess real-world pathologic response rates to NAC with different regimens in a large, multicenter cohort. DESIGN, SETTING, AND PARTICIPANTS Data were collected retrospectively at 19 centers on patients with clinical cT2-4aN0M0 urothelial carcinoma of the bladder who received at least three cycles of NAC, followed by radical cystectomy (RC), between 2000 and 2013. INTERVENTION NAC and RC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary outcome was pathologic stage at cystectomy. Univariable and multivariable analyses were used to determine factors predictive of pT0N0 and ≤pT1N0 stages. RESULTS AND LIMITATIONS Data were collected on 935 patients who met inclusion criteria. GC was used in the majority of the patients (n=602; 64.4%), followed by MVAC (n=183; 19.6%) and other regimens (n=144; 15.4%). The rates of pT0N0 and ≤pT1N0 pathologic response were 22.7% and 40.8%, respectively. The rate of pT0N0 disease for patients receiving GC was 23.9%, compared with 24.5% for MVAC (p=0.2). There was no difference between MVAC and GC in pT0N0 on multivariable analysis (odds ratio: 0.89 [95% confidence interval, 0.61-1.34]; p=0.6). CONCLUSIONS Response rates to NAC were lower than those reported in prospective randomized trials, and we did not discern a difference between MVAC and GC. Without any evidence from randomized prospective trials, the best NAC regimen for invasive BCa remains to be determined. PATIENT SUMMARY There was no apparent difference in the response rates to the two most common presurgical chemotherapy regimens for patients with bladder cancer.

Partial Nephrectomy Versus Radical Nephrectomy for Clinical T1b and T2 Renal Tumors: A Systematic Review and Meta-analysis of Comparative Studies

BACKGROUND Partial nephrectomy (PN) is the reference standard of management for a cT1a renal mass. However, its role in the management of larger tumors (cT1b and cT2) is still under scrutiny. OBJECTIVE To conduct a meta-analysis assessing functional, oncologic, and perioperative outcomes of PN and radical nephrectomy (RN) in the specific case of larger renal tumors (≥cT1b). The primary endpoint was an overall analysis of cT1b and cT2 masses. The secondary endpoint was a sensitivity analysis for cT2 only. EVIDENCE ACQUISITION A systematic literature review was performed up to December 2015 using multiple search engines to identify eligible comparative studies. A formal meta-analysis was performed for studies comparing PN to RN for both cT1b and cT2 tumors. In addition, a sensitivity analysis including the subgroup of studies comparing PN to RN for cT2 only was conducted. Pooled estimates were calculated using a fixed-effects model if no significant heterogeneity was identified; alternatively, a random-effects model was used when significant heterogeneity was detected. For continuous outcomes, the weighted mean difference (WMD) was used as summary measure. For binary variables, the odds ratio (OR) or risk ratio (RR) was calculated with 95% confidence interval (CI). Statistical analyses were performed using Review Manager 5 (Cochrane Collaboration, Oxford, UK). EVIDENCE SYNTHESIS Overall, 21 case-control studies including 11204 patients (RN 8620; PN 2584) were deemed eligible and included in the analysis. Patients undergoing PN were younger (WMD -2.3 yr; p<0.001) and had smaller masses (WMD -0.65cm; p<0.001). Lower estimated blood loss was found for RN (WMD 102.6ml; p<0.001). There was a higher likelihood of postoperative complications for PN (RR 1.74, 95% CI 1.34-2.2; p<0.001). Pathology revealed a higher rate of malignant histology for the RN group (RR 0.97; p=0.02). PN was associated with better postoperative renal function, as shown by higher postoperative estimated glomerular filtration rate (eGFR; WMD 12.4ml/min; p<0.001), lower likelihood of postoperative onset of chronic kidney disease (RR 0.36; p<0.001), and lower decline in eGFR (WMD -8.6ml/min; p<0.001). The PN group had a lower likelihood of tumor recurrence (OR 0.6; p<0.001), cancer-specific mortality (OR 0.58; p=0.001), and all-cause mortality (OR 0.67; p=0.005). Four studies compared PN (n=212) to RN (n=1792) in the specific case of T2 tumors (>7cm). In this subset of patients, the estimated blood loss was higher for PN (WMD 107.6ml; p<0.001), as was the likelihood of complications (RR 2.0; p<0.001). Both the recurrence rate (RR 0.61; p=0.004) and cancer-specific mortality (RR 0.65; p=0.03) were lower for PN. CONCLUSIONS PN is a viable treatment option for larger renal tumors, as it offers acceptable surgical morbidity, equivalent cancer control, and better preservation of renal function, with potential for better long-term survival. For T2 tumors, PN use should be more selective, and specific patient and tumor factors should be considered. Further investigation, ideally in a prospective randomized fashion, is warranted to better define the role of PN in this challenging clinical scenario. PATIENT SUMMARY We performed a cumulative analysis of the literature to determine the best treatment option in cases of localized kidney tumor of higher clinical stage (T1b and T2, as based on preoperative imaging). Our findings suggest that removing only the tumor and saving the kidney might be an effective treatment modality in terms of cancer control, with the advantage of preserving the kidney function. However, a higher risk of perioperative complications should be taken into account when facing larger tumors (clinical stage T2) with kidney-sparing surgery.

