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Alan Franciscus
Editor-in-Chief
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In This Issue:
Hepatitis C a Direct Cause
of Diabetes
First Patient Accepted in Delcath Phase III Liver
Cancer Study
Quebec Not Looking at Opening Injection Sites Despite Drug
User Support
Radiofrequency Ablation for Hepatocellular Carcinoma
Pennsylvania Sues 13 Drug Companies On Pricing
Living Donors Showed a 1.85-Fold Increase in Liver Volume
Effect of Maternal Antibody on Immunogenicity
of Hepatitis A Vaccine in Infants
Patients May Have Received Wrong Results for
HIV, Hepatitis Tests
Light and Moderate Alcohol Intake May Have Minimal
or No Effect on Fibrosis Development in HCV Infection
March 9th, 2004
Hepatitis C a Direct Cause of Diabetes
Source: Reuters Health
NEW YORK--Hepatitis C virus (HCV) infection
can directly cause insulin resistance, which commonly leads
to diabetes, Japanese researchers have found.
HCV infection has been linked to type 2
diabetes, the authors explain, but a definite cause-and-effect
relationship has not been established. To investigate, Dr.
Kazuhiko Koike, and colleagues from University of Tokyo, studied
the development of diabetes using mice that had been bred
to carry the core gene of HCV.
Excessive insulin levels were apparent
in the mice "as early as 1 month old," the authors
report in the medical journal Gastroenterology. Insulin
resistance was observed by the age of 2 months.
Administering of glucose to these mice
led to only mild glucose intolerance, but when they were fed
a high-fat diet they developed overt diabetes.
The authors conclude, "These results
indicate a direct involvement of HCV per se in the pathogenesis
of diabetes in patients with HCV infection and provide a molecular
basis for insulin resistance in such a condition."
This research "makes an important
contribution to putting the HCV-diabetes association on a
mechanistic footing, thus elevating it from a curious association
to an important disease process," write Dr. Steven A.
Weinman and Dr. L. Maria Belalcazar from University of Texas
Medical Branch, Galveston, in a related editorial.
SOURCE: Gastroenterology, March 2004.
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First Patient
Accepted in Delcath Phase III Liver Cancer Study
Source: PRNewswire
STAMFORD, Conn.,--Delcath Systems, Inc.
said the first patient has been accepted for enrollment in
its Phase III clinical trial for inoperable cancer in the
liver.
The patient will be treated at the Sydney
Melanoma Unit at the Royal Price Alfred Hospital in Sydney,
Australia, the initial clinical site for the company's pivotal
trial.
"This is an important milestone for
our company and marks the beginning of our final step toward
FDA approval," said M.S. Koly, CEO of Delcath. "Now
that the first patient is enrolled, the clinical team in Sydney
indicated to us that future enrollments should happen at a
more rapid pace."
Delcath is undertaking the Phase III pivotal
trial for FDA approval to commercialize its isolated liver
perfusion system for delivery of high dose chemotherapy directly
to the liver via the hepatic artery. The FDA-approved protocol
calls for enrolling 122 patients (including 61 controls) to
determine whether patients treated with Delcath's system experience
statistically longer survival versus the control group.
The Delcath system uses special catheters
and filters to direct and trap toxic anticancer chemicals,
so they can be delivered in high doses to the liver while
protecting the rest of the body from excessive toxicity.
The Phase III study is testing the drug
doxorubicin in patients with melanoma metastasized to the
liver.
Omnicare, Inc., a global contract research
organization with 29 principal offices and a presence in 27
countries, is managing the trial on behalf of Delcath.
The principal investigator of the Sydney
study is John Thompson, MD, Director of the Sydney Melanoma
Unit at the Royal Price Alfred Hospital and professor of surgery
(melanoma and surgical oncology) at the University of Sydney.
He is a world leader in the development of perfusion and infusion
therapies for regional treatment of recurrent melanoma.
The Sydney Melanoma Unit has accumulated
the largest database of melanoma patients in the world. It
has treated more than 15,000 melanoma patients since its inception
in 1968 and sees approximately 750 new melanoma patients yearly.
