Stesura Seveso 323Archivio Italiano di Urologia e Andrologia 2021; 93, 3 ORIGINAL PAPER No conflict of interest declared. When a patient is offered a URS for a ureteric stone, the possibility of spontaneous expulsion still exists before the procedure, eventually unnoticed by the patient. If no other measures are taken to detect persistence of stones before surgery, a “stoneless” or “negative” procedure (hence, unnec- essary) would be performed (14). Negative URS, with described rates up to 15%, represents a avoidable patient risk and use of medical resources (15-18). Predicting neg- ative URS preoperatively and cancelling the procedure would prevent this unnecessary burden (14). Several factors predicting negative URS have been studied. Smaller stone size is associated with increased probability of unnoticed expulsion and negative URS (15, 17); other reported factors include distal stone positioning (17) and female gender (15, 16). Time since last imaging study does not appear to influence stoneless procedure rates (17). Other potential influencing factors showed varying results (15-18). The objective of this paper is to describe rates and identify predictive factors of negative URS and to define strategies which would minimize patient and financial burden of these unnecessary procedures. MATERIALS AND METHODS A retrospective cohort study analyzed all patients who underwent URS in our Center over a period of 2 years. Only procedures to treat ureteric stones were included; all were performed in the same Center, with similar surgical equipment. Several factors were reviewed, including patient age, gender and comorbidities, previous proce- dures, as well as clinical, laboratory and imaging findings. To comply with the purpose of the study, patients with neg- ative URS were identified, and a potential correlation with the above-mentioned factors was investigated. Patients who had negative URS were followed with ultrasound or computerised tomography (CT), and those with presence of stone suspected of retrograde migration were not included; patients in which complete URS was not feasible were also not included. Statistical analysis was performed using SPSS 23®, including univariate Mann-Whitney and Kruskal- Wallis tests, and a multivariate logistic regression model. RESULTS During the defined period, 262 patients underwent URS as planned treatment for ureteric stones while meeting the selection criteria. The population was 50.8% female, Introduction: Urolithiasis is common world- wide, with ureteric stones being a particular burden. Ureteroscopy (URS) is one of the most useful proce- dures in treating ureteric stones not passed spontaneously; this procedure has a complication risk of 4%. Negative URS, with described rates up to 15%, represents an avoidable patient risk and use of medical resources. Objectives: To describe rates and identify predictive factors for negative URS and to define strategies which would minimize patient and financial burden from these unnecessary procedures. Materials and methods: A retrospective cohort study analyzed patients who underwent URS in our Center to treat ureteric stones over a period of 2 years. Patient age, gender, and comor- bidities, as well as laboratory and imaging findings, were ana- lyzed. Results: 262 patients underwent URS for ureteric stones. The female population was 50.8% with a mean age of 56.89 years. A total of 78 (29.8%) URS procedures were negative. Univariate analysis showed a higher prevalence of negative URS in female patients, as well as in primary, smaller, and radiolu- cent stones. At multivariate analysis, a logistic regression model correctly classified 76% of patients, with smaller stone size and radiolucency being significant predictors of negative URS. Discussion and conclusions: Our Center showed a high rate of negative URS, higher than commonly described in the literature. Female patients tend to have an even higher rate, possibly due to unnoticed passage of stones. Patients with small, radiolucent stones showed the highest rates of negative URS. KEY WORDS: Urolithiasis; Ureteric; Stone; Ureteroscopy; Negative. Submitted 2 January 2021; Accepted 2 July 2021 INTRODUCTION Urolithiasis is very common worldwide, with prevalence rates described in general population of 1-20% (1-4); countries with high standard of life show increasing rates over the past decades, with over 10% reported prevalence (5-7). Ureteric stones pose a particular burden with fre- quent need of emergency visits and possible need for admittance and invasive procedures (7, 8). Ureteroscopy (URS) is