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  • Wiley (CrossRef)  (68)
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  • 1
    In: Chemical Biology & Drug Design, March 2018, Vol.91(3), pp.691-706
    Description: The Notch pathway is a cell‐cell communication system where membrane‐bound ligands interact with the extracellular region of Notch receptors to induce intracellular, downstream effects on gene expression. Aberrant Notch signaling promotes tumorigenesis, and the Notch pathway has tremendous potential for novel targeting strategies in cancer treatment. While γ‐secretase inhibitors as Notch‐inhibiting agents are already promising in clinical trials, they are highly non‐specific with adverse side‐effects. One of the underlying challenges is that two of the four known human Notch paralogs, 1 and 2, share very high structural similarity but play opposing roles in some tumorigenesis pathways. This perspective explores the feasibility of developing Notch‐specific small molecule inhibitors targeting the anti‐2 antibody‐binding epitopes or the “S2‐Leu‐plug‐binding site” using a computer‐aided drug discovery approach. We review current Notch inhibitors of small molecules and expensive monoclonal antibodies. Our computational modeling of the Notch proteins suggests that the S2 cleavage site, blocked by a conserved Leucine residue in the receptor's inactive state, is a plausible Notch‐specific therapeutic site to target. Synthetic antibody mimics present an attractive future drug modality to target specific Notch paralogs and replace monoclonal antibodies.
    Keywords: Drug Discovery ; Monoclonal Antibodies ; Notch ; Small Molecule Drugs ; Stapled Peptides ; Therapeutic Target
    ISSN: 1747-0277
    E-ISSN: 1747-0285
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  • 2
    In: Cancer, 15 August 2014, Vol.120(16), pp.2424-2431
    Description: The authors performed a cost‐effectiveness study comparing sequential therapy with bacillus Calmette‐Guerin alone. The results suggest that sequential therapy is a cost‐effective treatment for patients with high‐risk non–muscle‐invasive bladder cancer.
    Keywords: Cost‐Effectiveness ; Bacillus Calmette‐Guerin Bcg ; Electromotive Mitomycin ; Sequential Therapy ; Non‐Muscle Invasive Bladder Cancer
    ISSN: 0008-543X
    E-ISSN: 1097-0142
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  • 3
    In: BJU International, March 2013, Vol.111(3), pp.419-426
    Description: Byline: , Keywords: bladder cancer; randomized controlled trial; radical cystectomy; transurethral resection; radiation; chemotherapy What's known on the subject? and What does the study add? Results from well designed randomized controlled trials usually provide the strongest evidence possible in favour of one medical intervention over another. For this reason, it is of paramount importance to conduct such trials in bladder cancer, where randomized trials are lacking, in particular to answer questions that have so far confounded us or to investigate the efficacy of new diagnostic tools or interventions. This study provides a demographic analysis of randomized controlled trials published in bladder cancer between the years of 1995 and 2010, with only 238 articles identified. Less than one-third of these reported a statistical power calculation, and only 8% were double-blinded. With many publications inaccurately labelled as randomized trials, we reveal the scarcity of trials performed over the given time period, even compared with other cancers with similar incidence, and highlight the need for more well designed trials to be conducted. Objective To demographically examine randomized controlled trials (RCTs) that have been conducted in bladder cancer over a predefined time period. Methods Various techniques have been described to detect RCTs using different databases. We searched the MEDLINE database by crossing the heading 'Urinary bladder neoplasms' with the MeSHs 'Clinical trial$.mp. OR clinical trial.pt. OR random:.mp. OR tu.xs.' between 1995 and 2010. For the RCTs identified, analysis was performed on each RCT, placing particular emphasis on modality of intervention, cohort size, principal author, region, journal type, disease status, histology, blinding, number of centres involved, performance of a statistical power calculation, accrual status and trial support. Results Of 5002 RCT bladder cancer papers retrieved over the given period, only 238 represented actual RCTs after manual appraisal. More than half of the RCTs investigated medical and surgical therapies (54.2%), and only half had a sample size of 〉100 patients. A small percentage of studies were double-blinded (8.0%), and there was an almost equal distribution of multicentre vs single centre trials (54.6% vs 45.4%). More studies were conducted in Europe (61.3%) than the rest of the world combined, with urologists principally the lead investigators in the majority (72.3%). Most studies were conducted on patients with urothelial carcinoma (97.1%), with less than one-third reporting a statistical power calculation (31.5%). Conclusions Only 238 RCTs were published for bladder cancer between 1995 and 2010. RCTs are under-utilized in bladder cancer. More trials need to be designed with larger sample sizes in order to optimize diagnostic and treatment strategies for patients with bladder cancer. Author Affiliation: Article Note:
