The Utility and Safety of Ureteral Access Sheath During Retrograde Intrarenal Surgery in Children.

OBJECTIVE: To compare retrograde intrarenal surgery (RIRS) with and without ureteral access sheath (UAS) in different pediatric age groups. METHODS: The data of RIRS for kidney stone in children were obtained from 9 institutions. Demographic characteristics of patients and stones, intraoperative and postoperative results were recorded. While analyzing the data, patients who underwent RIRS without UAS (group 1) (n = 195) and RIRS with UAS (group 2) (n = 194) were compared. RESULTS: Group 1 was found to be young, thin, and short (P <.001, P = .021, P <.001), but there was no gender difference and similar symptoms were present except hematuria, which was predominant in group 2 (10.6% vs 17.3%, P <.001). Group 1 had smaller stone diameter (9.91 ± 4.46 vs 11.59 ± 4.85 mm, P = .001), shorter operation time (P = .040), less stenting (35.7% vs 72.7%, P = .003). Re-intervention rates and stone-free rates (SFR) were similar between groups (P = .5 and P = .374). However, group 1 had significantly high re-RIRS (P = .009). SFR had a positive correlation with smaller stone size and thulium fiber laser usage compared to holmium fiber laser (HFL) (P <.001 and P = .020), but multivariate analysis revealed only large stone size as a risk factor for residual fragments (P = .001). CONCLUSION: RIRS can be performed safely in children with and without UAS. In children of smaller size or younger age (<5 years), limited use of UAS was observed. UAS may be of greater utility in stones larger than 1 cm, regardless of the age, and using smaller diameter UAS and ureteroscopes can decrease the complications.

Safety and Efficacy of "Dusting and Pop-Dusting" with High-Power Laser for Treatment of Large Pediatric Stones with Ureteroscopy and Lasertripsy: Prospective Outcomes from a University Teaching Hospital.

Introduction: The wide use of high-power laser has changed the landscape of ureteroscopy and lasertripsy (URSL). We wanted to look at the role and outcomes of high-power holmium:yttrium-aluminum-garnet laser for URSL in pediatric stone disease. Methods: A prospective analysis of consecutive pediatric patients treated with "Dusting and Pop-dusting" using a high-power laser was done between January 2016 and March 2022. The project was registered with our audit committee. Data were analyzed for patient demographics, stone characteristics, operative details, procedural outcomes, and complications. Stone-free rate (SFR) was defined as fragments ≤2 mm on postoperative ultrasound imaging 2-3 months after the procedure. Results: A total of 35 patients underwent 43 procedures (1.2 procedure/patient) during the study period with a mean age of 9.4 years (range 1-16 years) and a male:female ratio of 13:22. The stone location was in the kidney in 32 (91.4%) patients of which 8 were in multiple renal locations. The mean stone size was 18 mm (range 10-39 mm), with the pre- and post-stent rates of 37% and 56%, respectively. An access sheath was used in 19 (44%) procedures. The overall SFR on ultrasound scan was 94% (n = 33) with no procedural complications noted in our series and a mean length of stay of 0.9 days. Conclusion: Pediatric URSL using a high-power laser achieves a high SFR even for large and multiple renal stones with no complications noted in our prospective series. Parents must, however, be counseled about the need for staged procedures, which might be needed for large stones.

Worldwide trends of practice and intervention in paediatric endourology: comparison of European versus Non-European responses.

