Summary Background We previously reported the learning curve for open radical prostatectomy, reporting large decreases in recurrence rates with increasing surgeon experience. Here we aim to ...characterise the learning curve for laparoscopic radical prostatectomy. Methods We did a retrospective cohort study of 4702 patients with prostate cancer treated laparoscopically by one of 29 surgeons from seven institutions in Europe and North America between January, 1998, and June, 2007. Multivariable models were used to assess the association between surgeon experience at the time of each patient's operation and prostate-cancer recurrence, with adjustment for established predictors. Findings After adjusting for case mix, greater surgeon experience was associated with a lower risk of recurrence (p=0·0053). The 5-year risk of recurrence decreased from 17% to 16% to 9% for a patient treated by a surgeon with 10, 250, and 750 prior laparoscopic procedures, respectively (risk difference between 10 and 750 procedures 8·0%, 95% CI 4·4–12·0). The learning curve for laparoscopic radical prostatectomy was slower than the previously reported learning curve for open surgery (p<0·001). Surgeons with previous experience of open radical prostatectomy had significantly poorer results than those whose first operation was laparoscopic (risk difference 12·3%, 95% CI 8·8–15·7). Interpretation Increasing surgical experience is associated with substantial reductions in cancer recurrence after laparoscopic radical prostatectomy, but improvements in outcome seem to accrue more slowly than for open surgery. Laparoscopic radical prostatectomy seems to involve skills that do not translate well from open radical prostatectomy. Funding National Cancer Institute, the Allbritton Fund, and the David J Koch Foundation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Objective To develop performance metrics that objectively define a reference approach to a transurethral resection of bladder tumours (TURBT) procedure, seek consensus on the performance metrics from ...a group of international experts. Methods The characterisation of a reference approach to a TURBT procedure was performed by identifying phases and explicitly defined procedure events (i.e., steps, errors, and critical errors). An international panel of experienced urologists (i.e., Delphi panel) was then assembled to scrutinise the metrics using a modified Delphi process. Based on the panel's feedback, the proposed metrics could be edited, supplemented, or deleted. A voting process was conducted to establish the consensus level on the metrics. Consensus was defined as the panel majority (i.e., >80%) agreeing that the metric definitions were accurate and acceptable. The number of metric units before and after the Delphi meeting were presented. Results A core metrics group (i.e., characterisation group) deconstructed the TURBT procedure. The reference case was identified as an elective TURBT on a male patient, diagnosed after full diagnostic evaluation with three or fewer bladder tumours of ≤3 cm. The characterisation group identified six procedure phases, 60 procedure steps, 43 errors, and 40 critical errors. The metrics were presented to the Delphi panel which included 15 experts from six countries. After the Delphi, six procedure phases, 63 procedure steps, 47 errors, and 41 critical errors were identified. The Delphi panel achieved a 100% consensus. Conclusion Performance metrics to characterise a reference approach to TURBT were developed and an international panel of experts reached 100% consensus on them. This consensus supports their face and content validity. The metrics can now be used for a proficiency‐based progression training curriculum for TURBT.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
This paper studies the problem of the dynamic scaling and load balancing of transparent virtualized network functions (VNFs). It analyzes different particularities of this problem, such as loop ...avoidance when performing scaling-out actions, and bidirectional flow affinity. To address this problem, a software-defined networking (SDN)-based solution is implemented consisting of two SDN controllers and two OpenFlow switches (OFSs). In this approach, the SDN controllers run the solution logic (i.e., monitoring, scaling, and load-balancing modules). According to the SDN controllers instructions, the OFSs are responsible for redirecting traffic to and from the VNF clusters (i.e., load-balancing strategy). Several experiments were conducted to validate the feasibility of this proposed solution on a real testbed. Through connectivity tests, not only could end-to-end (E2E) traffic be successfully achieved through the VNF cluster, but the bidirectional flow affinity strategy was also found to perform well because it could simultaneously create flow rules in both switches. Moreover, the selected CPU-based load-balancing method guaranteed an average imbalance below 10% while ensuring that new incoming traffic was redirected to the least loaded instance without requiring packet modification. Additionally, the designed monitoring function was able to detect failures in the set of active members in near real-time and active new instances in less than a minute. Likewise, the proposed auto-scaling module had a quick response to traffic changes. Our solution showed that the use of SDN controllers along with OFS provides great flexibility to implement different load-balancing, scaling, and monitoring strategies.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
High grade non-muscle-invasive bladder tumours are treated with transurethral resection followed by recurrent intravesical instillations of Bacillus Calmette Guérin (BCG). Although most bladder ...cancer patients respond well to BCG, there is no clinical parameter predictive of treatment response, and when treatment fails, the prognosis is very poor. Further, a high percentage of NMIBC patients treated with BCG suffer unwanted effects that force them to stop treatment. Thus, early identification of patients in which BCG treatment will fail is really important. Here, to identify early stage non-invasive biomarkers of non-responder patients and patients at risk of abandoning the treatment, we longitudinally analysed the phenotype of cells released into the urine of bladder cancer patients 3-7 days after BCG instillations. Mass cytometry (CyTOF) analyses revealed a large proportion of granulocytes and monocytes, mostly expressing activation markers. A novel population of CD15
+
CD66b
+
CD14
+
CD16
+
cells was highly abundant in several samples; expression of these markers was confirmed using flow cytometry and qPCR. A stronger inflammatory response was associated with increased cell numbers in the urine; this was not due to hematuria because the cell proportions were distinct from those in the blood. This pilot study represents the first CyTOF analysis of cells recruited to urine during BCG treatment, allowing identification of informative markers associated with treatment response for sub-selection of markers to confirm using conventional techniques. Further studies should jointly evaluate cells and soluble factors in urine in larger cohorts of patients to characterise the arms of the immune response activated in responders and to identify patients at risk of complications from BCG treatment.
