Diruthenium Paddlewheel Complexes Attacking Proteins: Axial versus Equatorial Coordination.

Metallodrugs are an important group of medicinal agents used for the treatment of various diseases ranging from cancers to viral, bacterial, and parasitic diseases. Their distinctive features include the availability of a metal centre, redox activity, as well as the ability to multitarget. Diruthenium paddlewheel complexes are an intensely developing group of metal scaffolds, which can securely coordinate bidentate xenobiotics and transport them to target tissues, releasing them by means of substitution reactions with biomolecular nucleophiles. It is of the utmost importance to gain a complete comprehension of which chemical reactions happen with them in physiological milieu to design novel drugs based on these bimetallic scaffolds. This review presents the data obtained in experiments and calculations, which clarify the chemistry these complexes undergo once administered in the proteic environment. This study demonstrates how diruthenium paddlewheel complexes may indeed embody a new paradigm in the design of metal-based drugs of dual-action by presenting and discussing the protein metalation by these complexes.

Mechanism of Action of Antitumor Au(I) N-Heterocyclic Carbene Complexes: A Computational Insight on the Targeting of TrxR Selenocysteine.

The targeting of human thioredoxin reductase is widely recognized to be crucially involved in the anticancer properties of several metallodrugs, including Au(I) complexes. In this study, the mechanism of reaction between a set of five N-heterocyclic carbene Au(I) complexes and models of the active Sec residue in human thioredoxin reductase was investigated by means of density functional theory approaches. The study was specifically addressed to the kinetics and thermodynamics of the tiled process by aiming at elucidating and explaining the differential inhibitory potency in this set of analogous Au(I) bis-carbene complexes. While the calculated free energy profile showed a substantially similar reactivity, we found that the binding of these Au(I) bis-carbene at the active CysSec dyad in the TrxR enzyme could be subjected to steric and orientational restraints, underlining both the approach of the bis-carbene scaffold and the attack of the selenol group at the metal center. A new and detailed mechanistic insight to the anticancer activity of these Au(I) organometallic complexes was thus provided by consolidating the TrxR targeting paradigm.

Trifurcated Splitting of Water Droplets on Engineered Lithium Niobate Surfaces.

Controlled splitting of liquid droplets is a key function in many microfluidic applications. In recent years, various methodologies have been used to accomplish this task. Here, we present an optofluidic technique based on an engineered surface formed by coating a z-cut iron-doped lithium niobate crystal with a lubricant-infused layer, which provides a very slippery surface. Illuminating the crystal with a light spot induces surface charges of opposite signs on the two crystal faces because of the photovoltaic effect. If the light spot is sufficiently intense, millimetric water droplets placed near the illuminated spot split into two charged fragments, one fragment being trapped by the bright spot and the other moving away from it. The latter fragment does not move randomly but rather follows one of three well-defined trajectories separated by 120°, which reflect the anisotropic crystalline structure of Fe:LiNbO3. Numerical simulations explain the behavior of water droplets in the framework of the forces induced by the interplay of pyroelectric, piezoelectric, and photovoltaic effects, which originate simultaneously inside the illuminated crystal. Such a synergetic effect can provide a valuable feature in applications that require splitting and coalescence of droplets, such as chemical microreactors and biological encapsulation and screening.

Comparing Robotic-Assisted to Open Radical Cystectomy in the Management of Non-Muscle-Invasive Bladder Cancer: A Propensity Score Matched-Pair Analysis.

BACKGROUND: For non-muscle-invasive bladder cancer (NMIBC) requiring radical surgery, limited data are available comparing robotic-assisted radical cystectomy with intracorporeal urinary diversion (iRARC) to open radical cystectomy (ORC). The objective of this study was to compare the two surgical techniques. METHODS: A multicentric cohort of 593 patients with NMIBC undergoing iRARC or ORC between 2015 and 2020 was prospectively gathered. Perioperative and pathologic outcomes were compared. RESULTS: A total of 143 patients operated on via iRARC were matched to 143 ORC patients. Operative time was longer in the iRARC group (p = 0.034). Blood loss was higher in the ORC group (p < 0.001), with a consequent increased post-operative transfusion rate in the ORC group (p = 0.003). Length of stay was longer in the ORC group (p = 0.007). Post-operative complications did not differ significantly (all p > 0.05). DFS at 60 months was 55.9% in ORC and 75.2% in iRARC with a statistically significant difference (p = 0.033) found in the univariate analysis. CONCLUSION: We found that iRARC for patients with NMIBC is safe, associated with a lower blood loss, a lower transfusion rate and a shorter hospital stay compared to ORC. Complication rates were similar. No significant differences in survival analyses emerged across the two techniques.