Introduction: The area of paediatric endourology is unique and is recognised to be challenging, and it requires a certain level of focused training and expertise. Our aim was to conduct a worldwide survey in order to gain an overview regarding the current practice patterns for minimally invasive treatments of paediatric upper urinary tract stone patients. Material and methods: The survey was distributed between December 2021 and April 2022 through urology sections and societies in United Kingdom, Latin America and Asia. The survey was made up of 20 questions and it was distributed online using the free online Google Forms (TM). Results: 221 urologists answered the survey with 56 responses each from India, South America and UK and 53 responses from the rest of Europe (15 countries). In total, 163 responders (73.7%) managed paediatric stone patients in their daily practice. Of the responders, 60.2% were adult urologists and 39.8% were paediatric urologists. 12.9% adult urologists and 20.4% paediatric urologists run independent clinics while some run combined adult and paediatric clinics sometimes with the support of the nephrologists. Only 33.9% urologists offered all surgical treatments [extracorporeal shock wave lithotripsy (ESWL), percutaneous nephrolithotomy (PCNL), ureteroscopy (URS) and retrograde intrarenal surgery (RIRS)]. Conclusions: Treatment of paediatric stones can vary according to country and legislations. Based on the results of this survey, minimally invasive methods such as URS and mini PCNL seem to have become more popular. In most institutions a collaboration exists between adult and paediatric urologists, which is the key for a tailored decision making, counselling and treatment success.

Outcomes of Paediatric Cystine Stone Management: Results of a Systematic Review.

PURPOSE OF REVIEW: We wanted to analyse the outcomes of surgical (SWL, URS, PCNL) and medical management of cystine stones in the paediatric population in terms of stone-free status and complication rates, based on all the available literature evidence. RECENT FINDINGS: A systematic review of literature was performed for all studies with paediatric cystine stone management. Twelve studies met the eligibility criteria, of which 4 analysed outcomes of SWL, 2 of URS and 3 of PCNL and 3 focused on the effect of either alkalising agents (potassium citrate, citric acid) or cysteine-binding thiol (CBT) agents (tiopronin, penicillamine). The reported SFR in studies ranged from 50 to 83%, 59 to 100% and 63 to 80.6%, with a complication rate of 2.8-51%, 14-27% and 12.9-15.4% with SWL, URS and PCNL, respectively. Paediatric cystine stones treatment should aim at complete stone clearance, preservation of renal function and prevention of further recurrences. SWL achieves inferior results in case of cystine stones. URS and PCNL are safe and effective procedures in the paediatric population, with a low rate of major complications. Adherence to medical prevention therapies may prolong recurrence-free periods.

Comparison of Low-Power vs High-Power Holmium Lasers in Pediatric Retrograde Intrarenal Surgery Outcomes.

Objectives: To compare the outcomes of using low-power (up to 30 W) vs high-power (up to 120 W) holmium lasers in retrograde intrarenal surgery (RIRS) in children and to analyze if lasering techniques and the use of access sheath have any influence on the outcomes. Methods: We retrospectively reviewed data from 9 centers of children who underwent RIRS with holmium laser for the treatment of kidney stones between January 2015 and December 2020. Patients were divided into two groups: high-power and low-power holmium laser. Clinical, perioperative variables and complications were analyzed. Outcomes were compared between groups using Student's t-test for continuous variables, and Chi-square and Fisher's exact test for categorical variables. A multivariable logistic regression analysis model was also performed. Results: A total of 314 patients were included. A high-power and low-power holmium laser was used in 97 and 217 patients, respectively. Clinical and demographic variables were comparable between both groups, except for stone size where the low-power group treated larger stones (mean 11.11 vs 9.70 mm, p = 0.018). In the high-power laser group, a reduction in surgical time was found (mean 64.29 vs 75.27 minutes, p = 0.018) with a significantly higher stone-free rate (SFR) (mean 81.4% vs 59%, p < 0.001). We found no statistical differences in complication rates. The multivariate logistic regression model showed lower SFR in the low-power holmium group, especially with larger (p = 0.011) and multiple stones (p < 0.001). Conclusion: Our real-world pediatric multicenter study favors high-power holmium laser and establishes its safety and efficacy in children.

Role of Preoperative Ureteral Stent on Outcomes of Retrograde Intra-Renal Surgery (RIRS) in Children. Results From a Comparative, Large, Multicenter Series.

