Estimating the Effect of Radical Prostatectomy: Combining Data From the SPCG4 and PIVOT Randomized Trials With Contemporary Cohorts.

PURPOSE: Two randomized trials (SPCG4 and PIVOT) have compared surgery to conservative management for localized prostate cancer. The applicability of these trials to contemporary practice remains uncertain. We aimed to develop an individualized prediction model for prostate cancer mortality comparing immediate surgery at a high-volume center to active surveillance. MATERIALS AND METHODS: We determined whether the relative risk of prostate cancer mortality with surgery vs observation varied by baseline risk. We then used various estimates of relative risk to estimate 15-year mortality with and without surgery using, as a predictor, risk of biochemical recurrence calculated from a model. RESULTS: We saw no evidence that relative risk varied by baseline risk, supporting the use of a constant relative risk. Compared with observation, surgery was associated with negligible benefit for patients with Grade Group (GG) 1 disease (0.2% mortality reduction at 15 years) and small benefit for patients with GG2 with lower PSA and stage (≤5% mortality reduction). Benefit was greater (6%-9%) for patients with GG3 or GG4 though still modest, but effect estimates varied widely depending on choice of hazard ratio for surgery (6%-36% absolute risk reduction). CONCLUSIONS: Surgery should be avoided for men with low-risk (GG1) prostate cancer and for many men with GG2 disease. Surgical benefits are greater in men with higher-risk disease. Integration of findings with a life expectancy model will allow patients to make informed treatment decisions given their oncologic risk, risk of death from other causes, and estimated effects of surgery.

Cytoreductive nephrectomy in metastatic renal cell carcinoma.

BACKGROUND: Nephrectomy is the surgical removal of all or part of a kidney. When the aim of nephrectomy is to reduce tumor burden in people with established metastatic disease, the procedure is called cytoreductive nephrectomy (CN). CN is typically combined with systemic anticancer therapy (SACT). SACT can be initiated before or immediately after the operation or deferred until radiological signs of disease progression. The benefits and harms of CN are controversial. OBJECTIVES: To assess the effects of cytoreductive nephrectomy combined with systemic anticancer therapy versus systemic anticancer therapy alone or watchful waiting in newly diagnosed metastatic renal cell carcinoma. SEARCH METHODS: We performed a comprehensive search in the Cochrane Library, MEDLINE, Embase, Scopus, two trial registries, and other gray literature sources up to 1 March 2024. We applied no restrictions on publication language or status. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that evaluated SACT and CN versus SACT alone or watchful waiting. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies and extracted data. Primary outcomes were time to death from any cause and quality of life. Secondary outcomes were time to disease progression, treatment response, treatment-related mortality, discontinuation due to adverse events, and serious adverse events. We performed statistical analyses using a random-effects model. We rated the certainty of evidence using the GRADE approach. MAIN RESULTS: Our search identified 10 records of four unique RCTs that informed two comparisons. In this abstract, we focus on the results for the two primary outcomes. Cytoreductive nephrectomy plus systemic anticancer therapy versus systemic anticancer therapy alone Three RCTs informed this comparison. Due to the considerable heterogeneity when pooling across these studies, we decided to present the results of the prespecified subgroup analysis by type of systemic agent. Cytoreductive nephrectomy plus interferon immunotherapy versus interferon immunotherapy alone CN plus interferon immunotherapy compared with interferon immunotherapy alone probably increases time to death from any cause (hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.51 to 0.89; I²= 0%; 2 studies, 326 participants; moderate-certainty evidence). Assuming 820 all-cause deaths at two years' follow-up per 1000 people who receive interferon immunotherapy alone, the effect estimate corresponds to 132 fewer all-cause deaths (237 fewer to 37 fewer) per 1000 people who receive CN plus interferon immunotherapy. We found no evidence to assess quality of life. Cytoreductive nephrectomy plus tyrosine kinase inhibitor therapy versus tyrosine kinase inhibitor therapy alone We are very uncertain about the effect of CN plus tyrosine kinase inhibitor (TKI) therapy compared with TKI therapy alone on time to death from any cause (HR 1.11, 95% CI 0.90 to 1.37; 1 study, 450 participants; very low-certainty evidence). Assuming 574 all-cause deaths at two years' follow-up per 1000 people who receive TKI therapy alone, the effect estimate corresponds to 38 more all-cause deaths (38 fewer to 115 more) per 1000 people who receive CN plus TKI therapy. We found no evidence to assess quality of life. Immediate cytoreductive nephrectomy versus deferred cytoreductive nephrectomy One study evaluated CN followed by TKI therapy (immediate CN) versus three cycles of TKI therapy followed by CN (deferred CN). Immediate CN compared with deferred CN may decrease time to death from any cause (HR 1.63, 95% CI 1.05 to 2.53; 1 study, 99 participants; low-certainty evidence). Assuming 620 all-cause deaths at two years' follow-up per 1000 people who receive deferred CN, the effect estimate corresponds to 173 more all-cause deaths (18 more to 294 more) per 1000 people who receive immediate CN. We found no evidence to assess quality of life. AUTHORS' CONCLUSIONS: CN plus SACT in the form of interferon immunotherapy versus SACT in the form of interferon immunotherapy alone probably increases time to death from any cause. However, we are very uncertain about the effect of CN plus SACT in the form of TKI therapy versus SACT in the form of TKI therapy alone on time to death from any cause. Immediate CN versus deferred CN may decrease time to death from any cause. We found no quality of life data for any of these three comparisons. We also found no evidence to inform any other comparisons, in particular those involving newer immunotherapy agents (programmed death receptor 1 [PD-1]/programmed death ligand 1 [PD-L1] immune checkpoint inhibitors), which have become the backbone of SACT for metastatic renal cell carcinoma. There is an urgent need for RCTs that explore the role of CN in the context of contemporary forms of systemic immunotherapy.

