Laura E. Lamb

Modeling and Treatment of Radiation Cystitis

Radiation cystitis (RC) is a debilitating condition that, if not managed at an early stage, can have a major impact on the quality of life of a patient and can lead to severe hemorrhaging and even death. Current treatments are focused on arresting bladder hemorrhaging, but none are able to relieve other urological symptoms associated with cystitis. There is a strong need for in-depth studies using preclinical RC models to better understand the underlying disease progression and to test novel therapies. Here we review the most commonly used therapies for RC, novel treatment strategies, and the preclinical models used to date.

Advantage of urine based molecular diagnosis of Zika virus

Zika virus (ZIKV) infection is an emerging global health concern, and diagnostic recommendations are currently developing based on new information. Several case or small sample size studies using both urine and blood samples suggest that ZIKV RNA can be detected at higher levels and for a longer time after onset of infection in urine compared to blood. We recommend that urine and serum collection for molecular testing be a standard part of evaluating patients for ZIKV infection, and that urine is a good alternative testing sample when blood collection is problematic.

Underactive Bladder in Older Adults.

Overactive bladder is one of the most common bladder problems, but an estimated 20 million Americans have underactive bladder (UAB), which makes going to the bathroom difficult, increases the risk of urinary tract infections, and even leads to institutionalization. This article provides an overview of UAB in older adults, and discusses the prevalence, predisposing factors, cause, clinical investigations, and treatments. At present, there is no effective therapy for UAB. A great deal of work still needs to be done on understanding the pathogenesis and the development of effective therapies.

Modeling of chronic radiation-induced cystitis in mice

Purpose Radiation cystitis (RC), a severe inflammatory bladder condition, develops as a side effect of pelvic radiation therapy in cancer patients. There are currently no effective therapies to treat RC, in part from the lack of preclinical model systems. In this study, we developed a mouse model for RC and used a Small Animal Radiation Research Platform to simulate the targeted delivery of radiation as used with human patients. Methods and materials To induce RC, C3H mice received a single radiation dose of 20 Gy delivered through 2 beams. Mice were subjected to weekly micturition measurements to assess changes in urinary frequency. At the end of the study, bladder tissues were processed for histology. Results Radiation was well-tolerated; no change in weight was observed in the weeks after treatment, and there was no hair loss at the irradiation sites. Starting at 17 weeks after treatment, micturition frequency was significantly higher in irradiated mice versus control animals. Pathological changes include fibrosis, inflammation, urothelial thinning, and necrosis. At a site of severe insult, we observed telangiectasia, absence of uroplakin-3 and E-cadherin relocalization. Conclusions We developed an RC model that mimics the human pathology and functional changes. Furthermore, radiation exposure attenuates the urothelial integrity long-term, allowing for potential continuous irritability of the bladder wall from exposure to urine. Future studies will focus on the underlying molecular changes associated with this condition and investigate novel treatment strategies.

Challenges and Opportunities in Radiation-induced Hemorrhagic Cystitis.

As diagnosis and treatment of cancer is improving, medical and social issues related to cancer survivorship are becoming more prevalent. Hemorrhagic cystitis (HC), a rare but serious disease that may affect patients after pelvic radiation or systemic chemotherapy, has significant unmet medical needs. Although no definitive treatment is currently available, various interventions are employed for HC. Effects of nonsurgical treatments for HC are of modest success and studies aiming to control radiation-induced bladder symptoms are lacking. In this review, we present current and advanced therapeutic strategies for HC to help cancer survivors deal with long-term urologic health issues.

Development of an interstitial cystitis risk score for bladder permeability

Background Interstitial cystitis/bladder pain syndrome (IC) is a multifactorial syndrome of severe pelvic and genitalia pain and compromised urinary function; a subset of IC patients present with Hunner’s lesions or ulcers on their bladder walls (UIC). UIC is diagnosed by cystoscopy, which may be quite painful. The objective of this study was to determine if a calculated Bladder Permeability Defect Risk Score (BP-RS) based on non-invasive urinary cytokines could discriminate UIC patients from controls and IC patients without Hunner’s ulcers. Methods A national crowdsourcing effort targeted IC patients and age-matched controls to provide urine samples. Urinary cytokine levels for GRO, IL-6, and IL-8 were determined using a Luminex assay. Results We collected 448 urine samples from 46 states consisting of 153 IC patients (147 female, 6 male), of which 54 UIC patients (50 females, 4 male), 159 female controls, and 136 male controls. A defined BP-RS was calculated to classify UIC, or a bladder permeability defect etiology, with 89% validity. Conclusions The BP-RS Score quantifies UIC risk, indicative of a bladder permeability defect etiology in a subset of IC patients. The Bladder Permeability Defect Risk Score is the first validated urine biomarker assay for interstitial cystitis/bladder pain syndrome.

