41 minute read
Key articles from international medical journals
Dr. Guillaume Ploussard Section editor Toulouse (FR)
g.ploussard@ gmail.com
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No SARS-CoV-2 in semen specimens, abnormal sex hormone secretion
In the past several months, the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2)-associated infection (coronavirus disease 2019 [COVID-19]) developed rapidly and has turned into a global pandemic. Although SARS-CoV-2 mainly attacks respiratory systems, manifestations of multiple organs have been observed. A great concern was raised about whether COVID-19 may affect male reproductive functions.
In this study, investigators collected semen specimens from 12 male COVID-19 patients for virus detection and semen characteristics analysis. No SARS-CoV-2 was found in semen specimens. Eight out of 12 patients had normal semen quality.
They also compared the sex-related hormone levels between 119 reproductive-aged men with SARS-CoV-2 infection and 273 age-matched control men. Higher serum luteinizing hormone (LH) and a lower ratio of testosterone (T) to LH were observed in the COVID-19 group.
Multiple regression analysis indicated that serum T: LH ratio was negatively associated with white blood cell counts and C-reactive protein levels in COVID-19 patients.
This is the first report about semen assessment and sex hormone evaluation in reproductive-aged male COVID-19 patients. Although further studies are needed to clarify the reasons and underlying mechanisms, the present study presents an abnormal sex hormone secretion among COVID-19 patients, suggesting that attention should be paid to reproductive function evaluation in the follow-up.
Source: Evaluation of sex-related hormones and semen characteristics in reproductive-aged male COVID-19 patients. Ma L, Xie W, Li D, Shi L, Ye G, Mao Y, Xiong Y, Sun H, Zheng F, Chen Z, Qin J, Lyu J, Zhang Y, Zhang M.
Journal of medical virology, 2021-01, Vol.93 (1), p.456-462. DOI: 10.1002/jmv.26259 PMID: 32621617
Recurrent UTI in women: D-mannose may play a role
Urinary tract infections (UTI) are highly frequent in women, with a significant impact on healthcare resources. Although antibiotics still represent the standard treatment to manage recurrent UTI (rUTI), D-mannose, an inert monosaccharide that is metabolised and excreted in urine and acts by inhibiting bacterial adhesion to the urothelium, represents a promising non-antibiotic prevention strategy. The aim of this narrative review was to critically analyse clinical studies reporting data concerning the efficacy and safety of D-mannose in the management of rUTIs.
A non-systematic literature search, using the PubMed, EMBASE, Scopus, Web of science, Cochrane Central Register of Controlled Trials and Cochrane Central Database of Systematic Reviews databases, was performed for relevant articles published between January 2010 and January 2021. The following Medical Subjects Heading were used: “female/woman”, “urinary tract infection”, and “D-mannose”. Only clinical studies, systematic reviews, and metaanalyses reporting efficacy or safety data on D-mannose versus placebo or other competitors were selected. Evidence was limited to human data. The selected studies were organised in two categories based on the presence or absence of a competitor to D-mannose.
Most of the studies also showed D-mannose can play a role in the prevention of rUTI or urodynamicsassociated UTI and can overlap antibiotic treatment in some cases.
After exclusion of non-pertinent studies/articles, 13 studies were analysed. In detail, six were randomised controlled trials (RCTs), one was a randomised cross-over trial, five were prospective cohort studies, and one a retrospective analysis. Seven studies compared D-mannose to placebo or other drugs/ dietary supplements. Six studies evaluated the efficacy of D-mannose comparing follow-up data with the baseline.
D-mannose is well tolerated, with few reported adverse events (diarrhoea was reported in about 8% of patients receiving 2 g of D-mannose for at least 6 months). Most of the studies also showed D-mannose can play a role in the prevention of rUTI or urodynamics-associated UTI and can overlap antibiotic treatment in some cases. The possibility to combine D-mannose with polyphenols or Lactobacillus seems another important option for UTI prophylaxis. However, the quality of the collected studies was very low, generating, consequently, a weak grade of recommendations as suggested by international guidelines. Data on D-mannose dose, frequency, and duration of treatment are still lacking.
The authors conclude that D-mannose alone or in combination with several dietary supplements or Lactobacillus has a potential role in the non antimicrobial prophylaxis of recurrent UTI in women. Despite its frequent prescription in real-life practice, authors believe that further well-designed studies are urgently needed to definitively support the role of D-mannose in the management of recurrent UTIs in women.
Source: Role of D-Mannose in the Prevention of Recurrent Uncomplicated Cystitis: State of the Art and Future Perspectives. Cosimo De Nunzio, Riccardo Bartoletti, Andrea Tubaro, Alchiede Simonato and Vincenzo Ficarra.
Antibiotics 2021, 10(4), 373; https://doi.org/10.3390/ antibiotics10040373
Long-term corticosteroid treatment after renal transplantation has well known side-effects. However, cessation of corticosteroids is associated with a higher risk of short-term rejection. The long-term outcomes of patients who withdraw from corticosteroids remain uncertain. The aim of this prospective, randomised, double-blind and placebo-controlled trial was to compare long-term renal transplant outcomes of patients randomised to early steroid withdrawal or continued steroid treatment.
The trial was conducted in 28 US transplant centres between November 1999 and December 2002 with linkage to a mandatory national registry with validated outcome ascertainment. 386 low to moderate immune risk adult recipients of a living or deceased donor kidney transplant without delayed graft function or short-term rejection in the first week were included. Patients were randomised to receive tacrolimus and mycophenolate mofetil with or without corticosteroids 7 days after transplant. Outcome measures were allograft failure from any cause including death and allograft failure censored for patient death defined by the requirement for long-term dialysis or repeat transplant.
