ABSTRACT
BACKGROUND: A lack of consensus exists amongst national guidelines regarding who should be investigated for haematuria. Type of haematuria and age-specific thresholds are frequently used to guide referral for the investigation of haematuria. OBJECTIVES: To develop and externally validate the haematuria cancer risk score (HCRS) to improve patient selection for the investigation of haematuria. METHODS: Development cohort comprise of 3539 prospectively recruited patients recruited at 40 UK hospitals (DETECT 1; ClinicalTrials.gov: NCT02676180) and validation cohort comprise of 656 Swiss patients. All patients were aged >18 years and referred to hospital for the evaluation of visible and nonvisible haematuria. Sensitivity and specificity of the HCRS in the validation cohort were derived from a cut-off identified from the discovery cohort. RESULTS: Patient age, gender, type of haematuria and smoking history were used to develop the HCRS. HCRS validation achieves good discrimination (AUC 0.835; 95% CI: 0.789-0.880) and calibration (calibration slope = 1.215) with no significant overfitting (P = 0.151). The HCRS detected 11.4% (n = 8) more cancers which would be missed by UK National Institute for Health and Clinical Excellence guidelines. The American Urological Association guidelines would identify all cancers with a specificity of 12.6% compared to 30.5% achieved by the HCRS. All patients with upper tract cancers would have been identified. CONCLUSION: The HCRS offers good discriminatory accuracy which is superior to existing guidelines. The simplicity of the model would facilitate adoption and improve patient and physician decision-making.
Subject(s)
Hematuria/etiology , Risk Assessment , Urinary Bladder Neoplasms/diagnosis , Adolescent , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Prospective Studies , Reproducibility of Results , Risk Assessment/methods , Risk Factors , Sensitivity and Specificity , Smoking/adverse effects , Urinary Bladder Neoplasms/complications , Urinary Bladder Neoplasms/etiology , Young AdultABSTRACT
Amplification and overexpression of the E2F3 gene at 6p22 in human bladder cancer is associated with increased tumour stage, grade and proliferation index, and in prostate cancer E2F3 overexpression is linked to tumour aggressiveness. We first used small interfering RNA technology to confirm the potential importance of E2F3 overexpression in bladder cancer development. Knockdown of E2F3 expression in bladder cells containing the 6p22 amplicon strongly reduced the extent of bromodeoxyuridine (BrdU) incorporation and the rate of cellular proliferation. In contrast, knockdown of CDKAL1/FLJ20342, another proposed oncogene, from this amplicon had no effect. Expression cDNA microarray analysis on bladder cancer cells following E2F3 knockdown was then used to identify genes regulated by E2F3, leading to the identification of known E2F3 targets such as Cyclin A and CDC2 and novel targets including pituitary tumour transforming gene 1, Polo-like kinase 1 (PLK1) and Caveolin-2. For both bladder and prostate cancer, we have proposed that E2F3 protein overexpression may cooperate with removal of the E2F inhibitor retinoblastoma tumor suppressor protein (pRB) to drive cellular proliferation. In support of this model, we found that ectopic expression of E2F3a enhanced the BrdU incorporation, a marker of cellular proliferation rate, of prostate cancer DU145 cells, which lack pRB, but had no effect on the proliferation rate of PC3 prostate cancer cells that express wild-type pRB. BrdU incorporation in PC3 cells could, however, be increased by overexpressing E2F3a in cells depleted of pRB. When taken together, these observations indicate that E2F3 levels have a critical role in modifying cellular proliferation rate in human bladder and prostate cancer.