Holmium Laser Enucleation of the Prostate vs Robot-Assisted Simple Prostatectomy for Lower Urinary Tract Symptoms in Patients with Extremely Large Prostates ≥200 cc: A Comparative Analysis.

Introduction and Objectives: Robot-assisted simple prostatectomy (RASP) and holmium laser enucleation of the prostate (HoLEP) are both well-established, minimally invasive surgical treatment options for lower urinary tract symptoms caused by benign prostatic enlargement. We have reported the first comparative analysis of both techniques in patients with prostates of ≥200 cc. Materials and Methods: Between 2009 and 2020 a total of 53 patients with a prostate volume of ≥200 cc were surgically treated at OLV Hospital Aalst (Belgium): 31 underwent RASP and 22 underwent HoLEP. Preoperative and postoperative assessments included uroflowmetry with maximum urinary flow rate (Qmax) and postvoid residual volume (PVR), as well as the International Prostate Symptom Score (IPSS) and quality of life (IPSS-QoL). The complication rates were evaluated according to the Clavien-Dindo Classification. Results: Patients treated with RASP had significantly larger prostate volumes compared with HoLEP (median 226 cc vs 204.5 cc, p = 0.004). After a median follow-up of 14 months, both groups showed a significant improvement in the maximum flow rate (+10.60 mL/s vs +10.70 mL/s, p = 0.724) and a reduction of the IPSS score (-12.50 vs -9, p = 0.246) as well as improvement of the QoL (-3 vs -3, p = 0.880). Median operative time was similar in both groups (150 minutes vs 132.5 minutes, p = 0.665). The amount of resected tissue was lower in the RASP group (134.5 g vs 180 g, p = 0.029) and there was no significant difference in postoperative prostate-specific antigen (1.2 ng/mL vs 0.8 ng/mL, p = 0.112). Despite a similar median catheterization time (3 days vs 2 days, p = 0.748), the median hospitalization time was shorter in the HoLEP group (4 days vs 3 days, p = 0.052). Complication rates were similar in both groups (32% vs 36%, p = 0.987). Conclusion: Our results suggest similar outcomes for RASP and HoLEP in patients with very large prostates ≥200 cc. These findings will require external validation at other high-volume centers.

Age represents the main driver of surgical decision making in patients candidate to radical cystectomy.

BACKGROUND AND OBJECTIVES: Age might influence the choice of surgical approach, type of urinary diversion (UD) and lymph node dissection (LND) in patients candidate to radical cystectomy (RC) for urothelial bladder cancer (UBC). Similarly, age may enhance surgical morbidity and worsen perioperative outcomes. We tested the impact of age (octogenarian vs. younger patients) on surgical decision making and peri- and postoperative outcomes of RC. METHODS: Non-metastatic muscle-invasive UBC patients treated with RC at 18 high-volume European institutions between 2006 and 2021 were identified and stratified according to age (≥80 vs. <80 years). Intraoperative Complications Assessment and Reporting with Universal Standards and European Association of Urology guidelines recommendations were accomplished in collection and reporting of, respectively, intraoperative and postoperative complications. Multivariable logistic regression models (MVA) tested the impact of age on outcomes of interest. Sensitivity analyses after 1:3 propensity score matching were performed. RESULTS: Of 1955 overall patients, 251 (13%) were ≥80-year-old. Minimally invasive RC was performed in 18% and 40% of octogenarian and younger patients, respectively (p < 0.001). UD without bowel manipulation (ureterocutaneostomy, UCS) was performed in 31% and 7% of octogenarian and younger patients (p < 0.001). LND was delivered to 81% and 93% of octogenarian and younger patients (p < 0.001). At MVA, age ≥80 years independently predicted open approach (odds ratio [OR]: 1.55), UCS (OR: 3.70), and omission of LND (OR: 0.41; all p ≤ 0.02). Compared to their younger counterparts, octogenarian patients experienced higher rates of intraoperative (8% vs. 4%, p = 0.04) but not of postoperative complications (64% vs. 61%, p = 0.07). At MVA, age ≥80 years was not an independent predictor of length of stay, intraoperative or postoperative transfusions and complications, and readmissions (all p values >0.1). These results were replicated in sensitivity analyses. CONCLUSIONS: Age ≥80 years does not independently portend worse surgical outcomes for RC. However, octogenarians are unreasonably more likely to receive open approach and UCS diversion, and less likely to undergo LND.

