ALPHA PARTICLE-BASED BRACHYTHERAPY CAN ABOLISH SOLID MALIGNANT TUMORS AND ELIMINATE METASTASES BY ENFORCING ANTI-TUMOR IMMUNITY
Keisari1, A. Popovtzer2, I. Kelson3
1Clinical Microbiology and Immunology, Tel Aviv University, Israel
2Head and Neck Tumor Unit, Davidoff Cancer Center, Beilinson Hospital, Israel
3School of Physics and Astronomy, Sackler Faculty of Exact Sciences,, Tel Aviv university, Israel
Background: Alpha radiation is a lethal form of radiation whose short range limits its use for cancer treatment. A unique intra-tumoral alpha radiation-based brachytherapy treatment termed Diffusing Alpha emitters Radiation Therapy (DaRT) was developed in our laboratories. Radium-224 loaded sources (Alpha DaRT seeds) are inserted into the tumors and release by recoil short-lived alpha-particle emitting atoms. These atoms disperse in the tumor 2-3 mm from the source and kill the tumor cells. DaRT is the only efficient method for treatment of solid tumors by alpha radiation and will be applied for the treatment of prostate and renal cancer patients. Results: 1. Insertion of Ra-224 loaded seeds into solid tumors resulted in necrosis and retardation of tumor growth, and extended survival in mice bearing murine or human derived squamous cell carcinoma (SCC), lung, pancreatic, colon, prostate and breast tumors. 2. Local control was augmented when DaRT was combined with chemotherapy. 3. The radiosensitivity of tumor cells to alpha particles was in correlation with the formation of DNA double strand breaks. 4. Treatment of the primary tumor resulted in the elimination of lung metastases due to development of systemic anti-tumor immunity. 5. Treatment of cancer patients with skin or oral cavity SCC resulted in complete response in 11 out of 14 patients and partial response in three. Conclusions: DaRT is an effective treatment for solid malignant tumors and can be further potentiated by chemotherapy and immunotherapy. This combined treatment modality holds significant potential for the treatment of prostate and renal human cancers.
Purpose: Study aimed to identify urologic cancers’ characteristics predictive of response to IO. Currently, tumor characteristics (biomarkers) considered predictive of therapy response include: PD-L1 expression, DNA mismatch repair status and tumor mutational burden. Biomarkers for hyper-progression in IO (JAK1 and JAK2 inactivating mutations; MDM2 and MDM4 gene amplification) were recently identified. Methods: 728 urologic tumors’ profiling data (Caris Life Sciences, Phoenix, AZ) review included: gene sequences (592 genes) and amplifications, expression of PD-L1, DNA microsatellite stability (MSI) and total tumor mutational burden (TMB). Results: Overall, PD-L1 over-expression was detected in 16.6% of cases; most commonly in bladder carcinomas (33%), except in neuroendocrine type (0%). Renal carcinomas were frequently positive (25%), too. MSI-High was overall rare (1.4%), except in ureteral carcinomas (12%). Patients with MSI-H ureteral carcinomas were known Lynch syndrome (LS) carriers (MSH2 gene). TMB was high (16 mutations/megabase) in MSI-H/LS patients and in one microsatellite stable case (with TP53 mutation). Biomarkers of poor response (potential hyper-progression on IO) including inactivating mutations of JAK1, JAK2 and gene amplifications of MDM2 and MDM4 were detected in 8% of bladder, 4.5% prostate and 1% or renal cancers. Conclusions: A wide variation in detection of biomarkers for IO therapy across urologic malignancies necessitates individual case analysis. Biomarkers of potential benefit (e.g. MSI-H) may be associated with biomarkers of resistance (e.g. inactivating JAK2 mutation). Identification of ureteral carcinoma should raise a suspicion for LS.
