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Introduction

Comparative quantitative evaluation of the XIAP, survivin & Ki67 transcript levels in urine & tissue samples of bladder cancer patients. Introduction. Bladder cancer (BCa)- 5th most common cancer in European men & 6th leading cause of death

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Introduction

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  1. Comparative quantitative evaluation of the XIAP, survivin & Ki67 transcript levels in urine & tissue samples of bladder cancer patients

  2. Introduction • Bladder cancer (BCa)- 5th most common cancer in European men & 6th leading cause of death • Cystoscopy & urine cytology - current gold standards for diagnosis & surveillance of BCa • Ideal tumor marker for non-invasive diagnostics & surveillance does not yet exist

  3. Introduction • Survivin inhibitor of apoptosis protein (IAP) that is selectively over-expressed in most human malignancies • Objectives • determine suitability of survivin as diagnostic, surveillance (and prognostic) marker of BCa • compare the utility of survivin to other potential tumor markers e.g. Ki67 and XIAP

  4. Materials & Methods • Prospective study • Single, tertiary level referral centre • January - June 2006 • Inclusion criteria • patients undergoing transurethral resection (TUR) for newly diagnosed BCa, recurrent BCa & cystoscopically suspicious bladder lesions

  5. Materials & Methods • Exclusion criteria • Patients with PCa, IDC, UTI • Controls • BPH patients • Cystitis patients • Healthy volunteers

  6. Materials & Methods • BCa patients • Pre-operative urine sample • Intra-operative tumor tissue & “normal appearing” bladder mucosa • Post-operative urine sample (1 POD) • Above repeated for every session of TUR • Controls • 1 urine sample from each

  7. Materials & Methods • Quantitative evaluation of urinary & tissue levels of survivin, XIAP & Ki67 • Normalized ratios of survivin, XIAP & Ki67 correlated with clinicopathological data

  8. Results • Reference genes :HPRT & TBP • Negative correlation between reference gene expression & urinary contamination by RBCs & WBCs

  9. BCa patients 65 recruited 6 pts with both BCa & Pca, excluded from analysis > 59 pts analysed Age (median)= 69yrs (34 – 89) M:F= 39: 20 (66.1% : 33.9%) Newly dx: BCa recurr= 54: 5 (91.5% : 8.5%) PSA (median; 36 pts)= 0.90 (0.16 – 12.54)

  10. BCa patients Stage @ diagnosis (59) • No tumour (11) 18.6% • Superficial (38) = Ta+T1 64.5% • Invasive (10) = T2 16.9% Grade @ diagnosis (59) • No tumour (11) 18.6% • Low (14) = G1 23.8% • High (34) = G2+G3 57.6%

  11. benign atypia low high NA 9 (15.3%) 2 (3.3%) 9 (15.3%) 18 (30.5%) 21 (35.6%) BCa patients • cis • Pos: neg= 5: 54 (8.5% : 91.5%) • All with cis harbour high grade (G2/ G3) disease as well • Cytology • Sensitivity= 65.2%; Specificity= 80.0% • PPV= 83.3%; NPV= 60.0%

  12. BCa patients • 59 primary TURBT 42 second op (33 sec TUR, 9 cystec) 8 third op (6 tertiary TUR, 2 cystec)

  13. BPH Cystitis Healthy 53 13 27 68 yrs (52-85) 64 yrs (19-85) 31 yrs (18-59) PSA median 2.9 (0.3 – 33.9) M : F 3 (23.1%) :10 (76.9%) M : F 7 (25.9 %) :20 (74.1 %) Controls

  14. Clinical diagnosis Ki67/ HPRT Ki67/ TBP XIAP/ HPRT XIAP/ TBP SVV/ HPRT SVV/ TBP Bca(48) (positive histo) 0.82 1.96 28.33 47.25 1.50 2.59 No tumor (11) (negative histo) 0.52 1.73 14.74 37.65 1.11 1.23 BPH(53) 0.40 1.02 19.29 45.65 1.08 2.29 Cystitis (13) 0.79 0.31 73.98 42.44 1.35 0.56 Healthy (27)  0.00 0.00 0.00 0.00 0.00 0.14 Tumor markers in urine of BCa patients & controls  For healthy controls the absent values were substituted by zero Median values presented

