41 minute read
Key articles from international medical journals
Prof. Serdar Tekgül Section Editor Ankara (TR)
serdartekgul@ gmail.com
Advertisement
Do modern disposable diapers stimulate better bladder control in children?
Over the last decades, the availability of modern disposable diapers (DD) has changed the way we manage our children. They are safe, easy to use, comfortable and easy to dispose, compared to cloth diapers used previously. Meanwhile, this has also changed our attitude to toilet training. Initiation of toilet training usually starts later compared to the past. Diapers play an important role in the management of enuresis-related issues and have significantly increased the quality of life of children as well as their family.
Although many people will disagree, there is no evidence that the use of DD postpones the time of bladder control attainment, or that removal of the DD leads to resolution of enuresis. Yet many would recommend against using DD, as a first measure towards night-time dryness training. The NICE guideline on enuresis proposes trying non-diaper periods to assess any effect on enuresis frequency.
The aim of the review by the authors was to evaluate the scientific knowledge on DD use in children with urinary incontinence, to assess whether DD use is related to continence attainment.
A systematic literature search looked at 400 studies which were eligible for screening. Finally, 12 abstracts and only eight studies were eligible for review. No prospective intervention studies specifically evaluating the effect of a diaper on enuresis were identified.
The general idea is that disposable diapers have made a significant impact on toilet training in children, however, based on the available literature no secure conclusions can be drawn. There does seem to be some proof that diaper use is related to a delay in obtaining continence in children. Source: Does the development and use of modern disposable diapers affect bladder control? A systematic review. Breinbjerg A, Rittig S, Kamperis K. J Pediatr Urol 2021
Aug;17(4):463-471.
High rate of bulbar strictures in patients treated for hypospadias
Although the subject is still insufficiently studied, increasing data appear in literature addressing the long-term complications of hypospadias repair. The relationship with the initial procedure is a challenging process of exploring the frequency of complications and understanding the variations.
There will always be a selection bias in such data, as it is almost impossible to have a good and strict follow-up of children into adulthood. Often we only see patients with problems, but not all the others who had a satisfactory outcome. Additionally, the information available about past surgical history and technique employed is not good enough to draw any conclusion on causative factors.
The use of DD is increasing as they become more safe, reliable and accessible. DD have several advantages in terms of comfort; newer materials decrease the risk of diaper dermatitis, and many argue that they increase sleep quality in children with enuresis. Along with the development of better DD, there is a concern about an increase in age of initiating TT as well as an increase in the prevalence of LUTS in children, including enuresis. Although it is tempting, a robust correlation between diaper use and continence attainment cannot be found, as no large randomised prospective studies have been performed evaluating only diapering as intervention. The evidence on the effect of DD on enuresis and TT is not clear. It is not possible to draw any conclusions, although it seems that DD use might have a negative influence on continence attainment. One study reports a better chance of success when a child wears diapers, but these findings were in children > 11 years of age, and therefore not comparable to the other cohorts described. Therefore, impact of DD on TT is debatable. A common assumption would be that the more comfortable and convenient a diaper gets, the more it takes to motivate the child and the parents to stop using them.
Because of the lack of comfortable and convenient diapers or better alternatives, TT was initiated at an earlier age in the past. The fact that more parents both have full-time jobs and children spend the largest part of the day in day-care is an extra challenge. Parents have less time for TT, which makes the DD even more convenient, and necessary to cope with incontinence in small children.
The studies presented in this review show conflicting results. Several studies believe firmly in the association between diapering and prolonged enuresis, other studies do not find this link. Whether or not DD use has different effects on enuresis compared to daytime urinary incontinence is hard to assess from the included studies, as all daytime cessation of DD is combined with some kind of TT. For the children with enuresis, avoidance of night diapers may lead to discomfort awakenings of both child and parents, interrupted and poor sleep quality, further motivating the on-going use of DD until spontaneous resolution of symptoms occurs.
It is possible to try to see whether children could actually gain continence just by stopping the use of DD, but there is no good evidence to support this practice.
Long-term hypospadias complications leading to adult urologist consultation typically include stricture, cosmesis dissatisfaction, abnormal position of the meatus, urethrocutaneous fistula, and persistent penile curvature. Urethral strictures stand as the most frequent long-term complication after hypospadias surgery during childhood. Urethral strictures are more common at the site of the initial surgery or along the neo-urethra.
The management in adult men remains challenging, with several surgical strategies available and inconsistent results. This is especially true in men with a personal history of multiple stages of urethral reconstruction during childhood.
Bulbar strictures are unexpectedly common among patients treated for hypospadias and later presenting with urethral strictures in adulthood.
In this study, the authors look into a cohort of patients who had hypospadias surgery in childhood and presented with urethral strictures. Hence there is a potential bias in the recruitment pattern and the lack of knowledge of the denominator (namely the number of hypospadias patients treated during childhood) and unavailability of medical detail in ancient operative records.
Of the 42 consecutive adults eligible, a total of 28 patients had a persistent urethral stricture. During adulthood, initial urethral assessment revealed 29 urethral strictures in 28 patients (penile urethra 23/29, bulbar urethra 8/29). The early initial success rate of stricture treatment was 50% (median follow-up: 4 years). Additional surgical procedures were needed and performed in 11 patients. Eight patients were eventually diagnosed with a bulbar stricture, either isolated (n = 5) or combined with a distal stricture (n = 3), without significant relation with the initial position of meatus.
Bulbar strictures represent more than 25% of the overall strictures diagnosed in adult patients treated for hypospadias during childhood, independent of the original site of urethral reconstruction.
The study did not discuss length and exact location of bulbar strictures, because of absence of data in some patients. It was, however, observed that symptomatic bulbar strictures do exist in adults in the long term after penile hypospadias repair during childhood, independent of the initial site of hypospadias, initial success of primary repair, and the type of surgical reconstructions performed during childhood.
Source: Adults with previous hypospadias surgery during childhood: beware of bulbar strictures. Faraj S, Loubersac T, Bouchot O, et al.
