Key articles from international medical journals

RM (inter-patient variability) was closely related to adverse allograft outcomes, and hence, more attention must be given to pre-transplant PRA-positive patients.

Source: Combined impact of the inter and intra-patient variability of tacrolimus blood level on allograft outcomes in kidney transplantation.

Yohan Park, Hanbi Lee, Sang Hun Eum, Eun Jeong Ko, Ji Won Min, Se-Hee Yoon, Won-Min Hwang, Sung-Ro Yun, Chul Woo Yang, Jieun Shin, Byung Ha Chung.

Front Immunol 2022 Nov 16;13:1037566. doi: 10.3389/fimmu.2022.1037566. eCollection 2022.

No opioid strategy is feasible after major urologic surgery

Opioid analgesics have been correlated with an increased rate of death in the US. Such prescriptions after surgery remain a major contributor to the opioid misuse crisis, potentially leading to inadequate chronic use or overdose-related deaths.

High variability of tacrolimus trough levels impacts allograft outcomes

Tacrolimus (TAC) has been widely used as an immunosuppressant after kidney transplantation (KT). However, the combined effects of intra-patient variability (IPV) and inter-patient variability of TAC-trough level (C0) in blood remains controversial. This study aimed to determine the combined impact of TAC-IPV and TAC inter-patient variability on allograft outcomes of KT.

“Considerable tacrolimus serum level variations contribute to adverse allograft outcomes.”

In total, 1,080 immunologically low-risk patients who were not sensitised to donor human leukocyte antigen (HLA) were enrolled. TAC-IPV was calculated using the time-weighted co-efficient variation (TWCV) of TAC-C0, and values > 30% were classified as high IPV. Concentration-to-dose ratio (CDR) was used for calculating TAC interpatient variability, and CDR < 1.05 ng•mg/mL was classified as rapid metabolisers (RM). TWCV was calculated based on TAC-C0 up to 1 year after KT, and CDR was calculated based on TAC-C0 up to 3 months after KT. Patients were classified into four groups according to TWCV and CDR: low IPV/ non-rapid metaboliser (NRM), high IPV/NRM, low IPV/RM, and high IPV/RM. Subgroup analysis was performed for pre-transplant panel reactive antibody (PRA)-positive and negative patients (presence or absence of non-donor-specific HLA-antibodies). Allograft outcomes, including death-censored graft loss and biopsy-proven allograft rejection were compared.

The incidences of death-censored graft loss, allograft rejection and overall graft loss were the highest in the high-IPV/RM group. In addition, a high IPV/RM was identified as an independent risk factor for death-censored graft loss. The hazard ratio of high IPV/RM for death-censored graft loss and the incidence of active antibody-mediated rejection were considerably increased in the PRA-positive subgroup.

The authors conclude from their results that high intra-patient variability combined with inadequate pain control were similar between the controls. No patients in any group required an unplanned visit to the clinic or emergency department due to pain. The overall 30-day complication rates were similar between groups, ranging from 16% to 21 (P = .69).

In this prospective study, the authors have designed an intervention protocol aiming at avoiding any opioid prescriptions at discharge after major urologic surgery (nephrectomy, cystectomy, radical prostatectomy). The primary outcome was the number of patients receiving any opioid prescription and the opioid dose prescribed per patient. Secondary outcome measures included the need for additional opioid prescriptions, patient-reported outcomes, unplanned health care utilisation (telephone calls, clinic or emergency department visit, re-admissions), and complication rates.

The control (preintervention) group included 202 patients, from May 2017 to December 2018, who were given opioid prescriptions (dose, duration) at the discretion of discharging health care professional. In the initial feasibility, patients were given a 1-page informational handout that explained the rationale for avoiding opioids and using nonopioid medications for post-operative pain control. The opioid prescriptions were at the discretion of the prescribers who were given instructions to try to limit opioid prescriptions to four days or fewer. For the intervention (ie, NOPIOIDS group with 384 patients), a standardised workflow included preferential use of nonopioid analgesics during hospital stay using electronic order sets, with instructions to prescribers (via email). Instructions were repeated when staff rotations changed. In addition, an instruction sheet with visual guidance for use at home was provided at discharge.