    Keywords: Bladder Cancer ; Randomized Controlled Trial ; Radical Cystectomy ; Transurethral Resection ; Radiation ; Chemotherapy
    ISSN: 1464-4096
    E-ISSN: 1464-410X
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  • 4
    In: BJU International, May 2014, Vol.113(5b), pp.E28-E33
    Description: To purchase or authenticate to the full-text of this article, please visit this link: http://onlinelibrary.wiley.com/doi/10.1111/bju.12344/abstract Byline: Anthony N. Hoang, Piyush K. Agarwal, Annerleim Walton-Diaz, Christopher G. Wood, Adam R. Metwalli, Wassim Kassouf, Gordon A. Brown, Peter C. Black, Diana L. Urbauer, H. Barton Grossman, Colin P.N. Dinney, Ashish M. Kamat Keywords: bladder cancer; ureteral urothelial carcinoma; cystectomy; ureteral margin; upper tract recurrence Objective To assess the incidence and clinical significance of 'skip lesions' that are present in proximal but not in distal ureteric sections, which are occasionally found during the pathological examination of ureteric margins during radical cystectomy (RC). Patients and Methods We identified 660 patients who underwent a RC and had at least two permanent margins for a given ureter. In all, 1173 ureters were analysed and classified as follows: 'normal' (no tumour, reactive atypia, mild or moderate dysplasia) or 'abnormal' (severe dysplasia, carcinoma in situ (CIS), or tumour). Transitions from 'normal' distal pathology to 'abnormal' on proximal section(s) determined frequency of skip lesions. Fisher's exact test and the log-rank test were used to study correlations. Results Ureteric skip lesions were found in 4.8% patients (2.9% ureters). Pathology of skip lesions was CIS in 55.9%, transitional cell carcinoma in 23.5% and severe dysplasia in 20.6%. Skip lesions were associated with lymphovascular invasion (34.4% vs 13.7%, P = 0.004) and advanced pT stage (P = 0.007). On multivariate analysis, skip lesions correlated with lower median overall survival (OS) (inestimable vs 8.2 years, P = 0.014) in patients with pT0 or pTa disease and a trend towards lower OS (2.7 vs 8.8 years, P = 0.066) in pTis disease. Concordance between frozen distal margin and permanent proximal margin varied; sensitivity was 80% in those without and 20% in those with skip lesions. Conclusions The presence of a ureteric skip lesion may be associated with lower survival in patients with pT0, pTa or pTis urothelial carcinoma. Thus, while uncommon, ureteric skip lesions should be reported in pathological findings. Article Note: This research was supported by the M. D. Anderson Cancer Center Bladder SPORE (5P50CA091846-03) and a Department of Urology T32 Training Grant
    Keywords: Bladder Cancer ; Ureteral Urothelial Carcinoma ; Cystectomy ; Ureteral Margin ; Upper Tract Recurrence
    ISSN: 1464-4096
    E-ISSN: 1464-410X
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  • 5
    In: BJU International, July 2015, Vol.116(1), pp.72-78
    Description: To purchase or authenticate to the full-text of this article, please visit this link: http://onlinelibrary.wiley.com/doi/10.1111/bju.12801/abstract Byline: Ilaria Lucca, Wassim Kassouf, Anil Kapoor, Adrian Fairey, Ricardo A. Rendon, Jonathan I. Izawa, Peter C. Black, Harun Fajkovic, Christian Seitz, Mesut Remzi, Peter Nyirady, Morgan Roupret, Vitaly Margulis, Yair Lotan, Michela Martino, Sebastian L. Hofbauer, Pierre I. Karakiewicz, Alberto Briganti, Giacomo Novara, Shahrokh F. Shariat, Tobias Klatte Keywords: adjuvant chemotherapy; upper tract urothelial carcinoma; radical nephroureterectomy; survival; lymph node positive Objective To evaluate the effect of adjuvant chemotherapy (AC) on mortality after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) with positive lymph nodes (LNs) and to identify patient subgroups that are most likely to benefit from AC. Patients and methods We retrospectively analysed data of 263 patients with LN-positive UTUC, who underwent full surgical resection. In all, 107 patients (41%) received three to six cycles of AC, while 156 (59.3%) were treated with RNU alone. UTUC-related mortality was evaluated using competing-risks regression models. Results In all patients (T.sub.all N+), administration of AC had no significant impact on UTUC-related mortality on univariable (P = 0.49) and multivariable (P = 0.11) analysis. Further stratified analyses showed that only N+ patients with pT3-4 disease benefited from AC. In this subgroup, AC reduced UTUC-related mortality by 34% (P = 0.019). The absolute difference in mortality was 10% after the first year and increased to 23% after 5 years. On multivariable analysis, administration of AC was associated with significantly reduced UTUC-related mortality (subhazard ratio 0.67, P = 0.022). Limitations of this study are the retrospective non-randomised design, selection bias, absence of a central pathological review and different AC protocols. Conclusions AC seems to reduce mortality in patients with pT3-4 LN-positive UTUC after RNU. This subgroup of LN-positive patients could serve as target population for an AC prospective randomised trial.
