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CP1081584-1

CP1081584-1. Incidence of Cholangiocarcinoma. Cumulative incidence of cholangiocarcinoma (%). Years since PSC diagnosis. CP1042831-1. Relationship Between the Natural History of a Disease and Effective Screening. Ineffective therapy. Biologic onset. Early clinical diagnosis.

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CP1081584-1

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  1. CP1081584-1

  2. Incidence of Cholangiocarcinoma Cumulative incidence ofcholangiocarcinoma (%) Years since PSC diagnosis CP1042831-1

  3. Relationship Between the Natural History of a Disease and Effective Screening Ineffectivetherapy Biologiconset Earlyclinicaldiagnosis Usualclinicaldiagnosis Effectivetherapy CP1164484-1

  4. CP1081584-2

  5. ROC for CA 19-9 in Identifying Cholangiocarcinoma in PSC 41 128 100 180 Sensitivity 200 CA 19-9>100 Sensitivity 75% Specificity 80% Chalasani et al:Hepatology 31:7-11, 2000 1-specificity CP925977-1

  6. Performance for Routine Cytology Interpretation Harewood et al Am J Gastro, 2004

  7. Advances in Diagnostic Modalities

  8. Digital Image Analysis Improves the Diagnostic Yield of Brush Cytology • Feulgen dye to stain DNA • Employs computer-assisted technology to assess DNA content of cells • Quantitates ploidy at the single cell level • Aneuploidy = malignancy

  9. Fluorescent In Situ Hybridization (FISH) • Fluorescent hybridization oligonucleotides • chromosome 3 • chromosome 17 • chromosome 7 • locus 9p21

  10. Prospective Study of DIA vsBrush Cytology • Consecutive patients with bile duct strictures (n=97) • Classification of benign vs malignant • Surgical specimens • Follow-up CP1037610-6

  11. Sensitivity and Specific of Cytology, DIA, and FISH for Malignant Biliary Strictures Percent Cytology DIA FISH N=130, 69 malignant and 61 benign

  12. FISH • Polysomy of 2 or more chromosomes = cholangiocarcinoma • Trisomy of chromosome 7 can be observed without cholangiocarcinoma - 50% no cancer - ? Early marker of neoplasia

  13. CEP7/EGFR Probe PROBES CEP7=Green EGFR=Red

  14. Hypothesis EGFR amplification Trisomy 7 EGFRinhibition Growthadvance Cancer CP1164484-3

  15. PSC Screening? ERCP with cytology for FISH (1-2 years) Trisomy 7 EGFR Inhibitor ? Chemoprevention

  16. Position Emission Tomography(PET) • ? Cholangiocarcinoma

  17. Utility of PET scanning in cholangiocarcinoma (n=21) • Primary tumor • sensitivity 92% • specificity 93% • Metastases • sensitivity 15% Kluge, et al, Hepatololgy, 2001

  18. Initial Diagnosis of Symptomatic PSC PET scan ? • Brushings/biopsies • DIA • FISH PSC Serum CA 19-9 CP1037610-3

  19. Evaluation of Indeterminate Stricture Pathology (DIA, FISH) Postive Negative CA 19-9 >100 U/mL Treat as malignant <100 U/mL MRI + feredex Suspicious Negative PET CP1037610-4

  20. Cholangiocarcinoma • Incidence • Risk factors • Diagnosis • Staging • Treatment

  21. Submucosal tumor Submucosal tumor Staging Cholangiocarcinoma Periductal Extension CP1041236-2

  22. Staging of Cholangiocarcinoma • MR studies • Cholangiogram • Feredex • Angiogram • EUS • FNA of lymph nodes CP1037610-1

  23. Feredex MR • Feredex • Fe based • Kupffer cells •  signal on MR • Allows visualizaton of bile duct tumors CP1037610-5

  24. Endoscope Lymph node metastasis EUS and Staging Cholangiocarcinoma CP1041236-1

  25. Lymph Node

  26. Utility of EUS in the Staging of Cholangiocarcinoma • 30 patients • Operative candidates • Negative CT scans for nodal metastases • EUS with FNA • Positive in 17% CP1037610-2

  27. Cholangiocarcinoma • Incidence • Risk factors • Diagnosis • Staging • Treatment

  28. Surgical Resction for Cholangiocarcinoma

  29. Survival Following Resection for Perihilar Cholangiocarcinoma Survival rate (%) Rea et al: Archives of Surgery 139:54, 2004 Time (yr) CP1156855-2

  30. Liver Transplantation for Cholangiocarcinoma

  31. Liver Transplantation for Hepatobiliary Malignancy in PSC No HB-malignancy n=192 HCC n=9 GBC Survivalprobability n=4 CCA n=17 Brandsaeter et al: J Hept 40:815, 2004 Years post-transplantation CP1156855-1

  32. Criteria for LTx • Unresectable, perihilar • Mass if present <3 cm • If PSC, any ductal tumor <3 cm CP1041236-3

  33. Diagnosis of Cholangiocarcinoma • Cytology - routine cytology, positive DIA, or positive FISH • Malignant appearing stricture with CA-19 > 100 U/L in the absence of cholangitis

  34. Treatment Protocol External beam radiation therapy Brachytherapy Capecitabine Abdominal exploration for staging Liver transplantation CP1084287-3

  35. RESULTS 1993 - 2004 71 patients 4 deaths Irradiation + 5-FU 4 disease progression 6 waiting for lap 57 staging operation 14 positive 5 awaiting transplantation 38 liver transplantation 7 deaths 31 Alive CP1084287-6

  36. Patient Demographics at Enrollment into Protocol

  37. PATIENT SURVIVAL AFTER TRANSPLANTATION

  38. Patient Survival OLT Survival (%) No OLT Years CP1084287-7

  39. Cause of Death • Recurrent CCA 4 • Sudden death 1 • Complications following LDLT 2 • HAT, retransplant, bile leak, sepsis, MOF • Bile leak, sepsis CP1084287-8

  40. Rationale for Screening PSC Patients for Cholangiocarcinoma Ineffectivetherapy Biologiconset Early Dx:ERCP +RC/FISH/DIA Usualclinicaldiagnosis ? EGFRinhibition Liver Tx CP1164484-2

  41. CP1081584-4

  42. North Dakota Beer Cooler

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