OBJECTIVE: To assess outcomes of pre-stenting versus non-pre-stenting in children undergoing retrograde intrarenal surgery (RIRS) for intrarenal stones. METHODS: Children/adolescent with kidney stones undergoing RIRS in 9 centers between 2015 and 2020 were retrospectively reviewed. EXCLUSION CRITERIA: ureteral lithotripsy, bilateral procedures. Stone-free status was evaluated at 3-month and defined as a single residual fragment (RF) ≤2 mm/absence of multiple fragments. Patients were divided into two groups (Group 1 no-prestenting; Group 2 prestenting). Student's, Chi-square and Fisher's exact test was used to assess difference between groups. Univariable and multivariable logistic regression analysis were performed to predict RF. Statistical significance: P-value <0.05. RESULTS: Three hundred eighty-nine children/adolescents were included (192 patients in Group 1). Prestented patients were younger compared with non-prestented (mean age 8.30 ± 4.93 vs 10.43 ± 4.30 years, P < 0.001). There were no differences in stone characteristics (number, size, locations). Lasing and total surgical time were similar. Urinary tract infections were more prevalent in Group 2 (10.7%) compared to Group 1 (3.7%, P = 0.016). Sepsis occurred in 2.1% of patients in Group 2 and no patient in Group 1 (P = 0.146). 30.7% patients in Group 1 and 26.4% in Group 2 had RF (P = 0.322). In univariate logistic regression analysis, stone size was associated with RF (OR 1.12 95%CI 1.06-1.18, P < 0.001), whereas Thulium fiber laser with a lower incidence (OR 0.24 95%CI 0.06-0.69, p=0.020). Multivariate logistic regression analysis showed that stone size was associated with RF (OR 1.20 95%CI 1.08-1.36, P = 0.001). CONCLUSIONS: RIRS showed similar stone-free rate in pre and non-prestented children/adolescents, although prestented patients were younger. A higher risk of post-operative infections was reported in prestented patients.

Role of Pediatric Ureteral Access Sheath and Outcomes Related to Flexible Ureteroscopy and Laser Stone Fragmentation: A Systematic Review of Literature.

Context: Flexible ureteroscopy and laser lithotripsy (FURSL) represent a good treatment option for pediatric urolithiasis. Scarce evidence is available about the safety and efficacy of the concomitant use of a ureteral access sheath (UAS) in the setting of pediatric ureteroscopy (URS). Objective: To acquire all the available evidence on UAS usage in pediatric FURSL, focusing on intra- and postoperative complications and stone-free rates (SFRs). Evidence acquisition: We performed a systematic literature research using PubMed/MEDLINE, Embase, and Scopus databases. The inclusion criteria were cohorts of pediatric patients <18 yr old, submitted to URS for FURSL, reporting on more than ten cases of UAS placement. The primary outcomes were prestenting rates, operating time, ureteric stent placement rates after surgery, rates and grades of complications, ureteral injuries, and overall SFR. A total of 22 articles were selected. Evidence synthesis: In total, 26 intraoperative and 130 postoperative complications following URS with UAS placement were reported (1.8% and 9.18% of the overall procedures, respectively). According to the Clavien-Dindo classification, 32 were classified as Clavien I, 29 as Clavien II, 43 as Clavien I or II, six as Clavien III, and one as Clavien IV. Twenty-one cases of ureteral injuries (1.59%) were noted in the whole cohort; most of them were ureteral perforation or extravasation, and were treated with a temporary indwelling ureteric stent. The overall SFR after a single URS procedure was 76.92%; after at least a second procedure, it was 84.9%. Conclusions: FURSL is a safe and effective treatment option for pediatric urolithiasis. UAS use was associated with a low rate of ureteric injuries, mostly treated and resolved with a temporary indwelling ureteric stent. Patient summary: We performed a systematic literature research on the utilization of a UAS during ureteroscopy for stone treatment in pediatric patients. We assessed the outcomes related to the rates of intra- and postoperative complications and the rates of efficacy of the procedure in the clearance of stones. The evidence shows a low rate and grade of complications associated with UAS placement and good stone-free outcomes. A ureteric injury may occur in 1.6% of cases, but it is usually managed and resolved with a temporary indwelling ureteric stent.

Outcomes and lessons learnt from practice of retrograde intrarenal surgery (RIRS) in a paediatric setting of various age groups: a global study across 8 centres.

