Folding-Induced Promotion of Proton-Coupled Electron Transfers via Proximal Base for Light-Driven Water Oxidation.

Proton-coupled electron-transfer (PCET) processes play a key role in biocatalytic energy conversion and storage, for example, photosynthesis or nitrogen fixation. Here, we report a series of bipyridine-containing di- to tetranuclear Ru(bda) macrocycles 2 C-4 C (bda: 2,2'-bipyridine-6,6'-dicarboxylate) to promote O-O bond formation. In photocatalytic water oxidation under neutral conditions, all complexes 2 C-4 C prevail in a folded conformation that support the water nucleophilic attack (WNA) pathway with remarkable turnover frequencies of up to 15.5 s-1 per Ru unit respectively. Single-crystal X-ray analysis revealed an increased tendency for intramolecular π-π stacking and preorganization of the proximal bases close to the active centers for the larger macrocycles. H/D kinetic isotope effect studies and electrochemical data demonstrate the key role of the proximal bipyridines as proton acceptors in lowering the activation barrier for the crucial nucleophilic attack of H2 O in the WNA mechanism.

Large area ion beam sputtered dielectric ultrafast mirrors for petawatt laser beamlines.

The latest advances in petawatt laser technology within the ELI Beamlines project have stimulated the development of large surface area dielectrically coated mirrors meeting all demanding requirements for guiding the compressed 30 J, 25 fs HAPLS laser beam at 10 Hz repetition rate and a center wavelength of 810 nm entirely in vacuum. We describe the production and evaluation of Ta2O5/HfO2/SiO2 ion beam sputtered coated (440 × 290 × 75) mm3 beam transport mirrors. No crazing was observed after thirty vacuum-air cycles. A laser induced damage threshold of 0.76 J/cm2 (fluence on mirror surface) was achieved and maintained at high shot rates.

Direct comparison of the immunogenicity of major histocompatibility complex-I and -II deficient mesenchymal stem cells in vivo.

Mesenchymal stem cells (MSCs) play an important role in tissue engineering applications aiming at the regeneration or substitution of damaged tissues. In this context, off-the-shelf allogeneic MSCs would represent an attractive universal cell source. However, immune rejection is a major limitation for the clinical use of allogeneic MSCs. Immune rejection is mediated by the expression of major histocompatibility complexes (MHC)-I and -II on the donor cells. In this study, we eliminated MHC-I and/or MHC-II expression in human MSCs by using the CRISPR/Cas9 technology and investigated the effect of the individual or combined knockout of MHC-I and MHC-II on MSC survival after transplantation into immunocompetent mice. Elimination of MHC-I and/or MHC-II expression did not affect mesenchymal marker gene expression, viability, proliferation and the differentiation potential of MSCs in vitro. However, cell survival of transplanted MSCs was significantly elevated in MHC-I and MHC-II deficient MSCs. A direct side-by-side comparison does not reveal any significant difference in the immunogenicity of MHC-I and MHC-II knockout MSCs. Moreover, double knockout of MHC-I and MHC-II did not further increase in vivo cell survival of transplanted MSCs. Our results demonstrate that knockout of MHC-I and/or MHC-II represents an effective strategy to prevent immune rejection of allogeneic MSCs.

Visibility of significant prostate cancer on multiparametric magnetic resonance imaging (MRI)-do we still need contrast media?

