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TOUCH MY HEART
Touch my heart and I'll touch yours
With a gentle word or two
For kindness bears the sweetest fruit
That makes our dreams come true.
Touch my life with tenderness
And fill my cup with love
Share my dreams as i share yours
Beyond the stars above.
Take my hand as i grow old
And lead me when when I'm blind
Show me that you really care
Good friends are hard to find.
Touch my heart and I'll touch yours
A little more each day
And then we both find happiness
Somewhere along the way..
- Author Unknown -
Sunday, March 29, 2009
How common is sexual transmission of Hep C
From the Mayo Clinic
Question
Hepatitis C: How common is sexual transmission?
How common is sexual transmission of hepatitis C?
Answer
from James M. Steckelberg, M.D.
Hepatitis C is transmitted primarily by exposure to blood containing the hepatitis C virus. Transmission rarely occurs from exposure to other infected body fluids, such as semen.
If you're in a long-term, monogamous relationship with a partner who has hepatitis C, your risk of sexual transmission is low — 0 percent to 0.6 percent a year. For monogamous couples, the Centers for Disease Control and Prevention (CDC) doesn't recommend routine condom use to prevent transmission. But couples should avoid sharing razors, toothbrushes and nail clippers. The risk of transmission is slightly higher — about 1 percent a year — if you have multiple short-term sexual relationships with partners who have hepatitis C. This risk increases if a partner is also infected with HIV. Under these circumstances, the CDC recommends routine condom use to reduce your risk of transmission. If you're concerned about hepatitis C, talk to your doctor. Hepatitis C can be diagnosed by a blood test. Treatment may include medications to help clear the virus from the bloodstream.
Question
Hepatitis C: How common is sexual transmission?
How common is sexual transmission of hepatitis C?
Answer
from James M. Steckelberg, M.D.
Hepatitis C is transmitted primarily by exposure to blood containing the hepatitis C virus. Transmission rarely occurs from exposure to other infected body fluids, such as semen.
If you're in a long-term, monogamous relationship with a partner who has hepatitis C, your risk of sexual transmission is low — 0 percent to 0.6 percent a year. For monogamous couples, the Centers for Disease Control and Prevention (CDC) doesn't recommend routine condom use to prevent transmission. But couples should avoid sharing razors, toothbrushes and nail clippers. The risk of transmission is slightly higher — about 1 percent a year — if you have multiple short-term sexual relationships with partners who have hepatitis C. This risk increases if a partner is also infected with HIV. Under these circumstances, the CDC recommends routine condom use to reduce your risk of transmission. If you're concerned about hepatitis C, talk to your doctor. Hepatitis C can be diagnosed by a blood test. Treatment may include medications to help clear the virus from the bloodstream.
Saturday, March 28, 2009
Possible future Hep C vaccination
The study is to be published by the Journal of General Virology and is available in the journal's March 4 pre-print online edition.www.upi.com
Copyright 2009 by United Press International
Investigation of a role for lysine residues in non-structural proteins 2 and 2/3 of the hepatitis C virus for their degradation and virus assemblySarah Welbourn1, Vlastimil Jirasko2, Valérie Breton1, Simon Reiss2, Francois Penin3, Ralf Bartenschlager2 and Arnim Pause1,4
1 McGill University;2 University of Heidelberg;3 Université de Lyon
4 E-mail: arnim.pause@mcgill.ca
It has been demonstrated that both uncleaved, enzymatically inactive NS2/3 and cleaved NS2 proteins are rapidly degraded upon expression in cells, phenomena described to be blocked by the addition of proteasome inhibitors. As this degradation and its regulation potentially constitute an important strategy of the hepatitis C virus (HCV) to regulate the levels of its non-structural proteins, we further investigated the turnover of these proteins in relevant RNA replication systems. A lysine-mutagenesis approach was used in an effort to prevent protein degradation and determine any effect on various steps of the viral replication cycle. We show that while NS2-lysine mutagenesis of protease-inactive NS2/3 results in a partial stabilisation of this protein, the increased levels do not rescue the inability of NS2/3 protease inactive replicons to replicate, suggesting that uncleaved NS2/3 is unable to functionally replace NS3 in RNA replication. Furthermore, we show that the cleaved NS2 protein is rapidly degraded in several transient and stable RNA replicon systems and that NS2 from several different genotypes also has a short half-life, highlighting the potential importance of the regulation of NS2 levels for the viral life cycle. However, in contrast to uncleaved NS2/3, neither ubiquitin nor proteasomal degradation appear to be significantly involved in NS2 degradation. Finally, although NS2 lysine to arginine mutagenesis does not affect this protein's levels in a JFH-1 cell culture infection system, several of these residues are identified to be involved in virion assembly, further substantiating the importance of regions of this protein for production of infectious virus.
Received 24 December 2008; accepted 29 January 2009.
Copyright 2009 by United Press International
Investigation of a role for lysine residues in non-structural proteins 2 and 2/3 of the hepatitis C virus for their degradation and virus assemblySarah Welbourn1, Vlastimil Jirasko2, Valérie Breton1, Simon Reiss2, Francois Penin3, Ralf Bartenschlager2 and Arnim Pause1,4
1 McGill University;2 University of Heidelberg;3 Université de Lyon
4 E-mail: arnim.pause@mcgill.ca
It has been demonstrated that both uncleaved, enzymatically inactive NS2/3 and cleaved NS2 proteins are rapidly degraded upon expression in cells, phenomena described to be blocked by the addition of proteasome inhibitors. As this degradation and its regulation potentially constitute an important strategy of the hepatitis C virus (HCV) to regulate the levels of its non-structural proteins, we further investigated the turnover of these proteins in relevant RNA replication systems. A lysine-mutagenesis approach was used in an effort to prevent protein degradation and determine any effect on various steps of the viral replication cycle. We show that while NS2-lysine mutagenesis of protease-inactive NS2/3 results in a partial stabilisation of this protein, the increased levels do not rescue the inability of NS2/3 protease inactive replicons to replicate, suggesting that uncleaved NS2/3 is unable to functionally replace NS3 in RNA replication. Furthermore, we show that the cleaved NS2 protein is rapidly degraded in several transient and stable RNA replicon systems and that NS2 from several different genotypes also has a short half-life, highlighting the potential importance of the regulation of NS2 levels for the viral life cycle. However, in contrast to uncleaved NS2/3, neither ubiquitin nor proteasomal degradation appear to be significantly involved in NS2 degradation. Finally, although NS2 lysine to arginine mutagenesis does not affect this protein's levels in a JFH-1 cell culture infection system, several of these residues are identified to be involved in virion assembly, further substantiating the importance of regions of this protein for production of infectious virus.
Received 24 December 2008; accepted 29 January 2009.
Through the Storm
Through The Storm
I did not know his love before, the way I know it now. I could not see my need for Him, my pride would not allow. I had it all, without a care, the "Self-Sufficient" lie. My path was smooth, my sea was still, not a cloud was in my sky. I thought I knew His love for me, I thought I'd seen His grace, I thought I did not need to grow, I thought I'd found my place. But then the way grew rough and dark, the storm clouds quickly rolled; The waves began to rock my ship, my anchor would not hold. The ship that I had built myself was made of foolish pride. It fell apart and left me bare, with nowhere else to hide. I had no strength or faith to face the trials that lay ahead, and so I simply prayed to Him and bowed my weary head. His loving arms enveloped me, and then He helped me stand. He said, "You still must face this storm, but I will hold your hand." So through the dark and lonely night He guided me through the pain. I could not see the light of day or when the storm might wane. Yet through the aches and endless tears, my faith began to grow. I could not see it at the time, but my light began to glow. I saw God's love in brand new light, His grace and mercy, too. For only when all self was gone could God`s love shine through. It was not easy in the storm, I sometimes wondered, "Why?"At times I thought, "I can't go on. "I'd hurt, and doubt, and cry. But He never left my side, He guided me each day. Through pain and strife, through fire and flood, He helped me all the way. And now I see as never before how great His love can be. How in my weakness He is strong, how He cares for me! He worked it all out for my good, although the way was rough. He only sent what I could bear, and then He cried, "Enough!" He raised his hand and said, "Be still!" He made the storm clouds cease. He opened up the gates of joy and flooded me with peace. I see His face now clearer still, I felt His presence strong. I found anew his faithfulness, He never did me wrong. Now I know more storms will come, but only for my good, for pain and tears have helped me grow as naught else ever could. I still have so much more to learn as He works in me; If in the storm I'll love Him more, that's where I want to be.
Author
Wendy Greiner
I did not know his love before, the way I know it now. I could not see my need for Him, my pride would not allow. I had it all, without a care, the "Self-Sufficient" lie. My path was smooth, my sea was still, not a cloud was in my sky. I thought I knew His love for me, I thought I'd seen His grace, I thought I did not need to grow, I thought I'd found my place. But then the way grew rough and dark, the storm clouds quickly rolled; The waves began to rock my ship, my anchor would not hold. The ship that I had built myself was made of foolish pride. It fell apart and left me bare, with nowhere else to hide. I had no strength or faith to face the trials that lay ahead, and so I simply prayed to Him and bowed my weary head. His loving arms enveloped me, and then He helped me stand. He said, "You still must face this storm, but I will hold your hand." So through the dark and lonely night He guided me through the pain. I could not see the light of day or when the storm might wane. Yet through the aches and endless tears, my faith began to grow. I could not see it at the time, but my light began to glow. I saw God's love in brand new light, His grace and mercy, too. For only when all self was gone could God`s love shine through. It was not easy in the storm, I sometimes wondered, "Why?"At times I thought, "I can't go on. "I'd hurt, and doubt, and cry. But He never left my side, He guided me each day. Through pain and strife, through fire and flood, He helped me all the way. And now I see as never before how great His love can be. How in my weakness He is strong, how He cares for me! He worked it all out for my good, although the way was rough. He only sent what I could bear, and then He cried, "Enough!" He raised his hand and said, "Be still!" He made the storm clouds cease. He opened up the gates of joy and flooded me with peace. I see His face now clearer still, I felt His presence strong. I found anew his faithfulness, He never did me wrong. Now I know more storms will come, but only for my good, for pain and tears have helped me grow as naught else ever could. I still have so much more to learn as He works in me; If in the storm I'll love Him more, that's where I want to be.
Author
Wendy Greiner
Friday, March 27, 2009
Heptocellular Carcinoma Trends in the U.S.A. 1975-2005
Hepatocellular Carcinoma Incidence, Mortality, and Survival Trends in the United States From 1975 to 2005: "Age-adjusted HCC incidence rates tripled between 1975 and 2005"
Journal of Clinical Oncology, Vol 27, No 9 (March 20), 2009: pp. 1485-1491
Sean F. Altekruse, Katherine A. McGlynn, Marsha E. Reichman
From the Division of Cancer Control and Population Sciences, and the Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD.
"This report may underestimate recent increases in HCC incidence rates because of delays in reporting16 and an estimated rate of under-reporting of 2.5% because of absence of data on Veterans' Affairs hospital patients,5 a population which may be at elevated risk for HCC compared with the general population.45 Despite these limitations, the findings strongly suggest that HCC incidence and mortality continue to increase in the United States. In addition, this report provides reason for optimism that, with more HCC screening of high-risk groups and treatment of low-stage disease, the burden of HCC can be lessened." "Much of the increase in incidence between 2000 and 2005 occurred among men age 50 to 59 years. Not all racial/ethnic groups were equally affected, with black, Hispanic, and white men experiencing the greatest increases. Between 2003 and 2005, for both sexes, blacks in this age group had higher incidence rates than Asian/Pacific Islanders. The changing racial pattern of HCC in this age group may be partially attributable to an epidemic of HCV infection that occurred approximately four decades earlier, in the 1960s, when they were young adults" "High-risk individuals include cirrhotic patients, adult HBV carriers, and persons infected with HCV. Gaps in HCC screening in the United States include limited HCV testing of current and former injected drug users,33 pre-1990 transfusion recipients,34 and incomplete HBV testing of foreign-born Asians/Pacific Islanders.35 In addition, cultural and economic barriers to HCC screening of chronic viral carriers exist." "Asians/Pacific Islanders had the highest age-adjusted HCC incidence rates throughout the period, followed by Hispanics, blacks, American Indians/Alaska Natives and whites (Table 1). Although Asians/Pacific Islanders had the highest incidence, they experienced a smaller annual percent change in HCC incidence rates (annual percent change [APC] = 1.0%) than other racial/ethnic groups. American Indians/Alaska Natives experienced the greatest significant increase (APC = 5.0%), followed by blacks (APC = 4.9%), whites (APC = 4.6%), and Hispanics (APC = 4.0%)."
ABSTRACT
Purpose- Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide. Incidence rates are increasing in the United States. Monitoring incidence, survival, and mortality rates within at-risk populations can facilitate control efforts.
Methods
Age-adjusted incidence trends for HCC were examined in the Surveillance, Epidemiology, and End Results (SEER) registries from 1975 to 2005.. Age-specific rates were examined for birth cohorts born between 1900 and 1959. Age-adjusted incidence and cause-specific survival rates from 1992 to 2005 were examined in the SEER 13 registries by race/ethnicity, stage, and treatment. United States liver cancer mortality rates were also examined.
Results
Age-adjusted HCC incidence rates tripled between 1975 and 2005. Incidence rates increased in each 10-year birth cohort from 1900 through the 1950s. Asians/Pacific Islanders had higher incidence and mortality rates than other racial/ethnic groups, but experienced a significant decrease in mortality rates over time. From 2000 to 2005, marked increases in incidence rates occurred among Hispanic, black, and white middle-aged men. Between 1992 and 2004, 2- to 4-year HCC survival rates doubled, as more patients were diagnosed with localized and regional HCC and prognosis improved, particularly for patients with reported treatment. Recent 1-year survival rates remained, however, less than 50%.
Conclusion
HCC incidence and mortality rates continue to increase, particularly among middle-aged black, Hispanic, and white men. Screening of at-risk groups and treatment of localized-stage tumors may contribute to increasing HCC survival rates in the United States. More progress is needed.
INTRODUCTION
Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide.1 This malignancy occurs more often among men than women, with the highest incidence rates reported in East Asia.2 The incidence rates of HCC in the United States have historically been lower than in many countries. However, in recent decades, HCC age-adjusted incidence rates have doubled3 and primary liver cancer mortality rates have increased faster than mortality rates for any other leading cause of cancer.4,5 Approximately 90% of primary liver cancers in the United States are HCCs, while most of the remaining 10% are intrahepatic cholangiocarcinomas.6 The pathway leading to HCC generally begins with an acute hepatic insult which progresses over decades. Fibrosis and cirrhosis are typically precursors of HCC.7 Among patients with localized stage HCC, treatment options may include resection or transplantation. Chemoembolization, a combination of chemotherapy and occlusion of the tumor blood supply, is reported to improve survival in well-selected patients with unresectable HCC.8 Many patients who are diagnosed with HCC, however, have advanced disease and are only candidates for palliative care, contributing to a relatively low reported 5-year survival rate of approximately 10%.6 Most HCC is thought to be associated with either chronic hepatitis C virus (HCV) or hepatitis B virus (HBV) infection.9 In the United States, more than 3 million people are chronically infected with HCV.10 Many of these individuals were exposed as young adults beginning in the 1960s.10,11 HCV risk factors include contaminated blood product transfusion and injected drug use.10,11 Chronic infection with HBV, a major global risk factor for HCC, is less common overall in the United States than HCV infection is. Among some United States' ethnic groups, however, HBV is a more common risk factor than HCV. For example, a report from Los Angeles found that 74% of HCC among Asians was linked to HBV, while 90% of HCC in whites was linked to HCV.9 The etiology of HCC is likely to involve interactions between multiple risk factors. In a study which utilized the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked databases,12 the most commonly reported risk-factor was nonspecific cirrhosis (21%), followed by alcohol-induced liver disease (16%), HCV infection (10%), and HBV infection (5%). Obesity and type II diabetes6 are also suspected to increase risk. To monitor changes in the burden of HCC in the United States, this report provides analyses of incidence and survival of HCC and mortality of liver cancer. To define at-risk populations, data were examined by sex, race/ethnicity, and age.
DISCUSSION
The principal findings in this report were that incidence rates of HCC tripled in the United States from 1975 through 2005, with marked recent increases among middle-aged black, Hispanic, and white males; there was a birth-cohort effect on risk; and overall 1-year cause-specific survival rates for new HCC patients nearly doubled from 1992 to 2004 as more patients were diagnosed with low-stage HCC and their prognosis improved. Increases in cause-specific survival rates were experienced by all racial and ethnic groups, except for American Indians/Alaska Natives. However, despite increasing HCC survival rates, improvement is needed, with the 1-year cause-specific survival rate remaining lower than 50%. Much of the increase in incidence between 2000 and 2005 occurred among men age 50 to 59 years. Not all racial/ethnic groups were equally affected, with black, Hispanic, and white men experiencing the greatest increases. Between 2003 and 2005, for both sexes, blacks in this age group had higher incidence rates than Asian/Pacific Islanders. The changing racial pattern of HCC in this age group may be partially attributable to an epidemic of HCV infection that occurred approximately four decades earlier, in the 1960s, when they were young adults.10 Several findings in this report suggest, however, that risk of HCC is likely to be driven by additional factors. There has been a steady increase in age-adjusted HCC incidence rates among men and women since 1975. Age-specific rates have increased in each successive birth cohort between 1900 and 1959. Etiologic studies of recent HCC patients are recommended to elucidate factors contributing to the ongoing increase in HCC incidence. In contrast with other racial groups, most Asians/Pacific Islanders with HCC were born outside the United States. This predominance of foreign births is consistent with HBV infection being a major risk factor among most groups of Asians/Pacific Islanders9,20 as chronic HBV infection is notably more common in eastern Asian countries than in the United States, with higher HCC incidence rates among Southeast Asians compared with Filipinos, Japanese, and Asian Indians/Pakistanis.19 An exception is Japan, where more HCC patients are linked to HCV infection than HBV infection.21 The modest increase in HCC incidence rates and decrease in liver cancer mortality rates from 1992 to 2005 suggests that Asians/Pacific Islander populations born in the United States have, thus far, not been as affected by the factors that are driving the HCC increases in other populations. Worldwide, the incidence of HCC among Asians/Pacific Islanders is likely to decline as HBV vaccination becomes more widespread in Asian countries.22 In this study, HCC incidence rates among Hispanics were lower than among Asians/Pacific Islanders, but higher than among whites. Approximately one half of Hispanic HCC patients were born in the United States. In contrast to Asians/Pacific Islanders, HCC incidence rates are reported to be higher among Hispanics born in the United States than among foreign-born Hispanics.23 This suggests that factors associated with life in the United States, perhaps including HCV infection,10 alcohol abuse,24 or obesity,25 may be adversely affecting Hispanic populations.
Despite a paucity of new therapies for HCC during the surveillance years in this report, 1-year cause-specific survival rates for HCC nearly doubled between 1992 to 1993 and 2003 to 2004. This supports earlier evidence that survival rates for HCC are increasing.26 Initially, the increase in survival was restricted to short-term follow-up27; however, in this report 4-year survival rates doubled and 5-year survival rates increased by more than 60%. Furthermore, more patients were diagnosed with localized and regional stage HCC and survival rates increased for these patients. With greater awareness of HCC, more patients are being diagnosed with asymptomatic disease via active screening employing serum alpha-fetoprotein testing, abdominal ultrasound, and diagnostic imaging.28 Furthermore, aggressive treatments including transplantation and resection of localized-stage tumors appear to be improving long-term survival.29 The advent of targeted HCC therapies holds promise for further improvement in prognosis among patients with regional and distant-stage HCC.30 Racial variation was seen in 1-year cause-specific survival rates. In 2003 to 2004, survival was greatest among Asians/Pacific Islanders (49%) and lowest among blacks (40%) and American Indians/Alaska Natives (41%). In another study, racial and ethnic variations in survival were partially explained by stage at diagnosis and the therapy received by blacks and Hispanics compared with whites.26 While improvements in survival are needed across all racial and ethnic groups, blacks and American Indians/Alaska Natives may particularly benefit from targeted HCC control efforts. Coordination of existing HCC prevention efforts is needed. Primary HCC prevention measures include hepatitis B vaccination programs,22 screening of the blood supply for hepatitis viruses,31 and campaigns to discourage intravenous drug abuse. Secondary prevention measures focus on detecting asymptomatic HCC among at-risk individuals28 through periodic screening of high-risk patients by ultrasound, with follow-up tests when suspicious lesions are detected.32 High-risk individuals include cirrhotic patients, adult HBV carriers, and persons infected with HCV. Gaps in HCC screening in the United States include limited HCV testing of current and former injected drug users,33 pre-1990 transfusion recipients,34 and incomplete HBV testing of foreign-born Asians/Pacific Islanders.35 In addition, cultural and economic barriers to HCC screening of chronic viral carriers exist.36,37 Tertiary measures for HCC vary by stage of disease and comorbidity but include surgical resection, transplantation, radiofrequency ablation, and chemoembolization.28 A SEER-Medicare linked study of HCC patients diagnosed in the 1990s indicated that only one third of cases with favorable tumor features received potentially curative therapy.38 A limitation of this study is the absence of information on risk factors. There is a need for studies to estimate the current proportion of HCCs that are attributed to HCV and to HBV including differences across demographic groups.9,39 Studies are needed of the oncogenic potential of viral genotypes.40,41 Associations with suspected cofactors for HCC should also be examined, including alcoholism24 and steatohepatitis,25 obesity,42 diabetes mellitus,43 and iron storage diseases.44 This report may underestimate recent increases in HCC incidence rates because of delays in reporting16 and an estimated rate of under-reporting of 2.5% because of absence of data on Veterans' Affairs hospital patients,5 a population which may be at elevated risk for HCC compared with the general population.45 Despite these limitations, the findings strongly suggest that HCC incidence and mortality continue to increase in the United States. In addition, this report provides reason for optimism that, with more HCC screening of high-risk groups and treatment of low-stage disease, the burden of HCC can be lessened.
