Bacterial species cultured after electrofulguration in women with a history of antibiotic-recalcitrant urinary tract infections frequently compare with pre-fulguration findings: a pilot study.

Electrofulguration (EF) of areas of chronic cystitis in women with antibiotic-recalcitrant recurrent urinary tract infections (RUTIs) can result in improvement of their urinary tract infections (UTIs). We compared urine culture (UC) findings in patients before and after EF, as well as how they vary with cystitis stage at the time of EF, to evaluate for persistent species. After obtaining institutional review board approval, we retrospectively reviewed a prospectively maintained database of EF patients for those with positive UC findings in the 3-6 months preceding EF. Patient pre-EF UC was then compared with first positive UC after EF prompted by a new symptomatic UTI episode, with the hypothesis that the same species will be identified before and after EF. Exclusion criteria included UC from outside institution, neurogenic bladder, and need for catheterization. Ninety-nine women with pre- or post-EF UC-recorded organisms met the study criteria. The median age was 65 years (interquartile range 64-74), with a median time to first positive culture following fulguration of 9.7 months. For 26 patients with positive cultures both pre- and post-EF, the same organism was present in both cultures in 73% of the patients, with predominantly Escherichia coli. EF was effective at reducing the rate of UTIs in this population. For women undergoing EF for antibiotic-recalcitrant RUTIs and associated chronic cystitis lesions, 73% of those with a UC obtained at the time of a first symptomatic recurrent UTI episode post-EF expressed the same organism as before EF. Further study is needed to better understand the evolution of the microbiome post-EF.IMPORTANCEAmong women who experience a recurrent urinary tract infection after a fulguration procedure on areas of chronic cystitis in their bladder, there are no data available on whether the bacterial species found in urine cultures are the same or different from those present before fulguration. By removing the inflamed surface layer of cystitis during fulguration, it is possible that the procedure unmasks deep-seated bacteria. The bacterial kingdom in the bladder wall of these chronically infected women may be different from what is expressed sporadically in urine cultures. Confirming prior studies, we found that fulguration in women with antibiotic-recalcitrant recurrent urinary tract infections and cystitis lesions was effective at reducing the rate of urinary tract infections. At the time of a first symptomatic recurrent UTI episode post-fulguration, 73% expressed the same organism in urine culture as before fulguration. Further study is needed to better understand the evolution of the microbiome post-EF. This article evaluates persistent infections after electrofulguration of areas with chronic cystitis in post-menopausal women with antibiotic-recalcitrant recurrent urinary tract infections. Pre-fulguration urine cultures were compared with the first positive urine culture prompted by a new symptomatic UTI episode after electrofulguration, with the hypothesis that the same species will be identified before and after the fulguration procedure. Electrofulguration was effective at reducing the rate of UTIs in this population. However, 73% of those with a urine culture obtained at the time of a first symptomatic recurrent UTI episode post-electrofulguration expressed the same organism (predominantly Escherichia coli) as before the fulguration procedure. Further study is needed to better understand the evolution of the microbiome after electrofulguration.

Comparing costs associated with management of antibiotic-recalcitrant recurrent urinary tract infections for one year pre- and post-electrofulguration.

INTRODUCTION: To quantify and compare recurrent urinary tract infection costs between 1 year before and 1 year after electrofulguration. METHODS: Following IRB approval, a well-characterized cohort of non-neurogenic women with >3 symptomatic urinary tract infections (UTIs)/year, a negative upper and lower urinary tract evaluation, and inflammatory bladder lesions (cystitis) on office cystoscopy who underwent fulguration of these lesions was analyzed. Cost of visits, imaging, labs, and medications were summed for 1-year pre- and post-fulguration using the Medicare Physician Fee Schedule, local pharmacy pricing, and institutional expenses. Before fulguration, all patients underwent clinic visit, noninvasive flow study, and flexible cystoscopy, and post-fulguration, 6-week follow-up visit and 6-month cystoscopy. RESULTS: Ninety-three women met study criteria (mean age 64), with 100% 1-year follow-up. Before fulguration, 73% of patients used daily antibiotic suppression, 6% self-start antibiotics, and 5% postcoital prophylaxis. Some also used vaginal estrogens (17%), urinary analgesics (13%), and cranberry or d-mannose supplements (7%). At 1 year post-fulguration, 82% had 0-1 infections and no cystoscopy evidence of cystitis, while 14% required additional fulguration for new cystitis sites and recurrent infections. Patients had on average 0.7 infections in the 1-year post-fulguration, which was significantly lower than pre-fulguration (p < 0.05). Mean 1-year pre-fulguration cost was $1328 (median $1071, range $291-$5564). Mean 1-year post-fulguration cost was $617 (median $467, range $275-$4580). On average, post-fulguration costs were $710 lower than pre-EF (p < 0.05). CONCLUSION: For women with antibiotic-refractory recurrent urinary tract infections and cystoscopy evidence of cystitis, fulguration was associated with a significant reduction in UTI-related costs in the 1-year post-fulguration.

