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January 28, 2008
Hep C May Affect More than the Liver
A new study from Bulgaria proves that Hepatitis C infection is not only a liver disease, but affects many different parts of the body. Their research demonstrates that over three quarters of people with Hepatitis C have extra-hepatic manifestations and it helps physicians identify who is at the greatest risk.
Hepatitis C Virus Affects Many Organs And Tissues, Not Just Liver
www.sciencedaily.com
ScienceDaily (Jan. 18, 2008) — In 1994, the team of Tchernev and Petrova from Alexandrovska Hospital in Sofia examined a female patient with liver cirrhosis caused by chronic Hepatitis C virus (HCV). They were intrigued by the patient's many extra-hepatic manifestations -- vascular lesions on the lower limbs, acute pain in the joints, intense tingling of the fingers, and extreme labor-impairing fatigue. They were also intrigued by the presence of cryoglobulins in the patient's blood. Two years later, the patient developed enlarged lymph nodes on the neck. When one of the nodes was histologically tested, the patient was found to have lymphoma.
This case spurred the interest of the investigators in the extra-hepatic manifestations and complications of HCV infection, and for over a decade they studied the links between HCV infection, cryoglobulinemia, and lymphoma.
Hepatitis C virus is a major health problem worldwide, and more than 3 percent of the world's population is infected with HCV. Despite popular belief, HCV is not only a liver disease, but affects many organs, tissues, and systems.
In a new study of 136 Bulgarian patients with HCV, the team of Tchernev and Petrova found 76.5% of the patients had extra-hepatic manifestations. Common manifestations were fatigue (59.6%), renal impairment (25%), type 2 diabetes (22.8%), paresthesia (19.9%), arthralgia (18.4%), and purpura predominantly of the lower limbs (17.6%). Over 37% of the patients had cryoglobulins, and 8.8% had B-cell lymphoma.
The study found positive links between the presence of extra-hepatic manifestations and age, female gender, duration of the infection, infection by transfusion of blood and blood products, and extensive liver fibrosis. Therefore, elderly women with chronic HCV and advanced liver fibrosis, who were infected by transfusion during childbirth, are at the highest risk of developing extra-hepatic manifestations of HCV infection.
The study also showed most extra-hepatic manifestations of HCV infection are associated with the presence of cryoglobulins. In particular, the risks of developing B-cell non-Hodgkin lymphoma are much higher in cryoglobulin-positive than in cryoglobulin-negative patients. In the study, 17.6% of cryoglobulin-positive patients had lymphoma, whereas only 3.5% of cryoglobulin-negative patients did.
Given the prevalence of HCV around the world, it is important for physicians to recognize the extra-hepatic signs and symptoms of HCV infection. Patients who exhibit such manifestations should be tested for HCV infection. This can lead to prompt diagnosis and effective treatment of the infection before the development of cryoglobulinemia, when treatment gives poor results or is ineffective.
Journal reference: Stefanova-Petrova DV, Tzvetanska AH, Naumova EJ, Mihailova AP, Hadjiev EA, Dikova RP, Vukov MI, Tchernev KG. Chronic hepatitis C virus infection: Prevalence of extrahepatic manifestations and association with cryoglobulinemia in Bulgarian patients. World J Gastroenterol 2007; 13(48): 6518-6528 http://www.wjgnet.com/1007-9327/13/6518.asp
Adapted from materials provided by World Journal of Gastroenterology, via EurekAlert!, a service of AAAS.
Posted by Editors at 11:41 AM --- Printer-friendly version
Roche Stands By Their HCV Drugs Citing "IDEAL" Study Design Issues
Indicating patient preference for PegIntron™, Schering-Plough recently publicized their Hepatitis C trial, "IDEAL." However, competitor Roche indicates several IDEAL trial design issues that make for a poor comparison to their PEGASYS® with COPEGUS®.
Media Release
Contacts:
Brad Jenkins, Roche
+41 61 68 86404
Michelle Marchione
Axon Communications
+1 416 848 1419
Roche responds to announcement of “IDEAL” hepatitis C study
BASEL – January 14, 2008 – Following an announcement from Schering-Plough, Roche today affirmed the value of PEGASYS® (peginterferon alfa-2a) in combination with COPEGUS® (Roche’s brand of ribavirin) as the market-leading treatment for patients with hepatitis C. Despite clear biases in the design of the “IDEAL” study that potentially favoured patients taking PegIntron™ (peginterferon alfa-2b) regimens – particularly the ribavirin dose reduction protocol – the study results have shown that patients treated with a PEGASYS regimen had a similar chance of being successfully treated for hepatitis C.
“I do not expect that the results of the IDEAL study will meaningfully impact clinical practice, except to inform physicians on the appropriate dosing of PegIntron and to reinforce the already widely-accepted view that optimising ribavirin dosing throughout treatment is critical to achieving success and preventing treatment relapse in hepatitis C,” said Douglas Dieterich, M.D., Professor of Medicine in the Division of Hepatology at Mt. Sinai School of Medicine in New York, New York.
In 2001, the U.S. Food and Drug Administration (FDA) required Schering-Plough to conduct a post-approval commitment trial to determine if a lower dose of PegIntron (1.0 mcg/kg) was as effective as the approved dose of 1.5 mcg/kg, both in combination with identical ribavirin regimens.1 A third arm was added to the study in which patients received PEGASYS 180 mcg with a different ribavirin dosing schedule. This mismatch of ribavirin dosing introduces several potential biases into the study because experts agree that an optimised dose of ribavirin, with either pegylated interferon, is critical to achieving success in hepatitis C treatment. In particular, maintaining a full dose of ribavirin has shown an important ability to reduce relapse following the end of treatment.
“PEGASYS quickly became the market leader after its launch, based on robust clinical data and patient and physician preference. We are convinced that physicians and patients will continue to choose the PEGASYS plus COPEGUS combination therapy based on positive experience and sound clinical evidence,” said Rob Mitchell, Head of Viral Diseases Strategic Marketing at Roche. “Our current focus at Roche is on advancing the treatment of hepatitis C by optimising doses and duration of PEGASYS and ribavirin in patients with unmet medical need, while developing new compounds that have the potential to offer a successful outcome to even more patients.”
Roche believes that it is critical for patients and physicians to receive complete information to fully understand the results of “IDEAL” so that treatment decisions can be based on scientific data.
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Please see below for additional information about the “IDEAL” trial, Roche and PEGASYS including important safety information.