RESULTS
Age-Adjusted HCC Incidence Data
Overall age-adjusted incidence rates of HCC tripled between 1975 and 2005, rising from 1.6 per 100,000 to 4.9 per 100,000 (Fig 1). Incidence rates were approximately three times higher among men than among women throughout this time period. The best fitting model for overall HCC incidence trends had two segments. The first segment, from 1975 to 1980, showed no change in HCC incidence. The second segment, fitting HCC incidence trends from 1980 to 2005, estimated an annual percent change of 4.5% (P ≤ .05). When rates among males and females were modeled separately, the best-fitting joinpoint models had one segment. The annual percent changes in HCC incidence from 1975 to 2005 were statistically significant in both models (P ≤ .05).
Birth Cohort Analyses
Examining age-specific incidence by birth cohort revealed that rates increased in each successive birth cohort born between 1900 and 1959 (Fig 2). Incidence rates for the most recent surveillance years (marked with asterisks) were not adjusted for delayed reporting or final cases in the last birth years of each cohort.
Age-Adjusted Rates by Race and Ethnicity
Between 1992 and 2005, overall incidence rates of HCC increased, with an annual percent change of 4.3% (P ≤ .05; Table 1). Asians/Pacific Islanders had the highest age-adjusted HCC incidence rates throughout the period, followed by Hispanics, blacks, American Indians/Alaska Natives and whites (Table 1). Although Asians/Pacific Islanders had the highest incidence, they experienced a smaller annual percent change in HCC incidence rates (annual percent change [APC] = 1.0%) than other racial/ethnic groups. American Indians/Alaska Natives experienced the greatest significant increase (APC = 5.0%), followed by blacks (APC = 4.9%), whites (APC = 4.6%), and Hispanics (APC = 4.0%). For each trend, the best-fitting joinpoint model had one segment.
United States Versus Foreign Place of Birth
Data on place of birth were available for 81% of persons with HCC diagnosed in the SEER 13 registries between 2000 and 2005, including more than 80% of patients in all racial groups and 77% of Hispanic patients (data not shown). Among patients with data, 31% were born outside the United States; however, 80% of Asians/Pacific Islanders with data were born outside the United States, more than any other racial or ethnic group. Among Hispanics with HCC, 40% were born outside the United States. Compared with Asian/Pacific Islander and Hispanic HCC cases, foreign birth occurred less frequently among white (17%), black (6%), and American Indian/Alaska Native HCC patients (3%) with data.
Recent Incidence Trends
An examination of age-specific HCC incidence rates in SEER 13 registries in 2000 to 2002 and 2003 to 2005 revealed marked increases in incidence rates among men 50 to 59 years of age and 75 to 84 years of age (Fig 3) with slight increases in incidence rates among women in these age groups. Within the 50- to 59-year age group, the annual percent change in HCC incidence rates significantly increased from 2000 to 2005 for Hispanic men, black men, and white men, and for black and white women (P ≤ .05), with HCC incidence rates among blacks exceeding those of Asians/Pacific Islanders during 2003 to 2005 (Table 2). Among persons 75 to 84 years of age, increases in HCC incidence were seen among all men and white women (P ≤ .05). No other significant annual percent changes were seen from 2000 to 2005 by age, sex, or race/ethnicity (data not shown).
Age-Adjusted Liver Cancer Mortality Data
Between 1992 and 2005, patterns in liver cancer mortality were similar to patterns in HCC incidence. Overall age-adjusted mortality rates increased, with an annual percent change of 1.6% (P ≤ .05). Mortality rates were highest for Asians/Pacific Islanders, followed by Hispanics, blacks, American Indians/Alaska Natives, and finally whites (Table 1). Rates increased significantly among Hispanics and whites (APC = 1.7%) as well as blacks (APC = 1.3%). Mortality rates among Asians/Pacific Islanders, however, significantly declined (APC = –0.9%), with stable mortality rates among American Indian/Alaska Native populations.
Survival Rates
One-year cause-specific survival rates increased over time for all racial/ethnic groups except American Indians/Alaska Natives (Table 1). During the recent years, 2003 to 2004, the overall 1-year survival rate was 47% (range, 40% for blacks to 49% for Asian/Pacific Islanders).
Overall, survival rates increased for short, intermediate, and longer-term follow-up intervals over the time period of study, with a doubling of 2- to 4-year cause-specific survival rates (Table 3). These increases in survival rates occurred as more patients were diagnosed with localized stage HCC (28% in 1992 to 1993, 44% in 2003 to 2004) and 1-year survival rates for patients with localized HCC increased from 41% to 67%. Among patients with localized HCC that reported therapy, 1-year survival rates increased from 65% in 1992 to 1993 to 83% in 2003 to 2004. One-year survival rates for patients with localized HCC who received surgery increased from 81% to 91% between 1992 to 1993 and 2003 to 2004 (data not shown). Survival rates also increased among patients with regional HCC who reported therapy. Although changes in survival rates for cases with distant HCC were less pronounced, patients reporting treatment had higher survival rates.
METHODS
HCC Incidence Data
HCC patients in the SEER registries were defined by the International Classification of Diseases (ICD)-O-2/ICD-O-3 topography C22.0 (liver) and morphology 8170 (hepatocellular carcinoma, not otherwise specified). With release of ICD-O-3 in 2001, morphology codes for HCC were expanded to include specific histologies: 8171, 8172, 8173, 8174, and 8175,13 which were also included in the case definition for this report. Data were examined for 1975 through 2005 from the SEER 9 registries (Atlanta, Connecticut, Detroit, Hawaii, Iowa, New Mexico, San Francisco-Oakland, Seattle-Puget Sound, Utah), and for 1992 through 2005 from the SEER 13 registries (SEER 9 plus Los Angeles, San Jose-Monterey, Rural Georgia, Alaska Native Tumor Registry). The SEER 9 registries cover approximately 10% and the SEER 13 registries cover approximately 14% of the United States' population. Before 1990, the Census Bureau provided population denominators for white, black and other races. As of 1990, population denominators were available for Asians/Pacific Islanders, American Indians/Alaska Natives, and Hispanic ethnicity. Alaska Native registry data on Hispanic ethnicity included missing values and were not used in the present analyses. Place of birth was ascertained for patients diagnosed between 2000 and 2005 in the SEER 13 registries. Patients were classified as foreign-born versus United States natives including United States' territories. Point estimates and ranges of percent foreign birth were determined for racial/ethnic groups based on completeness of data.14 Annual age-adjusted HCC incidence rates were examined from 1975 to 2005. Age-adjusted HCC incidence rates were also examined by race and ethnicity for 1992 to 1993 and 3-year time periods from 1994 to 1996 to 2003 to 2005. Standard United States' population estimates were used to assign weights for 19 age groups: younger than 1, 5-year age groups up to 80 to 84, and 85+ years of age.15 Louisiana incidence data for the second half of 2005 were excluded due to hurricane-related disruptions. No adjustments were made for delays in case reporting to registries.16 In SEER 9 registries, approximately 5% of liver and intrahepatic bile duct cancer cases remain unreported in the first data submission for a surveillance year, with a 1% delay in case reporting 5 years after initial submission.17
A cohort analysis of incidence rates was performed with data from 1975 to 2005 with age-specific rates calculated by birth decade. The model included 22 age-specific rates, 18 with complete data for the age-range and four with data for 88% of person-years. The last three birth years in these four cohorts had yet to span the full age range.
Liver Cancer Mortality Data
Cancer deaths in the United States are reported by primary cancer site. Deaths from liver cancer other than intrahepatic bile duct cancer were examined. This site corresponds closely with HCC for SEER incidence data. Mortality rates were age-adjusted according to the United States 2000 standard population.15 The 2005 population estimate adjusted for hurricane-related shifts in the Gulf Coast area. Age-adjusted mortality rates were estimated by race/ethnicity for the same time periods examined for incidence rates. Nine states were excluded from mortality rate analyses for Hispanic ethnicity because of missing data: Connecticut, Maine, Maryland, Minnesota, New Hampshire, New York, North Dakota, Oklahoma, and Vermont.
Cause-Specific Survival
Cause-specific HCC survival estimates survival in the absence of other causes of death using standard life-tables, with other causes of death censored. These rates were calculated for time intervals from 1992 to 1993 through 2003 to 2004. Survival rates were also examined by stage at diagnosis and initial treatment after diagnosis.
Statistical Methods
Joinpoint models were used to fit age-adjusted HCC incidence trends from 1975 to 2005, as well as liver cancer mortality rates from 1992 to 2005 (Joinpoint 3.3; IMS, Silver Spring, MD).18 Cause-specific 12-month survival rates were fit from 1992 to 2004, with follow-up of vital status through 2005. Up to four joinpoints were allowed for trends from 1975 to 2005 and up to three joinpoints were allowed for trends from 1992 to 2004/2005. A minimum of four observations were required between joinpoints, with at least three observations in initial and final joinpoint segments.
Journal of Clinical Oncology, Vol 27, No 9 (March 20), 2009: pp. 1485-1491
Sean F. Altekruse, Katherine A. McGlynn, Marsha E. Reichman
From the Division of Cancer Control and Population Sciences, and the Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD.
"This report may underestimate recent increases in HCC incidence rates because of delays in reporting16 and an estimated rate of under-reporting of 2.5% because of absence of data on Veterans' Affairs hospital patients,5 a population which may be at elevated risk for HCC compared with the general population.45 Despite these limitations, the findings strongly suggest that HCC incidence and mortality continue to increase in the United States. In addition, this report provides reason for optimism that, with more HCC screening of high-risk groups and treatment of low-stage disease, the burden of HCC can be lessened." "Much of the increase in incidence between 2000 and 2005 occurred among men age 50 to 59 years. Not all racial/ethnic groups were equally affected, with black, Hispanic, and white men experiencing the greatest increases. Between 2003 and 2005, for both sexes, blacks in this age group had higher incidence rates than Asian/Pacific Islanders. The changing racial pattern of HCC in this age group may be partially attributable to an epidemic of HCV infection that occurred approximately four decades earlier, in the 1960s, when they were young adults" "High-risk individuals include cirrhotic patients, adult HBV carriers, and persons infected with HCV. Gaps in HCC screening in the United States include limited HCV testing of current and former injected drug users,33 pre-1990 transfusion recipients,34 and incomplete HBV testing of foreign-born Asians/Pacific Islanders.35 In addition, cultural and economic barriers to HCC screening of chronic viral carriers exist." "Asians/Pacific Islanders had the highest age-adjusted HCC incidence rates throughout the period, followed by Hispanics, blacks, American Indians/Alaska Natives and whites (Table 1). Although Asians/Pacific Islanders had the highest incidence, they experienced a smaller annual percent change in HCC incidence rates (annual percent change [APC] = 1.0%) than other racial/ethnic groups. American Indians/Alaska Natives experienced the greatest significant increase (APC = 5.0%), followed by blacks (APC = 4.9%), whites (APC = 4.6%), and Hispanics (APC = 4.0%)."
ABSTRACT
Purpose- Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide. Incidence rates are increasing in the United States. Monitoring incidence, survival, and mortality rates within at-risk populations can facilitate control efforts.
Methods
Age-adjusted incidence trends for HCC were examined in the Surveillance, Epidemiology, and End Results (SEER) registries from 1975 to 2005.. Age-specific rates were examined for birth cohorts born between 1900 and 1959. Age-adjusted incidence and cause-specific survival rates from 1992 to 2005 were examined in the SEER 13 registries by race/ethnicity, stage, and treatment. United States liver cancer mortality rates were also examined.
Results
Age-adjusted HCC incidence rates tripled between 1975 and 2005. Incidence rates increased in each 10-year birth cohort from 1900 through the 1950s. Asians/Pacific Islanders had higher incidence and mortality rates than other racial/ethnic groups, but experienced a significant decrease in mortality rates over time. From 2000 to 2005, marked increases in incidence rates occurred among Hispanic, black, and white middle-aged men. Between 1992 and 2004, 2- to 4-year HCC survival rates doubled, as more patients were diagnosed with localized and regional HCC and prognosis improved, particularly for patients with reported treatment. Recent 1-year survival rates remained, however, less than 50%.
Conclusion
HCC incidence and mortality rates continue to increase, particularly among middle-aged black, Hispanic, and white men. Screening of at-risk groups and treatment of localized-stage tumors may contribute to increasing HCC survival rates in the United States. More progress is needed.
INTRODUCTION
Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide.1 This malignancy occurs more often among men than women, with the highest incidence rates reported in East Asia.2 The incidence rates of HCC in the United States have historically been lower than in many countries. However, in recent decades, HCC age-adjusted incidence rates have doubled3 and primary liver cancer mortality rates have increased faster than mortality rates for any other leading cause of cancer.4,5 Approximately 90% of primary liver cancers in the United States are HCCs, while most of the remaining 10% are intrahepatic cholangiocarcinomas.6 The pathway leading to HCC generally begins with an acute hepatic insult which progresses over decades. Fibrosis and cirrhosis are typically precursors of HCC.7 Among patients with localized stage HCC, treatment options may include resection or transplantation. Chemoembolization, a combination of chemotherapy and occlusion of the tumor blood supply, is reported to improve survival in well-selected patients with unresectable HCC.8 Many patients who are diagnosed with HCC, however, have advanced disease and are only candidates for palliative care, contributing to a relatively low reported 5-year survival rate of approximately 10%.6 Most HCC is thought to be associated with either chronic hepatitis C virus (HCV) or hepatitis B virus (HBV) infection.9 In the United States, more than 3 million people are chronically infected with HCV.10 Many of these individuals were exposed as young adults beginning in the 1960s.10,11 HCV risk factors include contaminated blood product transfusion and injected drug use.10,11 Chronic infection with HBV, a major global risk factor for HCC, is less common overall in the United States than HCV infection is. Among some United States' ethnic groups, however, HBV is a more common risk factor than HCV. For example, a report from Los Angeles found that 74% of HCC among Asians was linked to HBV, while 90% of HCC in whites was linked to HCV.9 The etiology of HCC is likely to involve interactions between multiple risk factors. In a study which utilized the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked databases,12 the most commonly reported risk-factor was nonspecific cirrhosis (21%), followed by alcohol-induced liver disease (16%), HCV infection (10%), and HBV infection (5%). Obesity and type II diabetes6 are also suspected to increase risk. To monitor changes in the burden of HCC in the United States, this report provides analyses of incidence and survival of HCC and mortality of liver cancer. To define at-risk populations, data were examined by sex, race/ethnicity, and age.
DISCUSSION
The principal findings in this report were that incidence rates of HCC tripled in the United States from 1975 through 2005, with marked recent increases among middle-aged black, Hispanic, and white males; there was a birth-cohort effect on risk; and overall 1-year cause-specific survival rates for new HCC patients nearly doubled from 1992 to 2004 as more patients were diagnosed with low-stage HCC and their prognosis improved. Increases in cause-specific survival rates were experienced by all racial and ethnic groups, except for American Indians/Alaska Natives. However, despite increasing HCC survival rates, improvement is needed, with the 1-year cause-specific survival rate remaining lower than 50%. Much of the increase in incidence between 2000 and 2005 occurred among men age 50 to 59 years. Not all racial/ethnic groups were equally affected, with black, Hispanic, and white men experiencing the greatest increases. Between 2003 and 2005, for both sexes, blacks in this age group had higher incidence rates than Asian/Pacific Islanders. The changing racial pattern of HCC in this age group may be partially attributable to an epidemic of HCV infection that occurred approximately four decades earlier, in the 1960s, when they were young adults.10 Several findings in this report suggest, however, that risk of HCC is likely to be driven by additional factors. There has been a steady increase in age-adjusted HCC incidence rates among men and women since 1975. Age-specific rates have increased in each successive birth cohort between 1900 and 1959. Etiologic studies of recent HCC patients are recommended to elucidate factors contributing to the ongoing increase in HCC incidence. In contrast with other racial groups, most Asians/Pacific Islanders with HCC were born outside the United States. This predominance of foreign births is consistent with HBV infection being a major risk factor among most groups of Asians/Pacific Islanders9,20 as chronic HBV infection is notably more common in eastern Asian countries than in the United States, with higher HCC incidence rates among Southeast Asians compared with Filipinos, Japanese, and Asian Indians/Pakistanis.19 An exception is Japan, where more HCC patients are linked to HCV infection than HBV infection.21 The modest increase in HCC incidence rates and decrease in liver cancer mortality rates from 1992 to 2005 suggests that Asians/Pacific Islander populations born in the United States have, thus far, not been as affected by the factors that are driving the HCC increases in other populations. Worldwide, the incidence of HCC among Asians/Pacific Islanders is likely to decline as HBV vaccination becomes more widespread in Asian countries.22 In this study, HCC incidence rates among Hispanics were lower than among Asians/Pacific Islanders, but higher than among whites. Approximately one half of Hispanic HCC patients were born in the United States. In contrast to Asians/Pacific Islanders, HCC incidence rates are reported to be higher among Hispanics born in the United States than among foreign-born Hispanics.23 This suggests that factors associated with life in the United States, perhaps including HCV infection,10 alcohol abuse,24 or obesity,25 may be adversely affecting Hispanic populations.
Despite a paucity of new therapies for HCC during the surveillance years in this report, 1-year cause-specific survival rates for HCC nearly doubled between 1992 to 1993 and 2003 to 2004. This supports earlier evidence that survival rates for HCC are increasing.26 Initially, the increase in survival was restricted to short-term follow-up27; however, in this report 4-year survival rates doubled and 5-year survival rates increased by more than 60%. Furthermore, more patients were diagnosed with localized and regional stage HCC and survival rates increased for these patients. With greater awareness of HCC, more patients are being diagnosed with asymptomatic disease via active screening employing serum alpha-fetoprotein testing, abdominal ultrasound, and diagnostic imaging.28 Furthermore, aggressive treatments including transplantation and resection of localized-stage tumors appear to be improving long-term survival.29 The advent of targeted HCC therapies holds promise for further improvement in prognosis among patients with regional and distant-stage HCC.30 Racial variation was seen in 1-year cause-specific survival rates. In 2003 to 2004, survival was greatest among Asians/Pacific Islanders (49%) and lowest among blacks (40%) and American Indians/Alaska Natives (41%). In another study, racial and ethnic variations in survival were partially explained by stage at diagnosis and the therapy received by blacks and Hispanics compared with whites.26 While improvements in survival are needed across all racial and ethnic groups, blacks and American Indians/Alaska Natives may particularly benefit from targeted HCC control efforts. Coordination of existing HCC prevention efforts is needed. Primary HCC prevention measures include hepatitis B vaccination programs,22 screening of the blood supply for hepatitis viruses,31 and campaigns to discourage intravenous drug abuse. Secondary prevention measures focus on detecting asymptomatic HCC among at-risk individuals28 through periodic screening of high-risk patients by ultrasound, with follow-up tests when suspicious lesions are detected.32 High-risk individuals include cirrhotic patients, adult HBV carriers, and persons infected with HCV. Gaps in HCC screening in the United States include limited HCV testing of current and former injected drug users,33 pre-1990 transfusion recipients,34 and incomplete HBV testing of foreign-born Asians/Pacific Islanders.35 In addition, cultural and economic barriers to HCC screening of chronic viral carriers exist.36,37 Tertiary measures for HCC vary by stage of disease and comorbidity but include surgical resection, transplantation, radiofrequency ablation, and chemoembolization.28 A SEER-Medicare linked study of HCC patients diagnosed in the 1990s indicated that only one third of cases with favorable tumor features received potentially curative therapy.38 A limitation of this study is the absence of information on risk factors. There is a need for studies to estimate the current proportion of HCCs that are attributed to HCV and to HBV including differences across demographic groups.9,39 Studies are needed of the oncogenic potential of viral genotypes.40,41 Associations with suspected cofactors for HCC should also be examined, including alcoholism24 and steatohepatitis,25 obesity,42 diabetes mellitus,43 and iron storage diseases.44 This report may underestimate recent increases in HCC incidence rates because of delays in reporting16 and an estimated rate of under-reporting of 2.5% because of absence of data on Veterans' Affairs hospital patients,5 a population which may be at elevated risk for HCC compared with the general population.45 Despite these limitations, the findings strongly suggest that HCC incidence and mortality continue to increase in the United States. In addition, this report provides reason for optimism that, with more HCC screening of high-risk groups and treatment of low-stage disease, the burden of HCC can be lessened.
