Pain Related to Intradetrusor BotulinumtoxinA: A Randomized Clinical Trial.

IMPORTANCE: OnabotulinumtoxinA (BTX-A) is an effective treatment for overactive bladder (OAB), but few studies have been done to evaluate injection techniques. OBJECTIVE: The primary objective was to evaluate procedural discomfort between 2 commonly used injection techniques for BTX-A. STUDY DESIGN: This was a single-blinded, randomized clinical trial of women undergoing injection of 100 U BTX-A for idiopathic OAB. Patients were randomized to 5 mL/5 injection or 10 mL/10 injection groups. Bladder pain was assessed by a validated Numeric Pain Rating Scale. Overactive bladder symptoms were assessed with a standardized questionnaire (Overactive Bladder Questionnaire Short Form). Patient satisfaction, treatment efficacy, and adverse events were assessed at 30 days after procedure. RESULTS: One hundred eight patients were randomized to 52 in the 5 mL/5 injection arm and 56 in the 10 mL/10 injection arm. Mean procedural pain scores were 3.2 (±2.3) in the 5 mL/5 injection group versus 3.6 (±2.1) in the 10 mL/10 injection group (P = 0.21). No difference was found when categorizing pain scores into ordinal outcomes of low (P = 0.55), medium (P = 0.70), and high (P = 1.0) or a binary outcome of low (P = 0.55) versus medium + high (P = 0.55). Multivariate analyses did not effect statistical significance between the 2 groups for the ordinal outcome (odds ratio = 1.86; 95% confidence interval = 0.77 = 4.52; P = 0.17) or the binary outcome (odds ratio = 1.81; 95% confidence interval = 0.68-4.77; P = 0.28). No difference was observed between overall patient satisfaction, global impression of improvement, Overactive Bladder Questionnaire Short Form scores, or adverse outcomes. CONCLUSIONS: Procedural discomfort related to BTX-A injection for idiopathic OAB was not different between 2 injection protocols. Overall satisfaction was high for both groups, and there was no difference in symptom scores or adverse events.

Prospective Evaluation of Intradetrusor Injections of OnabotulinumtoxinA in Adults With Spinal Dysraphism.

OBJECTIVE: To prospectively evaluate the effectiveness of OnabotulinumtoxinA (BTX-A) on neurogenic overactive bladder (nOAB) in adults with congenital spinal dysraphism (CSD). METHODS: We conducted a prospective, nonrandomized pilot study of 24 adults with CSD and neurogenic overactive bladder. Patients were evaluated with baseline video-urodynamics (UDS) and validated questionnaires, underwent injection 200U BTX-A, and then underwent repeat evaluation with questionnaires and UDS 1-3 months postinjection. A high-risk subgroup was separately analyzed based on adverse clinical characteristics (ie, decrease bladder compliance, vesicoureteral reflux, hydronephrosis, chronic kidney disease). RESULTS: BTX-A injection improved patient recorded outcome measures seen in both I-QOL Score total (67.9 vs 75.5, P = .007) and Neurogenic Bladder Symptom Score total (38.0 vs 29.0, P = .001). On UDS, BTX-A injection significantly improved end filling pressure (16.0 vs 8.8, P = .036) and also improved bladder compliance (mL/cm H2O) (89.38 vs 135.81, P = .445). High-risk patients were found to have similar improvements in most subjective questionnaire scoring, a significant decrease in end filling pressures, and improved bladder compliance on UDS. CONCLUSION: BTX-A can be used as an effective treatment in adults with CSD. We found that BTX-A significantly improved quality of life from patient reported outcome measurements as well as improving end filling pressures and bladder compliance. These improvements were seen even within our high-risk subgroup. Further studies are needed to evaluate long-term efficacy and appropriate follow-up of this at-risk population.

Management of Recurrent Urinary Tract Infections in Women: How Providers Can Improve the Patient Experience.