“IDEAL” Trial Design Issues
· Starting doses of ribavirin were different in the PegIntron and PEGASYS arms of the study
· The design calls for a more drastic ribavirin dose reduction for side effect management in most patients in the PEGASYS arm compared to patients in the PegIntron arms; in some cases, ribavirin dose reductions for patients in the PEGASYS arm were three times greater than for patients in the PegIntron arms. This is important because a substantial number of patients being treated for hepatitis C require their ribavirin dose to be reduced to manage side effects, and this could have an impact on the efficacy of the regimen
· The PEGASYS arm was not blinded, meaning that patients and physicians knew which treatment was being administered. Many comparative studies are blinded to ensure that bias does not compromise the results
· Erythropoetin (EPO) is a medication that is often given to treat ribavirin-related anemia and help patients maintain a higher ribavirin dose. However, physicians could only prescribe EPO after the first dose ribavirin reduction in the “IDEAL” trial. Since patients in the PegIntron arms generally had smaller ribavirin dose reductions, this introduces another potential bias and means those PegIntron patients were potentially able to maintain a higher dose of ribavirin compared to PEGASYS patients
Efficacy of PEGASYS plus COPEGUS Combination Therapy
PEGASYS was launched by Roche in 2002 and quickly became the leading treatment for patients with hepatitis C. PEGASYS plus COPEGUS is the only pegylated interferon combination regimen to have demonstrated significantly superior benefits over conventional interferon combination therapy across all HCV genotypes, irrespective of viral load.2-4 The combination of PEGASYS and COPEGUS consistently shows high cure rates – up to 66% overall sustained virological response – across a number of large, randomised clinical studies including in patients with difficult-to-cure disease such as genotype 1 HCV, cirrhosis, and HIV-HCV co-infection.2-7
About Roche
Headquartered in Basel, Switzerland, Roche is one of the world’s leading research-focused healthcare groups in the fields of pharmaceuticals and diagnostics. As the world’s biggest biotech company and an innovator of products and services for the early detection, prevention, diagnosis and treatment of diseases, the Group contributes on a broad range of fronts to improving people’s health and quality of life. Roche is the world leader in diagnostics and drugs for cancer and transplantation, a market leader in virology and active in other major therapeutic areas such as autoimmune diseases, inflammation, metabolism and central nervous system. In 2006 sales by the Pharmaceuticals Division totalled 33.3 billion Swiss francs, and the Diagnostics Division posted sales of 8.7 billion Swiss francs. Roche employs roughly 75,000 worldwide and has R&D agreements and strategic alliances with numerous partners, including majority ownership interests in Genentech and Chugai.
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All trademarks used or mentioned in this release are protected by law.
References:
1. FDA letter to Schering-Plough, August 7, 2001. Accessed Nov. 26, 2007 at: http://www.fda.gov/cder/foi/appletter/2001/pegsche080701L.htm
2. Swan, T. Expediency, Cost-Cutting, Expediency Trump Science in Clinical Development Plan for Peg-Intron: The head-to-head that wasn’t. TAGLine 2003: 10(10)1-4. Also available at: http://www.aidsinfonyc.org/tag/taglines/0312.pdf
3. Raymond, D. The Real IDEAL: Peg-Intron vs. Pegasys. Hepatitis C Harm Reduction Project Web site. Accessed Dec. 17, 2007 at: http://hepcproject.typepad.com/hep_c_project/2004/05/the_real_ideal_.html
4. Hadziyannis SJ, Sette H, Jr., Morgan TR, et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004;140(5):346-55.
5. Torriani FJ, Rodriguez-Torres M, Rockstroh JK, et al. Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med 2004;351(5):438-50.
6. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347(13):975-82.
7. Marcellin P, Brillanti S, Cheinquer H. Peginterferon alfa-2a (40KD) (PEGASYS) plus ribavirin (COPEGUS) is an efficacious and safe treatment for chronic hepatitis C (CHC) in patients with compensated cirrhosis. . In: 38th Annual Meeting of the European Association for the Study of the Liver (EASL) July 3-6; 2003; Geneva, Switzerland; 2003.
Posted by Editors at 11:40 AM --- Printer-friendly version
Non-Hodgkin's Lymphoma Less Likely with Hepatitis C Treatment
After following participants for one year, a large Japanese study concludes that treating Hepatitis C aggressively reduces the occurrence of non-Hodgkin's lymphoma.
Treatment of Hepatitis C Reduces Incidence of Non-Hodgkin’s Lymphoma
http://professional.cancerconsultants.com
Researchers from Japan have reported that viral elimination in hepatitis C virus (HCV) infected patients reduces the incidence of non-Hodgkin’s lymphoma (NHL). The details of this study appeared in the December, 2007 issue of the American Journal of Medicine.
Hepatitis C affects approximately 170 million individuals worldwide. Following acute infection, the virus persists in many patients and a minority of patients develop chronic disease. Chronic hepatitis can progress slowly over many decades to chronic active hepatitis and cirrhosis, ultimately leading to end-stage liver disease or hepatocellular carcinoma. Studies from other countries, but not from the United States, have also shown an increased incidence of NHL in patients with HCV infection. Some researches suspect that this correlation can only be observed in populations where HCV is highly prevalent.
The current study was carried in 501 patients with HCV infection who had never received interferon and 2,708 patients who had received interferon. These authors reported that by one year, 0.6% of untreated patients had developed NHL which by 5 years had increased to 2.3% and by 10 years to 2.6%. In contrast, there were no cases at 5, 10 and 15 years for the 1,048 patients with HCV infection who had sustained virologic response. The remaining patients who were treated and had persistent viral infection had an incidence of NHL of 0.4% at the fifth year, 1.5% at the tenth year and 2.6% at the fifteenth year.
Comments: These data support the concept that treating HCV infection aggressively can reduce the incidence of NHL.
Posted by Editors at 11:39 AM --- Printer-friendly version
HCV Alert: Another Doctor Reuses Syringes
Unfortunately, another Long Island doctor put patients in jeopardy of acquiring Hepatitis C when it was discovered that he reused syringes between patients. Unlike the Finkelstein case, New York authorities are moving quickly to inform the public and notify patients.
Another Long Island Doctor Commits Malpractice By Reusing Syringes
www.newsinferno.com
Date Published: Wednesday, January 16th, 2008
It’s been revealed that another Long Island doctor has reused syringes when administering injections to patients. Dr. E. Jacob Simhaee, a Manhasset-based obstetrician-gynecologist reused syringes when administering flu shots to at least 36 patients last fall. Simhaee is not the first Long Island doctor to commit such medical malpractice. Late last year, it was learned that Dix Hills doctor Harvey Finkelstein had infected several of his patients with blood borne diseases after reusing syringes.
According to the New York State Department of Health, Simhaee is contacting these patients in writing. The state Department of Health composed the letter for the physician. Simhaee was asked to sign the letter and is also contacting patients by telephone. The state initiated its investigation of Simhaee’s practice in December following a complaint filed with the Nassau County Department of Health.