Under-representation of Diversity on American Urological Association and European Association of Urology Guideline Panels.

OBJECTIVE: To assess the panel composition of the 2 most important guideline developers in urology as equity and acceptability, important domains in clinical guideline development, require broad stakeholder representation. METHODS: Following a predefined protocol, we identified all current AUA and EAU guideline documents. Two authors independently abstracted data including guideline topic, number and roles of panel members, voting status, and academic rank. We determined panel member's gender (woman, man, or nonbinary) and racialization (White or non-White) status based on name, internet picture, pronouns used, bios available, and gender listed on their profile. RESULTS: We identified 31 AUA and 20 EAU guidelines for inclusion. Median panel size was 19 (interquartile range [IQR]: 17; 21) with 12 (IQR: 10; 14) voting members. The average composition of voting panels was predominantly male (81.8%) and White (86.8%). Eleven guideline panels (21.6%) did not include any women, and 9 (17.6%) panels had no representation of individuals from non-White groups. While gender distribution was similar among guidelines of the 2 organizations, the AUA included more voting members from non-White groups (14.3% vs 8.0%; P = .010). Analysis of the AUA panel composition over time revealed stable proportions of female and non-White individuals. CONCLUSION: Both AUA and EAU guidelines exhibit insufficient representation of females and non-White individuals, with no evident improvement observed over time. Implementing more transparent processes that advocate for diverse panel representation may enhance the incorporation of stakeholder values and preferences, thereby improving the dissemination and adoption of guidelines.

GRADE guidance 37: rating imprecision in a body of evidence on test accuracy.

OBJECTIVES: To provide guidance on rating imprecision in a body of evidence assessing the accuracy of a single test. This guide will clarify when Grading of Recommendations Assessment, Development and Evaluation (GRADE) users should consider rating down the certainty of evidence by one or more levels for imprecision in test accuracy. STUDY DESIGN AND SETTING: A project group within the GRADE working group conducted iterative discussions and presentations at GRADE working group meetings to produce this guidance. RESULTS: Before rating the certainty of evidence, GRADE users should define the target of their certainty rating. GRADE recommends setting judgment thresholds defining what they consider a very accurate, accurate, inaccurate, and very inaccurate test. These thresholds should be set after considering consequences of testing and effects on people-important outcomes. GRADE's primary criterion for judging imprecision in test accuracy evidence is considering confidence intervals (i.e., CI approach) of absolute test accuracy results (true and false, positive, and negative results in a cohort of people). Based on the CI approach, when a CI appreciably crosses the predefined judgment threshold(s), one should consider rating down certainty of evidence by one or more levels, depending on the number of thresholds crossed. When the CI does not cross judgment threshold(s), GRADE suggests considering the sample size for an adequately powered test accuracy review (optimal or review information size [optimal information size (OIS)/review information size (RIS)]) in rating imprecision. If the combined sample size of the included studies in the review is smaller than the required OIS/RIS, one should consider rating down by one or more levels for imprecision. CONCLUSION: This paper extends previous GRADE guidance for rating imprecision in single test accuracy systematic reviews and guidelines, with a focus on the circumstances in which one should consider rating down one or more levels for imprecision.

Immunotherapy for advanced or metastatic urothelial carcinoma: an abridged Cochrane review.

OBJECTIVES: To assess the effects of immunotherapy compared to chemotherapy as first- and second-line treatment of advanced or metastatic urothelial carcinoma. METHODS: Based on a published protocol, we performed a systematic search of multiple databases. Two review authors independently performed the literature selection, identified relevant studies, assessed the eligibility of studies for inclusion, and extracted data. We performed statistical analyses using a random-effects model and assessed the quality of the evidence on a per-outcome basis according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: We included five randomised controlled trials and also identified seven single-arm studies. When used as first-line therapy, immunotherapy probably has little to no effect on the risk of death from any cause compared to chemotherapy (hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.87-1.07; moderate-certainty evidence). immunotherapy probably has little to no effect on health-related quality of life (mean difference [MD] 4.10, 95% CI 3.83-4.37; moderate). Immunotherapy probably reduces grade 3-5 adverse events (risk ratio [RR] 0.47, 95% CI 0.29-0.75; moderate). In the second-line setting immunotherapy may reduce the risk of death from any cause (HR 0.72, 95% CI 0.63-0.81; low). Immunotherapy may have little to no effect on health-related quality of life when compared to chemotherapy (MD 4.82, 95% CI -3.11 to 12.75; low). Immunotherapy may reduce grade 3-5 adverse events (RR 0.89, 95% CI 0.81-0.97; low). CONCLUSIONS: Compared to chemotherapy, immunotherapy has little to no effect on the risk of death from any cause in a first-line setting. Nevertheless, it may reduce the risk of death from any cause when used as second-line therapy. The health-related quality of life of participants receiving first- and second-line therapy does not appear to be affected by immunotherapy. Immunotherapy probably reduces or may reduce grade 3-5 adverse events when used as first- and second-line therapy, respectively.

