The role of warm ischemia time on functional outcomes after robotic partial nephrectomy: a radionuclide renal scan study from the clock randomized trial.

PURPOSE: To evaluate the relationship between warm ischemia time (WIT) duration and renal function after robot-assisted partial nephrectomy (RAPN). METHODS: The CLOCK trial is a phase 3 randomized controlled trial comparing on- vs off-clamp RAPN. All patients underwent pre- and postoperative renal scintigraphy. Six-month absolute variation of eGFR (AV-GFR), rate of relative variation in eGFR over 25% (RV-GFR > 25), absolute variation of split renal function (SRF) at scintigraphy (AV-SRF). The relationships WIT/outcomes were assessed by correlation graphs and then modeled by uni- and multivariable regression. RESULTS: 324 patients were included (206 on-clamp, 118 off-clamp RAPN). Correlation graphs showed a threshold on WIT equal to 10 min. The differences in outcome measures between cases with WIT < vs ≥ 10 min were: AV-GFR - 3.7 vs - 7.5 ml/min (p < 0.001); AV-SRF - 1% vs - 3.6% (p < 0.001); RV-GFR > 25 9.3% vs 17.8% (p = 0.008). Multivariable models found that AV-GFR was related to WIT ≥ 10 min (regression coefficient [RC] - 0.52, p = 0.019), age (RC - 0.35, p = 0.001) and baseline eGFR (RC - 0.30, p < 0.001); RV-GFR > 25 to WIT ≥ 10 min (odds ratio [OR] 1.11, p = 0.007) and acute kidney injury defined as > 50% increase in serum creatinine (OR 19.7, p = 0.009); AV-SRF to WIT ≥ 10 min (RC - 0.30, p = 0.018), baseline SRF (RC - 0.76, p < 0.001) and RENAL score (RC - 0.60. p = 0.028). The main limitation was that the CLOCK trial was designed on a different endpoint and therefore the present analysis could be underpowered. CONCLUSIONS: Up to 10 min WIT had no consequences on functional outcomes. Above the 10-min threshold, a statistically significant, but clinically negligible impact was found.

Is off-clamp robot-assisted partial nephrectomy beneficial for renal function? Data from the CLOCK trial.

OBJECTIVES: To compare the functional outcomes of on- vs off-clamp robot-assisted partial nephrectomy (RAPN) within a randomized controlled trial (RCT). MATERIALS AND METHODS: The CLOCK study (CLamp vs Off Clamp the Kidney during robotic partial nephrectomy; NCT02287987) is a multicentre RCT including patients with normal baseline function, two kidneys and masses with RENAL scores ≤ 10. Pre- and postoperative renal scintigraphy was prescribed. Renal defatting and hilum isolation were required in both study arms; in the on-clamp arm, ischaemia was imposed until the completion of medullary renorraphy, while in the off-clamp condition it was not allowed throughout the procedure. The primary endpoint was 6-month absolute variation in estimated glomerular filtration rate (AV-GFR); secondary endpoints were: 12, 18 and 24-month AV-GFR; 6-month estimated glomerular filtration rate variation >25% rate (RV-GFR >25); and absolute variation in ipsilateral split renal function (AV-SRF). The planned sample size was 102 + 102 cases, after taking account crossover of cases to the alternate study arm; a 1:1 randomization was performed. AV-GFR and AV-SRF were compared using analysis of covariation, and RV-GFR >25 was assessed using multivariable logistic regression. Intention-to-treat (ITT) and per-protocol analyses (PP) were performed. RESULTS: A total of 160 and 164 patients were randomly assigned to on- and off-clamp RAPN, respectively; crossover was observed in 14% and 43% of the on- and off-clamp arms, respectively. We were unable to find any statistically significant difference between on- vs off-clamp with regard to the primary endpoint (ITT: 6-month AV-GFR -6.2 vs -5.1 mL/min, mean difference 0.2 mL/min, 95% confidence interval [CI] -3.1 to 3.4 [P = 0.8]; PP: 6-month AV-GFR -6.8 vs -4.2 mL/min, mean difference 1.6 mL/min, 95% CI -2.3 to 5.5 [P = 0.7]) or with regard to the secondary endpoints. The median warm ischaemia time was 14 vs 15 min in the ITT analysis and 14 vs 0 min in the PP analysis. CONCLUSION: In patients with regular baseline function and two kidneys, we found no evidence of differences in functional outcomes for on- vs off-clamp RAPN.