PURPOSE: To analyse and report the practice, outcomes and lessons learnt from a global series of retrograde intrarenal surgery (RIRS) in a paediatric multicentre series. METHODS: A retrospective review of anonymized pooled data gathered globally from 8 centres in paediatric patients (≤ 18 years of age) who had renal stones and underwent RIRS from 2015 to 2020 was performed. Patient demographics, perioperative parameters, stone characteristics, complications and stone-free rate (SFR; defined as endoscopically stone free and/or residual fragments < 2 mm on follow up imaging) were analysed. The cohort was stratified into 3 groups by age: < 5 years (Group A), 5-10 years (Group B) and > 10 years (Group C). Overall, post-operative complication rate was 13.7%. Chi-square comparisons were used for categorical variables; analysis of variance (ANOVA) or Kruskal-Wallis tests were used for continuous variables. RESULTS: 314 patients were analysed. The mean age was 9.54 ± 4.76 years. Groups A, B and C had 67 (21.3%), 83 (26.4%) and 164 (52.2%) patients, respectively. Mean stone size was 10.7 ± 4.62 mm. Pre-stenting was performed in 155 (49.4%) of patients, ureteral access sheaths (UAS) was used in 54.5% of patients with majority (71%) utilizing holmium laser for stone fragmentation. All complications were minor (Clavien-Dindo grade 1 and 2). SFR was 75.5%. CONCLUSIONS: RIRS is acceptable as a first-line intervention in the paediatric population with reasonable efficacy and low morbidity. Complications are slightly higher in patients < 5 years of age, which should be taken into account while counselling patients.

10-year experience of Paediatric varicocele embolization in a tertiary centre with long-term follow-up.

INTRODUCTION: Paediatric varicocele embolization has many benefits over surgical ligation, but lacks published long-term data. We investigated technical and clinical outcomes in this under reported patient group. OBJECTIVE: To evaluate technical success, complications and recurrence rates following varicocele embolization in paediatric patients. MATERIALS AND METHODS: A single-centre retrospective review of procedural data and electronic notes of consecutive patients referred for varicocele embolization over a 10-year period was performed (February 2010-March 2020). The primary outcomes were technical success and clinical efficacy (lack of symptom recurrence). Secondary outcomes included complications, testicular vein size reduction and procedural parameters including radiation exposure. Chi-square analysis was used to identify predictors of clinical success. Follow-up involved outpatient clinical assessment and telephone interview. RESULTS: 40 patients (median age 15) were referred for left-sided symptomatic varicocele. Technical embolization success was achieved in 36/40 patients (90%), with 4 procedures abandoned (inaccessible vein). Embolization technique was platinum-based coils ± sclerosant. There were no immediate or long-term procedural complications. 32/36 patients completed short term follow-up at a median interval of 2.8 months. 30/32 (93.78%) experienced early clinical success. We found a significant reduction in peritesticular vein size following embolization (pre-3.70 vs post-2.56 mm, p = 0.00017) and a significant relationship between varicocele grade and early clinical success (χ2 = 4.2, p = 0.04), but not pre-treatment peritesticular vein size (χ2 = 0.02, p = 0.88). 33/36 patients completed long-term follow-up (median 4.2 years, range 0.36-9.9 years) producing a late clinical success rate of 93.9% (31/33). No post procedural complications including hydroceles were identified. DISCUSSION: This study demonstrates technical success, matching rates described in adult patients which is reassuring and in support of embolization in the younger patient cohort. More importantly, the overall clinical success rate is comparable with previous embolization studies. Reassuringly, all symptom recurrences occurred early in follow-up, and there is a cogent argument for a single follow-up appointment at this juncture. Our long-term average follow-up duration, primarily gained via telephone interview, exceeds other studies. Although our study has the longest follow-up for varicocele embolization in children, it is limited by a few patients being lost to early and long-term follow-up. This is a recognised issue faced by studies attempting to follow-up benign conditions with a high clinical success rate. CONCLUSION: Paediatric varicocele embolization is a successful alternative to surgical ligation, with no complications and good clinical outcomes over a long-term follow-up.

Is Flexible Ureteroscopy and Laser Lithotripsy the New Gold Standard for Pediatric Lower Pole Stones? Outcomes from Two Large European Tertiary Pediatric Endourology Centers.