Delcath is a developer of isolated perfusion
technology for organ or region-specific delivery of therapeutic
agents. Six US, and three foreign issued patents cover its
technology. The company is headquartered in Stamford, CT.
This release contains "forward-looking
statements" based on current expectations but involving
known and unknown risks and uncertainties. Actual results
or achievements may be materially different from those expressed
or implied. Delcath plans and objectives are based on assumptions
involving judgments with respect to future economic, competitive
and market conditions, its ability to consummate, and the
timing of, acquisitions and future business decisions, all
of which are difficult or impossible to predict accurately
and many of which are beyond its control. Therefore, there
can be no assurance than any forward-looking statement will
prove to be accurate.
CONTACT: M.S. Koly, Chief
Executive Officer of Delcath Systems, Inc.,+1-203-323-8668;
or Thomas Redington of Redington, Inc., +1-203-222-7399, or+1-212-926-1733,
for Delcath Systems, Inc.
http://www.delcath.com/
http://www.redingtoninc.com/
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Quebec Not
Looking at Opening Injection Sites Despite Drug User Support
Ross Marowits
Canadian Press
Although a study published Tuesday suggested
Montreal's intravenous drugs users (IDUs) want a supervised
injection site similar to the one in Vancouver, British Columbia,
the Quebec government said it has no immediate plans to open
such sites. "I don't think that in Quebec we will see
that kind of site in the very short term," said Cathy
Rouleau, spokesperson for Health Minister Philippe Couillard.
"But if we do, it's going to be because we will take
a good lesson from what Vancouver is doing and make sure that
we're doing it properly."
Vancouver's site has had nearly 500 visits
a day since opening last September as a four-year pilot project.
The study, conducted by McGill University, questioned 251
Montreal IDUs. Most said they would like a safer place to
inject than in parks, alleys, cars or stairwells.
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March 10th, 2004
Radiofrequency
Ablation for Hepatocellular Carcinoma
Source: www.gastrohep.com
Radiofrequency ablation is a safe and effective
treatment for patients with hepatocellular carcinomas greater
than 3 cm in diameter, find doctors in the March issue of
Archives of Surgery.
In this study, doctors from Hong Kong,
China, evaluated 86 patients with hepatocellular carcinoma.
Patients were treated with radiofrequency
ablation between 2001 and 2002.
The team divided the patients into 2 groups;
those with tumors less than 3 cm in diameter (group 1) and
those with tumors between 3.1 and 8 cm in diameter (group
2).
They performed radiofrequency ablation
with a single or cluster cool-tip electrode.
The choice of treatment route was based
on tumor size and position. Complete ablation was achieved
in 94% of patients in group 1 and 91% of patients in group
2.
The doctors measured the rate of complication,
treatment mortality, and rate of complete ablation.
They performed the radiofrequency ablation
percutaneously in 26 patients in group 1 and 9 patients in
group 2, and laparoscopically in 2 patients in group 1 and
1 patient in group 2. The remaining patients underwent open
operation.
The team found that the complication rates
were 12% in group 1 and 17% group 2. Mortality rates were
0% in group 1 and 3% in group 2.
Complete ablation, after a single session
of ablation, occurred in 94% of patients in group 1 and 91%
of patients in group 2.
Dr Ronnie Poon's team concluded, "Radiofrequency ablation
is a safe and effective treatment for patients with hepatocellular
carcinomas 3.1 to 8 cm in diameter".
Arch Surg 2004; 139: 281-7
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Pennsylvania
Sues 13 Drug Companies On Pricing
By Kim Dixon
Reuters
Pennsylvania Wednesday became the latest
U.S. state to sue a slew of pharmaceutical companies, claiming
deceptive pricing and sales practices, bringing the number
of suits to about a dozen.
The lawsuit, which seeks recovery of hundreds
of millions of dollars, was filed in Commonwealth Court by
Pennsylvania Attorney General Jerry Pappert. It accuses the
drugmakers of artificially inflating prices to cheat taxpayers,
employees and Medicaid recipients.