OBJECTIVE: To provide guidance to providers on how to improve the patient experience for women with recurrent urinary tract infections (rUTIs). METHODS: The recently updated 2019 American Urological Association (AUA) guidelines for recurrent uncomplicated acute cystitis and other contemporary publications pertaining to recurrent UTIs in women were reviewed. These data were used to summarize practice-based methodology to formulate recommendations with an emphasis on education to enhance the patient experience. RESULTS: We summarize the guideline-based management of patients with rUTI and augment this with a patient-focused perspective to provide recommendations for how to best counsel patients regarding evaluation, treatment using antibiotic stewardship practices, and a comprehensive prevention plan. We focus on patient education as the foundation for successful provider-patient relationships as well as patient compliance with care pathways. CONCLUSION: rUTIs are costly, time-consuming, and painful for patients. For providers, rUTIs represent a frustrating aspect of clinical care facing the balance of antibiotic stewardship with effective treatment and patient expectations with limited data supporting nonantibiotic therapies. Urologists have the skills and knowledge to provide this patient population with competent and compassionate care. By investing in these patients, being responsive to their concerns and offering education, patients will have a better overall experience with this chronic condition.

Inhibition of Sphingosine Phosphate Receptor 1 Signaling Enhances the Efficacy of VEGF Receptor Inhibition.

Inhibition of VEGFR signaling is an effective treatment for renal cell carcinoma, but resistance continues to be a major problem. Recently, the sphingosine phosphate (S1P) signaling pathway has been implicated in tumor growth, angiogenesis, and resistance to antiangiogenic therapy. S1P is a bioactive lipid that serves an essential role in developmental and pathologic angiogenesis via activation of the S1P receptor 1 (S1P1). S1P1 signaling counteracts VEGF signaling and is required for vascular stabilization. We used in vivo and in vitro angiogenesis models including a postnatal retinal angiogenesis model and a renal cell carcinoma murine tumor model to test whether simultaneous inhibition of S1P1 and VEGF leads to improved angiogenic inhibition. Here, we show that inhibition of S1P signaling reduces the endothelial cell barrier and leads to excessive angiogenic sprouting. Simultaneous inhibition of S1P and VEGF signaling further disrupts the tumor vascular beds, decreases tumor volume, and increases tumor cell death compared with monotherapies. These studies suggest that inhibition of angiogenesis at two stages of the multistep process may maximize the effects of antiangiogenic therapy. Together, these data suggest that combination of S1P1 and VEGFR-targeted therapy may be a useful therapeutic strategy for the treatment of renal cell carcinoma and other tumor types.

Abemaciclib Is Active in Preclinical Models of Ewing Sarcoma via Multipronged Regulation of Cell Cycle, DNA Methylation, and Interferon Pathway Signaling.

PURPOSE: Ewing sarcoma (ES) is a rare and highly malignant cancer that occurs in the bone and surrounding tissue of children and adolescents. The EWS/ETS fusion transcription factor that drives ES pathobiology was previously demonstrated to modulate cyclin D1 expression. In this study, we evaluated abemaciclib, a small-molecule CDK4 and CDK6 (CDK4 and 6) inhibitor currently under clinical investigation in pediatric solid tumors, in preclinical models of ES. EXPERIMENTAL DESIGN: Using Western blot, high-content imaging, flow cytometry, ELISA, RNA sequencing, and CpG methylation assays, we characterized the in vitro response of ES cell lines to abemaciclib. We then evaluated abemaciclib in vivo in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse models of ES as either a monotherapy or in combination with chemotherapy. RESULTS: Abemaciclib induced quiescence in ES cell lines via a G1 cell-cycle block, characterized by decreased proliferation and reduction of Ki-67 and FOXM1 expression and retinoblastoma protein (RB) phosphorylation. In addition, abemaciclib reduced DNMT1 expression and promoted an inflammatory immune response as measured by cytokine secretion, antigen presentation, and interferon pathway upregulation. Single-agent abemaciclib reduced ES tumor volume in preclinical mouse models and, when given in combination with doxorubicin or temozolomide plus irinotecan, durable disease control was observed. CONCLUSIONS: Collectively, our data demonstrate that the antitumor effects of abemaciclib in preclinical ES models are multifaceted and include cell-cycle inhibition, DNA demethylation, and immunogenic changes.

Merestinib (LY2801653) inhibits neurotrophic receptor kinase (NTRK) and suppresses growth of NTRK fusion bearing tumors.