Background: We previously reported studies on a small number of patients on surveillance (n=18) showing a possible link between Prostate Cancer and anaerobe colonization of the prostate (see https://www.ncbi.nlm.nih.gov/pubmed/29123122). We report results on a further cohort of 21 patients. Methods: The second group were 21 new referrals with urinary symptoms for investigation. Post prostate massage urines were screened using Matrix-Assisted Laser Desorption/Ionization Time-of-Flight (MALDI-TOF) for identification of bacteria grown under anaerobic conditions. Ten preoperative urines investigated for non-urological conditions acted as controls. Findings: Eight of 18 patients in the Active surveillance group (41%) had anaerobic organisms identified. None of 10 control samples contained anaerobes. 9 of 21 in the second group were positive for anaerobes (43%). Pooling the two groups 1 of 11 (9%) with PSA 1.5 had anaerobes vs 16 of 28 (57%) with PSA =1.5 had them (Fishers exact test p= 0.011). Interpretation: The numbers of PC in this series and literature are still small (n=27) but the frequency of anaerobes compared with literature control urines cultured for anaerobes(n=551), was significantly different (OR 17.8(7.6,42.0) greater than the risk of smoking 5-9 cigarettes a day for 30-40 years OR 11.1(6.94,20.64)
Purpose: to determine the sensitivity, specificity and overall accuracy of CellDetect™ in diagnosing prostate cancer (PC) in urine samples following digital rectal examination (DRE). Methods: a group of PC patients and a group of controls with either a serum PSA level2.5ng/ml or a recent negative prostate biopsy were included. DRE was standardized according to the method specified with PCA3 testing. Urine samples were obtained and processed by fixation, CellDetect™ staining and inspected by a pathologist (AS). CellDetect™ stains malignant and benign cells with reddish or green colors, respectively. Samples were defined positive or negative when both CellDetect™ and cytomorphology were consistent. When cytology and CellDetect™ results disagreed, samples were defined undetermined. Sensitivity, specificity, positive and negative predictive values and overall accuracy were calculated. Results: 55 PC patients and 50 controls were included. Of 105 urine samples 44 were not diagnostic including 20 acellular and 24 undetermined samples. As the result, diagnostic accuracy was calculated on 34 PC samples and 27 controls. Of the 34 PC samples, 30 were positive and 4 negative. Of the controls 7 were positive and 20 negative. CellDetect™ had a sensitivity of 88%, specificity of 74%, a positive predictive value of 81%, a negative predictive value of 83%, and an overall accuracy of 82%.
Conclusions: CellDetect™ proved to be very sensitive and less specific. This test may support a prostate biopsy in a patient with an elevated PSA. However, a negative result does not obviate the need for a prostate biopsy.
Purpose: At the present, it is not possible to predict the ablation zone volume following irreversible electroporation (IRE) for prostate cancer (PCa). This study aimed to determine the necessary electrical field threshold to ablate human prostate tissue in vivo with IRE. Methods: In this prospective multi-center trial (NCT01790451), 16 patients with localized PCa were treated with IRE four weeks before their scheduled radical prostatectomy. Numerical models of the electrical field were generated and compared to the ablation zone volume on whole-mount pathology and multiparametric MRI. AMIRA software was used to calculate the ablation zone volumes on histology and MRI. The electric field threshold to ablate prostate tissue was determined for each patient. Results: Thirteen patients were included for histological and simulation analysis. The median electrical field threshold was 550.5 V/cm (interquartile range 383 to 750 V/cm) for the software-generated (AMIRA) histology volumes and 704.8 V/cm (interquartile range 534 to 826 V/cm) for the manually calculated volumes. The median electrical field threshold was 500.5 V/cm (interquartile range 386 to 580 V/cm) when the ablation zone volumes were used from the follow-up MRI. Conclusions: The electrical field threshold to ablate human prostate tissue in-vivo was determined using whole-mount pathology and MRI. These thresholds may be used to develop treatment planning or monitoring software for IRE prostate ablation, however further optimization of simulation methods may be required to decrease the variance that was observed between patients.
