cp1081584-1. incidence of cholangiocarcinoma cumulative incidence of cholangiocarcinoma (%) years...

CP1081584-1

Incidence of CholangiocarcinomaIncidence of CholangiocarcinomaC

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Years since PSC diagnosisYears since PSC diagnosisCP1042831-1

0.0

2.5

5.0

7.5

10.0

0 2 4 6

Relationship Between the Natural History of a Disease and Effective Screening

Relationship Between the Natural History of a Disease and Effective Screening

CP1164484-1CP1164484-1

BiologicBiologiconsetonset

BiologicBiologiconsetonset

EarlyEarlyclinicalclinical

diagnosisdiagnosis

EarlyEarlyclinicalclinical

diagnosisdiagnosis

UsualUsualclinicalclinical

diagnosisdiagnosis

UsualUsualclinicalclinical

diagnosisdiagnosis

IneffectiveIneffectivetherapytherapy

IneffectiveIneffectivetherapytherapy

EffectiveEffectivetherapytherapy

EffectiveEffectivetherapytherapy

CP1081584-2

ROC for CA 19-9 in Identifying Cholangiocarcinoma in PSC

ROC for CA 19-9 in Identifying Cholangiocarcinoma in PSC

SensitivitySensitivity

0.0

0.2

0.4

0.6

0.8

1.0

0.0 0.2 0.4 0.6 0.8 1.0

1-specificity1-specificity

CA 19-9>100CA 19-9>100SensitivitySensitivity 75%75%SpecificitySpecificity 80%80%

CP925977-1

Chalasani et al:Chalasani et al:Hepatology 31:7-11, 2000Hepatology 31:7-11, 2000

200200

180180

128128 100100

4141

Performance for Routine Cytology Interpretation

Performance for Routine Cytology Interpretation

0%

20%

40%

60%

80%

100%

Sensitivity Specificity Accuracy Equivocal

Initial

Path.#1Path.#2

0%

20%

40%

60%

80%

100%

Sensitivity Specificity Accuracy Equivocal

Initial

Path.#1Path.#2

Harewood et al Am J Gastro, 2004Harewood et al Am J Gastro, 2004

CP901472- 8

Advances in Diagnostic ModalitiesAdvances in Diagnostic Modalities

Digital Image Analysis Improves the Diagnostic Yield of Brush CytologyDigital 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

• Feulgen dye to stain DNA• Employs computer-assisted

technology to assess DNA content of cells

• Quantitates ploidy at the single cell level

• Aneuploidy = malignancy

Fluorescent In Situ Hybridization (FISH)Fluorescent In Situ Hybridization (FISH)

• Fluorescent hybridization oligonucleotides

chromosome 3chromosome 17chromosome 7locus 9p21

• Fluorescent hybridization oligonucleotides

chromosome 3chromosome 17chromosome 7locus 9p21

Prospective Study of DIA vsBrush Cytology

Prospective Study of DIA vsBrush Cytology

CP1037610-6

• Consecutive patients with bile duct strictures (n=97)

• Classification of benign vs malignant

Surgical specimens

Follow-up

• Consecutive patients with bile duct strictures (n=97)

• Classification of benign vs malignant

Surgical specimens

Follow-up

0

25

50

75

100sensitivity

specificity

CytologyCytology DIADIA FISHFISH

Per

cen

tP

erce

nt

N=130, 69 malignant and 61 benign

Sensitivity and Specific of Cytology, DIA, and FISHSensitivity and Specific of Cytology, DIA, and FISH for Malignant Biliary Stricturesfor Malignant Biliary Strictures

FISH

• Polysomy of 2 or more chromosomes = cholangiocarcinoma• Trisomy of chromosome 7 can be

observed without cholangiocarcinoma - 50% no cancer

- ? Early marker of neoplasia

CEP7/EGFR ProbeCEP7/EGFR Probe

CEP7=GreenEGFR=Red

PROBES

HypothesisHypothesis

CP1164484-3CP1164484-3

Trisomy 7Trisomy 7 EGFR amplificationEGFR amplification

GrowthadvanceGrowthadvance

CancerCancer

EGFRinhibition

EGFRinhibition

PSC Screening?PSC Screening?

