LiverHope
Volume 5, Issue 3 March 2003
LiverHope
Volume 5, Issue 3 March 2003
Are you newly diagnosed or do you want more information about Hepatitis
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In This Issue
Calendar.............................................................................................. 1
Italian
surgeons remove liver to treat cancer................................ 1
The outcome
of liver grafts procured from hepatitis C-positive donors 2
InterMune
initiates Phase I study of PEG-Alfacon (Infergen) for the treatment of chronic
hepatitis C infections 2
Liver Lag?........................................................................................... 3
Vaccine may
save livers of hepatitis C victims............................. 3
Study looks
at hepatitis drug, depression risk............................. 4
A Parable............................................................................................ 5
Italian surgeons remove liver to treat cancer
LONDON (Reuters) 12-18-2002 - Italian scientists have taken a new approach to treating liver cancer by removing the organ, dosing it with radiation and then replacing it in the patient.
A 48-year-old man who was the first patient to have the innovative treatment at the San Matteo Hospital in Pavia, Italy is cancer-free a year after he was treated during the 21-hour operation for more than 14 tumors in his liver.
"The out-of-body operation allows doctors to administer high doses of radiation to widespread tumors without affecting other organs," New Scientist magazine said Wednesday.
Surgeon Aris Zonta and physicist Tazio Pinelli of the National Institute of Nuclear Physics in Italy, who co-coordinated the procedure, are awaiting approval to treat six other patients with multiple tumors.
The original patient had cancer of the colon, which had spread to the liver. The cancer did not respond to chemotherapy and was so widespread that conventional radiotherapy would have destroyed the liver.
The Italian scientists decided to try boron neutron capture therapy, which they have been working on since 1987, and which was first attempted in the 1950s.
It involves injecting a fluid containing boron atoms into the patient and using a low-energy neutron beam to split the boron into particles that kill the cancerous cells.
But an even dose of neutrons is needed to treat the entire organ and bones in the body can block the beam so the surgeons removed the liver, treated it and then replaced in the body.
"By explanting the organ, we could give a high and uniform dose to all the liver, which is impossible to obtain inside the body without serious risk to the patient," Pinelli told the magazine.
Although the treatment, which has been dubbed TAORMINA, was successful and could give new hope to seriously ill patients it would only be suitable for patients whose cancer has spread to only one other organ and if they are strong to survive the operation. "The technique is currently being tested on patients with otherwise untreatable brain tumors -- obviously without removing the organ in question," the magazine added.
The outcome of liver grafts procured from hepatitis C-positive donors
BACKGROUND: The growing prevalence of hepatitis C virus (HCV) infection in the general population has resulted in an increased frequency of potential organ donors that carry the virus. The survival of grafts from HCV+ donors has not been studied in detail.
METHODS: Two study populations were examined retrospectively to assess the survival of liver grafts procured from HCV+ donors. First, we evaluated the survival of all 13 HCV+ and 103 HCV- grafts that were transplanted at our institution to HCV+ recipients from January 1, 1995 to December 31, 1999. In parallel, we analyzed a subset of the United Network for Organ Sharing (UNOS) liver transplant database from the same 5-year time period that was comprised of 14,195 adult patients for whom donor and recipient HCV serologies were known. Kaplan-Meier graft survival for both patient populations was calculated based on donor and recipient HCV serologic status. A Cox proportional hazards analysis was performed on UNOS data to identify variables independently predicting graft survival.
RESULTS: For transplants performed at our institution, we found no statistically significant difference in the Kaplan-Meier graft survival of HCV+ and HCV- grafts transplanted to HCV+ recipients. The incidence of biopsy-proven, recurrent HCV post transplant was similar in recipients receiving either HCV+ or HCV- grafts (4/13 vs. 18/103). Analysis of UNOS data revealed that the survival of HCV+ grafts in HCV+ recipients was equivalent to the survival of HCV- grafts in HCV+ recipients. Unexpectedly, the survival of grafts in HCV+ recipients in general was significantly inferior to that of grafts in HCV- recipients. Multivariate analysis of all patients found recipient but not donor HCV status to be independently predictive of graft survival.