Introduction and objective: Whole gland therapy for prostate cancer (PCa) is associated with significant adverse effects. Focal irreversible electroporation (IRE) is a developing treatment for localised clinically significant PCa which ablates cancerous tissue while preserving non-cancerous prostate tissue and adjacent structures. The objective of this study was to determine the oncological outcome of the primary IRE procedure. Methods: Patients who met the consensus guidelines on patient criteria and selection for primary focal therapy were eligible for analysis. Patient’s received a minimum of 12 months oncological follow up which included serial prostate-specific antigen (PSA) tests, mpMRI and repeat biopsy. Adverse events and Quality of Life (QoL) outcome data were also assessed. Results: Overall, 130 patients were included in the analysis. All patients had clinically significant PCa on pre-treatment biopsy. No high grade adverse effects occurred during the trial. Of the 130 patients, 95 had a transperineal biopsy at 12 months. In field oncological control on follow up biopsy was 94.7% (90/95), when excluding patients during the initial learning curve this increased to 98.7% (78/79). The whole prostate was clear of clinically significant PCa in 87.4% (83/95) of patients; this increased to 89.8% (71/79) when excluding the learning curve. 122 patients had multiparametric MRI at 6 months. 83.6% (102/122) had a clear MRI, 2.4% (3/122) had a suspicious lesion infield, 4.9% (6/122) had suspicious lesion adjacent to the treatment zone, 7.3% (9/122) had a suspicious outfield lesion and 1.2% (2/122) had suspicious lesion infield and outfield. Compared with baseline, a decline of 61% in PSA at 12 months. Conclusion: To our knowledge this is the largest cohort of patient that have undergone primary IRE for localised clinically significant PCa. Our data supports the oncological benefit of IRE in men with localised disease. Nevertheless, further multi-centre trial with longer follow up are warranted to validate these results.
Purpose: Prostate cancer and inguinal hernia are common diseases in adult men. Actually, 5-10% patients who are performed laparoscopic radical prostatectomy (LRP) have inguinal hernia. The purpose of this study was to evaluate the surgical outcome of simultaneous surgery of LRP and laparoscopic inguinal hernia repair (LIHR). Methods: A total of 16 patients performed simultaneous surgery of LRP and LIHR from June 2014 to November 2017 in Kameda Medical Center. Both LRP and totally extra-peritoneal hernia repair (TEPP) against inguinal hernia were performed by retroperitoneal approach. Polypropylene mesh and non-absorbable tacks were used for TEPP. Results: Median age was 71.6 years old (range: 65-76). Before the operation, the 4 patients (25%) had a history of inguinal hernia. The median operation time was 270 min (range: 178-357). The median blood loss was 240 ml (range: 30-810). By the laparoscopic findings, 8 patients (50%) had indirect hernia and 7 patients (44%) had direct hernia. Seven patients (44%) underwent TEPP for both sides of hernia. No sever postoperative-complication was observed. Two patients had post-operative inguinal hernia in contralateral side. Conclusions:Simultaneous surgery of LRP and LIHR are performed safely(186 words).
Objective: To evaluate the ability of PSMA-PET to detect significant intra-prostatic malignancy in an ISUP 2/3 cohort, and determine if PSMA-PET improves upon the diagnostic accuracy of mpMRI. Patients and Methods: 56 consecutive patients with ISUP 2/3 PCa following radical prostatectomy (RP), with both mpMRI and PSMA-PET CT performed pre-operatively were enrolled. Accuracy of PSMA-PET, mpMRI alone and in combination was analyzed for identifying ISUP 1-3 within a 12 segment model. Accuracy of a combined predictive model (PSMA-PET & mpMRI) was determined. A ROC analysis to determine the optimal standardised uptake value SUV for PSMA-PET in discriminating between ISUP 1 and ≥ 2 was performed. Results: On a per patient basis, identifying ISUP 2-3 PCa, sensitivity for PSMA-PET and mpMRI were 100% and 97% respectively. Assessing ISUP 2 using a 12 segment analysis, PSMA-PET demonstrated greater sensitivity, specificity, NPV and PPV: 88%, 93%, 95% and 85% than mpMRI (PIRADS 3-5) 68%, 91%, 87%, and 75% respectively. Sensitivity for both modalities reduced markedly when assessing ISUP 1, PSMA-PET 18% and mpMRI 10%. When used in combination (PSMA-PET & mpMRI PIRADS 4-5), sensitivity and NPV was 92% and 96% respectively. For hemi- gland analysis a SUVmax value of 3.95 achieved a sensitivity and specificity of 94% and 100% respectively for detecting ≥ ISUP 2. Conclusion: PSMA-PET is accurate in detecting ISUP 2/3 intra-prostatic malignancies, compared with and complementary to mpMRI. The detection rate for ISUP 1 disease for both PSMA-PET and mpMRI is low.