Testosterone replacement in men with sexual dysfunction.

BACKGROUND: Clinical practice guidelines recommend testosterone replacement therapy (TRT) for men with sexual dysfunction and testosterone deficiency. However, TRT is commonly promoted in men without testosterone deficiency and existing trials often do not clearly report participants' testosterone levels or testosterone-related symptoms. This review assesses the potential benefits and harms of TRT in men presenting with complaints of sexual dysfunction. OBJECTIVES: To assess the effects of testosterone replacement therapy compared to placebo or other medical treatments in men with sexual dysfunction. SEARCH METHODS: We performed a comprehensive search of CENTRAL (the Cochrane Library), MEDLINE, EMBASE, and the trials registries ClinicalTrials.gov and World Health Organization International Clinical Trials Registry Platform, with no restrictions on language of publication or publication status, up to 29 August 2023. SELECTION CRITERIA: We included randomized controlled trials (RCTs) in men (40 years or over) with sexual dysfunction. We excluded men with primary or secondary hypogonadism. We compared testosterone or testosterone with phosphodiesterase-5 inhibitors (PDEI5I) to placebo or PDE5I alone. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the literature, assessed the risk of bias, extracted data, and rated the certainty of evidence (CoE) according to GRADE using a minimally contextualized approach. We performed statistical analyses using a random-effects model and interpreted them according to standard Cochrane methodology. Predefined primary outcomes were self-reported erectile dysfunction assessed by a validated instrument, sexual quality of life assessed by a validated instrument, and cardiovascular mortality. Secondary outcomes were treatment withdrawal due to adverse events, prostate-related events, and lower urinary tract symptoms (LUTS). We distinguished between short-term (up to 12 months) and long-term (> 12 months) outcomes. MAIN RESULTS: We identified 43 studies with 11,419 randomized participants across three comparisons: testosterone versus placebo, testosterone versus PDE5I, and testosterone with PDE5I versus PDE5I alone. This abstract focuses on the most relevant comparison of testosterone versus placebo. Testosterone versus placebo (up to 12 months) Based on a predefined sensitivity analysis of studies at low risk of bias, and an analysis combing data from the similar International Index of Erectile Function (IIEF-EF) and IIEF-5 instruments, TRT likely results in little to no difference in erectile function assessed with the IIEF-EF (mean difference (MD) 2.37, 95% confidence interval (CI) 1.67 to 3.08; I² = 0%; 6 RCTs, 2016 participants; moderate CoE) on a scale from 6 to 30 with larger values reflecting better erectile function. We assumed a minimal clinically important difference (MCID) of greater than or equal to 4. TRT likely results in little to no change in sexual quality of life assessed with the Aging Males' Symptoms scale (MD -2.31, 95% CI -3.63 to -1.00; I² = 0%; 5 RCTs, 1030 participants; moderate CoE) on a scale from 17 to 85 with larger values reflecting worse sexual quality of life. We assumed a MCID of greater than or equal to 10. TRT also likely results in little to no difference in cardiovascular mortality (risk ratio (RR) 0.83, 95% CI 0.21 to 3.26; I² = 0%; 10 RCTs, 3525 participants; moderate CoE). Based on two cardiovascular deaths in the placebo group and an assumed MCID of 3%, this would correspond to no additional deaths per 1000 men (95% CI 1 fewer to 4 more). TRT also likely results in little to no difference in treatment withdrawal due to adverse events, prostate-related events, or LUTS. Testosterone versus placebo (later than 12 months) We are very uncertain about the longer-term effects of TRT on erectile dysfunction assessed with the IIEF-EF (MD 4.20, 95% CI -2.03 to 10.43; 1 study, 42 participants; very low CoE). We did not find studies reporting on sexual quality of life or cardiovascular mortality. We are very uncertain about the effect of testosterone on treatment withdrawal due to adverse events. We found no studies reporting on prostate-related events or LUTS. AUTHORS' CONCLUSIONS: In the short term, TRT probably has little to no effect on erectile function, sexual quality of life, or cardiovascular mortality compared to a placebo. It likely results in little to no difference in treatment withdrawals due to adverse events, prostate-related events, or LUTS. In the long term, we are very uncertain about the effects of TRT on erectile function when compared to placebo; we did not find data on its effects on sexual quality of life or cardiovascular mortality. The certainty of evidence ranged from moderate (signaling that we are confident that the reported effect size is likely to be close to the true effect) to very low (indicating that the true effect is likely to be substantially different). The findings of this review should help to inform future guidelines and clinical decision-making at the point of care.

Uncovering gaps in GRADE reporting of Eastern Association for the Surgery of Trauma (EAST) guidelines.