    Keywords: Adjuvant Chemotherapy ; Upper Tract Urothelial Carcinoma ; Radical Nephroureterectomy ; Survival ; Lymph Node Positive
    ISSN: 1464-4096
    E-ISSN: 1464-410X
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  • 6
    In: BJU International, December 2010, Vol.106(11), pp.1799-1804
    Description: To authenticate to the full-text of this article, please visit this link: http://dx.doi.org/10.1111/j.1464-410X.2010.09424.x Keywords: animal model; bioluminescence imaging; MRI; hypoxia; bladder cancer Abstract: OBJECTIVE To assess the correlation in orthotopic bladder xenografts of bioluminescence imaging (BLI) with tumour volume as determined by magnetic resonance imaging (MRI), and to define the potential role of hypoxia and necrosis in the relationship between BLI and tumour volume at autopsy. MATERIALS AND METHODS Orthotopic bladder tumours were established in nude mice with KU7 and 253J B-V cells expressing luciferase. BLI and MRI were performed weekly. Tumour volume was calculated from MR images at each time point. Autopsy was performed 4 weeks after inoculation and 45 min after injection of piminidazole. haematoxylin and eosin staining and immunohistochemical analysis of piminidazole adduct formation were performed on 1-mm step-sections through frozen whole bladder specimens to assess necrosis and hypoxia, respectively. CD31 staining was used to evaluate vascularity. Relative volumes of each specimen containing total tumour, hypoxic tumour and necrotic tumour were quantified. RESULTS The correlation between MRI volume and BLI was weak in KU7 xenografts (R.sup.2 〈 0.1) but strong in 253J B-V (R.sup.2= 0.93 at 4 weeks). KU7 xenografts had vasculature only peripherally and showed extensive hypoxic and necrotic areas. After subtraction of necrotic areas, the correlation of BLI to viable tumour volume improved (R.sup.2= 0.42). CONCLUSION The correlation between tumour BLI and tumour size varies by cell line and is poor in xenografts that rapidly outgrow their vascular supply and develop broad areas of hypoxia and necrosis. However, in these cases BLI does yield information about the amount of viable tumour, and should therefore still be considered as a useful imaging method. Author Affiliation: Departments of(*)Urology, ([dagger])Imaging Physics, and ([double dagger])Cancer Biology, the University of Texas, M.D. Anderson Cancer Center, TX, USA Article History: Accepted for publication 22 December 2009 Article note: Peter C. Black, Department of Urologic Sciences, University of British Columbia, Level 6, 2775 Laurel St., Vancouver, B.C. V5Z 1M9, Canada., e-mail: peter.black@ubc.ca
    Keywords: Animal Model ; Bioluminescence Imaging ; Mri ; Hypoxia ; Bladder Cancer
    ISSN: 1464-4096
    E-ISSN: 1464-410X
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  • 7
    In: BJU International, October 2015, Vol.116(4), pp.556-567
    Description: OBJECTIVE: To better characterize the genomics of patients with biochemical recurrence (BCR) who have metastatic disease progression in order to improve treatment decisions for prostate cancer.METHODS: The expression profiles of three clinical outcome groups after radical prostatectomy (RP) were compared: those with no evidence of disease (NED; n = 108); those with BCR (rise in prostate-specific antigen [PSA] level without metastasis; n = 163); and those with metastasis (n = 192). The patients were profiled using Human Exon 1.0 ST microarrays, and outcomes were supported by a median 18 years of follow-up. A metastasis signature was defined and verified in an independent RP cohort to ensure the robustness of the signature. Furthermore, bioinformatics characterization of the signature was conducted to decipher its biology.RESULTS: Minimal gene expression differences were observed between adjuvant treatment-naïve patients in the NED group and patients without metastasis in the BCR group. More than 95% of the differentially expressed genes (metastasis signature) were found in comparisons between primary tumours of metastasis patients and the two other outcome groups. The metastasis signature was validated in an independent cohort and was significantly associated with cell cycle genes, ubiquitin-mediated proteolysis, DNA repair, androgen, G-protein coupled and NOTCH signal transduction pathways.CONCLUSION: This study shows that metastasis development after BCR is associated with a distinct transcriptional programme that can be detected in the primary tumour. Patients with NED and BCR have highly similar transcriptional profiles, suggesting that measurement of PSA on its own is a poor surrogate for lethal disease. Use of genomic testing in patients undergoing RP with an initial rise in PSA level may be useful to improve secondary therapy decision-making.