Of 385 patients, 191 were assigned to steroid withdrawal (mean [SD] age, 46.5 [12.1] years), and 194 patients to continued corticosteroids (mean [SD] age, 46.3 [12.6] years). The median (interquartile range) follow-up time was 15.8 (12.0-16.3) years. Based on intent-to-treat analysis, the adjusted hazard ratio of allograft failure from any cause including death was 0.83 (95% CI, 0.62-1.10; p < 0.2) and for allograft failure censored for patient death it was 0.78 (95% CI, 0.52-1.19; p < 0.26) and did not differ between the two groups. In a per-protocol-analysis among 223 patients who continued the trial-assigned treatment (n = 114 vs n = 109) for at least 5 years, the results were the same. Also, the outcomes in both groups did not differ from similarly treated contemporary registry patients who met trial eligibility criteria and were treated with the same regimens. The authors concluded that long-term corticosteroid medication may not be necessary in low to medium immune risk renal transplantation.
Source: Early corticosteroid cessation vs long-term corticosteroid therapy in kidney transplant recipients: long-term outcomes of a randomized clinical trial. Woodle ES, Gill JS, Clark S, Stewart D, Alloway R, First R.
JAMA Surg. 2021 Feb 3:e206929. doi: 10.1001/ jamasurg.2020.6929. Epub ahead of print. PMID: 33533901; PMCID: PMC7859872. Prof. Serdar Tekgül Section Editor Ankara (TR)
serdartekgul@ gmail.com
Graft thrombosis is one of the leading causes of kidney graft failure. Currently there are no standardised protocols for thromboprophylaxis. Many transplant units use unfractionated heparin (UFH) and fractionated heparins (low molecular weight heparin; LMWH). Antiplatelet agents such as aspirin might have a role in preventing graft thrombosis. However, any pharmacological thromboprophylaxis comes with the risk of major blood loss following transplantation. This systematic review looked at benefits and harms of thromboprophylaxis in patients undergoing solid organ transplantation.
The authors searched the Cochrane Kidney and Transplant Register of Studies up to November 2020. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
Only randomised controlled trials (RCTs) and quasi-RCTs designed to examine interventions to prevent thrombosis in solid organ transplant recipients were included for all donor types without any age limit for recipients. Nine studies (712 participants) were identified. Seven studies (544 participants) included kidney transplant recipients. Selection bias was high or unclear in eight of the nine studies; five studies were at high risk of bias for performance and/or detection bias; while attrition and reporting biases were in general low or unclear.
Three studies (n = 180 participants) primarily investigated heparin in kidney transplantation. Only two studies reported on graft vessel thrombosis in kidney transplantation (n = 144). These small studies were at high risk of bias in several domains and reported only two graft thromboses between them. It therefore remains unclear whether heparin decreases the risk of early graft thrombosis or non-graft thrombosis (very low certainty). UFH may make little or no difference versus placebo to the rate of major bleeding events in kidney transplantation (3 studies, n = 155; RR 2.92, 95% CI 0.89 to 9.56; I² = 0%; low certainty evidence). Sensitivity analysis using a fixed-effect model suggested that UFH may increase the risk of haemorrhagic events compared to placebo (RR 3.33, 95% CI 1.04 to 10.67, p = 0.04). Compared to control, any heparin (including LMWH) may make little or no difference to the number of major bleeding events (3 studies, 180 participants: RR 2.70, 95% CI 0.89 to 8.19; I² = 0%; low certainty evidence). The effect of heparin on other outcomes (including death, patient and graft survival, transfusion requirements) remains unclear (very low certainty evidence).
Three studies (n = 144) investigated antiplatelet interventions in kidney transplantation: aspirin versus dipyridamole, and Lipo-PGE1 plus low-dose heparin to ’control’ in patients who had a diagnosis of acute rejection. None of these reported on early graft thromboses. The effect of aspirin, dipyridamole and Lipo PGE1 plus low-dose heparin on any outcomes is unclear (very low certainty evidence).
The authors concluded that UFH may increase the risk of major bleeding in kidney transplant recipients, however, this is based on low certainty evidence, and that currently there is no good evidence to guide antithrombotic prophylaxis in renal transplantation.
Source: Interventions for preventing thrombosis in solid organ transplant recipients. Surianarayanan V, Hoather TJ, Tingle SJ, Thompson ER, Hanley J, Wilson CH.
Cochrane Database Syst Rev. 2021 Mar 15;3:CD011557. doi: 10.1002/14651858.CD011557.pub2. PMID: 33720396.
The quest for an intermediate surrogate for overall survival in localised prostate cancer
Overall survival is considered the gold standard endpoint for cancer trials. However, the natural history of localised prostate cancer poses challenges in clinical trials design. Follow-up needs to be long before achieving a significant number of events. Thus, there is a growing interest in validating intermediate endpoints which could be correlated with overall survival. Previously, the international Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) working group established metastasis-free survival as a surrogate endpoint for overall survival for men with localised prostate cancer. However, patients included in this analysis have been treated by radiotherapy in 90% of cases. The diffusion of this model in a surgery setting may be questioned. No surgical trials were included in the event-free survival analysis.
In the present article, the authors performed a second two-stage meta-analytical approach to comprehensively assess intermediate clinical endpoints across the most common treatments in localised prostate cancer (radical radiotherapy, radical prostatectomy, and hormone therapy). Published randomised trials investigating a therapeutic option for localised or biochemically recurrent prostate cancer and reporting overall survival and at least one intermediate clinical endpoint were included. Intermediate clinical endpoints were: time to biochemical failure, time to local failure, time to distant metastases, time to biochemical failure plus clinical failure, biochemical failure-free survival, progression-free survival, and metastasis-free survival. Preplanned subgroups across treatment types were assessed. Postoperative radiotherapy was included in the surgical subgroup. Another analysis evaluated only patients with high-risk disease and those with duration of follow-up > 9 years. Overall, after screening, 75 randomised trials were included (53,631 patients).
Intermediate clinical endpoints evaluating biochemical failure showed poor correlation with overall survival. Correlation with local failure was also poor. Correlation of progression-free survival was moderate (R² 0.46). Metastasis-free survival showed the strongest correlation (R² 0.78).
Oliver.Hakenberg@ med.uni-rostock.de
Findings from radiotherapy trials were similar with good correlation between progression-free survival and overall survival. Nineteen trials used radical prostatectomy as primary treatment. Six (32%) trials included postoperative radiotherapy. Biochemical failure-free survival was poorly correlated with overall survival. Progression-free survival and biochemical failure showed moderate correlation. Distant metastases and metastasis-free survival showed strong correlation with overall survival.