OBJECTIVES: To formally evaluate the uptake and reporting of the Grading of Recommendation Assessments, Development and Evaluation (GRADE) approach in clinical practice guidelines (CPGs) developed by the Eastern Association for the Surgery of Trauma (EAST). STUDY DESIGN AND SETTING: Based on an a priori, written protocol, we developed a dedicated data abstraction form that included the six suggested criteria for using and applying GRADE. By searching the EAST website, we identified all EAST guidelines that referenced the use of GRADE. All steps of the data abstraction process were completed independently and in duplicate by two members of the research team. RESULTS: We identified a total of 48 CPGs that used GRADE. Trauma and violence prevention (n = 11; 23.9%) was the most common topic. The median number of patient/population, intervention, comparison, and outcomes (PICO) questions addressed was 3 (interquartile range: 2; 4) with a median of 2.5 (interquartile range: 1; 4) critical outcomes. A conditional/weak recommendation was provided for n = 79 (51.4%) PICOs, whereas a strong recommendation was provided for 33 PICOs (23.9%). For 22 PICOs (15.9%), no recommendation was made. Nearly all guideline documents provided search dates (n = 44; 95.7%) and a Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram (n = 44; 95.7%). Most described categories for rating down (n = 35; 76.1%). GRADE decision-making domains related to the ratio of benefits to harms, values and preferences, and resource utilization were referenced by 43.5% (n = 20), 43.5% (n = 20), and 30.4% (n = 14) of CPGs, respectively. For nearly half of PICO questions (n = 59; 44.2%) authors did not provide an evidence profile or summary of findings table. Comparing time periods from 2014-2018 to 2019-2022, the proportion of recommendations with an overall certainty of evidence increased (52.4% vs 83.9%; P < 0.001). CONCLUSION: EAST has successfully adopted GRADE to develop many trauma-related guidelines, each addressing a finite number of focused clinical questions based on systematic reviews conducted in-house. Overall reporting improved over time. There is for improvement when it comes to consistent provision of an overall certainty of evidence, the reporting of the evidence to decision-making process, and the justification of strong recommendations based on low/very low certainty evidence.

Percutaneous nephrolithotomy vs retrograde intrarenal surgery for renal stones: a Cochrane Review.

OBJECTIVES: To assess the effects of percutaneous nephrolithotomy (PCNL) vs retrograde intrarenal surgery (RIRS) for the treatment of renal stones in adults. METHODS: We performed a comprehensive search of the Cochrane Library, MEDLINE, Embase, three other databases, trials registries, other sources of the grey literature, and conference proceedings up to 23 March 2023. We applied no restrictions on publication language or status. Screening, data extraction, risk-of-bias assessment, and certainty of evidence (CoE) rating using the Grading of Recommendations Assessment, Development and Evaluations (GRADE) approach were done in duplicate by two independent reviewers. This co-publication focuses on the primary outcomes of this review only. RESULTS: We included 42 trials that met the inclusion criteria. Stone-free rate (SFR): PCNL may improve SFRs (risk ratio [RR] 1.13, 95% confidence interval [CI] 1.08-1.18; I2 = 71%; 39 studies, 4088 participants; low CoE). Major complications: PCNL probably has little to no effect on major complications (RR 0.86, 95% CI 0.59-1.25; I2 = 15%; 34 studies, 3649; participants; moderate CoE) compared to RIRS. Need for secondary interventions: PCNL may reduce the need for secondary interventions (RR 0.31, 95% CI 0.17-0.55; I2 = 61%; 21 studies, 2005 participants; low CoE) compared to RIRS. CONCLUSION: Despite shortcomings in most studies that lowered our certainty in the estimates of effect to mostly very low or low, we found that PCNL may improve SFRs and reduce the need for secondary interventions while not impacting major complications. Ureteric stricture rates may be similar compared to RIRS. We expect the findings of this review to be helpful for shared decision-making about management choices for individuals with renal stones.

Certainty of Evidence Assessment in Systematic Reviews Published by High-Impact Sports Science Journals: A Meta-epidemiological Study.

BACKGROUND: Assessing certainty of evidence is a key element of any systematic review. The aim of this meta-epidemiology study was to understand the frequency and ways with which certainty of evidence is assessed in contemporary systematic reviews published in high-impact sports science journals. METHODS: We searched PubMed and relevant journal web sites from 1 August 2016 to 11 October 2022 for systematic reviews published in the top-ten highest-impact journals within the 2020 Journal Citation Report for the Sports Sciences category. Pairs of independent reviewers screened items using a priori established criteria. RESULTS: Of 1250 eligible documents, 258 (20.6%) assessed the certainty of evidence, defined as using two or more distinct domains to provide an overall rating of the trustworthiness of findings across studies. Nine methods were cited for assessing certainty, with the most common being the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach (61.6%). The proportion of systematic reviews assessing certainty of evidence appeared to increase over the 6-year timeframe analyzed. Across all reviews analyzed, a large majority addressed the domains of risk of bias, imprecision, and inconsistency of the results. Other certainty domains including indirectness/applicability were less commonly assessed. DISCUSSION: Only one in five recent contemporary systematic reviews in the field of exercise and sports science assessed certainty of evidence. Organizational and institutional education on methods for assessing evidence may help further increase uptake of these methods and improve both the quality and clinical impact of systematic reviews in the field.

Tranexamic acid for percutaneous nephrolithotomy: an abridged Cochrane review.