OBJECTIVES: To assess the visibility of clinically significant prostate cancer (PCA) lesions on the sequences multiparametric MRI of the prostate (mpMRI) and to evaluate whether the addition of dynamic contrast-enhanced imaging (DCE) improves the overall visibility. METHODS: We retrospectively evaluated multiparametric MRI images of 119 lesions in 111 patients with biopsy-proven clinically significant PCA. Three readers assigned visual grading scores for visibility on each sequence, and a visual grading characteristic analysis was performed. Linear regression was used to explore which factors contributed to visibility in individual sequences. RESULTS: The visibility of lesions was significantly better with mpMRI when compared to biparametric MRI in visual grading characteristic (VGC) analysis, with an AUCVGC of 0.62 (95% CI 0.55-0.69; p < 0.001). This benefit was seen across all readers. Multivariable linear regression revealed that a location in the peripheral zone was associated with better visibility on T2-weighted imaging (T2w). A higher Prostate Imaging-Reporting and Data System (PI-RADS) score was associated with better visibility on both diffusion-weighted imaging (DWI) and DCE. Increased lesion size was associated with better visibility on all sequences. CONCLUSIONS: Visibility of clinically significant PCA is improved by using mpMRI. DCE and DWI images independently improve lesion visibility compared to T2w images alone. Further research into the potential of DCE to impact on clinical decision-making is suggested. KEY POINTS: • DCE and DWI images independently improve clinically significant prostate cancer lesion visibility compared to T2w images alone. • Multiparametric MRI (DCE, DWI, T2w) achieved significantly higher visibility scores than biparametric MRI (DWI, T2w). • Location in the transition zone is associated with poor visibility on T2w, while it did not affect visibility on DWI or DCE.

Widely tunable cavity-enhanced frequency combs.

We describe the cavity enhancement of frequency combs over a wide tuning range of 450-700 nm (${ \gt }7900\;{{\rm cm}^{ - 1}} $>7900cm-1), covering nearly the entire visible spectrum. Tunable visible frequency combs from a synchronously pumped optical parametric oscillator are coupled into a four-mirror, dispersion-managed cavity with a finesse of 600-1400. An intracavity absorption path length enhancement greater than 190 is obtained over the entire tuning range, while preserving intracavity spectral bandwidths capable of supporting sub-200 fs pulse durations. These tunable cavity-enhanced frequency combs can find many applications in nonlinear optics and spectroscopy.

Dynamic patterns of [68Ga]Ga-PSMA-11 uptake in recurrent prostate cancer lesions.

PURPOSE: Dual-time point PET/CT scanning with [68Ga]Ga-PSMA-11 in the diagnosis of prostate cancer (PC) has been advanced as a method to increase detection of PC lesions, particularly at early stages of biochemical recurrence and as a potential means to aid the discrimination between benign and pathological prostate-specific membrane antigen (PSMA) uptake. However, the assumption that all PC lesions uniformly exhibit increasing tracer uptake at delayed imaging has not yet been investigated, which this present study aims to address. METHODS: One hundred consecutive patients with biochemically recurrent PC who received standard and late [68Ga]Ga-PSMA-11 PET/CT (by local protocol at 1.5 h "standard" and 2.5 h p.i. "late") underwent retrospective evaluation. All lesions with a tracer uptake above local background were analysed with regard to their maximum standardised uptake values at standard and late images (SUVmax) and characterised according to their morphological characteristics. RESULTS: Seventy-nine of 100 patients had PSMA-positive scans, in whom a total of 185 individual PSMA-positive lesions were identified. These were morphologically characterised as bone lesions (n = 48), solid organ lesions (n = 3), lymph node (LN) lesions (n = 78) and locally recurrent lesions in the prostatic fossa or seminal vesicles (n = 56). The relative uptake between standard and late imaging was considered; all lesions classified as local recurrence presented with increasing (86%) or stable patterns of tracer uptake (14%). In contrast, only 58% of bone lesions exhibited increasing tracer uptake, with 21% exhibiting a stable pattern and 21% exhibiting a decreasing tracer uptake at late imaging. CONCLUSION: A heterogeneous pattern of dynamic tracer uptake was observed, with a largely increasing pattern observed for locally recurrent lesions and lymph nodes and a significant proportion of bone lesions exhibiting decreasing tracer uptake. The results are of significance not only in the imaging and identification of PC lesions, but they also have implications for PSMA-directed ligand therapy.

The role of additional late PSMA-ligand PET/CT in the differentiation between lymph node metastases and ganglia.