Journal of Pediatric Urology, published online November 11 2021.
In the present article, the authors reported the outcomes analysis of the phase III ACIS trial, comparing abiraterone acetate with or without apalutamide, in addition to androgen blockage, in metastatic, castration-resistant prostate cancer (PCa) patients. So far, no combination trial has proven any survival advantage at the mCRPC stage. The PLATO study, assessing the maintenance of enzalutamide at progression in addition to abiraterone, failed to demonstrate strong efficacy of the new hormonal agent combination, but this trial was conducted in the second-line setting.
In the ACIS trial, the primary endpoint was radiographic progression-free survival. Overall, 982 mCRPC, first-line, chemo-naive patients were included in this combination trial between 2014 and 2016. Secondary endpoints were overall survival, time to initiation of cytotoxic chemotherapy, time to chronic opioid use, and time to pain progression. Treatment with apalutamide plus abiraterone led to a significant improvement in radiographic progression-free survival compared with abiraterone (plus placebo) at the primary analysis (HR 0.69, 95% CI 0.58–0.83; p < 0.0001). At the final analysis (4.5 years of follow-up), the significant radiographic progression-free survival benefit persisted (HR 0.70; p < 0.0001). Thus, despite the use of an active and established therapy as the comparator, apalutamide plus abiraterone– prednisone improved radiographic progression-free survival. The concordance between central and investigator review of radiographic progressive disease was 75%, with a high positive correlation coefficient for both treatments.
No overall survival benefit was achieved by the combination. The median overall survival surpassed 3 years with apalutamide plus abiraterone (36.2 versus 33.7 months). At progression, about twothirds of the patients who discontinued treatment received subsequent life-prolonging therapy. Dr. Guillaume Ploussard Section editor Toulouse (FR)
g.ploussard@ gmail.com
Source: Apalutamide plus abiraterone acetate and prednisone versus placebo plus abiraterone and prednisone in metastatic, castrationresistant prostate cancer (ACIS): a randomised, placebo-controlled, double-blind, multinational, phase 3 study. Saad F, Efstathiou E, Attard G, et al; ACIS Investigators. Lancet Oncol. 2021 Sep
30:S1470-2045(21)00402-2
Positive signal for combined hormone therapy in mCRPC
Moreover, none of the other secondary endpoints of time to initiation of cytotoxic chemotherapy, time to chronic opioid use, and time to pain progression reached significance. Analyses of prespecified biomarker subgroups based on molecular signatures (PAM50-luminal and androgen receptor signalling activity) did not find any significant correlation with radiographic progression-free survival. Overall incidence of adverse events was similar between groups. Serious adverse events occurred in 40% versus 37% of patients receiving apalutamide plus abiraterone versus placebo plus abiraterone. Grade 3-4 adverse events were reported in 60% versus 51% of patients receiving apalutamide plus abiraterone versus placebo plus abiraterone. The most common adverse event was hypertension (10%-17%). Cardiac disorders occurred with similar frequency in both groups (19%) leading to 1% of deaths in both groups. Globally, safety was consistent with the previously reported tolerability profiles. Quality-of-line maintenance was equivalent in both arms.
This trial is the first combo phase 3 study in castration-resistant prostate cancer that has met its primary endpoint. Nevertheless, no benefit was observed in terms of overall survival. Such a combination probably does not lead to changes in current guideline treatment recommendations. However, subgroup analyses may help to identify patients that would be more likely to benefit. A positive signal was seen in patients aged 75 years and older. For this specific population who may be unfit to receive subsequent therapy sequences, the initial combination of two active drugs could be interesting to consider. Future trials are awaited to better define combinations and sequencing at the mCRPC stage, in the era of the use of new hormonal agents in the metastatic castration-sensitive prostate cancer stage.
STAMPEDE trial: Comparison of quality-of-life outcomes
Intensified systemic treatment is currently the standard treatment in metastatic prostate cancer. The choice is mainly based on new generation hormone therapy or docetaxel in addition to androgen therapy (ADT). Recently, after the presentation of the preliminary results of the PEACE1 trial during ESMO, the combination of abiraterone and docetaxel therapy has also been found to have an additional favourable impact. However, these different treatments may induce clinically meaningful side effects which may impact on the patient’s quality of life. In the present study, Rush et al report quality of life outcomes of men included in the same period in the Stampede trial, who were assigned to hormonal therapy plus docetaxel versus hormonal therapy plus abiraterone. Quality of life (QoL) was measured using the QLQ-C30 and PR25 questionnaires during a 2-year period.
Interestingly, patients who received ADT plus abiraterone were found to have a more favourable global quality of life score than men who received upfront docetaxel, mainly during the first year after treatment initiation. Thereafter, the differences in QoL between the arms decreased with little differences in the second year. The toxicity of docetaxel mainly explained the QoL scores differences. Short-term differences in fatigue, pain, physical functioning, social functioning, and role functioning were also observed, favouring abiraterone treatment over docetaxel. This data, derived from a randomised controlled trial, provide important insight in a field where not much level 1 evidence is available. Patient-reported
oliver.reich@ klinikum-muenchen.de
outcomes measurements should play an increasingly important role in assessing the value of therapy for prostate cancer, given the large number of available life-prolonging drugs. Several studies have also proven that QoL assessment can largely vary between the patient and the physician perspective. The cancer-specific and overall survival benefit should not be a stand-alone factor when deciding which drug is more suitable for an individual patient. Comorbidities, medical history, and own perspectives should be integrated into a patient-tailored decision-making process. Indeed, a patient may be more interested in side effects and impact on quality of life of the treatment options. As main limitation, we could highlight that even statistical differences were seen between both treatments in the present study, the thresholds described here remain subjective. Moreover, differences were totally amended after the first year, without sustainable benefit from long-term hormone therapy versus short-term chemotherapy.