OBJECTIVE: To assess the effects of tranexamic acid (TXA) in individuals with kidney stones undergoing percutaneous nephrolithotomy (PCNL). PATIENTS AND METHODS: We performed a literature search of Cochrane Library, PubMed (including MEDLINE), Embase, Scopus, Global Index Medicus, trials registries, grey literature, and conference proceedings. We included randomised controlled trials (RCTs) that compared treatment with PCNL with administration of TXA to placebo (or no TXA) for patients aged ≥18 years. Two review authors independently classified studies and abstracted data. Primary outcomes were blood transfusion, stone-free rate (SFR), thromboembolic events (TEE). We rated the certainty of evidence (CoE) according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach using a minimally contextualised approach with pre-defined thresholds for minimally clinically important differences (MCID). RESULTS: We included 10 RCTs assessing the effect of systemic TXA in PCNL vs placebo (or no TXA). Eight studies were published as full text. Based on an adjusted baseline risk of blood transfusion of 5.7%, systemic TXA may reduce blood transfusions (risk ratio [RR] 0.45, 95% confidence interval [CI] 0.27-0.76). Based on an adjusted baseline SFR of 75.7%, systemic TXA may increase SFR (RR 1.11, 95% CI 0.98-1.27). There is probably no difference in TEEs (risk difference 0.001, 95% CI -0.01 to 0.01). Systemic TXA may increase adverse events (AEs) (RR 5.22, 95% CI 0.52-52.72). Systemic TXA may have little to no effect on secondary interventions (RR 1.15, 95% CI 0.84-1.57). The CoE for most outcomes was assessed as low or very low. CONCLUSIONS: Based on a body of evidence of 10 RCTs, we found that systemic TXA in PCNL may reduce blood transfusions, major surgical complications, and hospital length of stay, as well as improve the SFR; however, it may increase AEs. These findings should inform urologists and their patients in making informed decisions about the use of TXA in the setting of PCNL.

Management of Lower Urinary Tract Symptoms Attributed to Benign Prostatic Hyperplasia (BPH): AUA Guideline Amendment 2023.

PURPOSE: The purpose of this American Urological Association (AUA) Guideline amendment is to provide a useful reference on the effective evidence-based management of male lower urinary tract symptoms secondary/attributed to BPH (LUTS/BPH). MATERIALS AND METHODS: The Minnesota Evidence Review Team searched Ovid MEDLINE, the Cochrane Library, and the Agency for Healthcare Research and Quality (AHRQ) database to identify studies relevant to the management of BPH. The guideline was updated in 2023 to capture eligible literature published between September 2020 and October 2022. When sufficient evidence existed, the body of evidence was assigned a strength rating of A (high), B (moderate), or C (low) for support of Strong, Moderate, or Conditional Recommendations. In the absence of sufficient evidence, additional information is provided as Clinical Principles and Expert Opinions. RESULTS: The BPH amendment resulted in changes to statements/supporting text on combination therapy, photoselective vaporization of the prostate (PVP), water vapor thermal therapy (WVTT), laser enucleation, and prostate artery embolization (PAE). A new statement on temporary implanted prostatic devices (TIPD) was added. In addition, statements on transurethral needle ablation (TUNA) and transurethral microwave thermotherapy (TUMT) were removed and information regarding these legacy technologies was added to the background section. References and the accompanying treatment algorithms were updated to align with the updated text. CONCLUSION: This guideline seeks to improve clinicians' ability to evaluate and treat patients with BPH/LUTS based on currently available evidence. Future studies will be essential to further support these statements to improve patient care.

Percutaneous nephrolithotomy versus retrograde intrarenal surgery for treatment of renal stones in adults.

