Sunday May 21: Liver Cell
Cancer Research Forum
N. Kemmer;
G. Neff; S. Satiwah; v. Zacharias;
F. Weber; J. Buell; R. Giesting;
D. Russell; M. Thomas; A. Tevar; R. Shukla; S. Rudich
Introduction:
The current UNOS criteria for Liver
Transplant (LTx) gives priority to patients with
elevated serum AFP > 500 ng/ml in the absence of radiologic evidence of Liver mass. Reports have shown that
an elevated serum AFP is a poor diagnostic indicator for Hepatocellular
Carcinoma (HCC) in patients with cirrhosis. Aim: To determine if AFP level
above 500 ng/ml in the absence of a liver mass by
imaging study correlates with the presence of HCC.
Methods:
Using the UNOS database we queried
all patients transplanted in the United States between 2/02 and 10/05 based on
these criteria. The data collected included; patient demographics, clinical
information and pathological outcomes. The data was analyzed using chi-square t
– test and confirmed by logistic regression modeling.
Results:
To date twenty-three patients have
received a liver transplant. Median age (range 40 – 69), 70% Caucasian, 61%
male and a median AFP 658 ng/ml (range 504 - 7836).
Etiology of liver disease: 83% Hepatitis C infection, 9% Primary biliary cirrhosis, 4% HCV-HBV Coinfection and 4%
cryptogenic cirrhosis. Twenty-two patients received a cadaveric liver
transplant, and one received a living donor transplant. HCC was confirmed
post-transplant in only six patients (26%). There was no difference in race,
gender, etiology of liver disease or AFP level between patients with and
without HCC but a significant difference in age (59.8 for HCC pts vs. 51.3 for
Non-HCC group; p = 0.01).
Conclusion:
Majority of the patients who received
extra MELD points based on an elevated AFP did not have HCC. Older age was a
significant predictor for the presence of HCC in patients with a serum AFP
greater than 500. These results demonstrate the poor correlation of an elevated
AFP with the presence of HCC in patients without a documented liver mass.
167. Risk Factors for Primary
Hepatocellular Carcinoma in Hispanic and Asian Americans in 2000
M. Dunnigan;
C. Howell
The incidence of primary
hepatocellular carcinoma (HCC) has been increasing in the USA during the past
20 years. Both the HCC incidence and mortality rates are greater in Black,
Asian, and other race groups compared to Whites. Analyzing the Nationwide
Inpatient Sample (NIS) 2000, we found higher rates of HBV, HCV, HBV plus HCV,
and diabetes plus viral hepatitis among Black HCC cases. However, there are few
recent data regarding HCC risk factors in US Hispanics and Asians.
Goal
To determine HCC risk factors in
Asian and Hispanic HCC cases in 2000 compared to White cases. Methods. HCC
cases were identified in the NIS 2000 using ICD-CM-9 code 155.00. HCC risk
factors including HBV, HCV, alcohol (ALD), cryptogenic, cirrhosis not otherwise
specified (NOS), autoimmune hepatitis, hemochromatosis, alpha-1-AT deficiency,
Wilson’s disease, tobacco use, and diabetes (DM) were identified by ICD-9
codes. The proportion of each HCC risk among the racial groups was compared
using chi-square tests. Odds ratios (OR) and 95% confidence intervals (CI) for
each risk factor in Asian and Hispanic relative to White HCC cases was
determined by logistic regression analysis.
Results
We identified 701 White, 216 Asian
and 226 Hispanic HCC cases. Asian (61.9 ± 13.7 yr.) and Hispanic (62.3±14.0
yr.) cases were younger than White HCC cases (65.1±13.7, p<0.002 ANOVA for
both). HBV, HBV plus HCV (OR 2.5 CI 1.04-6.0), and HBV plus DM (OR 2.5 CI
1.04-6.0, p=0.03) were more common among Asian than White HCC cases (OR 8.5,
95% CI 5.2-13.9, p<0.0001), whereas ALD was less common in Asian cases (OR
0.54, CI 0.3-0.9, p=0.02). Hispanic HCC cases were more likely to have HCV (OR
1.6, CI 1.2-2.2, p=0.005), DM (OR 1.5, CI 1.1-2.1, p=0.01), cirrhosis NOS (OR
1.6, CI 1.04-2.6, p=0.01) and DM plus HCV (OR 2.1, CI 1.2-3.8, p=0.01) than
White cases. White cases were more likely to have no identified HCC risk factor
than either Asian or Hispanic cases.