Source: Quality of life in men with prostate cancer randomly allocated to receive docetaxel or abiraterone in the STAMPEDE trial. Rush HL, Murphy L, Morgans AK, et al. J Clin Oncol. 2021 Nov Source: Adjuvant Chemotherapy for Muscleinvasive Bladder Cancer: A Systematic Review and Meta-analysis of Individual Participant Data from Randomised Controlled Trials. Burdett S, Fisher DJ, Vale CL, et all; Advanced Bladder Cancer (ABC) Meta-analysis
Collaborators Group. Eur Urol. 2021 Nov 18:S03022838(21)02058-3
Comprehensive evaluation of psychological distress, erectile function in patients recovered from COVID-19
The recommendation of performing neoadjuvant chemotherapy is mainly based on individual participant data meta-analysis, showing a 5% reduction in mortality. The same analyses have been performed for the adjuvant setting but were limited by the small number of trials and patients. Since the initial publication, 5 additional randomised controlled trials have been completed and reported. In the present article, the authors aimed to investigate the role of adjuvant cisplatinbased chemotherapy in the treatment of muscleinvasive bladder cancer. Eligible trials were those aimed to compare adjuvant cisplatin-based chemotherapy plus local treatment versus the same local treatment alone or the same local treatment and then adjuvant cisplatin-based chemotherapy on recurrence. Local treatment could include surgery with or without preoperative radiotherapy, or radical radiotherapy ± salvage cystectomy for local failure. The ten included trials (n = 1,183 participants) accrued between 49 and 284 participants, and radical cystectomy was the local treatment in all cases. The median follow-up was 6 years.
Overall survival results showed a significant benefit of adjuvant chemotherapy (HR = 0.82; 95% CI:0.70–0.96, p = 0.02). This corresponded to a 6% absolute improvement in overall survival at 5 years. Results were the same when a randomeffects model was used. Recurrence-free survival (615 events) results were only based on nine trials (1,075 participants) and demonstrated a benefit of adjuvant chemotherapy (HR = 0.71, 95% CI = 0.60–0.83, p < 0.001). This translates to an 11% improvement at 5 years. Metastasis-free survival results were based on six trials (884 participants, 425 events) and showed an 8% absolute improvement in metastasis-free survival.
This individual participant data meta-analysis confirmed a 6% absolute benefit of cisplatin-based adjuvant chemotherapy in 5-year survival of patients with muscle-invasive bladder cancer who received radical cystectomy as primary local treatment. Moreover, no clear evidence that the effect varied by trial or participant characteristics was reported. Adjuvant chemotherapy also improved recurrence-free survival, locoregional recurrence-free survival, and metastasis-free survival. Although neoadjuvant chemotherapy is currently recommended, the 5% absolute improvement in survival achieved by this preoperative regimen was no different from that reported here after adjuvant chemotherapy. Without high-level data comparing these two regimens, this meta-analysis demonstrates that adjuvant chemotherapy may be discussed and may become a new option. It may be part of the patient counselling and could be favoured depending on circumstances and clinician and patient preference.
However, it is worthy to note that almost one-third of the participants in these trials did not receive all the chemotherapy cycles as planned (fewer cycles, lower total doses). Thus, the completeness of chemotherapy may be more difficult in the adjuvant setting compared with neoadjuvant chemotherapy due to complications and impaired renal function after radical cystectomy and urinary diversion. Last point, immunotherapy may also be considered as a new competitive option in this setting, with potentially higher complete tumour response rates and better safety profile.
The psychological and sexual health of different populations are negatively affected by the coronavirus disease (COVID-19) pandemic. However, little is known about long-term psychological distress and erectile function of male patients who recovered from COVID-19. The authors aimed to evaluate these aspects in the mid to long term.
The investigators recruited 67 eligible male patients recovered from COVID-19 and performed a follow-up twice within approximately 6 months after their recovery. The psychological distress and erectile function were assessed by validated questionnaires.
During the first visit, COVID-19 patients with a median recovery time of 80 days presented the following positive symptoms: obsessivecompulsive, additional items (ADD), hostility, interpersonal sensitivity, depression, and somatisation; while the dimension scores in somatisation, anxiety, ADD, and phobia were higher than male norms. Besides, the prevalence of erectile dysfunction (ED) in the first-visit patients was significantly higher than controls. In the second visit, the primary psychological symptoms of COVID-19 patients with a median recovery time of 174 days were obsessive-compulsive, ADD, interpersonal sensitivity, and hostility, while all dimensions scores of symptom checklist 90 were lower than male norms. Moreover, second-visit patients showed no significant difference with controls in ED prevalence.
The study showed the changes in psychological symptoms and erectile function in patients recovered from COVID-19 and provided reference on whether psychological and sexual support is needed after a period of recovery. With less impact of COVID-19, the impaired erectile function and psychological distress improved in recovered patients, with a recovery time of approx. half a year. Source: A Mid-to-Long Term Comprehensive Evaluation of Psychological Distress and Erectile Function in COVID-19 Recovered Patients. Bintao Hu, Yajun Ruan, Kang Liu, , et
al. J Sex Med. 2021 Nov;18(11):1863-1871. doi: 10.1016/j.jsxm.2021.08.010. The authors aimed to evaluate the relationship between physical activity, both work and recreational, and urinary incontinence in women.
Women aged 20 years and older were assessed in 2008-2018 NHANES (National Health and Nutrition Examination Survey) cycles and answered selfreported urinary incontinence and physical activity questions. A weighted, multivariate logistic regression model was used to determine the association between incontinence and physical activity levels after adjusting for age, body mass index, diabetes, race, parity, menopause and smoking.
A total of 30,213 women were included in the analysis, of whom 23.15% had stress incontinence, 23.16% had urge incontinence, and 8.42% had mixed incontinence (answered "yes" to both stress and urge incontinence). Women who engaged in moderate recreational activity were less likely to report stress and urge incontinence (OR 0.79, 95% CI 0.62-0.99 and OR 0.66, 95% CI 0.48-0.90, respectively). Similarly, women who engaged in moderate activity work were less likely to report stress, urge and mixed incontinence (OR 0.84, 95% CI 0.70-0.99; OR 0.84, 95% CI 0.72-0.99; and OR 0.66 95% CI 0.45-0.97, respectively).