The state’s release of information yesterday contrasts sharply with its handling of the Dr. Harvey Finkelstein case. It waited three years before telling the public last fall and notifying nearly 11,000 patients that Finkelstein had reused syringes—exposing thousands of patients to blood-borne pathogen infections—resulting in transmission of hepatitis C. As of Tuesday, 13 of Finkelstein patients have tested positive for hepatitis B and nine for hepatitis C. The state said it is impossible to determine whether Finkelstein’s office was the source of these infections. Finkelstein has more malpractice settlements than any other pain-management specialist on Long Island and, was sued, on average, once or twice yearly. Fifteen suits concerned epidural injections; at least 10 led to settlements. On his resume—posted on his now offline Web site—Finkelstein was described as a 1985 fellow in pediatric and cardiac anesthesia and a 1986 fellow in pain management via Stony Brook Hospital. A hospital spokeswoman said they were not accredited to offer fellowships in pain management until 1994, in pediatric anesthesia until recently, and are not accredited in cardiac anesthesia.
Mary Curtis, Nassau’s deputy executive of health and human services said, regarding the Simhaee investigation, “It’s amazing that in this amount of time, they conducted an investigation and made a notification,” adding, “The state and Nassau County did a great job. We’ve really learned from the past.” State senator Kemp Hannon (R-Garden City) feels the discovery of a second such case might warrant legislative action. “We’re going to have to look into the prohibition of multiple-use vials or limiting the use of syringes to single-use syringes,” he said.
As with Finkelstein, the department determined Simhaee used a single syringe, which held up to six doses, on multiple patients; infection-control procedures require a new syringe be used for each patient. The state said no diseases have been transmitted and Simhaee has cooperated fully. Simhaee’s patients who received the flu shot between September and December are being urged to be tested for hepatitis C, hepatitis B, and HIV and to be revaccinated against the flu.
According to Simhaee’s attorney, Craig Schaum of Garden City “This is a very highly respected doctor who has been cooperating in every way with state and county officials and will continue to do so.” Simhaee graduated in 1982 from the Albert Einstein School of Medicine at Yeshiva University in the Bronx, according to the state health department Web site; completed his graduate medical education at Maimonides Medical Center in the Bronx in obstetrics and gynecology; and is board certified in obstetrics and gynecology.
Posted by Editors at 11:35 AM --- Printer-friendly version
January 24, 2008
New NYS Law to Improve Infection Control
A new law is aimed at preventing the Hepatitis C transmission that occurred in Dr. Harvey Finkelstein's office. In New York, more stringent accreditation and reporting guidelines are now required by certain medical practices to enforce good infection control practices.
Law enacts tough new guidelines for NYS outpatient facilities
BY RIDEGLY OCHS | ridgely.ochs@newsday.com
12:39 PM EST, January 14, 2008
www.newsday.com
With a new law going into effect Monday, New York's oversight of outpatient facilities -- including pain-management practices such as Dr. Harvey Finkelstein's -- will be among the toughest in the nation, advocates and health officials said.
But some said the law fails to address ways to ensure good infection control in all outpatient settings, an issue for Long Islanders in light of the state's recent notification of more than 10,000 of Finkelstein's patients after the Dix Hills doctor's re-use of syringes led to a transmission of hepatitis C in 2004.
Experts estimate that more than half of medical procedures, including surgeries and invasive procedures such as colonoscopies, take place in offices and clinics. The state has about 2,000 of these facilities, which, unlike hospitals, have not been required to be accredited.
The result has been little hard data on how well the practices operate as well as reports of botched surgeries and disease outbreaks like those among some of Finkelstein's former patients.
The new state law now requires any ambulatory surgery center that uses moderate or heavy sedation to be accredited by one of three national groups or the doctor will lose his or her license. The centers also will be obligated to report adverse events, including patient deaths, within 30 days or any other serious or life-threatening occurrence.
The reporting requirement begins Monday; practices have until July 14, 2009, to become accredited. Podiatrists and dentists, regulated by the state education department, are not included. Neither are medical offices that use only light sedation, such as Valium.
John Morley, the state health department's medical director of the office of health systems management, said he believed the law will "make a major difference" in office-based surgery practices.
Others agreed.
"We probably have the best legislation for this kind of thing nationwide," said Bernard Rosof, senior vice president for corporate relations and health affairs at North Shore-LIJ Health System.
In 1997, Rosof chaired a committee that developed guidelines on office-based surgery. Eight years later he chaired the committee whose recommendations led to the law signed by Gov. Eliot Spitzer in July.
Twenty-six states have some legislation on outpatient surgery, and New York's is the toughest, said Alan Gold, a Great Neck plastic surgeon. Gold is also president of the American Association for Accreditation of Ambulatory Surgery, one of the groups approved to accredit these facilities.\
"This is the law with the most significant degree of enforcement attached to it," he said.
To be accredited every three years by Gold's group, which has 1,100 members nationwide, the applicant must comply with a booklet full of requirements -- ranging from anesthesia to safety equipment to the office layout. In an announced visit, an inspector reviews procedures. A perfect score is required before accreditation is given, Gold said. After that, the group may periodically send in unannounced inspectors.
Arthur Levin, director of the Manhattan-based Center for Medical Consumers, called the law a "huge breakthrough." But Levin and others concede the law, based on sedation levels, may not be broad enough to include all outpatient facilities where invasive and potentially dangerous procedures are done.
Tom McKnight, a doctor from Fremont, Neb., whose wife, Evelyn, was one of 99 people to contract hepatitis C in 2002 at a nearby outpatient cancer treatment clinic -- the largest such outbreak ever -- called the New York law "a step toward reform." But because sedation wasn't used in the clinic where his wife was treated, "the legislation would not have helped Evelyn or any other victims," he said.
And although accreditation would make a doctor like Finkelstein show he understands good infection control, it is not clear under the law whether his infecting a patient with hepatitis C would have been reported as an adverse event, said health department spokeswoman Claudia Hutton. That's because, she said, Finkelstein didn't realize what was happening at the time.
So far, 11 of Finkelstein's former patients have tested positive for hepatitis B and nine for hepatitis C, according to the Nassau County Department of Health. The state health department has said it is impossible to tell whether Finkelstein's office was the source.
Sen. Kemp Hannon (R-Garden City), chairman of the Senate Health Committee, said he and Health Commissioner Richard Daines have discussed trying to find ways to ensure good infection control.
"The current [law] utilizes major accrediting agencies to ensure good practices," he said. "The next question is: Can we use something akin to that for sanitary practices, short of having to inspect 20,000 private offices?"
Copyright © 2008, Newsday Inc.
Posted by Editors at 05:07 PM --- Printer-friendly version
January 17, 2008
Fibrin Glue May Have Transmitted HCV
Used in Japan in the 1980s, a surgical adhesive made from fibrin is another suspect for the transmission of Hepatitis C. Primarily utilized for treating burns, nosebleeds and to aid in plastic surgery, fibrin glue may have been tainted with HCV-infected fibrinogen before proper testing was conducted.
