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In this short note, we express our viewpoint regarding declaring study success based on Bayesian predictive probability of study success., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Radical cystectomy represents the standard surgical treatment in case of muscle invasive bladder cancer. During the last two decades a change in the surgical approach of the MIBC has been observed, from open surgery to minimal invasive surgery. Nowadays, in the majority of tertiary urologic centers, robotic radical cystectomy with intracorporeal urinary diversion represents the standard surgical approach. The aim of the current study is to describe in detail the surgical steps of the robotic radical cystectomy and the reconstruction of the urinary diversion and to present our experience. From the surgical point of view, the most important principles which should guide the surgeon when performing this procedure are: 1. Good working place and access both to the pelvis and abdomen and use of the "technique of spaces" 2. Respect the oncological principles of the surgery with attention to the margin resection and limitation of the risk of tumour spillage; 3. Attention to both the ureter and bowel manipulation in order to avoid grasping lesions; 4. High care in realisation of the uretero-ileal anastomosis so that good long term functional results are achieved. We analyzed our database of 213 patients diagnosed with muscle invasive bladder cancer who underwent minimally invasive radical cystectomy (laparoscopic and robotic approaches) between January 2010 and December 2022. We identified 25 patients for whom the robotic approach was used to perform the surgery. Despite being one of the most challenging urologic surgical procedures, with careful preparation and training, the surgeon is able to achieve the maximum oncological and functional results by performing robotic radical cystectomy with intracorporeal urinary., (Celsius.)

Background: A recent analysis of a large registry showed differences in periprocedural outcomes of the Watchman left atrial appendage closure device in males compared with females. The objective of our study was to investigate the 5-year event rate in males and females enrolled in the Watchman device premarket clinical studies submitted for US Food and Drug Administration review., Methods: We conducted a patient-level meta-analysis of 2256 patients from 4 studies: the PROTECT AF (Embolic Protection in Patients with Atrial Fibrillation) and PREVAIL (Prospective Randomized Evaluation of the Watchman Left Atrial Appendage Closure Device in Patients with Atrial Fibrillation vs Long-Term Warfarin Therapy) randomized controlled trials and their continued-access registries-CAP1 (Continued Access to PROTECT AF) and CAP2 (Continued Access to PREVAIL). The outcomes evaluated were ischemic stroke (IS), IS/systemic embolism, hemorrhagic stroke (HS), and all-cause mortality. Mixed-effects Cox regression models and statistical testing for treatment-by-sex interaction were used to compare left atrial appendage closure vs warfarin in males and females. Hazard ratios adjusted (aHRs) for CHADS 2 scores were generated using the same model with CHADS 2 score as a covariate. Time-to-event end points were evaluated using the Kaplan-Meier method and log-rank test., Results: For Watchman vs warfarin in the 2 randomized controlled trials, there was no significant interaction between sex and treatment for IS, IS/systemic embolism, HS, and all-cause mortality ( P > .05); both males and females in the Watchman group had a lower aHR for HS than that in the warfarin group, which was statistically significant for males (aHR, 0.163; 95% CI, 0.045-0.593). In addition, there were no differences in outcomes between females and males treated with the Watchman device when pooling all studies., Conclusions: These data suggest that sex does not significantly affect the long-term safety and effectiveness of the Watchman device in patients with nonvalvular atrial fibrillation; however, further studies are needed.

Background and objectives: Systematic prostate biopsy (SB) has a low Gleason group (GG) accuracy when compared to final pathology. This may negatively impact the inclusion of patients into specific risk groups and treatment choice. The aim of our study was to assess the GG accuracy of magnetic resonance imaging-ultrasound (MRI-US) fusion prostate biopsy. Materials and Methods: Of a cohort of minimally invasive radical prostatectomy (RP), we selected all patients who were diagnosed with prostate cancer (PCa) via MRI-US fusion biopsy ( n = 115). Results: Combined biopsy had the highest rate for GG concordance (61.7% vs. 60.4% for SB vs. 45.3% for MRI-US fusion biopsy) and the lowest for upgrading (20.9% vs. 24.5% for SB vs. 34.9% for MRI-US fusion biopsy), p < 0.0001. No clinical data were predictive for upgrading or downgrading at final pathology. Locally advanced PCa was associated with a high Prostate Imaging-Reporting and Data System (PIRADS) score ( p = 0.0014) and higher percentages of positive biopsy cores (PBC)/targeted ( p = 0.0002) and PBC/total ( p = 0.01). Positive surgical margins were correlated with higher percentages of PBC/systematic ( p = 0.003) and PBC/total ( p = 0.009). Conclusions: Pre-biopsy prostate MRI improves GG concordance between biopsy and RP. Combined biopsy provides the highest grading accuracy when compared to final pathology. Targeted and systematic biopsy data are predictive for adverse pathologic outcomes.