Moderate physical activity and more time spent on participating in moderate physical activity is associated with a decreased likelihood of stress, urge and mixed incontinence in women. This relationship holds for both recreational and work-related activity. The authors hypothesise that the mechanism of this relationship is multifactorial, with moderate physical activity improving pelvic floor strength and modifying neurophysiological mediators (such as stress) involved in the pathogenesis of incontinence. Oliver.Hakenberg@ med.uni-rostock.de
Self-reported RE is common in European men aged over 40 years. The reported limited RErelated distress may explain the relatively low number of medical consultations for RE. RErelated distress is associated with worse sexual function, couple impairment, and more LUTS, resulting in a worse quality of life and mood disturbances.
Source: Self-Reported Shorter Than Desired Ejaculation Latency and Related DistressPrevalence and Clinical Correlates: Results From the European Male Ageing Study. Corona G, Rastrelli G, Bartfai G, et al. J Sex Med.
2021;18(5):908-919. doi: 10.1016/j.jsxm.2021.01.187.
Source: The Association of Physical Activity and Urinary Incontinence in US Women: Results from a Multi-Year National Survey. Kim MM, Ladi-Seyedian S-S, Ginsberg DA, et al. Urology.
2021 Oct 10;S0090-4295(21)00915-8. doi: 10.1016/j. urology.2021.09.022.
Study on self-reported shorter than desired ejaculation latency Nonlinear relationship between body mass index and clinical outcomes after kidney transplantation
A high body mass index (BMI) is a risk factor for complications in renal transplantation. The exact dose-response relation between body mass index at transplantation and clinical outcomes after kidney transplantation, however, remains unclear, and no specific body mass index threshold and pretransplant weight loss aims have been established.
The authors did a meta-analysis of the available literature after searching PubMed, Embase, Web of Science and the Cochrane Library for all relevant publications published until 31 December 2019. The two-stage, random-effect meta-analysis was performed to estimate the dose-response relation between BMI and clinical outcomes after kidney transplantation.
Few studies have looked at the occurrence and clinical correlation between self-reported shorter than desired ejaculation latency (rapid ejaculation, RE) and its related distress in the general population.
The subjects were recruited from population samples of men aged 40-79 years across 8 European centres. Self-reported RE and its related distress were derived from the European Male Aging Study (EMAS) sexual function questionnaire (EMAS-SFQ). Beck's Depression Inventory (BDI) was used for the quantification of depressive symptoms, the Short Form 36 health survey (SF-36) for the assessment of the quality of life, the International Prostate Symptom Score (IPSS) for the evaluation of lower urinary tract symptoms.
About 2,888 community dwelling men aged 40-79 years (mean 58.9 ± 10.8 years) were included in the analysis. Among the subjects included, 889 (30.8%) self-reported RE. Among them, 211 (7.3%) claimed to be distressed (5.9% and 1.4% reported mild or moderate-severe distress, respectively). Increasing levels of RE-related distress were associated with a progressively worse sexual functioning, higher risk of ED and with couple impairment, along with a higher prevalence of depressive symptoms (all p < 0.05). Furthermore, a worse quality of life and higher IPSS score were associated with RE-related distress (all p < 0.05). The above results were confirmed even when patients using drugs that possibly interfere with ejaculation or those without a stable relationship were excluded from the analysis.
Analysis of BMI, graft outcomes suggests clear margins for pre-transplant weight reduction
Ninety-four studies were included for qualitative assessment and 50 for dose-response metaanalyses. There was a U-shaped relation between graft loss, patient death and BMI. The body mass index with the lowest risk of graft loss was 25.2 kg/ m2, and the preferred BMI range was 22-28 kg/m2. Referring to a BMI of 22 kg/m2, the risk of graft loss was 1.088, 0.981, 1.003, and 1.685 for a body mass index of 18, 24, 28, and 40 kg/m2, respectively. The BMI with the lowest risk of patient death was 24.7 kg/m2, and the preferred BMI range was 22-27 kg/m2. Referring to a BMI of 22 kg/m2, the patient death risk was 1.115, 0.981, 1.032, and 2.634 for a body mass index of 18, 24, 28, and 40 kg/m2, respectively. J-shaped relations were observed between BMI and acute rejection, delayed graft function, primary graft non-function, and de novo diabetes. Pair-wise comparisons showed that higher BMI was also a risk factor for cardiovascular diseases, hypertension, infection, longer length of hospital stay, and lower estimated glomerular filtration rate level.
Oliver.Hakenberg@ med.uni-rostock.de
The authors conclude that underweight and severe obesity at transplantation are associated with a significantly increased risk of graft loss and patient death and suggest that a target BMI at kidney transplantation is 22-27 kg/m2. This analysis provides clear data on the aims that counselling of patients on the waiting list should have.
Source: Nonlinear relationship between body mass index and clinical outcomes after kidney transplantation: A dose-response meta-analysis of 50 observational studies. Yin S, Wu L, Huang
Z, Fan Y, Lin T, Song T. Surgery, 2021, doi: 10.1016/j. surg.2021.10.024, Online ahead of print.
Once daily administration of tacrolimus for immunosuppression is advantageous for patient compliance. In daily practice, pharmacokinetic data are often different from those observed in clinical trials. This is a multicentre, prospective, observational study to compare the relative bioavailability of once-daily tacrolimus formulations in de novo kidney transplant recipients.
De novo kidney transplant recipients who started a tacrolimus-based regimen were included 14 days post-transplant and followed up for 6 months. Data from 218 participants were evaluated: 129 in the ‘extended release’ group (Envarsus®) and 89 in the ‘prolonged release’ group (Advagraf®).
