Bladder Cancer Journal Vol. 5 Issue 3

Molecular/ Genetic/ Protein Characterizing of Bladder Cancer Circulating Tumor Cells

Background: Circulating tumor cells (CTCs) assays are a promising noninvasive way to interrogate the status of disease in bladder cancer. Since the molecular signature of cancer cells may dictate their susceptibility to targeted or immunotherapy, the full value of CTC assays may be in such subsequent characterization. These secondary features may help increasingly guide future clinical management of bladder cancer. Objective: This review aims to survey advances in the secondary molecular characterization of CTCs in bladder cancer. Methods: Using PRISMA guidelines, a systematic search of PubMed articles published between January 1990 to February 2019 was conducted to identify bladder CTCs studies that included protein, gene expression, or molecular characterization data. Results: Three original articles were identified. These articles assessed either PD-L1, HER2, or STn. Conclusions: Our systematic review reveals a relative paucity of studies that undertake molecular or genetic characterization of CTCs in bladder cancer. Studies of that identify prognostic markers in bladder cancer will become increasingly useful as targeted and immunotherapy become integrated into the management of bladder cancer. 

Investigating the STING Pathway to Explain Mechanisms of BCG Failures in Non-Muscle Invasive Bladder Cancer: Prognostic and Therapeutic Implications

Background: Intravesical Bacillus Calmette Guerin (BCG) has been the gold standard immunotherapy to treat high risk non-muscle invasive bladder cancer (NMIBC) for over 40 years. Attenuation of Mycobacterium bovis for clinical use as BCG results in loss of its ability to activate the “Stimulator of Interferon Genes” (STING) pathway and potentially limits local anti-tumor immune activity and subsequent BCG responsiveness due to reduced induction of the immune cell recruiting chemokines primarily, CXCL10. We conducted the current study to determine the potential of STING pathway agonist in synergizing with BCG to enhance chemokine induction. Methods: The TICE strain of BCG (OncoTICE) was used in combination with STING agonist to determine STING pathway activation and CXCL10 production in THP-1 monocytic cell line, THP-1 defNLRP3, THP-1 dual STING knock out cells, RT112 bladder cancer cells and primary bladder epithelial cells. NanoString platform-based gene expression profiling and multiplex cytokine analysis were performed to determine induction of interferon associated genes and secreted cytokines. Results: Activation of cytosolic pattern recognition receptor and downstream IFN1 pathways demonstrated synergistic activation of STING pathway enhanced BCG induced inflammasome and STING pathway gene expression in monocytes and bladder cancer cells. The significant differences in CXCL10, CCL5, IL-8 and MIP-1a/1b amongst the knock-out cell lines confirm the convergence of these pathways following combination treatment with BCG and STING agonist. Conclusions: Findings from our study are the first evidence indicating that STING pathway activators are promising new innate immune modulators with a potential to synergize with BCG therapy in the treatment of NMIBC.

Background: There is an association between higher hospital and urologist case volume and improved survival outcomes for patients with bladder cancer. Less data on facility volume and outcomes exists following trimodality bladder preservation with TURBT followed by definitive chemoradiation (CRT). Materials and Methods: The National Cancer Database was queried for patients from 2004–2013 with urothelial bladder cancer (cT2-4aN0M0) receiving definitive CRT after TURBT. We compared OS between high- and low- bladder preservation case volume (BPCV) centers using Cox proportional hazard models. BPCV was dichotomized into high versus low volume at the 70th percentile level (i.e. high volume defined as top 30th percentile of cases and low volume defined as bottom 70th percentile of cases). Propensity matching was performed to match high- and low-volume centers. Results: A total of 666 treatment facilities treating 1,635 patients with bladder preservation were identified with a median follow-up of 26 months (range, 2–136 months). A 70th percentile cutoff identified 497 patients that received treatment at 64 high-volume facilities. Median OS of patients treated at high BPCV centers was 37.0 months (95% CI, 27.3–46.7) versus 32.3 months (95% CI, 27.9–33.6) for patients treated at low BPCV centers (P  = 0.004). High BPCV facilities were independently associated with a decreased hazard of death (HR, 0.86, 95% CI, 0.75–0.98; P  = 0.031). In the propensity score matched cohort, median OS of patients treated at high BPCV was 36.1 months (95% CI, 26.5–45.8) versus 28.1 months (95% CI, 23.9–32.3) for patients treated at a low BPCV facility (P  = 0.016). Conclusions: In this observational cohort, treatment at a high BPCV facility was associated with improved OS. Causal factors for this finding may include superior bladder specific clinician expertise, technology, and multidisciplinary-care. 

Challenging Cases in Urothelial Cancer

Automated Urinalysis Machines: Potential Impact on the Diagnosis of Bladder Cancer