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|Innovations in bladder cancer|
Congress Organizer/Chairman: Prof. PF Bassi, Chairman Department of Urology, Catholic University Medical School, University Hospital "A. Gemelli"
Auditorium Centro Congressi Europa, Universita Cattlolica del Sacro Cuore, Facolta de medicina e Chirurgia "A. Gemelli"
Some of the best minds in Europe specialising in the field of uro-oncology collected together in Rome for a comprehensive look at innovations in the field of bladder cancer research.
2. Newer non-invasive diagnostic tools in bladder cancer
4 .Markers of recurrence and progression Prof. Fred Witjes Radboud UMC Nijmegen, the Netherlands; Innovations in Urology: Bladder cancer Rome; December 2, 2005
Dr. Sica’s presentation focused on new, improved techniques in diagnostics which will hopefully lead to ways of lessening the costliness of a lifetime of cystoscopies and follow ups and the anxiety this brings for people with TCC. The goals are to define invasiveness and predict response, saving time and cost by tailoring individual treatments most likely to be effective.
There are at least 3 ways to look at markers:
Dr. Sica talked covered advances in the field of proteonomics - the study of tissue proteins and body fluids. Whereas traditional biology deals with a single gene or protein of interest, the new, theoretical biology analyses a set of genes (the genome) or proteins (the proteome). The proteome is the group of proteins that are encoded by the genome and expressed in the same biological environment.
Ultimately we are looking for a panel of markers; more than one is needed to make testing reliable. Single markers give insufficient information on which to base individual treatment decisions.
Genetic studies being done today are attempting to identify the spectrum of genetic changes that occur during the transformation from normal tissue to cancerous tissue, and to clarify the natural history of bladder tumors with different clinical outcomes. Several known oncogenes and tumour suppressor genes are mutated in TCC. These include genes encoding several key G1 checkpoint proteins (p16, p14ARF, Rb, p53, cyclin D1). Whole genome analysis has been carried out by comparative genomic hybridization;
What can we do now?
Existing tissue collections and archival resources should be used to their full potential and this will require appropriate funding for coordinating mechanisms.
What can we start doing now?
What we already know:
•Growth factors and their receptors (tyrosinkinase [TKI] receptor)
EGF-R is a member of the TKI family, is over-expressed in 81% of primary bladder cancers and in 67% of metastases. Expression is correlated with stage, grade and survival.
HER2/neu over-expression in the development of muscle-invasive transitional cell carcinoma of the bladder - HER2 is a member of the tyrosine kinase family and encodes a 185-kDa transmembrane protein. HER2 is over-expressed in 81% of primary bladder cancers and in 67% of metastases.
Angiogenic factors elevated in the urine of TCC survivors:
Cytokines are signalling molecules contributing to the inflammatory response; they protect the body from pathogens and other environmental factors
IL-8 is a leukocyte chemo-attractant and induces angiogenesis. Sources of IL-8 include transitional epithelial cells, endothelial cells, mast cells, neutrophils, T cells, macrophages.
IL-4 induces the activation and differentiation of B cells; inhibits macrophage activation and may be involved in cancer formation; IL-4 gene intron-3 polymorphism is associated with TCC.
E-cadherin - Abnormal expression of E-cadherin has been associated with more rapid progression and reduced survival. The soluble form (sE-cadherin, 80kDa) is elevated in TCC [among other tumors] and is found in both serum and urine.
Uroplakin II is a membrane protein which is expressed in transitional cell carcinoma and associated with differentiation/grade and seems to be useful for detection of micro-metastases
BLCA 4 – This urine marker dialogues with IL-8 NS IL-1; has been shown to be a tumor anti-coagulant
Cytokeratin 20 (CK20) is a protein which is specifically expressed in epithelial cells of the urinary and gastrointestinal tract. CK-20 immunocytology is more sensitive than standard cytology in the detection of TCC, particularly of Stage pT1, grade 2, and grade 3 tumors.
Fascin 1 -a protein which binds actin microfilaments; an association with increased invasiveness has been found. This is a very new marker with limited studies to date, but it is associated with invasiveness.
Survivin - a unique member of the inhibitor of apoptosis (IAP) protein family. Survivin is highly expressed in urine but is undetectable in non-malignant tissues, suggesting a potential role in tumor genesis.
Major proteins that are either up or down-regulated in TCC/bladder cancer:
Down-regulated in tissue:
Diagnostic tools - what would we like to have?
On the horizon for urinary markers:
*voided urinary cytology, ** point of care; for an explanation of sensitivity and specificity go here
-Urine marker tests can be difficult to interpret if there are co-existing conditions such as stones, inflammation and infection.
A suggestion for current best practice might be:
3. ISUP-WHO tumor classification: really the gold standard?
Aim: to develop a universally acceptable classification system for bladder neoplasia that could be used effectively by urologists, pathologists and oncologists.
WHO-ISUP Consensus Classification (I)
* Option exists to add comment as to the presence of marked anaplasia
Non-invasive urothelial tumours -Definitions
*papillary neoplasm of low malignant potential
Open problems of WHO-ISUP Classification
______Papillary tumors may show heterogeneity (dissimilarites) of grade. It remains to be defined what percentage (if any) is minimally needed to place tumors in a higher category when the highest grade is focal.
______The distinction on transurethral resection of muscolaris mucosae from muscolaris propria invasion may occasionally be difficult.
______Do PNLMP and low grade papillary carcinoma have significative differences in clinical outcome ?
Experts have now published a simple calculator that can be downloaded free from the EORTC web site: www.eortc.be/tools/bladdercalculator/default.htm The following presentation discusses the details:
How to define risk groups with prognostic factors
Predicting recurrence and progression in stage Ta-T1 bladder cancer: the use of the EORTC risk tables Richard Sylvester. (EORTC Data Center, Brussels, Belgium, Ad van der Meijden, Wim Oosterlinck, Fred Witjes, KarlHeinz Kurth (for the EORTC GU Tract Cancer Group) PubMed
Factors of recurrence differ from that of progression; CIS increases risk of progression.
Probability of Recurrence
Probability of Progression
T1 G3 Tumors
Conclusions EORTC risk tables
Remarks: pT1 substaging and staging error
Staging error in high risk SBC after cystectomy (J Urol 166, 490, 2001)
A second look TUR in T1 TCC: why (Jakse et al, Eur Urol 2004)
The main issue in high risk superficial disease is that the natural (untreated) history over 3 years will see a greater than 70% recurrence rate, and a 30-50% risk of progression in cases of CIS.
The fate of progressive patients
74 progressive pts. matched to a group of 89 primary invasive pts.
The “BCG meta-analysis”; Death due to bladder cancer in case of progression is 64% in 2.5 years Sylvester et al, J Urol 2002
Potential progression markers for EORTC CIS study
p53/E-Cadherin Immunohistochemistry in Bladder Cancer
Take home messages:
|Last Updated ( Sunday, 15 June 2008 )|