PURPOSE: Differentiating between prostate cancer (PC) lesions and benign structures which exhibit radiotracer uptake in PSMA-ligand PET/CT can be challenging. Additional late imaging has been shown to be a powerful method for the discrimination between PC and non-PC lesions, owing to the increasing tracer uptake of the former. Nevertheless, there are no pre-existing studies which describe the dynamic tracer uptake for ganglia, which this present study aims to address. METHODS: Fifty consecutive patients with PC who received standard and late 68Ga-PSMA-11-PET/CT (by local protocol at 1.5 h "standard" and 2.5 h p.i. "late") underwent retrospective evaluation. All lesions with a tracer uptake above local background indicative for ganglia as well as PC lesions were analysed with regard to their maximum standardised uptake values (SUVmax) and localisation. RESULTS: Overall, 86 PSMA-positive ganglia were identified in 70% (n = 35) of the patients. Five ganglia exhibited PSMA avidity at late imaging only, and three at standard imaging only. A total of 66 lesions suggestive for PC were detected in 44 patients (88%), of which 45% (n = 30) were morphologically identified as lymph nodes (LN), the remainder being locally recurrent lesions or bone metastases. No solid organ metastases were present in our cohort. At late scanning, 73% of the LN exhibited an increase in SUVmax, whereas 65% of the ganglia exhibited a decreasing or stable SUVmax. CONCLUSION: Whereas the presence of increasing tracer uptake in potential PC lesions can provide additional data about the likelihood of malignancy, increasing SUVmax alone does not reliably differentiate between ganglia and PC lesions and is a potential diagnostic pitfall. We therefore recommend high-resolution CT to enable morphological characterisation of ganglia.

68Ga-PSMA-11 PET/CT in patients with recurrent prostate cancer-a modified protocol compared with the common protocol.

PURPOSE: 68Ga-PSMA-11 PET/CT is commonly performed at 1 h post injection (p.i.). However, various publications have demonstrated that most prostate cancer (PC) lesions exhibit higher contrast at later imaging. The aim of this study was to compare the "common" protocol of 68Ga-PSMA-11 PET/CT with a modified protocol. METHODS: In 2017, we used the following scanning protocol for 68Ga-PSMA-11 PET/CT in patients with recurrent PC: acquisition at 1 h p.i. without further preparations. From 2018, all scans were conducted at 1.5 h p.i. In addition, patients were orally hydrated with 1 L of water 0.5 h p.i. and were injected with 20 mg of furosemide 1 h p.i. Both protocols including 112 patients (2017) and 156 (modified protocol in 2018) were retrospectively compared. Rates of pathologic scans, maximum standardized uptake values (SUVmax), and tumor contrast (ratio lesion-SUVmax/background-SUVmean) as well as average standardized uptake values (SUVmean) of urinary bladder were analyzed. RESULTS: Both tumor contrast and tracer uptake were significantly (p < 0.001) higher in the novel protocol. Although statistically not significant, the rates of pathologic scans were also higher in the modified protocol: 76.3% vs. 68.8% for all PSA values including 38.9% vs. 25.0% for PSA < 0.5 ng/ml and 60.0% vs. 56.7% for PSA > 0.5-≤ 2.0 ng/ml. Average SUVmean of the urinary bladder was significantly (p < 0.001) lower with the modified protocol. CONCLUSIONS: The modified protocol, which includes a combination of delayed image acquisition at 1.5 h p.i., hydration, and furosemide resulted in higher tumor contrast and seems to have the potential to increase the rates of pathological scans, especially at low PSA levels.

Comparison of PSMA-ligand PET/CT and multiparametric MRI for the detection of recurrent prostate cancer in the pelvis.