RESULTS
Age-Adjusted HCC Incidence Data
Overall age-adjusted incidence rates of HCC tripled between 1975 and 2005, rising from 1.6 per 100,000 to 4.9 per 100,000 (Fig 1). Incidence rates were approximately three times higher among men than among women throughout this time period. The best fitting model for overall HCC incidence trends had two segments. The first segment, from 1975 to 1980, showed no change in HCC incidence. The second segment, fitting HCC incidence trends from 1980 to 2005, estimated an annual percent change of 4.5% (P ≤ .05). When rates among males and females were modeled separately, the best-fitting joinpoint models had one segment. The annual percent changes in HCC incidence from 1975 to 2005 were statistically significant in both models (P ≤ .05).
Birth Cohort Analyses
Examining age-specific incidence by birth cohort revealed that rates increased in each successive birth cohort born between 1900 and 1959 (Fig 2). Incidence rates for the most recent surveillance years (marked with asterisks) were not adjusted for delayed reporting or final cases in the last birth years of each cohort.
Age-Adjusted Rates by Race and Ethnicity
Between 1992 and 2005, overall incidence rates of HCC increased, with an annual percent change of 4.3% (P ≤ .05; Table 1). Asians/Pacific Islanders had the highest age-adjusted HCC incidence rates throughout the period, followed by Hispanics, blacks, American Indians/Alaska Natives and whites (Table 1). Although Asians/Pacific Islanders had the highest incidence, they experienced a smaller annual percent change in HCC incidence rates (annual percent change [APC] = 1.0%) than other racial/ethnic groups. American Indians/Alaska Natives experienced the greatest significant increase (APC = 5.0%), followed by blacks (APC = 4.9%), whites (APC = 4.6%), and Hispanics (APC = 4.0%). For each trend, the best-fitting joinpoint model had one segment.
United States Versus Foreign Place of Birth
Data on place of birth were available for 81% of persons with HCC diagnosed in the SEER 13 registries between 2000 and 2005, including more than 80% of patients in all racial groups and 77% of Hispanic patients (data not shown). Among patients with data, 31% were born outside the United States; however, 80% of Asians/Pacific Islanders with data were born outside the United States, more than any other racial or ethnic group. Among Hispanics with HCC, 40% were born outside the United States. Compared with Asian/Pacific Islander and Hispanic HCC cases, foreign birth occurred less frequently among white (17%), black (6%), and American Indian/Alaska Native HCC patients (3%) with data.
Recent Incidence Trends
An examination of age-specific HCC incidence rates in SEER 13 registries in 2000 to 2002 and 2003 to 2005 revealed marked increases in incidence rates among men 50 to 59 years of age and 75 to 84 years of age (Fig 3) with slight increases in incidence rates among women in these age groups. Within the 50- to 59-year age group, the annual percent change in HCC incidence rates significantly increased from 2000 to 2005 for Hispanic men, black men, and white men, and for black and white women (P ≤ .05), with HCC incidence rates among blacks exceeding those of Asians/Pacific Islanders during 2003 to 2005 (Table 2). Among persons 75 to 84 years of age, increases in HCC incidence were seen among all men and white women (P ≤ .05). No other significant annual percent changes were seen from 2000 to 2005 by age, sex, or race/ethnicity (data not shown).
Age-Adjusted Liver Cancer Mortality Data
Between 1992 and 2005, patterns in liver cancer mortality were similar to patterns in HCC incidence. Overall age-adjusted mortality rates increased, with an annual percent change of 1.6% (P ≤ .05). Mortality rates were highest for Asians/Pacific Islanders, followed by Hispanics, blacks, American Indians/Alaska Natives, and finally whites (Table 1). Rates increased significantly among Hispanics and whites (APC = 1.7%) as well as blacks (APC = 1.3%). Mortality rates among Asians/Pacific Islanders, however, significantly declined (APC = –0.9%), with stable mortality rates among American Indian/Alaska Native populations.
Survival Rates
One-year cause-specific survival rates increased over time for all racial/ethnic groups except American Indians/Alaska Natives (Table 1). During the recent years, 2003 to 2004, the overall 1-year survival rate was 47% (range, 40% for blacks to 49% for Asian/Pacific Islanders).
Overall, survival rates increased for short, intermediate, and longer-term follow-up intervals over the time period of study, with a doubling of 2- to 4-year cause-specific survival rates (Table 3). These increases in survival rates occurred as more patients were diagnosed with localized stage HCC (28% in 1992 to 1993, 44% in 2003 to 2004) and 1-year survival rates for patients with localized HCC increased from 41% to 67%. Among patients with localized HCC that reported therapy, 1-year survival rates increased from 65% in 1992 to 1993 to 83% in 2003 to 2004. One-year survival rates for patients with localized HCC who received surgery increased from 81% to 91% between 1992 to 1993 and 2003 to 2004 (data not shown). Survival rates also increased among patients with regional HCC who reported therapy. Although changes in survival rates for cases with distant HCC were less pronounced, patients reporting treatment had higher survival rates.
METHODS
HCC Incidence Data
HCC patients in the SEER registries were defined by the International Classification of Diseases (ICD)-O-2/ICD-O-3 topography C22.0 (liver) and morphology 8170 (hepatocellular carcinoma, not otherwise specified). With release of ICD-O-3 in 2001, morphology codes for HCC were expanded to include specific histologies: 8171, 8172, 8173, 8174, and 8175,13 which were also included in the case definition for this report. Data were examined for 1975 through 2005 from the SEER 9 registries (Atlanta, Connecticut, Detroit, Hawaii, Iowa, New Mexico, San Francisco-Oakland, Seattle-Puget Sound, Utah), and for 1992 through 2005 from the SEER 13 registries (SEER 9 plus Los Angeles, San Jose-Monterey, Rural Georgia, Alaska Native Tumor Registry). The SEER 9 registries cover approximately 10% and the SEER 13 registries cover approximately 14% of the United States' population. Before 1990, the Census Bureau provided population denominators for white, black and other races. As of 1990, population denominators were available for Asians/Pacific Islanders, American Indians/Alaska Natives, and Hispanic ethnicity. Alaska Native registry data on Hispanic ethnicity included missing values and were not used in the present analyses. Place of birth was ascertained for patients diagnosed between 2000 and 2005 in the SEER 13 registries. Patients were classified as foreign-born versus United States natives including United States' territories. Point estimates and ranges of percent foreign birth were determined for racial/ethnic groups based on completeness of data.14 Annual age-adjusted HCC incidence rates were examined from 1975 to 2005. Age-adjusted HCC incidence rates were also examined by race and ethnicity for 1992 to 1993 and 3-year time periods from 1994 to 1996 to 2003 to 2005. Standard United States' population estimates were used to assign weights for 19 age groups: younger than 1, 5-year age groups up to 80 to 84, and 85+ years of age.15 Louisiana incidence data for the second half of 2005 were excluded due to hurricane-related disruptions. No adjustments were made for delays in case reporting to registries.16 In SEER 9 registries, approximately 5% of liver and intrahepatic bile duct cancer cases remain unreported in the first data submission for a surveillance year, with a 1% delay in case reporting 5 years after initial submission.17
A cohort analysis of incidence rates was performed with data from 1975 to 2005 with age-specific rates calculated by birth decade. The model included 22 age-specific rates, 18 with complete data for the age-range and four with data for 88% of person-years. The last three birth years in these four cohorts had yet to span the full age range.
Liver Cancer Mortality Data
Cancer deaths in the United States are reported by primary cancer site. Deaths from liver cancer other than intrahepatic bile duct cancer were examined. This site corresponds closely with HCC for SEER incidence data. Mortality rates were age-adjusted according to the United States 2000 standard population.15 The 2005 population estimate adjusted for hurricane-related shifts in the Gulf Coast area. Age-adjusted mortality rates were estimated by race/ethnicity for the same time periods examined for incidence rates. Nine states were excluded from mortality rate analyses for Hispanic ethnicity because of missing data: Connecticut, Maine, Maryland, Minnesota, New Hampshire, New York, North Dakota, Oklahoma, and Vermont.
Cause-Specific Survival
Cause-specific HCC survival estimates survival in the absence of other causes of death using standard life-tables, with other causes of death censored. These rates were calculated for time intervals from 1992 to 1993 through 2003 to 2004. Survival rates were also examined by stage at diagnosis and initial treatment after diagnosis.
Statistical Methods
Joinpoint models were used to fit age-adjusted HCC incidence trends from 1975 to 2005, as well as liver cancer mortality rates from 1992 to 2005 (Joinpoint 3.3; IMS, Silver Spring, MD).18 Cause-specific 12-month survival rates were fit from 1992 to 2004, with follow-up of vital status through 2005. Up to four joinpoints were allowed for trends from 1975 to 2005 and up to three joinpoints were allowed for trends from 1992 to 2004/2005. A minimum of four observations were required between joinpoints, with at least three observations in initial and final joinpoint segments.
Circumcision may reduce HIV, HSV-2, HPV
Circumcision May Reduce Incidence of HIV, HSV-2, HPV Infection CME
News Author: Laurie Barclay, MDCME Author: Charles Vega, MD, FAAFP
Authors and Disclosures
Laurie Barclay, MDDisclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.
Charles Vega, MD, FAAFPDisclosure: Charles Vega, MD, FAAFP, has disclosed an advisor/consultant relationship to Novartis, Inc.
Brande Nicole MartinDisclosure: Brande Nicole Martin has disclosed no relevant financial information.
March 25, 2009 — Male circumcision significantly reduced the incidence of HIV and herpes simplex virus type 2 (HSV-2) infection and the prevalence of human papillomavirus (HPV) infection, suggesting potential public health benefits, according to the results of a randomized controlled trial reported in the March 26 issue of the New England Journal of Medicine.
"Male circumcision significantly reduced the incidence of...HIV infection among men in three clinical trials," write Aaron A.R. Tobian, MD, PhD, from Bloomberg School of Public Health, Johns Hopkins University in Baltimore, Maryland, and colleagues. "We assessed the efficacy of male circumcision for the prevention of...HSV-2 and...HPV infections and syphilis in HIV-negative adolescent boys and men." Two trials of male circumcision to prevent HIV and other sexually transmitted infections in a rural Ugandan population enrolled a total of 5534 HIV-negative, uncircumcised male subjects aged 15 to 49 years. Of 3393 subjects (61.3%) who were HSV-2 seronegative at enrollment, 1684 had been randomly assigned to undergo immediate circumcision (intervention group) and 1709 to undergo circumcision after 24 months (control group). Subjects were tested for HSV-2 and HIV infection and syphilis and underwent physical examinations and interviews at baseline and at 6, 12, and 24 months. A subgroup of subjects was also evaluated for HPV infection at baseline and at 24 months. The cumulative probability of HSV-2 seroconversion by 24 months was 7.8% in the intervention group vs 10.3% in the control group (adjusted hazard ratio [HR], 0.72; 95% confidence interval [CI], 0.56 - 0.92; P = .008). High-risk HPV genotypes were present at 24 months in 18.0% of the intervention group vs 27.9% of the control group (adjusted risk ratio, 0.65; 95% CI, 0.46 - 0.90; P = .009). The incidence of syphilis was not significantly different between groups (adjusted HR, 1.10; 95% CI, 0.75 - 1.65; P = .44). "In addition to decreasing the incidence of HIV infection, male circumcision significantly reduced the incidence of HSV-2 infection and the prevalence of HPV infection, findings that underscore the potential public health benefits of the procedure," the study authors write. "These findings, in conjunction with those of previous trials, indicate that circumcision should now be accepted as an efficacious intervention for reducing heterosexually acquired infections with HSV-2, HPV, and HIV in adolescent boys and men. However, it must be emphasized that protection was only partial, and it is critical to promote the practice of safe sex." Limitations of this study include evaluation of the use of circumcision to prevent HPV infection only in a subgroup of subjects observed both at enrollment and at 24 months.
"Male circumcision has now been shown to decrease the rates of HIV, HSV-2, and HPV infections in men and of trichomoniasis and bacterial vaginosis in their female partners," the study authors conclude. "Circumcision also reduces symptomatic ulceration in HIV-negative men and women and HIV-positive men. Thus, male circumcision reduces the risk of several sexually transmitted infections in both sexes, and these benefits should guide public health policies for neonatal, adolescent, and adult male circumcision programs." In an accompanying editorial, Matthew R. Golden, MD, MPH, and Judith N. Wasserheit, MD, MPH, from the University of Washington, Public Health–Seattle, note that this study contributes strong evidence that circumcision offers an important prevention opportunity and should be widely available. "Professional organizations have a leadership role to play in ensuring that medical providers actively educate all parents or guardians of newborn sons about the benefits and risks of circumcision," Drs. Golden and Wasserheit write. "The American Academy of Pediatrics, which previously concluded that evidence was insufficient to recommend routine neonatal circumcision, is reviewing its position in collaboration with other professional organizations. This process should optimally lead to a multidisciplinary consensus statement involving providers such as obstetricians, midwives, pediatricians, urologists, and family doctors and to the development and dissemination of educational materials for medical professionals and families." The National Institutes of Health, the Bill and Melinda Gates Foundation, the Fogarty International Center, and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases supported this study. Coauthor Patti E. Gravitt, PhD, has received research funding from Roche Molecular Diagnostics, maker of the HPV genotyping test used in this study. The other study authors have disclosed no relevant financial relationships. Dr. Golden has received lecture fees from Pfizer and drugs donated by Pfizer and Lupon Pharmaceuticals for research funded by the National Institutes of Health. Dr. Wasserheit has received research support from the Bill and Melinda Gates Foundation.
N Engl J Med. 2009;360:1298-1309.
Clinical Context
Circumcision has been demonstrated to reduce the risk for sexually transmitted infection, particularly with HIV, in previous research, and the current article describes potential mechanisms by which circumcision may be protective. In uncircumcised men, the retraction of the foreskin during intercourse exposes the inner preputial mucosa to potentially infectious fluids, and this area might be particularly prone to microtears, especially at the frenulum. The moist, humid environment of the subpreputial cavity may particularly promote infection. Moreover, this area is lightly keratinized, and this may facilitate viral access to underlying epithelial cells. Conversely, the scar and dense keratin after circumcision can create the opposite effect. The current study examines whether circumcision can reduce the rate of infection with HSV-2, HPV, and syphilis.
Study Highlights
The current study reports on 2 parallel trials performed in Uganda. Both trials enrolled uncircumcised male subjects between the ages of 15 and 49 years who had negative testing results for HIV. The current analysis focuses on participants who were HSV-2 seronegative at enrollment. Participants were randomly assigned to undergo immediate circumcision or circumcision at 24 months (control group). The main outcome of the study was the rate of sexually transmitted infection. Participants underwent testing at baseline and at 6, 12, and 24 months for infection with HSV-2 and syphilis. In addition, a subgroup of men was tested for infection with HPV at baseline and at 24 months. 1684 men were assigned to immediate circumcision, and 1709 comprised the control group. Demographic and sexual practice data were similar in comparing the 2 groups. Rates of condom use were higher in the circumcision vs the control group at 6 months, but these rates were similar thereafter. Although the number of sexual partners was similar in comparing randomized groups, more participants in the circumcision group reported nonmarital sexual relationships. The cumulative probability of HSV-2 infection was lower in the circumcised group (7.8%) vs the control group (10.3%) at 24 months. This yielded a significant adjusted HR of 0.72 for HSV-2 infection in the circumcised cohort. Circumcision was not protective against syphilis infection. At baseline, the prevalence of high-risk HPV genotypes was 38.1% in the circumcision group and 37.1% in the control group. At 24 months, the respective rates of HPV infection were 18% and 27.9%. The adjusted risk ratio of 0.65 in the circumcision group for this outcome was statistically significant.
Circumcision was also protective against infection with multiple high-risk HPV types as well as non–high-risk HPV types.
News Author: Laurie Barclay, MDCME Author: Charles Vega, MD, FAAFP
Authors and Disclosures
Laurie Barclay, MDDisclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.
Charles Vega, MD, FAAFPDisclosure: Charles Vega, MD, FAAFP, has disclosed an advisor/consultant relationship to Novartis, Inc.
Brande Nicole MartinDisclosure: Brande Nicole Martin has disclosed no relevant financial information.
March 25, 2009 — Male circumcision significantly reduced the incidence of HIV and herpes simplex virus type 2 (HSV-2) infection and the prevalence of human papillomavirus (HPV) infection, suggesting potential public health benefits, according to the results of a randomized controlled trial reported in the March 26 issue of the New England Journal of Medicine.
"Male circumcision significantly reduced the incidence of...HIV infection among men in three clinical trials," write Aaron A.R. Tobian, MD, PhD, from Bloomberg School of Public Health, Johns Hopkins University in Baltimore, Maryland, and colleagues. "We assessed the efficacy of male circumcision for the prevention of...HSV-2 and...HPV infections and syphilis in HIV-negative adolescent boys and men." Two trials of male circumcision to prevent HIV and other sexually transmitted infections in a rural Ugandan population enrolled a total of 5534 HIV-negative, uncircumcised male subjects aged 15 to 49 years. Of 3393 subjects (61.3%) who were HSV-2 seronegative at enrollment, 1684 had been randomly assigned to undergo immediate circumcision (intervention group) and 1709 to undergo circumcision after 24 months (control group). Subjects were tested for HSV-2 and HIV infection and syphilis and underwent physical examinations and interviews at baseline and at 6, 12, and 24 months. A subgroup of subjects was also evaluated for HPV infection at baseline and at 24 months. The cumulative probability of HSV-2 seroconversion by 24 months was 7.8% in the intervention group vs 10.3% in the control group (adjusted hazard ratio [HR], 0.72; 95% confidence interval [CI], 0.56 - 0.92; P = .008). High-risk HPV genotypes were present at 24 months in 18.0% of the intervention group vs 27.9% of the control group (adjusted risk ratio, 0.65; 95% CI, 0.46 - 0.90; P = .009). The incidence of syphilis was not significantly different between groups (adjusted HR, 1.10; 95% CI, 0.75 - 1.65; P = .44). "In addition to decreasing the incidence of HIV infection, male circumcision significantly reduced the incidence of HSV-2 infection and the prevalence of HPV infection, findings that underscore the potential public health benefits of the procedure," the study authors write. "These findings, in conjunction with those of previous trials, indicate that circumcision should now be accepted as an efficacious intervention for reducing heterosexually acquired infections with HSV-2, HPV, and HIV in adolescent boys and men. However, it must be emphasized that protection was only partial, and it is critical to promote the practice of safe sex." Limitations of this study include evaluation of the use of circumcision to prevent HPV infection only in a subgroup of subjects observed both at enrollment and at 24 months.
"Male circumcision has now been shown to decrease the rates of HIV, HSV-2, and HPV infections in men and of trichomoniasis and bacterial vaginosis in their female partners," the study authors conclude. "Circumcision also reduces symptomatic ulceration in HIV-negative men and women and HIV-positive men. Thus, male circumcision reduces the risk of several sexually transmitted infections in both sexes, and these benefits should guide public health policies for neonatal, adolescent, and adult male circumcision programs." In an accompanying editorial, Matthew R. Golden, MD, MPH, and Judith N. Wasserheit, MD, MPH, from the University of Washington, Public Health–Seattle, note that this study contributes strong evidence that circumcision offers an important prevention opportunity and should be widely available. "Professional organizations have a leadership role to play in ensuring that medical providers actively educate all parents or guardians of newborn sons about the benefits and risks of circumcision," Drs. Golden and Wasserheit write. "The American Academy of Pediatrics, which previously concluded that evidence was insufficient to recommend routine neonatal circumcision, is reviewing its position in collaboration with other professional organizations. This process should optimally lead to a multidisciplinary consensus statement involving providers such as obstetricians, midwives, pediatricians, urologists, and family doctors and to the development and dissemination of educational materials for medical professionals and families." The National Institutes of Health, the Bill and Melinda Gates Foundation, the Fogarty International Center, and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases supported this study. Coauthor Patti E. Gravitt, PhD, has received research funding from Roche Molecular Diagnostics, maker of the HPV genotyping test used in this study. The other study authors have disclosed no relevant financial relationships. Dr. Golden has received lecture fees from Pfizer and drugs donated by Pfizer and Lupon Pharmaceuticals for research funded by the National Institutes of Health. Dr. Wasserheit has received research support from the Bill and Melinda Gates Foundation.