Fibrin glue used for burns, facelifts
The Yomiuri Shimbun
www.yomiuri.co.jp
Fibrin glue, a surgical adhesive linked to the transmission of the hepatitis C virus, was used in a wide variety of areas, such as dealing with burns, stopping nosebleeds or in plastic surgery, according to doctors and other sources.
The tainted glue is estimated to have been used on about 79,000 patients, and those infected with the virus via the glue are eligible for relief under a law enacted Friday offering blanket relief to HCV suffers who contracted the disease through tainted blood products.
However, many patients do not realize the wide extent of the glue's use, causing delays in the investigation into how many patients have been infected with the virus via the glue. "The Health, Labor and Welfare Ministry should alert the public by announcing the names of hospitals that used the glue and for what kind of treatment the glue was often used," said Shiro Iino, former health ministry official in charge of research into issues concerning hepatitis.
The contaminated glue was made from a combination of substances including HCV-tainted fibrinogen manufactured by the defunct Green Cross Corp. mainly between 1981 and 1987. The glue was mostly used for stopping bleeding or as an adhesive during surgery. While it was not formally approved under the Pharmaceutical Affairs Law, Green Cross promoted the glue by issuing a booklet that gave details of how the glue could be used, resulting in many hospitals using it.
A private hospital in western Japan started using the glue from around 1982 as a surgical adhesive when it conducted major skin grafts on patients who had suffered severe burns. "As the glue had hemostatic and adhesive properties, we could conduct surgery quickly. I think we used the glue in treating between 10 to 20 patients a year," a doctor at the hospital said.
The hospital stopped using the glue in the late 1980s, when the risk of hepatitis infection came to light. They have not confirmed any cases of HCV infection via the glue.
"We no longer have the medical records of the patients as the storage term has already expired. But I think it's possible some patients will have contracted HCV via the glue as it was applied directly to the surface of the burned skin," the doctor said. "What has happened to those patients subsequently is a concern."
Meanwhile, a doctor in the ear, nose and throat department of another hospital in western Japan used the glue in the mid-1980s to treat patients suffering from nosebleeds. When it was difficult to identify from which part of the nose a patient was bleeding, the doctor filled the nose with the glue to stop the bleeding. The treatment was conducted on about 20 patients.
Several years ago, the doctor informed patients about the possibility of infection, and recommended them to undergo medical tests. But results obtained did not show any infection.
"As the glue was removed from the nose after treatment, that might have lowered the infection risk," the doctor said.
In the 1980s, the glue was also used in plastic surgery. According to an academic journal, an aesthetic plastic surgeon in Tokyo used the glue as a hemostatic agent or as a surgical adhesive in facelift operations.
According to a report submitted in 2001 to the Health, Labor and Welfare Ministry by the then Welfide Corp., which took over Green Cross, the glue was used in about 270 medical procedures, including some related to the treatment of pneumothorax and stomach ulcers.
(Jan. 15, 2008)
Posted by Editors at 03:15 PM --- Printer-friendly version
Proteomic Profiling Improves Liver Cancer Identification
Boston researchers have demonstrated that proteomics demonstrates a higher specificity and sensitivity for detecting liver cancer than traditional methods. This breakthrough may detect liver cancer tumors earlier, when they are easier to treat.
Proteomic profiling shown more accurate than traditional biomarkers in identifying liver cancer
Contact: Bonnie Prescott
bprescot@bidmc.harvard.edu
617-667-7306
Beth Israel Deaconess Medical Center
www.eurekalert.org
BOSTON – As the incidence of liver cancer continues to grow-- fueled in large part, by rising rates of hepatitis C infections – so too does the need for tests to help diagnose the disease at an earlier stage. A study appearing in the January 15 issue of Clinical Cancer Research demonstrates that a novel mass-spectrometry based form of proteomic profiling is more accurate than traditional biomarkers in distinguishing liver cancer patients from patients with hepatitis C liver cirrhosis, particularly with regard to identifying patients with small, curable tumors. Led by researchers at Beth Israel Deaconess Medical Center (BIDMC), the study could help lead to earlier diagnostic methods – and subsequent treatments -- for liver cancer.
“Proteomics represents a potentially powerful tool for the serologic recognition of protein profiles associated with cancer,” explains co-senior author Towia Libermann, PhD, Director of the Genomics Center at BIDMC and Associate Professor of Medicine at Harvard Medical School.
“Although this particular proteomics technology, SELDI-TOF MS [surface enhanced laser desorption/ionization time of flight mass spectrometry] had already proven capable of identifying liver cancer in some limited studies, this was the first time that the technology was compared side-by-side with the clinical standard biomarker in a cohort of patients at risk for developing the disease,” adds Liebermann, who is also Director of the Dana-Farber/Harvard Cancer Center Proteomics Core in the Division of Interdisciplinary Medicine and Biotechnology at BIDMC.
Over a single decade, the incidence of liver cancer (hepatocellular carcinoma) increased from 1.8 to 2.5 per 100,000 patients, in large part due to a rise in the spread of hepatitis C virus.
“Hepatitis C has become a tremendous public health problem,” explains co-senior author Nezam Afdhal, MD, Director of the Liver Center at BIDMC and Associate Professor of Medicine at Harvard Medical School. “And a significant number of hepatitis C-infected patients will go on to develop liver cirrhosis.” Cirrhosis results when healthy tissue is replaced by scar tissue, preventing the liver from properly functioning. Cirrhosis itself is responsible for more than 25,000 deaths each year. But, adds Afdhal, secondarily, cirrhosis greatly increases a person’s chances of developing liver cancer.
“Each year, cirrhosis patients have a two to five percent chance that their condition will escalate to cancer,” he explains. “And the problem is that, right now, there is no reliable means of detecting liver cancer at an early stage, when surgical treatment is an option. Typically by the time the disease is discovered, the cancer has advanced and treatment options become much more limited.”
The best hope for early detection is cancer biomarkers, serum proteins found in altered amounts in blood or other body fluids. The current biomarker for liver cancer in clinical use is alpha fetoprotein (AFP). In many cases, patients with hepatitis C undergo routine monitoring for AFP levels as an indicator of whether tumors may have developed in their livers.
But, as Libermann explains, the AFP biomarker has a number of shortcomings, including false positives and false negatives. “AFP not only fails to detect many early tumors, but it also lacks specificity. Consequently, elevated AFP levels could be indicators of not only cancer, but also of other liver diseases or even benign conditions, while on the other hand, many patients with small tumors will test negative for AFP.”
The authors, therefore, decided to evaluate the sensitivy and specificity of SELDI-TOF MS for the detection of liver cancer and to compare its effectiveness with AFP.
