37 minute read
Key articles from international medical journals
Prof. Oliver Reich Section editor Munich (DE)
oliver.reich@ klinikum-muenchen.de
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Evaluation of biomarkers and clinical scores to aid the identification of disease severity and intensive care requirement for suspected sepsis
Early diagnosis and treatment are mandatory for a successful outcome in sepsis. Few validated biomarkers or clinical score combinations exist which can discriminate between cases of infection and other non-infectious conditions following activation of an in-hospital sepsis code, as well as provide an accurate severity assessment of the corresponding host response. This study aimed to identify suitable blood biomarkers (MR-proADM (mid-regional proadrenomedullin), PCT (prolactin), CRP and lactate) or clinical score (SOFA and APACHE II) combinations to address this unmet clinical need.
A prospective, observational study of patients activating the Vall d’Hebron University Hospital sepsis code (ISC) within the emergency department (ED), hospital wards and intensive care unit (ICU). Area under the receiver operating characteristic (AUROC) curves, logistic and Cox regression analysis were used to assess performance.
One hundred and forty-eight patients met the Vall d’Hebron ISC criteria, of which 130 (87.8%) were retrospectively found to have a confirmed diagnosis of infection. Both PCT and MR-proADM had a moderate-to-high performance in discriminating between infected and non-infected patients following ISC activation, although the optimal PCT cut-off varied significantly across departments.
Similarly, MR-proADM and SOFA performed well in predicting 28 and 90-day mortality within the total infected patient population, as well as within patients presenting with a community-acquired infection or following a medical emergency or prior surgical procedure. Importantly, MR-proADM also showed a high association with the requirement for ICU admission after ED presentation [OR (95% CI) 8.18 (1.75–28.33)] or during treatment on the ward [OR (95% CI) 3.64 (1.43–9.29)], although the predictive performance of all biomarkers and clinical scores diminished between both settings.
Investigators conclude that the individual use of PCT and MR-proADM might help to accurately identify patients with infection and assess the overall severity of the host response, respectively. In addition, the use of MR-proADM could accurately identify patients requiring admission to the ICU, irrespective of whether patients presented to the ED or were undergoing treatment on the ward.
Initial measurement of both biomarkers might therefore facilitate early treatment strategies following activation of an in-hospital sepsis code. Finding the optimal biomarkers and clinical scores is an important research field also in urosepsis. Source: Biomarkers and clinical scores to aid the identification of disease severity and intensive care requirement following activation of an in-hospital sepsis code. Jaume Baldirà, Juan Carlos Ruiz-Rodriguez, Darius Cameron Wilson, Adolf Ruiz-Sanmartin, Alejandro Cortes, Luis Chiscano, Roser Ferrer-Costa, Inma Comas, Nieves Larrosa, Anna Fàbrega, Juan José Gonzalez-Lopez and Ricard Ferrer.
Ann Intensive Care 2020; 10:7. https://doi. org/10.1186/s13613-020-0625-5
Identification of intermediate clinical endpoints in localised prostate cancer
The long natural history of localised prostate cancer poses challenges in clinical trials design to improve overall survival. In order to overcome this 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, 90% of the patients enrolled in the trials evaluated were treated with radiotherapy meaning the validity of this endpoint in surgical trials in unknown. This paper used a broader set of inclusion criteria to identify potential intermediate clinical endpoints for individual patient-level validation.
In this meta-analysis eligible trials had to be randomised, therapeutic, reporting overall survival and at least one intermediate clinical endpoint, and with a sample size of at least 70 participants. Trials of metastatic disease were excluded. Intermediate clinical endpoints included biochemical failure, local failure, distant metastases, biochemical failure-free survival, progression-free survival, and metastasis-free survival.
Having identified 4,221 studies, 75 randomised trials published between March 1986 and January 2020 were included. (53,631 patients) Median trial level follow-up was 9.1 years (IQR 5.7-10.6), medium age was 68.7 years (66.6-70.5) and median baseline PSA was 12.1 ng/ml (10.0-15.9 ng/ ml). Intermediate clinical endpoints that included biochemical failure had poor correlation of the treatment effect with overall survival. Correlation with local failure was also poor. Correlation of progression-free survival was moderate (R2 0.46 [95% CI 0.22-0.67]) and metastasis-free survival had the strongest correlation (R2 0.78 [95% CI 0.59-0.89]). Interestingly this held true in subgroup analysis irrespective of primary radical treatment. The same result was also seen when including only high-risk trials.
More controversially they showed metastasis-free survival might not be a surrogate endpoint for radiotherapy-specific trials testing dose escalation, nodal irradiation, or hypofractionation. The goal of dose escalation is primarily to reduce local failure, and they showed that local failure did not correlate with overall survival in any of the subgroups examined. This finding could account for why dose-escalation trials to date, even those powered for overall survival, have not improved overall survival.
For men with biochemical recurrence, it remains true that non-prostate cancer deaths are more frequent than dying from the disease. As a consequence, it may be true that intensification of treatment for biochemical recurrence may worsen other cause mortality and as a result obscure any correlation between biochemical recurrence and overall survival. This is especially likely to be true for treatments aimed at local control. As a result, extreme caution should be used when considering treatment shifts based upon unvalidated surrogate endpoints.