Ileal Conduit Versus Orthotopic Neobladder Urinary Diversion in Robot-assisted Radical Cystectomy: Results from a Multi-institutional Series.

Background: Head-to-head comparisons between ileal conduit (IC) and orthotopic neobladder (ONB) in terms of peri- and postoperative outcomes and complications, in the specific setting of robot-assisted radical cystectomy (RARC), are not available. Objective: To address the impact of the type of urinary diversion (UD, IC vs ONB) on RARC morbidity, as well as operative time (OT), length of stay (LOS), and readmissions. Design setting and participants: Urothelial bladder cancer patients treated with RARC at nine high-volume European institutions between 2008 and 2020 were identified. Intervention: RARC with either IC or ONB. Outcome measurements and statistical analysis: Intra- and postoperative complications were collected and reported according to the Intraoperative Complications Assessment and Reporting with Universal Standards recommendations and European Association of Urology guidelines, respectively. Multivariable logistic regression models tested the impact of UD on outcomes, after adjustment for clustering at single hospital level. Results and limitations: Overall, 555 nonmetastatic RARC patients were identified. In 280 (51%) and 275 (49%) patients, an IC and an ONB were performed, respectively. Eighteen intraoperative complications were recorded. The rates of intraoperative complications were 4% in IC patients and 3% in ONB patients (p = 0.4). The median LOS and readmission rates were 10 versus 12 d (p < 0.001) and 20% versus 21% (p = 0.8) in IC versus ONB patients, respectively. At a multivariable logistic regression analyses, the type of UD (IC vs ONB) reached the independent predictor status for prolonged OT (odds ratio [OR]: 0.61, p = 0.03) and prolonged LOS (OR: 0.34, p < 0.001), but not for readmission (OR: 0.92, p = 0.7). Overall, 513 postoperative complications were experienced by 324 patients (58%). At least one postoperative complication was experienced by 160 (57%) IC patients versus 164 (60%) ONB patients (p = 0.6). The type of UD reached the status of an independent predictor of UD-related complications (OR: 0.64, p = 0.03). Conclusions: Compared with RARC with ONB, RARC with IC is less prone to UD-related postoperative complications, prolonged OT, and prolonged LOS. Patient summary: To date, the impact of the type of urinary diversion, namely, ileal conduit versus orthotopic neobladder, on peri- and postoperative outcomes of robot-assisted radical cystectomy is unknown. Based on a rigorous data accrual, which relied on established complication reporting systems (Intraoperative Complications Assessment and Reporting with Universal Standards and European Association of Urology recommended systems), we reported intra- and postoperative complications according to urinary diversion type. Moreover, we found that ileal conduit was associated with lower operative time and length of stay, and yielded a protective effect in terms of urinary diversion-related complications.

Do perioperative blood transfusions impact oncological outcomes of robot-assisted radical cystectomy with intracorporeal urinary diversion? Results from a large multi-institutional registry.

