SAN DIEGO—Reovirus can induce cell death in a range of multiple myeloma (MM) cell lines, and it is synergistic with drugs used to treat MM, according to research presented at the AACR Annual Meeting 2014.

Six of the 7 MM cell lines tested were at least moderately sensitive to reovirus, and introducing the virus in combination with the proteasome inhibitor carfilzomib or the Akt inhibitor perifosine increased antimyeloma activity.

Chandini M. Thirukkumaran, PhD, of The University of Calgary in Canada, and her colleagues presented these results at the meeting as abstract 1709. The study was funded by the Cancer Research Society of Canada.

“Our university, about 15 years ago, found that reovirus can infect all cells, but it will specifically kill cancer cells and not harm normal cells,” Dr Thirukkumaran said. “This is because cancer cells have aberrant Ras signaling pathways, and the virus utilizes that aberrant signaling for its replication.”

“Reovirus kills a lot of myeloma cell lines and cells from patients too, but you always find that therapy-resistant population. So we wondered if we could combine reovirus with common myeloma drugs, like carfilzomib and perifosine, and see whether we could get synergy.”

Dr Thirukkumaran and her colleagues first wanted to quantify the effect of reovirus alone on MM cell lines. So they incubated the cell lines RPMI 8226, MM1.S, NCIH929, U266, INA-6, KMS11, and OPM2 with live reovirus or UV-inactivated reovirus and assessed cell death.

They found that RPMI8226 was highly sensitive to reovirus, and OPM2 was resistant to it. The remaining cell lines were somewhat sensitive to the virus.

The researchers chose RPMI8226, KMS-11, and OPM2 to test reovirus in combination with either carfilzomib or perifosine. They tested the drugs at various concentrations to determine effective dose 50% (ED50) values. They combined ED50 values for each drug and reovirus at various concentrations but with consistent ratios and determined toxicity.

The team used software to generate combination index (CI) values and determine synergism per the Chou-Talalay method. A CI equal to 1 suggested an additive effect, a CI greater than 1 suggested an antagonistic effect, and a CI less than 1 suggested a synergistic effect.

Results showed that reovirus synergized with both carfilzomib and perifosine. Furthermore, the greater a cell line’s resistance to reovirus, the greater the synergy.

For instance, with reovirus and carfilzomib in combination, the ED50 was 1.06 + 0.15 in the reovirus-sensitive RPMI8226 cell line, 0.78 + 0.14 in the moderately sensitive KMS11 cell line, and 0.57 + 0.05 in the resistant OPM2 cell line.

When reovirus and perifosine were combined, the ED50 was 0.97 + 0.19 in the RMI8226 cell line, 0.26 + 0.11 in the KMS11 cell line, and 0.88 + 0.22 in the OPM2 cell line.

The researchers said these results highlight the significance of preclinical studies in evaluating reovirus-drug combinations that could be extrapolated to a clinical setting.

Two phase 2 trials evaluating reovirus in combination therapy for MM are now underway. Meanwhile, Dr Thirukkumaran and her colleagues are hoping to gain more insight into how reovirus-drug combinations work by testing them in mouse models of MM.

SAN DIEGO—Reovirus can induce cell death in a range of multiple myeloma (MM) cell lines, and it is synergistic with drugs used to treat MM, according to research presented at the AACR Annual Meeting 2014.

Six of the 7 MM cell lines tested were at least moderately sensitive to reovirus, and introducing the virus in combination with the proteasome inhibitor carfilzomib or the Akt inhibitor perifosine increased antimyeloma activity.

Chandini M. Thirukkumaran, PhD, of The University of Calgary in Canada, and her colleagues presented these results at the meeting as abstract 1709. The study was funded by the Cancer Research Society of Canada.

“Our university, about 15 years ago, found that reovirus can infect all cells, but it will specifically kill cancer cells and not harm normal cells,” Dr Thirukkumaran said. “This is because cancer cells have aberrant Ras signaling pathways, and the virus utilizes that aberrant signaling for its replication.”

“Reovirus kills a lot of myeloma cell lines and cells from patients too, but you always find that therapy-resistant population. So we wondered if we could combine reovirus with common myeloma drugs, like carfilzomib and perifosine, and see whether we could get synergy.”

Dr Thirukkumaran and her colleagues first wanted to quantify the effect of reovirus alone on MM cell lines. So they incubated the cell lines RPMI 8226, MM1.S, NCIH929, U266, INA-6, KMS11, and OPM2 with live reovirus or UV-inactivated reovirus and assessed cell death.

They found that RPMI8226 was highly sensitive to reovirus, and OPM2 was resistant to it. The remaining cell lines were somewhat sensitive to the virus.

The researchers chose RPMI8226, KMS-11, and OPM2 to test reovirus in combination with either carfilzomib or perifosine. They tested the drugs at various concentrations to determine effective dose 50% (ED50) values. They combined ED50 values for each drug and reovirus at various concentrations but with consistent ratios and determined toxicity.

The team used software to generate combination index (CI) values and determine synergism per the Chou-Talalay method. A CI equal to 1 suggested an additive effect, a CI greater than 1 suggested an antagonistic effect, and a CI less than 1 suggested a synergistic effect.

Results showed that reovirus synergized with both carfilzomib and perifosine. Furthermore, the greater a cell line’s resistance to reovirus, the greater the synergy.

For instance, with reovirus and carfilzomib in combination, the ED50 was 1.06 + 0.15 in the reovirus-sensitive RPMI8226 cell line, 0.78 + 0.14 in the moderately sensitive KMS11 cell line, and 0.57 + 0.05 in the resistant OPM2 cell line.

When reovirus and perifosine were combined, the ED50 was 0.97 + 0.19 in the RMI8226 cell line, 0.26 + 0.11 in the KMS11 cell line, and 0.88 + 0.22 in the OPM2 cell line.

The researchers said these results highlight the significance of preclinical studies in evaluating reovirus-drug combinations that could be extrapolated to a clinical setting.

Two phase 2 trials evaluating reovirus in combination therapy for MM are now underway. Meanwhile, Dr Thirukkumaran and her colleagues are hoping to gain more insight into how reovirus-drug combinations work by testing them in mouse models of MM.

SAN DIEGO—Reovirus can induce cell death in a range of multiple myeloma (MM) cell lines, and it is synergistic with drugs used to treat MM, according to research presented at the AACR Annual Meeting 2014.

Six of the 7 MM cell lines tested were at least moderately sensitive to reovirus, and introducing the virus in combination with the proteasome inhibitor carfilzomib or the Akt inhibitor perifosine increased antimyeloma activity.

Chandini M. Thirukkumaran, PhD, of The University of Calgary in Canada, and her colleagues presented these results at the meeting as abstract 1709. The study was funded by the Cancer Research Society of Canada.

“Our university, about 15 years ago, found that reovirus can infect all cells, but it will specifically kill cancer cells and not harm normal cells,” Dr Thirukkumaran said. “This is because cancer cells have aberrant Ras signaling pathways, and the virus utilizes that aberrant signaling for its replication.”

“Reovirus kills a lot of myeloma cell lines and cells from patients too, but you always find that therapy-resistant population. So we wondered if we could combine reovirus with common myeloma drugs, like carfilzomib and perifosine, and see whether we could get synergy.”

Dr Thirukkumaran and her colleagues first wanted to quantify the effect of reovirus alone on MM cell lines. So they incubated the cell lines RPMI 8226, MM1.S, NCIH929, U266, INA-6, KMS11, and OPM2 with live reovirus or UV-inactivated reovirus and assessed cell death.