Background: The aim of the current study was to evaluate and compare the learning curves of transrectal magnetic resonance imaging-ultrasound fusion biopsy for two urologists with different backgrounds (Operator 1: experienced, self-trained and Operator 2: novice, trained by a mentor/MRI reading courses)., Methods: A cohort of 400 patients who underwent fusion prostate biopsy in our department was analyzed. The learning curves were assessed in terms of overall and clinically significant prostate cancer (PCa) detection rates, percentage of positive biopsy cores/targeted and the percentage of PCa tissue on positive targeted cores., Results: Increasing trends were observed for both urologists in terms of all biopsy outcomes during the study time. For the novice urologist, a significant increase was observed for overall PCa detection rate, but not for clinically significant disease (25.44%, P=0.04/15%, P=0.145). Operator 1 showed an increasing diagnosis yield of clinically significant disease up to 104 cases. Similar cancer detection rates were observed when comparing the first and last biopsies performed by both operators. Multivariate analysis adjusted for age, PSA, prostate volume, lesion diameter and PIRADS score showed an increase of PCa detection with 51% for every 52 biopsies performed (P=0.022)., Conclusions: When starting with magnetic resonance imaging-ultrasound fusion prostate biopsy, mentoring and prostate magnetic resonance imaging reading training allow a novice urologist to demonstrate a good initial PCa detection rate. After about 52 cases, he reached a stable PCa and clinically significant PCa detection rate, that was similar to that of an experienced urologist., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tau-21-8). The authors have no conflicts of interest to declare., (2021 Translational Andrology and Urology. All rights reserved.)

Multiparametric magnetic resonance imaging (MRI) and MRI-guided prostate biopsy have become the standard for pros-tate cancer diagnosis. As their implementation is relatively recent, experience is still limited in various centres. MRI-guided biopsy requires basic knowledge in prostate MRI and ultrasound (US), but also in the image processing protocol specific for each device. Standardization of the method is needed to ensure the best results in terms of diagnosis accuracy. We hereby pre-sent our technique for MRI-US fusion guided prostate biopsy and the outcomes after performing more than 600 procedures.

(1) Introduction: The advent of robotic surgery led to the assumption that laparoscopic surgery would be replaced entirely. However, the high costs of robotic surgery limit its availability. The aim of the current study was to assess the feasibility of the 3D laparoscopic approach for the most complex urological procedures. (2) Materials and methods: We included in the current study all patients who had undergone complex 3D laparoscopic procedures in our department since January 2017, including radical nephrectomy (LRN) using a dual combined approach (19 patients), radical nephroureterectomy (LRNU) with bladder cuff excision (13 patients), and radical cystectomy (LRC) with intracorporeal urinary diversion (ICUD) (21 patients). (3) Results: The mean operative time was 345/230/478 min, the complications rate was 26%/30.76%/23.8% and positive surgical margins were encountered in 3/1/1 patients for the combined approach of LRN/LRNU/LRC with ICUD, respectively. A single patient was converted to open surgery during LRN due to extension of the vena cava thrombus above the hepatic veins. After LRC, sepsis was the most common complication and 8 patients were readmitted at a mean of 15.5 days after discharge. (4) Conclusions: In the era of robotic surgery, laparoscopy remains a plausible alternative for most complex oncological cases.