PURPOSE: So far, there have been very few studies which provide a direct comparison between MRI and PSMA-ligand PET/CT for the detection of recurrent prostate cancer (rPC). This present study therefore aims to provide further clinical data in order to resolve this urgent clinical question, and thereby strengthen clinical recommendations. METHODS: A retrospective analysis was performed for patients who were scanned at our institution with whole-body PSMA-PET/CT (tracer: 68Ga-PSMA-11) between January 2017 and September 2018 in order to detect rPC. Amongst them, 43 underwent an additional pelvic MRI within 2 months. Both modalities were compared as follows: a consensus read of the PET data was performed by two nuclear physicians. All lesions were recorded with respect to their type and localization. The same process was conducted by two radiologists for pelvic MRI. Thereafter, both modalities were directly compared for every patient and lesion. RESULTS: Overall, 30/43 patients (69.8%) presented with a pathologic MRI and 38/43 (88.4%) with a pathologic PSMA-PET/CT of the pelvis. MRI detected 53 pelvic rPC lesions (13 of them classified as "uncertain") and PSMA-PET/CT detected 75 pelvic lesions (three classified as "uncertain"). The superiority of PSMA-PET/CT was statistically significant only if uncertain lesions were classified as false-positive. CONCLUSIONS: PSMA-PET/CT detected more pelvic lesions characteristic for rPC when compared to MRI. In order to detect rPC, a potential future scenario could be conducting first a PSMA-PET/CT. Combining the advantages of both modalities in hybrid PET/MRI scanners would be an ideal future scenario.

Nerve-sparing radical cystectomy has a beneficial impact on urinary continence after orthotopic bladder substitution, which becomes even more apparent over time.

OBJECTIVE: To analyse urinary continence in long-term survivors after radical cystectomy (RC) and orthotopic bladder substitution (OBS) according to attempted nerve-sparing (NS) status. PATIENTS AND METHODS: We analysed 180 consecutive patients treated at our department between 1985 and 2007, who underwent RC with OBS, and survived ≥10 years after RC. We stratified patients by attempted NS status and evaluated continence outcomes using descriptive statistics and Cox proportional hazards regression models. A secondary analysis evaluated erectile function as a quality control for attempted NS. RESULTS: The median (interquartile range [IQR]) age at RC was 62 (57-71) years. Of 180 patients, attempted NS status was none in 24 (13%), unilateral in 100 (56%), and bilateral in 56 (31%). After a median (IQR) follow-up of 169 (147-210) months, 160 (89%) patients were continent during daytime and 124 (69%) during night-time. In multivariable analysis, any degree of attempted NS was significantly associated with daytime continence (odds ratio [OR] 2.08, 95% confidence interval [CI] 1.05-4.11; P = 0.04). Correspondingly, any attempted NS was significantly associated with night-time continence (OR 2.51, 95% CI 1.08-5.85; P = 0.03). Recovery of erectile function at 5 years was also significantly associated with attempted NS (P < 0.001). CONCLUSION: Nerve-sparing during RC and OBS was associated with better long-term continence outcomes. This becomes more apparent as the patients age with their OBS. We advocate a NS RC whenever an OBS is considered.

Reproductive organ-sparing cystectomy significantly improves continence in women after orthotopic bladder substitution without affecting oncological outcome.

OBJECTIVES: To compare functional and oncological outcomes of reproductive organ-sparing cystectomy (ROSC) compared with standard cystectomy (SC) in women undergoing orthotopic bladder substitution (OBS). PATIENTS AND METHODS: Between 1995 and 2016, 121 consecutive women undergoing OBS were prospectively included in this single-centre non-randomized clinical follow-up study comprising an ROSC and an SC group. Urinary continence, the need for intermittent self-catheterization (ISC), lateral standing micturition cystourethrogram (MCUG), urethral pressure profile findings, if available, and oncological outcomes were assessed and compared between ROSC and SC. RESULTS: After 12 months, patients who had undergone ROSC with OBS had significantly higher daytime and nighttime continence rates than patients who had undergone SC with OBS (87.5% vs 63.5%; P = 0.027 and 87.5% vs 57.7%; P = 0.008), whereas no significant differences were found between groups in ISC rates (12.5% vs 12.94%; P > 0.99). The degree of attempted nerve-sparing (none, unilateral, bilateral) positively affected continence rates in both groups. No significant differences were found in local recurrence rates (0% vs 9.4%; P = 0.126), 5- and 10-year overall survival rates (80.9% and 80.9% vs 64.9% and 55.7%; P = 0.443) or 5- and 10-year cancer-specific survival rates (84.3% and 84.3% vs 73% and 66.2%; P = 0.431). CONCLUSION: Superior continence rates were found for ROSC with an OBS compared with SC, without a negative impact on oncological outcome. ROSC should, therefore, be offered to women receiving an OBS whenever justifiable.

