Abstract
BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) can result from hepatitis C virus (HCV)-related liver disease and is the fastest-growing cause of cancer-related death in the United States. α-fetoprotein (AFP) has been used as a prognostic factor for HCC, but the value of AFP as a prognostic factor for HCV-related HCC in the United States is unknown. We investigated whether higher levels of AFP at the time of diagnosis are associated with increased mortality of patients with HCV-related HCC.
METHODS: In a retrospective study, we collected data from a cohort of HCV-infected veterans, identifying incident HCC cases from October 1, 1998, to January 1, 2007 (n = 1480 patients). The mean serum levels of AFP, obtained within 60 days before to 30 days after HCC diagnosis, were determined for 1064 patients and categorized as less than 10 ng/mL (18%), 10 to less than 100 ng/mL (30%), 100 to less than 1000 ng/mL (22%), or 1000 ng/mL or more (29%). Cox proportional hazard models were used to associate serum levels of AFP with mortality, adjusting for demographic features, clinical factors, and treatment.
RESULTS: The median survival times were significantly lower among patients with higher levels of AFP: 709 days for patients with less than 10 ng/mL, 422 days for patients with 10 to less than 100 ng/mL, 208 days for patients with 100 to less than 1000 ng/mL, and 68 days for patients with 1000 ng/mL or more. In the multivariate analysis, increased levels of AFP (10 to <100, 100 to <1000, and ≥1000) were associated significantly with increased mortality, compared with a serum AFP level of less than 10; hazard ratios were 1.50, 2.23, and 4.35, respectively.
CONCLUSIONS: Serum AFP level at the time of diagnosis with HCV-related HCC is an independent predictor of mortality.
REF: Clin Gastroenterol Hepatol. 2011 Nov;9(11):989-94. Epub 2011 Aug 4.
Thursday
Researchers design more accurate method of determining premature infants' risk of illness
Stanford University researchers have developed a revolutionary, non-invasive way of quickly predicting the future health of premature infants, an innovation that could better target specialized medical intervention and reduce health-care costs.
“What the PhysiScore does is open a new frontier,” said Anna Penn, MD, PhD, an assistant professor of pediatrics at the School of Medicine and a neonatologist at Lucile Packard Children’s Hospital. “The national push toward electronic medical records helped us create a tool to detect patterns not readily seen by the naked eye or by conventional monitoring. We’re now able to identify potential health problems before they become clinically obvious.”
Penn is a co-senior author of the research, published Sept. 8 in Science Translational Medicine. The other senior author is Daphne Koller, PhD, professor of computer science in the School of Engineering.
The paper's authors likened their PhysiScore to a more reliable, electronic version of an Apgar score. The Apgar, a simple, repeatable check done shortly after birth, has for more than half a century been the standard method of assessing a baby's physical well-being and predicting whether future medical treatment might be needed.
But by taking into account gestational age and birth weight and using a stream of real-time data routinely collected in neonatal intensive care units — such as heart rate, respiratory rate and oxygen saturation — the Stanford researchers developed a probability scoring system for the health of prematurely born infants that outperformed not only the Apgar but three other systems that require invasive laboratory measurements
Koller noted that sophisticated computational methods are critical to identifying the subtle patterns in the complex data about these young patients, as well as helping clinicians and researchers accurately discriminate between the different outcomes.
“Our method is similar to fetal heart-rate monitoring, a tool that has profoundly changed management of labor,” added Suchi Saria, the graduate student who led the research as part of her doctoral thesis in computer science. “Rather than observing a single physiological variable, however, we automatically integrate multiple physiological responses to improve accuracy.”
“And the beauty is we don’t have to stick anybody with a needle or do more expensive tests,” said Penn. “Now we have the possibility of using the power of data already available in the intensive care unit to greatly improve care for premature infants.”
The researchers relied on data recorded during the first three hours after an infant’s birth as part of a computer algorithm that predicted the baby’s likelihood of developing serious illnesses with an accuracy of between 91 and 98 percent. By comparison, the success of Apgar score predictions for the same conditions ranged from 69 to 74 percent.