To compare, the surrogate threshold effect for biochemical failure overall was 0.31 for all subgroups examined compared with 0.80 for metastasis-free survival overall. This effect was even superior (0.90) in studies assessing hormone therapy with or without radiotherapy.
This aggregate meta-analysis confirms the strong correlation between metastasis-free survival and overall survival, validating the use of this surrogate as potential across all eligible trials in localised prostate cancer, including trials dealing with surgery and hormone therapy. Thus, metastasis-free survival remains a valid surrogate endpoint after surgery, a result that was not shown in previous ICECaP studies.
However, no other endpoint appeared as a good surrogate for overall survival. The correlation between biochemical/local failure and overall survival was insufficient to use it as surrogate endpoint for overall survival.
These results raise concerns about the conclusions drawn in all studies evaluating biochemical-based endpoints, even in trials with long-term follow-up and those that included high-risk disease. Such conclusions may be particularly relevant in doseescalation trials powered to reduce local failure, which is clearly not correlated with overall survival. Future development should focus on the assessment of novel endpoints, such as new generation imaging or biomarkers, to identify potential additional surrogate endpoints.
Source: Intermediate clinical endpoints for surrogacy in localised prostate cancer: an aggregate meta-analysis. Gharzai LA, Jiang R, Wallington D, et al.
Lancet Oncol 2021;22:402-410.
Bipolar androgen therapy potentially improves quality of life
Although highly effective, therapeutic resistance to androgen deprivation therapy inevitably occurs. Second-generation hormone therapies have become standard therapy and provide overall survival benefits by inhibiting AR. But resistance increases with the number of treatment lines at castrationresistant stage. Preclinical studies have suggested that AR upregulation might induce cellular vulnerability allowing prostate cancer cells to be killed by exposure to supraphysiologic testosterone. This could lead to a downregulation of AR levels and potential resensitisation to androgen-ablative therapies. In this phase 2 study, the authors hypothesised that such a bipolar androgen therapy (BAT) would have superior efficacy in CRPC as a result of chronic exposure to low androgen and adaptively sensitise these cells to anti-androgens. The TRANSFORMER (multicentre, open-label, randomised) trial compared the effects of BAT versus enzalutamide in asymptomatic men with The primary end point was clinical or radiographic PFS. 195 men were randomly assigned to receive either BAT or enzalutamide. Median follow-up time among patients was 31.9 months. The median PFS was 5.6 months in the BAT arm versus 5.7 months in the enzalutamide arm (HR, 1.13; 95% CI, 0.82 to 1.57). OS was not different between arms (32.9 vs. 29.0 months). Survival outcomes in men with short prior response to abiraterone (< 6 months) favoured BAT (HR, 0.55). Overall, 39.3% of patients initially on BAT crossed over to receive enzalutamide, whereas 47.6% of patients crossed from enzalutamide to BAT. Crossover to enzalutamide following BAT was associated with greater benefits for all secondary end points including median OS (37.1 versus 30.2). Patients who received the treatment sequence of BAT followed by enzalutamide had significantly longer PFS2 compared with the opposite sequence (28.2 vs. 19.6 months; HR, 0.44; 95% CI, 0.22 to 0.88). AR-V7 status was not predictive of clinical outcomes irrespective of the treatment received. The incidence of adverse effects was comparable in the two groups, except for fatigue (48.5% of grade1-2 on enzalutamide versus 31.5% on BAT).
The TRANSFORMER trial is interesting, as it compares two diametrically opposite treatment options at 2nd line mCRPC stage. In the present trial, BAT was not superior to enzalutamide but outcomes showed similar efficacy in terms of PFS, OS, PSA progression. Interestingly, BAT could improve quality of life by limiting treatment effects on fatigue and sexual function, in this specific context of patients progressing after abiraterone. Further evaluation is warranted to assess the benefit from the sequence BAT followed by enzalutamide in mCRPC patients previously treated by abiraterone. They run a high risk of crossed resistance to a second-line new-generation hormone therapy as a single therapy.
Source: TRANSFORMER: A randomized phase II study comparing bipolar androgen therapy versus enzalutamide in asymptomatic men with castration-resistant metastatic prostate cancer. Denmeade SR, Wang H, Agarwal N, et al.
J Clin Oncol. 2021 Feb 22:JCO2002759.
Radical cystectomy remains a complex procedure with a high risk of postoperative complications and function impairment. Minimally invasive surgery including robotics aims at reducing surgical harms and facilitating patient recovery. However, the available randomised controlled trials failed to prove any significant difference between open (ORC) and robot-assisted (RARC) radical cystectomy. Only minor and major complications rates at 30 and 90 days from surgery were evaluated and all these were limited by an extracorporeal approach for urinary diversion. The impact of radical cystectomy on health-related quality of life (HRQoL) remains largely unexplored.
In the present article, the authors reported the intermediate year of a randomised trial comparing ORC and RARC with intracorporeal urinary diversion. The primary endpoint was an interim analysis of 1-yr HRQoL outcomes. HRQoL was assessed from patient-reported questionnaires (EORTC QLQ-C30 generic and bladder cancer–specific). The first 58 consecutive patients were included in this interim analysis (30 RARC, 28 ORC). Clinical characteristics were comparable since both groups were homogeneous. The mostly used urinary diversion was the orthotopic Padua ileal bladder for both approaches (75%). A totally intracorporeal approach with no need for open conversion was performed in the robotic group. The intraoperative transfusion rate was significantly lower for the robotic approach (RARC 0% vs. ORC 14%; p = 0.048) with a trend towards significance for the overall transfusion rate (p = 0.055). Operative time was longer in the robotic group (303 vs. 204 min; p < 0.001). Hospital stay was comparable between the groups (RARC 10 d vs. ORC 15 d; p = 0.464). Complication and readmission rates were similar. Seven patients experienced disease recurrence and received salvage chemotherapy. Survival analysis demonstrated comparable outcomes for the two groups at 1 year in terms of overall survival (RARC 86% vs. ORC 93%), and disease-free survival (RARC 82% vs. ORC 86%).