Value of urodynamic findings in predicting upper urinary tract damage in neuro-urological patients: A systematic review.

AIM: The main goals of neurogenic lower urinary tract dysfunction (NLUTD) management are preventing upper urinary tract damage (UUTD), improving continence, and quality of life. Here, we aimed to systematically assess all available evidence on urodynamics predicting UUTD in patients with NLUTD. METHODS: A systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement was performed in March 2017. Only neuro-urological patients assessed by urodynamics were included. Any outcome of upper urinary tract function were evaluated. RESULTS: Forty-nine studies (1 randomized controlled trial, 9 prospective, and 39 retrospective case series) reported urodynamic data on 4930 neuro-urological patients. Of those, 2828 (98%) were spina bifida (SB) children. The total number of adults was 2044, mainly having spinal cord injury (SCI) (60%). A low bladder compliance was found in 568 (46.3%) and 341 (29.3%) of the paediatric and adult population, respectively. Hydronephrosis (HDN) was detected in 557 children (27.8%) in 19/28 studies and 178 adults (14.6%), mainly SCI, in 14/21 studies. Nine out of 30 multiple sclerosis (MS) patients affected by HDN (16.8%) showed low compliance in 4/14 studies. CONCLUSIONS: Patients with SB and SCI have a higher risk of developing UUTD (mainly reported as HDN) compared to those with MS. Reduced compliance and high DLPP were major risk factors for UUTD. Although our findings clarify the mandatory role of urodynamics in the management of NLUTD, standardization and better implementation of assessments in daily practice may further improve outcomes of neuro-urological patients based on objective measurements, that is, urodynamics.

Continent catheterizable tubes/stomas in adult neuro-urological patients: A systematic review.

AIMS: To systematically review all available evidence on the effectiveness and complications of continent cutaneous stoma or tube (CCS/T) to treat bladder-emptying difficulties in adult neuro-urological patients. METHODS: The search strategy and studies selection were performed on Medline, Embase, and Cochrane using the PICOS method according to the PRISMA statement (CRD42015019212; http://www.crd.york.ac.uk/PROSPERO). RESULTS: After screening 3,634 abstracts, 11 studies (all retrospective, enrolling 213 patients) were included in a narrative synthesis. Mean follow-up ranged from 21.6 months to 8.7 years (median: 36 months, IQR 28.5-44). At last follow-up, the ability to catheterize rate was ≥84% (except in one study: 58.3%) and the continence rate at stoma was >75%. Data comparing health-related quality-of-life before and after surgery were not available in any study. Overall, 85/213 postoperative events required reoperation: 7 events (7 patients) occurring ≤3 months postoperatively, 22 events (16 patients) >3 months, and 56 events (55 patients) for which the time after surgery was not specified. Sixty additional complications (60 patients) were reported but did not require surgical treatment. Tube stenosis occurred in 4-32% of the cases (median: 14%, IQR 9-24). Complications related to concomitant procedures (augmentation cystoplasty, pouch) included neovesicocutaneous fistulae, bladder stones, and bladder perforations. Risk of bias and confounding was high in all studies. CONCLUSIONS: CCS/T appears to be an effective treatment option in adult neuro-urological patients unable to perform intermittent self-catheterization through the urethra. However, the complication rate is meaningful and the quality of evidence is low, especially in terms of long-term outcomes including the impact on the quality-of-life.

Long-term effectiveness and complication rates of bladder augmentation in patients with neurogenic bladder dysfunction: A systematic review.