one of the most useful methods for treating ureteric stones not passed spontaneously (4, 10, 11). This procedure is generally considered safe, involving a complication risk of 4%, with many being performed in an outpatient basis (12-14). A mean overall cost of $2801 per procedure has been described in a systematic review (13). Predicting negative ureteroscopy for stone disease – Minimizing risk and cost Miguel Eliseu, Roberto Jarimba, Pedro Moreira, Pedro Simões, Paulo Temido, Arnaldo Figueiredo Urology and Renal Transplantation Department, Coimbra Hospital and University Center, Coimbra, Portugal. DOI: 10.4081/aiua.2021.3.323 Summary Archivio Italiano di Urologia e Andrologia 2021; 93, 3 M. Eliseu, R. Jarimba, P. Moreira, P. Simões, P. Temido, A. Figueiredo 324 with a mean age of 56.89 years (SD +/- 15.705 years). Patients had a mean stone size of 7.7 mm (SD +/- mm); 47.8% of patients had stones between 5 and 9 mm. According to pre-procedure imaging, the lower ureter was the most common stone location (54.3%), followed by mid (23.7%) and upper ureter (22%). Approximately 86.3% of stones studied were radiopaque on plain X ray of Kidney-Ureter-Bladder (KUB). Regarding imaging tech- niques applied at initial diagnosis, renal ultrasound was most used (99.2% of patients); KUB X-ray was performed in 90.2% of cases and CT in 78.6%. Stenting in the acute setting was performed at physician discretion, with Center policy including best practice guidelines; stenting was performed in cases with associat- ed infection, compromised renal function or long-stand- ing pain (over 14 days) irrespective of planned URS or not. A significant proportion of patients underwent ureteric stenting in the acute setting (57.5%; n = 146); of those proposed to URS after stenting, 67.8% (n = 99) underwent KUB, 15.1% (n = 22) underwent CT, with 2.7% (n = 4) having both exams; 29 patients (19.9%) had no imaging between stenting and surgery. Cases where no evidence of stones was found were not considered for URS. The mean time between the acute episode and subse- quent URS was 61.8 days (+/- 27.076). In patients who underwent stenting prior to URS, mean time from stent- ing to surgery was 65.3 days (+/- 28.278). Patient and stone characteristics are displayed in Table 1. A total of 78 URS procedures were negative for stones, representing 29.8%. Several factors were investigated in univariate analysis, which showed a higher prevalence of negative URS in female patients (p = 0.023), as well as in primary (p = 0.001), smaller (p = 0.010), and radiolucent stones (p = 0.035). These results are displayed in Table 2. Several other factors were analyzed, but not found to be predictors of negative URS (Table 3). Namely, anatomical stone position (p = 0.646), mean time between the acute episode and subsequent URS (p = 0.207) and mean time from stenting to surgery (p = 0.614) did not appear to influence the risk of negative ureteroscopy. There was also no significant difference between patients who did or did not undergo CT scan (negative URS rates of 28.6% vs 33.9%, p = 0.139). At multivariate analysis, a logistic regression model cor- rectly classified 76% of patients, with smaller stone size (p = 0.026) and radiolucency (p = 0.011) being signifi- cant predictors of negative URS, and accounting for 47.7% of the variance. Each mm increase in stone size, showed an impact on OR for negative URS of 0.815 (expB=-0.204), while radiopaque stones showed an OR Table 1. Patient/stone characteristics and acute episode clinical variables; frequencies represented in percentage of valid results and absolute number of cases excluding missing values in brackets. Patient Frequency in valid % (n) and stone characteristics excluding missing Sex Female 50.8% (133) Male 49.2% (129) Age in years 20-34 7.3% (19) 35-49 22.9% (60) 50-64 37% (97) 65-80 24.4% (64) 80 or more 8.4% (22) Number of episodes *1 Primary 81.5% (203) Recurrent disease 18.5% (46) Stone anatomical location Upper ureter 22.0% (52) Mid-ureter 23.7%(56) Lower ureter 54.3% (128) Radiopacity *2 Radiopaque 86.3% (202) Radiolucent 13.7% (32) Medical expulsive therapy Alfa-blockers 53.8% (141) Corticosteroids 11.5% (30) Perc. nephrostomy in acute episode (performed) 11.8% (30) JJ stenting in acute episode (performed) 57.5% (146) *1 missing value in 12 cases with dubious history of stones (patient unsure and no previous imaging available); *2 based on KUB; missing value in 26 cases that did not undergo KUB and 2 cases for which KUB was not available to the authors (from other institutions). Table 2. Significant variables in