They found that RPMI8226 was highly sensitive to reovirus, and OPM2 was resistant to it. The remaining cell lines were somewhat sensitive to the virus.

The researchers chose RPMI8226, KMS-11, and OPM2 to test reovirus in combination with either carfilzomib or perifosine. They tested the drugs at various concentrations to determine effective dose 50% (ED50) values. They combined ED50 values for each drug and reovirus at various concentrations but with consistent ratios and determined toxicity.

The team used software to generate combination index (CI) values and determine synergism per the Chou-Talalay method. A CI equal to 1 suggested an additive effect, a CI greater than 1 suggested an antagonistic effect, and a CI less than 1 suggested a synergistic effect.

Results showed that reovirus synergized with both carfilzomib and perifosine. Furthermore, the greater a cell line’s resistance to reovirus, the greater the synergy.

For instance, with reovirus and carfilzomib in combination, the ED50 was 1.06 + 0.15 in the reovirus-sensitive RPMI8226 cell line, 0.78 + 0.14 in the moderately sensitive KMS11 cell line, and 0.57 + 0.05 in the resistant OPM2 cell line.

When reovirus and perifosine were combined, the ED50 was 0.97 + 0.19 in the RMI8226 cell line, 0.26 + 0.11 in the KMS11 cell line, and 0.88 + 0.22 in the OPM2 cell line.

The researchers said these results highlight the significance of preclinical studies in evaluating reovirus-drug combinations that could be extrapolated to a clinical setting.

Two phase 2 trials evaluating reovirus in combination therapy for MM are now underway. Meanwhile, Dr Thirukkumaran and her colleagues are hoping to gain more insight into how reovirus-drug combinations work by testing them in mouse models of MM.

New research may explain why patients with chronic lymphocytic leukemia (CLL) are vulnerable to severe, recurrent infections.

The study showed that plasmacytoid dendritic cells (pDCs), which orchestrate innate and adaptive immune responses, were eliminated in patients with aggressive CLL.

However, patients with a milder form of CLL appeared to have more pDCs, which suggests some protective effect.

Researchers reported these findings in Leukemia.

“These unprecedented findings reveal that these rare but critical cells can be restored at the experiment level, resulting in re-activated immune functions, including the destruction of cancer cells,” said study author Fabienne Mackay, PhD, of Monash University in Melbourne, Victoria, Australia.

“These results provide supporting evidence that a similar approach might have therapeutic benefits in patients with CLL.”

Dr Mackay and her colleagues noted that CLL patients’ vulnerability to infection is caused by a variety of immunological defects. But the initiating events of immunodeficiency in CLL are unclear.

To gain more insight, the researchers studied samples from CLL patients and conducted experiments in mouse models of the disease.

They found that, in progressive CLL, pDC numbers decreased, and their functionality was impaired. As a result, interferon alpha (IFNα) production decreased.

Additional investigation revealed that the decrease in pDCs and reduction in IFNα production resulted from decreased expression of FLT3 and TLR9.

However, the researchers were able to increase FLT3 expression using inhibitors of TGF-β and TNF. And this reduced the tumor load.

The team said these results offer new insight into mechanisms underpinning the immunodeficiency observed in CLL.

And they hope their discoveries will aid the development of new therapeutic strategies that reactivate the immune system and enhance the long-term survival of those CLL patients who are particularly vulnerable to fatal infectious complications.

New research may explain why patients with chronic lymphocytic leukemia (CLL) are vulnerable to severe, recurrent infections.

The study showed that plasmacytoid dendritic cells (pDCs), which orchestrate innate and adaptive immune responses, were eliminated in patients with aggressive CLL.

However, patients with a milder form of CLL appeared to have more pDCs, which suggests some protective effect.

Researchers reported these findings in Leukemia.

“These unprecedented findings reveal that these rare but critical cells can be restored at the experiment level, resulting in re-activated immune functions, including the destruction of cancer cells,” said study author Fabienne Mackay, PhD, of Monash University in Melbourne, Victoria, Australia.

“These results provide supporting evidence that a similar approach might have therapeutic benefits in patients with CLL.”

Dr Mackay and her colleagues noted that CLL patients’ vulnerability to infection is caused by a variety of immunological defects. But the initiating events of immunodeficiency in CLL are unclear.

To gain more insight, the researchers studied samples from CLL patients and conducted experiments in mouse models of the disease.

They found that, in progressive CLL, pDC numbers decreased, and their functionality was impaired. As a result, interferon alpha (IFNα) production decreased.

Additional investigation revealed that the decrease in pDCs and reduction in IFNα production resulted from decreased expression of FLT3 and TLR9.

However, the researchers were able to increase FLT3 expression using inhibitors of TGF-β and TNF. And this reduced the tumor load.

The team said these results offer new insight into mechanisms underpinning the immunodeficiency observed in CLL.

And they hope their discoveries will aid the development of new therapeutic strategies that reactivate the immune system and enhance the long-term survival of those CLL patients who are particularly vulnerable to fatal infectious complications.

New research may explain why patients with chronic lymphocytic leukemia (CLL) are vulnerable to severe, recurrent infections.

The study showed that plasmacytoid dendritic cells (pDCs), which orchestrate innate and adaptive immune responses, were eliminated in patients with aggressive CLL.

However, patients with a milder form of CLL appeared to have more pDCs, which suggests some protective effect.

Researchers reported these findings in Leukemia.

“These unprecedented findings reveal that these rare but critical cells can be restored at the experiment level, resulting in re-activated immune functions, including the destruction of cancer cells,” said study author Fabienne Mackay, PhD, of Monash University in Melbourne, Victoria, Australia.

“These results provide supporting evidence that a similar approach might have therapeutic benefits in patients with CLL.”

Dr Mackay and her colleagues noted that CLL patients’ vulnerability to infection is caused by a variety of immunological defects. But the initiating events of immunodeficiency in CLL are unclear.

To gain more insight, the researchers studied samples from CLL patients and conducted experiments in mouse models of the disease.

They found that, in progressive CLL, pDC numbers decreased, and their functionality was impaired. As a result, interferon alpha (IFNα) production decreased.

Additional investigation revealed that the decrease in pDCs and reduction in IFNα production resulted from decreased expression of FLT3 and TLR9.

However, the researchers were able to increase FLT3 expression using inhibitors of TGF-β and TNF. And this reduced the tumor load.

The team said these results offer new insight into mechanisms underpinning the immunodeficiency observed in CLL.

And they hope their discoveries will aid the development of new therapeutic strategies that reactivate the immune system and enhance the long-term survival of those CLL patients who are particularly vulnerable to fatal infectious complications.

A baby’s position prior to delayed umbilical cord clamping does not affect the volume of placental blood transferred, according to a study published in The Lancet.

Researchers found that placing a baby on the mother’s chest or abdomen before clamping does not decrease the amount of blood transferred when compared to holding the child in the recommended introitus position.

As the chest/abdomen position is more desirable, the researchers believe this discovery could help increase the use of delayed cord clamping, which has been shown to reduce the risk of iron deficiency in infancy.

Current recommendations for delayed cord clamping are based on studies conducted 35 years ago. They suggest that, for effective placental transfusion to occur, a baby must be held at the level of the placenta—the introitus position.

The researchers noted that this position can be uncomfortable for the person holding the baby and interferes with immediate contact between the mother and child. These issues could be contributing to low compliance with delayed cord clamping, ultimately resulting in higher-than-necessary levels of iron deficiency in babies.

So the team decided to examine whether the transfer of blood in delayed cord clamping procedures is affected by the position in which the baby is held immediately after birth.