AIMS: To systematically evaluate effectiveness and safety of bladder augmentation for adult neuro-urological patients. METHODS: The Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement was followed for review of publications. The Medline, Embase, and Cochrane controlled trial databases and clinicaltrial.gov were searched until January 2015. No limitations were placed on date or language. Non-original articles, conference abstracts, and publications involving children and animals were excluded. Risk-of-bias and confounder assessment was performed. RESULTS: A total of 20 studies including 511 patients were eligible for inclusion. The level of evidence for the included studies was low, most level 4 studies with only one level 3 study. The data were narratively synthesized. Across all studies high risk-of bias and confounding was found. Primary outcomes were assessed in 16 of the 20 studies and showed improved quality of life and anatomical changes as well as stable renal function. The secondary outcomes were reported in 17 of the 20 studies and urodynamic parameters and continence all demonstrated improvement after bladder reconstruction. Long-term complications continued up to 10 years post-operatively, including bowel dysfunction in 15% of the patients, stone formation in 10%, five bladder perforations and one bladder cancer. CONCLUSIONS: Available studies are not plentiful and of relatively poor quality, appropriately designed prospective studies are urgently needed. Despite this, bladder augmentation appears to be a highly effective procedure at protecting the upper urinary tract and improving quality of life. However, it is associated with relatively high morbidity in both the short and long term.

Characterization of CRISPR/Cas9 RANKL knockout mesenchymal stem cell clones based on single-cell printing technology and Emulsion Coupling assay as a low-cellularity workflow for single-cell cloning.

The homogeneity of the genetically modified single-cells is a necessity for many applications such as cell line development, gene therapy, and tissue engineering and in particular for regenerative medical applications. The lack of tools to effectively isolate and characterize CRISPR/Cas9 engineered cells is considered as a significant bottleneck in these applications. Especially the incompatibility of protein detection technologies to confirm protein expression changes without a preconditional large-scale clonal expansion creates a gridlock in many applications. To ameliorate the characterization of engineered cells, we propose an improved workflow, including single-cell printing/isolation technology based on fluorescent properties with high yield, a genomic edit screen (Surveyor assay), mRNA RT-PCR assessing altered gene expression, and a versatile protein detection tool called emulsion-coupling to deliver a high-content, unified single-cell workflow. The workflow was exemplified by engineering and functionally validating RANKL knockout immortalized mesenchymal stem cells showing bone formation capacity of these cells. The resulting workflow is economical, without the requirement of large-scale clonal expansions of the cells with overall cloning efficiency above 30% of CRISPR/Cas9 edited cells. Nevertheless, as the single-cell clones are comprehensively characterized at an early, highly parallel phase of the development of cells including DNA, RNA, and protein levels, the workflow delivers a higher number of successfully edited cells for further characterization, lowering the chance of late failures in the development process.

Swiss germ-cell cancer consensus recommendations.

Approximately 420 men are diagnosed with germ-cell cancer (GCC) in Switzerland each year. Recent international guidelines outline management issues, but many aspects remain controversial in an area of highly individualised treatments. Even more than in other tumour types, in GCC the challenge is to choose exactly the correct treatment for an individual patient. Overtreatment in patients likely to be cured must be avoided to reduce long-term toxicities. On the other hand, treatment intensification is required in patients presenting with adverse prognostic factors. Therefore, referral to expert centres or consultations with an expert for a second opinion is strongly recommended. In 2020, Swiss experts discussed their strategies in a consensus meeting during the virtual Swiss Oncology and Haematology Congress (SOHC) in order to harmonise their concepts and to suggest optimal strategies for the management of GCC patients in Switzerland. Votes on controversial issues were obtained and are presented in this review wherever applicable.

Complication reporting with the Bern Comprehensive Complication Index CCI after open radical prostatectomy: A longitudinal long-term single-center study.