CONCLUSIONS: Analysis of data from a single center and the national UNOS database suggests that transplantation of liver allografts from HCV+ donors to HCV+ recipients results in graft survival comparable to HCV- grafts transplanted to HCV+ recipients. In contrast, recipient HCV positivity is an independent predictor of graft failure compared with patients transplanted for other causes of liver disease.
Transplantation
2002 Feb 27;73(4):582-7
Velidedeoglu E,
Desai NM, Campos L, Olthoff KM, Shaked A, Nunes F, Zeldin G, Stewart C,
Blumberg E, Abrams J, Markmann JF Department of Surgery, University of
Pennsylvania Health System, Philadelphia, Pennsylvania 19104, USA
PMID: 11889435,
UI: 21886918
January 23, 2003
BRISBANE, Calif., Jan. 23 /PRNewswire-FirstCall/ -- InterMune, Inc. (Nasdaq: ITMN - News) announced today that it has initiated a Phase I clinical study to evaluate PEG-Alfacon, the PEGylated version of Infergen® (Interferon alfacon-1), as a potential new treatment for chronic hepatitis C virus (HCV). InterMune currently markets Infergen, a bio-engineered type I interferon alpha, for the treatment of patients with chronic hepatitis C infections. PEGylation is a technology designed to chemically modify drugs to decrease dosing frequency and possibly improve drug efficacy and safety.
The Phase I, open-label, dose-ascending study of PEG-Alfacon will enroll approximately 40 healthy volunteers. The study is designed to evaluate the pharmacokinetic and pharmacodynamic characteristics of PEG-Alfacon; to determine the maximum tolerated dose of this new chemical entity; and to evaluate its safety. The study is being conducted at a center specializing in pharmacokinetic analyses.
"We anticipate that the introduction of PEG-Alfacon will mark the beginning of a new era of HCV therapeutics where more potent bioengineered compounds are used to combat this disease," said Scott Harkonen, President and Chief Executive Officer of InterMune. "We look forward to completing this study and plan to initiate a Phase II dose-ranging study by the end of 2003 to further evaluate PEG-Alfacon in patients."
"We believe that the clinical potential of PEG-Alfacon is extremely promising given that Infergen -- the only bioengineered interferon in the hepatitis C market -- has been shown to have greater interferon receptor binding, and better immune activating and viral inhibition capabilities compared to other alpha interferons," said Dr. Curtis Ruegg, Vice President of Pre-Clinical and Process Development at InterMune. "We believe the advantages of Infergen and pegylation, when coupled, could result in higher response rates with PEG-Alfacon and ultimately a promising new treatment for the more than four million patients suffering from chronic hepatitis C infections."
Infergen is currently approved for treatment of adult patients with chronic hepatitis C infections, including therapy for patients who have never been treated with interferons and for patients following relapse or non-response to treatment with certain previous treatments. Please visit www.infergen.com for full prescribing information including the black box warning.
PEG-Alfacon is the result of chemical engineering using PEGylation technology to attach a polyethylene glycol (PEG) moiety to the active Infergen molecule. The expected effect of PEGylation is to increase drug circulation time in the bloodstream, decrease the rate of proteolysis by circulating enzymes, and reduce immunogenicity.
Source: InterMune, Inc
1 May 2000
Jeremy Thomson
Jet lag can last for up to a week, even though the brain's master body clock can reset itself in just a day. New research suggests that this could be because individual body clocks in the lungs, muscles and liver adapt at different rates, and may be thrown out of kilter for days.
Hajime Tai at the University of Tokyo, Japan and Michael Menaker at the University of Virginia, Charlottesville, Virginia and their team used genetically modified rats to monitor the impact of time shifts on body clocks or 'circadian rhythms' in different organs. The researchers engineered the rats so that their bodies produced a protein called 'luciferase' instead of another protein, 'Per1', which is central to circadian rhythms. Luciferase is the enzyme that gives fireflies their glow, so the rats' cells actually lit up in step with their body clocks. As they report in Science1, the team reared these rats with twelve hours light and twelve hours darkness per day. When they examined cells from the rats' 'suprachiasmatic nuclei' -- the brain region that acts as the master clock -- they saw a strong, regular twenty-four-hour rhythm that lasted up to a month outside the body. Cells from the lungs, muscles and liver also glowed in a daily rhythm, but these oscillations petered out after four or five days.