The state joins at least 12 others filing
suit against the industry, and more state attorneys general
are likely to pile on as they grapple with double-digit health
inflation and red ink, Pappert said.
"We work together, and I wouldn't
be surprised if you saw other state AGs taking a more critical
look,'' at the issue, Pappert told Reuters.
Named as defendants were: TAP Pharmaceutical
Products, Inc. a joint venture between Abbott Laboratories
and Takeda Chemical Industries Ltd., AstraZeneca Plc, Bayer
AG, GlaxoSmithKline Plc, Pfizer Inc. , Amgen Inc., Schering-Plough
Corp., Bristol-Myers Squibb Co., Johnson & Johnson, Baxter
International Inc., Aventis, Boehringer Ingelheim Corp. and
Dey Inc., a unit of Germany's Merck KGaA .
Dey “unequivocally denies any wrongdoing”
in its pricing, the company said in a statement.
Spokeswomen for Schering-Plough and AstraZeneca both said
they could not comment because they had not seen the suits
yet. Other companies could not be reached.
Ohio Tuesday said it would sue a handful
of drugmakers, including some of those named by Pennsylvania.
Pappert said he had not known about the
Ohio suit until he read about it. The first suit by a state
was by Texas in 2000, he said.
At issue are the prices drugmakers charge
the government for drugs in health plans like Medicaid, the
state-run health insurance for the poor, which serves 44 million
people.
Government and private health care payers buy prescription
drugs based upon a pricing list drawn up by drugmakers of
''average wholesale price.''
The suit accuses the companies of inflating
those prices.
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March 11th, 2004
Living Donors
Showed a 1.85-Fold Increase in Liver Volume
Source: www.gastrohep.com
Liver regeneration is greatest in split-liver
transplants recipients, find investigators in the latest issue
of Liver Transplantation.
The number of living donor and deceased
donor split-liver transplants have increased over the last
5 years.
In this study, investigators from the United
States measured differences in liver regeneration between
living donors, right-lobe living donor recipients, and split-liver
transplants recipients.
The team measured liver volume at 3 months
postoperatively by using by computed tomography (CT) volumetrics.
They compared the result to the patient's
ideal liver volume (ILV), which was calculated using a standard
equation.
Overall the team evaluated 70 adult patients
who either had donated their right lobe for living donor transplants
or undergone a partial-liver transplant. Living donors showed
a 1.85-fold increase in liver volume.
The team found that the deceased donors
were younger than the living donors, were heavier, and had
longer ischemic times.
At 3 months postoperatively, they found
that living donors had attained 79% of their ILV.
However, they determined that right-lobe
living donor recipients had attained 104% of their ILV, right-lobe
split-liver transplants recipients 114%, and left-lobe split-liver
recipients 120%.
When liver size 3 months postoperatively
was compared with liver size immediately postoperatively,
living donors showed a 1.85-fold increase.
However, the increase seen in right-lobe
living donor recipients, right-lobe split-liver transplants
recipients, and left-lobe split-liver transplants recipients
was 2.08-fold, 2.17-fold, and 2.52-fold, respectively.
Dr Abhinav Humar and colleagues concluded,
"Liver regeneration seems to be greatest in split-liver
transplants recipients".
"Living donor recipients seem to have
greater liver growth than their donors".
"The reason for this remains unclear".
Liver Transpl 2004; 10: 374-8
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March 12th, 2004
Effect of
Maternal Antibody on Immunogenicity of Hepatitis A Vaccine
in Infants
Source: www.gastrohep.com
Passively acquired maternal anti-hepatitis
A virus results in a lower final antibody response, find researchers
in the March issue of the Journal of Pediatrics.
In this study researchers from the United
States determined the effect of maternal antibody on hepatitis
A vaccine immunogenicity in infants.
The team administered hepatitis A vaccine
to the infants of mothers negative for antibody to hepatitis
A virus (anti-HAV) 2, 4, and 6 months of age.