ERCP with cytology for FISH (1-2 years)

Trisomy 7

? Chemoprevention

EGFR Inhibitor

Position Emission Tomography(PET)

• ? Cholangiocarcinoma

Utility of PET scanning in cholangiocarcinoma (n=21)Utility of PET scanning in

cholangiocarcinoma (n=21)

• Primary tumorsensitivity 92%specificity 93%

• Metastases sensitivity 15%

• Primary tumorsensitivity 92%specificity 93%

• Metastases sensitivity 15%

Kluge, et al, Hepatololgy, 2001Kluge, et al, Hepatololgy, 2001

Initial Diagnosis of Symptomatic PSCInitial Diagnosis of Symptomatic PSC

CP1037610-3

Brushings/biopsies• DIA• FISH

Brushings/biopsies• DIA• FISH

PET scanPET scan

Serum CA 19-9Serum CA 19-9

PSCPSC

??

Evaluation of Indeterminate StrictureEvaluation of Indeterminate Stricture

CP1037610-4

Pathology (DIA, FISH)Pathology (DIA, FISH)

PostivePostive NegativeNegative

CA 19-9CA 19-9

>100 U/mLTreat as malignant

>100 U/mLTreat as malignant

<100 U/mL<100 U/mL

MRI + feredexMRI + feredex

SuspiciousSuspicious NegativeNegative

PETPET

CholangiocarcinomaCholangiocarcinoma

• Incidence• Risk factors• Diagnosis• Staging• Treatment

• Incidence• Risk factors• Diagnosis• Staging• Treatment

Staging CholangiocarcinomaPeriductal ExtensionStaging CholangiocarcinomaPeriductal Extension

CP1041236-2

Submucosal tumor

Submucosal tumor

Staging of CholangiocarcinomaStaging of Cholangiocarcinoma

CP1037610-1

MR studies

• Cholangiogram

• Feredex

• Angiogram

EUS

• FNA of lymph nodes

MR studies

• Cholangiogram

• Feredex

• Angiogram

EUS

• FNA of lymph nodes

Feredex MRFeredex MR

CP1037610-5

Feredex

•Fe based

•Kupffer cells

signal on MR

Allows visualizaton of bile duct tumors

Feredex

•Fe based

•Kupffer cells

signal on MR

Allows visualizaton of bile duct tumors

Endoscope

CP1041236-1

EUS and Staging CholangiocarcinomaEUS and Staging Cholangiocarcinoma

Lymph node metastasis

Lymph Node

Utility of EUS in the Staging of Cholangiocarcinoma

Utility of EUS in the Staging of Cholangiocarcinoma

CP1037610-2

30 patients

• Operative candidates

• Negative CT scans for nodal metastases

EUS with FNA

• Positive in 17%

30 patients

• Operative candidates

• Negative CT scans for nodal metastases

EUS with FNA

• Positive in 17%

CholangiocarcinomaCholangiocarcinoma

• Incidence• Risk factors• Diagnosis• Staging• Treatment

• Incidence• Risk factors• Diagnosis• Staging• Treatment

Surgical Resction for Cholangiocarcinoma

0

20

40

60

80

100

0 1 2 3 4 5 6 7

Survival Following Resection for Perihilar Cholangiocarcinoma

Survival Following Resection for Perihilar Cholangiocarcinoma

CP1156855-2CP1156855-2

Survival rate (%)Survival rate (%)

Time (yr)Time (yr)Rea et al: Archives of Surgery 139:54, 2004Rea et al: Archives of Surgery 139:54, 2004

Liver Transplantation for Cholangiocarcinoma

0.0

0.2

0.4

0.6

0.8

1.0

0 1 2 3 4 5 6 7 8 9 10 11 12 13

Liver Transplantation for Hepatobiliary Malignancy in PSC

Liver Transplantation for Hepatobiliary Malignancy in PSC

CP1156855-1CP1156855-1

Survivalprobability

Survivalprobability

Years post-transplantationYears post-transplantation

No HB-malignancyNo HB-malignancy

HCCHCC

GBCGBC

CCACCA

n=192n=192

n=9n=9

n=4n=4

n=17n=17

Brandsaeter et al: J Hept 40:815, 2004Brandsaeter et al: J Hept 40:815, 2004

CP1041236-3

Criteria for LTx

•Unresectable, perihilar

•Mass if present <3 cm

• If PSC, any ductal tumor <3 cm

Diagnosis of CholangiocarcinomaDiagnosis of Cholangiocarcinoma

• Cytology - routine cytology, positive DIA, or positive FISH

• Malignant appearing stricture with CA-19 > 100 U/L in the absence of cholangitis