BACKGROUND: Blood transfusions (BT) have been associated with adverse oncologic outcomes in multiple malignancies including open radical cystectomy (ORC) for urothelial carcinoma of the bladder (UCB). Robot-assisted radical cystectomy (RARC) with intracorporeal urinary diversion (ICUD) delivers similar oncologic outcomes compared to ORC, yet with lower blood loss and reduced transfusions. However, the impact of BT after robotic cystectomy is still unknown. METHODS: This is a multicenter study including patients treated for UCB with RARC and ICUD in 15 academic institutions, between January 2015 and January 2022. BT were administered during surgery (intraoperative blood transfusions, iBT) or during the first 30 days after surgery (post-operative blood transfusions, pBT). The association of iBT and pBT with recurrence-free survival (RFS), cancer-specific survival (CSS) and overall survival (OS) were evaluated by univariate and multivariate regression analysis. RESULTS: A total of 635 patients were included in the study. Overall, 35/635 patients (5.51%) received iBT while 70/635 (11.0%) received pBT. After a mean follow-up of 23±18 months, 116 patients (18.3%) had died, including 96 (15.1%) from bladder cancer. Recurrence occurred in 146 patients (23%). iBT were associated with decreased RFS, CSS and OS (P<0.001) on univariate Cox analysis. After adjusting for clinicopathologic covariates, iBT were associated only with the risk of recurrence (HR: 1.7; 95% CI, 1.0-2.8, P=0.04). pBT were not significantly associated to RFS, CSS or OS on univariate and multivariate Cox regression models (P>0.05). CONCLUSIONS: In the present study, patients treated by RARC with ICUD for UCB have a higher risk of recurrence after iBT, yet no significant association with CSS and OS was found. pBT are not associated with worse oncological prognosis.

Photoelectrochemical C-H Activation Through a Quinacridone Dye Enabling Proton-Coupled Electron Transfer.

Dye-sensitized photoanodes for C-H activation in organic substrates are assembled by vacuum sublimation of a commercially available quinacridone (QNC) dye in the form of nanosized rods onto fluorine-doped tin oxide (FTO), TiO2 , and SnO2 slides. The photoanodes display extended absorption in the visible range (450-600 nm) and ultrafast photoinduced electron injection (<1 ps, as revealed by transient absorption spectroscopy) of the QNC dye into the semiconductor. The proton-coupled electron-transfer reactivity of QNC is exploited for generating a nitrogen-based radical as its oxidized form, which is competent in C-H bond activation. The key reactivity parameter is the bond-dissociation free energy (BDFE) associated with the N⋅/N-H couple in QNC of 80.5±2.3 kcal mol-1 , which enables hydrogen atom abstraction from allylic or benzylic C-H moieties. A photoelectrochemical response is indeed observed for organic substrates characterized by C-H bonds with BDFE below the 80.5 kcal mol-1 threshold, such as γ-terpinene, xanthene, or dihydroanthracene. This work provides a rational, mechanistically oriented route to the design of dye-sensitized photoelectrodes for selective organic transformations.

Cost-analysis of robot-assisted radical cystectomy in Europe: A cross-country comparison.

BACKGROUND: Robotic-assisted radical cystectomy (RARC) with intracorporeal urinary diversion (ICUD) is surging worldwide. Aim of the study was to perform a multicentric cost-analysis of RARC by comparing the gross cost of the intervention across hospitals in four different European countries. METHODS: Patients who underwent RARC + ICUD were recruited from eleven European centers in four European countries (Belgium, France, Netherlands, and UK) between 2015 and 2020. Costs were divided into six parts: cost for hospital stay, cost for ICU stay, cost for surgical theater occupation, cost for transfusion, cost for robotic instruments, and cost for stapling instruments. These costs were individually assessed for each patient. RESULTS: A total of 490 patients were included. Median operative time was 300(270-360) minutes and median hospital length-of-stay was 11(8-15) days. The average total cost of RARC was 14.794€ (95%CI 14.300-15.200€). A significant difference was found for the total cost, as well as the various subcosts abovementioned, between the four included countries. Different sets and types of robotic instruments were used by each center, leading to a difference in cost of robotic instrumentation. Nearly 84% of costs of RARC were due to hospital stay (42%), ICU stay (3%) and operative time (39%), while 16% of costs were due to robotic (8%) and stapling (8%) instruments. CONCLUSION: Costs and subcosts of RARC + ICUD vary significantly across European countries and are mainly dependent of hospital length-of-stay and operative time rather than robotic instrumentation. Decreasing length-of-stay and reducing operative time could help to decrease the cost of RARC and make it more widely accessible.

Validation of a Novel Three-Dimensional (3D Fusion) Gross Sampling Protocol for Clear Cell Renal Cell Carcinoma to Overcome Intratumoral Heterogeneity: The Meet-Uro 18 Study.