N Engl J Med. 2009;360:1298-1309.
Clinical Context
Circumcision has been demonstrated to reduce the risk for sexually transmitted infection, particularly with HIV, in previous research, and the current article describes potential mechanisms by which circumcision may be protective. In uncircumcised men, the retraction of the foreskin during intercourse exposes the inner preputial mucosa to potentially infectious fluids, and this area might be particularly prone to microtears, especially at the frenulum. The moist, humid environment of the subpreputial cavity may particularly promote infection. Moreover, this area is lightly keratinized, and this may facilitate viral access to underlying epithelial cells. Conversely, the scar and dense keratin after circumcision can create the opposite effect. The current study examines whether circumcision can reduce the rate of infection with HSV-2, HPV, and syphilis.
Study Highlights
The current study reports on 2 parallel trials performed in Uganda. Both trials enrolled uncircumcised male subjects between the ages of 15 and 49 years who had negative testing results for HIV. The current analysis focuses on participants who were HSV-2 seronegative at enrollment. Participants were randomly assigned to undergo immediate circumcision or circumcision at 24 months (control group). The main outcome of the study was the rate of sexually transmitted infection. Participants underwent testing at baseline and at 6, 12, and 24 months for infection with HSV-2 and syphilis. In addition, a subgroup of men was tested for infection with HPV at baseline and at 24 months. 1684 men were assigned to immediate circumcision, and 1709 comprised the control group. Demographic and sexual practice data were similar in comparing the 2 groups. Rates of condom use were higher in the circumcision vs the control group at 6 months, but these rates were similar thereafter. Although the number of sexual partners was similar in comparing randomized groups, more participants in the circumcision group reported nonmarital sexual relationships. The cumulative probability of HSV-2 infection was lower in the circumcised group (7.8%) vs the control group (10.3%) at 24 months. This yielded a significant adjusted HR of 0.72 for HSV-2 infection in the circumcised cohort. Circumcision was not protective against syphilis infection. At baseline, the prevalence of high-risk HPV genotypes was 38.1% in the circumcision group and 37.1% in the control group. At 24 months, the respective rates of HPV infection were 18% and 27.9%. The adjusted risk ratio of 0.65 in the circumcision group for this outcome was statistically significant.
Circumcision was also protective against infection with multiple high-risk HPV types as well as non–high-risk HPV types.
Thursday, March 26, 2009
Hep C in HIVers may cause rapid liver disease
Hep C in HIVers may cause rapid liver disease
NEWS
Published 03/26/2009
by Liz Highleyman
Bay Area Reporter (SF)
Dr. Daniel Fierer spoke about HIV-hepatitis C coinfection at a forum in San Francisco last week. While HIV continues to garner the lion's share of attention regarding gay men's health, a second forum in as many months focused on the growing epidemic of hepatitis C among HIV-positive men who have sex with men – and presenters noted that rapid liver disease could be a result. The March 17 forum – provocatively titled "Could you survive HIV only to die from hepatitis C?" – featured Dr. Daniel Fierer of Mt. Sinai School of Medicine in New York City, one of the leading American experts on HIV and hepatitis C virus (HCV) coinfection.
Dr. Marcus Conant, whose Conant Foundation sponsored the meeting in conjunction with Project Inform and the Black Coalition on AIDS, noted that while nearly 4 million people in the U.S. have hepatitis C, the rate of new infections in the general population has fallen dramatically in recent decades. But such is not the case for HIV-positive gay and bisexual men. Outbreaks of apparently sexually transmitted acute hepatitis C started cropping up among gay men in London and continental European cities around 2002. The first similar U.S. report, by researchers from the University of California at San Francisco, was published in 2006.. Dr. Brad Hare, a member of that team, said that today 42 percent of HIV-infected men in UCSF's Positive Health Program also have HCV. Fierer said these recent acute HCV coinfections in HIV-positive men appear to represent "a new 21st century clinical syndrome," since they depart in some important ways from the prevailing consensus about hepatitis C. Traditionally, experts have maintained that HCV is rarely spread through sex, a claim based on studies of monogamous HIV-negative heterosexual men and women, who have a sexual transmission rate under 5 percent. Though specific risk factors have varied from study to study, the recent acute hepatitis C outbreaks among gay men have been linked to fisting, unprotected anal intercourse, group sex, sharing sex toys, having other sexually transmitted diseases, and use of non-injected recreational drugs. Based on an analysis of a small but growing group of coinfected gay men in New York, Fierer said that acute HCV infection in a person who already has HIV may lead to unusually rapid liver disease progression. Over time, hepatitis C infection can lead to liver fibrosis, or buildup of scar tissue; ultimately, this can progress to cirrhosis, liver cancer, and end-stage liver failure. Typically, this process takes years or even decades.
But as Fierer first reported at the 2007 retrovirus conference, several HIV-positive men with acute hepatitis C at Mt. Sinai already showed evidence of moderate – and in some cases, severe – liver fibrosis, despite having had HCV for only weeks or months; this cohort has now expanded to 45 men. Fierer suggested that HIV-related immunocompromise may predispose people to accelerated fibrosis if they are subsequently infected with HCV. In contrast, injection drug users who become infected with both viruses usually get HCV first, since it is more easily transmitted than HIV, and do not show this type of unusually rapid progression. However, most coinfected men in the Mt. Sinai cohort were in "terrific shape" with regard to their HIV disease, Fierer said. Overall, they had well-preserved immune function, with an average CD4 cell count of 525, and many had never started antiretroviral therapy because their CD4 counts were still high. Fierer's findings have proved controversial, since they go against conventional wisdom about the normal course of hepatitis C. Researchers studying the coinfection outbreaks in the U..K. and Europe have not reported similar rapid progression, but they usually estimate liver damage using non-invasive methods that are not as accurate as the "gold standard" liver biopsies used by Fierer's team. "I would love to be completely wrong about this," Fierer said, "but somebody's got to look." The good news is that if hepatitis C treatment is started early, during the acute phase of infection, there is a very good chance of a cure. In addition to eliminating HCV, treatment also has the potential to improve existing liver damage. Fierer described one patient who achieved a sustained response after 24 weeks of pegylated interferon plus ribavirin, and a repeat liver biopsy showed that his liver inflammation and fibrosis were almost completely resolved. Fierer recommended HCV antibody tests every six to 12 months. Dr. Marion Peters from UCSF, also speaking at the forum, said the standard HCV antibody test is almost always accurate in HIV-positive people unless they have very low CD4 counts (below 100). After the acute stage of hepatitis C, when to start treatment is an open debate. Treatment should begin when liver disease starts to progress, but since it's generally been assumed that this takes a long time, doctors do not routinely recommend biopsies for people without long-standing infection. "We haven't been routinely biopsying patients with new HCV infection," Hare said, "but [Fierer's] data are making us rethink this."
NEWS
Published 03/26/2009
by Liz Highleyman
Bay Area Reporter (SF)
Dr. Daniel Fierer spoke about HIV-hepatitis C coinfection at a forum in San Francisco last week. While HIV continues to garner the lion's share of attention regarding gay men's health, a second forum in as many months focused on the growing epidemic of hepatitis C among HIV-positive men who have sex with men – and presenters noted that rapid liver disease could be a result. The March 17 forum – provocatively titled "Could you survive HIV only to die from hepatitis C?" – featured Dr. Daniel Fierer of Mt. Sinai School of Medicine in New York City, one of the leading American experts on HIV and hepatitis C virus (HCV) coinfection.
Dr. Marcus Conant, whose Conant Foundation sponsored the meeting in conjunction with Project Inform and the Black Coalition on AIDS, noted that while nearly 4 million people in the U.S. have hepatitis C, the rate of new infections in the general population has fallen dramatically in recent decades. But such is not the case for HIV-positive gay and bisexual men. Outbreaks of apparently sexually transmitted acute hepatitis C started cropping up among gay men in London and continental European cities around 2002. The first similar U.S. report, by researchers from the University of California at San Francisco, was published in 2006.. Dr. Brad Hare, a member of that team, said that today 42 percent of HIV-infected men in UCSF's Positive Health Program also have HCV. Fierer said these recent acute HCV coinfections in HIV-positive men appear to represent "a new 21st century clinical syndrome," since they depart in some important ways from the prevailing consensus about hepatitis C. Traditionally, experts have maintained that HCV is rarely spread through sex, a claim based on studies of monogamous HIV-negative heterosexual men and women, who have a sexual transmission rate under 5 percent. Though specific risk factors have varied from study to study, the recent acute hepatitis C outbreaks among gay men have been linked to fisting, unprotected anal intercourse, group sex, sharing sex toys, having other sexually transmitted diseases, and use of non-injected recreational drugs. Based on an analysis of a small but growing group of coinfected gay men in New York, Fierer said that acute HCV infection in a person who already has HIV may lead to unusually rapid liver disease progression. Over time, hepatitis C infection can lead to liver fibrosis, or buildup of scar tissue; ultimately, this can progress to cirrhosis, liver cancer, and end-stage liver failure. Typically, this process takes years or even decades.
But as Fierer first reported at the 2007 retrovirus conference, several HIV-positive men with acute hepatitis C at Mt. Sinai already showed evidence of moderate – and in some cases, severe – liver fibrosis, despite having had HCV for only weeks or months; this cohort has now expanded to 45 men. Fierer suggested that HIV-related immunocompromise may predispose people to accelerated fibrosis if they are subsequently infected with HCV. In contrast, injection drug users who become infected with both viruses usually get HCV first, since it is more easily transmitted than HIV, and do not show this type of unusually rapid progression. However, most coinfected men in the Mt. Sinai cohort were in "terrific shape" with regard to their HIV disease, Fierer said. Overall, they had well-preserved immune function, with an average CD4 cell count of 525, and many had never started antiretroviral therapy because their CD4 counts were still high. Fierer's findings have proved controversial, since they go against conventional wisdom about the normal course of hepatitis C. Researchers studying the coinfection outbreaks in the U..K. and Europe have not reported similar rapid progression, but they usually estimate liver damage using non-invasive methods that are not as accurate as the "gold standard" liver biopsies used by Fierer's team. "I would love to be completely wrong about this," Fierer said, "but somebody's got to look." The good news is that if hepatitis C treatment is started early, during the acute phase of infection, there is a very good chance of a cure. In addition to eliminating HCV, treatment also has the potential to improve existing liver damage. Fierer described one patient who achieved a sustained response after 24 weeks of pegylated interferon plus ribavirin, and a repeat liver biopsy showed that his liver inflammation and fibrosis were almost completely resolved. Fierer recommended HCV antibody tests every six to 12 months. Dr. Marion Peters from UCSF, also speaking at the forum, said the standard HCV antibody test is almost always accurate in HIV-positive people unless they have very low CD4 counts (below 100). After the acute stage of hepatitis C, when to start treatment is an open debate. Treatment should begin when liver disease starts to progress, but since it's generally been assumed that this takes a long time, doctors do not routinely recommend biopsies for people without long-standing infection. "We haven't been routinely biopsying patients with new HCV infection," Hare said, "but [Fierer's] data are making us rethink this."
Maintenance Therapy Does It Work ???
HALT-C in the final analysis: A molehill out of a mountain
Piero L. Almasio
published online 20 March 2009.
Uncorrected Proof
from Jules: is it possible that if you looked at patients who were able to stay on peginterferon in the treatment group, they would have shown benefit: "in the treatment group, a sizable number of patients (157 out of 517, 30.4%) discontinued the therapy mainly because of adverse effects (hematological abnormalities, depression) or simply refused to continue, with the result that at the end of the trial less than 60% of the cases still in the study, but without clinical outcomes, took the intended dose of peginterferon." Prolonged therapy of advanced chronic hepatitis C with low-dose peginterferon. Di Bisceglie AM, Shiffman ML, Everson GT, Lindsay KL, Everhart JE, Wright EC, Lee WM, Lok AS, Bonkovsky HL, Morgan TR, Ghany MG, Morishima C, Snow KK, Dienstag JL, HALT-C Trial Investigators.
Background
In patients with chronic hepatitis C who do not have a response to antiviral treatment, the disease may progress to cirrhosis, liver failure, hepatocellular carcinoma, and death. Whether long-term antiviral therapy can prevent progressive liver disease in such patients remains uncertain.
Methods
We conducted a randomized, controlled trial of peginterferon alfa-2a at a dosage of 90μg per week for 3.5 years, as compared with no treatment, in 1050 patients with chronic hepatitis C and advanced fibrosis who had not had a response to previous therapy with peginterferon and ribavirin. The patients, who were stratified according to stage of fibrosis (622 with noncirrhotic fibrosis and 428 with cirrhosis), were seen at 3-month intervals and underwent liver biopsy at 1.5 and 3.5 years after randomization. The primary end point was progression of liver disease, as indicated by death, hepatocellular carcinoma, hepatic decompensation, or, for those with bridging fibrosis at baseline, an increase in the Ishak fibrosis score of 2 or more points.
Results We randomly assigned the patients to receive peginterferon (517 patients) or no therapy (533 patients) for 3.5 years. The level of serum aminotransferases, the level of serum hepatitis C virus RNA, and histologic necroinflammatory scores all decreased significantly (P<0.001) with treatment, but there was no significant difference between the groups in the rate of any primary outcome (34.1% in the treatment group and 33.8% in the control group; hazard ratio, 1.01; 95% confidence interval, 0.81–1.27; P=0.90). The percentage of patients with at least one serious adverse event was 38.6% in the treatment group and 31.8% in the control group (P=0.07).
Conclusions
Long-term therapy with peginterferon did not reduce the rate of disease progression in patients with chronic hepatitis C and advanced fibrosis, with or without cirrhosis, who had not had a response to initial treatment with peginterferon and ribavirin. (ClinicalTrials.gov number, NCT00006164.) 2008 Massachusetts Medical Society.
[Abstract reproduced by permission of N Engl J Med 2008;359:2429–2441].
Article Outline
It seems reasonable to evaluate the efficacy of any interventional approach, whether prophylactic or therapeutic, and to ascertain to what extent the natural history of a disease has been modified in terms of morbidity and mortality. Therefore, an accurate knowledge of the clinical course of a particular medical condition, in the absence of active involvement on the part of the physician, is of paramount relevance when we want to appraise the long-term effect of a drug. In the field of chronic liver disease there is vast evidence that the removal of the etiological agent may reduce the risk complications, the occurrence of hepatocellular carcinoma (HCC), and liver-related mortality. In fact, it has been demonstrated that the persistent eradication of HBV or HCV after antiviral therapy, or removal of iron overload in patients with hereditary hemochromatosis, is associated with a better prognosis [1], [2], [3]. However, the rate of complete success in HCV-related liver disease is far from satisfactory, particularly in the treatment of an advanced form of hepatic damage, or if some co-factors, such as HBV or HIV co-infection, alcohol abuse or obesity are present. The scientific assumptions that led to the conception and organisation of the mega trial called “Hepatitis Antiviral Long-Term Treatment Against Cirrhosis (HALT-C)”, the results of which were recently published [4], are based on evidence that emerged in the late 1990s. The first finding was that interferon (IFN) therapy could reduce viral load, ameliorate histological activity and block progression of fibrosis even in non-responders [5]. The second was that prolonging IFN therapy up to 2 years was significantly associated with a decrease of necro-inflammatory activity and hepatic fibrosis compared to subjects treated for six months [6]. The randomised clinical trial was initiated under the sponsorship of the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) to find a treatment for non-responders with bridging fibrosis or cirrhosis on liver biopsy [7]. The main outcomes were the deterioration of liver disease in terms of an increase in the Ishak fibrosis score (evaluated histologically by liver biopsy), and decompensation, HCC development and death (observed in the clinical setting). Even with 10 liver units across the USA participating in the study, the duration of patient enrollment was quite long, lasting for 4 years, and ended in August 2004. From a screened population of 1739 patients, 1050 subjects were subsequently randomised and, among them, 899 cases completed the study. It is worth noting that in the same period, two other trials aimed at evaluating the efficacy of maintenance therapy in non-responders were also initiated (one under the sponsorship of the pharmaceutical industry) (Table 1), though neither has been published as a full paper, only in abstract form [8], [9].. The interpretation of the study from the perspective of the glass being half full showed that the treated arm of the trial had a greater reduction in HCV RNA, ALT and hepatic necroinflammation compared with the untreated group. Interestingly, 18 patients (3.5%) had a sustained virologic response after 3.5 years of peginterferon alone, in contrast to only one control subject. According to the “glass is half empty” view, on the other hand, was that at the end of the study the rate of fibrosis progression was similar among treated and untreated patients (20.7% vs. 22.4%), and the number of cases with primary outcomes was comparable (64/517 vs. 70/533), with an apparent excess of deaths (13 vs. 8) in patients receiving the active drug. Furthermore, when the authors separately analyzed the occurrence of primary outcomes in non-cirrhotic patients in whom peginterferon could have had a greater chance of efficacy, the treatment group had a higher incidence of events. Finally, in the treatment group, a sizable number of patients (157 out of 517, 30.4%) discontinued the therapy mainly because of adverse effects (hematological abnormalities, depression) or simply refused to continue, with the result that at the end of the trial less than 60% of the cases still in the study, but without clinical outcomes, took the intended dose of peginterferon. These negative results are perfectly in line with those observed in the COPILOT study [8]. By an intention-to-treat analysis, the rate of the patients with liver-related outcome was higher in those treated with peginterferon compared with the colchicine arm (21.2% vs. 18.5%), with a slight excess of HCC occurrence in the first group (22 out of 286 vs. 13 out of 269). Unfortunately, adjunctive data on efficacy of low-dose peginterferon long-term maintenance on relevant clinical endpoints are not yet available from the EPIC3 trial.
It is not an easy task to explain these negative results when a number of previous studies, even if derived from non-randomised controlled studies, have demonstrated a “protective” effect of IFN treatment on HCC development independently of viral clearance [10]. In the HALT-C study the vast majority of patients were previous non-responders, without any significant decline in serum HCV RNA during the previous full dose course of peginterferon plus ribavirin. In addition, more than 90% of patients had a decline of viremia less than one log during maintenance therapy, and no attempt was made to manipulate the dose of cytokine in order to maintain viral suppression in patients partially sensitive to the therapy. An additional analysis presented at the last EASL meeting, in Milan [11], could detect no benefit, even in the subgroup of patients with HCV RNA inhibition, in either the initial twelve week run-in phase, when patients received peginterferon at full dose in association with ribavirin, or the long-term maintenance phase during which viral suppression was achieved. The degree of lead-in HCV RNA suppression was associated with a decrease of clinical events at the end of the trial, but not in terms of fibrosis progression. The hypothesis that the non-use of ribavirin during the 3.5 years of maintenance therapy was a relevant factor in the clinical failure has yet to be assessed.
In conclusion, the publication of the final report of HALT-C is the “swan song” of maintenance therapy as an effective approach in non-responders with chronic HCV infection, and therefore its conclusions will find no place in clinical practice. However, the trial has left the scientific community a treasure trove of knowledge related to HCV-related liver disease with one freely available Internet site (www.haltctrial.org) and more than twenty papers published in top-flight medical journals.
ABSTRACT from EASL Milan:
144 SUPPRESSION OF SERUM HCVRNA LEVELS DURING
MAINTENANCE PEGINTERFERON (PEGIFN) ALFA-2A
THERAPY AND CLINICAL OUTCOMES IN THE HALT-C
TRIAL
M.L.. Shiffman1, C. Morishima2, K.L. Lindsay3, J.C. Hoefs4,
J.L. Dienstag5, G. Szabo6, W.M. Lee7, E.C. Wright8, for the HALT-C
Trial Group9. 1Hepatology Section, Virginia Commonwealth University
Medical Center, Richmond, VA, 2Department of Laboratory Medicine,
University of Washington, Seattle, WA, 3Division of Gastroenterology
and Liver Disease, University of Southern California, Los Angeles,
CA, 4Division of Gastroenterology, University of California – Irvine,
Irvine, CA, 5Gastrointestinal Unit, Massachusetts General Hospital,
Harvard Medical School, Boston, MA, 6Liver Center, University of
Massachusetts Medical School, Worcester, MA, 7Division of Digestive and
Liver Diseases, University of Texas Southwestern Medical Center, Dallas,
TX, 8Department of Health and Human Services, National Institute of
Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA
E-mail: mshiffma@vcu.edu
The primary analysis of the HALT-C Trial demonstrated that PEGIFN
maintenance therapy did not reduce complications of cirrhosis, HCC,
liver transplantation (LT) or mortality in patients with chronic HCV and
advanced fibrosis or cirrhosis (AASLD 2007). This analysis assessed the
relationship between viral suppression and clinical outcomes.