Patients in the ‘extended release’ group exhibited higher relative bioavailability (Cmin /total daily dose [TDD]) vs. ‘prolonged release’ tacrolimus (61% increase; p < 0.001) with similar Cmin and 30% lower TDD levels (p < 0.0001). The incidence of treatment failure was 3.9% in the ‘extended release’ group and 9.0% in the ‘prolonged release’ tacrolimus group (p = 0.117). Study discontinuation rates were 6.2% in the ‘extended release’ group and 12.4% in the ‘prolonged release’ tacrolimus group (p = 0.113). Adverse events, renal function and other complications were comparable between groups. The median accumulated dose of tacrolimus in the extended release group from day 14 to month 6 was 889 mg. Thus, the ‘extended release’ tacrolimus group showed higher relative bioavailability, similar effectiveness in preventing allograft rejection, comparable effects on renal function, safety, adherence, treatment failure and premature discontinuation rates.
Study estimates 19.7% of all global deaths are sepsis-related
Multiple cause-of-death data from 109 million individual death records were used to calculate mortality related to sepsis among each of the 282 underlying causes of death in GBD 2017. The percentage of sepsis-related deaths by underlying GBD cause in each location worldwide was modelled using mixed-effects linear regression. Sepsis-related mortality for each age group, sex, location, GBD cause, and year (1990-2017) was estimated by applying modelled cause-specific fractions to GBD 2017 cause-of-death estimates. Investigators used data for 8.7 million individual hospital records to calculate in-hospital sepsis-associated case-fatality, stratified by underlying GBD cause. In-hospital sepsis-associated case-fatality was modelled for each location using linear regression, and sepsis incidence was estimated by applying modelled case-fatality to sepsis-related mortality estimates.
In 2017, an estimated 48.9 million (95% uncertainty interval [UI] 38.9-62.9) incident cases of sepsis were recorded worldwide and 11 million (10.1-12.0) sepsis-related deaths were reported, representing 19.7% (18.2-21.4) of all global deaths. Agestandardised sepsis incidence fell by 37% (95% UI 11.8-54.5) and mortality decreased by 52.8% (47.7-57.5) from 1990 to 2017.
Sepsis incidence and mortality varied substantially across regions, with the highest burden in subSaharan Africa, Oceania, South Asia, East Asia, and Southeast Asia.
Despite declining age-standardised incidence and mortality, sepsis remains a major cause of health loss worldwide and has an especially high healthrelated burden in sub-Saharan Africa.
Source: Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study. Rudd KE, Johnson SC, Agesa KM, et al. Lancet 2020 Jan
18;395(10219):200-211. doi: 10.1016/S01406736(19)32989-7. PMID: 31954465 PMCID: PMC6970225
Source: Bioavailability of once-daily tacrolimus formulations used in clinical practice in the management of De Novo kidney transplant recipients: the better study. Fernandez Rivera CF, Rodríguez MC, Poveda JL, Pascua J, et al. Clin
Transplant 2021, doi: 10.1111/ctr.14550. Online ahead of print.
Global, regional, and national sepsis incidence and mortality, 1990-2017 Clinical characteristics and prognosis in patients with urosepsis in China
The purpose of this study was to retrospectively analyse clinical characteristics and prognostic risk factors of urosepsis patients admitted to two intensive care units in Shanghai (CN). Clinical data from patients diagnosed with urosepsis were retrieved retrospectively and analysed from ICU in two regional medical centres from January 2015 to December 2019.
Two hundred and two patients were included in the final analysis. The average age was 72.02 ± 9.66 years, 79% of the patients were female and the mortality rate was 15.84%. The proportion of patients with underlying chronic diseases, such as diabetes and hypertension, was 56.44% and 49.50%, respectively, and the incidence of shock was 41.58%, correspondingly.
Chinese study on urosepsis shows that lactate level and APACHE II score had excellent predictive value for prognosis.
The most common pathogen isolated was Escherichia coli (79.20%), of which the extended-spectrum β-lactamases (ESBL)(+) accounted for 42.57%.
In multivariate analysis, the strongest predictors for death were mechanical ventilation (OR 7.260, 95% CI 2.200–23.963; p = 0.001), chronic kidney disease (CKD)(OR 5.140, 95% CI 1.596–16.550; p = 0.006), APACHE II score (OR 1.321, 95% CI 1.184–1.473; p = 0.001) and lactate (OR 1.258, 95% CI 1.037–1.527; p = 0.020). Both APACHE II score and lactate showed excellent predictive values, with areas under the ROC curve (AUC) of 0.858 and 0.805, respectively. Patients with urosepsis were characterised by a higher proportion of females, older age and a higher percentage of comorbidities. Patients with ESBL(+) Escherichia coli infection were more prone to shock. Mechanical ventilation, comorbidity with CKD, APACHE II score and lactate were independent risk factors for death in urosepsis patients, but lactate level and APACHE II score had better predictive value for prognosis.
Sepsis is life-threatening organ dysfunction due to a dysregulated host response to infection. It is considered a major cause of health loss, but data for the global burden of sepsis are limited. As a syndrome caused by underlying infection, sepsis is not part of standard Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) estimates. Accurate estimates are important to inform and monitor health policy interventions, allocation of resources, and clinical treatment initiatives. The Source: Clinical characteristics and prognosis in patients with urosepsis from intensive care unit in Shanghai, China: a retrospective bicentre study. Ying Sheng, Wen long Zheng, Qi fang
Shi, et al. BMC Anesthesiology (2021) 21:296. h ttps://doi.org/10.1186/s12871-021-01520-5
Does mini-PCNL give higher risk of urosepsis in large renal stones?
Urosepsis is amongst the most fearsome postoperative complication of an endourological procedure as it may potentially lead to a fatality. The risk of this complication may increase in relation to multiple variables, including the invasiveness of the endourological intervention.
Percutaneous nephrolithotomy (PCNL) for the treatment of renal stones is regarded as the most invasive treatment and the risk of urosepsis may be as high as 7.6%, according to historical series published in literature.
