Manuela Costantini

Laparoscopic and Robotic Partial Nephrectomy With Controlled Hypotensive Anesthesia to Avoid Hilar Clamping: Feasibility, Safety and Perioperative Functional Outcomes

PURPOSEnWe evaluated the feasibility and safety of laparoscopic and robotic assisted partial nephrectomy with controlled hypotensive anesthesia to avoid hilar clamping and eliminate renal ischemia.nnnMATERIALS AND METHODSnA total of 60 patients with renal tumors who were candidates for nephron sparing surgery and had no contraindication to hypotensive anesthesia underwent partial nephrectomy without hilar clamping and with controlled hypotension during tumor excision. A total of 40 laparoscopic partial nephrectomies and 20 robotic assisted partial nephrectomies were done. All patients who were candidates for laparoscopic or robotic assisted partial nephrectomy regardless of tumor site, size or growth pattern were included in study. The surgical field was assessed for bleeding and visibility using a numerical rating scale.nnnRESULTSnMedian tumor size was 3.6 cm (range 1.8 to 10), median operative time was 2 hours (range 1 to 3.5), median blood loss was 200 ml (range 30 to 700 ml) and median hospital stay was 3 days (range 3 to 8). All margins were negative. The median duration of controlled hypotension with a median mean arterial pressure of 65 mm Hg (range 55 to 70) was 14 minutes (range 7 to 16). No patient required intraoperative transfusion but 4 (6.6%) required transfusion postoperatively. Complications developed postoperatively in 3 patients, ie port site bleeding, hemorrhage and hematoma, respectively. Median preoperative and postoperative serum creatinine was 0.9 and 1.10 mg/dl, respectively. The median preoperative and postoperative estimated glomerular filtration rate was 87.20 and 75.60 ml/minute/1.73 m2, respectively.nnnCONCLUSIONSnControlled hypotension allowed laparoscopic and robotic assisted partial nephrectomy to be done without renal hilar clamping. All procedures were completed safely and perioperative outcomes are encouraging.

PCA3 in prostate cancer and tumor aggressiveness detection on 407 high-risk patients: a National Cancer Institute experience

BackgroundProstate cancer (PCa) is the most common male cancer in Europe and the US. The early diagnosis relies on prostate specific antigen (PSA) serum test, even if it showed clear limits. Among the new tests currently under study, one of the most promising is the prostate cancer gene 3 (PCA3), a non-coding mRNA whose level increases up to 100 times in PCa tissues when compared to normal tissues. With the present study we contribute to the validation of the clinical utility of the PCA3 test and to the evaluation of its prognostic potential.Methods407 Italian men, with two or more PCa risk factors and at least a previous negative biopsy, entering the Urology Unit of Regina Elena National Cancer Institute, were tested for PCA3, total PSA (tPSA) and free PSA (fPSA and f/tPSA) tests. Out of the 407 men enrolled, 195 were positive for PCa and 114 of them received an accurate staging with evaluation of the Gleason score (Gs). Then, the PCA3 score was correlated to biopsy outcome, and the diagnostic and prognostic utility were evaluated.ResultsOut of the 407 biopsies performed after the PCA3 test, 195 (48%) resulted positive for PCa; the PCA3 score was significantly higher in this population (pu2009<u20090.0001) differently to tPSA (pu2009=u20090.87). Moreover, the PCA3 test outperformed the f/tPSA (pu2009=u20090.01). The sensitivity (94.9) and specificity (60.1) of the PCA3 test showed a better balance for a threshold of 35 when compared to 20, even if the best result was achieved considering a cutoff of 51, with sensitivity and specificity of 82.1% and 79.3%, respectively. Finally, comparing values of the PCA3 test between two subgroups with increasing Gs (Gsu2009≤u20096 versus Gsu2009≥u20097) a significant association between PCA3 score and Gs was found (pu2009=u20090.02).ConclusionsThe PCA3 test showed the best diagnostic performance when compared to tPSA and f/tPSA, facilitating the selection of high-risk patients that may benefit from the execution of a saturation prostatic biopsy. Moreover, the PCA3 test showed a prognostic value, as higher PCA3 score values are associated to a greater tumor aggressiveness.