Methods: 764 patients who failed to achieve SVR with PEGIFN 180
mg/week and ribavirin during the HALT-C lead-in phase were evaluated.
378 were randomized to maintenance PEGIFN (90 mg/week) and 386
received no additional treatment for 3.5 years (controls).. No patient
had a history of CTP>6, ascites, hepatic encephalopathy (HE), variceal
hemorrhage (VH) or HCC. HCVRNA was measured by Roche COBAS™
Monitor and/or Amplicor v.2.0 tests.
Results: During lead-in treatment 425 (56%) patients had <2 log decline in
HCVRNA from their pre-treatment baseline; 178 (23%) had >4 log decline
and/or became HCVRNA undetectable with subsequent breakthrough or
relapse. After randomization, serum HCVRNA remained within 1 log of
pre-treatment values in 381 (99%) control and 273 (72%) maintenance
patients. Only 30/88 patients with >4 log suppression in HCVRNA during
lead-in treatment maintained this degree of viral suppression with maintenance
PEGIFN. Clinical outcomes (2-point CTP increase, ascites, HE, VH,
HCC, LT, death) occurred in significantly fewer patients with profound
decline in HCVRNA during the lead-in. When HCVRNA declined by
<2>4 logs from the pre-treatment baseline during leadin
treatment outcomes occurred in 20%, 23% and 7% of patients on
maintenance PEGINF and 20%, 13% and 10% in controls (both p<0.05).
Outcomes occurred in 18%, 22% and 12% of patients on maintenance
PEGIFN when HCVRNA was continuously suppressed by these same
amounts (p = NS). 13/29 patients with repeatedly undetectable HCVRNA
over 3.5 years on maintenance PEGIFN achieved SVR.
Conclusions: A significant decline in clinical outcomes was observed
in patients with chronic HCV and advanced fibrosis or cirrhosis who
achieved a profound decline in HCVRNA (>4 log and/or undetectable with
subsequent breakthrough or relapse) with full-dose PEGIFN and ribavirin
whether or not they remained on maintenance therapy. Whether additional
clinical benefit can be derived when profound HCVRNA suppression is
maintained with PEGIFN remains unproven.
Piero L. Almasio
published online 20 March 2009.
Uncorrected Proof
from Jules: is it possible that if you looked at patients who were able to stay on peginterferon in the treatment group, they would have shown benefit: "in the treatment group, a sizable number of patients (157 out of 517, 30.4%) discontinued the therapy mainly because of adverse effects (hematological abnormalities, depression) or simply refused to continue, with the result that at the end of the trial less than 60% of the cases still in the study, but without clinical outcomes, took the intended dose of peginterferon." Prolonged therapy of advanced chronic hepatitis C with low-dose peginterferon. Di Bisceglie AM, Shiffman ML, Everson GT, Lindsay KL, Everhart JE, Wright EC, Lee WM, Lok AS, Bonkovsky HL, Morgan TR, Ghany MG, Morishima C, Snow KK, Dienstag JL, HALT-C Trial Investigators.
Background
In patients with chronic hepatitis C who do not have a response to antiviral treatment, the disease may progress to cirrhosis, liver failure, hepatocellular carcinoma, and death. Whether long-term antiviral therapy can prevent progressive liver disease in such patients remains uncertain.
Methods
We conducted a randomized, controlled trial of peginterferon alfa-2a at a dosage of 90μg per week for 3.5 years, as compared with no treatment, in 1050 patients with chronic hepatitis C and advanced fibrosis who had not had a response to previous therapy with peginterferon and ribavirin. The patients, who were stratified according to stage of fibrosis (622 with noncirrhotic fibrosis and 428 with cirrhosis), were seen at 3-month intervals and underwent liver biopsy at 1.5 and 3.5 years after randomization. The primary end point was progression of liver disease, as indicated by death, hepatocellular carcinoma, hepatic decompensation, or, for those with bridging fibrosis at baseline, an increase in the Ishak fibrosis score of 2 or more points.
Results We randomly assigned the patients to receive peginterferon (517 patients) or no therapy (533 patients) for 3.5 years. The level of serum aminotransferases, the level of serum hepatitis C virus RNA, and histologic necroinflammatory scores all decreased significantly (P<0.001) with treatment, but there was no significant difference between the groups in the rate of any primary outcome (34.1% in the treatment group and 33.8% in the control group; hazard ratio, 1.01; 95% confidence interval, 0.81–1.27; P=0.90). The percentage of patients with at least one serious adverse event was 38.6% in the treatment group and 31.8% in the control group (P=0.07).
Conclusions
Long-term therapy with peginterferon did not reduce the rate of disease progression in patients with chronic hepatitis C and advanced fibrosis, with or without cirrhosis, who had not had a response to initial treatment with peginterferon and ribavirin. (ClinicalTrials.gov number, NCT00006164.) 2008 Massachusetts Medical Society.
[Abstract reproduced by permission of N Engl J Med 2008;359:2429–2441].
Article Outline
It seems reasonable to evaluate the efficacy of any interventional approach, whether prophylactic or therapeutic, and to ascertain to what extent the natural history of a disease has been modified in terms of morbidity and mortality. Therefore, an accurate knowledge of the clinical course of a particular medical condition, in the absence of active involvement on the part of the physician, is of paramount relevance when we want to appraise the long-term effect of a drug. In the field of chronic liver disease there is vast evidence that the removal of the etiological agent may reduce the risk complications, the occurrence of hepatocellular carcinoma (HCC), and liver-related mortality. In fact, it has been demonstrated that the persistent eradication of HBV or HCV after antiviral therapy, or removal of iron overload in patients with hereditary hemochromatosis, is associated with a better prognosis [1], [2], [3]. However, the rate of complete success in HCV-related liver disease is far from satisfactory, particularly in the treatment of an advanced form of hepatic damage, or if some co-factors, such as HBV or HIV co-infection, alcohol abuse or obesity are present. The scientific assumptions that led to the conception and organisation of the mega trial called “Hepatitis Antiviral Long-Term Treatment Against Cirrhosis (HALT-C)”, the results of which were recently published [4], are based on evidence that emerged in the late 1990s. The first finding was that interferon (IFN) therapy could reduce viral load, ameliorate histological activity and block progression of fibrosis even in non-responders [5]. The second was that prolonging IFN therapy up to 2 years was significantly associated with a decrease of necro-inflammatory activity and hepatic fibrosis compared to subjects treated for six months [6]. The randomised clinical trial was initiated under the sponsorship of the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) to find a treatment for non-responders with bridging fibrosis or cirrhosis on liver biopsy [7]. The main outcomes were the deterioration of liver disease in terms of an increase in the Ishak fibrosis score (evaluated histologically by liver biopsy), and decompensation, HCC development and death (observed in the clinical setting). Even with 10 liver units across the USA participating in the study, the duration of patient enrollment was quite long, lasting for 4 years, and ended in August 2004. From a screened population of 1739 patients, 1050 subjects were subsequently randomised and, among them, 899 cases completed the study. It is worth noting that in the same period, two other trials aimed at evaluating the efficacy of maintenance therapy in non-responders were also initiated (one under the sponsorship of the pharmaceutical industry) (Table 1), though neither has been published as a full paper, only in abstract form [8], [9].. The interpretation of the study from the perspective of the glass being half full showed that the treated arm of the trial had a greater reduction in HCV RNA, ALT and hepatic necroinflammation compared with the untreated group. Interestingly, 18 patients (3.5%) had a sustained virologic response after 3.5 years of peginterferon alone, in contrast to only one control subject. According to the “glass is half empty” view, on the other hand, was that at the end of the study the rate of fibrosis progression was similar among treated and untreated patients (20.7% vs. 22.4%), and the number of cases with primary outcomes was comparable (64/517 vs. 70/533), with an apparent excess of deaths (13 vs. 8) in patients receiving the active drug. Furthermore, when the authors separately analyzed the occurrence of primary outcomes in non-cirrhotic patients in whom peginterferon could have had a greater chance of efficacy, the treatment group had a higher incidence of events. Finally, in the treatment group, a sizable number of patients (157 out of 517, 30.4%) discontinued the therapy mainly because of adverse effects (hematological abnormalities, depression) or simply refused to continue, with the result that at the end of the trial less than 60% of the cases still in the study, but without clinical outcomes, took the intended dose of peginterferon. These negative results are perfectly in line with those observed in the COPILOT study [8]. By an intention-to-treat analysis, the rate of the patients with liver-related outcome was higher in those treated with peginterferon compared with the colchicine arm (21.2% vs. 18.5%), with a slight excess of HCC occurrence in the first group (22 out of 286 vs. 13 out of 269). Unfortunately, adjunctive data on efficacy of low-dose peginterferon long-term maintenance on relevant clinical endpoints are not yet available from the EPIC3 trial.
It is not an easy task to explain these negative results when a number of previous studies, even if derived from non-randomised controlled studies, have demonstrated a “protective” effect of IFN treatment on HCC development independently of viral clearance [10]. In the HALT-C study the vast majority of patients were previous non-responders, without any significant decline in serum HCV RNA during the previous full dose course of peginterferon plus ribavirin. In addition, more than 90% of patients had a decline of viremia less than one log during maintenance therapy, and no attempt was made to manipulate the dose of cytokine in order to maintain viral suppression in patients partially sensitive to the therapy. An additional analysis presented at the last EASL meeting, in Milan [11], could detect no benefit, even in the subgroup of patients with HCV RNA inhibition, in either the initial twelve week run-in phase, when patients received peginterferon at full dose in association with ribavirin, or the long-term maintenance phase during which viral suppression was achieved. The degree of lead-in HCV RNA suppression was associated with a decrease of clinical events at the end of the trial, but not in terms of fibrosis progression. The hypothesis that the non-use of ribavirin during the 3.5 years of maintenance therapy was a relevant factor in the clinical failure has yet to be assessed.
In conclusion, the publication of the final report of HALT-C is the “swan song” of maintenance therapy as an effective approach in non-responders with chronic HCV infection, and therefore its conclusions will find no place in clinical practice. However, the trial has left the scientific community a treasure trove of knowledge related to HCV-related liver disease with one freely available Internet site (www.haltctrial.org) and more than twenty papers published in top-flight medical journals.
ABSTRACT from EASL Milan:
144 SUPPRESSION OF SERUM HCVRNA LEVELS DURING
MAINTENANCE PEGINTERFERON (PEGIFN) ALFA-2A
THERAPY AND CLINICAL OUTCOMES IN THE HALT-C
TRIAL
M.L.. Shiffman1, C. Morishima2, K.L. Lindsay3, J.C. Hoefs4,
J.L. Dienstag5, G. Szabo6, W.M. Lee7, E.C. Wright8, for the HALT-C
Trial Group9. 1Hepatology Section, Virginia Commonwealth University
Medical Center, Richmond, VA, 2Department of Laboratory Medicine,
University of Washington, Seattle, WA, 3Division of Gastroenterology
and Liver Disease, University of Southern California, Los Angeles,
CA, 4Division of Gastroenterology, University of California – Irvine,
Irvine, CA, 5Gastrointestinal Unit, Massachusetts General Hospital,
Harvard Medical School, Boston, MA, 6Liver Center, University of
Massachusetts Medical School, Worcester, MA, 7Division of Digestive and
Liver Diseases, University of Texas Southwestern Medical Center, Dallas,
TX, 8Department of Health and Human Services, National Institute of
Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA
E-mail: mshiffma@vcu.edu
The primary analysis of the HALT-C Trial demonstrated that PEGIFN
maintenance therapy did not reduce complications of cirrhosis, HCC,
liver transplantation (LT) or mortality in patients with chronic HCV and
advanced fibrosis or cirrhosis (AASLD 2007). This analysis assessed the
relationship between viral suppression and clinical outcomes.
Methods: 764 patients who failed to achieve SVR with PEGIFN 180
mg/week and ribavirin during the HALT-C lead-in phase were evaluated.
378 were randomized to maintenance PEGIFN (90 mg/week) and 386
received no additional treatment for 3.5 years (controls).. No patient
had a history of CTP>6, ascites, hepatic encephalopathy (HE), variceal
hemorrhage (VH) or HCC. HCVRNA was measured by Roche COBAS™
Monitor and/or Amplicor v.2.0 tests.
Results: During lead-in treatment 425 (56%) patients had <2 log decline in
HCVRNA from their pre-treatment baseline; 178 (23%) had >4 log decline
and/or became HCVRNA undetectable with subsequent breakthrough or
relapse. After randomization, serum HCVRNA remained within 1 log of
pre-treatment values in 381 (99%) control and 273 (72%) maintenance
patients. Only 30/88 patients with >4 log suppression in HCVRNA during
lead-in treatment maintained this degree of viral suppression with maintenance
PEGIFN. Clinical outcomes (2-point CTP increase, ascites, HE, VH,
HCC, LT, death) occurred in significantly fewer patients with profound
decline in HCVRNA during the lead-in. When HCVRNA declined by
<2>4 logs from the pre-treatment baseline during leadin
treatment outcomes occurred in 20%, 23% and 7% of patients on
maintenance PEGINF and 20%, 13% and 10% in controls (both p<0.05).
Outcomes occurred in 18%, 22% and 12% of patients on maintenance
PEGIFN when HCVRNA was continuously suppressed by these same
amounts (p = NS). 13/29 patients with repeatedly undetectable HCVRNA
over 3.5 years on maintenance PEGIFN achieved SVR.
Conclusions: A significant decline in clinical outcomes was observed
in patients with chronic HCV and advanced fibrosis or cirrhosis who
achieved a profound decline in HCVRNA (>4 log and/or undetectable with
subsequent breakthrough or relapse) with full-dose PEGIFN and ribavirin
whether or not they remained on maintenance therapy. Whether additional
clinical benefit can be derived when profound HCVRNA suppression is
maintained with PEGIFN remains unproven.
FDA approves re-treatment with Hep C drugs
March 16, 2009
FDA Expands Use of Schering's Hepatitis C Drugs
While previously only approved for patients who had never taken any Hepatitis C drugs, Pegintron and Rebetol are now approved by the FDA for re-treatment.
Schering say FDA expands hepatitis drug labels
Associated Press, 03.11.09, 04:39 PM EST
The Food and Drug Administration expanded the label for Schering-Plough Corp.'s hepatitis C drugs Pegintron and Rebetol, allowing the company to market the drugs for patients who have not recovered from the disease after previous treatment. Schering-Plough (nyse: SGP - news - people ) said Wednesday that the FDA approved the drugs for the treatment of chronic hepatitis C in patients with compensated liver disease. They were already approved for use in "treatment-naive" patients, or those who had never taken any drugs for the liver disease.
The drugs are approved for use in patients 3 and older. The company said more than 100,000 people in the U.S. have received at least one unsuccessful treatment for hepatitis C. Sales of Pegintron totaled $914 million in 2008, and Schering-Plough reported $260 million in Rebetol revenue. Schering-Plough on Monday accepted a buyout offer from Merck and Co. (nyse: MRK - news - people ) worth $41.1 billion.
Copyright 2009 by Associated Press
FDA Expands Use of Schering's Hepatitis C Drugs
While previously only approved for patients who had never taken any Hepatitis C drugs, Pegintron and Rebetol are now approved by the FDA for re-treatment.
Schering say FDA expands hepatitis drug labels
Associated Press, 03.11.09, 04:39 PM EST
The Food and Drug Administration expanded the label for Schering-Plough Corp.'s hepatitis C drugs Pegintron and Rebetol, allowing the company to market the drugs for patients who have not recovered from the disease after previous treatment. Schering-Plough (nyse: SGP - news - people ) said Wednesday that the FDA approved the drugs for the treatment of chronic hepatitis C in patients with compensated liver disease. They were already approved for use in "treatment-naive" patients, or those who had never taken any drugs for the liver disease.
The drugs are approved for use in patients 3 and older. The company said more than 100,000 people in the U.S. have received at least one unsuccessful treatment for hepatitis C. Sales of Pegintron totaled $914 million in 2008, and Schering-Plough reported $260 million in Rebetol revenue. Schering-Plough on Monday accepted a buyout offer from Merck and Co. (nyse: MRK - news - people ) worth $41.1 billion.
Copyright 2009 by Associated Press
Inhibiting the Hepatitis C Virus
March 23, 2009
Inhibiting the Hepatitis C Virus
Opening up new treatment possibilities, researchers from Scripps Institute have found molecules that prevent Hepatitis C viral production.
Study may lead to anti-hepatitis-C drug
JUPITER, Fla., Mar 12, 2009 (UPI via COMTEX) -- U.S. researchers say they have identified key molecules that inhibit viral production in a study that might lead to new treatments for hepatitis C. The research, led by Professor Donny Strosberg of the Scripps Institute in Jupiter, Fla., describes peptides (molecules of two or more amino acids) derived from the core protein of hepatitis C. The team found the peptides inhibit not only chemical reaction of the core protein -- the joining of two identical subunits -- but also production of the actual virus.
"We went for the simplest solution, taking a peptide from core to see if we could block the interaction," Strosberg said. "And it did."The study is to be published by the Journal of General Virology and is available in the journal's March 4 pre-print online edition.
www.upi.com
Copyright 2009 by United Press International
Inhibiting the Hepatitis C Virus
Opening up new treatment possibilities, researchers from Scripps Institute have found molecules that prevent Hepatitis C viral production.
Study may lead to anti-hepatitis-C drug
JUPITER, Fla., Mar 12, 2009 (UPI via COMTEX) -- U.S. researchers say they have identified key molecules that inhibit viral production in a study that might lead to new treatments for hepatitis C. The research, led by Professor Donny Strosberg of the Scripps Institute in Jupiter, Fla., describes peptides (molecules of two or more amino acids) derived from the core protein of hepatitis C. The team found the peptides inhibit not only chemical reaction of the core protein -- the joining of two identical subunits -- but also production of the actual virus.
"We went for the simplest solution, taking a peptide from core to see if we could block the interaction," Strosberg said. "And it did."The study is to be published by the Journal of General Virology and is available in the journal's March 4 pre-print online edition.
www.upi.com
Copyright 2009 by United Press International
Male Sexual Functuion during Hep C treatment
March 24, 2009
Male Sexual Function During Hepatitis C Treatment
Learn why recent statistics do not tell the entire story about how Hepatitis C treatment affects men’s sexuality.
by Nicole Cutler, L.Ac.
A new study presented at the November 2008 Annual Meeting of the American Association for the Study of Liver Diseases painted a grim picture of the sexual health of men with Hepatitis C who undergo treatment. However, further investigation into the details reveals this trial’s weakness and should put most men at ease. Although sex usually is a source of great pleasure, it can also be the cause of significant stress. Intertwined with aspects of one’s physical, emotional and spiritual health, an adult’s sexuality is complex. Despite the range of possible causes, a reduction in sexual desire, function or satisfaction can be extremely upsetting. Considering the complex union of neurological, psychological and physiological events that must unite for an optimal sexual experience to occur, it is not surprising when things occasionally are amiss. The StudyEight health centers across the U.S.A. collaborated on a study to determine the effect Hepatitis C combination therapy has on men’s sexual health. Self-administered sexual health questionnaires were given to over 400 participants with Hepatitis C genotype 1 receiving a 48-week course of combination therapy. Containing five sexual health questions that assessed sexual desire, function (erection and ejaculation) and satisfaction, the questionnaires were given six times throughout a 72-week period. At the start of therapy, the following was indicated: · 37 percent reported an impairment of sexual desire· 26 percent reported erectile dysfunction· 21 percent reported ejaculatory problems · 44 percent reported dissatisfaction with their sex lifeNot surprisingly, the respondents reported a worsening in all areas of sexual health during interferon-based therapy: · 53 percent reported an impairment of sexual desire· 39 percent reported erectile dysfunction· 31 percent reported ejaculatory problems· 54 percent reported dissatisfaction with their sex life Most areas of sexual health returned to their original levels at the end of the 72-week period. However, those who endured treatment for the full 48 weeks had a slightly higher erectile and ejaculatory dysfunction compared to before treatment began. RealityAlthough the percentages of men in this study with a lower than desired level of sexual function may seem like a lot, these numbers are meaningless without a comparison. · According to a 1999 survey from the University of Chicago and the Robert Wood Johnson Medical School, approximately 30 percent of men report sexual dysfunction. Although a slightly higher proportion of men with Hepatitis C said they had problems with sexual desire, function or satisfaction, the 1999 research based its findings on the general population. · According to a Portuguese study published in the June 2008 edition of The Journal of Sexual Medicine, the prevalence of erectile dysfunction is strongly related to age and health status. They concluded that adjusting for age, the total prevalence of erectile dysfunction in men was slightly higher than 48 percent, a statistic that is very close to what was reported by men in the Hepatitis C study. · According to a publication in the November 2008 edition of the International Journal of Impotence Research, testosterone levels fall as men age. Because testosterone plays a role in general and sexual health in men, it is no surprise that a higher percentage of older men report sexual dissatisfaction as opposed to younger men. Because the Hepatitis C study did not separate results according to age, its statistics are not specific enough to draw any conclusions. Besides AgeFor normal sexual arousal and function to occur, a person must feel good. Feeling well enough for sex involves feeling confident, being free from anxiety, having stamina for mental and physical stimulation, as well as the ability to focus attention on arousing thoughts or behavior. Anything that interferes with these conditions can disrupt a sexual encounter. The severe side effects that accompany Hepatitis C therapy definitely have the potential to interfere with feeling good. Those affected who discuss their sexual health concerns with their physician have a greater chance of finding solutions. For more information about sexual dysfunction with chronic Hepatitis C, read How Hepatitis C Can Affect a Patient’s Sex Life.