Systematic Review of the Global Literature on Uncomplicated Recurrent Urinary Tract Infections in Women: Underscoring Major Heterogeneity.

OBJECTIVE: To examine the global literature database on uncomplicated recurrent urinary tract infections (rUTI), this systematic review assesses the availability of rUTI data based on geographic region and elucidates the current state of research and gaps in knowledge. METHODS: The databases PubMed, Embase, WHO Global Index Medicus, and SciELO were searched for keywords related to rUTI between 2000 and 2023. Three independent reviewers screened studies restricted to female participants age ≥18 years with uncomplicated rUTIs. Studies were excluded if they did not provide a definition for rUTI or did not cite or report an estimate for rUTI prevalence. The review was registered in PROSPERO and conformed to PRISMA guidelines. RESULTS: The search yielded 2947 studies of which 124 were ultimately included. Convenience samples were used for 91% of studies and sample sizes were 30% n <50, 29% n = 50-99, 22% n = 100-199, 36% n ≥200. Most studies were conducted in Europe (41%) or North America (39%), were prospective (52%), at tertiary centers (49%) and included all ages ≥18 (60%). The most common definition for rUTI was 2 UTI/6 m or 3 UTI/1y (62%). Regardless of study location, most studies cited prevalence estimates for rUTI derived from U.S.-based populations. CONCLUSION: This study represents the first formal investigation of the global literature base on uncomplicated rUTI. Studies on rUTIs are globally of small scale and definitions used for rUTI are heterogeneous. More studies are needed to ascertain the true prevalence of rUTI outside of North America and Europe.

Histopathology Based AI Model Predicts Anti-Angiogenic Therapy Response in Renal Cancer Clinical Trial.

Background: Predictive biomarkers of treatment response are lacking for metastatic clearcell renal cell carcinoma (ccRCC), a tumor type that is treated with angiogenesis inhibitors, immune checkpoint inhibitors, mTOR inhibitors and a HIF2 inhibitor. The Angioscore, an RNA-based quantification of angiogenesis, is arguably the best candidate to predict anti-angiogenic (AA) response. However, the clinical adoption of transcriptomic assays faces several challenges including standardization, time delay, and high cost. Further, ccRCC tumors are highly heterogenous, and sampling multiple areas for sequencing is impractical. Approach: Here we present a novel deep learning (DL) approach to predict the Angioscore from ubiquitous histopathology slides. In order to overcome the lack of interpretability, one of the biggest limitations of typical DL models, our model produces a visual vascular network which is the basis of the model's prediction. To test its reliability, we applied this model to multiple cohorts including a clinical trial dataset. Results: Our model accurately predicts the RNA-based Angioscore on multiple independent cohorts (spearman correlations of 0.77 and 0.73). Further, the predictions help unravel meaningful biology such as association of angiogenesis with grade, stage, and driver mutation status. Finally, we find our model is able to predict response to AA therapy, in both a real-world cohort and the IMmotion150 clinical trial. The predictive power of our model vastly exceeds that of CD31, a marker of vasculature, and nearly rivals the performance (c-index 0.66 vs 0.67) of the ground truth RNA-based Angioscore at a fraction of the cost. Conclusion: By providing a robust yet interpretable prediction of the Angioscore from histopathology slides alone, our approach offers insights into angiogenesis biology and AA treatment response.

