A glance at imaging bladder cancer.

Purpose: Early and accurate diagnosis of Bladder cancer (BCa) will contribute extensively to the management of the disease. The purpose of this review was to briefly describe the conventional imaging methods and other novel imaging modalities used for early detection of BCa and outline their pros and cons. Methods: Literature search was performed on Pubmed, PMC, and Google scholar for the period of January 2014 to February 2018 and using such words as bladder cancer, bladder tumor, bladder cancer detection, diagnosis and imaging . Results: A total of 81 published papers were retrieved and are included in the review. For patients with hematuria and suspected of BCa, cystoscopy and CT are most commonly recommended. Ultrasonography, MRI, PET/CT using 18F-FDG or 11C-choline and recently PET/MRI using 18F-FDG also play a prominent role in detection of BCa. Conclusion: For initial diagnosis of BCa, cystoscopy is generally performed. However, cystoscopy can not accurately detect carcinoma insitu (CIS) and can not distinguish benign masses from malignant lesions. CT is used in two modes, CT and computed tomographic urography (CTU), both for dignosis and staging of BCa. However, they cannot differentiate T1 and T2 BCa. MRI is performed to diagnose invasive BCa and can differentiate muscle invasive bladder carcinoma (MIBC) from non-muscle invasive bladder carcinoma (NMIBC). However, CT and MRI have low sensitivity for nodal staging. For nodal staging PET/CT is preferred. PET/MRI provides better differentiation of normal and pathologic structures as compared with PET/CT. Nonetheless none of the approaches can address all issues related for the management of BCa. Novel imaging methods that target specific biomarkers, image BCa early and accurately, and stage the disease are warranted

Multifunctional targeting micelle nanocarriers with both imaging and therapeutic potential for bladder cancer.

BackgroundWe previously developed a bladder cancer-specific ligand (PLZ4) that can specifically bind to both human and dog bladder cancer cells in vitro and in vivo. We have also developed a micelle nanocarrier drug-delivery system. Here, we assessed whether the targeting micelles decorated with PLZ4 on the surface could specifically target dog bladder cancer cells.Materials and methodsMicelle-building monomers (ie, telodendrimers) were synthesized through conjugation of polyethylene glycol with a cholic acid cluster at one end and PLZ4 at the other, which then self-assembled in an aqueous solution to form micelles. Dog bladder cancer cell lines were used for in vitro and in vivo drug delivery studies.ResultsCompared to nontargeting micelles, targeting PLZ4 micelles (23.2 ± 8.1 nm in diameter) loaded with the imaging agent DiD and the chemotherapeutic drug paclitaxel or daunorubicin were more efficient in targeted drug delivery and more effective in cell killing in vitro. PLZ4 facilitated the uptake of micelles together with the cargo load into the target cells. We also developed an orthotopic invasive dog bladder cancer xenograft model in mice. In vivo studies with this model showed the targeting micelles were more efficient in targeted drug delivery than the free dye (14.3×; P < 0.01) and nontargeting micelles (1.5×; P < 0.05).ConclusionTargeting micelles decorated with PLZ4 can selectively target dog bladder cancer cells and potentially be developed as imaging and therapeutic agents in a clinical setting. Preclinical studies of targeting micelles can be performed in dogs with spontaneous bladder cancer before proceeding with studies using human patients

Shed urinary ALCAM is an independent prognostic biomarker of three-year overall survival after cystectomy in patients with bladder cancer.