Clearly, there are several clocks ticking away in rats' bodies, but how do these clocks cope with a change in 'time zone'? To find out, the researchers subjected the rats to a sudden six-hour delay in their daily cycle, rather like the jump caused by flying from Paris to New York. After one day on the new time zone, the rats' brains adapted fully and their lungs and muscles were not far behind, having already compensated by four hours. The liver, though, was a different story -- it didn't shift its rhythm at all. Even in rats given six days to adjust to the new regime, the liver only managed to compensate by three and a half hours while other organs caught up completely. In fact, after sixteen days, the liver still did not quite regain its normal cycle.
Tai's group believes that resetting the clocks throughout the body can take weeks, leaving metabolic processes uncoordinated. This slow rate of synchronization is no problem when an animal is adapting to the passing seasons. But, if the same occurs in humans, it might explain why sudden jumps such as long-haul flights or shift changes at work cause us such discomfort.
References Yamazaki, S. et
al. Resetting central and peripheral circadian oscillators in transgenic rats.
Science 288, 682 (2000)
C Nature News Service / Macmillan Magazines Ltd 2001
Vaccine may save livers of hepatitis C victims
01 November 02
Rachel Nowak
The livers of people infected with hepatitis C could be saved if one of a handful of experimental vaccines lives up to its early promise.
Innogenetics of Belgium has reported that its therapeutic vaccine - a vaccine designed to treat a disease rather than prevent it - stops and sometimes even reverses liver damage in hepatitis C patients. The company is one of at least five developing therapeutic vaccines for hepatitis C.
Hepatitis C is transmitted via blood-through transfusions, when drug users share needles and even from tattoo needles. The first symptoms are mild, such as fatigue.
But in around a third of people affected, the liver becomes scarred after a few decades and stops functioning properly, causing weakness, exhaustion and jaundice. In some cases, the liver fails completely or becomes cancerous. The disease is one of the commonest reasons for a liver transplant.
"The typical patient is a woman 60 years old who 25 years ago got infected with a blood transfusion following a Caesarean or some other operation," says Frank Hulstaert, head of clinical research at Innogenetics.
Even long-term treatments with the latest drugs cure just half those infected at most and have serious side effects, including severe depression, which many find intolerable.
Innogenetics' vaccine is based on one of the proteins found on the virus's coat. In the trial, 24 patients, who had been infected with the virus for 19 years on average, received five injections of the vaccine every three weeks and another six injections after a six-month interval.
Liver biopsies taken before and after the treatment showed that the vaccine prevented liver scarring and inflammation from getting worse in most patients. And in the nine who had the strongest response to the vaccine, the condition of the liver actually improved.
"Baffling"
is how virologist Matti Sallberg of the Karolinska Institute in Stockholm
describes one aspect of the results. The amount of virus in the blood - the
"viral load" - is usually seen as an indicator of the severity of
viral diseases. But the Innogenetics vaccine appears to work without altering viral
load.
So while the viral load may reveal the effectiveness of drugs that block viral replication, it might not be a true indicator of disease severity, says Sallberg, who is the co-founder of Tripep, a Swedish company developing a competing therapeutic vaccine.
Hulstaert emphasizes that further trials, including ones that compare treated patients with untreated patients, are needed to confirm the findings. But there is no doubt that such vaccines are needed.
In the US and Europe alone, nine million people are infected with hepatitis C. Although the number of new infections has plummeted since the 1990s, when blood banks started screening for the virus, the people infected earlier are only now developing end-stage symptoms.
And a WHO report due out in 2003 is expected to say that there are now 200 million people with hepatitis C worldwide. Unfortunately, the therapeutic vaccines are likely to be too costly for most patients in the developing world.
NewScientist.com
© Copyright Reed Business Information Ltd.
Study looks at hepatitis drug, depression risk
NEW YORK (Reuters Health) Nov 25, 2002 - Up to one third of patients with hepatitis C who are treated with interferon may become depressed, according to the results of a small study. However, many patients can take antidepressants while continuing their interferon therapy, the researchers report. Besides being used to treat the potentially life-threatening liver disease hepatitis C virus (HCV), interferon is also used to treat adult leukemia, certain kidney cancers, the skin cancer melanoma and hepatitis B. "The good news is that, in most cases, we could successfully treat the depression," lead study author Dr. Peter Hauser of the Portland VA Medical Center in Oregon said in a prepared statement.