Introduction: Although pediatric ureteroscopy has been increasingly performed, the evidence for its use in pediatric lower pole stones (LPS) is sparce. In this study we look at the effectiveness and outcomes of flexible ureteroscopy and laser lithotripsy (FURSL) in the management of LPS for a pediatric population. Materials and Methods: Data were collected from two large European tertiary endourology centers that specialize in pediatric kidney stone management. The study was registered as an audit at the respective hospitals. All data were cross-checked and analyzed using electronic operative notes, discharge records, laboratory systems, and patient correspondence. The inclusion criteria were patients ≤16 years with LPS having an FURSL procedure. Results: A total of 57 pediatric patients underwent FURSL for LPS. The mean age was 10.1 ± 4.7 years (range: 1-16.9 years) with a male-female ratio of 2:3. The mean single stone size was 9.45 ± 3.9 mm (range: 3-20 mm) and 31 (54.4%) had multiple stones. A preoperative stent was present in 18 (31.6%) patients and a postoperative stent or ureteral catheter was left behind in 32 (56.1%) patients. The initial and final stone-free rates were 82.4% and 98.2%, respectively, with 1.19 procedures per patient performed to be stone free. Although there were no intraoperative complications, there were only four (7%) minor complications (Clavien I) noted that were all simple urinary infections. No long-term complications were noted. Conclusion: Flexible ureteroscopy and lasertripsy achieve excellent outcomes for treatment of pediatric LPS. Although some patients might need a second procedure for complete stone clearance, FURSL may be considered as the first-line treatment of LPS.

MicroRNA-18a targeting of the STK4/MST1 tumour suppressor is necessary for transformation in HPV positive cervical cancer.

Human papillomaviruses (HPV) are a major cause of malignancy worldwide. They are the aetiological agents of almost all cervical cancers as well as a sub-set of other anogenital and head and neck cancers. Hijacking of host cellular pathways is essential for virus pathogenesis; however, a major challenge remains to identify key host targets and to define their contribution to HPV-driven malignancy. The Hippo pathway regulates epithelial homeostasis by down-regulating the function of the transcription factor YAP. Increased YAP expression has been observed in cervical cancer but the mechanisms driving this increase remain unclear. We found significant down-regulation of the master Hippo regulatory kinase STK4 (also termed MST1) in cervical disease samples and cervical cancer cell lines compared with healthy controls. Re-introduction of STK4 inhibited the proliferation of HPV positive cervical cells and this corresponded with decreased YAP nuclear localization and decreased YAP-dependent gene expression. The HPV E6 and E7 oncoproteins maintained low STK4 expression in cervical cancer cells by upregulating the oncomiR miR-18a, which directly targeted the STK4 mRNA 3'UTR. Interestingly, miR-18a knockdown increased STK4 expression and activated the Hippo pathway, significantly reducing cervical cancer cell proliferation. Our results identify STK4 as a key cervical cancer tumour suppressor, which is targeted via miR-18a in HPV positive tumours. Our study indicates that activation of the Hippo pathway may offer a therapeutically beneficial option for cervical cancer treatment.

Outcomes of Ureteroscopy vs Mini-Percutaneous Nephrolithotomy for Pediatric Upper Urinary Tract Calculi: Comparative Nonrandomized Outcomes from Two Tertiary Endourology Referral Centers.