Purpose: Clinical development of cancer drugs has a low success rate. Prognostic and predictive biomarkers using minimally invasive approaches hold promise for increasing the probability of success by enabling disease characterization, patient selection and early detection of drug treatment effect. Enumeration and molecular characterization of circulating tumor cells (CTC) may address some of these needs, and thus were evaluated for utility in a Phase I solid tumor clinical study., Experimental Design: Blood samples for CTC analysis were obtained from 24 cancer patients in a multi-center all-comer Phase I study of MEDI-575, a novel anti-PDGFRα antibody. Samples were taken at screening and analyzed for enumeration of CTC using the CellSearch(®) platform and for molecular characterization using a novel quantitative RT-PCR assay., Results: Fifty-nine percent of the patients showed at least 1 CTC per 7.5 ml of blood at baseline. Progression-free survival (PFS) and overall survival (OS) of patients with 0 CTCs at baseline were longer than PFS and Os for patients with 1-3 and >3 CTCs (8.8 versus 1.4 and 1.3 months PFS, P = 0.02; 9.0 vs 7.4 and 3.5 months OS, P = 0.20, respectively). Patients with 0 CTC showed a greater percentage of stable disease than the other 2 groups with 1-3 and >3 CTCs (57% vs 29% and 0%). The multimarker qRT-PCR method detected CTC in 40% of the patients, and 80% of these patients were positive for pre-selected drug target genes., Conclusion: CTC enumeration of patients in an all-comer study is feasible and may allow for patient stratification for PFS and Os to evaluate the clinical response of investigational agents. Gene expression profiling of isolated CTC may provide a means for molecular characterization of selected tumor targets.

Background: Targeting the cell-surface receptor EphA2, which is highly expressed in some solid tumors, is a novel approach for cancer therapy. We aimed to evaluate the safety profile, maximum tolerated dose (MTD), pharmacokinetics, and antitumor activity of MEDI-547, an antibody drug conjugate composed of the cytotoxic drug auristatin (toxin) linked to a human anti-EphA2 monoclonal antibody (1C1), in patients with solid tumors relapsed/refractory to standard therapy., Methods: In this phase 1, open-label study with planned dose-escalation and dose-expansion cohorts, patients received a 1-h intravenous infusion of MEDI-547 (0.08 mg/kg) every 3 weeks., Results: Six patients received 0.08 mg/kg; all discontinued treatment. Dose escalation was not pursued. The study was stopped before cohort 2 enrollment due to treatment-related bleeding and coagulation events (hemorrhage-related, n = 3; epistaxis, n = 2). Therefore, lower doses were not explored and an MTD could not be selected. The most frequently reported treatment-related adverse events (AEs) were increased liver enzymes, decreased hemoglobin, decreased appetite, and epistaxis. Three patients (50%) experienced treatment-related serious AEs, including conjunctival hemorrhage, pain (led to study drug discontinuation), liver disorder, and hemorrhage. Best response included progressive disease (n = 5; 83.3%) and stable disease (n = 1; 16.7%). Minimal or no dissociation of toxin from 1C1 conjugate occurred in the blood. Serum MEDI-547 concentrations decreased rapidly, ~70% by 3 days post-dose. No accumulation of MEDI-547 was observed at 0.08 mg/kg upon administration of a second dose 3 weeks following dose 1., Conclusions: The safety profile of MEDI-547 does not support further clinical investigation in patients with advanced solid tumors.

AlphaVbeta3 (alphavbeta3) is an important molecule for tumor-induced angiogenesis and is upregulated in metastatic melanoma (MM). We proposed to study the mechanism of action of etaracizumab, a monoclonal antibody targeting alphavbeta3, in MM. Patients with MM and biopsiable tumor were treated with etaracizumab in 3 dose cohorts starting from 8 mg/kg. Tumor saturation by etaracizumab using LM609 immunohistochemical staining of tumor sections was the primary endpoint. Subsequent dose cohorts were defined based on the tumor saturation by etaracizumab. Secondary end points were analysis of clinical benefit and changes from baseline of several tumor and peripheral blood biomarkers. Eighteen patients were enrolled at 3 dose levels. Etaracizumab showed better melanoma cell saturation at the 8mg/kg and 1 mg/kg dose compared with the 4 mg/kg dose and better vascular endothelial cell saturation at 8 mg/kg compared with lower dose groups. Etaracizumab demonstrated an acceptable safety profile. The optimal biologic dose out of those selected for investigation was 8 mg/kg. Patients treated at the highest dose may have had better clinical benefit secondary to suppression of the activated immediate downstream effector of alphavbeta3 signaling, FAK, in melanoma cells, but this alone did not ultimately affect melanoma cell proliferation or apoptosis. No apparent antiangiogenic or immunomodulatory effects of etaracizumab were noted.