R.E.N.A.L nephrometry score (NS) is used to compare the surgical complexity of renal tumors. NS showed moderate interobserver reliability. Recently, estimated Contact Surface Area (eCSA) of renal tumors has been introduced and shown to correlate with post-operative functional outcomes. Our aim is to determine the reproducibility of the eCSA scoring system among different observers and to compare the interobserver reliability between eCSA scoring and NS. The study included patients who were diagnosed with renal cell carcinoma,underwent nephron sparing surgery at our institute between 2015 and 2017 and had sufficient pre-operative imaging data. eCSA was calculated based on abdominal CT or MRI using the formula developed by Hsieh et al. eCSA was calculated by 3 observers. The interobserver agreement of eCSA, 4 components and overall NS was assessed by Interclass correlation coefficient (ICC). Ninty patients had sufficient radiographic information for calculating eCSA and NS. Median eCSA (interquartile range (IQR)) was 44.18 (19.04-80.21), 43.65 (22.75-105.40) and 37.28 (20.35-94.11). Median NS (IQR) was 8 (6-9), 8 (6.75-9) and 8 (5-10) respectively. We found strong interobserver agreement of eCSA (ICC-0.79 (p0.005). The corresponding ICC values of the NS components (Radius, Exophytic/Endophytic, Nearness, Location) and overall score were 0.82 (p0.01), 0.81 (p0.01), 0.53 (p0.01), 0.75 (p0.01), and 0.84 (p0.01) respectively. The eCSA scoring system has a strong interobserver reliability. NS interobserver reliability showed strong agreement between the observers for all components except Nearness which demonstrated moderate agreement. Our results add reliability to the eCSA model as a reproducible and accurate descriptor of surgical complexity of renal tumors. eCSA interobserver reliability is similar to NS, which is the gold standard complexity assessment tool.
Purpose: Recently Contact Surface Area (CSA) of renal tumors has been introduced and shown to correlate with post-operative renal function. The purpose of our study was to validate CSA as a predictive tool for renal function decline after nephron sparing surgery (NSS) of low complexity renal tumors. Methods: 86 patients who underwent NSS at our institute between 2014 and 2017 were included in the study. CSA was calculated based on pre-operative cross sectional imaging. eGFR was calculated using the most recent pre-operative and last follow-up creatinine. The correlation between CSA and RS, absolute and percent change in eGFR (ACE and PCE respectively) was examined by spearman correlation coefficient (µs). Linear regression model was fitted to examine the association of CSA with ACE and PCE. ROC curve analysis was performed to examine CSA ability to predict more than 10% loss in renal function. Results: Median (interquartile range (IQR)) CSA was 25.3 (10.2-44.1) cm2 and median (IQR) RS was 7 (5-8). Median follow-up was 15 months. CSA was significantly correlated with RS (µs 0.68, p0.001). Furthermore, CSA was significantly correlated with ACE (µs -0.98, p0.001(. Both CSA and RS affected change in renal function on univariable analysis (p0.001). However, only CSA was found to be an independent predictor of ACE on multivariable analysis. Furthermore, CSA accurately predicted PCE 10% on ROC curve analysis (AUC 0.92, 95%CI 0.84-0.99) Conclusions: Estimated contact surface area is an independent and accurate predictor of renal function decline after NSS and can be applied for low complexity renal tumors.
Our study aimed to determine whether characteristics of tumor-infiltrating T cells affect subsequent development of metastases in RCC.14 paraffin-embedded RCC samples were obtained from 12 nephrectomies. DNA was extracted and high throughput TCR Vβ CDR3 sequencing was performed using the `immunoseq` analyzer. DNA rearrangements (RA) and combined RA (predicted amino acid sequences) were analyzed. Entropy measures TCR diversity within a sample and clonality represents the extent of predominant RAs within a sample. Clinical data were collected from electronic records. Eight patients had clear-cell histology and four had papillary histology. Ten patients had pT3 at nephrectomy. Eight had metastatic disease at presentation or in follow-up period. In total, 15,182 different DNA RAs were found across all samples, most were patient-unique. In two patients with duplicate samples, most RA were shared between the duplicates, indicating high reproducibility of the results. Of all TCR amino acid sequences across all samples, one was shared by 4 /12 pts (33%) and two were shared by 3/12 pts (25%). The median clonality of four patients who remained disease free was significantly higher than the median clonality of eight metastatic patients (p=0.028) with no significant differences in the entropy between the two groups. Our work indicates that there is an association between higher clonality and decreased recurrence following nephrectomy for RCC, suggesting that intra-tumoral T cell repertoire influences outcome. TCR amino acids sequences shared by multiple patients suggests that renal tumors partly share common immunogenic antigens, and warrants further investigation with larger patient cohorts.
