The Cxbladder Rule-out of Recurrent Urothelial Carcinoma
The Cxbladder Rule-out of Recurrent Urothelial Carcinoma
This observational study is designed to collect urine and relevant clinical information from
 patients who have a known diagnosis of bladder cancer and currently on clinically driven
 surveillance. The study aims to compare the urine test to the flexible cystoscopy procedure
 (which the patient is already scheduled).
There are approximately 360,000 new cases of bladder cancer diagnosed globally each year. In
 addition, this disease is responsible for 145,000 deaths annually (Parkin et al 2005).
 Treatments for this cancer range from transurethral resection of the bladder tumor (TURBT)
 for low stage, non-invasive tumors, to the more drastic option of radical cystectomy with
 pelvic lymph node dissection for those tumors that are found to have invaded into the
 muscularis propria (Parekh et al 2006). Currently, the standard of care for diagnosing
 bladder cancer involves a combination of flexible cystoscopy and urine cytology, which is
 usually performed after the patient presents with episodes of gross hematuria. Following
 these evaluations, if evidence exists that warrants further investigation for bladder cancer
 a TURBT is performed and accurate staging and grading of the tumor can occur (O'Sullivan et
 al 2012). For those patients who have localized disease and have bladder preservation
 therapies, long term surveillance (in high grade disease this is life-long) is required to
 monitor for recurrence of tumor (Sylvester et al 2006). While cystoscopy has proven to be an
 accurate tool (sensitivity 80%) in the surveillance of bladder cancer, it is nonetheless a
 highly invasive procedure (Jocham et al 2008). In addition, urine cytology, which has served
 as the traditional adjunct to cystoscopy operates with a modest degree of sensitivity and
 therefore potential to deliver false negatives where malignant cells are not seen and false
 positives for bladder cancer in patients with an acute or chronically inflamed urothlelium
 (Grossman et al 2005). This leaves room for the development of a diagnostic test that is able
 to deliver results with the specificity of cystoscopy but without the potential for false
 negatives seen with urine cytology.

 Recently, studies have shown that certain genetic markers exist that accompany the occurrence
 of bladder cancer and can accurately discriminate between bladder tumors and normal tissue.
 These genetic markers also show promise in being able to deliver additional information
 regarding the disease state of this cancer, such the stage and grade of the tumor (Dyrskjot
 et al 2003; Dyrskjot et al 2005; Thykjaer et al 2001). The informative nature of these mRNA
 expression profiles, along with the frequency with which tumor exfoliation into the urine
 occurs, has led to the development of a urine-based test that has the potential to diagnose
 and stratify bladder cancer. This urine test, known as Cxbladder Monitor, was developed by
 Pacific Edge Limited and is able to perform a combinatory analysis of the expression profiles
 of five genetic biomarkers (IGF, HOXA, MDK, CDC and IL8R gene expression) and two clinical
 variables (whether the previous tumor was primary or recurrent and the time since the
 previous tumor was resected). This test has the potential, with further testing, to produce a
 consolidated diagnostic score that is able to accurately risk stratify a given patient for
 recurrence of bladder cancer based on tumor characteristics. The five genetic markers include
 CDC2 (a gene involved in cell cycle activity and DNA synthesis) (O'Sullivan et al 2012),
 HOXA13 (transcription factor involved in morphogenesis and differentiation of the
 genitourinary tract) (Scott et al 2005), IGFBP5 (affects processes such as such as
 development, differentiation, and cellular survival) (Beattie et al 2006), MDK (a heparin
 binding growth factor expressed during embryogenesis) (Kadomatsu et al 2004), and CXCR2 which
 is expressed in neutrophils and is increased in non-malignant, inflammatory conditions. This
 marker is essential as it is helpful in reducing the risk of false positive results in
 patients with an inflamed urothelium (O'Sullivan et al 2012). The Cxbladder test is able to
 take into account the expression of all these relevant genetic markers and analyze their
 expression profiles and interactions via a 2 way linear discriminate algorithm to form a
 score that is able to predict the recurrence of bladder cancer. The success of these
 preliminary studies with Cxbladder show that it has a strong potential to be used as a
 alternate to urine cytology and challenge cytology's routine accompaniment to cystoscopy.
 More importantly, the use of Cxbladder in the surveillance patient has the potential to
 decrease the frequency with which cystoscopy would need to be performed, adjudicate equivocal
 cystoscopy and cytology atypia.
Inclusion Criteria:

 1. Patient is undergoing investigative cystoscopies for the monitoring of recurrence of
 urinary tract UC at intervals prescribed by the clinical practitioner

 2. Patients on an "all-comers" basis

 3. Positive diagnosis for primary or recurrent bladder tumour within the past 5 years

 4. Able provide a voided urine sample of the required minimum volume

 5. Able to give written consent

 6. Able and willing to comply with study requirements

 7. Aged 18 years or older

 Exclusion Criteria:

 1. Prior genitourinary manipulation (flexible or rigid cystoscopy / catheterisation,
 urethral dilation) in the 14 days before urine collection,

 2. Patients who had exposure to intravesical BCG, had completed induction BCG but without
 a subsequent clear cystoscopy

 3. Recent history of glomerulonephritis, nephrosis or other renal inflammatory disorders,

 4. Recent history of pyelonephritis

 5. Total cystectomy of the bladder, neo bladders and illeal conduits

 6. Previous muscle invasive bladder tumour (pT2 or greater)