In developing the PhysiScore system, the researchers studied 138 infants cared for in the neonatal intensive care unit of Packard Children's Hospital from March 2008 to March 2009. All the babies were born at 34 or fewer weeks of gestation and weighed less than 2,000 grams, or 4 lbs, 6.5 oz. None had major congenital malformations but all suffered complications that ranged from long-term disorders affecting multiple organ systems to relatively mild problems such as slight respiratory distress.
The PhysiScore proved particularly accurate in predicting the overall risk of life-threatening events in subgroups of infants who had intestinal infections and cardiopulmonary complications, even when these were not diagnosed until days or weeks later. The researchers said that adding lab tests, such as blood-gas measurements required for other scoring methods, was not needed to make PhysiScore highly accurate.
The study authors envision infants’ PhysiScores being displayed on bedside monitors along with other vital measurements that would help guide care. “This could be done cheaply,” Saria said. “The hardware, the bedside monitor, already exists. It would just be a matter of layering in new software that would display the PhysiScore.”
The study said better neonatal risk assessment could have the practical effect of keeping more premature infants at their local birth centers, avoiding higher costs of specialized care and transportation and “thus potentially reducing the estimated $26 billion per year in U.S. health-care costs resulting from preterm birth.”
Penn said many preterm babies have relatively good Apgar scores, even those infants who go on to develop serious health complications. “So now, with a PhysiScore, I could have two 25-week-gestation, 700-gram babies and know that they each have a very different individual risk profile,” she said. “This really gives us another tool.”
Saria added that although the initial research focused on assessing the health of preterm infants, “the state-of-the-art techniques we used produced a flexible framework that can be optimized for other patient populations. This should make these results of interest to a wide range of physicians and researchers.”
The PhysiScore system must still go through additional testing before it could be considered for commercial use. Penn said the researchers hope to validate the new tool on a larger group of preterm babies, and study how it influences medical decision-making. “At the same time, we can try applying our methods to other groups of patients, such as children returning from surgery, to determine if there are similar early signals that can be integrated to predict complications during recovery,” she said.
Koller emphasized the broader long-term potential of the new approach. “To achieve truly personalized medicine, we have to integrate an enormous amount of data: clinical symptoms, diagnostic test results, physiological data streams and, soon, genetic and genomic data,” she said. “Computational methods derived from real patient records can deliver on the promise of personalized, evidence-based medicine.”
Other co-authors include Jeffrey Gould, MD, MPH, professor of neonatology; and Anand Rajani, MD, a senior fellow in neonatology.
The study was funded by the Department of Computer Science, and additional information about the department is available at http://www.cs.stanford.edu/. More information about the Department of Pediatrics, which also supported the work, is available at http://pediatrics.stanford.edu/.
“What the PhysiScore does is open a new frontier,” said Anna Penn, MD, PhD, an assistant professor of pediatrics at the School of Medicine and a neonatologist at Lucile Packard Children’s Hospital. “The national push toward electronic medical records helped us create a tool to detect patterns not readily seen by the naked eye or by conventional monitoring. We’re now able to identify potential health problems before they become clinically obvious.”
Penn is a co-senior author of the research, published Sept. 8 in Science Translational Medicine. The other senior author is Daphne Koller, PhD, professor of computer science in the School of Engineering.
The paper's authors likened their PhysiScore to a more reliable, electronic version of an Apgar score. The Apgar, a simple, repeatable check done shortly after birth, has for more than half a century been the standard method of assessing a baby's physical well-being and predicting whether future medical treatment might be needed.
But by taking into account gestational age and birth weight and using a stream of real-time data routinely collected in neonatal intensive care units — such as heart rate, respiratory rate and oxygen saturation — the Stanford researchers developed a probability scoring system for the health of prematurely born infants that outperformed not only the Apgar but three other systems that require invasive laboratory measurements
Koller noted that sophisticated computational methods are critical to identifying the subtle patterns in the complex data about these young patients, as well as helping clinicians and researchers accurately discriminate between the different outcomes.