We aimed to overcome intratumoral heterogeneity in clear cell renal cell carcinoma (clearRCC). One hundred cases of clearRCC were sampled. First, usual standard sampling was applied (1 block/cm of tumor); second, the whole tumor was sampled, and 0.6 mm cores were taken from each block to construct a tissue microarray; third, the residual tissue, mapped by taking pieces 0.5 × 0.5 cm, reconstructed the entire tumor mass. Precisely, six randomly derived pieces of tissues were placed in each cassette, with the number of cassettes being based on the diameter of the tumor (called multisite 3D fusion). Angiogenic and immune markers were tested. Routine 5231 tissue blocks were obtained. Multisite 3D fusion sections showed pattern A, homogeneous high vascular density (10%), pattern B, homogeneous low vascular density (8%) and pattern C, heterogeneous angiogenic signatures (82%). PD-L1 expression was seen as diffuse (7%), low (33%) and absent (60%). Tumor-infiltrating CD8 scored high in 25% (pattern hot), low in 65% (pattern weak) and zero in 10% of cases (pattern desert). Grading was upgraded in 26% of cases (G3-G4), necrosis and sarcomatoid/rhabdoid characters were observed in, respectively, 11 and 7% of cases after 3D fusion (p = 0.03). CD8 and PD-L1 immune expressions were higher in the undifferentiated G4/rhabdoid/sarcomatoid clearRCC subtypes (p = 0.03). Again, 22% of cases were set to intermediate to high risk of clinical recurrence due to new morphological findings of all aggressive G4, sarcomatoid/rhabdoid features by using 3D fusion compared to standard methods (p = 0.04). In conclusion, we propose an easy-to-apply multisite 3D fusion sampling that negates bias due to tumor heterogeneity.

A Fully Linear Response G0W0 Method That Scales Linearly up to Tens of Thousands of Cores.

We present a G0W0 approach that is based on the evaluation of the linear response of the actions of the G0 and W0 operators. In this way we avoid sums over empty one-particle orbitals and do not have to explicitly develop the screened Coulomb interaction W0 on a dedicated basis. For a given orbital, the self-energy is found by summing terms relative to a set of points in the real-space simulation cell. This permits us to easily control the ratio of the accuracy to the computational cost. A trivial parallelization strategy allows strong linear scaling up to tens of thousands of computing cores.

Defining the Morbidity of Robot-Assisted Radical Cystectomy with Intracorporeal Urinary Diversion: Adoption of the Comprehensive Complication Index.

Background and Objective: The Clavien-Dindo Classification (CDC) only reports the postoperative complication of highest grade. It is thus of limited value for radical cystectomy, after which patients usually experience multiple complications. The Comprehensive Complication Index (CCI) is a novel scoring system, which incorporates all postoperative events in one single value. The study aimed to adopt the CCI for the evaluation of complications in patients undergoing robot-assisted radical cystectomy (RARC) with intracorporeal urinary diversion (ICUD) and explore its advantages in the analysis of the morbidity of RARC with ICUD. Patients and Methods: A multicentric cohort of 959 patients undergoing RARC+ICUD between 2015 and 2020, whose complications are encoded in local prospective registries. Postoperative complications at 30 days were assessed using both the CDC and CCI. The CCI was calculated using an online tool (assessurgery.com). Risk factors for overall, major complications (CDC ≥III), and CCI were evaluated using uni- and multivariable logistic and linear regressions. To analyze the potential advantage of using the CCI in clinical trials, a sample size calculation of a hypothetic clinical trial was performed using as endpoint reduction of morbidity with either the CDC or CCI. Results: Overall, 885 postoperative complications were reported in 507 patients (53%). The CCI improved the definition of postoperative morbidity in 22.6% of patients. Male sex and neobladder were associated with major complications and to a significant increase in CCI on adjusted regressions. In a hypothetical clinical trial, 80 patients would be needed to demonstrate a ten-point reduction in CCI, compared with 186 needed to demonstrate an absolute risk reduction of 20% in overall morbidity using the CDC. Conclusion: CCI improves the evaluation of postoperative morbidity by considering the cumulative aspect of complications compared with the CDC. Implementing the CCI for radical cystectomy would help reducing sample sizes in clinical trials. Clinical Trial Registration number: NCT03049410.

Optical van-der-Waals forces in molecules: from electronic Bethe-Salpeter calculations to the many-body dispersion model.

