Mostafid, Hugh

Abstract Purpose: The CANON [CAVATAK in NON–muscle-invasive bladder cancer (NMIBC)] study evaluated a novel ICAM-1–targeted immunotherapeutic-coxsackievirus A21 as a novel oncolytic agent against bladder cancer. Patients and Methods: Fifteen patients enrolled in this “window of opportunity” phase I study, exposing primary bladder cancers to CAVATAK prior to surgery. The first 9 patients received intravesical administration of monotherapy CAVATAK; in the second stage, 6 patients received CAVATAK with a subtherapeutic dose of mitomycin C, known to enhance expression of ICAM-1 on bladder cancer cells. The primary endpoint was to determine patient safety and maximum tolerated dose (MTD). Secondary endpoints were evidence of viral replication, induction of inflammatory cytokines, antitumor activity, and viral-induced changes in resected tissue. Results: Clinical activity of CAVATAK was demonstrated by induction of tumor inflammation and hemorrhage following either single or multiple administrations of CAVATAK in multiple patients, and a complete resolution of tumor in 1 patient. Whether used alone or in combination with mitomycin C, CAVATAK caused marked inflammatory changes within NMIBC tissue biopsies by upregulating IFN-inducible genes, including both immune checkpoint inhibitory genes (PD-L1 and LAG3) and Th1-associated chemokines, as well as the induction of the innate activator RIG-I, compared with bladder cancer tissue from untreated patients. No significant toxicities were reported in any patient, from either virus or combination therapy. Conclusions: The acceptable safety profile of CAVATAK, proof of viral targeting, replication, and tumor cell death together with the virus-mediated increases in “immunological heat” within the tumor microenvironment all indicate that CAVATAK may be potentially considered as a novel therapeutic for NMIBC.

The aim of the present study was to review major organizational guidelines on the evaluation and management of asymptomatic microscopic haematuria ( AMH ). We reviewed the haematuria guidelines from: the American Urological Association; the consensus statement by the Canadian Urological Association, Canadian Urologic Oncology Group and Bladder Cancer Canada; the American College of Physicians; the Joint Consensus Statement of the Renal Association and British Association of Urological Surgeons; and the National Institute for Health and Care Excellence. All guidelines reviewed recommend evaluation for AMH in the absence of potential benign aetiologies, with the evaluation including cystoscopy and upper urinary tract imaging. Existing guidelines vary in their definition of AMH (role of urine dipstick vs urine microscopy), the age threshold for recommending evaluation, and the optimal imaging method (computed tomography vs ultrasonography). Of the reviewed guidelines, none recommended the use of urine cytology or urine markers during the initial AMH evaluation. Patients should have ongoing follow‐up after a negative initial AMH evaluation. Significant variation exists among current guidelines for AMH with respect to who should be evaluated and in what manner. Given the patient and health system implications of balancing appropriately focused and effective diagnostic evaluation, AMH represents a valuable future research opportunity.