Introduction: Pediatric upper urinary tract calculi can be treated by ureteroscopy (URS) or mini-percutaneous nephrolithotomy (mPCNL). We wanted to compare outcomes of URS and mPCNL from two tertiary referral centers that specialized in one of these treatments for pediatric stone disease. Materials and Methods: Data were collected from two tertiary centers for a 10-year period (2010-2019); one center specializing in URS and the other in mPCNL for consecutive patients ≤16 years undergoing either of these minimally invasive interventions. Upper urinary tract stones included stones in the kidney, pelviureteral junction, and proximal ureter, whereas mid or distal ureteral stones were excluded. Data were collected on patient and stone demographics. Outcomes of interest included stone-free rate (SFR) and complication rates. Results: During the study period, 55 patients underwent URS (group 1) and 40 patients underwent mPCNL (group 2). The mean stone size for groups 1 and 2 were 11.4 and 14.5 mm, respectively, whereas twice as many patients in group 1 had multiple stones. The final SFR and complication rates for groups 1 and 2 were 100% and 97.5%, and 5.4% and 12.5%, respectively. Although there were two Clavien II and one Clavien IV complication in the URS group, all five complications in mPCNL group were Clavien I. Conclusions: Our study shows excellent outcomes for upper urinary tract stones with both URS and mPCNL. Although treatment choices should be tailored to patients, each modality carries different advantages and our results reflect that high-volume centers specializing in a particular technique offer best outcomes, and this must also be borne in mind when counseling patients.

Outcomes of ureteroscopy (URS) for stone disease in the paediatric population: results of over 100 URS procedures from a UK tertiary centre.

PURPOSE: To report the outcomes of paediatric ureteroscopy (URS) for stone disease from a specialist endourology centre in the UK. Ureteroscopy for management of stone disease has increased worldwide and is now being done more commonly in the paediatric age group. METHODS: Data were analysed retrospectively from a database maintained between April 2010 and May 2018. Consecutive patients ≤ 16 years of age undergoing semi-rigid or flexible URS for stone disease were included. Stone size and stone-free rate (SFR) were routinely assessed using an ultrasound (USS) and/or plain KUB XR. Complications were graded according to the Clavien-Dindo classification and recorded within 30 days post-procedure and readmissions within 90 days after the procedure were also captured. RESULTS: Over the 8-year period between April 2010 and April 2018, 81 patients with a mean age of 8.8 years (range 18 months-16 years) and a male to female ratio 1:1.1 underwent 102 procedures (1.28 procedure/patient to be stone free). Of the 81 patients, 29 (35.8%) had comorbidities, with 26 (32%) having multiple comorbidities. The mean (± SEM) single and overall stone size was 9.2 mm (± 0.48, range 3-30 mm) and 11.5 mm (± 0.74, range 4-46 mm) respectively, with 22 (27.1%) having multiple stones. Thirty-five (34.7%) had stent in situ pre-operatively. The stone location was in the ureter (26.6%), lower pole (35.4%), and renal pelvis (16.5%), with 22/81(27%) having multiple stones and 21/102 (20.5%) where a ureteral access sheath (UAS) was used. With a mean hospital stay of 1.2 days, the initial and final SFR was 73% and 99%, respectively, and 61/102 (60%) had ureteric stent placed at the end of the procedure. While there were no intra-operative complications, the readmission rate was less than 1% and there were only three early complications recorded. This included a case each of prolonged admission for pain control (grade I), urinary retention (grade II) and post-operative sepsis requiring a brief ITU admission (grade IV). CONCLUSION: Our study demonstrates that in appropriate setting a high stone-free rate can be achieved with minimal morbidity for paediatric patients. There is potentially a need to factor the increasing role of URS in future paediatric urolithiasis guidelines.

Modulation of calcium signaling pathway by hepatitis C virus core protein stimulates NLRP3 inflammasome activation.

Hepatitis C virus (HCV) infection remains a major cause of hepatic inflammation and liver disease. HCV triggers NLRP3 inflammasome activation and interleukin-1ß (IL-1ß) production from hepatic macrophages, or Kupffer cells, to drive the hepatic inflammatory response. Here we examined HCV activation of the NLRP3 inflammasome signaling cascade in primary human monocyte derived macrophages and THP-1 cell models of hepatic macrophages to define the HCV-specific agonist and cellular processes of inflammasome activation. We identified the HCV core protein as a virion-specific factor of inflammasome activation. The core protein was both necessary and sufficient for IL-1ß production from macrophages exposed to HCV or soluble core protein alone. NLRP3 inflammasome activation by the HCV core protein required calcium mobilization linked with phospholipase-C activation. Our findings reveal a molecular basis of hepatic inflammasome activation and IL-1ß release triggered by HCV core protein.