BACKGROUND: Kidney stones (also called renal stones) can be a source of pain, obstruction, and infection. Depending on size, location, composition, and other patient factors, the treatment of kidney stones can involve observation, shock wave lithotripsy, retrograde intrarenal surgery (RIRS; i.e. ureteroscopic approaches), percutaneous nephrolithotomy (PCNL), or a combination of these approaches. OBJECTIVES: To assess the effects of percutaneous nephrolithotomy (PCNL) versus retrograde intrarenal surgery (RIRS) for the treatment of renal stones in adults. SEARCH METHODS: We performed a comprehensive search of the Cochrane Library, MEDLINE, Embase, Scopus, and two trials registries up to 23 March 2023. We applied no restrictions on publication language or status. SELECTION CRITERIA: We included randomized controlled trials that evaluated PCNL (grouped by access size in French gauge [Fr] into three groups: ≥ 24 Fr [standard PCNL], 15-23 Fr [mini-PCNL and minimally invasive PCNL], and < 15 Fr [ultra-mini-, mini-micro-, super-mini-, and micro-PCNL]) versus RIRS. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies and extracted data from the included studies. Our primary outcomes were stone-free rate, major complications, and need for secondary interventions. Our main secondary outcomes were unplanned medical visits to emergency/urgent care or outpatient clinic, length of hospital stay, ureteral stricture or injury, and quality of life. We performed statistical analyses using a random-effects model. We rated the certainty of evidence using GRADE criteria. We adopted a minimally contextualized approach with predefined thresholds for minimal clinically important differences (MCIDs). MAIN RESULTS: We included 42 trials assessing the effects of PCNL versus RIRS in 4571 randomized participants. Twenty-two studies were published as full-text articles, and 20 were published as abstract proceedings. The average size of stones ranged from 10.1 mm to 39.1 mm. Most studies did not report sources of funding or conflicts of interest. The main results for the most important outcomes are summarized below. Stone-free rate PCNL compared with RIRS may improve stone-free rates (risk ratio [RR] 1.13, 95% confidence interval [CI] 1.08 to 1.18; I2 = 71%; 39 studies, 4088 participants; low-certainty evidence). Based on 770 participants per 1000 being stone-free with RIRS, this corresponds to 100 more (62 more to 139 more) stone-free participants per 1000 with PCNL (an absolute difference of 10%, where the predefined MCID was 5%). Major complications PCNL compared with RIRS probably has little or no effect on major complications (RR 0.86, 95% CI 0.59 to 1.25; I2 = 15%; 34 studies, 3649 participants; moderate-certainty evidence). Based on 31 complications in the RIRS group, this corresponds to six fewer (13 fewer to six more) major complications per 1000 with PCNL (an absolute difference of 0.6%, where the predefined MCID was 2%). Need for secondary interventions PCNL compared with RIRS may reduce the need for secondary interventions (RR 0.31, 95% CI 0.17 to 0.55; I2 = 61%; 21 studies, 2005 participants; low-certainty evidence). Based on 222 secondary interventions in the RIRS group, this corresponds to 153 fewer (185 fewer to 100 fewer) secondary interventions per 1000 with PCNL (an absolute difference of 15.3%, where the predefined MCID was 5%). Unplanned medical visits No studies reported unplanned medical visits. Length of hospital stay PCNL compared with RIRS may extend length of hospital stay (mean difference 1.04 days more, 95% CI 0.27 more to 1.81 more; I2 = 100%; 26 studies, 2804 participants; low-certainty evidence). This effect size is greater than the predefined MCID of one day. Ureteral stricture or injury PCNL compared with RIRS may have little or no effect on the occurrence of ureteral strictures (RR 0.93, 95% CI 0.39 to 2.21; I2 = 0%; 13 studies, 1574 participants; low-certainty evidence). Based on 14 ureteral strictures in the RIRS group, this corresponds to one fewer (nine fewer to 17 more) ureteral strictures per 1000 with PCNL (an absolute difference of 0.1%, where the predefined MCID was 2%). Quality of life No studies reported quality of life. AUTHORS' CONCLUSIONS: Based on a large body of evidence from 42 trials, we found that PCNL compared with RIRS may improve stone-free rates and may reduce the need for secondary interventions, but probably has little or no effect on major complications. PCNL compared with RIRS may have little or no effect on ureteral stricture rates and may increase length of hospital stay. We found no evidence on unplanned medical visits or participant quality of life. Because of the considerable shortcomings of the included trials, the evidence for most outcomes was of low certainty. Access size for PCNL was less than 24 Fr in most studies that provided this information. We expect the findings of this review to be helpful for shared decision-making about management choices for individuals with renal stones.

Tranexamic acid for percutaneous nephrolithotomy.