They conducted the study in 3 university-affiliated hospitals in Argentina, evaluating 197 babies who were held in the introitus position and 194 babies who were immediately placed on the mother’s abdomen or chest.

By measuring the babies’ weights at the point of birth and immediately after the delayed cord clamping procedure, the researchers were able to measure the volume of blood that had transferred from the placenta to the child.

They found no statistically significant difference between the 2 groups in the volume of blood transferred. The mean weight change was 56 g for babies in the introitus group and 53 g for babies in the abdomen/chest group (P=0.45).

“Our study suggests that when umbilical cord clamping is delayed for 2 minutes, holding the baby on the mother’s chest or abdomen is no worse than the currently recommended practice of holding the baby below this level,” said study author Nestor Vain, MD, of the Foundation for Maternal and Child Health (FUNDASAMIN) in Buenos Aires, Argentina.

“Because of the potential of enhanced bonding between mother and baby, increased success of breastfeeding, and the compliance with the procedure, holding the infant by the mother immediately after birth should be strongly recommended.”

Writing in a related comment article, Tonse Raju, MD, of the National Institute of Child Health and Human Development in Bethesda, Maryland, noted that introducing delayed cord clamping into practice has not been easy, and logistical issues might be partly responsible.

“Intuitively, to keep the newborn baby’s position below the level of the placenta in situ should maximize the volume of placental transfusion,” Dr Raju wrote. “However, trying to hold on to a wet, vigorously crying, and wriggling infant at the perineum for 2 minutes, in gloved hands, is awkward and can be risky.”

“[This study] should bring a sigh of relief from those trying to incorporate delayed umbilical cord clamping into practice. The results are convincing and show that gravity did not have an effect on volume of placental transfusion.”

A baby’s position prior to delayed umbilical cord clamping does not affect the volume of placental blood transferred, according to a study published in The Lancet.

Researchers found that placing a baby on the mother’s chest or abdomen before clamping does not decrease the amount of blood transferred when compared to holding the child in the recommended introitus position.

As the chest/abdomen position is more desirable, the researchers believe this discovery could help increase the use of delayed cord clamping, which has been shown to reduce the risk of iron deficiency in infancy.

Current recommendations for delayed cord clamping are based on studies conducted 35 years ago. They suggest that, for effective placental transfusion to occur, a baby must be held at the level of the placenta—the introitus position.

The researchers noted that this position can be uncomfortable for the person holding the baby and interferes with immediate contact between the mother and child. These issues could be contributing to low compliance with delayed cord clamping, ultimately resulting in higher-than-necessary levels of iron deficiency in babies.

So the team decided to examine whether the transfer of blood in delayed cord clamping procedures is affected by the position in which the baby is held immediately after birth.

They conducted the study in 3 university-affiliated hospitals in Argentina, evaluating 197 babies who were held in the introitus position and 194 babies who were immediately placed on the mother’s abdomen or chest.

By measuring the babies’ weights at the point of birth and immediately after the delayed cord clamping procedure, the researchers were able to measure the volume of blood that had transferred from the placenta to the child.

They found no statistically significant difference between the 2 groups in the volume of blood transferred. The mean weight change was 56 g for babies in the introitus group and 53 g for babies in the abdomen/chest group (P=0.45).

“Our study suggests that when umbilical cord clamping is delayed for 2 minutes, holding the baby on the mother’s chest or abdomen is no worse than the currently recommended practice of holding the baby below this level,” said study author Nestor Vain, MD, of the Foundation for Maternal and Child Health (FUNDASAMIN) in Buenos Aires, Argentina.

“Because of the potential of enhanced bonding between mother and baby, increased success of breastfeeding, and the compliance with the procedure, holding the infant by the mother immediately after birth should be strongly recommended.”

Writing in a related comment article, Tonse Raju, MD, of the National Institute of Child Health and Human Development in Bethesda, Maryland, noted that introducing delayed cord clamping into practice has not been easy, and logistical issues might be partly responsible.

“Intuitively, to keep the newborn baby’s position below the level of the placenta in situ should maximize the volume of placental transfusion,” Dr Raju wrote. “However, trying to hold on to a wet, vigorously crying, and wriggling infant at the perineum for 2 minutes, in gloved hands, is awkward and can be risky.”

“[This study] should bring a sigh of relief from those trying to incorporate delayed umbilical cord clamping into practice. The results are convincing and show that gravity did not have an effect on volume of placental transfusion.”

A baby’s position prior to delayed umbilical cord clamping does not affect the volume of placental blood transferred, according to a study published in The Lancet.

Researchers found that placing a baby on the mother’s chest or abdomen before clamping does not decrease the amount of blood transferred when compared to holding the child in the recommended introitus position.

As the chest/abdomen position is more desirable, the researchers believe this discovery could help increase the use of delayed cord clamping, which has been shown to reduce the risk of iron deficiency in infancy.

Current recommendations for delayed cord clamping are based on studies conducted 35 years ago. They suggest that, for effective placental transfusion to occur, a baby must be held at the level of the placenta—the introitus position.

The researchers noted that this position can be uncomfortable for the person holding the baby and interferes with immediate contact between the mother and child. These issues could be contributing to low compliance with delayed cord clamping, ultimately resulting in higher-than-necessary levels of iron deficiency in babies.

So the team decided to examine whether the transfer of blood in delayed cord clamping procedures is affected by the position in which the baby is held immediately after birth.

They conducted the study in 3 university-affiliated hospitals in Argentina, evaluating 197 babies who were held in the introitus position and 194 babies who were immediately placed on the mother’s abdomen or chest.

By measuring the babies’ weights at the point of birth and immediately after the delayed cord clamping procedure, the researchers were able to measure the volume of blood that had transferred from the placenta to the child.

They found no statistically significant difference between the 2 groups in the volume of blood transferred. The mean weight change was 56 g for babies in the introitus group and 53 g for babies in the abdomen/chest group (P=0.45).

“Our study suggests that when umbilical cord clamping is delayed for 2 minutes, holding the baby on the mother’s chest or abdomen is no worse than the currently recommended practice of holding the baby below this level,” said study author Nestor Vain, MD, of the Foundation for Maternal and Child Health (FUNDASAMIN) in Buenos Aires, Argentina.

“Because of the potential of enhanced bonding between mother and baby, increased success of breastfeeding, and the compliance with the procedure, holding the infant by the mother immediately after birth should be strongly recommended.”

Writing in a related comment article, Tonse Raju, MD, of the National Institute of Child Health and Human Development in Bethesda, Maryland, noted that introducing delayed cord clamping into practice has not been easy, and logistical issues might be partly responsible.

“Intuitively, to keep the newborn baby’s position below the level of the placenta in situ should maximize the volume of placental transfusion,” Dr Raju wrote. “However, trying to hold on to a wet, vigorously crying, and wriggling infant at the perineum for 2 minutes, in gloved hands, is awkward and can be risky.”

“[This study] should bring a sigh of relief from those trying to incorporate delayed umbilical cord clamping into practice. The results are convincing and show that gravity did not have an effect on volume of placental transfusion.”

A new study¹ provides the first evidence of a direct effect of maternal metabolism on fetal brain activity, suggesting that insulin resistance, the precursor to type 2 diabetes, begins its formation prenatally.

DETAILS OF THE STUDY

Dr. Katarzyna Linder from the University Hospital Tübingen in Germany and colleagues included in their study 13 healthy pregnant women with normal, singleton pregnancies of between 27 and 36 weeks. All of the women underwent an oral glucose tolerance test, meaning that after a 5-hour overnight fast, each woman drank a solution containing 75 g glucose. The investigators ascertained blood glucose and plasma insulin levels from blood samples taken at 0, 60, and 120 minutes.