Molecular forces induced by optical excitations are connected to a wide range of phenomena, from chemical bond dissociation to intricate biological processes that underpin vision. Commonly, the description of optical excitations requires the solution of computationally demanding electronic Bethe-Salpeter equation (BSE). However, when studying non-covalent interactions in large-scale systems, more efficient methods are desirable. Here we introduce an effective approach based on coupled quantum Drude oscillators (cQDO) as represented by the many-body dispersion model. We find that the cQDO Hamiltonian yields semi-quantitative agreement with BSE calculations and that both attractive and repulsive optical van der Waals (vdW) forces can be induced by light. These optical-vdW interactions dominate over vdW dispersion in the long-distance regime, showing a complexity that grows with system size. Evidence of highly non-local forces in the human formaldehyde dehydrogenase 1MC5 protein suggests the ability to selectively activate collective molecular vibrations by photoabsorption, in agreement with recent experiments.

The Intraoperative Complications Assessment and Reporting with Universal Standards (ICARUS) Global Surgical Collaboration Project: Development of Criteria for Reporting Adverse Events During Surgical Procedures and Evaluating Their Impact on the Postoperative Course.

BACKGROUND: Intraoperative adverse events (iAEs) are surgical and anesthesiologic complications. Despite the availability of grading criteria, iAEs are infrequently reported in the surgical literature and in cases for which iAEs are reported, these events are described with significant heterogeneity. OBJECTIVE: To develop Intraoperative Complications Assessment and Reporting with Universal Standards (ICARUS) Global Surgical Collaboration criteria to standardize the assessment, reporting, and grading of iAEs. The ultimate aim is to improve our understanding of the nature and frequency of iAEs and our ability to counsel patients regarding surgical procedures. DESIGN, SETTING, AND PARTICIPANTS: The present study involved the following steps: (1) collecting criteria for assessing, reporting, and grading of iAEs via a comprehensive umbrella review; (2) collecting additional criteria via a survey of a panel of experienced surgeons (first round of a modified Delphi survey); (3) creating a comprehensive list of reporting criteria; (4) combining criteria acquired in the first two steps; and (5) establishing a consensus on clinical and quality assessment utility as determined in the second round of the Delphi survey. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Panel inter-rater agreement and consistency were assessed as the overall percentage agreement and Cronbach's α. RESULTS AND LIMITATIONS: The umbrella review led to nine common criteria for assessing, grading, and reporting iAEs, and review of iAE grading systems led to two additional criteria. In the first Delphi round, 35 surgeons responded and two criteria were added. In the second Delphi round, 13 common criteria met the threshold for final guideline inclusion. All 13 criteria achieved the consensus minimum of 70%, with agreement on the usefulness of the criteria for clinical and quality improvement ranging from 74% to 100%. The mean inter-rater agreement was 89.0% for clinical improvement and 88.6% for quality improvement. CONCLUSIONS: The ICARUS Global Collaboration criteria might aid in identifying important criteria when reporting iAEs, which will support all those involved in patient care and scientific publishing. PATIENT SUMMARY: We consulted a panel of experienced surgeons to develop a set of guidelines for academic surgeons to follow when publishing surgical studies. The surgeon panel proposed a list of 13 criteria that may improve global understanding of complications during specific procedures and thus improve the ability to counsel patients on surgical risk.

Immediate radical cystectomy versus BCG immunotherapy for T1 high-grade non-muscle-invasive squamous bladder cancer: an international multi-centre collaboration.

PURPOSE: To compare cancer-specific mortality (CSM) and overall mortality (OM) between immediate radical cystectomy (RC) and Bacillus Calmette-Guérin (BCG) immunotherapy for T1 squamous bladder cancer (BCa). METHODS: We retrospectively analysed 188 T1 high-grade squamous BCa patients treated between 1998 and 2019 at fifteen tertiary referral centres. Median follow-up time was 36 months (interquartile range: 19-76). The cumulative incidence and Kaplan-Meier curves were applied for CSM and OM, respectively, and compared with the Pepe-Mori and log-rank tests. Multivariable Cox models, adjusted for pathological findings at initial transurethral resection of bladder (TURB) specimen, were adopted to predict tumour recurrence and tumour progression after BCG immunotherapy. RESULTS: Immediate RC and conservative management were performed in 20% and 80% of patients, respectively. 5-year CSM and OM did not significantly differ between the two therapeutic strategies (Pepe-Mori test p = 0.052 and log-rank test p = 0.2, respectively). At multivariable Cox analyses, pure squamous cell carcinoma (SqCC) was an independent predictor of tumour progression (p = 0.04), while concomitant lympho-vascular invasion (LVI) was an independent predictor of both tumour recurrence and progression (p = 0.04) after BCG. Patients with neither pure SqCC nor LVI showed a significant benefit in 3-year recurrence-free survival and progression-free survival compared to individuals with pure SqCC or LVI (60% vs. 44%, p = 0.04 and 80% vs. 68%, p = 0.004, respectively). CONCLUSION: BCG could represent an effective treatment for T1 squamous BCa patients with neither pure SqCC nor LVI, while immediate RC should be preferred among T1 squamous BCa patients with pure SqCC or LVI at initial TURB specimen.