Unconventional mechanism of action and resistance to rapalogs in renal cancer.

mTORC1 is aberrantly activated in renal cell carcinoma (RCC) and is targeted by rapalogs. As for other targeted therapies, rapalogs clinical utility is limited by the development of resistance. Resistance often results from target mutation, but mTOR mutations are rarely found in RCC. As in humans, prolonged rapalog treatment of RCC tumorgrafts (TGs) led to resistance. Unexpectedly, explants from resistant tumors became sensitive both in culture and in subsequent transplants in mice. Notably, resistance developed despite persistent mTORC1 inhibition in tumor cells. In contrast, mTORC1 became reactivated in the tumor microenvironment (TME). To test the role of the TME, we engineered immunocompromised recipient mice with a resistance mTOR mutation (S2035T). Interestingly, TGs became resistant to rapalogs in mTORS2035T mice. Resistance occurred despite mTORC1 inhibition in tumor cells and could be induced by coculturing tumor cells with mutant fibroblasts. Thus, enforced mTORC1 activation in the TME is sufficient to confer resistance to rapalogs. These studies highlight the importance of mTORC1 inhibition in nontumor cells for rapalog antitumor activity and provide an explanation for the lack of mTOR resistance mutations in RCC patients.

Systematic Review of the Global Use of Validated Questionnaires in the Management of Stress Urinary Incontinence in Women.

INTRODUCTION: Our goal was to systematically review the most commonly used validated questionnaires in recent global literature on stress urinary incontinence (SUI) treatment. METHODS: PubMed, Embase, and Ovid databases were queried for manuscripts containing "female stress urinary incontinence" AND "diagnosis" AND "treatment" AND "questionnaire." Two independent reviewers screened studies for randomized controlled trials, prospective, and retrospective studies between 2018 and 2023. Exclusion criteria included male participants, non-SUI incontinence, and articles not originally written in English. The review was registered in PROSPERO [465721] and conformed to PRISMA guidelines. RESULTS: In 117 manuscripts meeting study criteria, the median of the mean ages was 52 years, with a median of 164 participants per study. Most studies originated in Europe (59/117). The International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form was the most frequently used (52%), followed by the Patient Global Impression of Improvement (31%), the Urinary Distress Inventory 6 Short Form (25%), the Incontinence Quality of Life (20%), and the Incontinence Impact Questionnaire Short Form (19%). These leading questionnaires were short, translated into several languages, and globally addressed important SUI-related domains, including the presence and severity of SUI, additional lower urinary tract symptoms, and the impact of SUI on quality of life, as well as changes perceived after treatment. CONCLUSIONS: This systematic review of the validated questionnaires used in contemporary SUI management literature could help guide recommendations for incorporating these favored instruments into future SUI treatment outcome documents.

Robotic simple cystectomy as a last resort for antibiotic-recalcitrant recurrent urinary tract infections in women.

OBJECTIVE: To report a series of women with antibiotic-recalcitrant recurrent urinary tract infections (rUTI) managed with robotic simple cystectomy and ileal conduit urinary diversion. METHODS: Following Institutional Review Board approval, all female patients who underwent robotic cystectomy for rUTI between 2011 and 2021 were identified from a prospectively-maintained internal database at a tertiary care center. Exclusion criteria included interstitial cystitis, neurogenic bladder, urinary tract neoplasm, or congenital abnormality. Electronic medical records were reviewed by an independent researcher. Patients were also administered the Quality of Life Questionnaire-C30. RESULTS: Twenty-four patients met inclusion criteria. Median age was 75 years (range 53-87). Median rUTI duration was 6 (interquartile range [IQR] 2-10) years. Median urinary tract infections count in the 12-month preceding cystectomy was 5 (IQR 3-9). Infections with multidrug resistant organisms were found in 21 patients (88%). The 30-day postoperative complication rate was 79% (19/24), of which 11% were Clavien-Dindo grade ≥III. The main late complication was parastomal hernia, with 17% requiring repair or revision. At a median of 36 months (range 12-61) post-operatively, the median Quality of Life Questionnaire-C30 global health status score was 50 (range 33-83). CONCLUSION: Cystectomy is a last-resort management option for women with severely symptomatic end-stage bladders in the setting of antibiotic-recalcitrant rUTI. Patients should be counseled thoroughly regarding possible acute and long-term postoperative complications. Select patients, managed in high-volume referral centers, can benefit from robotic simple cystectomy with ileal conduit urinary diversion.