infection is an important public health problem. Our objective was to assess the dynamics of the transmission of this infection, analysing the distribution of circulating
genotypes and multilocus ...sequence types of
in Spain as a function of clinical and epidemiological variables. During 2018 and 2019, we genetically characterized
in tertiary hospitals in six areas in Spain (Asturias, Barcelona, Gipuzkoa, Mallorca, Seville and Zaragoza), with a catchment population of 3.050 million people. Genotypes and sequence types were obtained using polymerase chain reaction techniques that amplify a fragment of the
gene, and five highly variable genes (
, CT058, CT144, CT172 and
), respectively. Amplicons were sequenced and phylogenetic analysis was conducted. We obtained genotypes in 636/698 cases (91.1%). Overall and by area, genotype E was the most common (35%). Stratifying by sex, genotypes D and G were more common among men, and genotypes F and I among women (
< 0.05). Genotypes D, G and J were more common in men who have sex with men (MSM) than in men who have sex with women (MSW), in whom the most common genotypes were E and F. The diversity index was higher in sequence typing (0.981) than in genotyping (0.791), and the most common sequence types were ST52 and ST108 in MSM, and ST30, ST148, ST276 and ST327 in MSW. Differences in genotype distribution between geographical areas were attributable to differences in population characteristics. The transmission dynamics varied with sexual behaviour: the predominant genotypes and most frequent sequence types found in MSM were different to those detected in MSW and women.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Correlation between systolic (SBP) and diastolic (DBP) blood pressure (BP) level and target organ damage, cardiovascular disease (CVD) risk, and long-term prognosis is much greater for ambulatory BP ...monitoring (ABPM) than daytime office measurements. The 2013 ABPM guidelines specified herein are based on ABPM patient outcomes studies and constitute a substantial revision of current knowledge. The asleep SBP mean and sleep-time relative SBP decline are the most significant predictors of CVD events, both individually as well as jointly when combined with other ABPM-derived prognostic markers. Thus, they should be preferably used to diagnose hypertension and assess CVD and other associated risks. Progressive decrease by therapeutic intervention of the asleep BP mean is the most significant predictor of CVD event-free interval. The 24-h BP mean is not recommended to diagnose hypertension because it disregards the more valuable clinical information pertaining to the features of the 24-h BP pattern. Persons with the same 24-h BP mean may display radically different 24-h BP patterns, ranging from extreme-dipper to riser types, representative of markedly different risk states. Classification of individuals by comparing office with either the 24-h or awake BP mean as "masked normotensives" (elevated clinic BP but normal ABPM), which should replace the terms of "isolated office" or "white-coat hypertension", and "masked hypertensives" (normal clinic BP but elevated ABPM) is misleading and should be avoided because it disregards the clinical significance of the asleep BP mean. Outcome-based ABPM reference thresholds for men, which in the absence of compelling clinical conditions are 135 85 mmHg for the awake and 120 70 mmHg for the asleep SBP DBP means, are lower by 10 5 mmHg for SBP DBP in uncomplicated, low-CVD risk, women and lower by 15 10 mmHg for SBP DBP in male and female high-risk patients, e.g., with diabetes, chronic kidney disease (CKD), and or past CVD events. In the adult population, the combined prevalence of masked normotension and masked hypertension is >35%. Moreover, >20% of "normotensive" adults have a non-dipper BP profile and, thus, are at relatively high CVD risk. Clinic BP measurements, even if supplemented with home self-measurements, are unable to quantify 24-h BP patterning and asleep BP level, resulting in potential misclassification of up to 50% of all evaluated adults. ABPM should be viewed as the new gold standard to diagnose true hypertension, accurately assess consequent tissue organ, maternal fetal, and CVD risk, and individualize hypertension chronotherapy. ABPM should be a priority for persons likely to have a blunted nighttime BP decline and elevated CVD risk, i.e., those who are elderly and obese, those with secondary or resistant hypertension, and those diagnosed with diabetes, CKD, metabolic syndrome, and sleep disorders. (Author Correspondence: rhermida@uvigo.es or prf@unife.it).