Variant histologies in bladder cancer: Does the centre have an impact in detection accuracy?

OBJECTIVE: To compare the accuracy in detecting variant histologies (VH) at transurethral resection of bladder (TURB) and radical cystectomy (RC) specimen among tertiary referral centres, in order to investigate potential reasons of discrepancies from the pathological point of view. PATIENTS AND METHODS: Clinical and histopathological data of TURB specimen and subsequent cystectomy specimen of 3,445 RC candidate patients have been retrospectively collected from 24 tertiary referral centres between 1980 and 2021. VH considered in the analysis were pure squamous cell carcinoma, urothelial carcinoma with squamous differentiation, pure adenocarcinoma, urothelial carcinoma with glandular differentiation, micropapillary bladder cancer (BCa), neuroendocrine BCa, and other variants. The degree of agreement between TURB and RC concerning the identification of VH was expressed as concordance, classified according to Cohen's kappa coefficient. RESULTS: A VH was reported in 17% of TURB specimens, 45% of which were not confirmed in RC. The lowest concordance rate was reported for micropapillary BCa with 11 out of 18 (61%) centres reporting no agreement, whereas neuroendocrine BCa achieved the highest concordance rate with only 3 centres (17%) reporting no agreement. Our results shows that even among centres with the advantage of a referent uropathologist the micropapillary variant is characterized by scarce accuracy between TURB and RC. Differences in TURB specimen acquisition by the urologist and in sampling methods among different centres are the main limitations of the study. CONCLUSIONS: Accuracy of TURB in detecting VH is poor for certain VH, in particular for micropapillary BCa, with evident variation among centres. Novel diagnostic tools are required to better identify these VH and drive patients toward a personalized treatment.

Continuing acetylsalicylic acid during Robotic-Assisted Radical Cystectomy with intracorporeal urinary diversion does not increase hemorrhagic complications: results from a large multicentric cohort.

OBJECTIVES: To evaluate whether continuing the antiplatelet drug acetylsalicylic acid≤100mg (ASA) during Robotic-assisted radical cystectomy (RARC) with intracorporeal urinary diversion (ICUD) increases the risk of peri-and postoperative hemorrhagic complications and overall morbidity. Indeed, guidelines recommend interrupting antiplatelet therapy before radical cystectomy; however, RARC with ICUD is associated to reduced estimated blood loss and blood transfusions compared to its open counterpart. METHODS: Data from a multicentric European database were analyzed. All participating centers maintained a prospective database of patients undergoing RARC with ICUD. We identified patients receiving antiplatelet therapy by acetylsalicylic acid ≤100mg. Patients were divided into three groups: those not taking acetylsalicylic acid (no-ASA), those where ASA was continued perioperatively (c-ASA) and those where ASA was interrupted perioperatively (i-ASA). Estimated blood loss and peri-and post-operative transfusions were recorded. Hemorrhagic complications, ischemic, thrombotic and cardiac morbidity was recorded and classified using the Clavien-Dindo score by a senior urologist. RESULTS: 640 patients were analyzed. Patients on acetylsalicylic acid were significantly older and had more comorbidities. No significant difference was found for estimated blood loss between no-ASA, c-ASA and i-ASA (280 vs. 300 vs. 200ml respectively; P = 0.09). Similarly, no significant difference was found for intraoperative (5% vs. 9% vs. 11%; P = 0.07) and postoperative transfusion rate (11% vs. 13% vs. 18%; P = 0.17). Higher ischemic complications were noted in the i-ASA group compared to no-ASA and c-ASA (4% vs. 0.6% vs. 1.4%; P = 0.03). On uni and multivariate logistic regression, continuing acetylsalicylic acid was not significantly associated to either major complications or post-operative transfusions. CONCLUSIONS: Peri-operative acetylsalicylic acid continuation in RARC with ICUD does not increase hemorrhagic complications. Interrupting acetylsalicylic acid peri-operatively may expose patients to a higher risk of ischemic events.