Merestinib is an oral multi-kinase inhibitor targeting a limited number of oncokinases including MET, AXL, RON and MKNK1/2. Here, we report that merestinib inhibits neurotrophic receptor tyrosine kinases NTRK1/2/3 which are oncogenic drivers in tumors bearing NTRK fusion resulting from chromosomal rearrangements. Merestinib is shown to be a type II NTRK1 kinase inhibitor as determined by x-ray crystallography. In KM-12 cells harboring TPM3-NTRK1 fusion, merestinib exhibits potent p-NTRK1 inhibition in vitro by western blot and elicits an anti-proliferative response in two- and three-dimensional growth. Merestinib treatment demonstrated profound tumor growth inhibition in in vivo cancer models harboring either a TPM3-NTRK1 or an ETV6-NTRK3 gene fusion. To recapitulate resistance observed from type I NTRK kinase inhibitors entrectinib and larotrectinib, we generated NIH-3T3 cells exogenously expressing TPM3-NTRK1 wild-type, or acquired mutations G595R and G667C in vitro and in vivo. Merestinib blocks tumor growth of both wild-type and mutant G667C TPM3-NTRK1 expressing NIH-3T3 cell-derived tumors. These preclinical data support the clinical evaluation of merestinib, a type II NTRK kinase inhibitor (NCT02920996), both in treatment naïve patients and in patients progressed on type I NTRK kinase inhibitors with acquired secondary G667C mutation in NTRK fusion bearing tumors.

Procedure Choice in Primary Versus Recurrent Prolapse: A Study of Fellowship-Trained Surgeons.

OBJECTIVE: This retrospective study describes procedures of choice in management of patients with primary prolapse compared with recurrence prolapse patients by fellowship-trained surgeons. METHODS: Surgically managed primary and recurrent prolapse cases from 2012 to 2015 at Houston Methodist Hospital were reviewed. Baseline characteristics, compartment defects, and stage were compared. Mean interval from the index surgeries to management of prolapse recurrence was recorded. In recurrence cases, mesh complaints were noted if present. Primary outcome was the procedure type used to manage cases of recurrence and primary prolapse. Logistic regression was used to determine odds ratio (OR) for the procedure of choice in recurrence and primary repairs of prolapse. RESULTS: Of 386 cases reviewed, 379 met criteria for inclusion; 25.8% of repairs were for recurrence. Recurrence patients were significantly older than primary cases (mean, 63.6 vs 60.5; P = 0.03) and had been postmenopausal for longer (P = 0.004). Median time interval to surgical management of recurrence was 8 years. Thirty percent of recurrence patients treated previously by mesh had mesh complaints. There was no difference in the distribution of defects or stage. Sacrocolpopexy was more frequently used to manage recurrent prolapse (OR, 2.6334; P < 0.0005). Vaginal mesh repairs showed no difference in utilization. Uterosacral ligament fixation (OR, 0.347; P = 0.002) was used more often in primary prolapse. Anterior colporrhaphy (OR, 0.398; P = 0.0005) and uterosacral ligament fixation (OR, 0.347; P = 0.002) were performed less in recurrence cases. CONCLUSION: Fellowship-trained urogynecologists at this institution utilize sacrocolpopexy mesh more frequently in recurrent prolapse, and uterosacral ligament fixation was used more frequently in primary prolapse cases.

Outcomes in Pelvic Organ Prolapse Surgery in Women Using Chronic Antithrombotic Therapy.

INTRODUCTION: Chronic antithrombotic therapy is common among patients requiring surgery for pelvic organ prolapse because of age and comorbidities. The impact of chronic anticoagulation on postoperative complications in pelvic organ prolapse surgery has not been investigated. This study aims to determine if patients on chronic antithrombotic therapy are at increased risk for postoperative complications. METHODS: This retrospective cohort study included women having prolapse surgery from 2012 to 2015, identified by Current Procedural Terminology codes, excluding patients undergoing concomitant major nonurogynecologic procedures. Baseline characteristics were compared and all procedures performed, operative duration, estimated blood loss, and length of hospitalization. Complications (blood transfusion, intensive care unit admission, reoperation, readmission, hematoma, thromboembolic event, and infection) were compared in women on chronic antithrombotic therapy and controls. Logistic regression determined odds ratio (OR) for complications in patients on chronic antithrombotics. Complications were graded by the Clavien-Dindo classification. RESULTS: A total of 388 charts were reviewed, and 386 patients met inclusion criteria. Twenty-one of the 386 patients were on chronic antithrombotic therapy. Chronic antithrombotic therapy increased overall complications (OR, 6.8; P < 0.0005), blood transfusion (OR, 165; P < 0.001), intensive care unit admission (OR, 19.10; P < 0.004), hospital readmission (OR, 20.7; P < 0.0005), vaginal hematoma (OR, 554.1; P < 0.001), infection (OR, 22.44; P < 0.004), and complications that required specific additional follow-up (OR, 9.42; P < 0.0005). There were no thromboembolic events. Antithrombotic therapy did not significantly increase reoperation rates (OR, 3.8; P = 0.275). Findings were maintained when adjusting for covariates of age and body mass index. CONCLUSIONS: Postoperative surgical complications after prolapse repair procedures are increased in patients who use chronic antithrombotic medication, the majority of cases are successfully managed conservatively.