Source: Intermediate clinical endpoints for surrogacy in localised prostate cancer: an aggregate meta-analysis. Gharzai LA, Jjang R, Wallington D et al.
Lancet Oncol 2021; 22: 402-10.
New consensus-report on research priorities in sepsis
Urosepsis is a feared situation in urology and its prevention and treatment is of utmost importance. The objective of this report was to identify priorities for administrative, epidemiological and diagnostic research in sepsis. The report is a follow-up to a previous consensus statement about sepsis research by members of the Surviving Sepsis Campaign Research Committee, representing the European Society of Intensive Care Medicine and the Society of Critical Care Medicine. They addressed six questions regarding care delivery, epidemiology, organ dysfunction, screening, identification of septic shock, and information that can predict outcomes in sepsis.
Six questions from the Scoring/Identification and Administration sections of the original Research Priorities publication were explored in greater detail to better examine the knowledge gaps and rationales for questions that were previously identified. The document provides a framework for priorities in research to address the following questions:
(1) What is the optimal model of delivering sepsis care? (2) What is the epidemiology of sepsis susceptibility and response to treatment? (3) What information identifies organ dysfunction? (4) How can we screen for sepsis in various settings? (5) How do we identify septic shock? (6) What in-hospital clinical information is associated with important outcomes in patients with sepsis?
The group concludes that there is substantial knowledge of sepsis epidemiology and ways to identify and treat sepsis patients, but many gaps remain. Areas of uncertainty identified in this manuscript can help prioritise initiatives to improve understanding of individual patients and demographic heterogeneity with sepsis and septic shock, biomarkers and accurate patient identification, organ dysfunction, and ways to improve sepsis care. The present report provides guidance also for research on urosepsis.
Source: The Surviving Sepsis Campaign: research priorities for the administration, epidemiology, scoring and identification of sepsis. Nunnally ME, Ferrer R, Martin GS, Martin-Loeches I, Machado FR, De Backer D, et al.
Intensive care medicine experimental. 2021;9(1):34 https://doi.org/10.1186/s40635-021-00400-z
Can we develop further bespoke treatments for men with mCRPC?
Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous lethal disease characterised by variable sensitivity to androgenreceptor signalling pathway therapy. All patients ultimately develop treatment-resistant, lifethreatening disease. One mechanism of resistance to androgen deprivation is activation of the PI3K/ AKT pathway Furthermore, the PTEN tumour suppressor is functionally lost in approximately 40–50% of patients with mCRPC. PTEN loss activates AKT signalling, leading to tumour growth and cell proliferation, worse outcomes, and reduced benefit from androgen-receptor pathway blockade.
Ipatasertib is a selective ATP-competitive small-molecule inhibitor of all three isoforms of AKT. It has been evaluated both as a single agent and in combination studies using dual AKT and androgen-receptor pathway blockade with ipatasertib and abiraterone and was shown to be feasible with manageable side-effects. This study assesses whether the combination is more effective than abiraterone alone.
Patients with previously untreated asymptomatic or mildly symptomatic mCRPC were recruited. Previous chemotherapy for metastatic hormonesensitive prostate cancer was permitted, provided it was initiated no more than 6 months after the time of first castration treatment, and that the patient had not progressed during chemotherapy or within 3 months after completion of chemotherapy. All patients were required to have a valid prostate cancer tumour PTEN immunohistochemistry result, using archival or newly collected tumour samples. Next-generation sequencing to detect PTEN status or PIK3CA/AKT1/PTEN alteration was also done using the FoundationOne CDx next-generation sequencing assay.
1,611 patients were screened and 1,101 (68%) were enrolled and assigned 1:1 to placebo-abiraterone versus ipatasertib-abiraterone. 521 patients had PTEN loss by immunohistochemistry and were equally split between the groups. In the intention to treat analysis median progression free survival was 16.6 months in the placebo-abiraterone group and 19.2 months in the ipatasertib-abiraterone group (HR 0.84 [95% CI 0.71-0.99] p = 0.043; ns at a = 0.01). In the patients with PTEN loss, median progression-free survival was 16.5 months in the placebo-abiraterone group and 18.5 months in the ipatasertib-abiraterone group (HR 0.77 [95% CI 0.61-0.98] p = 0.034; significant at a = 0.04). Adverse events leading to discontinuation of treatment occurred in 5% of the placeboabiraterone group and 21% of the ipatasertibabiraterone group, suggesting there is a balance between clinical benefit and quality of life.
Assoc. Prof. Francesco Sanguedolce Section editor Barcelona (ES)
fsangue@ hotmail.com
This study is significant in two ways. Firstly, it demonstrates that targeting the AKT pathway may have a role in mCRPC for men with PTEN loss, although further follow-up is required to demonstrate if this results in improved overall survival. It is also not clear what is the best test to determine what is clinically significant PTEN loss. In addition, it is the first randomised phase III trial in this setting to report a combination treatment suggesting there may be a benefit for other combinations.
Source: Ipatasertib plus abiraterone and prednisolone in metastatic castrationresistant prostate cancer (IPATential150): a multicentre, randomised, double-blind, phase 3 trial. Sweeney C, Bracarda S, Sternberg CN, et al.