OBJECTIVE: To impartially optimize complication reporting in patients after open radical prostatectomy (ORP) and pelvic lymph node dissection (PLND) by adopting the modified Bern Comprehensive Complication Index (CCI). ORP and PLND are associated with relevant postoperative morbidity. The CCI-ranging from 0 (no complications) to 100 (death)-is a tool that aims to integrate all complications occuring within 90 days postoperatively weighted by severity in a single formula. METHODS: In an observational single-center cohort, 90-day postoperative complications of 1,123 consecutive patients undergoing standardized ORP and PLND between 1996 and 2017 were evaluated. Prospectively collected complications were graded according to the Clavien-Dindo Classification. Grade I to II complications were defined as minor and grade IIIa to V as major. Finally, the recently developed modified Bern CCI using an exponential function, which transforms the sum of the weights into a value between 0 and 100 and the original CCI for each patient were extracted and compared. The correlation between the modified Bern and original CCI values was depicted graphically. RESULTS: The complication rate was 42%, with 18% minor and 24% major complications. With the original CCI, the threshold of 100 was exceeded in 1 patient who had a maximal index value of 101 within 90d postoperatively. The maximal value of the Bern CCI was 97.5. Mean Bern and original CCI scores and standard deviations were 6.2 (11.3) and 7.6 (12.2) at 30 days, and 9.3 (13.9) and 10.7 (14.2) at 90 days. CONCLUSIONS: The Bern CCI provides a more precise depiction of postoperative morbidity and represents the burden in patients with >1 complication after ORP and PLND more accurately than the original CCI allowing for a more reliable evaluation of quality of care and recovery. It therefore warrants consideration for standardized reporting of complications after ORP and PLND.

Comparison of the Diagnostic Performance of Contrast-enhanced Ultrasound with That of Contrast-enhanced Computed Tomography and Contrast-enhanced Magnetic Resonance Imaging in the Evaluation of Renal Masses: A Systematic Review and Meta-analysis.

CONTEXT: Contrast-enhanced ultrasound (CEUS) has the potential to be a valuable alternative to contrast-enhanced computed tomography (CECT) and contrast-enhanced magnetic resonance imaging (CEMR), the current gold standards in characterisation of renal masses. OBJECTIVE: To systematically review all available evidence on the qualitative diagnostic performance of CEUS versus that of CECT and CEMR in the evaluation of benign and malignant cystic and solid renal masses. EVIDENCE ACQUISITION: The review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. EVIDENCE SYNTHESIS: After screening 1483 articles, six cohort studies and 10 descriptive studies were included. Pooling data from included studies with final diagnosis of benign or malignant renal masses by pathology showed a significant difference in the sensitivity of CEUS (0.96; 95% confidence interval [CI] 0.94-0.98) versus that of CECT (0.90; 95% CI 0.86-0.93). Pooling data from included studies with final diagnosis by pathology report or reaffirmed diagnosis by follow-up imaging without pathology report showed significant difference in the sensitivity of CEUS (0.98; 95% CI 0.94-1.0) versus that of CEMR (0.78; 95% CI 0.66-0.91). CONCLUSIONS: Preliminary data imply that CEUS may perform at least as well as or better than CECT and CEMR in the diagnosis of renal masses. However, the evidence base is limited, and more high-quality, well-designed, adequately powered, and sampled studies are needed to reach definitive conclusions. PATIENT SUMMARY: Early data suggest that contrast-enhanced ultrasound is a promising option for the evaluation of renal masses, but more reliable evidence is required.

Prognostic Value of Biochemical Recurrence Following Treatment with Curative Intent for Prostate Cancer: A Systematic Review.