There are many components that must unite for sexual desire, function and satisfaction to work. Thus, isolating antiviral therapy as a predictor of sexual difficulties is unfair. The study disclosed in late 2008 makes it seem like receiving treatment for Hepatitis C spells trouble for a man’s sex life. However, men over 40 years of age who don’t have Hepatitis C and who are not undergoing combination therapy have a similar rate of sexual dysfunction. Therefore, do not dismiss the prospect of combination therapy on the basis of sex alone. Because, chances are, if the treatment works and you eliminate the virus, you will eventually feel good – and feeling good is the strongest predictor of vibrant sexual health.
References:
http://chronicle.uchicago.edu/990218/dysfunction.shtml, Researchers publish new study on sexual dysfunction, William Harms, Retrieved December 4, 2008, The University of Chicago Chronicle, February 1999.
http://www.healthnews.com/family-health/sexual-health/sexual-dysfunction-affects-almost-half-american-women-2062.html, Sexual Dysfunction Affects Almost Half of American Women, Madeline Ellis, Retrieved December 3, 2008, HealthNews.com, November 2008.
http://www.hivandhepatitis.com/2008icr/aasld/docs/111408_a.html, Sexual Desire, Function, and Satisfaction in Men Undergoing Treatment with Interferon-based Therapy for Chronic Hepatitis C, Liz Highleyman, Retrieved December 2, 2008, hivandhepatitis.com, November 2008.
http://www.mayoclinic.com/health/sexual-health/HQ01363, Sexual health: How to achieve a fulfilling sexual relationship, David Osborne, PhD, Retrieved December 3, 2008, Mayo Foundation for Medical Education and Research, 2008.
http://www.ncbi.nlm.nih.gov/pubmed/18194181?ordinalpos=12&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum, Prevalence, severity, and risk factors for erectile dysfunction in a representative sample of 3,548 Portuguese men aged 40 to 69 years attending primary healthcare centers: results of the Portuguese erectile dysfunction study, Teles AG, et al, Retrieved December 3, 2008, The Journal of Sexual Medicine, June 2008.
http://www.ncbi.nlm.nih.gov/pubmed/19037223?ordinalpos=5&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum, Are declining testosterone levels a major risk factor for ill-health in aging men?, Yeap BB, Retrieved December 3, 2008, International Journal of Impotence Research, November 2008.
Male Sexual Function During Hepatitis C Treatment
Learn why recent statistics do not tell the entire story about how Hepatitis C treatment affects men’s sexuality.
by Nicole Cutler, L.Ac.
A new study presented at the November 2008 Annual Meeting of the American Association for the Study of Liver Diseases painted a grim picture of the sexual health of men with Hepatitis C who undergo treatment. However, further investigation into the details reveals this trial’s weakness and should put most men at ease. Although sex usually is a source of great pleasure, it can also be the cause of significant stress. Intertwined with aspects of one’s physical, emotional and spiritual health, an adult’s sexuality is complex. Despite the range of possible causes, a reduction in sexual desire, function or satisfaction can be extremely upsetting. Considering the complex union of neurological, psychological and physiological events that must unite for an optimal sexual experience to occur, it is not surprising when things occasionally are amiss. The StudyEight health centers across the U.S.A. collaborated on a study to determine the effect Hepatitis C combination therapy has on men’s sexual health. Self-administered sexual health questionnaires were given to over 400 participants with Hepatitis C genotype 1 receiving a 48-week course of combination therapy. Containing five sexual health questions that assessed sexual desire, function (erection and ejaculation) and satisfaction, the questionnaires were given six times throughout a 72-week period. At the start of therapy, the following was indicated: · 37 percent reported an impairment of sexual desire· 26 percent reported erectile dysfunction· 21 percent reported ejaculatory problems · 44 percent reported dissatisfaction with their sex lifeNot surprisingly, the respondents reported a worsening in all areas of sexual health during interferon-based therapy: · 53 percent reported an impairment of sexual desire· 39 percent reported erectile dysfunction· 31 percent reported ejaculatory problems· 54 percent reported dissatisfaction with their sex life Most areas of sexual health returned to their original levels at the end of the 72-week period. However, those who endured treatment for the full 48 weeks had a slightly higher erectile and ejaculatory dysfunction compared to before treatment began. RealityAlthough the percentages of men in this study with a lower than desired level of sexual function may seem like a lot, these numbers are meaningless without a comparison. · According to a 1999 survey from the University of Chicago and the Robert Wood Johnson Medical School, approximately 30 percent of men report sexual dysfunction. Although a slightly higher proportion of men with Hepatitis C said they had problems with sexual desire, function or satisfaction, the 1999 research based its findings on the general population. · According to a Portuguese study published in the June 2008 edition of The Journal of Sexual Medicine, the prevalence of erectile dysfunction is strongly related to age and health status. They concluded that adjusting for age, the total prevalence of erectile dysfunction in men was slightly higher than 48 percent, a statistic that is very close to what was reported by men in the Hepatitis C study. · According to a publication in the November 2008 edition of the International Journal of Impotence Research, testosterone levels fall as men age. Because testosterone plays a role in general and sexual health in men, it is no surprise that a higher percentage of older men report sexual dissatisfaction as opposed to younger men. Because the Hepatitis C study did not separate results according to age, its statistics are not specific enough to draw any conclusions. Besides AgeFor normal sexual arousal and function to occur, a person must feel good. Feeling well enough for sex involves feeling confident, being free from anxiety, having stamina for mental and physical stimulation, as well as the ability to focus attention on arousing thoughts or behavior. Anything that interferes with these conditions can disrupt a sexual encounter. The severe side effects that accompany Hepatitis C therapy definitely have the potential to interfere with feeling good. Those affected who discuss their sexual health concerns with their physician have a greater chance of finding solutions. For more information about sexual dysfunction with chronic Hepatitis C, read How Hepatitis C Can Affect a Patient’s Sex Life.
There are many components that must unite for sexual desire, function and satisfaction to work. Thus, isolating antiviral therapy as a predictor of sexual difficulties is unfair. The study disclosed in late 2008 makes it seem like receiving treatment for Hepatitis C spells trouble for a man’s sex life. However, men over 40 years of age who don’t have Hepatitis C and who are not undergoing combination therapy have a similar rate of sexual dysfunction. Therefore, do not dismiss the prospect of combination therapy on the basis of sex alone. Because, chances are, if the treatment works and you eliminate the virus, you will eventually feel good – and feeling good is the strongest predictor of vibrant sexual health.
References:
http://chronicle.uchicago.edu/990218/dysfunction.shtml, Researchers publish new study on sexual dysfunction, William Harms, Retrieved December 4, 2008, The University of Chicago Chronicle, February 1999.
http://www.healthnews.com/family-health/sexual-health/sexual-dysfunction-affects-almost-half-american-women-2062.html, Sexual Dysfunction Affects Almost Half of American Women, Madeline Ellis, Retrieved December 3, 2008, HealthNews.com, November 2008.
http://www.hivandhepatitis.com/2008icr/aasld/docs/111408_a.html, Sexual Desire, Function, and Satisfaction in Men Undergoing Treatment with Interferon-based Therapy for Chronic Hepatitis C, Liz Highleyman, Retrieved December 2, 2008, hivandhepatitis.com, November 2008.
http://www.mayoclinic.com/health/sexual-health/HQ01363, Sexual health: How to achieve a fulfilling sexual relationship, David Osborne, PhD, Retrieved December 3, 2008, Mayo Foundation for Medical Education and Research, 2008.
http://www.ncbi.nlm.nih.gov/pubmed/18194181?ordinalpos=12&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum, Prevalence, severity, and risk factors for erectile dysfunction in a representative sample of 3,548 Portuguese men aged 40 to 69 years attending primary healthcare centers: results of the Portuguese erectile dysfunction study, Teles AG, et al, Retrieved December 3, 2008, The Journal of Sexual Medicine, June 2008.
http://www.ncbi.nlm.nih.gov/pubmed/19037223?ordinalpos=5&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum, Are declining testosterone levels a major risk factor for ill-health in aging men?, Yeap BB, Retrieved December 3, 2008, International Journal of Impotence Research, November 2008.
Wednesday, March 25, 2009
Bioprinting future possibilities
BIOPRINTING: DIRECTED TISSUE SELF-ASSEMBLY
Chemical Engineering Progress, Dec 2007 by Mironov, Vladimir, Kasyanov, Vladimir, Markwald, Roger
Imagine eliminating patient waiting lists for organ transplants. Bioprinting holds the promise of making this happen, but, much research must be done first. Traditional or classic tissue engineering is based on fabrication of porous solid biodegradable scaffolds with sequential cell seeding in bioreactors. The main rationale behind this approach is a need to maintain, at least initially, the shape and mechanical properties of the tissueengineered construct and to provide a substrate for cell attachment However, there are limitations to this approach - primarily the low level of precision in cell placement, especially when engineering multicellular constructs, an intrinsic problem with vascularization of thick tissue constructs, and the extremely laborious, slow and costly nonautomated tissue assembly process. Bioprinting is a transforming technology with potential for surpassing the traditional solid-scaffold-based approach in tissue engineering. Bioprinting, in essence, is a biomedical application of rapid prototyping technology or computeraided layered additive biofabrication. The main conceptual foundation of bioprinting technology is a directed tissue selfassembly (Figure 1). Tissue self-assembly is the forming of tissue and next-level biological structures, such as organs from single cells, cell aggregates, cell sheets, tissue spheroids, tissue rods, tissue tubes or more-complex 3D microtissue modules, tissue segments or tissue blocks and extracellular matrices or biomimetic hydrogels. Self-assembly is the autonomous organization of components into patterns or structures without human intervention (1). The term "directed" means precise automated robotic placement and positioning of cells and tissue spheroids according to computer-aided design. Direction or precise robotic placement of two tissue spheroids in close contact creates permissive, but not instructive, conditions for tissue fusion - since tissue fusion is an autonomous self-assembly process driven by surface tension. In other words, placing two cell aggregates into direct contact is necessary, but not sufficient, for tissue fusion. Self-assembly is an emerging concept in tissue engineering. Examples of various tissue self-assembly approaches include cell-sheet technology (rolling or stacking) (2-5), the fusion of linear rod-like structures (6), centrifugal casting (7) and magnetically driven tissue engineering (8, 9). What makes the bioprinting approach different is using selfassembled rounded tissue spheroids as building blocks. Tissue spheroids can be roboticalry dispensed and they have the capacity, when placed close to each other as hanging drops or in permissive hydrogel, to fuse into large tissue constructs of desirable geometrical shape due to their fluidic nature (10-13) and intrinsic capacity for tissue fusion.
The bioprinting process
Step 1 - Pre-processing. In order to build anything for example, a bridge or a house - one must first develop a blueprint. This is also true in the case of organ printing. Before building an organ, we must have a blueprint in the form of a computer-aided design of the desired organ. This gives the precise spatial information about the localization of cells in the 3D organ or, in other words, the "address" of each cellular or extracellular component of the tissue or organ that we want to build. There are several ways in which we can get the information about the anatomy, histological structure, composition and topology of human organs necessary for computer-aided design of printed organs. Recent progress in clinical bioimaging and ultrasound make it possible for us to discern the gross anatomical characteristics of organs, even while they are still inside their owner. The advantage of this approach lies in its capacity to demonstrate the patient's specific anatomical information as well that of his organs, not to mention the fact that we do not need to remove the individual's organ in order to examine it (a fact that many patients might well appreciate). However, resolution of this technique has not yet reached the histological and cellular level. More importantly, tissue composition and cell redistribution cannot be precisely identified. This method is not yet refined enough to be utilized in the process of organ printing. A second approach is based on computer-aided reconstruction of serial histological sections. This method provides a high level of resolution and information about the size and shape of the organ, as well as details about its composition. The problem inherent in this method lies in the fact that human organs are available for this sort of inspection only after death, and are, hence, subject to change and distortion. Other limitations of the histological approach are that it is enormously labor-intensive and is not patient-specific. However, considering that organs have a polymeric structure and consist of repeating structural functional units, one can reconstruct a typical organ unit, and then assemble the whole organ in silico by adding a reconstructed unit based on the gross anatomical structure or by filling the available space. A third approach is based on a mathematical-computational-anatomical model. For example, by knowing the mathematics of vascular branching, it is possible to reconstruct a very realistic model of the vascular tree found inside the organ using computer simulation. In fact, several commercially available pieces of software permit the creation of a realistic anatomical model from bioimages. Furthermore, several laboratories around the world have developed virtual cadavers with gross-anatomical and microanatomical-level resolution and have made them available through the Internet. These successes suggest that the computer-aided design of printed organs is feasible, although prior to finalizing the task of printing a viable organ, the existing software will need to be upgraded to embody more capacities and greater flexibility. One potential problem is post-printing tissue fusion, compaction and remodeling. It means that software for the organ blueprint must be able to incorporate post-processing changes. Our research has demonstrated that tissue compaction and tissue retraction after a fusion process can be very dramatic (11). Tissue maturation and remodeling can lead to additional changes. In other words, blueprints for printing organ constructs can be 2-3 times larger than the actual organ size. However, we do not see these as insurmountable technical challenges. Step 2 - Processing. Processing or actual printing of tissue and organ constructs can be physically carried out by various material-transfer dispensing and deposition devices. One of most promising technologies is inkjet printers, because they are inexpensive and operate at fast speeds of several thousand drops per second or more. Several research groups have already demonstrated that cells survive the process of printing, and that one drop can contain a single cell. Utilizing cell aggregates in inkjet printers is a trickier proposition, but may be possible if the former are enhanced by the inclusion of a highly porous scaffold or using mechanically enforced tissue spheroids. The relatively morestable, and thus more-processible, tissue spheroids or encapsulated living cells (e.g., enzymatically removable hydrogel) could be another possible option. Rapid prototyping technologies offer another possibility, although the use of high temperatures, toxic resin, or resin and plastic with a toxic catalyst is a counter-indication. It has been reported that several rapid prototyping systems can be used to design solid biodegradable scaffolds for tissue engineering with sequential bioreactor-based scaffold seeding with cells or printed scaffold embedding, or injection with hydrogel containing living cells. The biggest problem with this approach is the limited extent to which we can control the position of cells in the 3D scaffold. What makes the direct bioprinting approach different from printed scaffold-based techniques is simultaneous (one-step procedure) layer-by-layer deposition of cells and stimuli-sensitive hydrogel. The rapid prototyping technology that matches this description is stereolithography, using cells in a photo-sensitive hydrogel. The cells are positioned in the gel by using a special mask and dielectrophoresis, or by directing the cells using a special laser with a different light frequency than that used for the polymerization of photosensitive hydrogel (14,15).
A popular bioprinting method employs an automatic robotic deposition device - basically a syringe and a robotic hand. This allows the deposition of biological material, such as a hydrogel containing living cells, in a very precise manner. Initial cell density in this case is not optimal, but it has been reported that after incubation, the printed construct's cell density increases (16). Spraying a layer of hydrogel with sequential, precise punching of cell aggregates and tissue spheroids in this layer holds a great deal of promise. The repeating cycles of in situ cross-linkable hydrogel spraying and tissue spheroids placed by punching could allow us to build a multilayer construct with the tissue spheroids precisely positioned. Step 3 - Post-processing. After printing, we have nothing more than printed tissue and organ constructs. They are not yet mature, functional tissues and organs, and do not represent finished products. In order to be functional organs, they must undergo a rapid process of self-assembly, maturation and differentiation, or post-processing. Biophysically, they have the physical properties of a viscoelastic fluid, whereas mature organs usually have physical properties of an elastic solid. The process of becoming solid organs may be referred to as "accelerated tissue maturation." If printed constructs are to become viable organs, they require a wet environment that can only be achieved by using a special perfusion device - a bioreactor that allows the cells to survive. As yet, we have not solved the problem as to whether or not the bioreactor should be an essential, integrated component of the bioprinter. From both the perspective of cost and engineering, it is preferable that the organ be removed from the printer and placed in a separate environment for further post-processing in order to use the bioprinter more productively. Another factor essential to accelerated tissue maturation is the chemical and mechanical conditioning of the printed tissue and organ construct. In this case, each specific organ will require a specially designed perfusion media and regime of perfusion. Finally, it must be possible during post-printing to provide for the non-invasive, non-destructive biomonitoring of the maturation of the printed tissue and organ construct.
The top 10 challenges
The general challenges in the field of tissue engineering are clearly outlined in several publications (17). Here, we will focus on ten specific challenges. 1. Organ blueprint - The organ blueprint, especially in "bioprinter-friendly" stereolithography (STL) format, is basically a software-based computer program providing detailed instruction for layer-by-layer placement of specific biocomponents using a dispensing device in accordance with the original computer-aided design (CAD). The main challenge for organ blueprint design, as previously noted, is post-processing fusion, retraction, remodeling and compaction of the printed soft-tissue construct (11,18). Thus, in order to get the desirable mature organ size and shape, the organ blueprint must be larger and probably have a slightly different shape. The CAD must include experimentally estimated and validated coefficients of specific tissue compaction, retraction and remodeling. Effective collaboration of mathematical biologists, biophysicists, computer scientists, biologists and tissue engineers could lead to the development of novel software and organ blueprints. CAD or blueprints for 3D soft-organ printing could not be automatically derived from a 3D clinical imaging file, as is the case for CAD for solid-organ scaffolds.
2. In silico tissue self-assembly - Decoupling of design and fabrication is one of the main principles of engineering. Detailed computational simulation of the tissue self-assembly process based on predictive mathematical modeling and packing theory is a prerequisite for organ printing. Initial data strongly demonstrate that this is not only a desirable goal, but also a feasible task (19). Moreover, in silico tissue assembly is necessary for designing mechanical engineering aspects of the entire robotic biomanufacturing process. So-called computational tissue engineering is still focusing predominantly on CAD of rigid solid scaffolds (20-22). Thus, computer simulation of dynamic tissue self-assembly and post-processing remodeling of bioprinted 3D soft-tissue constructs are important tasks for the rapidly evolving field of computational tissue engineering. 3. Design of the biofabrication process - It is becoming increasingly obvious that fabrication of complex 3D organs, such as the kidney, will require several steps and a broad spectrum of specially designed equipment. The future organ-printing plant will likely resemble assembly plants for cars or planes. Modern software will allow one to design the whole organ biomanufacturing process and the corresponding robotic biofabrication equipment, as well as sequential and/or parallel fabrication steps. 4. Biopaper - Biopaper can be defined as bioprocessible biomimetic hydrogels that are specially designed for the bioprinting process. The first comprehensive review about hydrogels as extracellular matrices for organ printing was recently published (23). Criteria for ideal hydrogels for organ printing technology include:
* bioprocessible (dispensible and fast solidification)
* biomimetic (with functional peptide and growth factors)
* biocompatible (non-toxic, high cell viability)
* intelligent (stimuli-sensitive, in situ cross-linkable)
* tissue-fusion permissive (optimal physicochemical properties)
* shape maintenance
* hydrophilic (efficient diffusion)
* biodegradable (removable on demand)
* naturally derived hydrogels (collagen, fibrin, hyaluronan based)
* pro-angiogenic and loaded with anti-apoptotic and angiogenic factors
* affordable
Bioink - Bioink is defined as the standardized modular tissue and organ building blocks. The fundamental biological principle of organ printing technology is the tissue fusion process. The large-scale fabrication of self-assembled tissue spheroids with viscoelastic, fusogenic fluid-like properties is essential for reproducible organ printing (10, 24, 25). Smallscale fabrication of tissue spheroids and cell aggregates is well-established and can be achieved by different approaches, such as hanging drop, shaking, rentrifugation and cutting, extrusion and cutting (26-29), and many other techniques. However, scalable fabrication of standardized tissue spheroids suitable for robotic dispensing is still an important challenge in developing organ printing technology. Possible novel tools and devices for developing scalable technologies include a coaxial extruder, spinning disk atomizer, acoustic excitator, chaotic advection stirrer and mixer, and microfluidic device. Designing cartridges for bioink is another serious challenge
6. Bioprinters - Design and fabrication of the bioprinter or robotic dispenser and a biologically friendly rapid prototyping rnachine are important challenges for engineers involved in the development of organ printing technology and adaptation of existing rapid prototyping technologies for bioprinting and biofabrication. Organ bioprinting can also be considered as an integral part of the ongoing desktop manufacturing revolution. Some engineers define a desktop rapid prototyping system as a "personal fabricator,"analogous to a personal computer. A group at Cornell Univ. designed the first affordable, easy-to-assemble personal fabricator (29). If mass produced, it was predicted that the price of a personal fabricator could be as low as $250. It has already been shown that this personal fabricator can be used for rapid prototyping of tissue-engineered cartilage (29). An affordable personal biofabricator or bioprinter is an important accomplishment, and it will definitely enable and enhance further development, expansion and broad applications of robotic biofabrication technology.