Baseline HRQoL assessment was comparable between the groups. Overall, both cohorts reported significant worsening of physical functioning, body image, and sexual functioning at 1 year. Patients undergoing ORC reported a greater 1-yr impairment of role functioning, fatigue, dyspnoea, insomnia, constipation, diarrhoea, financial difficulties, and abdominal bloating and flatulence. Conversely, patients receiving RARC reported 1-yr significant impairment of urinary symptoms and problems.
These results highlighted the important impact of radical cystectomy on body image and physical and sexual functioning, irrespective of the surgical approach. No statistically significant difference favoured RARC or suggested a faster return to normal activities of daily life with robotic surgery. However, patients experienced higher impairment in terms of symptoms such as fatigue, insomnia, and gastrointestinal symptoms after ORC and a more invasive approach.
Longer follow-up and larger cohort are awaited to obtain higher evidence and to comment on potential impact of robotic surgery, in terms of immediate postoperative outcomes (hospital stay, transfusion) and of mid-term functional and quality of life outcomes.
Source: Comparison of patient-reported health-related quality of life between open radical cystectomy and robot-assisted radical cystectomy with intracorporeal urinary diversion: Interim analysis of a randomised controlled trial. Mastroianni R, Tuderti G, Anceschi U, et al.
Eur Urol Focus 2021 :00059-6.
Comparison prostatic artery embolisation and TURP in single-centre trial
Prostatic artery embolisation (PAE) for the treatment of lower urinary tract symptoms secondary to benign prostatic obstruction (LUTS/BPO) still remains under investigation.
The investigators compared the efficacy and safety of PAE and transurethral resection of the prostate (TURP) in the treatment of LUTS/BPO at 2 years of follow-up. A randomised, open-label trial was conducted. There were 103 participants aged ≥ 40 with refractory LUTS/ BPO. International Prostate Symptoms Score (IPSS) and other questionnaires, functional measures, prostate volume, and adverse events were evaluated. Changes from baseline to 2 years were tested for differences between the two interventions with standard two-sided tests.
The mean reduction in IPSS after 2 years was 9.21 points after PAE and 12.09 points after TURP (difference of 2.88 [95% confidence interval 0.04-5.72]; p = 0.047). Superiority of TURP was also found for most other patient-reported outcomes except for erectile function. PAE was less effective than TURP regarding the improvement of maximum urinary flow rate (3.9 vs. 10.23 ml/s, difference of -6.33 [-10.12 to -2.54]; p < 0.001), reduction of postvoid residual urine (62.1 vs. 204.0 ml; 141.91 [43.31-240.51]; p = 0.005), and reduction of prostate volume (10.66 vs. 30.20 ml; 19.54 [7.70-31.38]; p = 0.005). Adverse events were less frequent after PAE than after TURP (total occurrence n = 43 vs. 78, p = 0.005), but the distribution among severity classes was similar. Ten patients (21%) who initially underwent PAE required TURP within 2 years due to unsatisfying clinical outcomes, which prevented further assessment of their outcomes and, therefore, represents a limitation of the study.
The authors conclude that inferior improvements in LUTS/BPO and a relevant re-treatment rate were found 2 years after PAE compared with TURP. PAE is associated with fewer complications than TURP. The disadvantages of PAE regarding functional outcomes should be considered for patient selection and counselling. philip.cornford@ rlbuht.nhs.uk
Source: Prostatic artery embolisation versus transurethral resection of the prostate for benign prostatic hyperplasia: 2-yr outcomes of a randomised, open-label, single-centre trial. Dominik Abt, Gautier Müllhaupt, Lukas Hechelhammer, Stefan Markart, Sabine Güsewell, Hans-Peter Schmid, Livio Mordasini, Daniel S Engeler.
Eur Urol 2021 Feb 18;S0302-2838(21)00092-0. doi: 10.1016/j.eururo.2021.02.008. Online ahead of print.
Increased risk of cardiac failure with α-blockers in hypertension studies and 5-alpha reductase inhibitors in prostate studies have raised safety concerns for long-term management of benign prostatic hyperplasia. The objective of this study was to determine if these medications are associated with an increased risk of cardiac failure in routine care.
This population-based study used administrative databases including all men over 66 with a diagnosis of benign prostatic hyperplasia between 2005 and 2015. Men were categorised based on 5-alpha reductase inhibitor exposure and/or α-blocker exposure with a primary outcome of new cardiac failure utilising competing risk models.
The data set included 175,201 men with a benign prostatic hyperplasia diagnosis with 8,339, 55,383, and 41,491 exposed to 5-alpha reductase inhibitor, α-blocker and combination therapy, respectively. Men treated with 5-alpha reductase inhibitor and α-blocker, alone or in combination, had a statistically increased risk of being diagnosed with cardiac failure compared to no medication use. Cardiac failure risk was highest for α-blockers alone (HR 1.22; 95% CI 1.18-1.26), intermediate for combination α-blockers/5alpha reductase inhibitors (HR 1.16; 95% CI 1.12-1.21) and lowest for 5-alpha reductase inhibitors alone (HR 1.09; 95% CI 1.02-1.17). Nonselective α-blockers showed a higher risk of cardiac failure than selective α-blockers (HR 1.08; 95% CI 1.00-1.17).
In routine care, men with a benign prostatic hyperplasia diagnosis and exposed to both 5-alpha reductase inhibitor and α-blocker therapy had an increased association with cardiac failure, with the highest risk for men exposed to nonselective α-blockers.
Source: Cardiac failure associated with medical therapy of benign prostatic hyperplasia: A population based study. Avril Lusty, D Robert Siemens, Mina Tohidi, Marlo Whitehead, Joan Tranmer, J Curtis Nickel.
J Urol2021 Feb 22;101097JU0000000000001561. doi: 10.1097/JU.0000000000001561. Online ahead of print.
tebj@medisin.uio.no
The majority of high-grade renal trauma can be managed conservatively. However, nephrectomy is still common for acute management. The investigators hypothesised that when controlling for multiple injury severity measures, nephrectomy would be associated with increased mortality.