BACKGROUND: Percutaneous nephrolithotomy (PCNL) is the gold standard for the treatment of large kidney stones but comes with an increased risk of bleeding compared to other treatments, such as ureteroscopy and shock wave lithotripsy. Tranexamic acid (TXA) is an antifibrinolytic agent that has been used to reduce bleeding complications in other settings. OBJECTIVES: To assess the effects of TXA in individuals with kidney stones undergoing PCNL. SEARCH METHODS: We performed a comprehensive literature search of the Cochrane Library, PubMed (including MEDLINE), Embase, Scopus, Global Index Medicus, trials registries, other sources of the grey literature, and conference proceedings. We applied no restrictions on the language of publication nor publication status. The latest search date was 11 May 2023. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that compared treatment with PCNL with administration of TXA to placebo (or no TXA) for patients ≥ 18 years old. DATA COLLECTION AND ANALYSIS: Two review authors independently classified studies and abstracted data. Primary outcomes were: blood transfusion, stone-free rate (SFR), and thromboembolic events (TEEs). Secondary outcomes were: adverse events (AEs), secondary interventions, major surgical complications, minor surgical complications, unplanned hospitalizations or readmissions, and hospital length of stay (LOS). We performed statistical analyzes using a random-effects model. We rated the certainty of evidence (CoE) according to the GRADE approach using a minimally contextualized approach with predefined thresholds for minimally clinically important differences (MCIDs). MAIN RESULTS: We analyzed 10 RCTs assessing the effect of systemic TXA in PCNL versus placebo (or no TXA) with 1883 randomized participants. Eight studies were published as full text. One was published in abstract proceedings, but it was separated into two separate studies for the purpose of our analyzes. Average stone surface area ranged 3.45 to 6.62 cm2. We also found a single RCT published in full text assessing the effects of topical TXA in PCNL versus placebo (or no TXA) with 400 randomized participants, the results of which are further described in the review. Here we focus only on the results of TXA used systemically. Blood transfusion - Based on a representative baseline risk of 5.7% for blood transfusions taken from a large presentative observational studies, systemic TXA may reduce blood transfusions (risk ratio (RR) 0.45, 95% confidence interval (CI) 0.27 to 0.76; I2 = 28%; 9 studies, 1353 participants; low CoE). We assumed an MCID of ≥ 2%. Based on 57 participants per 1000 with placebo (or no TXA) being transfused, this corresponds to 31 fewer (from 42 fewer to 14 fewer) participants being transfused per 1000. Stone-free rate - Based on a representative baseline risk of 75.7% for SFR, systemic TXA may increase SFRs (RR 1.11, 95% CI 0.98 to 1.27; I2 = 62%; 4 studies, 603 participants; low CoE). We assumed an MCID of ≥ 5%. Based on 757 participants per 1000 being stone free with placebo (or no TXA), this corresponds to 83 more (from 15 fewer to 204 more) stone-free participants per 1000. Thromboembolic events - There is probably no difference in TEEs (risk difference (RD) 0.00, 95% CI -0.01 to 0.01; I2 = 0%; 6 studies, 841 participants; moderate CoE). We assumed an MCID of ≥ 2%. Since there were no thromboembolic events in intervention and/or control groups in 5 out of6 studies, we opted to assess a risk difference with systemic TXA for this outcome. Adverse events - Systemic TXA may increase AEs (RR 5.22, 95% CI 0.52 to 52.72; I2 = 75%; 4 studies, 602 participants; low CoE). We assumed an MCID of ≥ 5%. Based on 23 participants per 1000 with placebo (or no TXA) having an adverse event, this corresponds to 98 more (from 11 fewer to 1000 more) participants with adverse events per 1000. Secondary interventions - Systemic TXA may have little to no effect on secondary interventions (RR 1.15, 95% CI 0.84 to 1.57; I2 = 0%; 2 studies, 319 participants; low CoE). We assumed an MCID of ≥ 5%. Based on 278 participants per 1000 with placebo (or no TXA) having a secondary intervention, this corresponds to 42 more (from 44 fewer to 158 more) participants with secondary interventions per 1000. Major surgical complications - Based on a representative baseline risk for major surgical complications of 4.1%, systemic TXA may reduce major surgical complications (RR 0.36, 95% CI 0.21 to 0.62; I2 = 0%; 5 studies, 733 participants; moderate CoE). We assumed an MCID of ≥ 2%. Based on 41 participants per 1000 with placebo (or no TXA) having a major surgical complication, this corresponds to 26 fewer (from 32 fewer to 16 fewer) participants with major surgical complications per 1000. Minor surgical complications - Systemic TXA may reduce minor surgical complications (RR 0.71, 95% CI 0.45 to 1.10; I2 = 76%; 5 studies, 733 participants; low CoE). We assumed an MCID of ≥ 5%. Based on 396 participants per 1000 with placebo (or no TXA) having a minor surgical complication, this corresponds to 115 fewer (from 218 fewer to 40 more) participants with minor surgical complications per 1000. Unplanned hospitalizations or readmissions - We are very uncertain how unplanned hospitalizations or readmissions are affected (RR 1.55, 95% CI 0.45 to 5.31; I2 = not applicable; 1 study, 189 participants; very low CoE). We assumed an MCID of ≥ 2%. Hospital length of stay - Systemic TXA may reduce hospital LOS (mean difference 0.52 days lower, 95% CI 0.93 lower to 0.11 lower; I2 = 98%; 7 studies, 1151 participants; low CoE). We assumed an MCID of ≥ 0.5 days. AUTHORS' CONCLUSIONS: Based on 10 RCTs with substantial methodological limitations that lowered all CoE of effect, we found that systemic TXA in PCNL may reduce blood transfusions, major and minor surgical complications, and hospital LOS, as well as improve SFRs; however, it may increase AEs. We are uncertain about the effects of systemic TXA on other outcomes. Findings of this review should assist urologists and their patients in making informed decisions about the use of TXA in the setting of PCNL.

Evaluating the Certainty of Evidence in Evidence-based Medicine.

Certainty of evidence (formerly known as quality of evidence) is defined as the extent to which our confidence in an estimate of the effect is correct or our certainty that such estimate supports a particular recommendation for a clinical practice guideline. Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) is a structured and reproducible framework for assigning a level of certainty on a per-outcome basis for evidence derived from randomized and nonrandomized studies. The level of certainty starts as high or low and can be increased or decreased after considering several criteria (eg, risk of bias, inconsistency of results, publication bias, dose-response gradient, large magnitude of effect, among others). Here we describe in brief the GRADE process for summarizing and assigning a certainty rating for evidence. PATIENT SUMMARY: The GRADE framework is a way to work out how much we can trust results from medical research studies. This helps doctors in making informed decisions with their patients.

Immunotherapy for advanced or metastatic urothelial carcinoma.