Lancet 2021; 398: 131-42.
g.ploussard@ gmail.com
Stringent anemia correction prolongs graft survival
Anemia and vitamin D deficiency are common among renal transplant recipients and are associated with allograft failure. Therefore, both are potential therapeutic targets among kidney transplant recipients. In this Japanese multicentre, two-by-two factorial, open-label, randomised clinical trial the aim was to examine the effects of anemia correction and vitamin D supplementation on 2-year change in eGFR among kidney transplant recipients.
153 patients with anemia and > 1-year history of transplantation were recruited among 23 hospitals in Japan, and randomly assigned to either a high or low hemoglobin target (> 12.5 vs. < 10.5 g/dl) and to either cholecalciferol 1,000 IU/ day or control. The trial was terminated early based on the planned interim intention-to-treat analyses (α = 0.034).
2-year decline in eGFR was smaller in the high vs. low hemoglobin group …, but did not differ between the cholecalciferol and control groups.
Among 125 patients who completed the study, 2-year decline in eGFR was smaller in the high vs. low hemoglobin group (-1.6 ± 4.5 vs. -4.0 ± 6.9 ml/min/1.73 m2; p < 0.022), but did not differ between the cholecalciferol and control groups. These findings were supported by the fully adjusted mixed effects model evaluating the rate of eGFR decline among all 153 participants. There were no significant between-group differences in all-cause death or the renal composite outcome in either arm. The authors conclude that ‘aggressive’ anemia correction shows a potential to preserve allograft kidney function.
Source: Correcting anemia and native vitamin D supplementation in kidney transplant recipients: a multicenter, 2 × 2 factorial, open-label, randomized clinical trial. Obi Y, Ichimaru N, Sakaguchi Y, Iwadoh K, et al. CANDLE-KIT Trial Investigators.
Transpl Int 2021;34(7):1212-1225.
Although adjuvant cisplatin-based chemotherapy has been shown to prolong disease-free survival in patients with locally advanced upper tract urothelial carcinoma, the role of adjuvant chemotherapy after cystectomy is less clear. In addition, despite a high risk of metastatic recurrence, no standard adjuvant systemic therapies have been shown to improve outcomes in patients with pathological evidence of residual disease after neoadjuvant cisplatin-based chemotherapy. Nivolumab is a monoclonal antibody against programmed death 1 and has been shown to be effective after cisplatin chemotherapy in patients with metastatic urothelial carcinoma. This study evaluates its role compared with placebo, in patients with muscle-invasive urothelial carcinoma after radical surgery (with or without previous neoadjuvant cisplatin-based combination chemotherapy).
CheckMate 274 was a phase 3, multicentre, double-blind, randomised, controlled trial, in patients with muscle-invasive urothelial carcinoma who had undergone radical surgery Neoadjuvant cisplatin-based chemotherapy before trial entry was allowed and occurred in approximate 43% of patients equally distributed between the groups. The primary endpoints were disease-free survival among all the patients (intention-to-treat population) and among patients with a tumour programmed death ligand 1 (PD-L1) expression level of 1% or more. Survival free from recurrence outside the urothelial tract was a secondary endpoint.
The median disease-free survival in the intentionto-treat population was 20.8 months (95% CI, 16.5 to 27.6) with nivolumab and 10.8 months (95% CI, 8.3 to 13.9) with placebo. The percentage of patients who were alive and disease-free at 6 months was 74.9% with nivolumab and 60.3% with placebo (hazard ratio for disease recurrence or death, 0.70; 98.22% CI, 0.55 to 0.90; p < 0.001). There were 282 patients with a PD-L1 expression level of 1% or more, 140 in the nivolumab group and 142 in the placebo group.
Among these the percentage alive at 6 months was 74.5% and 55.7%, respectively (hazard ratio, 0.55; 98.72% CI, 0.35 to 0.85; p < 0.001). However, treatment-related adverse events of grade 3 or higher were more common in the nivolumab group (17.2%) than the placebo group (7.2%). Two treatment-related deaths due to pneumonitis and one treatment-related death due to bowel perforation were noted in the nivolumab group.
The patients included in this study had a very high risk of recurrence, 47% had node positive disease whilst just over 74% of patients has pT3/4 disease on final histology. However, in this group adjuvant immunotherapy showed a significant and clinically meaningful benefit regardless of PD-L1 expression. Data for overall survival is awaited but patients will want to know about these results
Source: Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. Bajorin DF, Witjes JA, Gschwend JE, et al.
N Engl J Med 2021; 384: 2102-14.
Searching for better longterm immunosuppressive regimens
Withdrawal of either steroids or calcineurin inhibitors are two strategies to reduce treatmentrelated side effects of long-term immunosuppression after kidney transplantation and to improve long-term graft survival. This study aimed to evaluate the efficacy and safety of these two strategies. In a multicentre randomised controlled trial, 151 incipient kidney transplant recipients received cyclosporine (CsA), mycophenolic acid (MPA), and steroids for three months, then followed by either steroid withdrawal (CsA/MPA) or replacement of cyclosporine with everolimus (EVL) (EVL/MPA/ steroids).
5-year patient survival (89% vs. 86%; p = n.s.) and death-censored graft survival (95% vs. 96%; p = n.s.) were comparable in the CsA/MPA and EVL/ MPA/steroids arm, respectively. 51 CrEDTA clearance was comparable between both groups in the intention-to-treat analysis, but in the treatment-received analysis the EVL/MPA/steroids Numerically, there were more and more severe rejections in the EVL/MPA/steroids arm, which also showed a higher incidence of post-transplant diabetes (26% vs. 6%, p < 0.002) and infections. No significant differences were observed in cardiovascular outcomes and malignancy.