univariate analysis with respective rates of negative URS in each subgroup and corresponding p values. Negative URS was more common in females, primary cases, small and radiolucent stones. Clinical Variables % negative URS p value Primary 32.5% < 0.001 Recurrence 8.7% Female 36.1% 0.023 Male 23.3% 0-4.9 mm 56.3% 0.010 5-9.9 mm 33.7% 10 mm or more 15.5 % Radiopaque 19.8% 0.035 Radiolucent 43.8% Table 3. Non-significant variables which did not show influence on the rate of negative URS. Univariate non-significant patient Frequency of negative p value and stone characteristics URB (%) Age in years 20-34 47.4% 0.442 35-49 26.7% 50-64 30.9% 65-80 28.1% 80 or more 22.7% Stone anatomical location Upper ureter 25% 0.646 Mid-ureter 28.6% Lower ureter 27.3% Diagnosis Imaging Including CT 28.6% 0.139 No CT 33.9% Medical expulsive therapy Alfa-blockers 33.1% 0.282 Corticosteroids 40% None 27% Time from acute episode to URS 0-29 days 28.6% 0.207 30-59 days 33.1% 60-89 days 27.9% ≥ 90 days 21.4% Time from stenting to URS 0-29 days 35.7% 0.614 30-59 days 36.8% 60-89 days 37.9% ≥ 90 days 29.4% Percutaneous nephrostomyin acute episode Yes 30% 0.777 No 28.6% JJ stenting in acute episode Yes 36.3% 0.464 No 21.3% 325Archivio Italiano di Urologia e Andrologia 2021; 93, 3 Predicting negative ureteroscopy for negative ureteroscopy of 0.240 (expB=-3.716). Table 4 summarises these results. DISCUSSION AND CONCLUSIONS Our Center showed a high rate of negative URS, more than previously described in the literature. A recent sys- tematic review suggests that a publication bias may exist, resulting in series with higher rates of URS not being sub- mitted for peer review, leading to underestimation of its prevalence (19). Stone position has been described in one previous study as an influencing factor, with distal stones resulting in higher negative URS rates (17); this did not seem to be the case with our population. In accordance with previ- ously reported data (17) time to surgery from last imag- ing study or stenting also did not influence negative URS rates. Of note, our series presents a significant number of pre-stented patients, more than in previously reported retrospective studies (15) and 19.9% of those did not undergo further imaging before URS. Female patients tend to have a higher rate of negative URS, as described in two recent studies (15, 16). This is possibly explained by frequent unnoticed passage of stones (due to shorter urethral length and lower voiding pressure) or by a higher frequency of pelvic phleboliths mistaken as ureteric stones (19). Patients with small, radiolucent stones showed the highest rates of negative URS; this is also in accordance with previ- ously described series (15, 17). These patients would ben- efit the most from pre-operative repeat imaging studies, eventually with non-contrast CT, to identify and preclude unnecessary treatments and costs (14). Prospective studies could help identify more precisely which imaging studies, in which patients and in what timeframe would impact the most in terms of change in planned treatment, to suggest clear guidelines regarding this matter. REFERENCES 1. Trinchieri A. Epidemiology of urolithiasis.Arch Ital Urol Androl. 1996; 68:203-49. 2. Trinchieri A. Epidemiology of urolithiasis: an update. Clin Cases Miner Bone Metab. 2008; 5:101-106. 3. 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Predictors and results of negative ureteroscopy for treatment of consecutive ureteric stones done as a primary procedure: prospective outcomes from a University Hospital. Urol Int. 2019; 103:143-148. 19. Rice P, Prattley S, Somani BK.’Negative ureteroscopy’ for stone dis- ease: evidence from a systematic review. Curr Urol Rep. 2019; 20:13. Table 4. Logistic regression model accounting for 47.7% of the variance in the dependent variable (probability of negative URS), correctly classifying 76% of patients; each mm increase in stone size with OR of 0.815 and radiopaque stones with OR of 0.240 for negative URS. Applied variables Significance (p) B exp (B) Sex 0.234 - Stone size (absolute value in mm) 0.026 -0.204 0.815 Primary vs Recurrence 0.198 - Radiopacity 0.011 -3.716 0.240 Correspondence Miguel Eliseu, MD (Corresponding Author) mgl.nobre@gmail.com Roberto Jarimba - rjarim-ba@gmail.com Pedro Moreira - pedronetomoreira@gmail.com Pedro Simões - pedrocorreiasimoes@gmail.com Paulo Temido - ptemido@gmail.com Arnaldo Figueiredo - ajcfigueiredo@gmail.com Urology and Renal Transplantation Department, Coimbra Hospital and University Center Praceta Professor Mota Pinto, 3004-561 Coimbra (Portugal)