“Our method is similar to fetal heart-rate monitoring, a tool that has profoundly changed management of labor,” added Suchi Saria, the graduate student who led the research as part of her doctoral thesis in computer science. “Rather than observing a single physiological variable, however, we automatically integrate multiple physiological responses to improve accuracy.”
“And the beauty is we don’t have to stick anybody with a needle or do more expensive tests,” said Penn. “Now we have the possibility of using the power of data already available in the intensive care unit to greatly improve care for premature infants.”
The researchers relied on data recorded during the first three hours after an infant’s birth as part of a computer algorithm that predicted the baby’s likelihood of developing serious illnesses with an accuracy of between 91 and 98 percent. By comparison, the success of Apgar score predictions for the same conditions ranged from 69 to 74 percent.
In developing the PhysiScore system, the researchers studied 138 infants cared for in the neonatal intensive care unit of Packard Children's Hospital from March 2008 to March 2009. All the babies were born at 34 or fewer weeks of gestation and weighed less than 2,000 grams, or 4 lbs, 6.5 oz. None had major congenital malformations but all suffered complications that ranged from long-term disorders affecting multiple organ systems to relatively mild problems such as slight respiratory distress.
The PhysiScore proved particularly accurate in predicting the overall risk of life-threatening events in subgroups of infants who had intestinal infections and cardiopulmonary complications, even when these were not diagnosed until days or weeks later. The researchers said that adding lab tests, such as blood-gas measurements required for other scoring methods, was not needed to make PhysiScore highly accurate.
The study authors envision infants’ PhysiScores being displayed on bedside monitors along with other vital measurements that would help guide care. “This could be done cheaply,” Saria said. “The hardware, the bedside monitor, already exists. It would just be a matter of layering in new software that would display the PhysiScore.”
The study said better neonatal risk assessment could have the practical effect of keeping more premature infants at their local birth centers, avoiding higher costs of specialized care and transportation and “thus potentially reducing the estimated $26 billion per year in U.S. health-care costs resulting from preterm birth.”
Penn said many preterm babies have relatively good Apgar scores, even those infants who go on to develop serious health complications. “So now, with a PhysiScore, I could have two 25-week-gestation, 700-gram babies and know that they each have a very different individual risk profile,” she said. “This really gives us another tool.”
Saria added that although the initial research focused on assessing the health of preterm infants, “the state-of-the-art techniques we used produced a flexible framework that can be optimized for other patient populations. This should make these results of interest to a wide range of physicians and researchers.”
The PhysiScore system must still go through additional testing before it could be considered for commercial use. Penn said the researchers hope to validate the new tool on a larger group of preterm babies, and study how it influences medical decision-making. “At the same time, we can try applying our methods to other groups of patients, such as children returning from surgery, to determine if there are similar early signals that can be integrated to predict complications during recovery,” she said.
Koller emphasized the broader long-term potential of the new approach. “To achieve truly personalized medicine, we have to integrate an enormous amount of data: clinical symptoms, diagnostic test results, physiological data streams and, soon, genetic and genomic data,” she said. “Computational methods derived from real patient records can deliver on the promise of personalized, evidence-based medicine.”
Other co-authors include Jeffrey Gould, MD, MPH, professor of neonatology; and Anand Rajani, MD, a senior fellow in neonatology.
The study was funded by the Department of Computer Science, and additional information about the department is available at http://www.cs.stanford.edu/. More information about the Department of Pediatrics, which also supported the work, is available at http://pediatrics.stanford.edu/.
Immunohistochemistry is an Essential Diagnostic Tool for Children With Hepatic Tumors and Low Alpha Fetoprotein
Malignant rhabdoid tumor (MRT) of the liver is a rare malignancy with grave prognosis. This entity should be considered in the differential diagnosis of any aggressive liver tumor with low levels of alpha fetoprotein. We report 2 cases of hepatic MRT presenting in infancy.