They identified high-grade renal trauma patients from the US National Trauma Data Bank® from 2007-2016. Exclusion criteria were age <18 years, severe head injury and death within 4 hours of admission. Conditional logistic regression analysis was performed to determine if nephrectomy was independently associated with mortality, controlling for age, gender, race/ethnicity, mechanism of injury, shock, blood transfusion, Glasgow Coma Scale, Revised Trauma Score and Injury Severity Score.
The authors identified 42,898 patients with high-grade renal trauma (grade III-V), of whom 3,204 (7.5%) underwent nephrectomy. Unadjusted mortality was 16.6% in nephrectomy vs. 5.7% in non-nephrectomy patients. In multivariable logistic regression, nephrectomy was associated with 82% increased odds of death (OR 1.82, 95% CI 1.63-2.03, p < 0.001). Other significant associations with death included age, non-white race, penetrating mechanism, hypotension, blood transfusion, lower Glasgow Coma Scale, lower Revised Trauma Score and higher Injury Severity Score. The association between nephrectomy and death did not differ by mechanism of injury.
In the US National Trauma Data Bank, nephrectomy is independently associated with increased risk of mortality after adjusting for patient demographics, injury characteristics and multiple measures of overall injury severity. Nephrectomy may impact overall survival and must be avoided when possible.
Source: Nephrectomy is associated with increased mortality after renal trauma: An analysis of the National Trauma Data Bank from 2007-2016. Ross E Anderson, Sorena Keihani, Rupam Das, Heidi A Hanson, Marta L McCrum, James M Hotaling, Jeremy B Myers.
J Urol 2021 Mar;205(3):841-847. doi: 10.1097/ JU.0000000000001366. Epub 2020 Oct 6.
Next frontier in stone disease: Predicting outcomes through Artificial Intelligence
This was the first attempt to introduce AI in the prediction of the SFR after PCNL, which may open the way to multiple future applications, including the ability to predict different outcomes.
Regardless of the limitations of the study, it was the first attempt to introduce AI in the prediction of SFR after PCNL. The main points of interest are the versatility of such technology, including the ability to predict different outcomes (and not just the SFR) as well as to continuously refine the models according to the machine learning process. One of the main issues is the need to share the ’big-data dataset, which faces restrictions from the General Data Protection Regulation currently in force.
Source: Application of Artificial Intelligence-based classifiers to predict the outcome measures and stone-free status following percutaneous nephrolithotomy for staghorn calculi: Crossvalidation of data and estimation of accuracy. Bm Zeeshan Hameed, Milap Shah, Nithesh Naik, Harneet Singh Khanuja, Rahul Paul, Bhaskar K Somani.
J Endourol, 2021 Mar 10. doi: 10.1089/end.2020.1136. Online ahead of print.
The need to appropriately counsel a patient suitable for a percutaneous nephrolithotomy (PCNL) is a very important aspect of a patient’s treatment. It may have an impact on the way the surgery is approached psychologically, on patient expectations, and on how any potential complication or sequela may affect his/ her quality of life.
Over the last years, a number of algorithms have been reported in literature to support clinicians and patients and help the decision-making process in case different indications overlap. All these tools have been built upon the basis of predefined variables, traditionally recognised as playing a role in the outcomes of interest, with the stone-free rate being the first and foremost one.
On the other hand, none of them (Guy’s stone score, CROES nomogram, S.T.O.N.E. nephrolithometry, S-ReSC score) has been widely adopted in clinical practice, as their characteristics have been variably criticised and robust validations are still lacking, so they are mostly used for investigational purposes. Artificial Intelligence (AI) is an evolving technology that may overcome such a limitation: with a process called “machine learning”, data are variably selected or deselected according to how a model is predicting the outcome. When the machine is fed with new data, the predicting models may change adapting to possible new findings.
AI is the last frontier in medicine. Over the last years, it has been applied in different fields of health care, especially in cancer care.
Its use in the context of benign diseases has been more limited but there is mounting evidence in this area as well.
An Indian group has recently published a pivotal study to determine the accuracy of models built up by means of AI to predict the stone-free rate after PCNL. 100 patients were recruited as harbouring partial or complete staghorn renal calculi according to CT findings. Different classes of variables were included in the machine learning process, involving patients’ past medical history, kidney stones characteristics, renal anatomy, stone’s composition and biochemical findings.
The output was defined as SFR yes/no at post-op imaging, although no details were provided in terms of SFR definition and time point at which SFR were assessed. Moreover, the study was retrospectively designed.
The authors tested different AI methods to select variables and build up predicting models. They found that the Linear Discriminant Analysis was the best approach to select the features of interest, and that the Random Forest was the best performing classifier with 81% of accuracy.
USIQoL: A New, effective tool for evaluation of quality of life in urinary stone patients
Measurements of health-related quality of life (HRQoL) are becoming an essential part of the outcomes assessment of intervention in medicine, especially if they are developed from the patients’ perspective with the aid of the so-called patient-reported outcome measure (PROM).
Usually, PROMs are available in the form of questionnaires which at first glance may appear obvious and simple. However, the methodology which is behind these tools is quite complex. It may require lengthy and challenging steps for development and refinement, that have been standardised by the COSMIN (Consensus-based Standards for the Selection of Health Measurement Instruments) checklist. These are among the main reasons why there still is a paucity of PROMs in many fields of medicine, including urology. Stone disease is one of the most frequently occurring urological diseases and certainly is a condition where PROMs are urgently needed.
The Ureteric Stent Symptoms Questionnaire was the first tool of this type dealing with one of the most common interventions in stone disease: the insertion of a ureteric stent. After its introduction in 2003, the urological community noticed for the first time how a simple stent insertion could actually significantly affect a patient’s quality of life.
The first PROM introduced to properly assess stone disease conditions was the Wisconsin Quality of Life (WISQoL), which has mainly been used in the research field.