The Investigational Aurora Kinase A Inhibitor MLN8237 Induces Defects in Cell Viability and Cell-Cycle Progression in Malignant Bladder Cancer Cells In Vitro and In Vivo

Purpose: Despite more than 70,000 new cases of bladder cancer in the United States annually, patients with advanced disease have a poor prognosis due to limited treatment modalities. We evaluated Aurora kinase A, identified as an upregulated candidate molecule in bladder cancer, as a potential therapeutic target. Experimental Design: Gene expression in human bladder cancer samples was evaluated using RNA microarray and quantitative reverse transcriptase PCR. Effects of the Aurora kinase A inhibitor MLN8237 (Millennium) on cell dynamics in malignant T24 and UM-UC-3 and papilloma-derived RT4 bladder cells were evaluated in vitro and in vivo in a mouse xenograft model. Results: A set of 13 genes involved in the mitotic spindle checkpoint, including Aurora kinases A and B, were upregulated in human urothelial carcinoma compared with normal urothelium. The Aurora kinase A inhibitor MLN8237 induced cell-cycle arrest, aneuploidy, mitotic spindle failure, and apoptosis in the human bladder cancer cell lines T24 and UM-UC-3. MLN8237 also arrested tumor growth when administered orally over 4 weeks in a mouse bladder cancer xenograft model. Finally, in vitro sequential administration of MLN8237 with either paclitaxel or gemcitabine resulted in synergistic cytotoxic effects in T24 cells. Conclusions: Mitotic spindle checkpoint dysfunction is a common characteristic of human urothelial carcinoma and can be exploited with pharmacologic Aurora A inhibition. Given our demonstration of the ability of the Aurora A inhibitor MLN8237 to inhibit growth of bladder cancer in vitro and in vivo, we conclude that Aurora kinase inhibitors warrant further therapeutic investigation in bladder cancer. Clin Cancer Res; 19(7); 1717–28. ©2013 AACR.

Predictors of precision of excision and reconstruction in partial nephrectomy.