Examining serum samples of 92 patients – including 51 patients with liver cirrhosis and 41 patients with liver cancer, and among the cancer patients, individuals with both large and small (less than 2 cm) tumors -- by SELDI-TOF mass spectrometry, the investigators were able to identify an 11-protein signature that accurately discriminated between the cirrhosis and cancer patients, first in a training set (made up of 26 cirrhosis and 20 liver cancer patients), and then again in an independent validation set (consisting of 25 cirrhosis and 19 liver cancer patients). The resulting diagnostic value – 74 percent sensitivity and 88 percent specificity – compared favorably with the diagnostic accuracy of AFP (73 percent sensitivity and 71 percent specificity) as well as with two other biomarkers currently in clinical development for liver cancer, AFP-L3 and PIVKA-IL.
“Most strikingly,” notes Libermann, “in patients with small tumors (less than 2 cm), where AFP identified only three, and AFP-L3 and PIVKA-II only one each, the 11-protein signature correctly identified seven of eight patients at this early stage of disease.
“Biomarkers play a major role in all aspects of personalized medicine, not only in early disease detection, but also in outcome prediction and evaluation of therapeutic responses,” he adds. “This study provides strong evidence that serum contains early detection biomarkers and supports the notion that a combination of multiple biomarkers may prove more effective than individual biomarkers for diagnosis of liver cancer, as well as other cancers.”
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This study was funded by grants from the National Institutes of Health.
In addition to Libermann and Afdhal, study coauthors include BIDMC investigators Noah Zinkin MD, and Franck Grall, PhD, (joint first authors), Killimanagalam Bhaskar, MD, Hasan Otu, PhD, Dimitrios Spentzos, MD, Brett Kalmowitz, MD, Meghan Wells, Manuel Guerrero, BSc, and John Asara, PhD.
Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School and consistently ranks among the top four in National Institutes of Health funding among independent hospitals nationwide. BIDMC is clinically affiliated with the Joslin Diabetes Center and is a research partner of Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox. For more information, visit www.bidmc.harvard.edu.
Posted by Editors at 03:11 PM --- Printer-friendly version
Japan Offers Aid to Recipients of HCV Tainted Blood
Lawmakers in Japan have publicly recognized the government's responsibility in Hepatitis C transmission from tainted blood products. While a recently passed bill will offer compensation to those affected, it will be interesting to see if other administrations follow suit.
Saturday, Jan. 12, 2008
Hepatitis C bill offering aid, apology clears Diet
Compiled from staff, Kyodo reports
http://search.japantimes.co.jp
The House of Councilors voted unanimously Friday to enact a law to give uniform relief to people who contracted hepatitis C from tainted blood products.
With the passage of the hepatitis C bill, about 1,000 people, including the 207 hepatitis C plaintiffs who sued the government and drugmakers, will receive an apology and compensation from the government.
In a statement issued following the law's enactment, Prime Minister Yasuo Fukuda said: "We must frankly admit the state's responsibility for causing huge harm to the victims and for failing to prevent the harm from spreading. I express my apologies from my heart."
With the enactment, the plaintiffs plan to conclude a basic agreement Tuesday with the government to pave the way for the pending lawsuits nationwide to be settled out of court.
Watching the Upper House approve the legislation in the chamber, plaintiffs smiled and some wiped away tears. Michiko Yamaguchi, who leads the plaintiffs' group, said, "I feel that the five years of fighting (since the lawsuit was filed in 2002) have at last paid off."
Fukuda plans to meet with the plaintiffs Tuesday.
Stalled negotiations on out-of-court settlements saw a breakthrough after Fukuda announced Dec. 23 his decision as president of the ruling Liberal Democratic Party to seek a lawmaker-sponsored bill to provide blanket relief to the sufferers.
The bill was submitted Monday to the Diet, was passed unanimously Tuesday by the Lower House and was sent to the Upper House for final legislative approval.
Under the law, people who contracted hepatitis C from contaminated blood products, including fibrinogen, will receive compensation ranging from ¥12 million to ¥40 million per person depending on the severity of the case.
The government will provide around ¥20 billion to set up a fund at the Pharmaceuticals and Medical Devices Agency to pay the relief. The drugmakers will also be required to offer contributions.
Gist of hepatitis C relief law
The following is the gist of a law enacted Friday to offer blanket relief for people with hepatitis C caused by tainted blood products:
* The government admits responsibility for causing huge harm to victims and failing to prevent the harm from spreading.
* The law will provide relief to those who contracted hepatitis C from contaminated blood products, such as fibrinogen.
* Victims entitled to relief are required to submit certification as hepatitis C sufferers, such as court rulings.
* Compensation ranging from ¥12 million to ¥40 million per person will be paid depending on the severity of the case and the balance will be paid if the condition worsens within 10 years.
* A fund will be set up to ensure payments, with the government providing the resources.
* The fund will call for drugmakers to provide contributions.
Posted by Editors at 03:08 PM --- Printer-friendly version
January 14, 2008
Hepatitis C, Liver Fibrosis and Marijuana
According to a recently published California study, daily use of marijuana may increase the risk of fibrosis in people with Hepatitis C.
Chronic Marijuana Use May Increase Fibrosis for Hep C Patients
Sunday, January 06 2008 @ 11:05 PM EST
Edited by: Michael Hess
Daily cannabis use increases the risk of liver fibrosis in patients with hepatitis C
http://bbsnews.net
BBSNews 2008-01-06 -- (IACM) According to research at the University of California at San Francisco daily cannabis use was associated with moderate to severe liver fibrosis in 204 patients with hepatitis C. Between 2001 and 2004, participants underwent interviews to assess demographic data, risk factors for HCV, and use of cannabis and alcohol. In addition, virologic testing and liver biopsy was performed.
The median age of the group was 46.8 years, 69 per cent were male, 49 per cent were white. Cannabis use frequency within prior 12 months was daily in 13.7 per cent, occasional in 45.1 per cent, and never in 41.2 per cent. There was no fibrosis in 27.5 per cent, mild fibrosis in 55.4 per cent and moderate to severe fibrosis in 17.2 per cent of subjects.
Current daily cannabis use increased the odds of moderate to severe fibrosis by nearly 7-fold. There was no association between current daily cannabis use and mild fibrosis. A major limitation of the study is the method, since only one examination was performed, which limits the ability to establish a temporal relationship between cannabis use and fibrosis stage.
However, the study confirms an earlier French study of 2004, in which daily cannabis use was also associated with an increased risk for liver fibrosis. Authors conclude that "HCV-infected individuals should be counseled to reduce or abstain from cannabis use."
(Source: Ishida JH, Peters MG, Jin C, Louie K, Tan V, Bacchetti P, Terrault NA. Influence of cannabis use on severity of hepatitis C disease. Clin Gastroenterol Hepatol 2008;6(1):69- 75)
Posted by Editors at 10:38 AM --- Printer-friendly version
ANA598 Shows Potential as an HCV Anti-Viral Drug
Animal studies of Anadys Pharmaceutical's new non-nucleoside Hepatitis C inhibitor have delivered some hopeful results. Although the subjects were primates, ANA598's demonstration of rapid viral load decline, favorable pharmacokinetics, safety, and tolerability profiles support its continued development.