In addition, the infants of anti-HAV-positive
mothers were randomized to receive either hepatitis A vaccine
(group 2) or hepatitis B vaccine (group 3). Infants in group
3 received hepatitis A vaccine at 8 and 10 months of age.
The researchers found that at 15 months
of age, 100% of infants in group 1, 93% in group 2, and 92%
in group 3 had protective levels of antibody.
However, the team identified significant
differences in the geometric mean concentration (GMC) of anti-HAV
between groups:
• Group 1 = 231 mIU/mL
• Group 2 = 85 mIU/mL
• Group 3 = 84 mIU/mL.
Dr William Letson and colleagues concluded,
"Passively acquired maternal anti-HAV resulted in a significantly
lower final antibody response."
J Pediatrics 2004; 144(3)
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Patients
May Have Received Wrong Results for HIV, Hepatitis Tests
ALEX DOMINGUEZ
Associated Press
BALTIMORE -- Maryland General Hospital
has mailed more than 500 letters to doctors and patients,
urging retesting for those who may have received incorrect
HIV and hepatitis test results, officials said Friday.
The hospital also set up a 24-hour hot
line. By Thursday night, 22 people had called and three were
recommended to get a retest, said hospital spokesman Lee Kennedy.
"We want to make sure the individuals
who are affected get retested properly, and we want to allay
any fears they may have that the first tests were improper,"
Kennedy said. He declined to comment further.
State health officials, meanwhile, were
looking into how the problems occurred at the hospital, where
laboratory staff apparently manipulated the results of control
tests that showed the tests might be inaccurate, according
to a report filed by state inspectors.
State health secretary Nelson Sabatini
said the problem appeared to be a personnel issue and not
an equipment issue.
"It wasn't that the malfunction was
unknown. The problem was that nothing was done about it; they
overrode the malfunction," Sabatini said.
The testing problems continued for about
14 months before the hospital decided in August to have the
testing done elsewhere, Sabatini said.
Meanwhile, a lawsuit against the hospital
was filed by a former laboratory worker who said hospital
officials knew of equipment defects that could cause inaccurate
test results and that led her to become infected with HIV
and hepatitis C.
The (Baltimore) Sun reported Friday that
Kristin Turner was seeking $10 million in compensatory damages
and $20 million in punitive damages, claiming she warned officials
last year of problems in equipment used to perform HIV and
other tests. The hospital had said it didn't learn of the
problems until January, the newspaper reported.
Maryland General confirmed Friday that
the lawsuit had been filed, but declined to comment further.
Turner's attorney, Michael Pulver, wasn't available for comment
Friday, his office said.
Sabatini said his top priority was tracking
down the patients for retesting.
"Are there more problems, are there
other fundamental, systemic problems? I can't answer that;
that's going to warrant further inquiry," the health
secretary said.
Maryland General President Timothy Miller
told The Sun that hospital executives knew nothing about the
problem until the state notified them in late January.
Testing problems can be deadly. St. Agnes
Medical Center in Philadelphia was fined $447,500 in 2001
for testing errors blamed for the deaths of three patients
who were given overdoses of a blood thinner. In 1993, a review
of 19,000 Pap smear tests was ordered at a Newport, R.I. hospital
after a woman who tested negative four times died of cervical
cancer.
At Maryland General, some patients may
have been told they were HIV-negative when they were positive
or positive when they were negative.
Hepatitis C, for which some patients were
tested, can cause a chronic liver infection that could eventually
lead to liver failure and cancer.
The state investigated after receiving
a complaint, according to the report. Inspectors found that
over a 14-month period ending in August, 10 percent to 15
percent of the HIV tests performed might have been inaccurate.
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Light
and Moderate Alcohol Intake May Have Minimal or No Effect
on Fibrosis Development in HCV Infection
Source: www.hivandhepatitis.com
Heavy alcohol use contributes to liver
disease in chronic hepatitis C virus (HCV) infection. Whether
this is true for light or moderate alcohol use has not been
shown.