This study shows that an improved perioperative protocol may virtually eliminate opioid prescriptions after major abdominopelvic surgery. Preoperative patient engagement to set appropriate expectations and post-discharge analgesic instructional handout made this intervention readily acceptable by the prescribers and the patients. Some limitations may be highlighted such as the lack of patient-reported outcomes data for the control group and only from a small number in the lead-in group. However, this prospective, interventional study clearly demonstrates that a perioperative program involving both patients and caregivers, focusing on education and team engagement may drastically change the prescription of opioids after major abdominopelvic cancer surgery without adversely affecting pain control, complications, or recovery.

Source: Implementation and assessment of no opioid prescription strategy at discharge after major urologic cancer surgery. Mian BM, Singh Z, Carnes K, Lorenz L, Feustel P, Kaufman RP Jr, Avulova S, Bernstein A, Cangero T, Fisher HAG. JAMA Surg. 2023 Feb 8:e227652. doi: 10.1001/jamasurg.2022.7652. Epub ahead of print. PMID: 36753170; PMCID: PMC9909575.

Which laser is better for the endoscopic treatment of stone disease?

Technology in urological endoscopy continually evolves. Advances involve the use of new lasers for the fragmentation, dusting, and vaporisation of urinary stones.

Thulium Fibre Laser (TFL) has been recently introduced in the market as an effective alternative to the Holmium-YAG lasertripsy due to its high-absorption coefficient (four times higher than holmium), substantial versatility in terms of range of settings, and physical characteristics allowing for thinner fibres as small as 50 µm. TFL has been proposed as the ideal solution not only for the lasertripsy of urinary stones but also for other applications on soft tissue (e.g. prostate enucleation, ablation of upper tract urothelial tumours, etc).

A number of in-vitro and in-vivo publications have shown a superiority of TFL over standard Ho:YAG laser for lasertripsy of urinary stones, even though several biases have been identified. None of them included the latest generation of Ho:YAG embedded with the so-called Moses technology, consisting in high-powered pulse-modulated Ho:YAG laser.

calculated sample size consisted of 45 patients per arm with a statistical power set to 80% to detect a difference of 6 minutes or more of operative time. Whether or not this primary endpoint reflects a meaningful clinical issue is out the aims of the present report.

Secondary endpoints included laser firing time, total laser energy, ablation efficiency (defined as total laser energy/stone volume), stone-free rates (defined as either no visible at all or <3mm stone fragments on KUB X-ray at four to eight weeks after JJ stent removal), complication rate and quality of life scores at WISQOL (Wisconsin Stone Quality of Life) questionnaire.

Inclusion criteria involved ureteric and renal stones of maximum 20 mm per stone without restriction of overall number of stones. In both patient groups, a 200 µm core laser-fibre was used with an initial default setting of 0.8 J and 8 Hz for fragmentation and 0.3 J and 80 Hz for dusting. However, surgeons were free to customise the settings during the surgeries according the circumstances.

Overall, no differences for baseline characteristics regarding patients (age, gender, ASA [American Society of Anesthesiology] score, etc) and stones (number, size, sites, overall volume burden, etc) details were recorded.

The null hypothesis was accepted, as no difference in terms of ureteroscope length of time was detected between groups (21.4 vs 19.9 minutes for Moses and TFL groups, respectively). Furthermore, no differences were reported for most of the secondary endpoints, including stone-free rate, complication rate, and QoL scores.

Nevertheless, lower total energy and higher ablation efficiency was observed in favour of the Moses group. According to the authors impressions, less ablation efficiency for the TFL laser was observed anecdotally in cases of harder/denser calcium stones; however, the increased need of energy for the TFL not necessarily translates to a higher risk for harms to patients.