Comparative genomics incorporating translocation renal cell carcinoma mouse model reveals molecular mechanisms of tumorigenesis.

Translocation renal cell carcinoma (tRCC) most commonly involves an ASPSCR1-TFE3 fusion, but molecular mechanisms remain elusive and animal models are lacking. Here, we show that human ASPSCR1-TFE3 driven by Pax8-Cre (a credentialed clear cell RCC driver) disrupted nephrogenesis and glomerular development, causing neonatal death, while the clear cell RCC failed driver, Sglt2-Cre, induced aggressive tRCC (as well as alveolar soft part sarcoma) with complete penetrance and short latency. However, in both contexts, ASPSCR1-TFE3 led to characteristic morphological cellular changes, loss of epithelial markers, and an epithelial-mesenchymal transition. Electron microscopy of tRCC tumors showed lysosome expansion, and functional studies revealed simultaneous activation of autophagy and mTORC1 pathways. Comparative genomic analyses encompassing an institutional human tRCC cohort (including a hitherto unreported SFPQ-TFEB fusion) and a variety of tumorgraft models (ASPSCR1-TFE3, PRCC-TFE3, SFPQ-TFE3, RBM10-TFE3, and MALAT1-TFEB) disclosed significant convergence in canonical pathways (cell cycle, lysosome, and mTORC1) and less established pathways such as Myc, E2F, and inflammation (IL-6/JAK/STAT3, interferon-γ, TLR signaling, systemic lupus, etc.). Therapeutic trials (adjusted for human drug exposures) showed antitumor activity of cabozantinib. Overall, this study provides insight into MiT/TFE-driven tumorigenesis, including the cell of origin, and characterizes diverse mouse models available for research.

Identifying Patient and Surgical Criteria for Same-Day Discharge After Robotic-Assisted Sacrocolpopexy.

Introduction: To review the postrobotic-assisted sacrocolpopexy (RASC) course of women admitted for 23 hours post-RASC and identify events requiring intensive medical care or potentially leading to deleterious outcome or urgent readmission if that patient had same-day discharge (SDD) instead of observed overnight. Methods: Patients undergoing RASC from January to December 2020 at one institution were identified and relevant data were obtained via retrospective chart review. Patient exclusions: RASC start time after 12:00 PM, concurrent posterior colporrhaphy, rectopexy, or hysterectomy, or conversion to open. Results: Sixty-nine patients (median age 71 years old) met study criteria with majority American Society of Anesthesiologists class 2 (n = 46, 67%) or 3 (n = 22, 32%). Patient characteristics included prior abdominal surgeries (n = 58, 84%), prior hysterectomy/prolapse repair (n = 25, 37%), known allergy to pain medication (n = 25, 36%), and administration of a postoperative antiemetic (n = 37, 54%) or intra-/postoperative keterolac (n = 36, 52%). Median surgery length was 269 minutes. Postoperative events that may have resulted in urgent readmissions if they had SDD were observed in 6% of patients. In the 1st week post-RASC, there were no readmissions. Conclusions: In this limited quality assurance study, patients undergoing RASC experienced no major complications requiring intensive care. Postoperative events were almost entirely nausea and pain, with no readmissions within the 1st week.

Long-term Outcomes With Macroplastique in Women With Stress Urinary Incontinence Secondary to Intrinsic Sphincter Deficiency.