Miniaturised PCNL (mPCNL) has been introduced in an attempt to reduce the overall risk of complications of a standard PCNL, by reducing the loss of functional renal parenchyma and reducing the risk of bleeding and pain as well.
Nevertheless, some concerns have been raised about the potential higher risk of post-operative infection during an mPCNL: the higher intrarenal pressure and longer surgical time may facilitate the spread of bacteria trapped in the stones, evolving eventually to urosepsis. This may occur regardless of an appropriate pre-surgical screening - including antibiotic targeted courses - to sterilise urine.
Recently, a group of scholars from China have reviewed their series of mPCNL in large renal stones, defined as > 3 cm in terms of overall maximum length, performed in the span of six years.
According to the inclusion/exclusion criteria, a total of 171 patients were included in the study. Urosepsis was defined according to the 2001 International Sepsis Definitions Conference as: fever > 380 or hypothermia < 360; tachycardia > 90 bpm; tachypnoea > 20/min in presence of signs of hypoxia; leucocytosis (WCC > 12,000 cells/µl) or leucopoenia (WCC < 4,000).
Mini-PCNL were performed by placing an Amplatz sheath of 20 ch in order to use a 12 ch nephroscope. Lithotripsy was realised by means of Holmium laser fibres. tebj@medisin.uio.no
Source: Analysis of pre-operative risk factors for post-operative urosepsis following minipercutaneous nephrolithotomy in patients with large kidney stones. Yirixiatijiang Amier, Yucong Zhang, Jiaqiao Zhang, et al. J Endourol . 2021 Sep 25.
doi: 10.1089/end.2021.0406. Online ahead of print.
Identifying better and safer training processes in endourology
The overall urosepsis rate was 17% (29/171), a value by far higher than those available in literature. By analysing all the clinical variables of interest at univariate analysis pre-operative urine-leukocytes count, urine nitrite, stones in adjacent calices on the coronal plane, the maximum cross-sectional area of stones, the diameter of hydronephrosis and number of stones were found to be associated with the events. Other factors, such as proportion of multiple tracts, surgical time or medical history of diabetes were not found to be associated to the events.
Furthermore, at multivariate analysis only the pre-operative urine-leukocytes count (≥ 450/µl) remained statistically correlated to the urosepsis (OR = 5.514, CI [1.866–16.795], p = 0.002). All these results could be attributed to the small number of the sample size, especially with regard to the presence of nitrite in the urine, stones in adjacent calyx, and maximum cross-sectional area of stones, where a trend towards a potential association could be observed.
Overall, regardless of its limitations, this study is the first of its kind to demonstrate that mPCNL for the treatment of large renal stones may increase the risk of urosepsis. Unfortunately, this study could not address which actual stone size should be considered the upper limit to be approached by means of mPCNL.
Surgical training is a very challenging issue nowadays, due to the complexity and variety of the technological instrumentation that has been introduced in the last decades. The ‘old-style’ method of mentor training in theatre without any skills preparation beforehand is known to expose patients to a relevant risk of complications, a significant amount of additional stress to the supervising operator, and an increased amount of surgical time that might alter surgical planning.
Simulation-based training (SBT) models have been developed in several surgical disciplines to obviate these issues, and their effects have been explored in few trials. Nevertheless, the robustness of available studies is quite weak, due to the complexity and difficulties in identifying measurement tools, standardised models and assessment protocols to verify the transfer of simulation-based skills in real-life interventions.
A group of researchers from the UK has been able to design a randomised clinical trial that could satisfy all the desired criteria: they recruited urological residents from different training centres across Europe, North-America and Asia. Main inclusion criteria included: they did not receive any significant prior surgical or simulation exposure in the field of ureteroscopy for the treatment of either ureteric or renal stones by means of semi-rigid and flexible ureteroscopy, respectively.
A sample size of 44 residents per arm was calculated in order to satisfy the primary outcome, consisting of a reduction of 33% of procedures (i.e. ≤ 10 operations) needed by the SBT group in order to achieve proficiency in the intervention of interest. Simulationbased training included dry-lab, virtual reality and wet-lab models, which were available in differing extents in the recruiting centres. Proficiency was defined as the ability of a trainee to score 28 (out of a maximum score of 35) or above in three consecutive operations according to the Objective Structured Assessment of Technical Skill (OSATS) assessment scale, without any complications. The complication rate was considered as secondary endpoint.
Resident’s development skills were followed up for a maximum of 25 surgery sessions or 18 months spent in surgical theatre.
An overall of 65 participants (SBT = 32, non-SBT = 33) completed the overall curriculum, as 29 (SBT = 14 and NSBT = 15) were lost in follow up, which consisted of more than the 10% drop-off rate expected at the time the study was designed. On the other hand, nearly 1,200 operations were evaluated for the residents’ curricula.
Although no statistical difference was identified in the overall proficiency rates achieved in the two groups, a sub-analysis regarding the proficiency in flexible URS
fsangue@ hotmail.com
– a more complex procedure - showed statistically significant better proficiency outcomes in favour of the SBT group. Similar outcomes were found for other metric units in observation, including OSATS mean score and number of cases with scores above 28.
Furthermore, complication rates favoured the SBT group, confirming that a simulation-based training model may serve as a safer programme for patients. Source: Supine versus Prone Percutaneous Nephrolithotomy for Complex Stones: A Multicenter Randomized Controlled Trial. Rodrigo Perrella, Fabio C Vicentini, Eliane D
Paro, et al. J Urol. 2021 Oct 25;101097JU0000000000002291. doi: 10.1097/ JU.0000000000002291. Online ahead of print.
Source: Effect of Simulation-based Training on Surgical Proficiency and Patient Outcomes: A Randomised Controlled Clinical and Educational Trial. Aydın A, Ahmed K, Abe T, et all; SIMULATE
Trial Group. Eur Urol. 2021 Nov 14:S03022838(21)02133-3. doi: 10.1016/j.eururo.2021.10.030.