The authors conclude that both regimens provide good long-term patient survival and graft survival. While the EVL/MPA/steroids regimen is an attractive strategy, it does lead to more rejection and secondary morbidity. (ClinicalTrials.gov number: NCT00903188; EudraCT Number 2007-005844-26).
Source: 5-Year outcomes of the prospective and randomized CISTCERT study comparing steroid withdrawal to replacement of cyclosporine with everolimus in de novo kidney transplant patients. CISTCERT study group. Pipeleers L, Abramowicz D, Broeders N, Lemoine A, et al.
Transpl Int 2021;34(2):313-326
Tumour volume increase of index MRI visible lesions during PCA active surveillance: Monitor annually?
Modern active surveillance (AS) of prostate cancer (PCa) implies surveillance of visible lesions on MRI, and the assessment of any change based on the PRECISE score. MRI progression leads to targeted biopsies aiming to look for potential histological progression and tumour grade change. However, the characteristics of MRI changes of visible lesions are currently not well evaluated, and no data exist to compare such modifications according to the initial tumour grade of the disease.
The most useful implication of this work for routine practice may be that, …, annual MRI scans may be too frequent to detect meaningful change…
In the present study, the authors followed MRI visible lesions in 160 patients under active surveillance, and compared the lesion volume evolution over time between ISUP grade 1 (low-risk) and grade 2 (intermediate-risk) cancers. The index lesion was measured by planimetry on the sequence best showing the tumour by an expert radiologist blinded to all clinical and pathological data. All lesions were scored using PI-RADS v2.1 recommendations.
The percentage change per year was calculated between two serial scans. From a dataset of active surveillance patients, only those undergoing targeted biopsies for visible lesion were included. Median follow-up was 38 months. There was no significant difference in the percentage change per year between ISUP grade 1 (n = 84; 18% change) and grade 2 (n = 76; 23% change) lesions. This corresponded to annual increases in mean tumour diameter of 6% and 7%, respectively. The findings remain unchanged in patients having more than 10% of Gleason pattern 4 on targeted biopsies.
Thus, radiological evolution of visible cancers on AS was not markedly different between low- and intermediate-risk prostate cancers when considering the key parameter of tumour volume. However, the authors highlighted that MRI could overestimate volume as small lesions are often surrounded by areas of inflammation or atrophy that can mimic low grade areas. Conversely, imaging may underestimate low grade disease extension. The most useful implication of this work for routine practice may be that, given the low annual increase in size of MRI visible lesion, annual MRI scans may be too frequent to detect clinically meaningful tumour change in most patients. serdartekgul@ gmail.com
Source: Tumour growth rates of prostate cancer during active surveillance: is there a difference between MRI-visible low and intermediate-risk disease? Giganti F, Allen C, Stavrinides V, Stabile A, Haider A, Freeman A, Pashayan N, Punwani S, Emberton M, Moore CM, Kirkham A.
Br J Radiol. 2021 Jul 8:20210321. doi: 10.1259/ bjr.20210321.
Lateral pedicle control during RARP: Clips or bipolar energy? Does it matter?
The initially described technique for lateral prostatic pedicles ligation during robotic radical prostatectomy is based on the use of surgical clips. Indeed, monopolar or bipolar energy have been suggested to increase the risk of nerve injury. In this retrospective study, the authors have evaluated the alternative use of bipolar energy, in a prospectively collected cohort of 338 patients. A total of 144 (43%) and 194 (57%) men underwent clipless surgery with bipolar energy (RARP-bi), and surgery with clips (RARP-c). The RARP-bi technique involves cauterisation of the pedicle with the Maryland bipolar forceps on both the specimen and the stay side at the location where the clips would otherwise be placed. Then, cold section is performed. The primary objective was to compare both techniques for differences in functional and oncological outcomes.
Both groups were comparable regarding baseline data. Nerve-sparing procedures were performed in 95% of patients. Complication (only grade 1-2) and bladder neck contracture rates were similar in both groups. No difference was reported in terms of lymphoceles. Pathological and oncological outcomes were also comparable in RARP-bi and RARP-c groups. RARP-bi was not associated with impaired outcomes in terms of positive surgical margin rates. Urinary and sexual function scores were not significantly different according to the technique, even on a multivariable linear regression model. There was a significant trend towards better zero daily pads rates in the RARP-bi groups (68% versus 52%, p = 0.005).
This analysis suggests that bipolar energy can be used safely for pedicle ligation during RARP without compromising functional and oncological outcomes. It could also be cost-effective by decreasing operative time and instruments use.
The main limitation of the present study is its retrospective nature and the lack of randomisation. Moreover, patients undergoing RARP-bi were operated in a later period than those undergoing RARP-c. The experience accumulated between these two periods of the single surgeon involved in this study may have introduced an expertise bias when evaluating study endpoints.
Source: Robotic-assisted Radical Prostatectomy and Impact on Outcomes. Basourakos SP, Lewicki PJ, Ramaswamy A, Cheng E, Dudley V, Yu M, Karir B, Hung AJ, Khani F, Hu JC. Clipless.