Laparoscopic and robotic partial nephrectomy without renal ischaemia for tumours larger than 4 cm: perioperative and functional outcomes

PurposeTo evaluate the technical feasibility, safety and functional outcomes of zero ischaemia laparoscopic and robotic partial nephrectomy with controlled hypotension for renal tumours larger than 4xa0cm.MethodsWe evaluated 121 consecutive patients with American Society of Anaesthesiologists (ASA) scores 1–2 who underwent laparoscopic (nxa0=xa070) or robotic (nxa0=xa051) partial nephrectomy with controlled hypotension with either tumour size ≤4xa0cm (group 1, nxa0=xa078) or tumour size >4 cm (group 2, nxa0=xa043) performed by a single surgeon from December 2010 to December 2011. Operative data, complications, serum creatinine, estimated glomerular filtration rates and effective renal plasma flow calculated from 99mTc-mercaptoacetyltriglycine renal scintigraphy were compared. Differences between groups were evaluated by the Chi-square test and the Student’s t test.ResultsA significant difference in mean intraoperative blood loss and postoperative complications was found between the two groups: 168xa0ml (range: 10–600xa0ml in group 1) and 205xa0ml (range: 90–700xa0ml in group 2); pxa0=xa00.005, and 6.4xa0% versus 18.6xa0%; pxa0=xa00.004, respectively. The mean percentage decrease of ERPF of the operated kidney was 1.8xa0% in group 1 and 4.1xa0% in group 2.ConclusionsLaparoscopic and robotic partial nephrectomy with controlled hypotension for tumours >4xa0cm in ASA 1–2 patients was feasible with significant higher intraoperative blood loss and postoperative complications compared to smaller renal masses. The benefits of avoiding hilar clamping to preserve kidney function seem excellent.

Collecting duct carcinoma of the kidney is associated with CDKN2A deletion and SLC family gene up-regulation

The genetic landscape and molecular features of collecting duct carcinoma (CDC) of the kidney remain largely unknown. Herein, we performed whole exome sequencing (WES) and transcriptome sequencing (RNASeq) on 7 CDC samples (CDC1 −7). Among the 7 samples, 4 samples with matched non-tumor tissue were used for copy number analysis by SNP array data. No recurrent somatic SNVs were observed except for MLL, which was found to be mutated (p.V297I and p.F407C) in 2 samples. We identified somatic SNVs in 14 other cancer census genes including: ATM, CREBBP, PRDM1, CBFB, FBXW7, IKZF1, KDR, KRAS, NACA, NF2, NUP98, SS18, TP53, and ZNF521. SNP array data identified a CDKN2A homozygous deletion in 3 samples and SNV analysis showed a non-sense mutation of the CDKN2A gene with unknown somatic status. To estimate the recurrent rate of CDKN2A abnormalities, we performed FISH screening of additional samples and confirmed the frequent loss (62.5%) of CDKN2A expression. Since cisplatin based therapy is the common treatment option for CDC, we investigated the expression of solute carrier (SLC) family transporters and found 45% alteration. In addition, SLC7A11 (cystine transporter, xCT), a cisplatin resistance associated gene, was found to be overexpressed in 4 out of 5 (80%) cases of CDC tumors tested, as compared to matched non-tumor tissue. In summary, our study provides a comprehensive genomic analysis of CDC and identifies potential pathways suitable for targeted therapies.

Keap1/Nrf2 pathway in kidney cancer: frequent methylation of KEAP1 gene promoter in clear renal cell carcinoma