Outcomes and Long-Term Follow-Up with the Use of Ureteral Access Sheath for Pediatric Ureteroscopy and Stone Treatment: Results from a Tertiary Endourology Center.

PURPOSE: The aim of this study was to retrospectively analyze outcomes of flexible ureteroscopy and laser fragmentation (FURSL) of renal stones with the use of ureteral access sheath (UAS) in the pediatric population. MATERIALS AND METHODS: We retrospectively collected data between January 2011 and January 2018 for patient demographics, stone characteristics, and outcomes in 21 children who underwent FURSL with the use of UAS. RESULTS: Twenty-one patients (10 boys and 11 girls) with a mean age of 11.8 years (range: 2-16 years) underwent FURSL using an access sheath. The stone location was in the lower pole in 13 patients (62%) with 12 patients (57%) having multiple stones. A 9.5F (35 cm) Cook Flexor UAS was used in all cases. The mean and overall stone size was 12 mm (range: 5-30 mm) and 15.4 mm (range: 5-35 mm), respectively. Preoperative stent was present in 8(38%) patients, and a postoperative stent or overnight ureteric catheter was inserted in 14 patients (67%). Thirty-one procedures (average: 1.5/patient) were needed to achieve a stone-free rate of 95%. There were no procedural or long-term complications noted over a mean follow-up of 26 months (4-37 months). CONCLUSION: The use of UAS in the treatment of pediatric renal stones is safe and feasible with good outcomes and without any long-term sequelae.

Alkyl-imino sugars inhibit the pro-oncogenic ion channel function of human papillomavirus (HPV) E5.

Despite the availability of prophylactic vaccines the burden of human papillomavirus (HPV) associated malignancy remains high and there is a need to develop additional therapeutic strategies to complement vaccination. We have previously shown that the poorly characterised E5 oncoprotein forms a virus-coded ion channel or viroporin that was sensitive to the amantadine derivative rimantadine. We now demonstrate that alkylated imino sugars, which have antiviral activity against a number of viruses, inhibit E5 channel activity in vitro. Using molecular modelling we predict that imino sugars intercalate between E5 protomers to prevent channel oligomerisation. We explored the ability of these viroporin inhibitors to block E5-mediated activation of mitogenic signalling in keratinocytes. Treatment with either rimantadine or imino sugars prevented ERK-MAPK phosphorylation and reduced cyclin B1 expression in cells expressing E5 from a number of high-risk HPV types. Moreover, viroporin inhibitors also reduced ERK-MAPK activation and cyclin B1 expression in differentiating primary human keratinocytes containing high-risk HPV18. These observations provide evidence of a key role for E5 viroporin function during the HPV life cycle. Viroporin inhibitors could be utilised for stratified treatment of HPV associated tumours prior to virus integration, or as true antiviral therapies to eliminate virus prior to malignant transformation.

Intravenous delivery of oncolytic reovirus to brain tumor patients immunologically primes for subsequent checkpoint blockade.

Immune checkpoint inhibitors, including those targeting programmed cell death protein 1 (PD-1), are reshaping cancer therapeutic strategies. Evidence suggests, however, that tumor response and patient survival are determined by tumor programmed death ligand 1 (PD-L1) expression. We hypothesized that preconditioning of the tumor immune microenvironment using targeted, virus-mediated interferon (IFN) stimulation would up-regulate tumor PD-L1 protein expression and increase cytotoxic T cell infiltration, improving the efficacy of subsequent checkpoint blockade. Oncolytic viruses (OVs) represent a promising form of cancer immunotherapy. For brain tumors, almost all studies to date have used direct intralesional injection of OV, because of the largely untested belief that intravenous administration will not deliver virus to this site. We show, in a window-of-opportunity clinical study, that intravenous infusion of oncolytic human Orthoreovirus (referred to herein as reovirus) leads to infection of tumor cells subsequently resected as part of standard clinical care, both in high-grade glioma and in brain metastases, and increases cytotoxic T cell tumor infiltration relative to patients not treated with virus. We further show that reovirus up-regulates IFN-regulated gene expression, as well as the PD-1/PD-L1 axis in tumors, via an IFN-mediated mechanism. Finally, we show that addition of PD-1 blockade to reovirus enhances systemic therapy in a preclinical glioma model. These results support the development of combined systemic immunovirotherapy strategies for the treatment of both primary and secondary tumors in the brain.