Eur Urol Focus. 2021 Jul 7:S2405-4569(21)00175-9.
Oliver.Hakenberg@ med.uni-rostock.de
Multicentre phase II trial: High-dose salvage radiotherapy and shortterm hormone therapy for oligorecurrent nodal disease in PCa patients
The era of metastasis-directed therapy is open. However, a high number of evidence data is still missing. In this French multicentre and openlabel phase II trial, patients experiencing oligorecurrent pelvic node relapse after primary treatment for prostate cancer have received high-dose intensity-modulated radiotherapy combined with a six-month hormone therapy. Radiotherapy was directed to node positive spots detected by fluorocholine PET-CT. The maximum number of pelvic positive nodes on imaging was five for inclusion. Pelvic disease was defined by nodes located below the aortic bifurcation.
The primary endpoint was the two-year progression-free survival defined by two consecutive PSA levels above the level at inclusion (and/or clinical recurrence and/or death). Overall, 67 patients were recruited in 15 centres. Only four patients had a concurrent local relapse in the prostate or at the prostatic bed. The median age was 68 years. The median number of positive spots was one (61% patients with only one positive spot on PET-CT). At two years, grade 2 or more toxicity was 10% for genitourinary symptoms and 2% for gastrointestinal ones. No significant alteration of urinary or intestinal quality of life was reported.
The two-year progression-free survival was 81% but decreased to 58% after three years of follow-up. Interestingly, in patients with only radical prostatectomy as primary treatment, the two-year survival rate (97%) was significantly higher than that reported in patients who had undergone surgery plus salvage radiotherapy to the surgical bed.
The present study demonstrated high rates of biochemical progression after metastasis-directed therapy and short-term hormone therapy for nodal relapse. Nearly half of patients are in complete remission after three years. This trial adds initial evidence of benefit.
However, a randomised controlled trial remains necessary. Moreover, the question of intensified therapy by adding new generation hormone therapies still remains, as overall survival benefit from these regimens have been recently demonstrated in phase III trials for patients with oligometastases or relapse after primary prostate cancer treatment.
Source: OLIGOPELVIS GETUG P07, a Multicentre Phase II Trial of Combined High-dose Salvage Radiotherapy and Hormone Therapy in Oligorecurrent Pelvic Node Relapses in Prostate Cancer. Supiot S, Vaugier L, Pasquier D, Buthaud X, Magné N, Peiffert D, Sargos P, Crehange G, Pommier P, Loos G, Hasbini A, Latorzeff I, Silva M, Denis F, Lagrange JL, Morvan C, Campion L, Blanc-Lapierre A.
Eur Urol. 2021 Jul 8:S0302-2838(21)01816-9. The authors sought to determine the prevalence of sexual dysfunction and to identify the factors associated with sexual dysfunction in young adult survivors of childhood cancer.
All survivors of childhood cancer (aged 19-40 years) in Sweden were invited to this populationbased study, wherein 2,546 men and women (59%) participated. Sexual function was examined with the PROMIS Sexual Function and Satisfaction Measure. Logistic regression was used to assess the differences between survivors and a general population sample (n = 819) and to identify the factors associated with sexual dysfunction in survivors.
Sexual dysfunction in at least one domain was reported by 57% of female and 35% of male survivors. Among females, dysfunction was most common for Sexual interest (36%), Orgasm - ability (32%) and Vulvar discomfort - labial (19%). Among males, dysfunction was most common for the domains Satisfaction with sex life (20%), Sexual interest (14%) and Erectile function (9%). Compared with the general population, male survivors more frequently reported sexual dysfunction in ≥ 2 domains (OR = 1.67, 95% CI: 1.03-2.71), with an increased likelihood of dysfunction regarding Orgasm - ability (OR = 1.82; 95% CI: 1.01-3.28) and Erectile function (OR = 2.30; 95% CI: 1.18-4.49). Female survivors reported more dysfunction regarding Orgasm - pleasure (9% versus 5%, OR = 1.86; 95% CI: 1.11-3.13). A more intensive cancer treatment, emotional distress and body image disturbance were associated with sexual dysfunction in survivors.
The findings underscore the need for routine assessment of sexual health in follow-up care of childhood cancer survivors, and highlight that those treated with more intensive cancer treatment and experience concurrent psychological concerns may benefit from targeted screening and interventions.
Source: Sexual dysfunction in young adult survivors of childhood cancer - A population-based study. Emma Hovén, Kristina Fagerkvist, Kirsi Jahnukainen, Lisa Ljungman, Päivi M Lähteenmäki, Ove Axelsson, Claudia Lampic, Lena Wettergren.
Eur J Cancer. 2021 Jul 14;154:147-156. doi: 10.1016/j. ejca.2021.06.014. Online ahead of print.
Outcomes of European male ageing study on rapid ejaculation
Few data have looked at the occurrence and clinical correlates of self-reported shorter than desired ejaculation latency (rapid ejaculation, RE) and its related distress in the general population. Thus, the investigators tried to determine the prevalence and clinical correlates of self-reported RE and RE-related distress in middle age and older European men.
Subjects were recruited from population samples of men aged 40-79 years across eight 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 About 2,888 community-dwelling men aged 40-79 years old (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 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).