The Keap1/Nrf2 pathway is a master regulator of the cellular redox state through the induction of several antioxidant defence genes implicated in chemotherapeutic drugs resistance of tumor cells. An increasing body of evidence supports a key role for Keap1/Nrf2 pathway in kidney diseases and renal cell carcinoma (RCC), but data concerning the molecular basis and the clinical effect of its deregulation remain incomplete. Here we present a molecular profiling of the KEAP1 and NFE2L2 genes in five different Renal Cell Carcinoma histotypes by analysing 89 tumor/normal paired tissues (clear cell Renal Carcinoma, ccRCCs; Oncocytomas; Papillary Renal Cell Carcinoma Type 1, PRCC1; Papillary Renal Cell Carcinoma Type 2, PRCC2; and Chromophobe Cell Carcinoma). A tumor-specific DNA methylation of the KEAP1 gene promoter region was found as a specific feature of the ccRCC subtype (18/37, 48.6%) and a direct correlation with mRNA levels was confirmed by in vitro 5-azacytidine treatment. Analysis of an independent data set of 481 ccRCC and 265 PRCC tumors corroborates our results and multivariate analysis reveals a significant correlation among ccRCCs epigenetic KEAP1 silencing and staging, grading and overall survival. Our molecular results show for the the first time the epigenetic silencing of KEAP1 promoter as the leading mechanism for modulation of KEAP1 expression in ccRCCs and corroborate the driver role of Keap1/Nrf2 axis deregulation with potential new function as independent epigenetic prognostic marker in renal cell carcinoma.

C-Met/miR-130b axis as novel mechanism and biomarker for castration resistance state acquisition

Although a significant subset of prostate tumors remain indolent during the entire life, the advanced forms are still one of the leading cause of cancer-related death. There are not reliable markers distinguishing indolent from aggressive forms. Here we highlighted a new molecular circuitry involving microRNA and coding genes promoting cancer progression and castration resistance. Our preclinical and clinical data demonstrated that c-Met activation increases miR-130b levels, inhibits androgen receptor expression, promotes cancer spreading and resistance to hormone ablation therapy. The relevance of these findings was confirmed on patients’ samples and by in silico analysis on an independent patient cohort from Taylor’s platform. Data suggest c-Met/miR-130b axis as a new prognostic marker for patients’ risk assessment and as an indicator of therapy resistance. Our results propose new biomarkers for therapy decision-making in all phases of the pathology. Data may help identify high-risk patients to be treated with adjuvant therapy together with alternative cure for castration-resistant forms while facilitating the identification of possible patients candidates for anti-Met therapy. In addition, we demonstrated that it is possible to evaluate Met/miR-130b axis expression in exosomes isolated from peripheral blood of surgery candidates and advanced patients offering a new non-invasive tool for active surveillance and therapy monitoring.

Papillary type 2 versus clear cell renal cell carcinoma: Survival outcomes

AIMnTo compare the cancer specific survival (CSS) between p2-RCC and a Propensity Score Matched (PSM) cohort of cc-RCC patients.nnnMETHODSnFifty-five (4.6%) patients with p2-RCC and 920 cc-RCC patients were identified within a prospectively maintained institutional dataset of 1205 histologically proved RCC patients treated with either RN or PN. Univariable and multivariable Cox regression analyses were used to identify predictors of CSS after surgical treatment. A 1:2 PSM analysis based on independent predictors of oncologic outcomes was employed and CSS was compared between PSM selected cc-RCC patients using Kaplan-Meier and Cox regression analysis.nnnRESULTSnOverall, 55 (4.6%) p2-RCC and 920 (76.3%) cc-RCC patients were selected from the database; p2-RCC were significantly larger (pxa0=xa00.001), more frequently locally advanced (pxa0<xa00.001) and node positive (pxa0<xa00.001) and had significantly higher Fuhrman grade (pxa0<xa00.001) than cc-RCC. On multivariable Cox regression analysis age (pxa0=xa00.025), histologic subtype (pxa0=xa00.029), pN stage (pxa0=xa00.006), size, pT stage, cM stage, sarcomatoid features and Fuhrman grade (all pxa0<xa00.001) were independent predictors of CSS. After applying the PSM, 82 cc-RCC selected cases were comparable to 41 p2-RCC for age (pxa0=xa00.81), tumor size (pxa0=xa00.39), pT (pxa0=xa01.00) and pN (pxa0=xa00.62) stages, cM stage (pxa0=xa00.71) and Fuhrman grade (pxa0=xa01). In this PSM cohort, 5xa0yr CSS was significantly lower in the p2-RCC (63% vs 72.4%; pxa0=xa00.047). At multivariable Cox analysis p2 histology was an independent predictor of CSM (HR 2.46, 95% CI 1.04-5.83; pxa0=xa00.041).nnnCONCLUSIONSnWe confirmed the tendency of p2-RCC to present as locally advanced and metastatic disease more frequently than cc-RCC and demonstrated p2-RCC histology as an independent predictor of worse oncologic outcomes.