CONTEXT: In men with prostate cancer (PCa) treated with curative intent, controversy exists regarding the impact of biochemical recurrence (BCR) on oncological outcomes. OBJECTIVE: To perform a systematic review of the existing literature on BCR after treatment with curative intent for nonmetastatic PCa. Objective 1 is to investigate whether oncological outcomes differ between patients with or without BCR. Objective 2 is to study which clinical factors and tumor features in patients with BCR have an independent prognostic impact on oncological outcomes. EVIDENCE ACQUISITION: Medline, Medline In-Process, Embase, and the Cochrane Central Register of Controlled Trials were searched. For objective 1, prospective and retrospective studies comparing survival outcomes of patients with or without BCR following radical prostatectomy (RP) or radical radiotherapy (RT) were included. For objective 2, all studies with at least 100 participants and reporting on prognostic patient and tumor characteristics in patients with BCR were included. Risk-of-bias and confounding assessments were performed according to the Quality in Prognosis Studies tool. Both a narrative synthesis and a meta-analysis were undertaken. EVIDENCE SYNTHESIS: Overall, 77 studies were included for analysis, of which 14 addressed objective 1, recruiting 20 406 patients. Objective 2 was addressed by 71 studies with 29 057, 11 301, and 4272 patients undergoing RP, RT, and a mixed population (mix of patients undergoing RP or RT as primary treatment), respectively. There was a low risk of bias for study participation, confounders, and statistical analysis. For most studies, attrition bias, and prognostic and outcome measurements were not clearly reported. BCR was associated with worse survival rates, mainly in patients with short prostate-specific antigen doubling time (PSA-DT) and a high final Gleason score after RP, or a short interval to biochemical failure (IBF) after RT and a high biopsy Gleason score. CONCLUSIONS: BCR has an impact on survival, but this effect appears to be limited to a subgroup of patients with specific clinical risk factors. Short PSA-DT and a high final Gleason score after RP, and a short IBF after RT and a high biopsy Gleason score are the main factors that have a negative impact on survival. These factors may form the basis of new BCR risk stratification (European Association of Urology BCR Risk Groups), which needs to be validated formally. PATIENT SUMMARY: This review looks at the risk of death in men who shows rising prostate-specific antigen (PSA) in the blood test performed after curative surgery or radiotherapy. For many men, rising PSA does not mean that they are at a high risk of death from prostate cancer in the longer term. Men with PSA that rises shortly after they were treated with radiotherapy or rapidly rising PSA after surgery and a high tumor grade for both treatment modalities are at the highest risk of death. These factors may form the basis of new risk stratification (European Association of Urology biochemical recurrence Risk Groups), which needs to be validated formally.

EAU-EANM-ESTRO-ESUR-SIOG Prostate Cancer Guideline Panel Consensus Statements for Deferred Treatment with Curative Intent for Localised Prostate Cancer from an International Collaborative Study (DETECTIVE Study).

BACKGROUND: There is uncertainty in deferred active treatment (DAT) programmes, regarding patient selection, follow-up and monitoring, reclassification, and which outcome measures should be prioritised. OBJECTIVE: To develop consensus statements for all domains of DAT. DESIGN, SETTING, AND PARTICIPANTS: A protocol-driven, three phase study was undertaken by the European Association of Urology (EAU)-European Association of Nuclear Medicine (EANM)-European Society for Radiotherapy and Oncology (ESTRO)-European Association of Urology Section of Urological Research (ESUR)-International Society of Geriatric Oncology (SIOG) Prostate Cancer Guideline Panel in conjunction with partner organisations, including the following: (1) a systematic review to describe heterogeneity across all domains; (2) a two-round Delphi survey involving a large, international panel of stakeholders, including healthcare practitioners (HCPs) and patients; and (3) a consensus group meeting attended by stakeholder group representatives. Robust methods regarding what constituted the consensus were strictly followed. RESULTS AND LIMITATIONS: A total of 109 HCPs and 16 patients completed both survey rounds. Of 129 statements in the survey, consensus was achieved in 66 (51%); the rest of the statements were discussed and voted on in the consensus meeting by 32 HCPs and three patients, where consensus was achieved in additional 27 statements (43%). Overall, 93 statements (72%) achieved consensus in the project. Some uncertainties remained regarding clinically important thresholds for disease extent on biopsy in low-risk disease, and the role of multiparametric magnetic resonance imaging in determining disease stage and aggressiveness as a criterion for inclusion and exclusion. CONCLUSIONS: Consensus statements and the findings are expected to guide and inform routine clinical practice and research, until higher levels of evidence emerge through prospective comparative studies and clinical trials. PATIENT SUMMARY: We undertook a project aimed at standardising the elements of practice in active surveillance programmes for early localised prostate cancer because currently there is great variation and uncertainty regarding how best to conduct them. The project involved large numbers of healthcare practitioners and patients using a survey and face-to-face meeting, in order to achieve agreement (ie, consensus) regarding best practice, which will provide guidance to clinicians and researchers.