Heavy alcohol consumption has been found
in many studies to contribute to the progression of HCV-related
liver disease. Patients with HCV are generally counseled by
their physicians to abstain from drinking alcohol, despite
the fact that light alcohol intake, which most patients practice,
has not been shown to lead to worse liver disease.
Additionally, there is increasing evidence
that light alcohol consumption produces significant health
benefits. As such, researchers in the Department of Gastroenterology,
University of California at San Francisco, San Francisco,
CA sought to address how deleterious different amounts of
alcohol intake are to patients with chronic HCV.
In this study, 800 patients with HCV undergoing
liver biopsy at three sites had detailed alcohol histories
recorded and the relationship between alcohol and hepatic
fibrosis was assessed.
On univariate analysis, heavy alcohol use
(>50 g/day) was associated with an increase in mean fibrosis
(P = .01). Such an association could not be demonstrated for
light and moderate alcohol use.
For each category of alcohol intake (none,
light, moderate, and heavy), a spectrum of fibrosis was observed.
On multivariate analysis, age, serum alanine
aminotransferase (ALT), and histological inflammation were
the independent predictors of fibrosis (P = <.0001, .0003,
<.0001, respectively).
In conclusion, write the authors, “Heavy
alcohol use exerts a greater effect on fibrosis than light
or moderate use. There is a range of fibrosis at each level
of alcohol use. Age, serum ALT, and inflammation are independently
associated with fibrosis in multivariate analysis, highlighting
the fact that variables other than alcohol intake predominate
in the production of hepatic fibrosis.”
Discussion
One important question has been: is there a safe level of
alcohol intake in patients with chronic HCV infection? This
study does not find this to be the case.
The researchers did not find a statistically
significant association between alcohol intake and mean fibrosis
on liver biopsy until a consumption level of 50 g/day of alcohol,
and this only in univariate analysis.
In the cohort overall, however, both mean
fibrosis and the odds ratio for fibrosis increased step-wise
even among patients with less than 50 g/day of alcohol consumption.
Light and moderate alcohol intake may be
playing a role in fibrosis, but even with 800 patients, the
cohort size may be inadequate to demonstrate the subtle effect
of low amounts of alcohol on fibrosis.
A safe level of alcohol intake is not demonstrated,
note the investigators. Light and moderate intake exert less
of an effect on fibrosis than heavy intake, however, and may
indeed have minimal or no effect.
Balancing this small risk of liver disease
progression against potential cardiovascular benefit may be
particularly pertinent to middle-aged men, who worldwide constitute
the majority of patients with HCV, and who are also at high
risk for cardiovascular disease. Risk-benefit assessment should
be individualized for each patient, say the researchers.
Another interesting finding of the study
is that patients with hepatitis C may have differing susceptibility
to the effects of alcohol. This is accepted in alcoholic liver
disease in the absence of hepatitis C, where only a subset
of heavy drinkers develop cirrhosis.
In this study, patients with HCV who drink
heavily have, on average, more liver disease than those who
do not. Individual heavy drinkers, however, may have minimal
liver disease, and in fact 47% of heavy drinkers (>50 g/day)
in this study had Stage 0 or Stage 1 liver disease.
In summary, the authors write, “We
have quantified alcohol intake in 800 patients undergoing
liver biopsy at three sites. A history of heavy alcohol intake
correlated with a higher degree of histological fibrosis.”
“Light or moderate drinkers did not
have statistically greater fibrosis than nondrinkers, but
alcohol may play a role in their liver disease. At each level
of alcohol intake, there is a broad range of liver disease;
successively heavier intake leads to subtle increases in risk
for fibrosis.”
“Patient age, serum ALT, and histological
inflammation retained independent correlations with fibrosis
in multivariate analysis, whereas heavy alcohol intake (>50
g/day) did not.”
“The variability in natural history
for a given level of alcohol intake points to a central role
for immunological and/or genetic variables in HCV disease
progression.”
Reference
A Monto and others. Risks of a range of alcohol intake on
hepatitis C-related fibrosis. Hepatology 39(3): 826-834.
March 2004.
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