Purpose: The aim of the study was to determine the performance and accuracy of CellDetect®, a novel cytochemical test, in comparison with urine cytology (Pap stain) and UroVysion FISH (U-FISH), for bladder cancer (BC) diagnosis in routinely monitored patients. Methods: Voided-urine samples were obtained from subjects presenting hematuria or BC patients under routine surveillance. Liquid-based smears were prepared for each specimen, separately stained with either Pap stain or CellDetect®, and for most cases also U-FISH test was performed. The smears were blindly reviewed by two pathologists, and the performance of all three techniques was compared using biopsy/cystoscopy/acceptable clinical assessments as gold standard. Results: The study included 63 patients. 17 were positive, and 46 were negative, according to the gold standard. The diagnostic accuracy of each test was computed based on determined readings (49% of Pap, 89% of CellDetect® and 91% of U-FISH), with CellDetect® exhibiting markedly higher sensitivity (100%, as compared to 43% and 60% of Pap and U-FISH respectively). Specificity was 85% for CellDetect®, 96% for Pap and 67% for U-FISH. Importantly, of the 24 atypical Pap diagnoses, CellDetect® correctly identified 20 cases, out of which all 5 positive cases. Conclusions: CellDetect® outperforms both urine cytology and U-FISH sensitivities in BC detection, by 57% and 40%, respectively. Additionally, when compared to Pap, CellDetect® reduces the number of undetermined readings by 80%. Moreover, though missed by Pap testing, 16% of all cases were positively detected by CellDetect®. Thus, adjunctive testing with CellDetect® may aid in a confirmatory diagnosis of BC.
Introduction & Objective: We propose to measure cortisol levels in serum, urine and saliva during acute ureteric stone colic assuming it will be elevated due to spasm and stress cause by the stone obstruction. Methods: An observational blinded prospective controlled study was designed to enroll all patients who were admitted to emergency room and hospitalized urgently following NCCT (non-contrast CT) diagnosis of single ureteral stone obstruction. In addition to routine laboratory examination we measured also serum, urine, and, saliva cortisol levels at 07:00 am the first morning post admission. Multivariente analysis with clinical data, laboratory results and, out come will be presented. Results: We studied 59 patients. The average age is 46±14 years, average VAS scale 8±1.5 average stone size 6.2±4.1 mm, average creatinine 1.3±0.6 mg/dl , wbc 11,300±3,700 counts /ml, CRP level 34±47 mg/l. Control group consist of healthy voluntaries with average age of 38±14. The study group average cortisol levels in the serum, urine, and, saliva is 122±39 nm/l, 122±42 nm/l , 6.4±5.9 nm/l, compare to control 102±49 nm/l, 145±49 nm/l, and, 6.8±6.1 nm/l. 55% of the patients required urgent procedure. There was no significant difference between the groups in each category. Contradicting our hypothesis we observed no surge in serum, urine or, saliva cortisol level during the first 24 hours of admission due to acute ureteral stone obstruction, neither, relation to renal injury. Conclusions: We observed no serum, urine, or, saliva cortisol surge during acute stress due to ureteral stone obstruction. We suggest suppression effect during acute renal colic.
Introduction: Stress urinary incontinence (SUI) is a common phenomenon among women aged 35-60. Physiotherapy is not suitable to each person and surgical approach may be related to complications. Nolix is a new OTC tampon-like silicon device that appears to control the leaks. The aim of this study was to appreciate the efficacy and safety of this device among women suffering of SUI. Methods: A programmed provocative exercises were done with a full bladder assessed by an abdominal bladder volume scan. Only if the bladder volume was above 300 Ml women were enrolled in the provocative PWG test. Women were their own control group with urinary leak measurements done using Pad Weight Gain (PWG) recorded by an electronic scale. Questionnaires were filled by the enrolled women regarding Nolix insertion and removal as well as satisfaction of usage of the device. Results: 38 tests were performed. Average reduction in PWG was 81%. 21 tests (55%) presented more than 90% reduction of urine loss (below 1 Ml defined as within continence range) and more than 80% reduction of the urine loss observed in 76% of women . 97% were satisfied with use of Nolix and are willing to continue using Nolix. All women reported an easy insertion and removal of the device without evidence if side effects. Conclusion: This is the first study evaluating the Nolix device. The reduction of urine loss was significant among most of women participating the study. More prospective studies are needed.