In these 2 cases, we show that loss of INI1 facilitates making the correct diagnosis of primary hepatic MRT utilizing BAF 47 (INI1 gene product) immunostains. Difficulty encountered in making this rare diagnosis, including the need for repeated biopsies, can be avoided if MRT is considered in the differential diagnosis early on and BAF 47 immunohistochemistry is ordered
Journal of Pediatric Hematology/Oncology:
POST AUTHOR CORRECTIONS, 30 December 2009
In these 2 cases, we show that loss of INI1 facilitates making the correct diagnosis of primary hepatic MRT utilizing BAF 47 (INI1 gene product) immunostains. Difficulty encountered in making this rare diagnosis, including the need for repeated biopsies, can be avoided if MRT is considered in the differential diagnosis early on and BAF 47 immunohistochemistry is ordered
Journal of Pediatric Hematology/Oncology:
POST AUTHOR CORRECTIONS, 30 December 2009
Tuesday
The alpha-fetoprotein enhancer region activates the albumin and alpha-fetoprotein promoters during liver development
Developmental Biology Volume 336, Issue 2, 15 December 2009, Pages 294-300
Abstract
The four members of the albumin gene family encode the serum transport proteins albumin, alpha-fetoprotein, α-albumin, and vitamin D-binding protein. These genes are transcribed primarily in the liver with each having a different pattern of developmental expression. The tight linkage of these genes, particularly that of albumin, alpha-fetoprotein and α-albumin, and their liver-specific expression, has led to the suggestion that these genes share common regulatory elements.
To directly examine whether the α-fetoprotein enhancer region could regulate the albumin gene family, expression of these genes was monitored in mice in which this region was deleted by homologous recombination. Our data indicate that this enhancer region is required for alpha fetoprotein and albumin activation early in liver development and α-fetoprotein reactivation during liver regeneration, but that albumin, α-albumin, and vitamin D-binding protein expression later in hepatic development is not affected by the absence of these enhancers.
We also demonstrate that RNA polymerase II loading on the α-fetoprotein and albumin promoters is reduced in the absence of this enhancer region, indicating a direct role for these enhancers in the assembly of the RNA Polymerase II complex during liver development
Abstract
The four members of the albumin gene family encode the serum transport proteins albumin, alpha-fetoprotein, α-albumin, and vitamin D-binding protein. These genes are transcribed primarily in the liver with each having a different pattern of developmental expression. The tight linkage of these genes, particularly that of albumin, alpha-fetoprotein and α-albumin, and their liver-specific expression, has led to the suggestion that these genes share common regulatory elements.
To directly examine whether the α-fetoprotein enhancer region could regulate the albumin gene family, expression of these genes was monitored in mice in which this region was deleted by homologous recombination. Our data indicate that this enhancer region is required for alpha fetoprotein and albumin activation early in liver development and α-fetoprotein reactivation during liver regeneration, but that albumin, α-albumin, and vitamin D-binding protein expression later in hepatic development is not affected by the absence of these enhancers.
We also demonstrate that RNA polymerase II loading on the α-fetoprotein and albumin promoters is reduced in the absence of this enhancer region, indicating a direct role for these enhancers in the assembly of the RNA Polymerase II complex during liver development
Friday
Deliberate termination of life of newborns with spina bifida, a critical reappraisal
Objects
Deliberate termination of life of newborns (involuntary euthanasia) with meningomyelocele (MMC) is practiced openly only in the Netherlands. ‘Unbearable and hopeless suffering’ is the single most cited criterion for this termination, together with the notion that ‘there are no other proper medical means to alleviate this suffering’. In this paper, both (and other) statements are questioned, also by putting them in a broader perspective.
Methods
First, a historical overview of the treatment of newborns with MMC is presented, concentrating on the question of selection for treatment. Second, a thorough analysis is made of the criteria used for life termination. Third, a case of a newborn with a very severe MMC is presented as a ‘reference case’.