BACKGROUND: Immune checkpoint inhibitors are increasingly important in the treatment algorithm for locally advanced and metastatic bladder cancer. Numerous ongoing studies are investigating these agents as first- and second-line therapies, both alone and in combination with chemotherapy or in a maintenance therapy setting. OBJECTIVES: To assess the effects of immune checkpoint inhibitors compared to chemotherapy as first- and second-line treatment of advanced or metastatic urothelial carcinoma. SEARCH METHODS: We performed a comprehensive search including the Cochrane Library, MEDLINE, Embase, three other databases, several trial registers, other sources of gray literature, and conference proceedings, with no restrictions on language of publication. We limited the search period to run from 2000 until August 2022. SELECTION CRITERIA: We included randomized controlled trials (RCTs) using immunotherapy versus chemotherapy and would have considered non-randomized trials in the absence of randomized trial data. Participants had locally advanced inoperable (cT4b or N+, or both) or metastatic (M1) (or both) urothelial carcinoma of the bladder or upper urinary tract. We excluded studies of people in whom immunotherapy was used in combination with chemotherapy or in a surveillance setting. DATA COLLECTION AND ANALYSIS: Two review authors independently classified studies for inclusion and abstracted data from included studies. We performed statistical analyses using a random-effects model and interpreted them according to the Cochrane Handbook for Systematic Reviews of Interventions. We used GRADE guidance to rate the certainty of evidence on a per-outcome basis. MAIN RESULTS: We included five RCTs and identified seven single-armed studies. The RCTs included 3572 participants comparing immunotherapy versus chemotherapy for the treatment of locally advanced and metastatic bladder cancer. First-line therapy Immunotherapy probably has little to no effect on the risk of death from any cause when used as first-line therapy compared to chemotherapy (hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.87 to 1.07; I2 = 0%; 3 studies, 2068 participants; moderate-certainty evidence). This corresponds to 750 deaths per 1000 participants with chemotherapy and 11 fewer (45 fewer to 26 more) deaths per 1000 participants with immunotherapy at 36 months. Immunotherapy probably has little to no effect on health-related quality of life (mean difference (MD) 4.10, 95% CI 3.83 to 4.37; 1 study, 393 participants; moderate-certainty evidence), when assuming a minimal clinically important difference (MCID) of at least 6 points (using the Functional Assessment of Cancer Therapy - Bladder [FACT-BL] tool; scale 0 to 156 with higher scores representing better quality of life). Immunotherapy probably reduces adverse events grade 3 to 5 (RR 0.47, 95% CI 0.29 to 0.75; I2 = 97%; 3 studies, 2046 participants; moderate-certainty evidence). This corresponds to 908 grade 3 to 5 adverse events per 1000 participants with chemotherapy, with 481 fewer (644 fewer to 227 fewer) grade 3 to 5 adverse events per 1000 participants with immunotherapy. We found no evidence for the outcome time to death from bladder cancer. Immunotherapy probably increases the risk of time to disease progression (HR 1.33, 95% CI 1.17 to 1.50; I2 = 0%; 2 studies, 1349 participants; moderate-certainty evidence). This corresponds to 660 events per 1000 participants with chemotherapy and 102 more (57 more to 152 more) events per 1000 participants with immunotherapy at 36 months. Immunotherapy may reduce discontinuations due to adverse effects (RR 0.47, 95% CI 0.20 to 1.10; I2 = 94%; 3 studies, 2046 participants; low-certainty evidence). This corresponds to 338 discontinuations per 1000 participants with chemotherapy and 179 fewer (271 fewer to 34 more) discontinuations per 1000 participants with immunotherapy. Second-line therapy Immunotherapy may reduce the risk of death from any cause when used as second-line therapy (HR 0.72, 95% CI 0.63 to 0.81; I2 = 0%; 2 studies, 1473 participants; low-certainty evidence). This corresponds to 920 deaths per 1000 participants with chemotherapy (vinflunine, paclitaxel, docetaxel) and 59 fewer (95 fewer to 28 fewer) deaths per 1000 participants with immunotherapy at 36 months. Immunotherapy may have little to no effect on health-related quality of life when compared to chemotherapy (MD 4.82, 95% CI -3.11 to 12.75; I2 = 85%; 2 studies, 727 participants; low-certainty evidence), assuming an MCID of at least 10 points (using the EORTC QLQ tool; scale 0 to 100 with higher scores representing better quality of life). Immunotherapy may reduce adverse events grade 3 to 5 in participants undergoing second-line therapy (RR 0.89, 95% CI 0.81 to 0.97; I2 = 9%; 2 studies, 1423 participants; low-certainty evidence). This corresponds to 630 grade 3 to 5 adverse events per 1000 participants with chemotherapy and 76 fewer (126 fewer to 25 fewer) grade 3 to 5 adverse events per 1000 participants with immunotherapy. We found no evidence for the outcome of time to death from bladder cancer. We are very uncertain if immunotherapy reduces the risk of disease progression (HR 0.99, 95% CI 0.84 to 1.16; I2 = 0%; 2 studies, 1473 participants; very low-certainty evidence). Immunotherapy may reduce discontinuations due to adverse events in participants undergoing second-line therapy (RR 0.35, 95% CI 0.17 to 0.72; I2 = 69%; 2 studies, 1473 participants; low-certainty evidence). This corresponds to 110 discontinuations per 1000 participants with chemotherapy and 72 fewer (91 fewer to 31 fewer) discontinuations per 1000 participants with immunotherapy. AUTHORS' CONCLUSIONS: Compared to chemotherapy, immunotherapy for treating advanced or metastatic urothelial carcinoma probably has little to no effect on the risk of death from any cause when used as first-line therapy. Still, it may reduce the risk of death from any cause when used as second-line therapy. Health-related quality of life for participants receiving first- and second-line therapy does not appear to be affected by immunotherapy. Immunotherapy probably reduces or may reduce adverse events grade 3 to 5 when used as first- and second-line therapy, respectively.