Perioperative outcomes of patients undergoing urological elective surgery during the COVID-19 pandemic: a national overview across 28 Italian institutions.

INTRODUCTION: The aim of this study was to assess the safety of elective urological surgery performed during the pandemic by estimating the prevalence of COVID-19-like symptoms in the postoperative period and its correlation with perioperative and clinical factors. MATERIAL AND METHODS: In this multicenter, observational study we recorded clinical, surgical and postoperative data of consecutive patients undergoing elective urological surgery in 28 different institutions across Italy during initial stage of the COVID-19 pandemic (between February 24 and March 30, 2020, inclusive). RESULTS: A total of 1943 patients were enrolled. In 12%, 7.1%, 21.3%, 56.7% and 2.6% of cases an open, laparoscopic, robotic, endoscopic or percutaneous surgical approach was performed, respectively. Overall, 166 (8.5%) postoperative complications were registered, 77 (3.9%) surgical and 89 (4.6%) medical. Twenty-eight (1.4%) patients were readmitted to hospital after discharge and 13 (0.7%) died. In the 30 days following discharge, fever and respiratory symptoms were recorded in 101 (5.2%) and 60 (3.1%) patients. At multivariable analysis, not performing nasopharyngeal swab at hospital admission (HR 2.3; CI 95% 1.01-5.19; p = 0.04) was independently associated with risk of developing postoperative medical complications. Number of patients in the facility was confirmed as an independent predictor of experiencing postoperative respiratory symptoms (p = 0.047, HR:1.12; CI95% 1.00-1.05), while COVID-19-free type of hospitalization facility was a strong independent protective factor (p = 0.02, HR:0.23, CI95% 0.07-0.79). CONCLUSIONS: Performing elective surgery during the COVID-19 pandemic does not seem to affect perioperative outcomes as long as proper preventive measures are adopted, including nasopharyngeal swab before hospital admission and hospitalization in dedicated COVID-19-free facilities.

The dramatic COVID 19 outbreak in Italy is responsible of a huge drop of urological surgical activity: a multicenter observational study.

OBJECTIVE: To describe the trend in surgical volume in urology in Italy during the coronavirus disease 2019 (COVID-19) outbreak, as a result of the abrupt reorganisation of the Italian national health system to augment care provision to symptomatic patients with COVID-19. METHODS: A total of 33 urological units with physicians affiliated to the AGILE consortium (Italian Group for Advanced Laparo-Endoscopic Surgery; www.agilegroup.it) were surveyed. Urologists were asked to report the amount of surgical elective procedures week-by-week, from the beginning of the emergency to the following month. RESULTS: The 33 hospitals involved in the study account overall for 22 945 beds and are distributed in 13/20 Italian regions. Before the outbreak, the involved urology units performed overall 1213 procedures/week, half of which were oncological. A month later, the number of surgeries had declined by 78%. Lombardy, the first region with positive COVID-19 cases, experienced a 94% reduction. The decrease in oncological and non-oncological surgical activity was 35.9% and 89%, respectively. The trend of the decline showed a delay of roughly 2 weeks for the other regions. CONCLUSION: Italy, a country with a high fatality rate from COVID-19, experienced a sudden decline in surgical activity. This decline was inversely related to the increase in COVID-19 care, with potential harm particularly in the oncological field. The Italian experience may be helpful for future surgical pre-planning in other countries not so drastically affected by the disease to date.

Y RNA: An Overview of Their Role as Potential Biomarkers and Molecular Targets in Human Cancers.

Y RNA are a class of small non-coding RNA that are largely conserved. Although their discovery was almost 40 years ago, their function is still under investigation. This is evident in cancer biology, where their role was first studied just a dozen years ago. Since then, only a few contributions were published, mostly scattered across different tumor types and, in some cases, also suffering from methodological limitations. Nonetheless, these sparse data may be used to make some estimations and suggest routes to better understand the role of Y RNA in cancer formation and characterization. Here we summarize the current knowledge about Y RNA in multiple types of cancer, also including a paragraph about tumors that might be included in this list in the future, if more evidence becomes available. The picture arising indicates that Y RNA might be useful in tumor characterization, also relying on non-invasive methods, such as the analysis of the content of extracellular vesicles (EV) that are retrieved from blood plasma and other bodily fluids. Due to the established role of Y RNA in DNA replication, it is possible to hypothesize their therapeutic targeting to inhibit cell proliferation in oncological patients.