At approximately the same time points, but before they drew each blood sample, the authors obtained a fetal magnetoencephalography (fMEG) measurement in an effort to noninvasively record brain activity in utero. During each measurement, they presented an auditory sequence to the fetus. Most (75%) of the time, the sound presented had a frequency of 500 Hz, but 25% of the time the researchers presented a deviant tone with a frequency of 750 Hz to prevent habituation.

The researchers found that maternal insulin sensitivity significantly correlated with response latency of the fetus at the 60-minute time point, so that the higher the insulin sensitivity of the mother, the shorter the response time of the fetus to the sound. The association remained significant even after the investigators controlled for relative maternal weight gain, gestational age, and the child’s birth weight. No significant correlation existed at baseline or at 120 minutes.

The investigators then split the women into 2 groups: those who were insulin-resistant and those who were insulin-sensitive. They found that the fetuses of the insulin-resistant moms were almost 40% slower to respond to the auditory stimuli than those of the insulin-sensitive moms (mean [SD], 283 [79] ms vs 178 [46] ms; P=.03).

INTERPRETING THE FINDINGS

According to the US Centers for Disease Control and Prevention, almost one-third (30.3%) of US adults between the ages of 20 and 39 years—the primary child-bearing years—are obese,² as are 17% of our children and adolescents—triple the rate of 1 generation previous.³ Furthermore, 25.8 million people in the United States have diabetes, including 1 in every 400 children and adolescents.⁴

Experts know that the children of obese or diabetic mothers are at increased risk for obesity and type 2 diabetes as adults, and that the connection is not purely genetic; environmental and epigenetic (environmental elements that affect genetics) factors also play key roles. The latter is the basis for the fetal or developmental origins hypothesis,⁵ which posits that a pregnant woman’s exposure to certain environmental factors can affect the programming of her unborn child and impact adult health.

The authors of the current study demonstrate that the metabolism of a pregnant woman after a sugar load directly affects the response time and brain activity of her developing fetus. They suggest as a mechanism for the effect that “insulin-resistant mothers have higher glucose levels accompanied by increased insulin levels in the postprandial state. As glucose passes the placenta, these postprandially increased glucose levels induce hyperinsulinaemia in the fetus.” The resulting chronic hyperinsulinemia “might induce insulin resistance in the fetal brain.”

A new study¹ provides the first evidence of a direct effect of maternal metabolism on fetal brain activity, suggesting that insulin resistance, the precursor to type 2 diabetes, begins its formation prenatally.

DETAILS OF THE STUDY

Dr. Katarzyna Linder from the University Hospital Tübingen in Germany and colleagues included in their study 13 healthy pregnant women with normal, singleton pregnancies of between 27 and 36 weeks. All of the women underwent an oral glucose tolerance test, meaning that after a 5-hour overnight fast, each woman drank a solution containing 75 g glucose. The investigators ascertained blood glucose and plasma insulin levels from blood samples taken at 0, 60, and 120 minutes.

At approximately the same time points, but before they drew each blood sample, the authors obtained a fetal magnetoencephalography (fMEG) measurement in an effort to noninvasively record brain activity in utero. During each measurement, they presented an auditory sequence to the fetus. Most (75%) of the time, the sound presented had a frequency of 500 Hz, but 25% of the time the researchers presented a deviant tone with a frequency of 750 Hz to prevent habituation.

The researchers found that maternal insulin sensitivity significantly correlated with response latency of the fetus at the 60-minute time point, so that the higher the insulin sensitivity of the mother, the shorter the response time of the fetus to the sound. The association remained significant even after the investigators controlled for relative maternal weight gain, gestational age, and the child’s birth weight. No significant correlation existed at baseline or at 120 minutes.

The investigators then split the women into 2 groups: those who were insulin-resistant and those who were insulin-sensitive. They found that the fetuses of the insulin-resistant moms were almost 40% slower to respond to the auditory stimuli than those of the insulin-sensitive moms (mean [SD], 283 [79] ms vs 178 [46] ms; P=.03).

INTERPRETING THE FINDINGS

According to the US Centers for Disease Control and Prevention, almost one-third (30.3%) of US adults between the ages of 20 and 39 years—the primary child-bearing years—are obese,² as are 17% of our children and adolescents—triple the rate of 1 generation previous.³ Furthermore, 25.8 million people in the United States have diabetes, including 1 in every 400 children and adolescents.⁴

Experts know that the children of obese or diabetic mothers are at increased risk for obesity and type 2 diabetes as adults, and that the connection is not purely genetic; environmental and epigenetic (environmental elements that affect genetics) factors also play key roles. The latter is the basis for the fetal or developmental origins hypothesis,⁵ which posits that a pregnant woman’s exposure to certain environmental factors can affect the programming of her unborn child and impact adult health.

The authors of the current study demonstrate that the metabolism of a pregnant woman after a sugar load directly affects the response time and brain activity of her developing fetus. They suggest as a mechanism for the effect that “insulin-resistant mothers have higher glucose levels accompanied by increased insulin levels in the postprandial state. As glucose passes the placenta, these postprandially increased glucose levels induce hyperinsulinaemia in the fetus.” The resulting chronic hyperinsulinemia “might induce insulin resistance in the fetal brain.”

A new study¹ provides the first evidence of a direct effect of maternal metabolism on fetal brain activity, suggesting that insulin resistance, the precursor to type 2 diabetes, begins its formation prenatally.

DETAILS OF THE STUDY

Dr. Katarzyna Linder from the University Hospital Tübingen in Germany and colleagues included in their study 13 healthy pregnant women with normal, singleton pregnancies of between 27 and 36 weeks. All of the women underwent an oral glucose tolerance test, meaning that after a 5-hour overnight fast, each woman drank a solution containing 75 g glucose. The investigators ascertained blood glucose and plasma insulin levels from blood samples taken at 0, 60, and 120 minutes.

At approximately the same time points, but before they drew each blood sample, the authors obtained a fetal magnetoencephalography (fMEG) measurement in an effort to noninvasively record brain activity in utero. During each measurement, they presented an auditory sequence to the fetus. Most (75%) of the time, the sound presented had a frequency of 500 Hz, but 25% of the time the researchers presented a deviant tone with a frequency of 750 Hz to prevent habituation.

The researchers found that maternal insulin sensitivity significantly correlated with response latency of the fetus at the 60-minute time point, so that the higher the insulin sensitivity of the mother, the shorter the response time of the fetus to the sound. The association remained significant even after the investigators controlled for relative maternal weight gain, gestational age, and the child’s birth weight. No significant correlation existed at baseline or at 120 minutes.

The investigators then split the women into 2 groups: those who were insulin-resistant and those who were insulin-sensitive. They found that the fetuses of the insulin-resistant moms were almost 40% slower to respond to the auditory stimuli than those of the insulin-sensitive moms (mean [SD], 283 [79] ms vs 178 [46] ms; P=.03).

INTERPRETING THE FINDINGS

According to the US Centers for Disease Control and Prevention, almost one-third (30.3%) of US adults between the ages of 20 and 39 years—the primary child-bearing years—are obese,² as are 17% of our children and adolescents—triple the rate of 1 generation previous.³ Furthermore, 25.8 million people in the United States have diabetes, including 1 in every 400 children and adolescents.⁴

Experts know that the children of obese or diabetic mothers are at increased risk for obesity and type 2 diabetes as adults, and that the connection is not purely genetic; environmental and epigenetic (environmental elements that affect genetics) factors also play key roles. The latter is the basis for the fetal or developmental origins hypothesis,⁵ which posits that a pregnant woman’s exposure to certain environmental factors can affect the programming of her unborn child and impact adult health.