Self-reported RE is relatively common in European men aged more than 40 years. The reported limited RE-related distress may explain the relatively low number of medical consultations for RE. RE-related 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. Giovanni Corona, Giulia Rastrelli, Gyorgy Bartfai, Felipe F Casanueva, Aleksander Giwercman, Leen Antonio, Jolanta Slowikowska, Jos Tournoy, Margus Punab, Ilpo T Huhtaniemi, Dirk Vanderschueren, Terence W O'Neill, Frederick C W Wu, Mario Maggi.
J Sex Med. 2021 May;18(5):908-919. doi: 10.1016/j. jsxm.2021.01.187. Epub 2021 Apr 2.
Opioids after ureteroscopy for urinary stones? No, thank you
Pain control after surgery is an issue that may affect the patient’s treatment journey in terms of worsening quality of life and return to normal life. Usually, medications that are prescribed include non-steroidal anti-inflammatory drugs (NSAID) and opioids. Nevertheless, all these drugs may provoke side effects, among which NSAID-induced peptic ulcer and opiate dependence and/or overdose.
Unfortunately, the abuse of opioids is quite common in some countries, especially in the US, where a drastic reduction of their use has been warranted by the relevant authorities. Regardless, the opioids are still very common for pain control during colic pain in stone disease as well as after endo-urological minimally invasive surgery for their treatment.
In the last years, evidence has been mounting to show that NSAID are as effective as opioids for the short term control of colic pain. Recently, a randomised controlled trial has been developed to test the non-inferiority of NSAID vs opioids as first-line treatment option for pain control after ureteroscopic lithotripsy of urinary stones.
According to the study sample size calculated, 81 patients were enrolled in the span of the 2-year recruitment period, 38 randomised in the ketorolac (10 mg) arm and 43 in the oxycodone (5 mg) one. It is worth mentioning that most of the patients screened were not eligible, as more than 500 patients did not fulfil entry criteria and/or refused to participate.
Medications were provided blinded in the same presentation and were taken on demand every 6 hours maximum for 5 post-operative days. All patients were provided with a further 3 non-blinded 5 mg oxycodone pills as rescue medication, if no Primary end-point included difference in pain control from day 1 to 5 post-op according to the visual analogues scale pain score. Secondary end-points included differences in the Ureteric Stent Symptom Questionnaire (USSQ) at the same time points, differences in medication patterns, and access to medical assistance.
The baseline groups’ characteristics were comparable, and no difference was recorded in the number of either protocol (overall mean of 7.2) or rescue medications (39%); 9% of patients did not require any medication, equally distributed in both arms.
No differences were found in terms of VAS and USSQ scores at the different time points; most of the medication drugs were taken at the recovery unit, and their use progressively decreased after post-operative day 1.
Nevertheless, the NSAID group of patients experienced a significantly lower number of days spent in bed (p = 0.022), as well as a reduced number of drug side-effects (p = 0.025). Overall, this RCT provides robust evidence that NSAID for post-operative pain control is as effective as opioids. Given the risk that the latter conveys in terms of higher side effects and dependence, NSAID should be used as first line drug after ureteroscopy for stone fragmentation.
Source: SKOPE-Study of ketorolac vs opioid for pain after endoscopy: a double-blinded randomized control trial in patients undergoing ureteroscopy. Donald Fedrigon, Anna Faris, Naveen Kachroo, Rajat Jain, Marlie Elia, Lamont Wilkins, Jianbo Li, Smita De, Mark Noble, Manoj Monga, Sri Sivalingam.
J Urol. 2021 Aug;206(2):373-381. doi: 10.1097/ JU.0000000000001772. Epub 2021 Apr 5.
Ureteroscopy for the treatment of urinary stone disease is a very common surgical treatment worldwide. It has gained huge popularity in the last two decades thanks to the achieved high stone-free rates with a low risk for complications. Nevertheless, severe complications may occur, even when surgery is performed by experienced surgeons. Infectious complications are among the most common, with a wide spectrum of severity, from urinary tract infection to sepsis; the latter is potentially fatal.
Multiple factors have been investigated to predict urosepsis, in order to eventually lead to preventive measures. The available data are mostly based on retrospective cohort series and the reported outcomes are not consistent.
In order to shed some light on this topic, a systematic review has been undertaken recently. According to the search terms chosen, 251 articles were screened from Medline, Embase, and the Cochrane Central Register of Controlled Trials databases. After reviewing for the eligibility criteria, 13 papers reporting data on the association between at least one clinical factor and postoperative urosepsis were finally selected and included in the analysis.
There were 8 retrospective and 5 prospective studies selected, with an overall number of 5,597 patients; pooled rate of urosepsis was 5% (95% CI: 2.4-8.2). Notably, criteria used to define urosepsis varied among the studies, but – as by inclusion criteria - they met at least two of the following criteria: high fever (> 380), high pulse rate, high respiration rate or PcCO2, altered white blood cell count, and a few others.
philip.cornford@ rlbuht.nhs.uk
The authors evaluated 13 risk factors and found a statistical association with urosepsis in 6 of them: pre-operative stent placement, positive preoperative urine culture, older age, diabetes mellitus, ischaemic heart disease and longer procedure time. Nevertheless, these latter two factor outcomes resulted from pooled analysis of only 2 and 1 studies.