Safety of on- vs off-clamp robotic partial nephrectomy: per-protocol analysis from the data of the CLOCK randomized trial.

PURPOSE: To compare the safety of on- vs off-clamp robotic partial nephrectomy (RAPN). METHODS: 302 patients with RENAL masses ≤ 10 were randomized to undergo on-clamp (150) vs off-clamp (152) RAPN (CLOCK trial-ClinicalTrials.gov NCT02287987) at seven institutions by one experienced surgeon per institution. Intra-operative data, complications, and positive surgical margins were compared. RESULTS: Due to a relevant rate of shift from the assigned treatment, the per-protocol analysis only was considered and the data from 129 on-clamp vs 91 off-clamp RAPNs analyzed. Tumor size (off-clamp vs on-clamp, 2.2 vs 3.0 cm, p < 0.001) and RENAL score (5 vs 6, p < 0.001) significantly differed. At univariate analysis, no differences were found regarding intra-operative estimated blood loss (off- vs on-clamp, 100 vs 100 ml, p = 0.7), post-operative complications rate (19% vs 26%, p = 0.2), post-operative anemia (Hb decrease > 2.5 g/dl 26% vs 27%, p = 0.9; transfusion rate 3.4% vs 6.3%, p = 0.5; re-intervention due to bleeding 1.1% vs 4%, p = 0.4), acute kidney injury (4% vs 6%, p = 0.8), and positive surgical margins (3.5% vs 8.2%, p = 0.1). At multivariate analysis accounting for tumor diameter and complexity, considering the on-clamp group as the reference category, a significant difference was noted in the off-clamp group exclusively for blood loss (OR 0.3, 95% CI 0.09-0.52, p = 0.008). CONCLUSIONS: The on-clamp and off-clamp approaches for RAPN showed a comparable safety profile.

Predictors of the Transition from Off to On Clamp Approach during Ongoing Robotic Partial Nephrectomy: Data from the CLOCK Randomized Clinical Trial.

PURPOSE: We sought to identify predictive factors of the transition from off clamp to on clamp robotic partial nephrectomy following an intraoperative decision. MATERIALS AND METHODS: In the multicenter, randomized, prospective CLOCK (CLamp vs Off Clamp the Kidney during robotic partial nephrectomy) trial 152 and 149 of the 301 patients with a localized renal mass were assigned to undergo off clamp and on clamp robotic partial nephrectomy, respectively. Surgery was done at a total of 7 referral institutions by 1 surgeon per institution. A localized renal mass was defined as having a R.E.N.A.L. (radius, exophytic/endophytic, nearness to collecting system or sinus, anterior/posterior, location relative to polar lines, hilar) score less than 10. Surgeons had similar experience with at least 100 previous robotic partial nephrectomies. All patients underwent a preoperative and a 6-month renal scan. The current study deals with one of the secondary end points of the trial, comparing cases finalized as clampless (off robotic partial nephrectomy group) with those which were converted (shift robotic partial nephrectomy group). RESULTS: Of the 152 patients randomized to off clamp 61 (40%) were shifted to clamp with a median ischemia time of 15 minutes. In the shift robotic partial nephrectomy group the masses were larger (3.5 vs 2.2 cm) and more complex (R.E.N.A.L. score 7 vs 6). A significant association with transition was found for tumor diameter (OR 1.4) and the R.E.N.A.L. score continuously (OR 1.4) and when recoded in groups, including 4-no risk (referent OR 1), 5-6-low risk (OR 1.8), 7-8-intermediate risk (OR 3.6) and 9 or greater-high risk (OR 6.6). The shift robotic partial nephrectomy group had longer operative time, higher blood loss and increased performance of 2-layer renorrhaphy. No significant differences were noted in postoperative complications or renal function after 6 months. CONCLUSIONS: The transition from off to on clamp robotic partial nephrectomy is associated with renal mass diameter and complexity. Under the specific conditions of the current trial no harm was related to this decision.

The role of vascular clamping during robot-assisted partial nephrectomy for localized renal cancer: rationale and design of the CLOCK randomized phase III study.