The authors of the current study demonstrate that the metabolism of a pregnant woman after a sugar load directly affects the response time and brain activity of her developing fetus. They suggest as a mechanism for the effect that “insulin-resistant mothers have higher glucose levels accompanied by increased insulin levels in the postprandial state. As glucose passes the placenta, these postprandially increased glucose levels induce hyperinsulinaemia in the fetus.” The resulting chronic hyperinsulinemia “might induce insulin resistance in the fetal brain.”

Congress has once again delayed implementation of draconian Medicare cuts tied to the sustainable growth rate (SGR) formula, but this time, the vote by lawmakers to patch the ailing physician reimbursement program rather than scrap it also pushes back the pending debut of ICD-10.

And that's frustrating some hospitalists.

"For about 12 hours, I felt relief about the ICD-10 and then I just realized, it's still coming, presumably," says John Nelson, MD, MHM, a co-founder and past president of SHM and medical director of the hospitalist practice at Overlake Hospital in Bellevue, Wash. "[It's] like a patient who needs surgery and finds out it's canceled for the day and he'll have it tomorrow. Well, that's good for right now, but [he] still has to face this eventually."

The SGR extension through year's end means that physicians do not face a 24% cut to physician payments under Medicare. The delay in transitioning healthcare providers from the ICD-9 medical coding classification system to the more complicated ICD-10 could mean the upgraded system may not go into effect until at least Oct. 1, 2015. This comes after the Centers for Medicare & Medicaid Services already pushed back the original implementation date for ICD-10 by one year.

SHM Public Policy Committee member Joshua Lenchus, DO, RPh, SFHM, says he expects the majority of doctors to be content with the delay, particularly in light of some estimates that show only 20% or so of physicians "have actually initiated the ICD-10 transition," but that it's unfair to those health systems that have prepared.

"ICD-9 has a little more than 14,000 diagnostic codes and nearly 4,000 procedural codes. That is to be contrasted to ICD-10, which has more than 68,000 diagnostic codes...and over 72,000 procedural codes," Dr. Lenchus writes in an e-mail to The Hospitalist's eWire. "So, it is not surprising that many take solace in the delay."

"It's distressing and frustrating for hospitalists, but less disruptive than it might be for hospitals," Dr. Nelson says. "And, of course in some places, hospitalists may be the physician leads on ICD-10 efforts, so [they are] very much wrapped up in the problem of 'What do we do now?'"

 

Visit our website for more information about ICD-10.

 

 

Congress has once again delayed implementation of draconian Medicare cuts tied to the sustainable growth rate (SGR) formula, but this time, the vote by lawmakers to patch the ailing physician reimbursement program rather than scrap it also pushes back the pending debut of ICD-10.

And that's frustrating some hospitalists.

"For about 12 hours, I felt relief about the ICD-10 and then I just realized, it's still coming, presumably," says John Nelson, MD, MHM, a co-founder and past president of SHM and medical director of the hospitalist practice at Overlake Hospital in Bellevue, Wash. "[It's] like a patient who needs surgery and finds out it's canceled for the day and he'll have it tomorrow. Well, that's good for right now, but [he] still has to face this eventually."

The SGR extension through year's end means that physicians do not face a 24% cut to physician payments under Medicare. The delay in transitioning healthcare providers from the ICD-9 medical coding classification system to the more complicated ICD-10 could mean the upgraded system may not go into effect until at least Oct. 1, 2015. This comes after the Centers for Medicare & Medicaid Services already pushed back the original implementation date for ICD-10 by one year.

SHM Public Policy Committee member Joshua Lenchus, DO, RPh, SFHM, says he expects the majority of doctors to be content with the delay, particularly in light of some estimates that show only 20% or so of physicians "have actually initiated the ICD-10 transition," but that it's unfair to those health systems that have prepared.

"ICD-9 has a little more than 14,000 diagnostic codes and nearly 4,000 procedural codes. That is to be contrasted to ICD-10, which has more than 68,000 diagnostic codes...and over 72,000 procedural codes," Dr. Lenchus writes in an e-mail to The Hospitalist's eWire. "So, it is not surprising that many take solace in the delay."

"It's distressing and frustrating for hospitalists, but less disruptive than it might be for hospitals," Dr. Nelson says. "And, of course in some places, hospitalists may be the physician leads on ICD-10 efforts, so [they are] very much wrapped up in the problem of 'What do we do now?'"

 

Visit our website for more information about ICD-10.

 

 

Congress has once again delayed implementation of draconian Medicare cuts tied to the sustainable growth rate (SGR) formula, but this time, the vote by lawmakers to patch the ailing physician reimbursement program rather than scrap it also pushes back the pending debut of ICD-10.

And that's frustrating some hospitalists.

"For about 12 hours, I felt relief about the ICD-10 and then I just realized, it's still coming, presumably," says John Nelson, MD, MHM, a co-founder and past president of SHM and medical director of the hospitalist practice at Overlake Hospital in Bellevue, Wash. "[It's] like a patient who needs surgery and finds out it's canceled for the day and he'll have it tomorrow. Well, that's good for right now, but [he] still has to face this eventually."

The SGR extension through year's end means that physicians do not face a 24% cut to physician payments under Medicare. The delay in transitioning healthcare providers from the ICD-9 medical coding classification system to the more complicated ICD-10 could mean the upgraded system may not go into effect until at least Oct. 1, 2015. This comes after the Centers for Medicare & Medicaid Services already pushed back the original implementation date for ICD-10 by one year.

SHM Public Policy Committee member Joshua Lenchus, DO, RPh, SFHM, says he expects the majority of doctors to be content with the delay, particularly in light of some estimates that show only 20% or so of physicians "have actually initiated the ICD-10 transition," but that it's unfair to those health systems that have prepared.

"ICD-9 has a little more than 14,000 diagnostic codes and nearly 4,000 procedural codes. That is to be contrasted to ICD-10, which has more than 68,000 diagnostic codes...and over 72,000 procedural codes," Dr. Lenchus writes in an e-mail to The Hospitalist's eWire. "So, it is not surprising that many take solace in the delay."

"It's distressing and frustrating for hospitalists, but less disruptive than it might be for hospitals," Dr. Nelson says. "And, of course in some places, hospitalists may be the physician leads on ICD-10 efforts, so [they are] very much wrapped up in the problem of 'What do we do now?'"

 

Visit our website for more information about ICD-10.

 

 

Danielle Scheurer, MD, MSCR, SFHM, has her sights set on quality improvement when it comes to serving on SHM's Board of Directors over the next three years. As a representative of a society she considers well managed and efficient, Dr. Scheurer plans to continue fulfilling the goals she set for herself when she began her career in hospital medicine.

"I realized very quickly that I was not going to be satisfied being a good doctor with individual patients because of the barriers to good care and became compelled to attack the issues at the system level," says Dr. Scheurer, who also serves as physician editor of The Hospitalist.

After earning a medical degree from the University of Tennessee in Knoxville and completing a dual residency in internal medicine and pediatrics at Duke University in Durham, N.C., Dr. Scheurer immersed herself in patient-centered care practices as a hospitalist at Brigham and Women's Hospital in Boston from 2005 to 2010. She continues to stress the importance of quality in her current role as chief quality officer at the Medical University of South Carolina in Charleston.