Conclusion
‘Unbearable and hopeless suffering’ cannot be applied to newborns with MMC. They are not ‘terminally ill’ and do have ‘prospects of a future’. In these end-of-life decisions, ‘quality of life judgments’ should not be applied. When such a newborn is not treated, modern palliative care always will suffice in eliminating possible discomfort. There is no reason whatsoever for active life-termination of these newborns.
Sophia Children’s Hospital, Erasmus Medical Centre, P.O.Box 2060, 3000 CB Rotterdam, The Netherlands
Deliberate termination of life of newborns (involuntary euthanasia) with meningomyelocele (MMC) is practiced openly only in the Netherlands. ‘Unbearable and hopeless suffering’ is the single most cited criterion for this termination, together with the notion that ‘there are no other proper medical means to alleviate this suffering’. In this paper, both (and other) statements are questioned, also by putting them in a broader perspective.
Methods
First, a historical overview of the treatment of newborns with MMC is presented, concentrating on the question of selection for treatment. Second, a thorough analysis is made of the criteria used for life termination. Third, a case of a newborn with a very severe MMC is presented as a ‘reference case’.
Conclusion
‘Unbearable and hopeless suffering’ cannot be applied to newborns with MMC. They are not ‘terminally ill’ and do have ‘prospects of a future’. In these end-of-life decisions, ‘quality of life judgments’ should not be applied. When such a newborn is not treated, modern palliative care always will suffice in eliminating possible discomfort. There is no reason whatsoever for active life-termination of these newborns.
Sophia Children’s Hospital, Erasmus Medical Centre, P.O.Box 2060, 3000 CB Rotterdam, The Netherlands
Thursday
Elevated Serum Levels of IGF- binding protein 2 (IGFBP-2) in patients with non-seminomatous germ cell cancer - Correlation with tumor markers Alpha-Fe
Background/Aims:
Alterations of the IGF-system have been described in different types of cancer. However, no information is available about the role of the IGF-system in patients with non-seminomatous germ cell cancer.
Methods:
Free IGF-I, IGF-II, acid-labile subunit and IGFBP-1 to -4 were analyzed by specific radioimmunoassays in 32 patients with untreated non-seminomatous germ cell cancer and compared to IGFBP-levels of 38 healthy controls. Serum-IGFBPs were analyzed by western ligand- and imuno - blotting. In 16 patients, IGFBP-profiles were measured before, during and after treatment.
Results:
In patients with non-seminomas, IGF-II levels were on average 1.44-fold higher than in the healthy control group (1027±48 vs. 711±30 ng/ml, P<0.0001). IGFBP-2 levels were on average 2.6 - fold higher (586±58 ng/ml vs. 226±17 ng/ml, P<0.001). During follow up, a decrease in IGFBP-2 levels was observed in all successfully treated patients, which correlated closely with the decrease of the tumor markers Alpha Fetoprotein (AFP) and Human Chorionic Gonadotropin (HCG). Additionally, in all patients with recurrent disease, a significant further increase of IGFBP-2-levels (from 358±97 ng/ml to 976±260 ng/ml) was detected. IGFBP-3 levels, as measured by RIA, were not different in patients with testicular cancer compared to controls. However, WLB-analysis demonstrated markedly decreased intact IGFBP-3 bands in untreated patients and a significant increase after successful therapy.
Conclusion:
Our results demonstrate markedly elevated IGF-II and IGFBP-2 serum levels in non-seminoma patients, showing a significant decrease after successful therapy and an increase in recurrent disease. Additionally, indirect evidence points to an increased proteolytic activity for IGFBP-3 in untreated testicular cancer patients.
Alterations of the IGF-system have been described in different types of cancer. However, no information is available about the role of the IGF-system in patients with non-seminomatous germ cell cancer.
Methods:
Free IGF-I, IGF-II, acid-labile subunit and IGFBP-1 to -4 were analyzed by specific radioimmunoassays in 32 patients with untreated non-seminomatous germ cell cancer and compared to IGFBP-levels of 38 healthy controls. Serum-IGFBPs were analyzed by western ligand- and imuno - blotting. In 16 patients, IGFBP-profiles were measured before, during and after treatment.