Anadys Pharmaceuticals Announces Positive Results for ANA598 in Animal Model of Chronic Hepatitis C Virus Infection
ANA598 demonstrates significant antiviral activity in vivo
January 03, 2008: 05:49 PM EST
http://money.cnn.com
SAN DIEGO, Jan. 3 /PRNewswire-FirstCall/ -- Anadys Pharmaceuticals, Inc. announced preliminary data today from two studies of ANA598, a non-nucleoside inhibitor of the hepatitis C virus (HCV) NS5B polymerase, in a primate model of chronic HCV infection.
Two animals chronically infected with HCV genotype 1b each received once-daily oral doses of ANA598 at 30 mg/kg for four days. A rapid viral load decline was seen in both animals. At 48 hours (24 hours after the second dose), viral load declines were 2.2 and 2.6 log10 in the individual animals. In one animal the viral load reduction was sustained throughout the remaining dosing period, while in the second animal a modest rise in viral load was seen over days 3 and 4, although the rise observed (0.6 log10) was within the baseline variability seen in this animal prior to dosing.
In a previous study conducted to assess the pharmacokinetics (PK), safety, tolerability and preliminary antiviral activity of ANA598, two HCV genotype 1a infected animals received a single oral dose of ANA598 at 30 mg/kg. At 24 hours after dosing, plasma levels of ANA598 exceeded the replicon EC95 values. At 48 hours after dosing, the mean viral load decline in the two animals was 1.0 log10. ANA598 was well tolerated by all of the animals in both studies.
"These positive animal efficacy data reinforce our continued enthusiasm for development of ANA598 as a potential new direct antiviral treatment for chronic HCV," said Steve Worland, Ph.D., President and Chief Executive Officer of Anadys. "The rapid viral load decline and the favorable PK, safety and tolerability profile demonstrated in these animal efficacy studies further support continued development of ANA598 as a candidate for use in combination with other agents for the treatment of chronic HCV infection."
In June 2007, Anadys announced the nomination of ANA598 as a clinical development candidate. The selection of ANA598 represented the culmination of a comprehensive structure-based drug design program directed towards NS5B. ANA598 was selected based on an optimized balance of preclinical properties, including intrinsic potency as an NS5B inhibitor, cellular activity in the replicon assay, oral bioavailability and early indicators of safety and tolerability. ANA598 is a low-nanomolar inhibitor of HCV genotype 1a and 1b replicons. It exhibits good in vitro metabolic stability properties and does not significantly inhibit or induce cytochrome P450 enzymes. In vivo, ANA598 was well tolerated in 14-day dose range finding (DRF) animal toxicology studies. At doses corresponding to estimated human doses, 24 hour trough plasma concentrations of ANA598 exceeded the EC95 for HCV genotype 1a and 1b replicon inhibition. The EC95 is the concentration required in vitro to suppress hepatitis C viral RNA levels by 95% in the replicon assay.
ANA598 is currently completing IND enabling activities and an IND submission is targeted for the second quarter of 2008. "After completing the necessary IND enabling studies, we look forward to exploring the potential clinical utility of ANA598," said James Freddo, MD, Anadys' Chief Medical Officer. "Based on the in vitro and in vivo potency, pharmacokinetic and preliminary toxicologic properties of ANA598 demonstrated to date, we believe that this is an exciting new direct antiviral to investigate for the treatment of patients with hepatitis C virus infection."
About Anadys
Anadys Pharmaceuticals, Inc. is a biopharmaceutical company dedicated to improving patient care by developing novel medicines in the areas of hepatitis C and oncology. The Company is developing ANA598, a small-molecule, non-nucleoside inhibitor of the NS5B polymerase for the treatment of chronic hepatitis C virus (HCV) infection and ANA773, an oral TLR7 agonist prodrug for cancer.
Safe Harbor Statement
Statements in this press release that are not strictly historical in nature constitute "forward-looking statements." Such statements include, but are not limited to, references to the expected timing and planned development activities for ANA598 and the belief that ANA598 is an exciting new direct antiviral to investigate for the treatment of patients with HCV infection. Such forward-looking statements involve known and unknown risks, uncertainties and other factors, which may cause Anadys' actual results to be materially different from historical results or from any results expressed or implied by such forward-looking statements. For example, the results of preclinical studies, including the animal studies described in this press release, may not be predictive of future results, and Anadys cannot provide any assurances that any of its product candidates will not have unforeseen safety issues, will have favorable results in future clinical trials or will receive regulatory approval. In addition, Anadys' results may be affected by risks related to competition from other biotechnology and pharmaceutical companies, its effectiveness at managing its financial resources, its ability to successfully develop and market products, difficulties or delays in its preclinical studies or clinical trials, difficulties or delays in manufacturing its clinical trials materials, the scope and validity of patent protection for its products, regulatory developments involving future products and its ability to obtain additional funding to support its operations. Risk factors that may cause actual results to differ are more fully discussed in Anadys' SEC filings, including Anadys' Form 10-K for the year ended December 31, 2006 and Anadys' Form 10-Q for the quarter ended September 30, 2007. All forward-looking statements are qualified in their entirety by this cautionary statement. Anadys is providing this information as of this date and does not undertake any obligation to update any forward-looking statements contained in this document as a result of new information, future events or otherwise.
Posted by Editors at 10:25 AM --- Printer-friendly version
January 10, 2008
An Updated Report on Hepatitis C Genotypes
The importance of learning your Hepatitis C genotype is crucial in determining a recommended treatment plan. As researchers discover yet another genotype, prescribed medicines will become increasingly tailored to each individual's Hepatitis C infection.
by Nicole Cutler, L.Ac.
As more detailed information becomes known about any illness, treatment strategies can be increasingly focused on that specific ailment. Treating viral hepatitis exemplifies the advantage of increasing therapeutic specificity. Because higher success rates are associated with how well the hepatitis strain is matched with its prescribed therapy, differentiation between infections is paramount.
Brief History of Viral Hepatitis
Although outbreaks of epidemic jaundice were known in both Greek and Roman times, viral hepatitis was first recognized as a distinct clinical entity in the United States and Europe during the late 18th and early 19th centuries. Originally, viral hepatitis was classified by its route of transmission:
· Through oral and/or fecal route (infectious)
· Through the blood (serum)
During World War II, these two types of viral hepatitis were officially acknowledged; infectious hepatitis was designated as Hepatitis A and serum hepatitis became known as Hepatitis B.
In 1977, the Hepatitis D virus was detected and the development of serological assays for Hepatitis A and Hepatitis B proved that additional hepatitis viruses existed. Hepatitis due to viruses other than the Hepatitis A, Hepatitis B or Hepatitis D viruses were referred to as non-A, non-B hepatitis. In the late 1980s, those infected with non-A, non-B hepatitis were further differentiated with the identification of two more viruses: Hepatitis C and Hepatitis E.