Ureteroscopy for paediatric calculi: The twin-surgeon model.

We describe our 'Tips and tricks' of ureteroscopy and lasertripsy (URSL) for paediatric ureteric calculi. All regional referrals directed to the paediatric urologist are discussed in a formal stone multidisciplinary team (MDT) meeting with urologists, radiologists, and biochemical pathologist. A paediatric urologist (SG) and an experienced adult endourologist (BS) do these stone procedures jointly as a twin-surgeon team approach for each patient.

Oncolytic reovirus as a combined antiviral and anti-tumour agent for the treatment of liver cancer.

OBJECTIVE: Oncolytic viruses (OVs) represent promising, proinflammatory cancer treatments. Here, we explored whether OV-induced innate immune responses could simultaneously inhibit HCV while suppressing hepatocellular carcinoma (HCC). Furthermore, we extended this exemplar to other models of virus-associated cancer. DESIGN AND RESULTS: Clinical grade oncolytic orthoreovirus (Reo) elicited innate immune activation within primary human liver tissue in the absence of cytotoxicity and independently of viral genome replication. As well as achieving therapy in preclinical models of HCC through the activation of innate degranulating immune cells, Reo-induced cytokine responses efficiently suppressed HCV replication both in vitro and in vivo. Furthermore, Reo-induced innate responses were also effective against models of HBV-associated HCC, as well as an alternative endogenous model of Epstein-Barr virus-associated lymphoma. Interestingly, Reo appeared superior to the majority of OVs in its ability to elicit innate inflammatory responses from primary liver tissue. CONCLUSIONS: We propose that Reo and other select proinflammatory OV may be used in the treatment of multiple cancers associated with oncogenic virus infections, simultaneously reducing both virus-associated oncogenic drive and tumour burden. In the case of HCV-associated HCC (HCV-HCC), Reo should be considered as an alternative agent to supplement and support current HCV-HCC therapies, particularly in those countries where access to new HCV antiviral treatments may be limited.

Ureteroscopy for Stone Disease in Paediatric Population is Safe and Effective in Medium-Volume and High-Volume Centres: Evidence from a Systematic Review.

PURPOSE OF REVIEW: The incidence of urinary stone disease among the paediatric population is increasing. Whilst there has been a rise in the number of original studies published on ureteroscopy (URS) in children, critical review still remains under-reported. RECENT FINDINGS: A Cochrane style systematic review was performed to identify all original articles on URS (minimum of 25 cases) for stone disease in paediatric patients between Jan. 1996 and Dec. 2016. Based on the number of reported cases, centres were divided into medium (25-49 cases) and high (≥ 50 cases) volume studies. Thirty-four studies (2758 children) satisfied our search criteria and were included in this review. The mean stone size was 8.6 mm with an overall stone-free rate (SFR) of 90.4% (range 58-100). Medium-volume centres reported a mean SFR of 94.1% (range 87.5-100), whilst high-volume centres reported a mean SFR of 88.1% (range 58-98.5). Mean number of sessions to achieve stone-free status in medium-volume and high-volume groups was 1.1 and 1.2 procedures/patient respectively. The overall complication rate was 11.1% (327/2994). Breakdown by Clavien grade was as follows: Clavien I 69% and Clavien II/III 31%. There were no Clavien IV/V complications, and no mortality was recorded across any of the studies. The overall failure to access rate was 2.5% (76/2944). Medium-volume and high-volume studies had overall complication rates of 6.9% (37/530) and 12.1% (287/2222) respectively, but there was no significant difference in major or minor complications between these two groups. Ureteroscopy is a safe and effective treatment for paediatric stone disease. Medium-volume centres can achieve equally high SFRs and safety profiles as high-volume centres. Despite the rarity of paediatric stone disease, our findings might increase the uptake of paediatric URS procedures.