Conclusion
The prevalence of HCC risk factors
varied between Hispanic, Asian, and White HCC cases in 2000. Higher rates of
viral hepatitis and concurrent HCC risk factors might account for the higher
incidence and younger age of HCC in Asian and Hispanic cases.
|
|
Asian |
Hispanic
|
White |
p value |
|
ALD |
20 (9.3%) |
43 (19.0%) |
111 (15.8%) |
0.01 |
|
HBV |
55 (25.5%) |
14 (6.2%) |
27 (3.9%) |
< 0.0001 |
|
HCV |
40 (18.5%) |
74 (32.7%) |
163 (23.3%) |
0.001 |
|
Cirrhosis NOS |
18 (8.3%) |
32 (14.1%) |
64 (9.1%) |
0.06 |
|
Cryptogenic |
17 (7.9%) |
30 (13.0%) |
66 (9.4%) |
0.13 |
|
DM |
53 (24.5%) |
72 (32.0%) |
165 (23.5%) |
0.04 |
|
No HCC Risk Factor |
74 (34.3%) |
66 (29.2%) |
303 (43.0%) |
0.0003 |
168. Survival and recurrence
after radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC)
S. Shiina;
T. Teratani; R. Tateishi;
M. Akamatsu; H. Yoshida; Y. Kondo; M. Yanase; J. Imamura; T. Ohki; S. Kondo; H. Nakagawa; R. Masuzaki; N. Yamashiki; S. Obi;
H. Yoshida; T. Kawabe; M. Omata
RFA has been widely performed for
HCC. Our randomized controlled trial demonstrated that RFA had higher survival
and lower recurrence than ethanol injection, although there was no difference
in adverse events between the two therapies (Gastroenterology, 2005;129:122).
There have not been many reports, however, on its long-term results. We
evaluated survival and recurrence after RFA.
Subjects
& Methods
Indications of RFA were; 1) unresectable lesions or refusal of surgery, 2) no
extrahepatic metastasis or vascular invasion, 3) no refractory ascites, 4) PT
> 50% and Plt > 50,000, 4) T. Bil < 3.0, 5) obtainment of informed consent. We put no
restrictions on lesion location. The subjects were 556 consecutive patients
with HCC who received RFA as the initial treatment. There were 366 males and
190 females. The age was 67.7 + 8.0 (mean + S.D.) yrs. Lesion number was 1.8 +
1.3 (1-12). Maximum lesion size was 2.68 + 1.13 (0.9-9.7) cm. Liver function
was in Child-Pugh A in 388 cases, in B in 162, and in C in 6. We performed RFA percutaneously with a cooled-tip electrode. As a general
rule, we ablated not only the tumor but also some
amount of the surrounding tissue. One to three days after RFA, CT was performed
to determine the efficacy. If there were any possible undestroyed
portions, RFA was repeated. All patients had CT and US every 4 months to find
any recurrence. We examined 20 factors (age, sex, tumor
size, tumor number, AFP, AFP-L3 & DCP before
& after RFA, histological tumor differentiation,
Alb, T. Bil, ALT, PT, Plt,
Child-Pugh class, presence of cirrhosis, HBs-Ag, HCV-Ab) to predict survival and recurrence.
Results
Survival after RFA was 96% at 1-yr,
88% at 2-yrs, 79% at 3-yrs, 69% at 4-yrs, and 55% at 5-yrs. Age, Ascites, Alb,
T. Bil, tumor size, and AFP
were significant predictive factors for survival. Overall recurrence was 20% at
1-yr, 46% at 2-yrs, 62% at 3-yrs, 69% at 4-yrs, and 74% at 5-yrs. Age, anti-HCV,
tumor size, tumor number
and AFP were significant predictive factors for overall recurrence. Local
recurrence was 1.3% at 1-yr, 3.1% at 2-yrs, and 3.5% at 3-, 4-, and 5-yrs.