Hepatitis C Classification
Although discovering the root of someone’s liver disease as Hepatitis C is a task in and of itself, there is much more differentiation required to properly address this virus. As of late 2007, the number of known genotypes for Hepatitis C (the genetic make-up of the virus) grew from six to seven distinct viruses. In addition to being classified by genotype, there are over 50 known subtypes of Hepatitis C. As of the end of December 2007, the newly acknowledged genotype 7 has been associated with three separate subtypes.
Hepatitis C genotypes are most common in the following locations:
· Genotypes 1, 2 and 3 = North America and Western Europe
· Genotype 4 = Africa, Egypt and the Middle East, but is increasingly seen in some parts of Europe
· Genotype 5 = Africa and the Middle East
· Genotype 6 = Southeast Asia
· Genotype 7 = Central Africa
In order to prescribe a treatment plan with the highest chances of success, a person must have their particular Hepatitis C genotype and subtype identified. Additionally, knowing the exact strain of Hepatitis C virus is helpful in defining its epidemiology. Once the genotype is identified, it need not be tested again; genotypes do not change during the course of infection.
While the therapeutic responses between Hepatitis C subtypes are not disclosed here, some of the differences among genotypes include:
1. Those with genotypes 2 and 3 are almost three times more likely than patients with genotype 1 to respond to therapy with alpha interferon or the combination of alpha interferon and ribavirin.
2. A 24-week course of combination treatment is typically adequate for those with genotypes 2 and 3.*
3. A 48-week course of combination treatment is typically adequate for those with genotype 1.*
4. Data are mixed concerning genotype 4, though its response to combination treatment seems to be somewhere in between the response of genotypes 2 and 3, and genotype 1.
5. Recently published research on treating genotype 5 shows that its response to combination treatment is similar to those with genotype 1. However, previous results show that genotype 5 appears to be an easy to treat virus with response rates similar to those of genotypes 2 and 3 after a 48-week course of therapy.
6. Preliminary study results show that the response to treatment in those with genotype 6 lies at an intermediate level, between that seen with genotype 1 and genotypes 2 or 3.
7. Since it has just recently been discovered as having a distinct genetic make-up, the response to standard combination therapy is not yet established for genotype 7.
*Although some studies claim this duration of time to be ‘typically adequate,’ other trials have demonstrated that longer courses of treatment have lower relapse rates.
Our understanding of the various strains of the Hepatitis C virus is exponentially greater than the knowledge of viral hepatitis just a few decades ago. As more specificity about each type of viral infection is discerned, treatment approaches can be individually tailored. The one-size-fits-all method of prescribing medications is continually shown to be outdated, causing our medical practices to become more advanced. Accompanying this more advanced evolution of infectious hepatology, people fighting Hepatitis C stand their best chance ever of ridding themselves of their particular viral strain.
References:
M. H. Nguyen, E. B. Keefe, Prevalence and treatment of hepatitis C virus: genotypes 4, 5, and 6, Clinical Gastroenterology and Hepatology, October 2005.
www.abbottdiagnostics.com, Hepatitis Learning Guide, Abbott Laboratories, 2006.
www.cdc.gov, Frequently Asked Questions About Hepatitis C, Centers for Disease Control and Prevention, 2007.
www.hivandhepatitis.com, Epidemiology and Treatment Response of Genotype 5 HCV: Researchers Find New Seventh Genotype, Liz Highleyman, hivandhepatitis.com, 2007.
www.stanford.edu, The History of Hepatitis, Tiffany Chang, Stanford University, 1999.
Posted by Editors at 03:04 PM --- Printer-friendly version
January 02, 2008
Weight-Based Ribavirin Dosing = Superior Hepatitis C Treatment
A substantial, five-year study confirms that when it comes to treating Hepatitis C, one size does not fit all. When combined with pegylated interferon, researchers discovered basing the dosage of ribavirin on a patient's weight could yield better results than giving all participants a flat dosage of ribavirin. In addition, the weight-based ribavirin dosage demonstrated a clear advantage to African Americans with Hepatitis C, whose outcomes has previously lagged behind those of Caucasian patients.
Weight-based Dosing Of Ribavirin Improves Outcomes For Patients With Hepatitis C
www.sciencedaily.com
ScienceDaily (Oct. 26, 2007) — Patients with hepatitis C treated with combination therapy of pegylated interferon and ribavirin had better outcomes when taking a weight-based dosage of ribavirin compared to a flat dosage. This treatment technique also improved the response rates of African American patients, whose outcomes have lagged behind those of Caucasian patients. These findings are in the October issue of Hepatology, a journal published by John Wiley & Sons on behalf of the American Association for the Study of Liver Diseases (AASLD).
Combination therapy of pegylated interferon and ribavirin is the standard of care for patients with chronic hepatitis C, allowing more than half to achieve a sustained viral response. However, previous studies have suggested that a weight-based dose of ribavirin might lead to even better results. To examine this possibility, researchers, led by Ira Jacobson of Cornell University, conducted a large, multi-center, randomized, prospective, open-label study between December 2000 and June 2005.
They enrolled 5,027 patients with hepatitis C from more than 200 centers around the country. All participants were 18 to 70 years old, weighed less than 125 kg, had detectable HCV RNA in their blood, and had never been treated for it. They were randomly assigned to receive interferon and a flat dose of ribavirin (800 mg/day), or interferon and a weight-based dose of ribavirin, which started at 800 mg/day for patients weighing under 65 kg, and increased by 200 mg/day for up to each additional 20 kg of weight up to a maxiumum dose of 1400 mg. Those with HCV genotype 2 or 3, which is more responsive to interferon-based therapy, also tested treatment durations of 24 and 48 weeks. Each patient was followed up for 24 weeks after treatment.
"A sustained viral response was achieved by significantly more patients who received a weight-based dose (44.2 percent) than fixed dose (40.5 percent) ribavirin," the authors report. "Overall, response rates decreased as weight increased when a fixed dose was used but remained unaltered with a weight-based dose." Discontinuation rates and reported adverse events did not differ significantly between the two treatment schemes, and relapse rates were lower for patients who had received weight-based dosing. The researchers also found that 48 weeks of treatment offered no additional benefit compared to 24 weeks for patients with genotypes 2 or 3..
Another group of researchers from the same study, also lead by Jacobson, used the study data to understand the impact of weight-based ribavirin with peginterferon alfa-2b in African American patients with HCV genotype 1. Genotype 1 is the hardest to treat, and it afflicts African Americans disproportionately.
Three hundred eighty seven African American patients with genotype 1 were included in the analysis: of those weighing 65 kg or more, and therefore receiving different doses of ribavirin in each arm, 188 had received flat-dose ribavirin, and 174 had received weight-based dosing. Significantly fewer patients in the flat-dose group (10 percent) attained a sustained virological response, compared to 21 percent in the flat-dose group. Relapse rates were 30 percent and 22 percent, respectively.