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BFBNIB, GIS, IJS, KISLJ, NUK, PNG, UL, UM, UPUK
ABO blood groups have recently been related to COVID19 infection. In the present work, we performed this analysis using data from 412 COVID19 patients and 17796 blood donors, all of them from ...Gipuzkoa, a region in Northern Spain. The results obtained confirmed this relation, in addition to showing a clear importance of group O as a protective factor in COVID19 disease, with an OR = 0.59 (CI95% 0.481-0.7177, p<0.0001) while A, B and AB are risk factors. ABO blood groups are slightly differently distributed in the populations and therefore these results should be replicated in the specific areas with a proper control population.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objectives
To assess time to progression to castrate‐resistant prostate cancer (CRPC) and factors influencing longer‐term outcomes in patients receiving androgen‐deprivation therapy (ADT) in an ...extension to the Triptocare study (NCT01020448). This is pertinent as the Triptocare study did not show that urinary prostate cancer antigen‐3 (PCA3) score was a reliable marker of cancer stage in advanced prostate cancer and was not useful for assessing response 6 months after initiation of ADT with triptorelin 22.5 mg.
Patients and Methods
An international, multicentre, non‐interventional, observational, longitudinal, prospective study involving patients from the Triptocare study. CRPC status of patients was collected for up to 3 years from ADT initiation. Patient treatment and assessments were at the investigator's discretion. Co‐primary endpoints were rate of CRPC at 3 years after initiating ADT and the median time to CRPC. An exploratory endpoint was the association of Triptocare baseline variables (including TMPRSS2‐ERG and PCA3 scores) and PCA3 score at Triptocare last value available with CRPC onset.
Results
Of the 325 patients in the Triptocare study safety population, 180 patients were enrolled in the Triptocare LT study (102 received continuous and 78 received intermittent ADT). CRPC rates at 3 years were 24/102 (23.5%) and 6/78 (7.7%) patients in the continuous and intermittent ADT groups, respectively. The median time to CRPC was not reached for either group. PCA3 score status at baseline was the only variable associated with a higher risk of progression to CRPC in both the intermittent and continuous ADT groups; compared with a baseline PCA3 score of ≥35, a PCA3 score below the level of quantification had a hazard ratio (HR) of 20.04 (95% confidence interval (CI) 2.71–148.34 and a HR of 9.44 95% CI 2.39–37.27, respectively). Baseline metastatic disease and testosterone level were additionally associated with progression to CRPC in the continuous ADT population (HR 5.20, 95% CI 1.68–16.06 and HR 0.995, 95% CI 0.991–0.999, respectively).
Conclusion
In men with locally advanced or metastatic prostate cancer, a PCA3 score of ≥35 at the time of initiating ADT may predict a lower risk of developing CRPC in the following 3 years.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Von Hippel-Lindau (VHL) syndrome is a rare inherited cancer disease where the lack of VHL protein triggers the development of multisystemic tumors such us retinal hemangioblastomas (HBs), CNS-HBs, ...and clear cell renal cell carcinoma (ccRCC). Since standard therapies in VHL have shown limited response, leaving surgery as the only possible treatment, targeting of the β2-adrenergic receptor (ADRB2) has shown therapeutic antitumor benefits on VHL-retinal HBs (clinical trial), VHL-CNS HBs, and VHL-ccRCC (in vitro and in vivo). In the present study, we wanted to look deep into the effects of the ADRB2 blockers propranolol and ICI-118,551 on two main aspects of cancer progression: (i) the changes on the inflammatory response of ccRCC cells; and (ii) the modulation on the Warburg effect (glycolytic metabolism), concretely, on the expression of genes involved in the cell reactive oxygen species (ROS) balance and levels. Accordingly, in vitro studies with primary VHL-ccRCC and 786-O cells measuring ROS levels, ROS-expression of detoxifying enzymes, and the expression of p65/NF-κB targets by RT-PCR were carried out. Furthermore, histological analyses of ccRCC samples from heterotopic mouse xenografts were performed. The obtained results show that ADRB2 blockade in ccRCC cells reduces the level of oxidative stress and stabilizes the inflammatory response. Thus, these data further support the idea of targeting ADRB2 as a promising strategy for the treatment of VHL and other non-VHL tumors.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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