Furthermore, the TFL potentiality is still to be fully explored, so that at the end of the study there is no “winner” but rather the confirmation that both laser are excellent options for stones lasertripsy.

Source: Pulse-modulated Holmium:YAG laser vs the thulium fiber laser for renal and ureteral stones: A singlecentre prospective randomised clinical trial. Christopher R Haas, Margaret A Knoedler, Shuang Li, Daniel R Gralnek, Sara L Best, Kristina L Penniston, Stephen Y Nakada J Urol . 2023 Feb;209(2):374-383. doi: 10.1097/JU.0000000000003050. Epub 2023 Jan 9.

Of 686 patients, 202 (29.4%) were in the control group, 100 (14.6%) were in the lead-in group, and 384 (56%) were in the NOPIOIDS group. Thirty-nine patients (5.7%) were using opioids prior to surgery. No difference in baseline patient characteristics was noted including the use of robotic approach among the groups. Among 647 opioid-naive patients, the proportion of patients receiving any opioid prescription at discharge decreased significantly from 80.9% in the control group, to 57.9% in the lead-in group, and 2.2% in the NOPIOIDS group, mainly for kidney surgery (p<.001). None of the 229 patients undergoing radical cystectomy or prostatectomy required any opioid prescriptions at discharge in the NOPIOIDS group. The number of calls related to

Recently, a randomised trial of a single institution has been conducted to test the efficacy of the latest generation of the two lasers (i.e. the TFL and the advanced pulse-modulated Ho:YAG [Moses]) at the same range of settings and conditions.

QPM assay: A promising rapid, first-stage tool for infection and AMR diagnosis

Effective antibiotics should be administered within one hour after diagnosis of severe urinary tract infections and sepsis. However, current state-of-the-art infection and antimicrobial resistance (AMR) diagnostics are based on culture-based methods with a detection time of 48–96hrs. Therefore, it is essential to develop novel methods that can provide real-time diagnoses. In this paper investigators demonstrate that the complimentary use of label-free optical assay with whole-genome sequencing (WGS) can enable rapid diagnosis of infection and AMR.

The primary endpoint was the ureteroscope time, calculated from the insertion of the scope (either semi-rigid or flexible ones) in the ureteric orifice. Accordingly, the

The presented assay is based on microscopy methods exploiting label-free, highly sensitive quantitative phase microscopy (QPM) followed by deep convolutional neural networks-based classification. The workflow was benchmarked on 21 clinical isolates from four WHO priority pathogens that were antibiotic susceptibility tested, and their AMR profile was determined by WGS. systemic treatment options for mHSPC across patient subgroups in a “living” systematic review and network meta-analysis. The method of a living review is unique and allows for continuous evidence updates in part through advanced computer programming and artificial intelligence.

The proposed optical assay was in good agreement with the WGS characterisation. Accurate classification based on the gram staining was 100% recall for gram-negative and 83.4% for gram-positive, species identification was 98.6%, and assessment of resistant/susceptible type was 96.4%. At the individual strain level there was 100% sensitivity in predicting 19 out of the 21 strains, with an overall accuracy of 95.45%.

The results from this proof-of-concept study demonstrate the potential of the QPM assay as a rapid and first-stage tool for species and strain-level classification, and for detecting the presence or absence of AMR, which WGS can follow-up for confirmation. Overall, a combined workflow with QPM and WGS complemented with deep learning data analyses could, in the future, be transformative for detecting and identifying pathogens and characterisation of the AMR profile and antibiotic susceptibility.

The present paper demonstrates that use of label-free optical assay with whole-genome sequencing complemented with deep learning data analyses is a method of bacterial identification that warrants further studies as it has minimum dependencies on the still time-consuming approach of bacterial culturing.

Source: Highly sensitive quantitative phase microscopy and deep learning aided with whole genome sequencing for rapid detection of infection and antimicrobial resistance. Ahmad A, Hettiarachchi R, Khezri A, Singh Ahluwalia B, Wadduwage DN and Ahmad R. Front. Microbiol. 2023;14:1154620. doi: 10.3389/ fmicb.2023.1154620

Which men with metastatic hormone-sensitive prostate cancer should be offered triple therapy?