The prone position is the most common worldwide approach to perform a percutaneous nephrolithotomy (PCNL) for the fragmentation of large renal stones. Supine PCNL has been introduced in the eighties and became more popular in the last two decades, thanks to the possibility to perform a combined retrograde ureteroscopy at the same time.
Nevertheless, there are concerns about the efficacy of supine PCNL for complex/challenging renal stones. Traditionally, the initial access to the upper tract via a prone PCNL was considered the standard of care.
The statistical difference of the immediate SFR was not significant… so that the non-inferiority supine approach was confirmed.
Evidence in literature is contrasting, but mostly based on retrospective studies. In order to shed some light on this matter, a randomised controlled trial has been conducted to compare stone-free rates at day 1 and day 90 post-op in patients harbouring complex renal stones, defined as Guy’s Stone Score (GSS) 3 and 4 and treated via a supine or prone PCNL. Basal stone burden and stone free rate (SFR) at the two time points were evaluated with a non-contrasted CT scan. SFR at day 1 included residual fragments < 4 mm, while at day 90 post-op it was defined as lack of any fragments.
The RCT was designed as a non-inferiority trial for supine PCNL to have an immediate (i.e. at day 1 post-op) SFR no worse than 15% as a non-inferior margin. Sample size calculation to test the null hypothesis resulted in the need of recruiting 56 patients per arm. Secondary outcomes included complication rates. Patients were recruited in the span of 13 months, and demographics of basal conditions were comparable among the two groups.
The statistical difference of the immediate SFR was not significant - 62.5% and 57.1% for the supine and prone PCNL, respectively (p = 0.563) - so that the non-inferiority supine approach was confirmed.
The difference of SFR at day 90 post-op was also not statistically significant: 55.4% and 50% for supine and prone PCNL, respectively.
Regardless of the fact that first renal puncture was attempted more frequently in the lower pole via a supine approach (87.3% vs. 39.3%, p = 0.001), the overall proportion of patients requiring a supracostal puncture was similar. The latter data may be explained by a larger proportion of patients in the supine PCNL group requiring more than 1 access (although this is statistically not significant). Complication rates were higher in the prone PCNL Nevertheless, the study was not powered for the complication rate, so that no definitive conclusion on safety profile could be drawn by the authors. Overall, both approaches showed similar efficacy meaning that both options should be equally considered for the treatment of complex renal stones via a PCNL.
Improving prostate cancer screening
The use of MRI in men eligible for prostate biopsy has been established as a means to avoid unnecessary biopsies whilst increasing detection of clinically significant prostate cancer. There are also several emerging blood-based tests to estimate prostate cancer risk that have shown potential to reduce the harm compared with using PSA alone for biopsy referral. Among these emerging tests is the Stockholm3 test, which incorporates clinical variables (age and previous prostate biopsy), plasma protein concentrations (PSA, free PSA, human kallikrein 2, β-microseminoprotein, and growth differentiation factor-15), and a polygenic risk score derived from single-nucleotide polymorphisms to yield a percentage risk of clinically significant prostate cancer, defined as ISUP group 2 or higher. The question is: would the combination give added value, especially in a screening scenario?
This study invited a randomly allocated cohort of men aged 50-74 years living in Stockholm county to participate in screening. those with an elevated risk of prostate cancer, defined as either a PSA of 3 ng/mL or higher or a Stockholm3 score of 0.11 or higher were eligible for randomisation. Men with a previous prostate cancer diagnosis, who had undergone a prostate biopsy within 60 days before the invitation to participate, with a contraindication for MRI, or with severe illness were excluded. Eligible participants were randomly assigned (2:3) using computergenerated blocks of five, stratified by clinically significant prostate cancer risk, to receive either systematic prostate biopsies (standard group) or biparametric MRI followed by MRI-targeted and systematic biopsy in MRI-positive participants (experimental group). The primary outcome was the detection of clinically significant prostate cancer at prostate biopsy, defined as a Gleason score of 3 + 4 or higher.
Between 5 February 2018 and 4 March 2020, 49,118 men were invited to participate, of whom 12,750 were enrolled and provided blood specimens, and 2,293 with elevated risk were randomly assigned to the experimental group (n = 1,372) or the standard group (n = 921). Compared with PSA of 3 ng/mL or higher, a Stockholm3 of 0.15 or higher provided identical sensitivity to detect clinically significant cancer and led to fewer MRI procedures (545 vs. 846; 0.64 [0.55–0.82]) and fewer biopsy procedures (311 vs. 338; 0.92 (0.86–1.03). Compared with screening using PSA and systematic biopsies, a Stockholm3 of 0.11 or higher combined with MRI-targeted and systematic biopsies was associated with higher detection of clinically significant cancers (227 [3.0%] men tested vs. 106 [2·1%] men tested; RP 1.44 [95% CI 1.15–1.81]), lower detection of low-grade cancers (50 [0.7%] vs. 73 [1.4%]; 0.46 [0.32–0.66]) and led to fewer biopsy procedures.
Compared with the screening approach used in ERSPC, this approach using Stockholm3 testing followed by MRI-targeted biopsy, improved the detection of clinically significant prostate cancers and reduced the detection of low-grade cancers. These findings should lead to a re-evaluation of populationbased prostate cancer screening in countries with high prostate cancer mortality. 2021; 22: 1240-9.
VISION: Does it let us see clearly?
As an increasing number of treatments developed in men with mCRPC are used earlier in the disease, there is a need for new options when men progress. Radioligand therapies offer an alternative mechanism to destroy cancer cells whilst sparing most normal tissues. Prostate-specific membrane antigen (PSMA) is a transmembrane glutamate carboxypeptidase that is highly expressed on prostate cancer cells. Metastatic lesions are PSMA-positive in most patients with castration-resistant prostate cancer. 177Lu-PSMA-617 delivers beta-particle radiation selectively to PSMA-positive cells and the surrounding microenvironment. The VISION trial was a phase 3 trial investigating the efficacy and safety of 177Lu-PSMA-617 plus protocol-permitted standard care in a population of previously treated patients with metastatic castration-resistant prostate cancer who were selected for PSMA positivity on the basis of PSMA positronemission tomographic (PET) imaging.