OBJECTIVE: To evaluate the long-term outcomes of polydimethylsiloxane (Macroplastique (MPQ)) in women with stress urinary incontinence (SUI) secondary to intrinsic sphincter deficiency (ISD) using validated questionnaires. METHODS: Following IRB approval, charts of non-neurogenic women with SUI secondary to ISD who underwent MPQ injection were reviewed from a prospectively maintained database. ISD was defined as positive stress test with a well-supported urethra and low Valsalva leak point pressure when available. Excluded were women with follow-up <5years. Baseline data included validated questionnaire scores (UDI-6 question 3 (0-3), VAS Quality of Life, Incontinence Impact Questionnaire (IIQ-7)) and urodynamic study findings. Patients were followed with same questionnaires and three-dimensional ultrasound evaluating volume/configuration of MPQ. All three-dimensional ultrasound measurements were performed by the same imaging team blinded to clinical outcomes. Outcomes were evaluated in four groups based on prior SUI treatment. Success was defined as UDI-6 question 3 score of 0-1 and not requiring additional anti-incontinence therapy at the last visit after the last MPQ injection. RESULTS: From April 2011-December 2016, 106 patients (median age 67) met study criteria. Median follow-up time was 7.4years. Median MPQ injected was 5 mL. Overall success was 43%, with 54% successful after one injection and 46% requiring ≥2 injections. Across all groups, patients had improvement in Quality of Life and IIQ-7 Question 7 (frustration). Among the failure group, 17% opted for a secondary autologous sling procedure. CONCLUSION: MPQ demonstrated long-term favorable outcomes in a subset of women with SUI secondary to ISD.

Characteristics of Nationwide Urinary Tract Infection (UTI) Visits by Age and Type II Diabetes Status in Women.

Background Through a national database search of office visits, we studied the contribution of two known risk factors for urinary tract infections (UTIs) in women: age and type 2 diabetes mellitus (T2DM). Methodology The National Ambulatory Medical Care Survey (NAMCS) database was queried for visits including a UTI diagnosis and a urine culture order. Data were included for all visits involving adult women for available years, 2014-2016 and 2018. Data on demographics, reason for visit, T2DM status, UTI workup, and UTI treatment were collected. Patients with Alzheimer's disease or chronic kidney disease were excluded. Descriptive statistics were displayed as weighted means with standard errors for continuous variables. The effect of age was compared based on a 65-year-old cutoff. Results One hundred sixty-seven surveyed visits were analyzed for the years 2014-2016 and 2018, representing an estimated 7.4 million visits nationwide. Women ≥65 years were more likely to be white, non-Hispanic/non-Latino, from the Midwest or West, from metropolitan areas, and on Medicare/Medicaid than their younger counterparts. T2DM and urinalysis rates did not significantly vary between the two age groups (7.7% vs. 14.6%, P = 0.3; 78% vs. 76%, P = 0.9, respectively). For urinalysis rates between patients with and without T2DM, there was no significant difference in the <65-year-old group (80% vs. 78%, P = 0.9) or the ≥65-year-old group (93% vs. 73%, P = 0.12). Antibiotic prescription rates were also similar for T2DM and non-T2DM patients (67% vs. 75%, P = 0.7). Conclusions Through a national database analysis, we reported the demographic and visit differences aged <65 years and ≥65 years who sought care for UTIs in the United States over a four-year period. T2DM rates and urinalysis did not vary between age groups, and urinalysis rates and antibiotic prescription rates did not vary between T2DM and non-T2DM groups in an age-dependent matter. More research is needed to understand the demographic makeup and risk factors of UTI patients across the nation.

Very Long-term Outcomes After Electrofulguration for Antibiotic-refractory Recurrent Urinary Tract Infections in a Predominantly Menopausal Cohort of Women.