The Checkpoint Kinase 1 Inhibitor Prexasertib Induces Regression of Preclinical Models of Human Neuroblastoma.

Purpose: Checkpoint kinase 1 (CHK1) is a key regulator of the DNA damage response and a mediator of replication stress through modulation of replication fork licensing and activation of S and G2-M cell-cycle checkpoints. We evaluated prexasertib (LY2606368), a small-molecule CHK1 inhibitor currently in clinical testing, in multiple preclinical models of pediatric cancer. Following an initial assessment of prexasertib activity, this study focused on the preclinical models of neuroblastoma.Experimental Design: We evaluated the antiproliferative activity of prexasertib in a panel of cancer cell lines; neuroblastoma cell lines were among the most sensitive. Subsequent Western blot and immunofluorescence analyses measured DNA damage and DNA repair protein activation. Prexasertib was investigated in several cell line-derived xenograft mouse models of neuroblastoma.Results: Within 24 hours, single-agent prexasertib promoted γH2AX-positive double-strand DNA breaks and phosphorylation of DNA damage sensors ATM and DNA-PKcs, leading to neuroblastoma cell death. Knockdown of CHK1 and/or CHK2 by siRNA verified that the double-strand DNA breaks and cell death elicited by prexasertib were due to specific CHK1 inhibition. Neuroblastoma xenografts rapidly regressed following prexasertib administration, independent of starting tumor volume. Decreased Ki67 and increased immunostaining of endothelial and pericyte markers were observed in xenografts after only 6 days of exposure to prexasertib, potentially indicating a swift reduction in tumor volume and/or a direct effect on tumor vasculature.Conclusions: Overall, these data demonstrate that prexasertib is a specific inhibitor of CHK1 in neuroblastoma and leads to DNA damage and cell death in preclinical models of this devastating pediatric malignancy. Clin Cancer Res; 23(15); 4354-63. ©2017 AACR.

Stromal-Based Signatures for the Classification of Gastric Cancer.

Treatment of metastatic gastric cancer typically involves chemotherapy and monoclonal antibodies targeting HER2 (ERBB2) and VEGFR2 (KDR). However, reliable methods to identify patients who would benefit most from a combination of treatment modalities targeting the tumor stroma, including new immunotherapy approaches, are still lacking. Therefore, we integrated a mouse model of stromal activation and gastric cancer genomic information to identify gene expression signatures that may inform treatment strategies. We generated a mouse model in which VEGF-A is expressed via adenovirus, enabling a stromal response marked by immune infiltration and angiogenesis at the injection site, and identified distinct stromal gene expression signatures. With these data, we designed multiplexed IHC assays that were applied to human primary gastric tumors and classified each tumor to a dominant stromal phenotype representative of the vascular and immune diversity found in gastric cancer. We also refined the stromal gene signatures and explored their relation to the dominant patient phenotypes identified by recent large-scale studies of gastric cancer genomics (The Cancer Genome Atlas and Asian Cancer Research Group), revealing four distinct stromal phenotypes. Collectively, these findings suggest that a genomics-based systems approach focused on the tumor stroma can be used to discover putative predictive biomarkers of treatment response, especially to antiangiogenesis agents and immunotherapy, thus offering an opportunity to improve patient stratification. Cancer Res; 76(9); 2573-86. ©2016 AACR.