Complications were encountered in 78 (4.0%) of 1930 cases. One patient died from
cerebellar bleeding on the 15th post-RFA day.
Conclusion
Although RFA achieved considerably
good survival, HCC frequently recurred after RFA. Most recurrence was
appearance of new lesions in other portions than the ablated site, which was
partly because of micro metastasis and partly because of metachronous
multicentric carcinogenesis. Strategy to prevent
recurrence separate from the treated lesion is mandatory to improve long-term
outcomes.
169. Title: Molecular Evidence
for the Neoplastic Transformation of Hepatic von-Meyenburg
Complexes
W. Ahrens; M. E. Robert; S.
Finkelstein; D. Jain
Background:
The majority of the cholangiocarcinomas in the Western world arise in an
otherwise normal liver and no precursor of these tumors
has been identified. von-Meyenburg complexes (vMC) are a common, under reported finding both in surgical
and autopsy liver specimens. The authors have previously reported cases of cholangiocarcinoma (CC) arising in a background of
cirrhosis with multiple vMC. Two cases that revealed
many vMC, a gradual transition from vMC to hyperplastic/adenomatous
lesions and finally to cholangiocarcinoma were
selected for this study. The goal was to determine if vMC
harbor genetic alterations and whether histologic progression was accompanied by progressive
accumulation of genetic alterations/mutations.
Design:
Two cases which showed many vMC and transition through hyperplastic/adenomatous
lesions to cholangiocarcinoma were analyzed. Three
separate histologically benign vMC and three foci of
CC were identified on H/E stained slides and separately microdissected
in each case under stereoscopic guidance. Aliquots of DNA were analyzed for
allelic imbalance (LOH) using PCR/electrophoresis and a panel of 20 polymorphic
microsatellite markers targeting
1p,3p,5q,9p,10q,11q,14q,17p,17q,21q,22q. The temporal sequence of mutation
acquisition was based on a clonal expansion model and
correlated with the topographic distribution and extent of imbalance.
Result:
The two cases of CC manifested 5 and
7 acquired mutations involving different genomic loci specific for each
patient. Co-existing vMC also exhibited acquired LOH
mutations ranging from 0-3 in total amount. In each case of CC, the earliest
acquired mutations were present in the vMC supporting
a causal relationship for neoplastic progression.
Discordant LOH mutations were also present in the vMC
providing support that mutations detected at these sites did not passively
migrate or reflect contamination.
Conclusion:
The concept of hyperplasia, dysplasia, neoplasia pathway has
been proposed in cholangiocarcinoma and the cases
examined here show a histologic and genetic
progression from vMC to cholangiocarcinoma.
Malignant transformation of vMC has rarely been
reported in the literature. However, this may be an underrecognized
phenomenon and vMC may be the precursor of sporadic changiocarcinoma in some cases. Further studies are needed
to determine the premalignant potential of vMC. Patients with multiple vMC's
may be at a higher risk of developing CC and could be clinically followed with
serial imaging similar to patients with cirrhosis.
170. Aberrant IL-6 Signaling in Cholangiocarcinoma
Cells is Due to SOCS-3 Epigenetic Silencing
H. Isomoto;
S. F. Bronk; N. W. Werneburg;
G. Gores
Background
and aims:
Interleukin 6 (IL-6) is a critical mitogen and survival factor for human cholangiocarcinoma
cells. Indeed, we have recently demonstrated that IL-6 signaling
in human cholangiocarcinoma cells is sustained and
therefore aberrant, likely contributing to the malignant phenotype. Because
suppressor of cytokine signaling 3 (SOCS-3) inhibits
IL-6 signaling by a negative feedback loop, our aim
was to determine if SOCS-3 expression is disabled in a human cholangiocarcinoma cell line.
Methods:
The studies were performed in the
human cholangiocarcinoma cell line, Mz-ChA-1 and the nonmalignant human cholangiocyte
cell line, H69. Phosphorylated signal transducers and
activators of transcription 3 (STAT-3), a down stream target in the IL-6 signaling cascade, was assessed by phospho-immunoblot
analysis. SOCS-3 protein and mRNA expression were examined by immunoblotting and real-time PCR, respectively. Methylation status in CpG islands
of the socs-3 promoter was determined by methylation-specific
PCR and sequencing using bisulfite-treated genomic
DNA.