The USIQoL measure was developed based on multiple phases in the framework of a complex and upto-date psychometric methodology, innovative in the field of urology
A further PROM in stone disease has been recently published by a British group: the Urinary Stones and Intervention Quality of Life (USIQoL) group. Its measure was developed following multiple phases in the framework of a complex and up-to-date psychometric methodology, innovative in the field of urology. Among the most relevant features, it is worth mentioning that the very first phase involved patients and their families in order to collect items that could be of interest from merely a patient’s point of view. An initial draft with 60 items was developed in three phases, before it was tested with 212 patients (phase 4) which led to the removal of unstable items. The final questionnaire was then tested with 369 patients and validated (phase 5), with very good psychometric indicators. The tool consists of 15 items grouped in 3 scales, involving pain with physical health (six items), psychosocial health (seven items) and work performance (two items). An overall score on a 0-100 (logit) scale is then obtained, with higher scores indicating greater bother from the symptoms. The USIQoL can be tested on patients either with the disease or after an intervention. However, it needs external and linguistic validations before widespread use.
Source: Urinary Stones and Intervention Quality of Life (USIQOL): Development and validation of a new core universal patient-reported outcome measure for urinary calculi. Hrishikesh B Joshi, Hans Johnson, Amelia Pietropaolo, Aditya Raja, Adrian D Joyce, Bhaskar Somani, Joe Philip, Chandra Shekhar Biyani, Tim Pickles.
Eur Urol Focus. 2021 Jan 8;S2405-4569(20)30313-8. doi: 10.1016/j.euf.2020.12.011. Online ahead of print.
TISU trial: Which treatment option is better for ureteric stones
The active treatment of renal and ureteric stones offers multiple options according to stone size and site. Shock Wave Lithotripsy (SWL) and ureteroscopy (URS) are both considered first options for the treatment of ureteric stone < 10 mm in diameter (either distal or proximal), while URS is the preferred option for larger ureteric stones.
Nevertheless, the debate whether one option is to be preferred is still ongoing among practitioners, with SWL supporters highlighting its minimal invasiveness versus others who value the greater effectiveness of URS.
To address this issue, the Therapeutic Interventions for symptomatic Stones – TISU - trial has been undertaken with the participation of 25 centres in the UK. Its results have been published recently.
The design of the study was a non-inferiority trial to test SWL (max. 2 sessions) as a non-inferior treatment option compared to URS in terms of no further treatment needed after 6 months from randomisation, with a margin of 20% of success rate with respect to URS on the upper bound of the estimated 95% Confidence Interval (95%CI). The secondary endpoints involved health-related quality of life measurements, including pain scale, QoL questionnaires and use of analgesic.
Between July 2013 and June 2017 a total of 613 patients were randomised; crossover was asymmetrical, with more patients from the SWL group changing group of intervention (12% vs 4%); 86 patients of the SWL arm received 2 sessions of the intervention (40% of those who eventually undertook SWL); patients who passed their stones before intervention were similarly distributed (17% vs. 12%).
No differences were found in terms of stone size, location and main demographics.
The primary outcome showed a difference of 11.7% of patients needing further treatment after 6 months between SWL (22.1%) and URS (10.3%), with the upper bound of the 95%CI being 17.8% (5.6-17.8%), which was below the margin of 20% to establish noninferiority. Nevertheless, this non-inferiority margin was not found in the remaining 3 sets of populations.
Complication rates, such as Clavien-Dindo grade ≥ 3, were similarly low in both arms (3.6 vs. 2.7%).
With respect to the secondary outcomes, more patients in the SWL arm took analgesics than those in the URS arm, but this was the only difference found by the investigators.
Overall, these data confirm that SWL may be considered a non-inferior treatment when an active treatment is deemed necessary in the case of a ureteric stone. Similarly, URS confirms better stone clearance with a lower rate of re-intervention needed. The trial did not provide a cost-effectiveness analysis.
Source: Shockwave lithotripsy versus ureteroscopic treatment as therapeutic interventions for stones of the ureter (TISU): A multicentre randomised controlled non-inferiority trial. Ranan Dasgupta, Sarah Cameron, Lorna Aucott, Graeme MacLennan, Ruth E Thomas, James N'Dow, John Norrie, Ken Anson, Francis X Keeley Jr, Sara J MacLennan, Kath Starr, Sam McClinton.
Eur Urol 2021; S0302-2838(21)00171-8. https://doi: 10.1016/j.eururo.2021.02.044. Online ahead of print.
Assisted reproductive technologies (ART) have become the mainstay of therapy for infertility. ART mainly include intrauterine insemination, in vitro fertilization (IVF), embryo transfer, artificial insemination, in vitro maturation, intracytoplasmic sperm injection (ICSI), cryopreservation of egg, sperm, and embryo and pre-transplant genetic testing. Due to its invasive nature and the multiple endocrine manipulations required, the use of ART has raised concerns about an increased risk of congenital malformations.
The authors report the results of a systematic review screening 33 papers and a total of 1316 cases of ART offspring with urogenital tract malformations and 24,516 cases of naturally conceived offspring with urogenital tract malformations. Six studies were conducted in Asia, 18 studies in Europe, 7 studies in North America, and 2 studies in Oceania.
A total of 21 studies investigated the correlation between ART and the risk of hypospadias. The meta-analysis showed that ART were correlated with an increased risk of hypospadias in male infants. Male ART offspring were 1.87 times more likely to have hypospadias than naturally conceived male offspring.
oliver.reich@ klinikum-muenchen.de
A total of 9 studies investigated the correlation between ART and the risk of postnatal cryptorchidism in infants. The meta-analysis showed that ART were correlated with an increased risk of congenital cryptorchidism in infants. The ART offspring were 1.83 times more likely to have cryptorchidism than the naturally conceived offspring.
The meta-analysis showed that compared with ICSI, IVF showed no significant correlation with the risks of hypospadias and cryptorchidism.
Parents undergoing ART are at risk for the generation of CUTM overall, hypospadias, and cryptorchidism in their offspring.
In offspring conceived by ART, multiple pregnancies may result in a higher risk of CUTM than singleton pregnancies. The effects of the IVF and ICSI techniques on urogenital tract malformations in offspring were not significantly different. Future studies on the relationship between ART and congenital malformations should include a sub-fertile group as control. There is a need for more studies to explore the relationships between the causes of infertility and congenital malformations.
Source: Assisted reproductive technologies and the risk of congenital urogenital tract malformations: A systematic review and metaanalysis. ZhiCheng Zhang, Xing Liu, Chun Wei, Jin Luo, Yan Shi, Tao Lin, DaWei He, GuangHui Wei.