PURPOSE The precision of excision and reconstruction to optimize vascularized parenchymal preservation is a major determinant of renal function after partial nephrectomy. We assessed partial nephrectomy surgical precision using volumetric computerized tomography and analyzed predictive factors. MATERIALS AND METHODS We analyzed the records of 122 patients treated with partial nephrectomy in whom detailed analysis of the precision of excision and reconstruction specific to the operated kidney could be performed. We used volumetric computerized tomography to measure functional parenchymal volume before and after partial nephrectomy in the operated kidney. The glomerular filtration rate in the operated kidney was determined by the MDRD2 (Modification of Diet in Renal Disease 2) equation along with renal scan in patients with a contralateral kidney. Surgical precision was defined as actual postoperative parenchymal volume/predicted postoperative parenchymal volume, presuming loss of a 5 mm rim of normal parenchyma related to excision and reconstruction. RESULTS Median patient age was 61 years and 64 patients (52%) underwent an open procedure. Cold ischemia was used in 50 patients (median 26 minutes) and limited warm ischemia (median 20 minutes) was used in 72. The R.E.N.A.L. (radius, exophytic/endophytic, nearness of tumor to collecting system or sinus, anterior/posterior and location relative to polar line) nephrometry score indicated low, intermediate and high complexity in 43 (35%), 55 (45%) and 24 patients (20%), respectively. A total of 45 patients (37%) with a solitary kidney were included in analysis. The median precision of excision and reconstruction was 93%. The median preserved glomerular filtration rate was 80% in the operated kidney. A solitary kidney was the only significant predictor of excision and reconstruction precision on univariable and multivariable analysis. CONCLUSIONS A solitary kidney significantly impacted partial nephrectomy surgical precision. This was likely related to the recognized need to preserve as much renal parenchyma as possible to optimize renal function in the absence of a contralateral kidney.

Optimal definition of biochemical recurrence after radical prostatectomy depends on pathologic risk factors: Identifying candidates for early salvage therapy

BACKGROUND The use of prostate-specific antigen (PSA) thresholds (<0.2 ng/ml) below currently accepted biochemical recurrence (BCR) definitions for patients treated with radical prostatectomy may be useful in the identification of candidates for early salvage therapy with improved outcome; however, the practice risks overtreatment, as the risk of subsequent PSA progression may be low. OBJECTIVE To analyze 14 BCR definitions for their association with subsequent PSA and treatment progression among subgroups of patients at varying risk of prostate cancer-specific mortality. DESIGN, SETTING, AND PARTICIPANTS The subsequent risk of PSA and treatment progression after BCR based on 14 BCR definitions (six standard definitions and eight definitions requiring one or more successive PSA rises ≤0.1 ng/ml) was analyzed according to various clinicopathologic risk criteria among 2348 patients with a detectable PSA ≥0.03 ng/ml at least 6 wk after radical prostatectomy. INTERVENTION Radical prostatectomy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Probability of subsequent PSA progression after BCR, defined as a PSA rise >0.1 ng/ml above BCR PSA, initiation of secondary treatment, or clinical progression. RESULTS AND LIMITATIONS Using standard BCR definitions, the risk of PSA progression was >70%, regardless of clinicopathologic features. A single PSA ≤0.1 ng/ml was associated with PSA progression in only 30-55% of patients but ranged from 18-25% to 73-88% for patients without and with adverse pathologic features, respectively. Based on discrimination and calibration analysis, the optimal BCR definition for patients with 5-yr progression-free probability of <50%, 50-75%, 76-90%, and >90% was a single PSA ≥0.05 ng/ml, two or more rising PSAs ≥0.05 ng/ml, PSA ≥0.2 ng/ml and rising, and PSA ≥0.4 ng/ml and rising. CONCLUSIONS BCR definitions below currently accepted PSA thresholds appear to be valid for selecting patients with adverse clinicopathologic risk factors for secondary therapy. This information may be useful in selecting for early salvage radiotherapy to improve clinical outcome.

Autophagic flux determines cell death and survival in response to Apo2L/TRAIL (dulanermin)