Rapid Detection of Zika Virus in Urine Samples and Infected Mosquitos by Reverse Transcription-Loop-Mediated Isothermal Amplification

Infection with Zika virus (ZIKV) is of growing concern since infection is associated with the development of congenital neurological disease. Quantitative reverse transcription PCR (qRT-PCR) has been the standard for ZIKV detection; however, Reverse Transcription Loop-Mediated Isothermal Amplification (RT-LAMP) may allow for faster and cheaper testing. Studies have suggested that ZIKV detection in urine is more sensitive and has a longer window of detection compared to serum and saliva. The objective of this study was to develop a urine diagnostic test that could be completed in under 30 minutes. Urine samples spiked with ZIKV or dengue virus were tested using RT-LAMP as well as by conventional quantitative qRT-PCR. These techniques were then validated using crude lysates made from ZIKV infected mosquitoes in addition to urine and serum samples from ZIKV infected patients. RT-LAMP specifically detected ZIKV in urine and serum for ZIKV infected patients and crude mosquito lysates. This test was performed in under 30 minutes and did not require RNA extraction from urine nor mosquitos. This approach could be used for monitoring of exposed individuals, especially pregnant women, couples wanting to conceive, or individuals with suspicious symptoms as well as surveillance of mosquito populations.

New technology assessment and current and upcoming therapies for underactive bladder

Stakeholders from around the world came together to address the unmet needs of underactive bladder (UAB) at the 3rd International Congress for Underactive Bladder.

Crowdsourcing Disease Biomarker Discovery Research: The IP4IC Study

Purpose: Biomarker discovery is limited by readily assessable, cost efficient human samples available in large numbers that represent the entire heterogeneity of the disease. We developed a novel, active participation crowdsourcing method to determine BP‐RS (Bladder Permeability Defect Risk Score). It is based on noninvasive urinary cytokines to discriminate patients with interstitial cystitis/bladder pain syndrome who had Hunner lesions from controls and patients with interstitial cystitis/bladder pain syndrome but without Hunner lesions. Materials and Methods: We performed a national crowdsourcing study in cooperation with the Interstitial Cystitis Association. Patients answered demographic, symptom severity and urinary frequency questionnaires on a HIPAA (Health Insurance Portability and Accountability Act) compliant website. Urine samples were collected at home, stabilized with a preservative and sent to Beaumont Hospital for analysis. The expression of 3 urinary cytokines was used in a machine learning algorithm to develop BP‐RS. Results: The IP4IC study collected a total of 448 urine samples, representing 153 patients (147 females and 6 males) with interstitial cystitis/bladder pain syndrome, of whom 54 (50 females and 4 males) had Hunner lesions. A total of 159 female and 136 male controls also participated, who were age matched. A defined BP‐RS was calculated to predict interstitial cystitis/bladder pain syndrome with Hunner lesions or a bladder permeability defect etiology with 89% validity. Conclusions: In this novel participation crowdsourcing study we obtained a large number of urine samples from 46 states, which were collected at home, shipped and stored at room temperature. Using a machine learning algorithm we developed BP‐RS to quantify the risk of interstitial cystitis/bladder pain syndrome with Hunner lesions, which is indicative of a bladder permeability defect etiology. To our knowledge BP‐RS is the first validated urine biomarker assay for interstitial cystitis/bladder pain syndrome and one of the first biomarker assays to be developed using crowdsourcing.

Reply to the letter: Urine based molecular diagnosis of Zika virus by Viroj Wiwanitkit

We first want to thank the writer for their interest and agree that the “urine diagnostic tool is useful for diagnostic of infectious infection”. While it is true that secretion of Zika virus in urine does not occur in all phases of infection, we believe that the reports we evaluated support that Zika virus can be detected at higher levels and for a longer timeframe after initial infection than blood, and may allow for the detection of more Zika infection cases. We like to thank the writer for referring to a new method that was also just published. We are excited about what new technologies may soon develop to address this unmet need, and are also seeking to address this.