7. Bioreactors - Bioreactors are one of the enabling tools in the field of tissue engineering. However, a bioreactor for bioprinted 3D thick-tissue constructs must have certain essential characteristics that are different from bioreactors used in traditional tissue engineering. First, it must be a perfused bioreactor that will allow perfusion of the intraorgan branched vascular tree. second, it must provide a temporal, removable irrigation system that will give the necessary time until the bioprinted intraorgan branched vascular system becomes mature and functional enough for initiation of intravascular perfusion (Figure 2). Third, it must provide dynamic bio-mechanical conditioning for accelerated tissue maturation during post-processing (30). Finally, the bioreactor must be seamlessly integrated with the bioprinter or rapid prototyping machine and allow easy placing and damage-free removal of bioprinted tissue constructs in sterile wet conditions. 8. Viability and vascularization - The viability of printed tissue constructs depends on several factors: preprocessing cell survival during loading of bioprinter cartridges; cell survival during processing; and tissue construct survival during post-processing. The last factor can be addressed by a combination of technological approaches: rapid assembly of a perfusable branched vascular tree using solid vascular tissue spheroids, and uni-lumenal vascular tissue spheroids (Figure 3); using special hydrophilic hydrogels loaded with survival factors coupled with a special bioreactor with temporal removable irrigation system; and, finally, by mathematical modeling and precisely controlling the tissue compaction process and construct diffusion properties. Simultaneously printing the organ with a "built-in" intraorgan branched macrovascular tree is probably the most challenging engineering task. Preliminary data strongly suggest that it is technically possible. There are also several evolving approaches for microvascular bed self-assembly when using endothelialized and microvascularized tissue spheroids as building blocks in organ printing technology (Figure 4). The effectiveness of these approaches in ensuring adequate perfusion and viability of bioprinted 3D thicktissue constructs and organs remains to be demonstrated.
9. Accelerated tissue maturation - Due to the fluidic nature of additive biomanufacturing processes and the absence of solid scaffolding, accelerated tissue maturation is one of the most important biological challenges of organ printing technology. Bioprinting technology is based on the assumptions that precisely placed cell populations at high density can rapidly form and assemble authentic tissues through cell adhesion, cell sorting and tissue fusion processes, and then start to synthesize the tissue and organ-specific extracellular matrices, which will provide and maintain the desirable geometrical shape and mechanical properties of the organ. Identification of biologically effective and econo-mically reliable accelerated tissue maturation procedures and so-called "maturogens," or physical, chemical and biological factors that accelerate post-printing or post-processing tissue maturation and assembly, is not only essential and integral, but also poses one of the biggest challenges in organ-printing technology development. 10. Non-invasive biomonitoring - Development of non-invasive, non-destructive quantitative methods and biosensors for monitoring the kinetics of post-processing tissue self-assembly, remodeling and maturation is another important challenge. It includes development of objective and reliable criteria, or "tissue maturation biomarkers," for achieving sufficient levels of tissue maturation and organ functionality using genomics and proteomics technologies. Optical, biomechanical and physical methods, as well as biochemical analysis of perfusate fluid, could be used for non-destructive biomonitoring of tissue maturation and for identification of structural and functional tissue maturation biomarkers. A combination of predictive mathematical models and computer simulations as a reference point with real-time registration of tissue-maturation biomarkers will provide an intelligent and automated tissue maturation biomonitoring system.
Practical applications
There are several potential biomedical applications of bioprinting technology. Biopatteming of 2D cell-based in vitro assays can create cell-based assays for cellomics and high-throughput and high-content drug discovery and drug toxicity assays. Precision Therapeutics is already using ex vivo 2D assays from patient tumor biopsies for personalized medicine or testing patient-specific sensitivity or responsiveness to anti-tumor drugs. Theoretically, printed 3D patient-specific morecomplex tumor assays are more predictive and could improve the effectiveness of anti-tumor therapy. Bioprinted complex authentic 3D human tissue-based in vitro drug discovery and drug toxicity assays can potentially be more predictable than small-animal or even largeanimal testing. It can dramatically reduce the cost of drug development and improve drug safety. 3D human tissue-based in vitro assays can also be used as models of human disease both for basic and applied therapeutic research. In vitro robotic biofabrication of organ printing from autologous cells can make allogenic organ transplantation obsolete, and once and forever eliminate patient waiting lists for organ transplantation. In situ robotic biofabrication of tissue and organs can revolutionize and reinvent surgery (31). Sciperio/nScript as well as The Pittsburgh Robotic Institute are seriously considering this direction.
Acknowledgement
This work was funded by NSF FIBR Grant (EF-0526854) and the MUSC Bioprinting Research Center Grant.
Literature Cited
1. Whiteskles, G. M., and B. Grzybowski, "Self-Assembly at All Scales," Science, 295, pp. 2418-2421 (2002).
2. Auger, F. A., et al, "A Truly New Approach for Tissue Engineering: The LOEX Self-Assembly Technique," presented at Ernst Schering Res. Found. Workshop, pp. 73-88 (2002).
3. Laflamme K., et al., "Tissue-Engineered Human Vascular Media Produced in vitro by the Self-Assembly Approach Present Functional Properties Similar to Those of Their Native Blood Vessels," Tissue Eng., 12, pp. 2275-2281 (2006).
4. L'Heureux N., et al., "A Completely Biological TissueEngineered Human Blood Vessel," Faseb J., 12, pp. 47-56 (1998).
5. Yang J., et al., "Reconstruction of Functional Tissues with Cell Sheet Engineering," Biomaterials, 28, pp. 5033-5043 (2007).
6. Shi Y., L. Rittman, and I. Vesely, "Novel Geometries for Tissue-Engineered Tendonous Collagen Constructs," Tissue Eng., 12, pp. 2601-2609 (2006).
7. Mironov, V., et al., "Fabrication of Tubular Tissue Constructs by Centrifugal Casting of Cells Suspended in an in situ Crosslinkable Hyaluronan-Gelatin Hydrogel," Biomaterials, 76, pp. 7628-7635 (2005).
8. Ito A., et al., "Novel Methodology for Fabrication of TissueEngineered Tubular Constructs Using Magnetite Nanoparticles and Magnetic Force," Tissue Eng., 11, pp. 1553-1561 (2005).
9. Shirnizu, K., et al., "Construction of Multi-Layered Cardiomyocyte Sheets Using Magnetite Nanoparticles and Magnetic Force," Biotechnol Bioeng., 96, pp. 803-809 (2007).
10. Jakab, K., et al., "Organ Printing: Fiction or Science," Biorheology, 41, pp. 371-375 (2004).
11. Jakab, K.,et al., "Engineering Biological Structures of Prescribed Shape Using Self-Assembling Multicellular Systems," Proc. Natl. Acad. Sci. USA., 101, pp. 2864-2869 (2004).
12. Kehu, J. M., et al., 'Tissue-Transplant Fusion and Vascularization of Myocardial Microtissues and Macrotissues Implanted into Chicken Embryos and Rats," Tissue Eng., 12, pp. 2541-2553 (2006).
13. Kelm, J. M., et al., "Design of Custom-Shaped Vascularized Tissues Using Microtissue Spheroids as Minimal Building Units," Tissue Eng., 12, pp. 2151-2160 (2006).
14. Liu Tsang, V., et al., "Fabrication of 3D Hepatic Tissues by Additive r^topatterning of Cellular Hydrogels," Faseb J., 21, pp, 790-801 (2007).
15. Tsang, V. L. and S. N. Bhatia, "Fabrication of Three-Dimensional Tissues," Adv Biochem Eng Biotechnol., 103, pp. 189-205 (2007).
16. Yan, Y., et al., "Fabrication of Viable Tissue-Engineered Constructs with 3D Cell-Assembly Technique," Biomaterials. 26, pp. 5864-5871 (2005).
17. Langer, R. S. and J. P. Vacanti, "Tissue Engineering: The Challenges Ahead," Sci. Am., 280, pp. 86-89 (1999).
18. Napolitano, A. P., et al., "Dynamics of the Self-Assembly of Complex Cellular Aggregates on Micromolded Nonadhesive Hydrogels," Tissue Eng., 13, pp. 2087-2094 (2007).
19. Neagu, A., et al., "Role of Physical Mechanisms in Biological Self-Organization," Phys. Rev. Letters, 95, p. 178104 (2005).
20. Hollister, S. J., "Porous Scaffold Design for Tissue Engineering," Nat. Mater.,. 4, pp. 518-524 (2005).
21. Hutmacher, D. W., et al., "Scaffold-Based Tissue Engineering: Rationale for Computer-Aided Design and Solid Free-Form Fabrication Systems," Trends Biotechnol, 22, pp. 354-362 (2004).
22. Sun, W., et al., "Computer-Aided Tissue Engineering: Overview, Scope and Challenges," Biotechnol. Appl. Biochem., 39, pp. 29-47 (2004).
23. Fedorovfch, N. E., et al., "Hydrogels as Extracellular Matrices for Skeletal Tissue Engineering: State-of-the-art and Novel Application in Organ Printing," Tissue Eng., 8, pp, 1905-1925 (2007).
24. Mironov V.,et al., "Organ Printing: Computer-Aided Jet-Based 3D Tissue Engineering," Trends Biotechnol., 21, pp. 157-161 (2003).
25. Mironov, V, N. Reis, and B. Derby, "Review: Bioprinting: A Beginning," Tissue Eng., 12, pp. 631-634 (2006).
26. Kehn, J. M., et al., "Design of Artificial Myocardial Microtissues," Tissue Eng., 10, pp. 201-214 (2004).
27. Kelm, J. M., and M. Fussenegger, "Microscale Tissue Engineering Using Gravity-Enforced Cell Assembly," Trends Biotechnol., 22, pp. 195-202 (2004).
28. McGuigan, A. P., and M. V. Sefton, "Design and Fabrication of Sub-mm-sized Modules Containing Encapsulated Cells for Modular Tissue Engineering," Tissue Eng., 13, pp. 1069-1078 (2007).
29. Cohen, D. L., et al., "Direct Free Form Fabrication of seeded Hydrogels in Arbitrary Geometries," Tissue Eng., 12, pp. 1325-1335(2006).
30. Mironov, V., et al., "Perfusion Bioreactor for Vascular Tissue Engineering with Capacities for Longitudinal Stretch," J. Craniofac. Surg., 14, pp. 340-347 (2003).
31. Campbell, P. G., and L. E. Weiss, "Tissue Engineering with me Aid of Inkjet Printers," Expert. Opin. Biol. Ther., 7, pp. 1123-1127 (2007).
VLADIMIR MIRONOV
MEDICAL UNIV. OF SOUTH CAROLINA
VLADIMIR KASYANOV
RIGA STRADINS UNIV.
ROGER MARKWALD
MEDICAL UNIV. OF SOUTH CAROLINA
VLADIMIR MIRONOV. MD, PhD, is an associate professor in the Dept. of Cell Biology and Anatomy at the Medical Univ. of South Carolina (MUSC; Charleston, SC 29425; Emalt: mironow@musc.edu). He is a director of the MUSC Bioprinting Research Center. He received his MD at the Ivanovo State Medical Institute in Russia and PhD in developmental biology at the second Moscow Pirogov Medical Institute. His research interests are in cardiovascular developmental biology, vascular tissue engineering and bioprinting. Mironov is the author of several books and 150 publications. He holds three patents, is a co-founder of two biotech companies, and does consulting work for several biotech companies. He serves on the editorial boards of two journals and is a vice president of the World Academy for Bioprinting.
VLADIMIR A. KASYANOV, PhD, is a professor in the Institute of Anatomy and Anthropology at the Riga Stradins Univ. in Latvia and head of the Laboratory of Biomechanics at the Institute of Biomaterials and Biomechanics at Riga Technical Univ. He earned an MS in civil engineering at the Riga Polytechnic Institute and a PhD in engineering sciences at the Institute of Polymer Mechanics, Latvian Academy of Science. His research interests are in biomaterials, biomechanics of the cardiovascular system, cardiovascular tissue engineering and perfusion bioreactor technologies. He is the author of 150 papers and the monograph "Biomechanics of Human Large Blood Vessels." He holds 13 patents, serves on the editorial boards of two journals, and is a member of the Latvian Academy of Sciences.
ROGER MARKWALD, PhD, is a distinguished university professor and chair of the Dept. of Cell Biology and Anatomy at the MUSC. He is also the MUSC Cardiovascular Developmental Biology Center director. He completed his BS in biology and chemistry at California Polytechnic Institute and then received both his MS and PhD from Colorado State Univ.
He is a leading expert in cardiovascular developmental biology, and author of several books on heart development and more than 150 peer-reviewed publications. Markwald is the recipient of numerous awards, including the South Carolina Governor's Award for Excellence in Science and the MERIT award from the National Heart, Lung & Blood Institute. He also completed a 10-yr stint as the Anatomical Record's editor-in-chief, and serves on the editorial boards of Tissue and Cell Research, Circulation Research and Endothelium.
Copyright American Institute of Chemical Engineers Dec 2007Provided by ProQuest Information and Learning Company. All rights Reserved
Chemical Engineering Progress, Dec 2007 by Mironov, Vladimir, Kasyanov, Vladimir, Markwald, Roger
Imagine eliminating patient waiting lists for organ transplants. Bioprinting holds the promise of making this happen, but, much research must be done first. Traditional or classic tissue engineering is based on fabrication of porous solid biodegradable scaffolds with sequential cell seeding in bioreactors. The main rationale behind this approach is a need to maintain, at least initially, the shape and mechanical properties of the tissueengineered construct and to provide a substrate for cell attachment However, there are limitations to this approach - primarily the low level of precision in cell placement, especially when engineering multicellular constructs, an intrinsic problem with vascularization of thick tissue constructs, and the extremely laborious, slow and costly nonautomated tissue assembly process. Bioprinting is a transforming technology with potential for surpassing the traditional solid-scaffold-based approach in tissue engineering. Bioprinting, in essence, is a biomedical application of rapid prototyping technology or computeraided layered additive biofabrication. The main conceptual foundation of bioprinting technology is a directed tissue selfassembly (Figure 1). Tissue self-assembly is the forming of tissue and next-level biological structures, such as organs from single cells, cell aggregates, cell sheets, tissue spheroids, tissue rods, tissue tubes or more-complex 3D microtissue modules, tissue segments or tissue blocks and extracellular matrices or biomimetic hydrogels. Self-assembly is the autonomous organization of components into patterns or structures without human intervention (1). The term "directed" means precise automated robotic placement and positioning of cells and tissue spheroids according to computer-aided design. Direction or precise robotic placement of two tissue spheroids in close contact creates permissive, but not instructive, conditions for tissue fusion - since tissue fusion is an autonomous self-assembly process driven by surface tension. In other words, placing two cell aggregates into direct contact is necessary, but not sufficient, for tissue fusion. Self-assembly is an emerging concept in tissue engineering. Examples of various tissue self-assembly approaches include cell-sheet technology (rolling or stacking) (2-5), the fusion of linear rod-like structures (6), centrifugal casting (7) and magnetically driven tissue engineering (8, 9). What makes the bioprinting approach different is using selfassembled rounded tissue spheroids as building blocks. Tissue spheroids can be roboticalry dispensed and they have the capacity, when placed close to each other as hanging drops or in permissive hydrogel, to fuse into large tissue constructs of desirable geometrical shape due to their fluidic nature (10-13) and intrinsic capacity for tissue fusion.
The bioprinting process
Step 1 - Pre-processing. In order to build anything for example, a bridge or a house - one must first develop a blueprint. This is also true in the case of organ printing. Before building an organ, we must have a blueprint in the form of a computer-aided design of the desired organ. This gives the precise spatial information about the localization of cells in the 3D organ or, in other words, the "address" of each cellular or extracellular component of the tissue or organ that we want to build. There are several ways in which we can get the information about the anatomy, histological structure, composition and topology of human organs necessary for computer-aided design of printed organs. Recent progress in clinical bioimaging and ultrasound make it possible for us to discern the gross anatomical characteristics of organs, even while they are still inside their owner. The advantage of this approach lies in its capacity to demonstrate the patient's specific anatomical information as well that of his organs, not to mention the fact that we do not need to remove the individual's organ in order to examine it (a fact that many patients might well appreciate). However, resolution of this technique has not yet reached the histological and cellular level. More importantly, tissue composition and cell redistribution cannot be precisely identified. This method is not yet refined enough to be utilized in the process of organ printing. A second approach is based on computer-aided reconstruction of serial histological sections. This method provides a high level of resolution and information about the size and shape of the organ, as well as details about its composition. The problem inherent in this method lies in the fact that human organs are available for this sort of inspection only after death, and are, hence, subject to change and distortion. Other limitations of the histological approach are that it is enormously labor-intensive and is not patient-specific. However, considering that organs have a polymeric structure and consist of repeating structural functional units, one can reconstruct a typical organ unit, and then assemble the whole organ in silico by adding a reconstructed unit based on the gross anatomical structure or by filling the available space. A third approach is based on a mathematical-computational-anatomical model. For example, by knowing the mathematics of vascular branching, it is possible to reconstruct a very realistic model of the vascular tree found inside the organ using computer simulation. In fact, several commercially available pieces of software permit the creation of a realistic anatomical model from bioimages. Furthermore, several laboratories around the world have developed virtual cadavers with gross-anatomical and microanatomical-level resolution and have made them available through the Internet. These successes suggest that the computer-aided design of printed organs is feasible, although prior to finalizing the task of printing a viable organ, the existing software will need to be upgraded to embody more capacities and greater flexibility. One potential problem is post-printing tissue fusion, compaction and remodeling. It means that software for the organ blueprint must be able to incorporate post-processing changes. Our research has demonstrated that tissue compaction and tissue retraction after a fusion process can be very dramatic (11). Tissue maturation and remodeling can lead to additional changes. In other words, blueprints for printing organ constructs can be 2-3 times larger than the actual organ size. However, we do not see these as insurmountable technical challenges. Step 2 - Processing. Processing or actual printing of tissue and organ constructs can be physically carried out by various material-transfer dispensing and deposition devices. One of most promising technologies is inkjet printers, because they are inexpensive and operate at fast speeds of several thousand drops per second or more. Several research groups have already demonstrated that cells survive the process of printing, and that one drop can contain a single cell. Utilizing cell aggregates in inkjet printers is a trickier proposition, but may be possible if the former are enhanced by the inclusion of a highly porous scaffold or using mechanically enforced tissue spheroids. The relatively morestable, and thus more-processible, tissue spheroids or encapsulated living cells (e.g., enzymatically removable hydrogel) could be another possible option. Rapid prototyping technologies offer another possibility, although the use of high temperatures, toxic resin, or resin and plastic with a toxic catalyst is a counter-indication. It has been reported that several rapid prototyping systems can be used to design solid biodegradable scaffolds for tissue engineering with sequential bioreactor-based scaffold seeding with cells or printed scaffold embedding, or injection with hydrogel containing living cells. The biggest problem with this approach is the limited extent to which we can control the position of cells in the 3D scaffold. What makes the direct bioprinting approach different from printed scaffold-based techniques is simultaneous (one-step procedure) layer-by-layer deposition of cells and stimuli-sensitive hydrogel. The rapid prototyping technology that matches this description is stereolithography, using cells in a photo-sensitive hydrogel. The cells are positioned in the gel by using a special mask and dielectrophoresis, or by directing the cells using a special laser with a different light frequency than that used for the polymerization of photosensitive hydrogel (14,15).