PURPOSE: Antibiotic-refractory recurrent urinary tract infections are challenging to manage. Prior studies have shown that, in selected patients, electrofulguration of cystitis may disrupt potential nidus of recurrent urinary tract infections. We report on long-term outcomes of electrofulguration in women with at least 5 years of follow-up. MATERIALS AND METHODS: Following Institutional Review Board approval, we analyzed a cohort of nonneurogenic women with ≥3 symptomatic recurrent urinary tract infections/y and inflammatory lesions on cystoscopy who underwent electrofulguration, excluding those with alternate identifiable etiology for recurrent urinary tract infections or less than 5-year follow-up. Preoperative characteristics, antibiotic regimens, and annual urinary tract infections were reported. Primary outcome was clinical cure (0-1 urinary tract infection/y), improvement (>1 and <3/y) or failure (≥3/y) at last follow-up. Secondary outcomes included need for antibiotics or repeat electrofulguration. A subanalysis was performed for women with >10-year follow-up. RESULTS: From 2006 to 2012, 96 women met study criteria with median age 64. Median follow-up was 11 years (IQR: 10-13.5); 71 women had >10-year follow-up. Prior to electrofulguration, 74% used daily antibiotic suppression, 5% used postcoital prophylaxis, 14% used self-start therapy, and 7% were not on prophylaxis. At last post-electrofulguration visit, 72% of women were cured, 22% improved, and 6% failed. Antibiotic usage decreased post-electrofulguration (P < .05). Five percent were on continuous antibiotics at last follow-up as compared to 74% on continuous antibiotics pre-electrofulguration (McNemar P < .05). Nineteen percent of women underwent a repeat electrofulguration. CONCLUSIONS: In menopausal women with over 5-year follow-up after electrofulguration for antibiotic-refractory recurrent urinary tract infections, there appears to be durable clinical cure and improvement, with decreased need for long-term antibiotics.

Life-threatening hemoptysis in patients with metastatic kidney cancer.

Hemoptysis is a complication of intrathoracic tumors, both primary and metastatic, and the risk may be increased by procedural interventions as well as Stereotactic Ablative Radiation (SAbR). The risk of hemoptysis with SAbR for lung cancer is well characterized, but there is a paucity of data about intrathoracic metastases. Here, we sought to evaluate the incidence of life-threatening/fatal hemoptysis (LTH) in patients with renal cell carcinoma (RCC) chest metastases with a focus on SAbR. We systematically evaluated patients with RCC at UT Southwestern Medical Center (UTSW) Kidney Cancer Program (KCP) from July 2005 to March 2020. We queried Kidney Cancer Explorer (KCE), a data portal with clinical, pathological, and experimental genomic data. Patients were included in the study based on mention of "hemoptysis" in clinical documentation, if they had a previous bronchoscopy, or had undergone SAbR to any site within the chest. Two hundred and thirty four patients met query criteria and their records were individually reviewed. We identified 10 patients who developed LTH. Of these, 4 had LTH as an immediate procedural complication whilst the remaining 6 had prior SAbR to ultra-central (UC; abutting the central bronchial tree) metastases. These 6 patients had a total of 10 lung lesions irradiated (UC, 8; central 1, peripheral 1), with a median total cumulative SAbR dose of 38 Gray (Gy/ lesion) (range: 25-50 Gy). Other risk factors included intrathoracic disease progression (n = 4, 67%), concurrent anticoagulant therapy (n = 1, 17%) and concurrent systemic therapy (n = 4, 67%). Median time to LTH from first SAbR was 26 months (range: 8-61 months). Considering that 130 patients received SAbR to a chest lesion during the study period, the overall incidence of LTH following SAbR was 4.6% (6/130). The patient population that received SAbR (n = 130) was at particularly high risk for complications, with 67 (52%) having two or more chest metastaes treated, and 29 (22%) receiving SAbR to three or more lesions. Overall, the risk of LTH following SAbR to a central or UC lesion was 10.5% (6/57). In conclusion, SAbR of RCC metastases located near the central bronchial tree may increase the risk of LTH.

Erratum to: Extended Disease Control with Unconventional Cabozantinib Dose Increase in Metastatic Renal Cell Carcinoma.

[This corrects the article DOI: 10.3233/KCA-210117.].

Phase 2 Trial of Stereotactic Ablative Radiotherapy for Patients with Primary Renal Cancer.