Journal of Pediatric Urology, Volume 17, Issue 1, 2021, Pages 9-20.
The value of Doppler US to evaluate the clinical significance of echogenic focuses on ultrasonography in children
There are some controversies in diagnosis of small size renal stones in children. The initial diagnostic modality to be used to detect kidney stones in children is ultrasonography (US). Computed tomography is the gold standard but there are concerns about radiation exposure. Especially in the asymptomatic patient or in patients with vague symptoms, clinical significance of US findings is highly questionable and the need for further imaging is hard to define.
Nephrolithiasis is detected on ultrasound by the presence of an echogenic focus, posterior acoustic shadowing and/or twinkle artefact (TA).
Ultrasonographic (US) colour Doppler twinkling (or twinkle) artefact is a phenomenon that may aid in the detection of nephrolithiasis and this has been investigated mainly in adults. This artefact is likely due to a form of intrinsic noise known as phase jitter within the Doppler circuitry of the US machine.
TA has been shown to be highly predictive of nephrolithiasis in adults with renal colic and ureteral stones. The authors investigate if TA is reliable for diagnosing nephrolithiasis in the paediatric population.
Renal ultrasound reports indicating presence or absence of TA associated with a single echogenic focus in the kidney or ureter were evaluated by the authors. Exclusion criteria were age > 18, multiple echogenic foci or medullary calcinosis, no follow-up, or TA located outside the kidney or ureter. Stone was confirmed either by CT within 3 months of colour Doppler ultrasound, visualisation on ureteroscopy, or patient report of passing the stone.
Renal twinkling artifact detected using colour Doppler ultrasound may be a non-invasive tool to identify kidney stones in children. Although this finding is TA in children has lower sensitivity, specificity and positive predictive value, but similar negative predictive value for diagnosing nephrolithiasis.
599 ultrasound reports were reviewed and 293 met inclusion criteria. 69 had diffuse twinkle without echogenic focus and 224 showed TA with single echogenic focus. 135 patients had confirmatory information available. Nephrolithiasis was diagnosed using TA and confirmed on confirmatory studies for 49 ultrasounds. The majority of confirmed stones were in the kidney (n = 40; 82%) and mean size of confirmed stones on ultrasound was 5 mm (range 1.5-10). Sensitivity, specificity, positive predictive value and negative predictive value of TA for detecting nephrolithiasis were 83%, 78%, 74% and 86% respectively.
Compared to the adult literature, TA in children has lower sensitivity, specificity and positive predictive value, but similar negative predictive value for diagnosing nephrolithiasis. The presence of TA should be weighed in the setting of other clinical and radiographic evidence of nephrolithiasis.
Source: Does twinkle artifact truly represent a kidney stone on renal ultrasound? Kathleen Puttmann, Daniel Dajusta, Alexandra W. Rehfuss.
In Press, Journal of Pediatric Urology Available online 30 March 2021 https://doi.org/10.1016/j.jpurol.2021.03.026
More radiotherapy: Is there a cost?
Multiple studies have suggested an oncological benefit for dose-escalation of external-beam radiotherapy (EBRT) in the management of localised prostate cancer. However, escalation beyond certain thresholds is not feasible given the narrow therapeutic ratio from added toxicity. The addition of low dose-rate (LDR) brachytherapy boost to ERBT (ERBT-LDR) can maximise the biologically equivalent dose. In observational studies, it has been suggested to improve diseasespecific and overall survival for men with intermittent risk and high-risk disease. However, there is a dearth of randomised studies using modern ERBT doses and validated patient reported outcomes (PROs) to adequately assess this combination. This paper presents PROs from men undergoing EBRT alone and ERBT-LDR for localised prostate cancer enrolled in the Comparative Effectiveness Analysis of Surgery and Radiation (CESAR) study.
Participants completed the 26-item Expanded Prostate Cancer Index Composite (EPIC), the 36-item Medical Outcomes Study Short-Form Health Survey (SF-36) and a 5-item treatment regret scale at baseline, 6-months, 1 year, 3 years and 5 years. The minimum clinically important difference in scores on EPIC is from 5 to 7 for urinary irritation and from 4 to 6 for bowel function.
695 men met inclusion criteria and received either EBRT (n = 583) or EBRT-LDR (n = 112). Patients in the EBRT-LDR group were younger (median age, 66 years [interquartile range [IQR], 60-71 years] vs 69 years [IQR, 64-74 years]; p < .001), were less likely to receive pelvic radiotherapy (10% vs 18%; p = 0.04) and had higher baseline SF-36 (median score, 95 [IQR, 86-100] vs 90 [IQR, 70-100]; p < .001). Over a 3-year period, compared with EBRT, EBRT-LDR was associated with worse urinary irritative scores (adjusted mean difference at 3 years, −5.4; 95% CI, −9.3, −1.6) and bowel function scores (−4.1; 95% CI, −7.6, −0.5). The differences were no longer clinically meaningful at 5 years (difference in urinary irritative scores: −4.5; 95% CI, −8.4, −0.5; difference in bowel function scores: −2.1; 95% CI, −5.7, −1.4). However, men who received EBRT-LDR were more likely to report moderate or big problems with urinary function bother (adjusted odds ratio, 3.5; 95% CI, 1.5-8.2) and frequent urination (adjusted odds ratio, 2.6; 95% CI, 1.2-5.6) through 5 years. There were no This study should inform patients considering ERBT-LDR that it comes with a cost in terms of worse urinary irritative and bowel function. It may have a benefit based upon case series, but we await long-term data from this trial.
Source: Five-year outcomes from a prospective comparative effectiveness study evaluating external-beam radiotherapy with or without low-dose-rate brachytherapy boost for localised prostate cancer. Pasalic D, Barocas DA, Huang L-C et al.
Cancer 2021; doi: 10.1002/cncr.33388.