  15. Ki67in urine of BCa patients & controls

  16. XIAP in urine of BCa patients & controls

  17. Survivin in urine of BCa patients & controls

  18. BT stage @ pri TUR (59) Ki67/ HPRT Ki67/ TBP XIAP/ HPRT XIAP/ TBP SVV/ HPRT SVV/ TBP No tumor (11) 0.52 1.73 14.74 37.65 1.11 1.23 Superficial (38) 0.82 2.05 22.02 50.21 1.48 2.65 Invasive (10) 1.79 2.84 48.9 63.35 1.51 1.64 Tumor markers vs BCa stage Median values presented

  19. Ki67vs BCa stage

  20. XIAP vs BCa stage

  21. Survivin vs BCa stage

  22. BT grade @ pri TUR (59) Ki67/ HPRT Ki67/ TBP XIAP/ HPRT XIAP/ TBP SVV/ HPRT SVV/ TBP No tumor (11) 0.52 1.73 14.74 37.65 1.11 1.23 Low grade (14) 0.60 0.73 33.60 38.19 1.61 2.70 High grade (34) 0.91 2.18 23.35 81.29 1.20 2.34 Tumor markers vs BCa grade Median values presented

  23. Ki67 vs BCa grade

  24. XIAP vs BCa grade

  25. Survivin vs BCa grade

  26. BT paired urine samples (33) Ki67/ HPRT Ki67/ TBP XIAP/ HPRT XIAP/ TBP SVV/ HPRT SVV/ TBP Op1 0.69 1.81 21.63 55.95 1.34 2.57 Op2 0 0 25.19 83.45 0.95 2.25 Tumor markers in urine at primary & secondary TURBT Median values presented

  27. Ki67 in urine at primary & secondary TURBT

  28. XIAP in urine at primary & secondary TURBT

  29. Survivin in urine at primary & secondary TURBT

  30. Unpaired tissue samples Ki67/ HPRT Ki67/ TBP XIAP/ HPRT XIAP/ TBP SVV/ HPRT SVV/ TBP Tumor tissue (26) 1.55 5.08 6.13 13.98 0.41 1.03 Tumor free (27) 1.24 1.23 8.25 11.92 0.26 0.35 Tumor markers for unpaired tissue samples Median values presented

  31. Ki67for unpaired tissue samples

  32. XIAP for unpaired tissue samples

  33. Survivinfor unpaired tissue samples

  34. Unpaired tissue samples Ki67/ HPRT Ki67/ TBP XIAP/ HPRT XIAP/ TBP SVV/ HPRT SVV/ TBP Median Tu / Median Tf 1.25 4.13 0.74 1.17 1.57 2.94 Median Tu / Median Tf for unpaired tissue samples

  35. Paired tissue samples (13) Ki67/ HPRT Ki67/ TBP XIAP/ HPRT XIAP/ TBP SVV/ HPRT SVV/ TBP Tumor tissue 1,73 5,99 6,42 13,61 0,53 1,11 Tumor free 1,52 2,01 8,22 14,26 0,35 0,41 Tumor markers for paired tissue samples Median values presented

  36. Ki67 for paired tissue samples

  37. XIAP for paired tissue samples

  38. Survivin for paired tissue samples

  39. Paired tissue samples (13) Ki67/ HPRT Ki67/ TBP XIAP/ HPRT XIAP/ TBP SVV/ HPRT SVV/ TBP Ratio 3.32 3.39 0.72 0.71 1.67 2.66 >1 8 (61.5%) 10 (76.9%) 3 (23.1%) 6 (46.2%) 8 (61.5%) 8 (61.5%) <1 5 (38.5%) 3 (23.1%) 10 (76.6%) 7 (53.8%) 5 (38.5%) 5 (38.5%) Ratio Tu / Tf for paired tissue samples Median values presented

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