BACKGROUND: Most renal cell carcinomas (RCCs) are localized and managed by active surveillance, surgery, or minimally invasive techniques. Stereotactic ablative radiation (SAbR) may provide an innovative non-invasive alternative although prospective data are limited. OBJECTIVE: To investigate whether SAbR is effective in the management of primary RCCs. DESIGN, SETTING, AND PARTICIPANTS: Patients with biopsy-confirmed radiographically enlarging primary RCC (≤5 cm) were enrolled. SAbR was delivered in either three (12 Gy) or five (8 Gy) fractions. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was local control (LC) defined as a reduction in tumor growth rate (compared with a benchmark of 4 mm/yr on active surveillance) and pathologic evidence of tumor response at 1 yr. Secondary endpoints included LC by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1), safety, and preservation of kidney function. Exploratory tumor cell-enriched spatial protein and gene expression analysis were conducted on pre- and post-treatment biopsy samples. RESULTS AND LIMITATIONS: Target accrual was reached with the enrollment of 16 ethnically diverse patients. Radiographic LC at 1 yr was observed in 94% of patients (15/16; 95% confidence interval: 70, 100), and this was accompanied by pathologic evidence of tumor response (hyalinization, necrosis, and reduced tumor cellularity) in all patients. By RECIST, 100% of the sites remained without progression at 1 yr. The median pretreatment growth rate was 0.8 cm/yr (interquartile range [IQR]: 0.3, 1.4), and the median post-treatment growth rate was 0.0 cm/yr (IQR: -0.4, 0.1, p < 0.002). Tumor cell viability decreased from 4.6% to 0.7% at 1 yr (p = 0.004). With a median follow-up of 36 mo for censored patients, the disease control rate was 94%. SAbR was well tolerated with no grade ≥2 (acute or late) toxicities. The average glomerular filtration rate declined from a baseline of 65.6 to 55.4 ml/min at 1 yr (p = 0.003). Spatial protein and gene expression analyses were consistent with the induction of cellular senescence by radiation. CONCLUSIONS: This clinical trial adds to the growing body of evidence suggesting that SAbR is effective for primary RCC supporting its evaluation in comparative phase 3 clinical trials. PATIENT SUMMARY: In this clinical trial, we investigated a noninvasive treatment option of stereotactic radiation therapy for the treatment of primary kidney cancer and found that it was safe and effective.

Empiric versus culture-based antibiotic therapy for UTIs in menopausal women.

PURPOSE: To assess the benefits and risks associated with empiric prescription of antibiotic therapy for treatment of a urinary tract infection (UTI). METHODS: Following IRB approval menopausal women presenting with a symptomatic UTI to a single urology clinic were prospectively assigned to one of the two treatment groups based on day of presentation: culture-based treatment (CB) (Monday, Tuesday, Wednesday) or empiric treatment (ET) (Thursday, Friday) and started on nitrofurantoin (NF) pending culture results. Both groups were contacted at 7 and 14 days following treatment. Side effects and answers to a standardized questionnaire (UTISA) were recorded. Success was defined as a total UTISA score < 3. Any NF retreatment, use of another antibiotic therapy, or extension of the original antibiotic course was considered treatment failures. RESULTS: From July 2020 to March 2022, 65 women with 80 UTI events were included in the study, with CB treatment used for 60 UTIs and ET used for 23 UTIs. At 7 days after start of treatment, questionnaire failure rate was 44% (20/45) for the CB group and 16% (3/19) for the ET group (P = 0.076). At 14 days following start of treatment, questionnaire failure rate was 31% (13/42) for the CB group and 17% (3/18) for the ET group (P = 0.3). In the ET group, 11% of cultures were found to be resistant to NF. CONCLUSION: Outcomes for the empiric treatment of uncomplicated UTI with NF at both 7 and 14 days are not significantly different than outcomes with culture-based treatment.

d-mannosuria levels measured 1 h after d-mannose intake can select out favorable responders: A pilot study.

BACKGROUND: d-mannose is used as preventive measure against recurrent urinary tract infections (RUTIs). We studied d-mannosuria after a challenge test to identify favorable responders that could be targeted for long-term preventive therapy. MATERIAL AND METHODS: Following institutional review board approval, women attending a specialized tertiary care center urology clinic with a history of RUTIs were invited to participate by providing a urine sample (baseline), followed by the intake of home-dose d-mannose, and a second urine sample 1 h later (post). Urine samples were processed according to a d-mannosuria assay technique reported previously by our group. d-mannose concentrations were normalized to urinary creatinine. RESULTS: From July 2020 to March 2021, 26 patients met study criteria. Thirteen had a lower or unchanged ratio of baseline to post d-mannose, whereas 13 were responders. Among 19 taking 2 g, 12 had a lower or unchanged trend and 7 were responders with >20% increase in the d-mannose/creatinine ratio. Comparison of urinary baseline d-mannose/creatinine ratios was significantly different between the responder (mean = 0.337 ± 0.158) and nonresponder (mean = 0.692 ± 0.444; p = 0.016) groups. Urinary post d-mannose/creatinine ratios did not significantly differ between the two groups (p = 0.46). d-mannose-naïve patients had few responders, and age and urinary creatinine did not affect the findings. CONCLUSION: This preliminary study on d-mannose challenge tests indicates a urine response if urinary d-mannose/creatinine ratio is low, which it was in some women with a history of RUTIs.