Since becoming involved with SHM in 2003, Dr. Scheurer has spent time educating hospitalists on tactics to make hospital systems more effective and she blogs about clinical and practice issues. Dr. Scheurer also serves on SHM’s Education Committee, a role that she plans to continue in tandem with her work on the board.

Dr. Scheurer's hard work for the society not gone unnoticed. SHM President Burke T. Kealey, MD, SFHM, notes, "I'm very pleased to have Danielle on the board with us. I think she is going to add a great voice. Danielle has already been a great contributor to SHM. She has done a great job of getting out the message about SHM to our members and to others."

One of Dr. Scheurer's biggest accomplishments has been her role developing medical knowledge modules on quality and patient safety for the American Board of Internal Medicine's Recognition in Focused Practice in Hospital Medicine maintenance of certification (MOC) program. She has presented numerous MOC pre-courses at SHM's annual meetings. She says her involvement with fledgling hospitalists has made her optimistic about the future of the specialty.

"People in hospital medicine are already very focused on quality," she says. "We are getting better at understanding that it's not just about being a good doctor, its about creating systems that can effectively and reliably deliver high-quality care."

 

Danielle Scheurer, MD, MSCR, SFHM, has her sights set on quality improvement when it comes to serving on SHM's Board of Directors over the next three years. As a representative of a society she considers well managed and efficient, Dr. Scheurer plans to continue fulfilling the goals she set for herself when she began her career in hospital medicine.

"I realized very quickly that I was not going to be satisfied being a good doctor with individual patients because of the barriers to good care and became compelled to attack the issues at the system level," says Dr. Scheurer, who also serves as physician editor of The Hospitalist.

After earning a medical degree from the University of Tennessee in Knoxville and completing a dual residency in internal medicine and pediatrics at Duke University in Durham, N.C., Dr. Scheurer immersed herself in patient-centered care practices as a hospitalist at Brigham and Women's Hospital in Boston from 2005 to 2010. She continues to stress the importance of quality in her current role as chief quality officer at the Medical University of South Carolina in Charleston.

Since becoming involved with SHM in 2003, Dr. Scheurer has spent time educating hospitalists on tactics to make hospital systems more effective and she blogs about clinical and practice issues. Dr. Scheurer also serves on SHM’s Education Committee, a role that she plans to continue in tandem with her work on the board.

Dr. Scheurer's hard work for the society not gone unnoticed. SHM President Burke T. Kealey, MD, SFHM, notes, "I'm very pleased to have Danielle on the board with us. I think she is going to add a great voice. Danielle has already been a great contributor to SHM. She has done a great job of getting out the message about SHM to our members and to others."

One of Dr. Scheurer's biggest accomplishments has been her role developing medical knowledge modules on quality and patient safety for the American Board of Internal Medicine's Recognition in Focused Practice in Hospital Medicine maintenance of certification (MOC) program. She has presented numerous MOC pre-courses at SHM's annual meetings. She says her involvement with fledgling hospitalists has made her optimistic about the future of the specialty.

"People in hospital medicine are already very focused on quality," she says. "We are getting better at understanding that it's not just about being a good doctor, its about creating systems that can effectively and reliably deliver high-quality care."

 

Danielle Scheurer, MD, MSCR, SFHM, has her sights set on quality improvement when it comes to serving on SHM's Board of Directors over the next three years. As a representative of a society she considers well managed and efficient, Dr. Scheurer plans to continue fulfilling the goals she set for herself when she began her career in hospital medicine.

"I realized very quickly that I was not going to be satisfied being a good doctor with individual patients because of the barriers to good care and became compelled to attack the issues at the system level," says Dr. Scheurer, who also serves as physician editor of The Hospitalist.

After earning a medical degree from the University of Tennessee in Knoxville and completing a dual residency in internal medicine and pediatrics at Duke University in Durham, N.C., Dr. Scheurer immersed herself in patient-centered care practices as a hospitalist at Brigham and Women's Hospital in Boston from 2005 to 2010. She continues to stress the importance of quality in her current role as chief quality officer at the Medical University of South Carolina in Charleston.

Since becoming involved with SHM in 2003, Dr. Scheurer has spent time educating hospitalists on tactics to make hospital systems more effective and she blogs about clinical and practice issues. Dr. Scheurer also serves on SHM’s Education Committee, a role that she plans to continue in tandem with her work on the board.

Dr. Scheurer's hard work for the society not gone unnoticed. SHM President Burke T. Kealey, MD, SFHM, notes, "I'm very pleased to have Danielle on the board with us. I think she is going to add a great voice. Danielle has already been a great contributor to SHM. She has done a great job of getting out the message about SHM to our members and to others."

One of Dr. Scheurer's biggest accomplishments has been her role developing medical knowledge modules on quality and patient safety for the American Board of Internal Medicine's Recognition in Focused Practice in Hospital Medicine maintenance of certification (MOC) program. She has presented numerous MOC pre-courses at SHM's annual meetings. She says her involvement with fledgling hospitalists has made her optimistic about the future of the specialty.

"People in hospital medicine are already very focused on quality," she says. "We are getting better at understanding that it's not just about being a good doctor, its about creating systems that can effectively and reliably deliver high-quality care."

 

WASHINGTON – Being married is independently associated with a significantly reduced rate of vascular disease across all arterial beds, according to a population-based study of more than 3.5 million subjects.

This apparent protective effect was strongest in younger individuals. In a multivariate regression analysis adjusted for demographics and cardiovascular risk factors, married subjects under age 50 years were 12% less likely to have prevalent vascular disease than were those who were single. The risk advantage shrank with advancing age such that married participants above age 70 years had a 4% lower risk of vascular disease than did those who were single, a difference that was statistically significant because of the huge size of the study population. And those who were single were at lower risk than were widowed or divorced subjects, Dr. Carlos L. Alviar reported at the annual meeting of the American College of Cardiology.

He presented an analysis of slightly more than 3.5 million participants in the Life Line Screening Diabetes Mellitus and Vascular Disease survey conducted during 2003-2008. Unlike most other studies of the relationship between marital status and health, which have focused on the risk of coronary disease, this study also included screening for peripheral artery disease, abdominal aortic aneurysm, and cerebrovascular disease.

Among participants of all ages, the risk of prevalent vascular disease was 5% less in those who were married than in those who were single. The risk was 3.2% greater in subjects who were divorced than in those who were single, and 5.1% greater in subjects who were widowed, according to Dr. Alviar of New York University.

The mean age of the study population was 63.7 years. Among women, 63.4% were married, 8.1% were single, 10.5% divorced, and 18% widowed. The male demographics were somewhat different: 80.4% of the men were married, 8.8% single, 6.1% divorced, and 4.7% were widowed.

Being widowed was associated with a higher prevalence of diabetes, hypertension, physical inactivity, and dyslipidemia, although investigators adjusted for that in their multivariate analysis. Divorced subjects were more likely to be smokers and have a family history of premature cardiovascular disease.

Dr. Alviar proposed as potential explanations for the reduced prevalence of vascular disease among married individuals their possibly lower levels of psychologic and physical stress, better access to medical care, and improved adherence to medication.

He reported having no financial disclosures regarding this study.

[email protected]

WASHINGTON – Being married is independently associated with a significantly reduced rate of vascular disease across all arterial beds, according to a population-based study of more than 3.5 million subjects.