Future options for mCRPC
As standard treatment options for men with metastatic castration-resistant prostate cancer (mCRPC) are used earlier in the disease, there is a need for new options for men escaping androgen deprivation. Cabazitaxel, however, remains an option. It is known to improve survival in men with mCRPC progressing after previous treatment with docetaxel. [177Lu]Lu-PSMA-617 is a radiolabelled small molecule which may also play a role. It delivers high doses of radiation to prostate cancer cells via β-particulate emission with highly specific tumour targeting, thus limiting damage to normal tissues. Encouraging activity and safety has been reported in several non-randomised studies in men with mCRPC that progressed after standard therapies. The TheraP trial compared the activity and safety of [177Lu]Lu-PSMA-617 with cabazitaxel, in men for whom cabazitaxel was considered the next appropriate standard treatment.
TheraP was a multicentre, unblinded randomised phase 2 trial. It enrolled men with mCRPC and previous treatment with docetaxel and PSA progression. Previous treatment with androgen receptor-targeted therapy was allowed. Men underwent both a [68Ga]Ga-PMSA-11 and a 2-[18F]FDG PET-CT scan. Only men in whom all metastatic deposits were clearly PMSA-positive were included. Men were randomly assigned (1:1) to [177Lu] Lu-PSMA-617 (6.0–8.5 GBq intravenously every 6 weeks for up to six cycles) or cabazitaxel (20 mg/ml intravenously every 3 weeks for up to ten cycles). The primary endpoint was prostate-specific antigen (PSA) response defined by a reduction of at least 50% from baseline.
291 men were screened to identify 200 who were eligible on PET imaging. Study treatment was received by 98 (99%) of 99 men randomly assigned to [177Lu] Lu-PSMA-617 versus 85 (84%) of 101 randomly assigned to cabazitaxel. PSA responses were more frequent among men in the [177Lu]Lu-PSMA-617 group than in the cabazitaxel group (65 vs 37 PSA responses; 66% vs 37% by intention to treat; difference 29% (95% CI 16–42; p < 0.0001; and 66% vs 44% by treatment received; difference 23% [9–37]; p = 0.0016). In addition, they demonstrated a longer progression-free survival (hazard ratio 0.63 [95% CI 0.46–0·86]; p = 0.0028). They also showed a clinically meaningful improvement in patient-reported quality of life and symptoms. Grade 3–4 adverse events occurred in 32 (33%) of 98 men in the [177Lu]Lu-PSMA-617 group versus 45 (53%) of 85 men in the cabazitaxel group. No deaths were attributed to [177Lu]Lu-PSMA-617. fsangue@ hotmail.com
New standard for metastatic papillary renal cell carcinoma
Papillary renal cell carcinoma (PRCC) is the most frequent subtype of non-clear-cell renal cell carcinoma (RCC); however, it remains a rare and heterogeneous malignancy. PRCC is divided into type 1 and type 2, on the basis of different histological, molecular, and prognostic features. Alterations in the MET pathway are frequent in PRCC, mostly observed in type 1 tumours (80%), but have also been described in up to half of type 2 tumours. Randomised comparisons suggest modestly improved clinical outcomes with sunitinib, a VEGF-directed multikinase inhibitor (when compared with everolimus (mTOR inhibitor)) and it has become the standard of care for patients with metastatic PRCC.
SWOG 1500 is a randomised open-label phase 2 trial done at 65 academic and community centres in North America comparing sunitinib (50 mg 4 weeks on and 2 weeks off) to cabozantinib (60 mg od), crizotinib (250 mg bd), and savolitinib (600 mg od), with the aim of determining if MET-directed therapy could improve clinical outcomes in patients with PRCC compared with conventional VEGFdirected agents. Dose reductions were allowed if required. PRCC patients who had received one previous therapy (excluding VEGF and MET-directed agents) were eligible. PRCC subtype was the main stratification criterion, based on local assessment, whereas a post-inclusion central review was mandated. Progression-free survival was the primary endpoint.
152 patients were randomly assigned to one of four study groups. Five patients were identified as ineligible post-randomisation and were excluded from these analyses, resulting in 147 eligible patients. Assignment to the savolitinib (29 patients) and crizotinib (28 patients) groups was halted after a prespecified futility analysis; planned accrual was completed for both sunitinib (46 patients) and cabozantinib (44 patients) groups. PFS was longer in patients in the cabozantinib group (median 9.0 months, 95% CI 6–12) than in the sunitinib group (5.6 months, 3–7; hazard ratio for progression or death 0.60, 0.37–0.97, one-sided p = 0.019). Response rate for cabozantinib was 23% versus 4% for sunitinib (two-sided p = 0,010). Savolitinib and crizotinib did not improve PFS compared with sunitinib. Grade 3 or 4 adverse events occurred in 31 (69%) of 45 patients receiving sunitinib, 32 (74%) of 43 receiving cabozantinib, ten (37%) of 27 receiving crizotinib, and 11 (39%) of 28 receiving savolitinib; one grade 5 thromboembolic event was recorded in the cabozantinib group.
The discordance rate between central and local review was 37% for PRCC subtyping, and up to 24% of the tumours were ultimately not considered as PRCC after central review. However, they provided a prespecified estimation of the cabozantinib effect within each histological subset according to local or central assessment, which did not seem to modify the favourable results for cabozantinib. As a consequence, cabazantinib may supplant sunitinib as standard of care for patients with metastatic papillary kidney cancer.
We await the results of the VISION trial which should report shortly but this trial suggests we are at the beginning of radiopharmaceutical therapy for men with prostate cancer. There are issues around availability of PMSA both for scanning and therapeutics and the cost of doing both a [68Ga]Ga-PMSA-11 and a 2-[18F]FDG PET-CT scan in order to identify the patients most likely to benefit. It is too early for survival outcomes but TheraP showed better activity, safety, and patient-reported outcomes with [177Lu]Lu-PSMA-617 than with cabazitaxel in men with mCRPC progressing after docetaxel.
Source: [177Lu]Lu-PMSA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, openlabel, phase 2 trial. Hofman MS, Emmett L, Sandhu S et al.
Lancet 2021; https://doi.org/10.1016/S0140-6736(21)00237-3. Source: A comparison of sunitinib with cabozantinib, crizotinib and savolitinib for treatment of advanced papillary renal cell carcinoma: a randomised open-label, phase 2 trial. Pal SK, Tangen C, Thompson IM, et al.
Lancet 2021; 397: 695-703.