    Keywords: Prostate Cancer ; Gene Expression ; Metastasis ; Biochemical Recurrence ; Gene Functional Analysis
    ISSN: 1464-4096
    E-ISSN: 1464-410X
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  • 8
    In: BJU International, November 2019, Vol.124(5), pp.719-721
    ISSN: 1464-4096
    E-ISSN: 1464-410X
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  • 9
    Language: English
    In: International journal of cancer, 01 October 2018, Vol.143(7), pp.1764-1773
    Description: Urachal cancer (UrC) is a rare but aggressive malignancy often diagnosed in advanced stages requiring systemic treatment. Although cytotoxic chemotherapy is of limited effectiveness, prospective clinical studies can hardly be conducted. Targeted therapeutic treatment approaches and potentially immunotherapy...
    Keywords: Colorectal Cancer ; Molecular Genetics ; Targeted Therapy ; Urachal Cancer ; Urothelial Carcinoma
    ISSN: 00207136
    E-ISSN: 1097-0215
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  • 10
    In: Journal of Magnetic Resonance Imaging, September 2017, Vol.46(3), pp.861-869
    Description: Byline: Shirin Sabouri, Ladan Fazli, Silvia D. Chang, Richard Savdie, Edward C. Jones, S. Larry Goldenberg, Peter C. Black, Piotr Kozlowski Keywords: prostate; prostatic luminal space; MR T.sub.2 mapping Purpose To determine the relationship between parameters measured from luminal water imaging (LWI), a new magnetic resonance imaging (MRI) T.sub.2 mapping technique, and the corresponding tissue composition in prostate. Materials and Methods In all, 17 patients with prostate cancer were examined with a 3D multiecho spin echo sequence at 3T prior to undergoing radical prostatectomy. Maps of seven MR parameters, called N, T.sub.2-short, T.sub.2-long, A.sub.short, A.sub.long, geometric mean T.sub.2 time (gmT.sub.2), and luminal water fraction (LWF), were generated using nonnegative least squares (NNLS) analysis of the T.sub.2 decay curves. MR parametric maps were correlated to digitized whole-mount histology sections. Percentage area of tissue components, including luminal space, nuclei, and cytoplasm plus stroma, was measured on the histology sections by using color-based image segmentation. Spearman's rank correlation test was used to evaluate the correlation between MR parameters and the corresponding tissue components, with particular attention paid to the correlation between LWF and percentage area of luminal space. Results N, T.sub.2-short, A.sub.long, gmT.sub.2, and LWF showed significant correlation (P 〈 0.05) with percentage area of luminal space and stroma plus cytoplasm. T.sub.2-short and gmT.sub.2 also showed significant correlation (P 〈 0.05) with percentage area of nuclei. Overall, the strongest correlation was observed between LWF and luminal space (Spearman's coefficient of rank correlation=0.75, P 〈 0.001). Conclusion Results of this study show that LWF measured with MRI is strongly correlated with the fractional amount of luminal space in prostatic tissue. This result suggests that LWI can potentially be applied for evaluation of prostatic diseases in which the extent of luminal space differs between normal and abnormal tissues. Level of Evidence: 1 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2017;46:861-869
    Keywords: Prostate ; Prostatic Luminal Space ; Mr T 2 Mapping
    ISSN: 1053-1807
    E-ISSN: 1522-2586
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