Overall, these outcomes are consistent with previous reports on the association between clinical factors and generalised infectious complications, especially for pre-operative stent placement and positive pre-operative urine culture.
These results are easily explained, as stent placement may result in bacterial colonisation, which is a factor directly associated with the time a stent is left in place. Positive pre-operative urine culture should be treated before any manipulation of the upper urinary tract. Patients may be re-tested to confirm urine sterilisation. Nevertheless, several conditions may jeopardise the efficacy of an antibiotic treatment - especially in the case of stone formation with recurrent UTIs – such as antibiotic resistance, presence of infected urine proximal to the obstruction or spread of pathogenic bacteria during fragmentation of infectious stones.
In these patient groups, a urine sample for urine culture should be collected at the very beginning of an ureteroscopy. Furthermore, antibiotic treatment should be continued post-operatively instead of being limited to a one shot preoperative prophylaxis.
Source: Risk Factors for Urosepsis After Ureteroscopy for Stone Disease: A Systematic Review with Meta-Analysis. Naeem Bhojani, Larry E Miller, Samir Bhattacharyya, Ben Cutone, Ben H Chew.
J Endourol. 2021 Jul;35(7):991-1000. doi: 10.1089/ end.2020.1133. Epub 2021 Mar 15.
Appropriate selection of patients for endoscopic management of upper tract urothelial cancer
The appropriate selection of patients for conservative management of upper urinary tract tumours (UTUC) guarantees the best oncologic and functional outcomes. Mounting evidence shows that patients harbouring low-risk UTUC may preserve their kidneys without compromising the neoplastic control. In such patients, radical nephroureterectomy (RNU) –the standard of care - may result in overtreatment.
Clinical T3 at imaging was the strongest predictor …, which was consistent with the EAU and NCCN algorithms.
Several algorithms have been proposed in the last years to help practitioners in their decisionmaking process, among which those in the EAU and the NCCN guidelines, which included clinical and pathological factors based on evidence available and expert opinions.
Recently, a multicentre study has been undertaken to retrospectively identify clinical factors and endoscopic characteristics of patients who underwent ureterorenoscopy (URS) + biopsy that may associated with ≥ pT2/pN+ disease at the subsequent RNU. After reviewing patient records, the authors were able to include the data of 1,214 patients treated in 21 centres over a 17-year span (2000-2017). Full data for all the variables in observation were available for 458 patients (37%). Missing data varied from 0 to 24%, with tumour architecture (papillary vs sessile) and estimated lesion size being among the most affected variables. Regardless of this limitation, the authors were able to conduct their main analysis on the overall population by applying relevant statistical methods.
At the multivariable logistic regression, the authors found age, high-grade biopsy, cT1+ at biopsy, pre-operative hydronephrosis, tumour size, ≥ cT3 at imaging, and sessile architecture as the variables associated with ≥ pT2/pN+ disease at the subsequent RNU.
Regardless of the fact that other variables - among which high-grade cytology, tumour multifocality, cT stage at biopsy - were not statistically significant at the multivariable analysis, they were included in the final nomogram, as the authors found that they provided a clinical net benefit in a decision-curve analysis.
When comparing predictive accuracy, the authors’ nomogram outperformed the EAU and NCCN nomograms with an Area Under the Curve of 75% vs. 71%, respectively.
Clinical T3 at imaging was the strongest predictor (odds ratio 5.10, 95% CI:3.32–7.81, p = < 0.001), which was consistent with the EAU and NCCN algorithms. Tumour size was also an important predictive factor, but - conversely to the EAU and NCCN algorithms - no cut-off was provided, as the variable was found to work better when used continuously in the context of the nomogram.
Regardless of the biases introduced (especially those related to the retrospective nature of the study and the amount of missing data), the manuscript provides further evidence to support patient selection for endoscopic management of UTUC.
Source: Pretreatment Risk Stratification for Endoscopic Kidney-sparing Surgery in Upper Tract Urothelial Carcinoma: An International Collaborative Study. Beat Foerster, Mohammad Abufaraj, Surena F Matin, et al.
Eur Urol. 2021 May 19;S0302-2838(21)00328-6. doi: 10.1016/j.eururo.2021.05.004. Online ahead of print.
Does hospital transfer increase orchiectomy rate in children with testicular torsion?
Testicular torsion is a urological emergency which must be differentiated from other complaints of testicular pain, because a delay in diagnosis and management can lead to loss of a testicle.
Orchiectomy rates after torsion range from 32% to 64% and may be the result of a series of medical and logistical factors that delay both diagnosis and management. It has been established that detorsion within the first six hours increases the chances of salvage before significant ischemia has occurred.
The authors aim to elucidate the effect of hospital transfer on paediatric testicular torsion outcomes through a systematic review and meta-analysis. In paediatric patients with testicular torsion, hospital transfer does not affect orchiectomy rate when data from all presentation time frames are analysed. However, within 24 hours of the onset of symptoms, orchiectomy rates increase significantly with hospital transfer.
The authors included prospective and retrospective studies investigating outcomes for testicular torsion in patients < 18 years who underwent treatment at their presenting institution, as well as, those who were transferred from one institution to another for treatment. Studies must have reported the primary outcomes as orchiectomy for testicular detorsion (attempted salvage) for confirmed torsion.