The treatment recommendations for metastatic hormone-sensitive prostate cancer (mHSPC) have changed dramatically in the last decade. New treatment combinations have shown compelling overall survival (OS) benefits, leading to a treatment intensification at this stage of the disease.

Last year, the results from PEACE-1 and ARASENS were published and guideline recommendations were changed. It is now recommended in the EAU Guidelines to offer docetaxel in combination with androgen deprivation therapy (ADT) plus an androgen pathway inhibitor (API) to men with mHSPC fit for docetaxel.

PEACE-1 and ARASENS were randomised clinical trials that investigated the addition of an API, abiraterone plus prednisone (AAP) and darolutamide respectively, to a backbone of ADT + docetaxel. The addition of an API provided an OS benefit over placebo. While the addition of an API to ADT + docetaxel has been shown to improve OS, it has not formally been shown if the addition of docetaxel to ADT + API infers similar OS benefits.

Riaz et al. sought to compare the current and practising optimal toilet posture. These trials reported that few children experienced complete resolution of nocturnal enuresis (5 to 33%). tebj@medisin.uio.no

The authors had a particular interest in comparing triplet therapy with an API + ADT. In all, 10 randomised clinical trials comprising 11,043 patients across nine unique treatment options were assessed. The triple therapy regimens were ranked the potentially most efficacious treatments for mHSPC. The patients that seemed to benefit the most were those with synchronous and high-volume mHSPC. Interestingly, the triple therapies were associated with better OS when compared with ADT + docetaxel, but not when compared with an API + ADT, i.e. ADT + enzalutamide, ADT + apalutamide or ADT + AAP. At the same time, the triple therapies were associated with a higher risk of Grade 3 and above adverse events.

The authors conclude that triple therapy may be preferred for men with high-volume synchronous mHSPC while omitting docetaxel may be preferred for metachronous low volume mHSPC. For those with high-volume metachronous disease or low-volume synchronous mHSPC an individualised risk-based approach must be taken.

This study highlights the importance of carefully selecting the right patients for triple therapy and considering the benefits versus potential harms of adding docetaxel to an API doublet with ADT. The extend of metastatic disease and time of metastatic presentation are some of the variables that may guide treatment selection. However, further efforts to individualise treatment and better understand the heterogeneity of mHSPC are warranted.

Source: First-line Systemic Treatment Options for Metastatic CastrationSensitive Prostate Cancer: A Living Systematic Review and Network Metaanalysis. Riaz IB, Naqvi SAA, He H, et al. JAMA Oncol. 2023 Mar 2:e227762. doi: 10.1001/jamaoncol.2022.7762.

The efficacy of standard urotherapy in the treatment of nocturnal enuresis in children is not well-supported by the current evidence

Initial conservative management of primary nocturnal enuresis (PNE) is about information and demystification. PNE involves mainly informing the family about urinary tract dysfunction and spontaneous resolution; lifestyle, and dietary changes (fluid intake and diet for constipation); registration of symptoms and voiding habits; and support and encouragement in children. PNE is usually the initial preferred treatment modality for many physicians and also other health personnel as it is conservative approach. There may be inconveniencies to employ them properly as it requires some strict life style changes such as fluid intake restriction.

The study includes a systematic literature search to look at the impact of this standard approach. Out of 2,476 studies 22 randomised controlled trial (RCT) studies were included to the study. Most other studies scored poorly in terms of evidence quality as studies combined several urotherapy interventions and studied different study populations. Twenty-two RCTs reported 0 to 92% of children being dry after standard urotherapy treatment. Three RCTs with the highest quality scores individualise and optimise drinking, voiding during the day,

There is insufficient evidence for offering standard urotherapy to children with PNE as first-line treatment modality. Until better evidence becomes available, considering other treatment modalities such as medical treatment or alarm treatment, may save time for children who are suffering from nocturnal enuresis.