This apparent protective effect was strongest in younger individuals. In a multivariate regression analysis adjusted for demographics and cardiovascular risk factors, married subjects under age 50 years were 12% less likely to have prevalent vascular disease than were those who were single. The risk advantage shrank with advancing age such that married participants above age 70 years had a 4% lower risk of vascular disease than did those who were single, a difference that was statistically significant because of the huge size of the study population. And those who were single were at lower risk than were widowed or divorced subjects, Dr. Carlos L. Alviar reported at the annual meeting of the American College of Cardiology.

He presented an analysis of slightly more than 3.5 million participants in the Life Line Screening Diabetes Mellitus and Vascular Disease survey conducted during 2003-2008. Unlike most other studies of the relationship between marital status and health, which have focused on the risk of coronary disease, this study also included screening for peripheral artery disease, abdominal aortic aneurysm, and cerebrovascular disease.

Among participants of all ages, the risk of prevalent vascular disease was 5% less in those who were married than in those who were single. The risk was 3.2% greater in subjects who were divorced than in those who were single, and 5.1% greater in subjects who were widowed, according to Dr. Alviar of New York University.

The mean age of the study population was 63.7 years. Among women, 63.4% were married, 8.1% were single, 10.5% divorced, and 18% widowed. The male demographics were somewhat different: 80.4% of the men were married, 8.8% single, 6.1% divorced, and 4.7% were widowed.

Being widowed was associated with a higher prevalence of diabetes, hypertension, physical inactivity, and dyslipidemia, although investigators adjusted for that in their multivariate analysis. Divorced subjects were more likely to be smokers and have a family history of premature cardiovascular disease.

Dr. Alviar proposed as potential explanations for the reduced prevalence of vascular disease among married individuals their possibly lower levels of psychologic and physical stress, better access to medical care, and improved adherence to medication.

He reported having no financial disclosures regarding this study.

[email protected]

WASHINGTON – Being married is independently associated with a significantly reduced rate of vascular disease across all arterial beds, according to a population-based study of more than 3.5 million subjects.

This apparent protective effect was strongest in younger individuals. In a multivariate regression analysis adjusted for demographics and cardiovascular risk factors, married subjects under age 50 years were 12% less likely to have prevalent vascular disease than were those who were single. The risk advantage shrank with advancing age such that married participants above age 70 years had a 4% lower risk of vascular disease than did those who were single, a difference that was statistically significant because of the huge size of the study population. And those who were single were at lower risk than were widowed or divorced subjects, Dr. Carlos L. Alviar reported at the annual meeting of the American College of Cardiology.

He presented an analysis of slightly more than 3.5 million participants in the Life Line Screening Diabetes Mellitus and Vascular Disease survey conducted during 2003-2008. Unlike most other studies of the relationship between marital status and health, which have focused on the risk of coronary disease, this study also included screening for peripheral artery disease, abdominal aortic aneurysm, and cerebrovascular disease.

Among participants of all ages, the risk of prevalent vascular disease was 5% less in those who were married than in those who were single. The risk was 3.2% greater in subjects who were divorced than in those who were single, and 5.1% greater in subjects who were widowed, according to Dr. Alviar of New York University.

The mean age of the study population was 63.7 years. Among women, 63.4% were married, 8.1% were single, 10.5% divorced, and 18% widowed. The male demographics were somewhat different: 80.4% of the men were married, 8.8% single, 6.1% divorced, and 4.7% were widowed.

Being widowed was associated with a higher prevalence of diabetes, hypertension, physical inactivity, and dyslipidemia, although investigators adjusted for that in their multivariate analysis. Divorced subjects were more likely to be smokers and have a family history of premature cardiovascular disease.

Dr. Alviar proposed as potential explanations for the reduced prevalence of vascular disease among married individuals their possibly lower levels of psychologic and physical stress, better access to medical care, and improved adherence to medication.

He reported having no financial disclosures regarding this study.

[email protected]

DENVER – In 15 minutes, Dr. M. Christine Lee brings you a definitive guide to lasers for various patient needs, including tattoo removal, treatment of cellulite, skin tightening, and skin resurfacing. Learn more about lasers that you might want to add to your practice and get ideas on how to make the most of devices you already have.

Dr. Lee is with the department of dermatologic surgery at the University of California, San Francisco, and director of East Bay Laser & Skin Care Center in Walnut Creek, Calif. In this video, she also shares clinical pearls about different types of laser procedures.

[email protected]

On Twitter @naseemmiller

DENVER – In 15 minutes, Dr. M. Christine Lee brings you a definitive guide to lasers for various patient needs, including tattoo removal, treatment of cellulite, skin tightening, and skin resurfacing. Learn more about lasers that you might want to add to your practice and get ideas on how to make the most of devices you already have.

Dr. Lee is with the department of dermatologic surgery at the University of California, San Francisco, and director of East Bay Laser & Skin Care Center in Walnut Creek, Calif. In this video, she also shares clinical pearls about different types of laser procedures.

[email protected]

On Twitter @naseemmiller

DENVER – In 15 minutes, Dr. M. Christine Lee brings you a definitive guide to lasers for various patient needs, including tattoo removal, treatment of cellulite, skin tightening, and skin resurfacing. Learn more about lasers that you might want to add to your practice and get ideas on how to make the most of devices you already have.

Dr. Lee is with the department of dermatologic surgery at the University of California, San Francisco, and director of East Bay Laser & Skin Care Center in Walnut Creek, Calif. In this video, she also shares clinical pearls about different types of laser procedures.

[email protected]

On Twitter @naseemmiller

SAN DIEGO—Preclinical research has revealed a mechanism of rituximab resistance in chronic lymphocytic leukemia (CLL), as well as a possible new treatment approach.

The study suggests the TNF-family member BAFF contributes to CLL cells’ resistance to direct and rituximab-induced natural killer (NK) cell reactivity.

However, the BAFF-specific antibody belimumab can overcome this resistance and restore CLL cells’ sensitivity to chemotherapy.

Julia Wild, a PhD student at Eberhard Karls University in Tuebingen, Germany, and her colleagues presented these findings at the AACR Annual Meeting 2014 as abstract 148.

“It is widely known that NK cells’ ability to react against lymphoblastic leukemia is impaired, as compared to myeloid leukemia,” Wild said. “And we now think we’ve identified a factor involved in this—a member of the tumor necrosis factor family called BAFF.”

Previous research showed that NK cells’ ability to target malignant cells and mediate antibody-dependent cellular cytotoxicity (ADCC) is compromised in CLL, but the underlying mechanisms were not clear. Wild and her colleagues therefore speculated that BAFF, which regulates B-cell proliferation and survival, plays a role.

The researchers’ initial experiments revealed that NK cells express BAFF at the mRNA level and release the protein in a soluble form, with levels depending on the state of activation.

The team then assessed BAFF expression in primary CLL cells. They collected cells from 17 CLL patients and analyzed surface expression of the 3 BAFF receptors. All 17 samples were positive for BAFF-R and TACI, and about 53% (9/17) were positive for BCMA.

Additional experiments revealed that BAFF enhances the metabolic activity of primary CLL cells. To uncover this result, the researchers incubated the cells with increasing concentrations of BAFF. And they compared untreated cells to cells treated with belimumab, isotype control, BAFF, BAFF plus belimumab, and BAFF plus isotype control.

The team then compared untreated CLL cells to cells treated with fludarabine and cyclophosphamide (Flu/Cy); Flu/Cy plus BAFF; and Flu/Cy, BAFF, and belimumab.

They found that BAFF protects CLL cells from chemotherapy-induced death. However, belimumab inhibits the protective effects of BAFF and restores CLL cells’ sensitivity to chemotherapy.