Assessment of predictors of renal cell carcinoma progression after nephrectomy at short- and medium-term follow-up and implication on surveillance protocols.

BACKGROUND: Prediction of risk of RCC progression after surgery is important for follow-up planning. We identified predictors of progression-free survival (PFS) and cancer-specific survival (CSS) in a large single institutional cohort and investigated patterns and sites of progression according to stage and grade. METHODS: Node-negative non-metastatic clear-cell RCC (ccRCC) patients treated with radical or partial nephrectomy from 2000 to 2020 were included. Sites of progression were defined as thoracic, abdominal and others (bone/brain). Kaplan-Meier curves and multivariable Cox regression (MCR) models tested for PFS and CSS. RESULTS: Of 384 clear cell RCC N0M0 patients, 301 (78.4%) vs. 83 (21.6%) were pT1-2 vs. pT3-4, respectively; 253 (65.9%) vs. 130 (33.9%) were G1-G2 vs. G3-G4. Thoracic progressions occurred in 2.7% pT1-T2 vs. 21.7% pT3-T4 and 2.8% G1-G2 vs. 14.6% G3-G4 tumors. Abdominal progressions occurred in 4.0% pT1-T2 vs. 13.3% pT3-T4 and 4.3% G1-G2 vs. 9.2% G3-G4. Other progressions occurred in 0.3% pT1-T2 vs. 9.6% pT3-T4 and 0.8% G1-G2 vs. 5.4% G3-G4 (5.4%). Five-year PFS and CSS were 81.7 and 90.6%, respectively. At MCR models, pT3-4 (HR 9.1, P<0.001), G3-G4 (HR 2.7, P=0.003) and PSMs (HR 6.1, P<0.001) independently predicted PFS. Similarly, pT3-4 (HR 10.1, P<0.001), G3-G4 (HR 4.1, P=0.02), and PSMs (HR 5.2, P=0.04) independently predicted CSS. CONCLUSIONS: In ccRCC N0M0 patients, G3-G4, pT3-4, PSMs were independent predictors of progression after surgery. Lower stage and grade ccRCCs progress predominantly in the abdominal sites and may be followed with less frequent extra-abdominal imaging compared to more advanced/aggressive tumors.

Oncological outcomes of active surveillance and percutaneous cryoablation of small renal masses are similar at intermediate term follow-up.

BACKGROUND: Active surveillance (AS) and minimally invasive ablative therapies such as percutaneous cryoablation (PCA) are emerging as alternative treatment modalities in the management of small renal masses (SRMs). METHODS: Fifty-nine patients underwent PCA since 2011 and 75 underwent AS since 2010 at two different institutions. Only patients with follow-up ≥6 months were included. All patients were followed with a standardized protocol. Treatment failure was defined by dimensional progression for AS and renal recurrence for PCA, in addition to stage and/or metastatic progression for both groups. RESULTS: Treatment failure was observed in 14 cases (18.7%) during AS (mainly due to dimensional progression) and 12 patients (16%) underwent delayed intervention with a mean follow-up of 36.83 months. Seven patients (11.9%) in the PCA group experienced treatment failure with a mean follow-up of 33.39 months and three of them underwent re-ablation successfully. Cancer-specific-survival at 2 and 5 years was 100% and 95,8% in AS-group vs. 98.2% and 98.2% in PCA-group (P=0.831). One patient in both groups died from metastatic disease. Overall-survival at 2 and 5 years was 91.7% and 82.4% in the AS group vs. 96.5% and 96.5% in the PCA group (P=0.113). Failure-free survival at 2 and 5 years was 90.9% and 70.1% in the AS group vs. 93.1% and 70.9% in the PCA group (P=0.645). CONCLUSIONS: AS and PCA provide similar survival outcomes and are safe and valid treatment options for elderly and comorbid patients with SRMs.