BackgroundMacroautophagy is a catabolic process that can mediate cell death or survival. Apo2 ligand (Apo2L)/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) treatment (TR) is known to induce autophagy. Here we investigated whether SQSTM1/p62 (p62) overexpression, as a marker of autophagic flux, was related to aggressiveness of human prostate cancer (PCa) and whether autophagy regulated the treatment response in sensitive but not resistant PCa cell lines.MethodsImmunostaining and immunoblotting analyses of the autophagic markers p62 [in PCa tissue microarrays (TMAs) and PCa cell lines] and LC3 (in PCa cell lines), transmission electron microscopy, and GFP-mCherry-LC3 were used to study autophagy induction and flux. The effect of autophagy inhibition using pharmacologic (3-methyladenine and chloroquine) and genetic [(short hairpin (sh)-mediated knock-down of ATG7 and LAMP2) and small interfering (si)RNA-mediated BECN1 knock-down] approaches on TR-induced cell death was assessed by clonogenic survival, sub-G1 DNA content, and annexinV/PI staining by flow cytometry. Caspase-8 activation was determined by immunoblotting.ResultsWe found that increased cytoplasmic expression of p62 was associated with high-grade PCa, indicating that autophagy signaling might be important for survival in high-grade tumors. TR-resistant cells exhibited high autophagic flux, with more efficient clearance of p62-aggregates in four TR-resistant PCa cell lines: C4-2, LNCaP, DU145, and CWRv22.1. In contrast, autophagic flux was low in TR-sensitive PC3 cells, leading to accumulation of p62-aggregates. Pharmacologic (chloroquine or 3-methyladenine) and genetic (shATG7 or shLAMP2) inhibition of autophagy led to cell death in TR-resistant C4-2 cells. shATG7-expressing PC3 cells, were less sensitive to TR-induced cell death whereas those shLAMP2-expressing were as sensitive as shControl-expressing PC3 cells. Inhibition of autophagic flux using chloroquine prevented clearance of p62 aggregates, leading to caspase-8 activation and cell death in C4-2 cells. In PC3 cells, inhibition of autophagy induction prevented p62 accumulation and hence caspase-8 activation.ConclusionsWe show that p62 overexpression correlates with advanced stage human PCa. Pharmacologic and genetic inhibition of autophagy in PCa cell lines indicate that autophagic flux can determine the cellular response to TR by regulating caspase-8 activation. Thus, combining various autophagic inhibitors may have a differential impact on TR-induced cell death.

Robot-assisted Laparoscopic Adrenalectomy: Step-by-Step Technique and Comparative Outcomes

BACKGROUND Recent evidence supports the use of robotic surgery for the minimally invasive surgical management of adrenal masses. OBJECTIVE To describe a contemporary step-by-step technique of robotic adrenalectomy (RA), to provide tips and tricks to help ensure a safe and effective implementation of the procedure, and to compare its outcomes with those of laparoscopic adrenalectomy (LA). DESIGN, SETTING, AND PARTICIPANTS We retrospectively reviewed the medical charts of consecutive patients who underwent RA performed by a single surgeon between April 2010 and October 2013. LA cases performed by the same surgeon between January 2004 and May 2010 were considered the control group. SURGICAL PROCEDURE The main steps of our current surgical technique for RA are described in this video tutorial: patient positioning, port placement, and robot docking; exposure of the adrenal gland; identification and control of the adrenal vein; circumferential dissection of the adrenal gland; and specimen retrieval and closure. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Demographic parameters and main surgical outcomes were assessed. RESULTS AND LIMITATIONS A total of 76 cases (RA: 30; LA: 46) were included in the analysis. Median tumor size on computed tomography (CT) was significantly larger in the LA group (3cm [interquartile range (IQR): 3] vs 4cm [IQR: 3]; p=0.002). A significantly lower median estimated blood loss was recorded for the robotic group (50ml [IQR: 50] vs 100ml [IQR: 288]; p=0.02). The RA group presented five minor complications (16.7%) and one major (Clavien 3b) complication (3.3%), whereas four minor complications (8.7%) and one major (Clavien 3b) complication (2.3%) were observed in the LA group. No significant difference was noted between groups in terms of malignant histology (p=0.66) and positive margin rate (p=0.60). Distribution of pheochromocytomas in the LA group was significantly higher than in the RA group (43.5% vs 16.7%; p=0.02). CONCLUSIONS The standardization of each surgical step optimizes the RA procedure. The robotic approach can be applied for a wide range of adrenal indications, recapitulating the safety and effectiveness of open surgery and potentially improving the outcomes of standard laparoscopy. PATIENT SUMMARY In this report we detail our surgical technique for robotic removal of adrenal masses. This procedure has been standardized and can be offered to patients, with excellent outcomes.