The researchers then performed cytotoxicity assays in primary CLL cells, comparing untreated cells to cells exposed to BAFF alone; rituximab alone; BAFF and rituximab; BAFF and belimumab; and rituximab, BAFF, and belimumab.

They found that lysis was highest among cells treated with rituximab alone or rituximab, BAFF, and belimumab, with comparable results in these 2 groups.

The team also evaluated CLL cell lysis due to ADCC induction. They analyzed peripheral blood mononuclear cells from CLL patients, comparing untreated cells to cells exposed to rituximab alone; rituximab and BAFF; rituximab, belimumab, and BAFF; and rituximab, bevacizumab, and BAFF.

Results showed that CLL cell survival was lowest (and comparable) in cells treated with rituximab alone or rituximab, belimumab, and BAFF.

“When CLL cells are cultured in the presence of BAFF, cytotoxicity is decreased as compared to untreated cells, and this is not only for direct NK-cell activity, but also for ADCC-mediated activity,” Wild summarized.

“But we can block this effect with belimumab, which suggests we could use this antibody for CLL treatment.”

SAN DIEGO—Preclinical research has revealed a mechanism of rituximab resistance in chronic lymphocytic leukemia (CLL), as well as a possible new treatment approach.

The study suggests the TNF-family member BAFF contributes to CLL cells’ resistance to direct and rituximab-induced natural killer (NK) cell reactivity.

However, the BAFF-specific antibody belimumab can overcome this resistance and restore CLL cells’ sensitivity to chemotherapy.

Julia Wild, a PhD student at Eberhard Karls University in Tuebingen, Germany, and her colleagues presented these findings at the AACR Annual Meeting 2014 as abstract 148.

“It is widely known that NK cells’ ability to react against lymphoblastic leukemia is impaired, as compared to myeloid leukemia,” Wild said. “And we now think we’ve identified a factor involved in this—a member of the tumor necrosis factor family called BAFF.”

Previous research showed that NK cells’ ability to target malignant cells and mediate antibody-dependent cellular cytotoxicity (ADCC) is compromised in CLL, but the underlying mechanisms were not clear. Wild and her colleagues therefore speculated that BAFF, which regulates B-cell proliferation and survival, plays a role.

The researchers’ initial experiments revealed that NK cells express BAFF at the mRNA level and release the protein in a soluble form, with levels depending on the state of activation.

The team then assessed BAFF expression in primary CLL cells. They collected cells from 17 CLL patients and analyzed surface expression of the 3 BAFF receptors. All 17 samples were positive for BAFF-R and TACI, and about 53% (9/17) were positive for BCMA.

Additional experiments revealed that BAFF enhances the metabolic activity of primary CLL cells. To uncover this result, the researchers incubated the cells with increasing concentrations of BAFF. And they compared untreated cells to cells treated with belimumab, isotype control, BAFF, BAFF plus belimumab, and BAFF plus isotype control.

The team then compared untreated CLL cells to cells treated with fludarabine and cyclophosphamide (Flu/Cy); Flu/Cy plus BAFF; and Flu/Cy, BAFF, and belimumab.

They found that BAFF protects CLL cells from chemotherapy-induced death. However, belimumab inhibits the protective effects of BAFF and restores CLL cells’ sensitivity to chemotherapy.

The researchers then performed cytotoxicity assays in primary CLL cells, comparing untreated cells to cells exposed to BAFF alone; rituximab alone; BAFF and rituximab; BAFF and belimumab; and rituximab, BAFF, and belimumab.

They found that lysis was highest among cells treated with rituximab alone or rituximab, BAFF, and belimumab, with comparable results in these 2 groups.

The team also evaluated CLL cell lysis due to ADCC induction. They analyzed peripheral blood mononuclear cells from CLL patients, comparing untreated cells to cells exposed to rituximab alone; rituximab and BAFF; rituximab, belimumab, and BAFF; and rituximab, bevacizumab, and BAFF.

Results showed that CLL cell survival was lowest (and comparable) in cells treated with rituximab alone or rituximab, belimumab, and BAFF.

“When CLL cells are cultured in the presence of BAFF, cytotoxicity is decreased as compared to untreated cells, and this is not only for direct NK-cell activity, but also for ADCC-mediated activity,” Wild summarized.

“But we can block this effect with belimumab, which suggests we could use this antibody for CLL treatment.”

SAN DIEGO—Preclinical research has revealed a mechanism of rituximab resistance in chronic lymphocytic leukemia (CLL), as well as a possible new treatment approach.

The study suggests the TNF-family member BAFF contributes to CLL cells’ resistance to direct and rituximab-induced natural killer (NK) cell reactivity.

However, the BAFF-specific antibody belimumab can overcome this resistance and restore CLL cells’ sensitivity to chemotherapy.

Julia Wild, a PhD student at Eberhard Karls University in Tuebingen, Germany, and her colleagues presented these findings at the AACR Annual Meeting 2014 as abstract 148.

“It is widely known that NK cells’ ability to react against lymphoblastic leukemia is impaired, as compared to myeloid leukemia,” Wild said. “And we now think we’ve identified a factor involved in this—a member of the tumor necrosis factor family called BAFF.”

Previous research showed that NK cells’ ability to target malignant cells and mediate antibody-dependent cellular cytotoxicity (ADCC) is compromised in CLL, but the underlying mechanisms were not clear. Wild and her colleagues therefore speculated that BAFF, which regulates B-cell proliferation and survival, plays a role.

The researchers’ initial experiments revealed that NK cells express BAFF at the mRNA level and release the protein in a soluble form, with levels depending on the state of activation.

The team then assessed BAFF expression in primary CLL cells. They collected cells from 17 CLL patients and analyzed surface expression of the 3 BAFF receptors. All 17 samples were positive for BAFF-R and TACI, and about 53% (9/17) were positive for BCMA.

Additional experiments revealed that BAFF enhances the metabolic activity of primary CLL cells. To uncover this result, the researchers incubated the cells with increasing concentrations of BAFF. And they compared untreated cells to cells treated with belimumab, isotype control, BAFF, BAFF plus belimumab, and BAFF plus isotype control.

The team then compared untreated CLL cells to cells treated with fludarabine and cyclophosphamide (Flu/Cy); Flu/Cy plus BAFF; and Flu/Cy, BAFF, and belimumab.

They found that BAFF protects CLL cells from chemotherapy-induced death. However, belimumab inhibits the protective effects of BAFF and restores CLL cells’ sensitivity to chemotherapy.

The researchers then performed cytotoxicity assays in primary CLL cells, comparing untreated cells to cells exposed to BAFF alone; rituximab alone; BAFF and rituximab; BAFF and belimumab; and rituximab, BAFF, and belimumab.

They found that lysis was highest among cells treated with rituximab alone or rituximab, BAFF, and belimumab, with comparable results in these 2 groups.

The team also evaluated CLL cell lysis due to ADCC induction. They analyzed peripheral blood mononuclear cells from CLL patients, comparing untreated cells to cells exposed to rituximab alone; rituximab and BAFF; rituximab, belimumab, and BAFF; and rituximab, bevacizumab, and BAFF.

Results showed that CLL cell survival was lowest (and comparable) in cells treated with rituximab alone or rituximab, belimumab, and BAFF.

“When CLL cells are cultured in the presence of BAFF, cytotoxicity is decreased as compared to untreated cells, and this is not only for direct NK-cell activity, but also for ADCC-mediated activity,” Wild summarized.

“But we can block this effect with belimumab, which suggests we could use this antibody for CLL treatment.”