Purpose: Hypospadias is a relatively common condition, occurring in approximately one in every 100 live male births. Surgical repair is generally performed between 6 and 18 months of age. The need for surgical intervention raises questions as to the proper timing of newborn circumcision, a procedure performed on the majority of males born in the United States. Current medical dogma (including Campbell’s Urology) explicitly dictates that circumcision should be delayed until after hypospadias repair. This trend stems from the belief that an earlier circumcision could lead to complications, as well as the possible need to use the foreskin as part of the hypospadias repair. Recent studies have questioned the necessity of this delay. Some go further and indicate greater positive outcomes of neonatal circumcision before hypospadias repair. This study will investigate the hypothesis that ritual circumcision (prior to repair) does not negatively impact the outcome of hypospadias patients. Methods: Retrospective chart review of the past five years of neonates who have had a ritual circumcision at eight days of age followed by hypospadias repair at 6-12 months of age at The Mount Sinai Hospital in New York. Conclusions: The outcome of this study has particular significance to Jewish patients who observe the Bible`s commandment to circumcise males at eight days of age. As a supplement to this study, we will investigate the Jewish jurisprudence regarding postponing 8th day circumcisions due to hypospadias and the practical applications that such deferrals may have for patients and their families.
INTRODUCTION & OBJECTIVES: "Hypospadias cripple" cases caries high complication rates even when compared to severe proximal hypospadias ranging up to 60%. Hyperbaric oxygen therapy (HBOT) is a well-established modality for the treatment of compromised tissue and grafts. The use of HBOT for hypospadias cripple has not been extensively studied. MATERIAL & METHODS: Cases defined as "hypospadias cripple" and required two stage surgeries were included in the study. A retrospective study design was used to compare graft take in pediatric hypospadias cripples after first stage reoperation comparing patients receiving HBOT and those without HBOT (controls). Results: 21 children (mean age of 4) were defined as hypospadias cripple and composed our study group. 7 patients received HBOT and 14 patients comprised the control group. There were no differences between the groups in age, original location of meatus or type of graft harvested. HBOT group had significantly more prior episodes of graft contraction, residual chordee, meatal stenosis and dehiscence than the controls. In the HBOT group, 7 procedures were performed, in all cases, there was good graft take with no graft contraction. In the non-HBOT group 14 procedures were performed Although graft-take was reported as acceptable in 85% at 3 month follow up, only 57% could proceed to second stage surgery due to graft inelasticity and contraction therefore additional oral graft from different sights was carried out. Conclusions: Two-stage surgical repair combined with hyperbaric oxygen therapy for pediatric hypospadias cripple patients increases success rate for graft take and reduces need for repeat procedures.
Purpose: To evaluate the association between the microorganisms causing urinary tract infection (UTI) and stent colonization in children with indwelling double J ureteral stents (DJS) after minimally invasive pyeloplasty. Patients and methods: We conducted a retrospective review of the medical records of 30 (22males and 8females) consecutive children who underwent laparoscopic and robotic assisted pyeloplasty with DJS insertion during 2011—2017. Urinary cultures were obtained before surgery, before stent removal if any UTI was suspected during the indwelling period and one month after removal. The stent was removed under sterile conditions and sent for culture. Univariate and multivariable logistic regression analyses were utilized to find predictors for post-operative UTI and stent colonization Results: The median age at surgery was 2.1 years (range 2 month to 17 years).The median period for stent indwelling was 5.09 (IQR: 4.57-6.00) weeks. UTI during the stent indwelling period occurred in 30% of cases. 63% of stent cultures were positive. Stent and urinary cultures were identical in only one case. There were no cases of UTI one month after stent extraction, however, 3 cases of asymptomatic bacteriuria were observed. There was no statistically significant association between clinical UTI, gender, stent diameter and indwelling period duration. Conclusion: The causative pathogen of UTI after minimally invasive pyeloplastyis unrelated to the isolated bacteria from stent cultures. Therefore, routine stent culturing is of low clinical significance. Small caliber stents and longer indwelling periods do not seem to be risk factors for UTI.