A popular bioprinting method employs an automatic robotic deposition device - basically a syringe and a robotic hand. This allows the deposition of biological material, such as a hydrogel containing living cells, in a very precise manner. Initial cell density in this case is not optimal, but it has been reported that after incubation, the printed construct's cell density increases (16). Spraying a layer of hydrogel with sequential, precise punching of cell aggregates and tissue spheroids in this layer holds a great deal of promise. The repeating cycles of in situ cross-linkable hydrogel spraying and tissue spheroids placed by punching could allow us to build a multilayer construct with the tissue spheroids precisely positioned. Step 3 - Post-processing. After printing, we have nothing more than printed tissue and organ constructs. They are not yet mature, functional tissues and organs, and do not represent finished products. In order to be functional organs, they must undergo a rapid process of self-assembly, maturation and differentiation, or post-processing. Biophysically, they have the physical properties of a viscoelastic fluid, whereas mature organs usually have physical properties of an elastic solid. The process of becoming solid organs may be referred to as "accelerated tissue maturation." If printed constructs are to become viable organs, they require a wet environment that can only be achieved by using a special perfusion device - a bioreactor that allows the cells to survive. As yet, we have not solved the problem as to whether or not the bioreactor should be an essential, integrated component of the bioprinter. From both the perspective of cost and engineering, it is preferable that the organ be removed from the printer and placed in a separate environment for further post-processing in order to use the bioprinter more productively. Another factor essential to accelerated tissue maturation is the chemical and mechanical conditioning of the printed tissue and organ construct. In this case, each specific organ will require a specially designed perfusion media and regime of perfusion. Finally, it must be possible during post-printing to provide for the non-invasive, non-destructive biomonitoring of the maturation of the printed tissue and organ construct.
The top 10 challenges
The general challenges in the field of tissue engineering are clearly outlined in several publications (17). Here, we will focus on ten specific challenges. 1. Organ blueprint - The organ blueprint, especially in "bioprinter-friendly" stereolithography (STL) format, is basically a software-based computer program providing detailed instruction for layer-by-layer placement of specific biocomponents using a dispensing device in accordance with the original computer-aided design (CAD). The main challenge for organ blueprint design, as previously noted, is post-processing fusion, retraction, remodeling and compaction of the printed soft-tissue construct (11,18). Thus, in order to get the desirable mature organ size and shape, the organ blueprint must be larger and probably have a slightly different shape. The CAD must include experimentally estimated and validated coefficients of specific tissue compaction, retraction and remodeling. Effective collaboration of mathematical biologists, biophysicists, computer scientists, biologists and tissue engineers could lead to the development of novel software and organ blueprints. CAD or blueprints for 3D soft-organ printing could not be automatically derived from a 3D clinical imaging file, as is the case for CAD for solid-organ scaffolds.
2. In silico tissue self-assembly - Decoupling of design and fabrication is one of the main principles of engineering. Detailed computational simulation of the tissue self-assembly process based on predictive mathematical modeling and packing theory is a prerequisite for organ printing. Initial data strongly demonstrate that this is not only a desirable goal, but also a feasible task (19). Moreover, in silico tissue assembly is necessary for designing mechanical engineering aspects of the entire robotic biomanufacturing process. So-called computational tissue engineering is still focusing predominantly on CAD of rigid solid scaffolds (20-22). Thus, computer simulation of dynamic tissue self-assembly and post-processing remodeling of bioprinted 3D soft-tissue constructs are important tasks for the rapidly evolving field of computational tissue engineering. 3. Design of the biofabrication process - It is becoming increasingly obvious that fabrication of complex 3D organs, such as the kidney, will require several steps and a broad spectrum of specially designed equipment. The future organ-printing plant will likely resemble assembly plants for cars or planes. Modern software will allow one to design the whole organ biomanufacturing process and the corresponding robotic biofabrication equipment, as well as sequential and/or parallel fabrication steps. 4. Biopaper - Biopaper can be defined as bioprocessible biomimetic hydrogels that are specially designed for the bioprinting process. The first comprehensive review about hydrogels as extracellular matrices for organ printing was recently published (23). Criteria for ideal hydrogels for organ printing technology include:
* bioprocessible (dispensible and fast solidification)
* biomimetic (with functional peptide and growth factors)
* biocompatible (non-toxic, high cell viability)
* intelligent (stimuli-sensitive, in situ cross-linkable)
* tissue-fusion permissive (optimal physicochemical properties)
* shape maintenance
* hydrophilic (efficient diffusion)
* biodegradable (removable on demand)
* naturally derived hydrogels (collagen, fibrin, hyaluronan based)
* pro-angiogenic and loaded with anti-apoptotic and angiogenic factors
* affordable
Bioink - Bioink is defined as the standardized modular tissue and organ building blocks. The fundamental biological principle of organ printing technology is the tissue fusion process. The large-scale fabrication of self-assembled tissue spheroids with viscoelastic, fusogenic fluid-like properties is essential for reproducible organ printing (10, 24, 25). Smallscale fabrication of tissue spheroids and cell aggregates is well-established and can be achieved by different approaches, such as hanging drop, shaking, rentrifugation and cutting, extrusion and cutting (26-29), and many other techniques. However, scalable fabrication of standardized tissue spheroids suitable for robotic dispensing is still an important challenge in developing organ printing technology. Possible novel tools and devices for developing scalable technologies include a coaxial extruder, spinning disk atomizer, acoustic excitator, chaotic advection stirrer and mixer, and microfluidic device. Designing cartridges for bioink is another serious challenge
6. Bioprinters - Design and fabrication of the bioprinter or robotic dispenser and a biologically friendly rapid prototyping rnachine are important challenges for engineers involved in the development of organ printing technology and adaptation of existing rapid prototyping technologies for bioprinting and biofabrication. Organ bioprinting can also be considered as an integral part of the ongoing desktop manufacturing revolution. Some engineers define a desktop rapid prototyping system as a "personal fabricator,"analogous to a personal computer. A group at Cornell Univ. designed the first affordable, easy-to-assemble personal fabricator (29). If mass produced, it was predicted that the price of a personal fabricator could be as low as $250. It has already been shown that this personal fabricator can be used for rapid prototyping of tissue-engineered cartilage (29). An affordable personal biofabricator or bioprinter is an important accomplishment, and it will definitely enable and enhance further development, expansion and broad applications of robotic biofabrication technology.
7. Bioreactors - Bioreactors are one of the enabling tools in the field of tissue engineering. However, a bioreactor for bioprinted 3D thick-tissue constructs must have certain essential characteristics that are different from bioreactors used in traditional tissue engineering. First, it must be a perfused bioreactor that will allow perfusion of the intraorgan branched vascular tree. second, it must provide a temporal, removable irrigation system that will give the necessary time until the bioprinted intraorgan branched vascular system becomes mature and functional enough for initiation of intravascular perfusion (Figure 2). Third, it must provide dynamic bio-mechanical conditioning for accelerated tissue maturation during post-processing (30). Finally, the bioreactor must be seamlessly integrated with the bioprinter or rapid prototyping machine and allow easy placing and damage-free removal of bioprinted tissue constructs in sterile wet conditions. 8. Viability and vascularization - The viability of printed tissue constructs depends on several factors: preprocessing cell survival during loading of bioprinter cartridges; cell survival during processing; and tissue construct survival during post-processing. The last factor can be addressed by a combination of technological approaches: rapid assembly of a perfusable branched vascular tree using solid vascular tissue spheroids, and uni-lumenal vascular tissue spheroids (Figure 3); using special hydrophilic hydrogels loaded with survival factors coupled with a special bioreactor with temporal removable irrigation system; and, finally, by mathematical modeling and precisely controlling the tissue compaction process and construct diffusion properties. Simultaneously printing the organ with a "built-in" intraorgan branched macrovascular tree is probably the most challenging engineering task. Preliminary data strongly suggest that it is technically possible. There are also several evolving approaches for microvascular bed self-assembly when using endothelialized and microvascularized tissue spheroids as building blocks in organ printing technology (Figure 4). The effectiveness of these approaches in ensuring adequate perfusion and viability of bioprinted 3D thicktissue constructs and organs remains to be demonstrated.
9. Accelerated tissue maturation - Due to the fluidic nature of additive biomanufacturing processes and the absence of solid scaffolding, accelerated tissue maturation is one of the most important biological challenges of organ printing technology. Bioprinting technology is based on the assumptions that precisely placed cell populations at high density can rapidly form and assemble authentic tissues through cell adhesion, cell sorting and tissue fusion processes, and then start to synthesize the tissue and organ-specific extracellular matrices, which will provide and maintain the desirable geometrical shape and mechanical properties of the organ. Identification of biologically effective and econo-mically reliable accelerated tissue maturation procedures and so-called "maturogens," or physical, chemical and biological factors that accelerate post-printing or post-processing tissue maturation and assembly, is not only essential and integral, but also poses one of the biggest challenges in organ-printing technology development. 10. Non-invasive biomonitoring - Development of non-invasive, non-destructive quantitative methods and biosensors for monitoring the kinetics of post-processing tissue self-assembly, remodeling and maturation is another important challenge. It includes development of objective and reliable criteria, or "tissue maturation biomarkers," for achieving sufficient levels of tissue maturation and organ functionality using genomics and proteomics technologies. Optical, biomechanical and physical methods, as well as biochemical analysis of perfusate fluid, could be used for non-destructive biomonitoring of tissue maturation and for identification of structural and functional tissue maturation biomarkers. A combination of predictive mathematical models and computer simulations as a reference point with real-time registration of tissue-maturation biomarkers will provide an intelligent and automated tissue maturation biomonitoring system.
Practical applications
There are several potential biomedical applications of bioprinting technology. Biopatteming of 2D cell-based in vitro assays can create cell-based assays for cellomics and high-throughput and high-content drug discovery and drug toxicity assays. Precision Therapeutics is already using ex vivo 2D assays from patient tumor biopsies for personalized medicine or testing patient-specific sensitivity or responsiveness to anti-tumor drugs. Theoretically, printed 3D patient-specific morecomplex tumor assays are more predictive and could improve the effectiveness of anti-tumor therapy. Bioprinted complex authentic 3D human tissue-based in vitro drug discovery and drug toxicity assays can potentially be more predictable than small-animal or even largeanimal testing. It can dramatically reduce the cost of drug development and improve drug safety. 3D human tissue-based in vitro assays can also be used as models of human disease both for basic and applied therapeutic research. In vitro robotic biofabrication of organ printing from autologous cells can make allogenic organ transplantation obsolete, and once and forever eliminate patient waiting lists for organ transplantation. In situ robotic biofabrication of tissue and organs can revolutionize and reinvent surgery (31). Sciperio/nScript as well as The Pittsburgh Robotic Institute are seriously considering this direction.
Acknowledgement
This work was funded by NSF FIBR Grant (EF-0526854) and the MUSC Bioprinting Research Center Grant.
Literature Cited
1. Whiteskles, G. M., and B. Grzybowski, "Self-Assembly at All Scales," Science, 295, pp. 2418-2421 (2002).
2. Auger, F. A., et al, "A Truly New Approach for Tissue Engineering: The LOEX Self-Assembly Technique," presented at Ernst Schering Res. Found. Workshop, pp. 73-88 (2002).
3. Laflamme K., et al., "Tissue-Engineered Human Vascular Media Produced in vitro by the Self-Assembly Approach Present Functional Properties Similar to Those of Their Native Blood Vessels," Tissue Eng., 12, pp. 2275-2281 (2006).
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VLADIMIR MIRONOV
MEDICAL UNIV. OF SOUTH CAROLINA
VLADIMIR KASYANOV
RIGA STRADINS UNIV.
ROGER MARKWALD
MEDICAL UNIV. OF SOUTH CAROLINA
VLADIMIR MIRONOV. MD, PhD, is an associate professor in the Dept. of Cell Biology and Anatomy at the Medical Univ. of South Carolina (MUSC; Charleston, SC 29425; Emalt: mironow@musc.edu). He is a director of the MUSC Bioprinting Research Center. He received his MD at the Ivanovo State Medical Institute in Russia and PhD in developmental biology at the second Moscow Pirogov Medical Institute. His research interests are in cardiovascular developmental biology, vascular tissue engineering and bioprinting. Mironov is the author of several books and 150 publications. He holds three patents, is a co-founder of two biotech companies, and does consulting work for several biotech companies. He serves on the editorial boards of two journals and is a vice president of the World Academy for Bioprinting.
VLADIMIR A. KASYANOV, PhD, is a professor in the Institute of Anatomy and Anthropology at the Riga Stradins Univ. in Latvia and head of the Laboratory of Biomechanics at the Institute of Biomaterials and Biomechanics at Riga Technical Univ. He earned an MS in civil engineering at the Riga Polytechnic Institute and a PhD in engineering sciences at the Institute of Polymer Mechanics, Latvian Academy of Science. His research interests are in biomaterials, biomechanics of the cardiovascular system, cardiovascular tissue engineering and perfusion bioreactor technologies. He is the author of 150 papers and the monograph "Biomechanics of Human Large Blood Vessels." He holds 13 patents, serves on the editorial boards of two journals, and is a member of the Latvian Academy of Sciences.
ROGER MARKWALD, PhD, is a distinguished university professor and chair of the Dept. of Cell Biology and Anatomy at the MUSC. He is also the MUSC Cardiovascular Developmental Biology Center director. He completed his BS in biology and chemistry at California Polytechnic Institute and then received both his MS and PhD from Colorado State Univ.
He is a leading expert in cardiovascular developmental biology, and author of several books on heart development and more than 150 peer-reviewed publications. Markwald is the recipient of numerous awards, including the South Carolina Governor's Award for Excellence in Science and the MERIT award from the National Heart, Lung & Blood Institute. He also completed a 10-yr stint as the Anatomical Record's editor-in-chief, and serves on the editorial boards of Tissue and Cell Research, Circulation Research and Endothelium.
Copyright American Institute of Chemical Engineers Dec 2007Provided by ProQuest Information and Learning Company. All rights Reserved
Nanotechnology future possibilities
Nanotechnology Offers Hope For Treating Spinal Cord Injuries, Diabetes, And Parkinson's Disease
ScienceDaily (Apr. 23, 2007) — Imagine a world where damaged organs in your body--kidneys, liver, heart--can be stimulated to heal themselves. Envision people tragically paralyzed whose injured spinal cords can be repaired. Think about individuals suffering from the debilitating effects of Parkinson's or Alzheimer's relieved of their symptoms -- completely and permanently. Dr. Samuel I. Stupp, director of the Institute of BioNanotechnology in Medicine at Northwestern University, is one of a new breed of scientists combining nanotechnology and biology to enable the body to heal itself -- and who are achieving amazing early results. Dr. Stupp's work suggests that nanotechnology can be used to mobilize the body's own healing abilities to repair or regenerate damaged cells. In a dramatic demonstration of what nanotechnology might achieve in regenerative medicine, paralyzed lab mice with spinal cord injuries have regained the ability to walk using their hind limbs six weeks after a simple injection of a purpose-designed nanomaterial. "By injecting molecules that were designed to self-assemble into nanostructures in the spinal tissue, we have been able to rescue and regrow rapidly damaged neurons," said Dr. Stupp at an April 23 session hosted by the Project on Emerging Nanotechnologies. "The nanofibers -- thousands of times thinner than a human hair -- are the key to not only preventing the formation of harmful scar tissue which inhibits spinal cord healing, but to stimulating the body into regenerating lost or damaged cells." Stupp's work hinges on a fundamental area of nanotechnology -- self-assembly -- that someday should enable medical researchers to tailor and deliver individualized patient treatments in previously unimaginable ways. Stupp and his coworkers designed molecules with the capacity to self-assemble into nanofibers once injected into the body with a syringe. When the nanofibers form they can be immobilized in an area of tissue where it is necessary to activate some biological process, for example saving damaged cells or regenerating needed differentiated cells from stem cells. This same work also has implications for Parkinson's and Alzheimer's, both diseases in which key brain cells stop working properly. During his presentation, Dr. Stupp allowed a rare glimpse into ongoing research with collaborators in Mexico and Canada, showing the impressive visual of mice recovering from the symptoms of Parkinson's disease after being exposed to the bioactive nanostructures developed in Stupp's laboratory at Northwestern University. Stupp also showed another nanotechnology achievement in joint work with Jon Lomasney at Northwestern demonstrating the use of nanostructures and proteins to achieve recovery of heart function after an infarction. "This research provides an early glimpse into the new and exciting places where nanotechnology can take us," said Project on Emerging Nanotechnologies Director David Rejeski at the session, which also served as the release of the new report NanoFrontiers: Visions for the Future of Nanotechnology. http://www.nanotechproject.org/114 "This type of work helps us to see beyond first generation, 'gee-whiz' nanotech applications like better tennis racquets or anti-static fabrics, and reach for an end to human suffering from Parkinson's, heart disease, and even cancer."
About Nanotechnology
Nanotechnology entails the measurement, prediction and construction of materials on the scale of atoms and molecules. A nanometer is one-billionth of a meter, and nanotechnology typically deals with particles and structures larger than 1 nanometer, but smaller than 100 nanometers. A nanometer-size particle is about twice the diameter of a gold atom and a very small fraction of the size of a living cell. Such a particle can be seen only with the most powerful microscopes.
ScienceDaily (Apr. 23, 2007) — Imagine a world where damaged organs in your body--kidneys, liver, heart--can be stimulated to heal themselves. Envision people tragically paralyzed whose injured spinal cords can be repaired. Think about individuals suffering from the debilitating effects of Parkinson's or Alzheimer's relieved of their symptoms -- completely and permanently. Dr. Samuel I. Stupp, director of the Institute of BioNanotechnology in Medicine at Northwestern University, is one of a new breed of scientists combining nanotechnology and biology to enable the body to heal itself -- and who are achieving amazing early results. Dr. Stupp's work suggests that nanotechnology can be used to mobilize the body's own healing abilities to repair or regenerate damaged cells. In a dramatic demonstration of what nanotechnology might achieve in regenerative medicine, paralyzed lab mice with spinal cord injuries have regained the ability to walk using their hind limbs six weeks after a simple injection of a purpose-designed nanomaterial. "By injecting molecules that were designed to self-assemble into nanostructures in the spinal tissue, we have been able to rescue and regrow rapidly damaged neurons," said Dr. Stupp at an April 23 session hosted by the Project on Emerging Nanotechnologies. "The nanofibers -- thousands of times thinner than a human hair -- are the key to not only preventing the formation of harmful scar tissue which inhibits spinal cord healing, but to stimulating the body into regenerating lost or damaged cells." Stupp's work hinges on a fundamental area of nanotechnology -- self-assembly -- that someday should enable medical researchers to tailor and deliver individualized patient treatments in previously unimaginable ways. Stupp and his coworkers designed molecules with the capacity to self-assemble into nanofibers once injected into the body with a syringe. When the nanofibers form they can be immobilized in an area of tissue where it is necessary to activate some biological process, for example saving damaged cells or regenerating needed differentiated cells from stem cells. This same work also has implications for Parkinson's and Alzheimer's, both diseases in which key brain cells stop working properly. During his presentation, Dr. Stupp allowed a rare glimpse into ongoing research with collaborators in Mexico and Canada, showing the impressive visual of mice recovering from the symptoms of Parkinson's disease after being exposed to the bioactive nanostructures developed in Stupp's laboratory at Northwestern University. Stupp also showed another nanotechnology achievement in joint work with Jon Lomasney at Northwestern demonstrating the use of nanostructures and proteins to achieve recovery of heart function after an infarction. "This research provides an early glimpse into the new and exciting places where nanotechnology can take us," said Project on Emerging Nanotechnologies Director David Rejeski at the session, which also served as the release of the new report NanoFrontiers: Visions for the Future of Nanotechnology. http://www.nanotechproject.org/114 "This type of work helps us to see beyond first generation, 'gee-whiz' nanotech applications like better tennis racquets or anti-static fabrics, and reach for an end to human suffering from Parkinson's, heart disease, and even cancer."
About Nanotechnology
Nanotechnology entails the measurement, prediction and construction of materials on the scale of atoms and molecules. A nanometer is one-billionth of a meter, and nanotechnology typically deals with particles and structures larger than 1 nanometer, but smaller than 100 nanometers. A nanometer-size particle is about twice the diameter of a gold atom and a very small fraction of the size of a living cell. Such a particle can be seen only with the most powerful microscopes.
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