"An unexpected finding of our study was the increase in efficacy with an increase in ribavirin dose in heavier patients," the authors report. That is, sustained viral response rates increased as body weight increased, suggesting that "ribavirin distribution may be more complex than realized and body weight may only approximate the marker for size required to dose RBV consistently," the authors say.
In conclusion, weight-based dosing of ribavirin offered a significant advantage in efficacy of treatment for African American patients, however, the rate of sustained viral response in this population remains low. "Further studies are needed to elucidate the fundamental basis for the impaired responsiveness in this population," they say.
In an accompanying editorial, Steven-Huy Han, MD and Jason Smith, PharmD of Los Angeles, report that this study adds significantly to our understanding of interferon therapy in African American patients. It will change the approach to ribavirin dosing and will benefit a difficult-to-treat population.
They suggest that the larger question of whether true weight-based dosing of ribavirin is superior to the currently approved standard dosing schemes still awaits head-to-head studies to answer. "At the minimum," they conclude, "the traditional notion that ribavirin dosage should be fixed has now been sidelined by the idea that we should tailor ribavirin dosing to our patients."
Article: "Peginterferon alfa-2b and Weight-Based or Flat-Dose Ribavirin in Chronic Hepatitis C Patients: A Randomized Trial." Jacobson, Ira; Brown, Robert; Freilich, Bradley; Afdhal, Nezam; Kwo, Paul; Santoro, John; Becker, Scott; Wakil, Ed; Pound, David; Godofsky, Eliot; Strauss, Robert; Bernstein, David; Flamm, Steven; Pauley, Mary Pat; Griffel, Louis; Brass, Clifford A. Hepatology; October 2007; (DOI: 10.1002/hep.21932).
Adapted from materials provided by John Wiley & Sons, Inc.
Posted by Editors at 04:12 PM --- Printer-friendly version
Cirrhosis to Liver Cancer: Progression May be Genetic
Collaboration between French and American researchers has uncovered a possible genetic link among those who progress from cirrhosis to liver cancer. If this genetic variation is confirmed to be behind the development of hepatocellular carcinoma, this gene will be evaluated in cirrhotic patients and may be the basis for future therapies.
Gene Variation May Elevate Risk Of Liver Tumor In Patients With Cirrhosis
www.sciencedaily.com
ScienceDaily (Jan. 2, 2008) — A particular gene variation appears to significantly increase the risk that individuals with cirrhosis of the liver will go on to develop hepatocellular carcinoma (HCC), a liver tumor that is the third leading cause of cancer death. Researchers from Massachusetts General Hospital (MGH) Cancer Center and colleagues in France describe finding that a single alteration in the epidermal growth factor (EFG) gene may greatly increase the risk of developing HCC.
"If these results are confirmed, this EGF variation could be used to determine which cirrhotic patients should be screened more intensively for tumor development," says Kenneth Tanabe, MD, chief of Surgical Oncology at the MGH Cancer Center, the study's lead author. "In addition, the molecular pathway controlled by EGF and its receptor EGFR -- which is known to be important in several types of cancer -- appears to be an excellent target for chemoprevention studies. This is a deadly cancer and so progress in prevention and early detection is critically important."
HCC is the sixth most common solid tumor worldwide and most commonly develops in individuals with cirrhosis, which may be caused by infection with the hepatitis B or C viruses. There are currently no effective treatments for most HCC patients, so there is considerable interest in strategies that may prevent development of the tumor.
EGF's normal function is to stimulate tissue growth. Animal studies have shown that elevated levels of this protein in the liver lead to tumor development and that blocking the protein's receptor can prevent development of liver cancer. The current study was designed to determine whether cirrhotic patients with higher EGF levels are at greater risk for liver cancer and to determine the influence of a particular inherited gene on EGF levels in cirrhotic patients.
The researchers focused on a known variation in the EGF gene -- the presence of the nucleotide guanine (G) instead of the more common adenine (A) in a particular location -- which has been shown to increase EGF secretion in blood cells and raise the risk for malignant melanoma. Individuals inherit one copy of the gene from each parent and therefore have this gene with either two copies of A (A/A), two copies of G (G/G), or one copy of each (A/G). Genetic analysis of liver tumor cell lines showed that messenger RNA transcribed from DNA strands with the G allele was more stable that that transcribed from the A version, which could explain why cells with two G copies tend to secrete higher levels of EGF.
The researchers then studied tissue samples from all patients in the MGH Cancer Center Tumor Bank who had cirrhosis. Among the 207 patients with cirrhosis, most of whom were infected with the hepatitis C virus, 59 also had HCC. Patients with at least one copy of the G nucleotide had a significantly higher risk of developing HCC than did A/A patients -- ranging from a more than twofold increase for those with one G to an over fourfold increase for those with two G alleles. In all three genotypes, tissue analysis showed that EGF levels were highest in the G/G patients, as was activation of the EGFR receptor. In addition, blood levels of EGF were highest in those with two copies of the G allele.
To confirm these finding in a different patient population, the MGH team worked with colleagues from the Paul Brousse Hospital in Paris. Samples from this group, all of whom had alcoholic cirrhosis, also showed that patients with the G/G version of the EGF gene had a significantly greater risk of developing the liver tumor than did the A/A patients, in this instance an almost threefold risk increase.
In both the MGH and French study groups, controlling for factors such as age and gender did not change the increased risk associated with the G allele. While both groups primarily consisted of Caucasian patients, in the MGH group, it was noted that the G allele was more common among Asian patients; and it is well known that more than half the cases of HCC worldwide occur in China.
"We now need to prospectively study EGF levels in cirrhotic patients, to see if elevated levels will correlate with a greater risk of developing HCC, and look at factors such as diet, drugs or ethnicity that may modulate EGF levels," Tanabe says. "I think this is a terrific opportunity to see if targeting a specific pathway will prevent HCC in this group of patients, who are at risk for liver cancer because of their cirrhosis." Tanabe is an associate professor of Surgery at Harvard Medical School.
This research was published in the January 2 issue of JAMA.
The study was supported by grants from the National Institutes of Health, the MGH Department of Surgery, Tucker Gosnell Gastrointestinal Cancer Center, and the Fund for Medical Discovery. Co-authors of the JAMA article are Dianne Finkelstein, PhD, Hiroshi Kawasaki, Tsutomu Fujii, MD, PhD, Raymond Chung, MD, Gregory Lauwers, MD, Yakup Kulu, Alona Muzikansky, Darshini Kuruppu, PhD, Michael Lanuti, MD, Jonathan Goodwin and Bryan Fuch, PhD, of the MGH; and Antoinette Lemoine, MD, and Daniel Azoulay, MD, PhD, Paul Brousse Hospital, Paris.
Adapted from materials provided by Massachusetts General Hospital.
Posted by Editors at 04:08 PM --- Printer-friendly version