• Cytology - routine cytology, positive DIA, or positive FISH

• Malignant appearing stricture with CA-19 > 100 U/L in the absence of cholangitis

CP1084287-3CP1084287-3

Treatment ProtocolTreatment Protocol

External beam radiation therapy

Brachytherapy

Capecitabine

Abdominal exploration for staging

Liver transplantation

External beam radiation therapy

Brachytherapy

Capecitabine

Abdominal exploration for staging

Liver transplantation

CP1084287-6CP1084287-6CP1084287-6CP1084287-6

RESULTS 1993 - 2004RESULTS 1993 - 2004RESULTS 1993 - 2004RESULTS 1993 - 200471 patients71 patients71 patients71 patients

4 deaths4 deaths4 deaths4 deaths4 disease progression4 disease progression4 disease progression4 disease progression

5 awaiting transplantation5 awaiting transplantation5 awaiting transplantation5 awaiting transplantation

57 staging 57 staging operationoperation57 staging 57 staging operationoperation 14 positive14 positive14 positive14 positive

38 liver 38 liver transplantationtransplantation

38 liver 38 liver transplantationtransplantation

Irradiation Irradiation + 5-FU+ 5-FU

Irradiation Irradiation + 5-FU+ 5-FU

7 deaths 7 deaths 7 deaths 7 deaths

6 waiting for lap 6 waiting for lap 6 waiting for lap 6 waiting for lap

31 Alive31 Alive 31 Alive31 Alive

Patient Demographics at Enrollment into Protocol

Characteristic Transplanted(n=38)

(+) staging lap.(n=14)

Age 45 45

Male: Female 28:10 8:6

PSC 29 (76%) 11 (78%)

IBD 10 (26%) 7 (50%)

Cirrhosis 12 (31%) 6 (43%)

CA 19-9 100 13 (34%) 6 (43%)

CA 19-9 >100 3 (8%) 4 (14%)

PATIENT SURVIVAL AFTER TRANSPLANTATION

PATIENT SURVIVAL AFTER TRANSPLANTATION

0

20

40

60

80

100

0 1 2 3 4 5 6 7

Year

Percent Survival

CCA

0

20

40

60

80

100

0 1 2 3 4 5 6 7

Year

Percent Survival

CCA

CP1084287-7CP1084287-7

Patient SurvivalPatient Survival

Survival(%)

Survival(%)

YearsYears

OLTOLT

No OLTNo OLT0

20

40

60

80

100

0 2 4 6 8 10

CP1084287-8CP1084287-8

Cause of DeathCause of Death

Recurrent CCA 4

Sudden death 1

Complications following LDLT 2

HAT, retransplant, bile leak, sepsis, MOF

Bile leak, sepsis

Recurrent CCA 4

Sudden death 1

Complications following LDLT 2

HAT, retransplant, bile leak, sepsis, MOF

Bile leak, sepsis

Rationale for Screening PSC Patients for Cholangiocarcinoma

Rationale for Screening PSC Patients for Cholangiocarcinoma

CP1164484-2CP1164484-2

BiologicBiologiconsetonset

BiologicBiologiconsetonset

Early Dx:Early Dx:ERCP +ERCP +

RC/FISH/DIARC/FISH/DIA

Early Dx:Early Dx:ERCP +ERCP +

RC/FISH/DIARC/FISH/DIA

UsualUsualclinicalclinical

diagnosisdiagnosis

UsualUsualclinicalclinical

diagnosisdiagnosis

IneffectiveIneffectivetherapytherapy

IneffectiveIneffectivetherapytherapy

? EGFR? EGFRinhibitioninhibitionLiver TxLiver Tx

? EGFR? EGFRinhibitioninhibitionLiver TxLiver Tx

CP1081584-4

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