AMBRA1 and SQSTM1 expression pattern in prostate cancer

Prostate cancer is among the most commonly diagnosed male diseases and a leading cause of cancer mortality in men. There is emerging evidence that autophagy plays an important role in malignant cell survival and offers protection from the anti-cancer drugs in prostate cancer cells. AMBRA1 and the autophagic protein sequestosome-1 (SQSTM1; p62) expression were evaluated by immunohistochemistry and western blot on tissue samples from both benign and malignant prostatic lesions. The data reported in this pilot study demonstrated an increased expression of AMBRA1 and SQSTM1, which were also associated with an accumulation of LC3II in prostate cancer but not in benign lesion. In the present study we found that: (i) at variance with benign lesion, prostate cancer cells underwent SQSTM1 accumulation, i.e., clearly displayed a defective autophagic process but, also, (ii) prostate cancer accumulated AMBRA1 and (iii) this increase positively correlated with the Gleason score. These results underscore a possible implication of autophagy in prostate cancer phenotype and of AMBRA1 as possible cancer progression biomarker in this malignancy.

Purely off‐clamp robotic partial nephrectomy: Preliminary 3‐year oncological and functional outcomes

To describe our surgical technique and to report perioperative, 3‐year oncological and functional outcomes of a single‐center series of purely off‐clamp robotic partial nephrectomy.

Outcomes of Robot-assisted Partial Nephrectomy for Clinical T2 Renal Tumors: A Multicenter Analysis (ROSULA Collaborative Group)

BACKGROUNDnWhile partial nephrectomy (PN) represents the standard surgical management for cT1 renal masses, its role for cT2 tumors is controversial. Robot-assisted PN (RAPN) is being increasingly implemented worldwide.nnnOBJECTIVEnTo analyze perioperative, functional, and oncological outcomes of RAPN for cT2 tumors.nnnDESIGN, SETTING, AND PARTICIPANTSnRetrospective analysis of a large multicenter, multinational dataset of patients with nonmetastatic cT2 masses treated with robotic surgery (ROSULA: RObotic SUrgery for LArge renal mass).nnnINTERVENTIONnRobotic-assisted PN.nnnOUTCOME MEASUREMENTS AND STATISTICAL ANALYSISnPatients demographics, lesion characteristics, perioperative variables, renal functional data, pathology, and oncological data were analyzed. Univariable and multivariable regression analyses assessed the relationships with the risk of intra-/postoperative complications, recurrence, and survival.nnnRESULTS AND LIMITATIONSnA total of 298 patients were analyzed. Median tumor size was 7.6 (7-8.5) cm. Median RENAL score was 9 (8-10). Median ischemia time was 25 (20-32) min. Median estimated blood loss was 150 (100-300) ml. Sixteen patients had intraoperative complications (5.4%), whereas 66 (22%) had postoperative complications (5% were Clavien grade ≥3). Multivariable analysis revealed that a lower RENAL score (odds ratio [OR] 0.46, 95% confidence interval [CI] 0.21-0.65, p=0.02) and pathological pT2 stage (OR 0.51, 95% CI 0.12-0.86, p=0.001) were protective against postoperative complications. A total of 243 lesions (82%) were malignant. Twenty patients (8%) had positive surgical margins. Ten deaths and 25 recurrences/metastases occurred at a median follow-up of 12 (5-35) mo. At univariable analysis, higher pT stage was predictive of a likelihood of recurrences/metastases (p=0.048). While there was a significant deterioration of renal function at discharge, this remained stable over time at 1-yr follow-up. The main limitation of this study is its retrospective design.nnnCONCLUSIONSnRAPN in the setting of select cT2 renal masses can safely be performed with acceptable outcomes. Further studies are warranted to corroborate our findings and to better define the role of robotic nephron sparing for this challenging indication.nnnPATIENT SUMMARYnThis report shows that robotic surgery can be used for safe removal of a large renal tumor in a minimally invasive fashion, maximizing preservation of renal function, and without compromising cancer control.