VISION is an open-label phase 3 trial evaluating 177Lu-PSMA-617 in patients who had metastatic castration-resistant prostate cancer previously treated with at least one androgen-receptor–pathway inhibitor and one or two taxane regimens and who had PSMA-positive 68Ga–PSMA-11 PET-CT scans. Patients were randomly assigned in a 2:1 ratio to receive either 177Lu-PSMA-617 (7.4 GBq every 6 weeks for four to six cycles) plus protocol-permitted standard care or standard care alone. Chemotherapy, immunotherapy, radium-223 (223Ra), and investigational drugs were excluded.
Of the 1,170 patients screened, 1,003 underwent 68Ga–PSMA-11 PET-CT scanning and 831 met all the trial eligibility criteria and were randomised. However, just 581 were included in the data on image-based progression-free survival. In this sub-group of patients, the median imaging-based progression-free survival was 8.7 months in 385 men in the 177Lu PSMA-617 group, as compared with 3.4 months in the 196 men in the control group (HR, 0.40; CI, 0.29 to 0.57; p < 0.001). Overall survival was also longer in the treatment group, median, 15.3 vs. 11.3 months; (HR, 0.62; 95% CI, 0.52 to 0.74; p < 0.001). Quality of life was maintained in the 177Lu-PSMA-617 group although the incidence of grade 3 adverse events was higher (52.7% vs. 38%).
Issues include an extremely high incidence of withdrawal in the control arm (56%), initially suggesting a lack of equipoise. Although this dropped to 16.3% after enhanced trial-site education this was much higher than in the 177Lu-PSMA-617 arm (3.2%). In addition, this trial elected to compare against standard of care rather than cabazitaxel. It was recorded that 38% had already had the drug, but for the rest this option with proven efficacy was delayed. Other data does suggest 177Lu-PSMA-617 is more effective at delaying radiographic progression, but data on survival will have to be implied. Lastly other studies have used 2 PET scans to ensure the majority of metastasis are PMSA positive. This study did not, but we are likely to see further refinement in selecting appropriate patients. Despite all of this, 177LuPSMA-617 is likely to be an important new therapeutic option for men with mCRPC
Source: Lutetium=177-PMSA-617 for metastatic castration-resistant prostate cancer. Sartor Q, de
Bono J, Chi KN, et al. NEJM 2021; 385: 1091-103.
Increased prostate cancer risk: Variants in mismatch repair gene?
Lynch syndrome is an autosomal, dominantly inherited, multicancer syndrome caused by a germline pathogenic variant in one of the mismatch repair genes: MLH1, MSH2, MSH6, or PMS2. Each gene has a different cancer incidence spectrum, with colorectal and endometrial cancers being the predominant phenotype. These pathogenic variants are also associated with an increased risk of other cancers including those of the ovary, stomach, small bowel, ureter, kidney, and brain. It has been reported to increase the risk of prostate cancer by two to ten times. Most evidence has come from studies of men with prostate cancer from families with mismatch repair pathogenic variants. Tumour testing has shown loss of expression of mismatch repair proteins and microsatellite instability. However, mismatch repair deficiency does not conclusively prove that a tumour is caused by a germline variant and not all studies show an increased risk of prostate cancer with Lynch syndrome.
The IMPACT study is prospectively assessing PSA screening in men with germline mismatch repair pathogenic variants. In this paper, they report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants.
Men aged 40–69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries and underwent a baseline PSA screening. Men who had a PSA level higher than 3.0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years’ annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls.
Between 28 September 2012 and 1 March 2020, 828 men were recruited (644 carriers of mismatch repair pathogenic variants [204 carriers of MLH1, 305 carriers of MSH2, and 135 carriers of MSH6] and 184 noncarrier controls [65 non-carriers of MLH1, 76 noncarriers of MSH2, and 43 non-carriers of MSH6]), and in order to boost the sample size for the non-carrier control groups, they randomly selected 134 noncarriers from the BRCA1 and BRCA2 cohort of the IMPACT study, who were included in all three non-carrier cohorts. Men had a mean age of 52.8 years (SD 8.3). Within the first screening round, 56 (6%) men had a PSA concentration of more than 3.0 ng/mL and 35 (4%) biopsies were done. The overall incidence of prostate cancer was 1.9% (18 of 962; 95% CI 1.1–2.9). The incidence among MSH2 carriers was 4.3% (13 of 305; 95% CI 2.3–7.2), MSH2 non-carrier controls was 0.5% (one of 210; 0.0–2.6), MSH6 carriers was 3.0% (four of 135; 0.8–7.4), and none were detected among the MLH1 carriers, MLH1 non-carrier controls, and MSH6 non-carrier controls. Prostate cancer incidence, using a PSA threshold of higher than 3.0 ng/mL, was higher in MSH2 carriers than in MSH2 non-carrier controls (4.3% vs. 0.5%; p = 0.011) and MSH6 carriers than MSH6 non-carrier controls (3.0% vs. 0%; p = 0.034). The overall positive predictive value of biopsy using a PSA threshold of 3.0 ng/mL was 51.4% (95% CI 34.0–68.6), and the overall positive predictive value of a PSA threshold of 3.0 ng/ mL was 32.1% (20.3–46.0).
IMPACT has found a significantly higher incidence of prostate cancer in men with pathogenic variants in MSH2 and MSH6 compared with non-carrier controls, supporting the theory that the risk of prostate cancer is increased with Lynch syndrome, and specifically with MSH2 and MSH6. The overall incidence of cancer for our study cohort was 1.9%, which is similar to the 2.4% reported in the BRCA1 and BRCA2 cohort of IMPACT. Urologists will need to consider PSA screening for these men. philip.cornford@ rlbuht.nhs.uk
Source: A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initial results from an international prospective study. Bancroft E, Page EC, Brook MN, et al. Lancet Oncol