To outline the design and rationale of clock, a large, phase III randomized controlled trial which examines the role vascular clamping during robot-assisted partial nephrectomy (RAPN) for localized renal cancer. To be eligible for study entry, patients must have normal coagulative function, preoperative estimated glomerular filtration rate (eGFR) >60 mL/min, normal contralateral kidney and a single renal mass with RENAL Score ≤10. Eligible patients are to be randomized in a 1:1 ratio between two arms. Randomized allocation was assigned by a permuted block design, stratified by center. Allocation arm was notified by the study internet-based e-form, managed by an independent software house. Arm A=RAPN with ischemia; Arm B=RAPN without ischemia. At any moment, from randomization to the end of the procedure, the investigators could amend the indication given by randomization and shift to the alternative clamping option, detailing the timing and reasons of their decision. CLOCK is a randomized controlled trial, which addresses two questions relating to the management of localized renal cancer treated by RAPN with or without ischemia: 1) what is the impact of the surgical technique on long-term renal function; 2) what are the factors influencing the shift from one technique to the other. The study will be completed 24 months after the last enrollment.

Non-Coding RNAs and Endometrial Cancer.

Non-coding RNAs (ncRNAs) are involved in the regulation of cell metabolism and neoplastic transformation. Recent studies have tried to clarify the significance of these information carriers in the genesis and progression of various cancers and their use as biomarkers for the disease; possible targets for the inhibition of growth and invasion by the neoplastic cells have been suggested. The significance of ncRNAs in lung cancer, bladder cancer, kidney cancer, and melanoma has been amply investigated with important results. Recently, the role of long non-coding RNAs (lncRNAs) has also been included in cancer studies. Studies on the relation between endometrial cancer (EC) and ncRNAs, such as small ncRNAs or micro RNAs (miRNAs), transfer RNAs (tRNAs), ribosomal RNAs (rRNAs), antisense RNAs (asRNAs), small nuclear RNAs (snRNAs), Piwi-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs), competing endogenous RNAs (ceRNAs), lncRNAs, and long intergenic ncRNAs (lincRNAs) have been published. The recent literature produced in the last three years was extracted from PubMed by two independent readers, which was then selected for the possible relation between ncRNAs, oncogenesis in general, and EC in particular.

Perineural invasion in prostatic carcinoma treated with radical prostatectomy: the role of TR systematic biopsy.

Perineural invasion (PNI) is a morphological entity which has been known for many years, though its significance in prostatic neoplasms has only been studied recently. Therefore, we tried to assess, with the help our experience, its presence and its significance. Ninety-four patients, aged between 49 and 74 (average 65.8)--with a PSA between 2.69 and 52 ng/ml (average 11.44)--underwent RP for prostatic carcinoma; 58 patients had stage T2 and 36 had T3. 48 patients had Gleason 7 or higher, and 46 had G 6 or lower. Fifty patients (53,1%) were PNI+ and 44 (46,9%) PNI-. Between the two groups there was no significant difference as to age (1" group: average age 67 years; 2nd group: 68) and PSA (1st group: average 9.73 ng/ml, 2nd group: average 8,17) (Z 0,639). The distribution according to the stage showed that 24 patients (48%) PNI+ were T2 and 26 (52%) PNI+ T3, 34 (77.2%) PNI- T2 and 10 (22%) PNI- T3 and therefore 72,23% of the T3's were PNI+ and 41.3% of the T2's were PNI+; 34 patients (70.8%) with G>7 were PNI+ and 14 (29.16%) PNI-, 16 patients (34,78%) with G<6 were PNI+ and 30 (65.2%) PNI-. Among the PNI+ 50 patients, 36 had undergone biopsy in our hospital, and therefore we re-examined the operation tissue and found out that 16 (44%) were biopsy PNI+ while for 22 (55.5%) it was not possible to assess the PNI on the biopsy tissue. PNI is an important morphological element in the staging of prostatic cancer and is connected with the disease negative prognostic factors: in fact, it can be traced with a high frequency in stage diseases and higher Gleasons. It does not seem to be connected with PSA, above all for values between 4 and 20 ng/ml. We think that a very important element to be stressed is the fact that this condition is not always detected with biopsy (about 45%) and this does not allow, in such cases, an adequate therapy plan. Also our experience seems to confirm that, therefore, in spite of the above said limits, it is advisable to search PNI both with biopsy--in order to have a further prognostic element and therefore arrange the most suitable therapy plan--and on the surgery piece, in order to better determine the biological nature of the disease and to be able to suggest adequate integrative therapies.