Results:
In patients with non-seminomas, IGF-II levels were on average 1.44-fold higher than in the healthy control group (1027±48 vs. 711±30 ng/ml, P<0.0001). IGFBP-2 levels were on average 2.6 - fold higher (586±58 ng/ml vs. 226±17 ng/ml, P<0.001). During follow up, a decrease in IGFBP-2 levels was observed in all successfully treated patients, which correlated closely with the decrease of the tumor markers Alpha Fetoprotein (AFP) and Human Chorionic Gonadotropin (HCG). Additionally, in all patients with recurrent disease, a significant further increase of IGFBP-2-levels (from 358±97 ng/ml to 976±260 ng/ml) was detected. IGFBP-3 levels, as measured by RIA, were not different in patients with testicular cancer compared to controls. However, WLB-analysis demonstrated markedly decreased intact IGFBP-3 bands in untreated patients and a significant increase after successful therapy.
Conclusion:
Our results demonstrate markedly elevated IGF-II and IGFBP-2 serum levels in non-seminoma patients, showing a significant decrease after successful therapy and an increase in recurrent disease. Additionally, indirect evidence points to an increased proteolytic activity for IGFBP-3 in untreated testicular cancer patients.
Tuesday
Targeting alpha-fetoprotein represses the proliferation of hepatoma cells via regulation of the cell cycle
Background
alpha fetoprotein (AFP) is a biomarker for primary liver cancer, yet little is known about its effect in the pathogenesis of hepatoma. We examined how AFP modulates the proliferation of hepatoma cells.
Methods
Recombinant adenovirus expressing siRNA against alpha fetoprotein (AFP) was created. The repression of cell proliferation in vitro and growth of hepatoma in vivo were examined by colony formation assay and tumor xenograft in SCID mice, respectively. Cell cycle was assayed by flow cytometry. Expression profile was determined by microarrays.
Results
siRNA targeting reduced expression of alpha fetoprotein (AFP) specifically and markedly inhibited the proliferation of hepatoma cells. Local treatment using Adv-AFPsiRNA caused significant repression of the growth of hepatoma derived HepG2 cells in xenograft in SCID mice. Knockdown of AFP resulted in an obvious delay in the G1/S transition of cell cycle, but did not affect apoptosis in HepG2 cells. Some genes related to the cell cycle, including SKP2, Cyclin D1, Csk and EBAG9 were identified.
Conclusions
The endogenous alpha fetoprotein (AFP) is a critical determinant of the growth of hepatoma cells, which functions by regulating the cell cycle. This study suggests that targeting of AFP with siRNA could be a potential therapeutic approach for hepatoma.
ARTICLE
alpha fetoprotein (AFP) is a biomarker for primary liver cancer, yet little is known about its effect in the pathogenesis of hepatoma. We examined how AFP modulates the proliferation of hepatoma cells.
Methods
Recombinant adenovirus expressing siRNA against alpha fetoprotein (AFP) was created. The repression of cell proliferation in vitro and growth of hepatoma in vivo were examined by colony formation assay and tumor xenograft in SCID mice, respectively. Cell cycle was assayed by flow cytometry. Expression profile was determined by microarrays.
Results
siRNA targeting reduced expression of alpha fetoprotein (AFP) specifically and markedly inhibited the proliferation of hepatoma cells. Local treatment using Adv-AFPsiRNA caused significant repression of the growth of hepatoma derived HepG2 cells in xenograft in SCID mice. Knockdown of AFP resulted in an obvious delay in the G1/S transition of cell cycle, but did not affect apoptosis in HepG2 cells. Some genes related to the cell cycle, including SKP2, Cyclin D1, Csk and EBAG9 were identified.
Conclusions
The endogenous alpha fetoprotein (AFP) is a critical determinant of the growth of hepatoma cells, which functions by regulating the cell cycle. This study suggests that targeting of AFP with siRNA could be a potential therapeutic approach for hepatoma.
ARTICLE
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