Bayesian experimental design for a clinical trial involves specifying a utility function that models the purpose of the trial, in this case the selection of patients for a diagnostic test. The best sample of patients is selected by maximizing expected utility. This optimization task poses difficulties due to a high-dimensional discrete design space and, also, to an expected utility formula of high complexity. A simulation-based optimal design method is feasible in this case. In addition, two deterministic algorithms that perform a systematic search over the design space are developed to address the computational issues.

Obtaining accurate estimates of the performance of a diagnostic test for some population of patients might be difficult when the sample of subjects used for this purpose is not representative for the whole population. Thus, in the motivating example of this paper a test is evaluated by comparing its results with those given by a gold standard procedure, which yields the disease status verification. However, this procedure is invasive and has a non-negligible risk of serious complications. Moreover, subjects are selected to undergo the gold standard based on some risk factors and the results of the test under study. The test performance estimates based on the selected sample of subjects are biased. This problem was presented in previous studies under the name of verification bias. The current paper introduces a Bayesian method to adjust for this bias, which can be regarded as a missing data problem. In addition, it addresses the case of non-ignorable verification bias. The proposed Bayesian estimation approach provides test performance estimates that are consistent with the results obtained using likelihood-based approach. In addition, the paper studies how valuable the statistical findings are from the perspective of clinical decision making., ((c) 2007 John Wiley & Sons, Ltd.)

Bronchiolitis obliterans syndrome (BOS) represents a major limitation in lung transplantation. While acute rejection is widely considered the most important risk factor for BOS, the impact of HLA-specific antibodies is less understood. Of 51 lung recipients who were prospectively tested during a 4.2 +/- 1.6-year period, 14 patients developed HLA-specific antibodies. A multi-factorial analysis was performed to correlate the prevalence of BOS with HLA antibodies, persistent-recurrent acute rejection (ACR-PR), lymphocytic bronchiolitis, and HLA-A, -B, and -DR mismatches. HLA-specific antibodies were associated with ACR-PR (10/14 vs. 11/37 with no antibodies, p < 0.05), lymphocytic bronchiolitis (8/14 vs. 10/37, p < 0.05), and BOS (10/14, vs. 9/37, p < 0.005). Other risk factors for BOS were: lymphocytic bronchiolitis (13/18 vs. 6/33 with no lymphocytic bronchiolitis, p < 0.0001), ACR-PR (12/21 vs. 7/30 with no ACR-PR, p < 0.05), and the number of HLA-DR mismatches (1.7 +/- 0.48 in BOS vs. 1.2 +/- 0.63 without BOS, p < 0.05). The presence of antibodies exhibited a cumulative effect on BOS when it was associated with either lymphocytic bronchiolitis or ACR-PR. The complex relationship between the development of HLA antibodies and acute and chronic lung allograft rejection determines the importance of post-transplant screening for HLA-specific antibodies as a prognostic element for lung allograft outcome.

To ensure and to confirm the required traceability according to the definition given in the International Vocabulary of Basic and Standard Terms in Metrology, three main aspects need to be considered in practice: "stated reference", "unbroken chain of calibration" and "stated uncertainty". For a certain spectrochemical result, each of the aspects above mentioned is highly dependent on measurement uncertainty, both on its magnitude and how it was estimated. The paper describes the experience of the Romanian National Institute of Metrology (INM) in estimating measurement uncertainty during certification of reference materials, in metrological calibration and during specific analytical processes. Practical examples of the use of reference materials or certified reference materials issued by the INM to estimate measurement uncertainty are discussed for their applicability in spectrochemical and turbidity analysis. Some aspects of the use of analysis of variance (ANOVA) to obtain additional information on the components of measurement uncertainty and to identify the magnitude of individual random effects are presented.