Electro-fulguration for extensive inflammatory bladder lesions in post-menopausal women with antibiotic-recalcitrant recurrent urinary tract infections.

INTRODUCTION AND HYPOTHESIS: To evaluate how women with uncomplicated antibiotic-recalcitrant recurrent urinary tract infections (RUTIs) and extensive inflammatory bladder lesions on office cystoscopy responded to electro-fulguration (EF) to eliminate these chronic bladder sites. METHODS: After IRB approval, a retrospective study of non-neurogenic women with RUTIs, inflammatory lesions on cystoscopy, and who underwent EF was performed. Lesions were classified through a simplified staging system based on the extent of bladder wall involvement. Only those with extensive bladder wall involvement (stages 3 and 4) at the time of EF were analyzed in this report. Six months after EF, an office cystoscopy was performed, with endoscopic success defined as no lesions seen. The primary clinical outcome was number of symptomatic UTIs after EF, defined as cure (0/year), improvement (1-2/year), and failure (≥3/year). RESULTS: From 2007 to 2019, a total of 57 women met the study criteria, 30 stage 3 and 27 stage 4. Nineteen (63%) were endoscopically successful in stage 3 and 11 (41%) in stage 4. Mean follow-up was 2.9 years (stage 3) and 3.1 years (stage 4). All had at least a 6-month UTI follow-up after the 6 months of office cystoscopy, with 15 patients cured, 37 improved, and 5 failed (all stage 4). CONCLUSIONS: Although EF only resulted in 63% complete endoscopic resolution, the majority experienced a decrease in the frequency of UTIs, suggesting that EF can be durably effective even in women with very extensive cystitis lesions.

HIF2 Inactivation and Tumor Suppression with a Tumor-Directed RNA-Silencing Drug in Mice and Humans.

PURPOSE: HIF2α is a key driver of kidney cancer. Using a belzutifan analogue (PT2399), we previously showed in tumorgrafts (TG) that ∼50% of clear cell renal cell carcinomas (ccRCC) are HIF2α dependent. However, prolonged treatment induced resistance mutations, which we also identified in humans. Here, we evaluated a tumor-directed, systemically delivered, siRNA drug (siHIF2) active against wild-type and resistant-mutant HIF2α. EXPERIMENTAL DESIGN: Using our credentialed TG platform, we performed pharmacokinetic and pharmacodynamic analyses evaluating uptake, HIF2α silencing, target gene inactivation, and antitumor activity. Orthogonal RNA-sequencing studies of siHIF2 and PT2399 were pursued to define the HIF2 transcriptome. Analyses were extended to a TG line generated from a study biopsy of a siHIF2 phase I clinical trial (NCT04169711) participant and the corresponding patient, an extensively pretreated individual with rapidly progressive ccRCC and paraneoplastic polycythemia likely evidencing a HIF2 dependency. RESULTS: siHIF2 was taken up by ccRCC TGs, effectively depleted HIF2α, deactivated orthogonally defined effector pathways (including Myc and novel E2F pathways), downregulated cell cycle genes, and inhibited tumor growth. Effects on the study subject TG mimicked those in the patient, where HIF2α was silenced in tumor biopsies, circulating erythropoietin was downregulated, polycythemia was suppressed, and a partial response was induced. CONCLUSIONS: To our knowledge, this is the first example of functional inactivation of an oncoprotein and tumor suppression with a systemic, tumor-directed, RNA-silencing drug. These studies provide a proof-of-principle of HIF2α inhibition by RNA-targeting drugs in ccRCC and establish a paradigm for tumor-directed RNA-based therapeutics in cancer.