This meta-analysis of 2,564 patients for nine published studies demonstrates hospital transfer does not seem to significantly affect overall testicular torsion outcomes. Quantitative analysis suggests patients who are transferred for treatment of testicular torsion are not at increased risk of orchiectomy (641/2,032, 31.5%) compared to patients who undergo treatment at the initial, presenting institution (196/532, 36.8%; RR 0.96 [95% CI 0.78-1.17].
However, subgroup analysis for torsion patients presenting within 24 hours of symptom onset shows patients who are transferred to another facility for management are more likely to undergo orchiectomy than those treated at their presenting institution. Pooled data for torsion patients presenting 24 hours of symptom onset also suggests that patients who are transferred for treatment of acute testicular torsion are more likely to undergo orchiectomy (41/66, 62.1%) than those patients treated at the initial, presenting institution (32/155, 20.6%; RR 0.35 [95% CI 0.24-0.51];
In this meta-analysis, hospital transfer does not affect orchiectomy rate in paediatric patients with testicular torsion when pooling data from all presentation time frames. Subgroup analysis of patients presenting with testicular torsion in an acute setting (< 24 hours of symptom onset) suggests the delay associated with hospital transfer has a deleterious effect on testicular viability.
Source: Impact of hospital transfer on testicular torsion outcomes: A systematic review and meta-analysis. Kwenda EP, Locke RA, DeMarco RT, Bayne CE.
J Pediatr Urol. 2021 Jun;17(3):293-8.
Children with posterior urethral valves diagnosed shortly after birth are at higher risk for renal failure than children diagnosed later in life. Based on this finding, one would assume prenatal diagnosis and even prenatal intervention would bring better clinical outcomes to the patients. Studies have shown that although in-utero vesica-amniotic shunting for foetal lower urinary obstruction (LUTO) is known to improve perinatal survival, its impact on renal outcome is limited.
More recently, studies including centres performing foetal cystoscopy (FC) have suggested benefit on longer-term survival and renal outcome, with limitations of small numbers and limited follow-up.
The authors aim to report the current evidence on the role of therapeutic intervention for foetal LUTO, discuss and propose the concepts stated below.
Prenatal USG has a 23% rate of false positive diagnosis with variations according to timing of investigation and criteria being used. Improvement of diagnostic accuracy can be achieved by using strict criteria on USG findings. The imaging fusion of real-time ultrasound and MRI is feasible and may improve the foetal diagnosis of LUTO. FC, although technically challenging, will allow direct visualisation to increase accuracy and treatment at the same time.
The prediction of foetal renal function is currently based on ultrasound appearances of the foetal renal cortex, amniotic fluid volume, and foetal urine biochemistry. The effectiveness of foetal urinary biochemical markers to predict renal function remains controversial. Urinary peptidome analysis is promising as a helpful tool for the discovery and validation of biomarkers of renal disease.
A prenatal staging system which classifies LUTO based on amniotic fluid volume, echogenicity, renal structure, and urine biochemistry may be helpful in selecting foetuses which may benefit from intervention.
The interventions with FC or vesicoamniotic shunting improve perinatal survival and have limited long-term benefit on renal outcome. They carry significant risks, and therefore patient selection and optimum timing are key factors.
tebj@medisin.uio.no
The interventions with foetal cystoscopy or vesicoamniotic shunting improve perinatal survival and have limited long term benefit on renal outcome. They carry significant risks, and therefore patient selection, and optimum timing, are key factors.
Identifying risk factors for foetal and postnatal renal failure is helpful. Multivariate analysis showed that foetal intervention, absence of anhydramnios or renal cortical cysts, and favourable foetal urine biochemistry were the best predictors of survival.
Foetal intervention is not a risk-free endeavour. There is about 30% risk of losing pregnancies. There is a high complication rate of 74 - 92% consecutively for FC and vesicoamniotic shunt (VAS). The main maternal complication was premature rupture of membranes (25% with FC, 33% with VAS). Foetal complications occurred in 54% of procedures: shunt migration (38% of VAS cases), omentum or bowel herniation (25% in both VAS and FC cases), urinoma with urethralperineal fistula (25% of FC cases).
The ideal timing for renal functional preservation is difficult to determine. Based on fatal lamb models, the only recommendation that can be given is to intervene before signs of cystic renal dysplasia and foetal renal failure ensue.
FC with flexible fetoscope has been employed for both diagnosis and treatment of LUTO. The development of a customised foetal cystoscope should help overcome the current technical challenges of FC. There is considerable scope for improving VAS technology to minimise complications of shunt dislodgement and blockage occurring in approximately 20% of cases.
Foetal intervention for LUTO improves perinatal survival, with the potential of longer-term survival and renal functional preservation. The underlying challenges include the accurate antenatal diagnosis of the cause of obstruction, patient selection, and mode and timing of intervention.
Smaller studies show a possible benefit of FC cystoscopy over VAS, but the procedure is technically demanding and has a high complication rate. Improved accuracy of prenatal diagnosis, and better patient selection with the aim of intervention before renal failure ensues, may result in better outcomes.
Source: Therapeutic intervention for fetal lower urinary tract obstruction: Current evidence and future strategies. Farrugia MK, Kilby MD.
J Pediatr Urol. 2021 Apr;17(2):193-199. doi: 10.1016/j. jpurol.2021.01.034. Epub 2021 Jan 31. PMID:33583743.