Results:
Incubation of Mz-ChA-1 cells with
IL-6 resulted in a sustained increase in phosphorylated
STAT-3 over 6 hours. In contrast, the phospho-STAT-3 response to IL-6 in H69
cells was terminated within an hour following addition of the cytokine.
Consistent with the phospho-STAT-3 response, SOCS-3 expression was not induced
by IL-6 in Mz-ChA-1 cells, but was increased 20-fold in H69 cells. Treatment
with a demethylating agent, 5-aza-2’-deoxycytidine
restored SOCS-3 expression in Mz-ChA-1 cells. This “re-expression” of SOCS-3
terminated the sustained IL-6/STAT-3 response observed in the absence of
5-aza-2’-deoxycytidine. Methylation-specific PCR
yielded a methylated 143-bp DNA product and bisulfite sequencing analysis demonstrated methylation of 57% of CpG sites
in the socs-3 promoter.
Conclusions:
Our results indicate that SOCS-3
epigenetic silencing due to promoter hypermethylation
is responsible for the aberrant sustained IL-6 signaling
observed in human cholangiocarcinoma cells. Methylation inhibitors may be a therapeutic strategy to
abrogate aberrant IL-6 signaling in this neoplasm.
C. W. Brady; A. D. Smith; K.
M. Stechuchak; C. J. Coffman; J. E. Tuttle-Newhall;
D. Provenzale; A. J. Muir
Background:
Use of the Model for End Stage Liver
Disease (MELD) score has increased the rate of orthotopic liver transplantation
(OLT) among patients listed for hepatocellular carcinoma (HCC). As a result,
patients listed for reasons other than HCC are at risk of developing de novo
HCC, being removed from the waiting list, and dying without OLT. Existing data
on the development of de novo HCC in this population have been described for
only a small sample of subjects.
Aim:
To characterize the development of de
novo HCC in a national sample of patients listed for OLT. Methods: Using the
Organ Procurement and Transplantation Network database of the United Network
for Organ Sharing, we abstracted clinical and demographic data on patients aged
18 years or older who were listed for OLT between February 2002 and December
2004 and underwent OLT. We excluded patients with HCC, cholangiocarcinoma,
other primary and metastatic liver cancers, fulminant
hepatic failure, and a history of previous organ transplant at the time of
listing.
Results:
Of 8627 patients identified, 1200
(13.9%) developed de novo HCC while awaiting OLT. Among those who developed
HCC, 967 (80.6%) were diagnosed with HCC before OLT, 118 (9.8%) had HCC that
was found incidentally at explant, and 115 (9.6%)
were diagnosed before OLT and had an incidental tumor
reported at explant. The mean age of those who
developed HCC was 54.9 ± 8.0 years and of those who did not develop HCC was
51.4 ± 9.6 years. Among those who developed HCC, 268 (22.3%) were female and
932 (77.7%) were male. Among those who did not develop HCC, 2544 (34.3%) were
female and 4883 (65.8%) were male. The racial distribution of patients who
developed HCC was 72.9% White, 7.4% Black, 5.2% Asian, and 14.5% other. The
racial distribution of patients who did not develop HCC was 77.4% White, 7.9%
Black, 2.3% Asian, and 12.4% other. The median number of days on the waiting
list for those who developed HCC was 68.5 days (Q1-Q3: 23 –205.5) and was 61.0
days (Q1-Q3: 16-168) for those who did not develop HCC. Patients who developed
HCC had initial and final mean calculated MELD scores of 13.6 ± 5.4 and 15.3 ±
7.0, respectively. Patients who did not develop HCC had initial and final mean
calculated MELD scores of 19.0 ± 7.9 and 21.6 ± 9.1, respectively.
Conclusions:
A clinically significant proportion
of patients develop de novo HCC while awaiting OLT. For patients listed for
OLT, current HCC surveillance practices identify most cases of de novo HCC that
develop prior to OLT. Future studies will examine specific diagnoses and comorbid conditions that may influence the development of
de novo HCC in this population.