While previous studies have identified depression as a potential side effect of interferon therapy, little is known about how common depression occurs in such patients. And, while physicians have been inclined to halt interferon therapy when depression arises, Hauser and colleagues now say that, according to their study findings, most patients can be treated with antidepressants while remaining on the drug. Writing in the November issue of Molecular Psychiatry, Hauser's team reports on a group of 39 HCV-infected patients who were treated with interferon. All of the patients were monitored for depression each week during the study period.
"Our results showed that 13 of 39 patients (33%) developed interferon-induced major depressive disorder," the authors write. Notably, the investigation revealed depressive symptoms typically developed between the 6th and 22nd week of interferon therapy. "We found that when depression developed in our patients it developed rapidly," Hauser and colleagues write. As such, the investigators recommend that patients be screened for depression every 2 weeks. Of the 13 patients who developed depression, 11 of them responded positively to antidepressants, the report indicates.
"Treating HCV patients with antidepressants may ultimately reduce deaths as well as permit HCV patients to complete a full course of interferon therapy and possibly avoid the complications of advanced liver disease," the authors conclude.
The study was funded by grants from Integrated Therapeutics, a subsidiary of Schering-Plough Pharmaceuticals, and Forest Laboratories.
SOURCE: Molecular Psychiatry Nov 2002;7:942-947.
A group of frogs were hopping contentedly through the woods, going about their froggy business, when two of them fell into a deep pit. All of the other frogs gathered around the pit to see what could be done to help their companions. When they saw how deep the pit was, they agreed that it was hopeless and told the two frogs in the pit that they should prepare themselves for their fate, because they were as good as dead.
Unwilling to accept this terrible fate, the two frogs began to jump with all of their might. Some of the frogs shouted into the pit that it was hopeless, and that the two frogs wouldn't be in that situation if they had been more careful, more obedient to the froggy rules, and more responsible.
The other frogs continued sorrowfully shouting that they should save their energy and give up, since they were already as good as dead. The two frogs continued jumping with all their might, and after several hours of this, were quite weary.
Finally, one of the frogs took heed to the calls of his fellow frogs. Exhausted, he quietly resolved himself to his fate, lay down at the bottom of the pit, and died.
The other frog continued to jump as hard as he could, although his body was wracked with pain and he was quite exhausted. Once again, his companions began yelling for him to accept his fate, stop the pain and just die. The weary frog jumped harder and harder and, wonder of wonders, finally leaped so high that he sprang from the pit. Amazed, the other frogs celebrated his freedom and then gathering around him asked, "Why did you continue jumping when we told you it was impossible?"
The astonished frog explained to them that he was deaf, and as he saw their gestures and shouting, he thought they were cheering him on. What he had perceived as encouragement inspired him to try harder and to succeed against all odds.
This simple story contains a powerful lesson. The book of Proverbs says, "There is death and life in the power of the tongue." Your encouraging words can lift someone up and help them make it through the day. Your destructive words can cause deep wounds; they may be the weapons that destroy someone's desire to continue trying - or even their life. Your destructive, careless words can diminish someone in the eyes of others, destroy their influence and have a lasting impact on the way others respond to them.
Be careful what you say. There is enormous power in words. If you have words of kindness, praise or encouragement - speak them now to, and about, others. Listen to your heart and respond.
Someone, somewhere, is waiting for your words...
August 1999 LiverHope
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[1] John Lake, M.D., is Medical Director of the Liver Transplant Program at Fairview-University Medical Center in Minneapolis, MN. Dr. Lake has served as the Medical/Scientific Organ Representative of the UNOS Board Directors, as well as a member of the Liver Review Board and the Liver Disease Severity Scale and Liver/Intestine Transplantation Committees. Outside of UNOS, Dr. Lake serves on the ASTP Education Committee and the Board of Directors to the Minnesota Chapter of the American Liver Foundation. He has served on numerous community and national committees. He is a member of numerous societies, including the American Federation for Clinical Research and International Liver Transplantation Society. He was named “One of the Best Doctors in the U.S.” in 1996 by Modern Medicine Magazine and won ASTP’s Young Investigator Awards in 1997. He has published numerous scientific papers in professional journals. He earned his M.D. degree from the University of Minnesota Medical School.