Proteins involved in tumor cell migration can potentially serve as markers of invasive disease. Activated Leukocyte Cell Adhesion Molecule (ALCAM) promotes adhesion, while shedding of its extracellular domain is associated with migration. We hypothesized that shed ALCAM in biofluids could be predictive of progressive disease. ALCAM expression in tumor (n = 198) and shedding in biofluids (n = 120) were measured in two separate VUMC bladder cancer cystectomy cohorts by immunofluorescence and enzyme-linked immunosorbent assay, respectively. The primary outcome measure was accuracy of predicting 3-year overall survival (OS) with shed ALCAM compared to standard clinical indicators alone, assessed by multivariable Cox regression and concordance-indices. Validation was performed by internal bootstrap, a cohort from a second institution (n = 64), and treatment of missing data with multiple-imputation. While ALCAM mRNA expression was unchanged, histological detection of ALCAM decreased with increasing stage (P = 0.004). Importantly, urine ALCAM was elevated 17.0-fold (P < 0.0001) above non-cancer controls, correlated positively with tumor stage (P = 0.018), was an independent predictor of OS after adjusting for age, tumor stage, lymph-node status, and hematuria (HR, 1.46; 95% CI, 1.03-2.06; P = 0.002), and improved prediction of OS by 3.3% (concordance-index, 78.5% vs. 75.2%). Urine ALCAM remained an independent predictor of OS after accounting for treatment with Bacillus Calmette-Guerin, carcinoma in situ, lymph-node dissection, lymphovascular invasion, urine creatinine, and adjuvant chemotherapy (HR, 1.10; 95% CI, 1.02-1.19; P = 0.011). In conclusion, shed ALCAM may be a novel prognostic biomarker in bladder cancer, although prospective validation studies are warranted. These findings demonstrate that markers reporting on cell motility can act as prognostic indicators

Discriminant analysis of exfoliated cells in bladder urothelium cancer

Objective To explore the method of computer discriminant on exfoliated cells in bladder urothelium cancer by Pap stain. Methods The exfoliated cells in 107 urine smears included 386 uroepi-thelium normal exfoliated cells (UNC) , 439 urothelium dysplastic exfoliated cells (UDC) and 500 blad-der urothelial cancer exfoliated cells (UCC). The cells were randomly divided into training group (n = 1077) and identifying group (n = 248) , and the chromatic and geometric shape parameters of cytoplasm and nuclear were tested. The stepwise discriminant analysis was used in cells of the training group to establish a discriminant function and analyze the rate of back substitution discriminant. The function was evaluated by cells of identifying group, and the coincidence rate was analyzed in 107 specimens. Results The back discriminant coincidence rate of cells in training group was 80.8%. The coincidence rate of identifying group and 107 specimens were 80.2% and 92.5% respectively. The discriminant effect was significantly better than function based on chromatics and geometric shape parameters individually (P < 0.05). Conclusions The function combined with chromatics and geometric shape parameters has good discriminant performance in bladder urothelium cancer

Applications of Raman micro-spectroscopy for cancer diagnostics

Bladder cancer has the highest recurrence rate of any cancer, and as with most solid organ malignancies, early diagnosis, detection, and treatment are imperative for good clinical outcomes. Cystoscopy is the cornerstone of bladder diagnostics for real-time visualization of the bladder mucosa. However, it is an uncomfortable, invasive procedure, and is not without significant risk and potential complications for the patient. Urine cytology is currently the only non-invasive diagnostic tool available for the diagnosis of bladder cancer; this method is highly sensitive for high grade tumours, but has low sensitivity for low grade tumours, which accounts for the majority of cases. Therefore, there exists a clinical need to develop and integrate a non-invasive, accurate technique to assist in the diagnosis of bladder cancer. The combination of Raman micro-spectroscopy and voided urine cytology may provide an ideal platform to replace cystoscopy for bladder cancer diagnostics. By recording Raman spectra from cells obtained from urine cytology, it is possible to analyse the spectral differences associated with the biomolecular continuum of disease progression, as well as being able to classify between different pathological subgroups. Previous studies to date have shown promising results in the application of Raman based urine cytology; however, there appears a high degree of variability across experimental protocols, which is believed to have hindered the advancement of this technique into the clinic. This thesis involves the design and building of a confocal Raman micro-spectrometer to be utilised for the analysis of urine cytology samples, with a key emphasis on the translation of Raman based urine cytology into the clinic. In order to achieve this, a range of traditional protocols and consumables are systematically examined in terms of their compatibility with Raman micro-spectroscopy, as well as comparing the differences between Raman micro-spectroscopy and another form of vibrational spectroscopy for bladder and prostate cancer diagnostics. Although no patient urine cytology samples are used in this thesis, simulated samples are generated using bladder and prostate cell lines along with commercially available synthetic urine. Additional experimentation is provided in order to investigate the impact of hypoxia and exosomal communication on cellular biochemistry