The available literature in the field of standard urotherapy concerning the treatment of children with PNE lacks high level of evidence due to heterogeneity of the study populations and interventions. The limited number of high-quality studies does not really support the use of standard urotherapy for PNE.

Due to the presence of insufficient evidence for recommending standard urotherapy to children with PNE as a first-line treatment modality, other treatment options such as medical treatment or alarm treatment should be considered earlier especially for the patient group who suffers significantly.

Source: The efficacy of standard urotherapy in the treatment of nocturnal enuresis in children: A systematic review. Cecilie Siggaard Jørgensen, Konstantinos Kamperis, Johan Vande Walle, Søren Rittig, Ann Raes, Lien Dossche.

Journal of Pediatric Urology, Volume 19, Issue 2, 2023, Pages 163-172

Oral tebipenem pivoxil hydrobromide in complicated urinary tract infection

There is a need for oral antibiotic agents that are effective against multidrug-resistant gram-negative uropathogens. Tebipenem pivoxil hydrobromide is an orally bioavailable carbapenem with activity against uropathogenic Enterobacterales, including extended-spectrum beta-lactamaseproducing and fluoroquinolone-resistant strains.

In this phase 3, international, double-blind, double-dummy trial, the investigators evaluated the efficacy and safety of orally administered tebipenem pivoxil hydrobromide as compared with intravenous ertapenem in patients with complicated urinary tract infection or acute pyelonephritis. Patients were randomly assigned, in a 1:1 ratio, to receive oral tebipenem pivoxil hydrobromide (at a dose of 600 mg every 8 hours) or intravenous ertapenem (at a dose of 1 g every 24 hrs) for 7- 10 days (or up to 14 days in patients with bacteraemia). The primary efficacy end point was overall response (a composite of clinical cure and favourable microbiologic response) at a test-of-cure visit

(on day 19, within a ±2-day window) in the microbiologic intention-to-treat population. The noninferiority margin was 12.5%.

"…oral tebipenem pivoxil hydrobromide was noninferior to intravenous ertapenem in the treatment of complicated urinary tract infection…"

A total of 1372 hospitalised adult patients were enrolled; 868 patients (63.3%) were included in the microbiologic intention-totreat population (50.8% of whom had complicated urinary tract infections and 49.2% of whom had pyelonephritis). An overall response was seen in 264 of 449 patients (58.8%) who received tebipenem pivoxil hydrobromide, as compared with 258 of 419 patients (61.6%) who received ertapenem (weighted difference, -3.3 percentage points; 95% confidence interval [CI], -9.7 to 3.2). Clinical cure at the test-ofcure visit was observed in 93.1% of the patients in the microbiologic intention-to-treat population who received tebipenem pivoxil hydrobromide and 93.6% of patients who received ertapenem (weighted difference, -0.6 percentage point; 95% CI, -4.0 to 2.8); the majority of patients with microbiologic response failures at the test-of-cure visit were asymptomatic patients with recurrent bacteriuria. Adverse events were observed in 25.7% of patients who received tebipenem pivoxil hydrobromide and in 25.6% of patients who received ertapenem; the most common adverse events were mild diarrhoea and headache.

The authors conclude that oral tebipenem pivoxil hydrobromide was noninferior to intravenous ertapenem in the treatment of complicated urinary tract infection and acute pyelonephritis and had a similar safety profile. (Funded by Spero Therapeutics and the Department of Health and Human Services; ADAPT-PO ClinicalTrials.gov number, NCT03788967).

Source: Oral Tebipenem Pivoxil Hydrobromide in Complicated Urinary Tract Infection. Eckburg PB, Muir L, Critchley IA, Walpole S, Kwak H, Phelan A-M, Moore G, Jain A, Keutzer T, Dane A, Melnick D, Talley AK. N Engl J Med 2022 7;386(14):1327-1338. doi: 10.1056/NEJMoa2105462