User login
Drug granted orphan designation for GVHD
The European Commission has granted orphan drug designation for intravenous (IV) alpha-1 antitrypsin (AAT) to treat graft-versus-host disease (GVHD).
AAT is a protein derived from human plasma that has demonstrated immunomodulatory, anti-inflammatory, tissue-protective, antimicrobial, and anti-apoptotic properties.
AAT may attenuate inflammation by lowering levels of pro-inflammatory mediators such as cytokines, chemokines, and proteases associated with GVHD.
The European Commission granted IV AAT orphan designation based on preliminary clinical and preclinical research.
Orphan designation is granted to a medicine intended to treat a rare condition occurring in not more than 5 in 10,000 people in the European Union. The designation allows the drug’s maker to benefit from incentives such as a 10-year period of market exclusivity, reduced regulatory fees, and protocol assistance from the European Medicines Agency.
IV AAT also has orphan designation to treat GVHD in the US.
Studies of AAT
AAT is being investigated in a phase 1/2 study involving 24 patients with GVHD who had an inadequate response to steroid treatment. The patients are enrolled in 4 dose cohorts, in which they receive up to 8 doses of AAT.
Interim results from this study were presented at the 2014 ASH Annual Meeting (abstract 3927). Preliminary results indicated that continuous administration of AAT as therapy for steroid-resistant gut GVHD is feasible in the subject population.
Following AAT administration, the researchers observed a decrease in diarrhea, a decrease in intestinal AAT loss, and improvement in endoscopic evaluation. In addition, AAT administration suppressed serum levels of pro-inflammatory cytokines and interfered with GVHD biomarkers.
Investigators have also published research on AAT in Blood. This study suggested that AAT has a protective effect against GVHD and enhances graft-vs-leukemia effects.
Kamada Ltd., the company developing IV AAT, plans to begin a phase 3 trial of the treatment in 2016 and get the product to market in 2019 or later. 
The European Commission has granted orphan drug designation for intravenous (IV) alpha-1 antitrypsin (AAT) to treat graft-versus-host disease (GVHD).
AAT is a protein derived from human plasma that has demonstrated immunomodulatory, anti-inflammatory, tissue-protective, antimicrobial, and anti-apoptotic properties.
AAT may attenuate inflammation by lowering levels of pro-inflammatory mediators such as cytokines, chemokines, and proteases associated with GVHD.
The European Commission granted IV AAT orphan designation based on preliminary clinical and preclinical research.
Orphan designation is granted to a medicine intended to treat a rare condition occurring in not more than 5 in 10,000 people in the European Union. The designation allows the drug’s maker to benefit from incentives such as a 10-year period of market exclusivity, reduced regulatory fees, and protocol assistance from the European Medicines Agency.
IV AAT also has orphan designation to treat GVHD in the US.
Studies of AAT
AAT is being investigated in a phase 1/2 study involving 24 patients with GVHD who had an inadequate response to steroid treatment. The patients are enrolled in 4 dose cohorts, in which they receive up to 8 doses of AAT.
Interim results from this study were presented at the 2014 ASH Annual Meeting (abstract 3927). Preliminary results indicated that continuous administration of AAT as therapy for steroid-resistant gut GVHD is feasible in the subject population.
Following AAT administration, the researchers observed a decrease in diarrhea, a decrease in intestinal AAT loss, and improvement in endoscopic evaluation. In addition, AAT administration suppressed serum levels of pro-inflammatory cytokines and interfered with GVHD biomarkers.
Investigators have also published research on AAT in Blood. This study suggested that AAT has a protective effect against GVHD and enhances graft-vs-leukemia effects.
Kamada Ltd., the company developing IV AAT, plans to begin a phase 3 trial of the treatment in 2016 and get the product to market in 2019 or later.
The European Commission has granted orphan drug designation for intravenous (IV) alpha-1 antitrypsin (AAT) to treat graft-versus-host disease (GVHD).
AAT is a protein derived from human plasma that has demonstrated immunomodulatory, anti-inflammatory, tissue-protective, antimicrobial, and anti-apoptotic properties.
AAT may attenuate inflammation by lowering levels of pro-inflammatory mediators such as cytokines, chemokines, and proteases associated with GVHD.
The European Commission granted IV AAT orphan designation based on preliminary clinical and preclinical research.
Orphan designation is granted to a medicine intended to treat a rare condition occurring in not more than 5 in 10,000 people in the European Union. The designation allows the drug’s maker to benefit from incentives such as a 10-year period of market exclusivity, reduced regulatory fees, and protocol assistance from the European Medicines Agency.
IV AAT also has orphan designation to treat GVHD in the US.
Studies of AAT
AAT is being investigated in a phase 1/2 study involving 24 patients with GVHD who had an inadequate response to steroid treatment. The patients are enrolled in 4 dose cohorts, in which they receive up to 8 doses of AAT.
Interim results from this study were presented at the 2014 ASH Annual Meeting (abstract 3927). Preliminary results indicated that continuous administration of AAT as therapy for steroid-resistant gut GVHD is feasible in the subject population.
Following AAT administration, the researchers observed a decrease in diarrhea, a decrease in intestinal AAT loss, and improvement in endoscopic evaluation. In addition, AAT administration suppressed serum levels of pro-inflammatory cytokines and interfered with GVHD biomarkers.
Investigators have also published research on AAT in Blood. This study suggested that AAT has a protective effect against GVHD and enhances graft-vs-leukemia effects.
Kamada Ltd., the company developing IV AAT, plans to begin a phase 3 trial of the treatment in 2016 and get the product to market in 2019 or later.
Team advocates liver MRI to measure iron
Magnetic resonance imaging (MRI) should be the gold standard for measuring liver iron concentration (LIC) in patients receiving ongoing transfusion therapy, according to a group of researchers.
The team found evidence suggesting that liver MRI is more accurate than liver biopsy in determining total body iron balance in patients with sickle cell disease and other disorders requiring regular blood transfusions.
The findings have been published in Magnetic Resonance Imaging.
“Measuring total body iron using MRI is safer and less painful than biopsy,” said study author John Wood, MD, PhD, of Children’s Hospital Los Angeles in California.
“In this study, we’ve demonstrated that it is also more accurate. MRI should be recognized as the new gold standard for determining iron accumulation in the body.”
Dr Wood and his colleagues came to this conclusion after analyzing data from 49 patients who were undergoing treatment with deferitazole, an experimental chelating agent.
The team looked at the amount of iron the patients were receiving by transfusion and the amount of chelating agent they consumed, providing insights into the expected changes in iron levels at 12, 24, and 48 weeks after the start of deferitazole.
To compare MRI and liver biopsy, the researchers used serial estimates of iron chelation efficiency (ICE) calculated by R2 and R2* MRI LIC estimates as well as by simulated liver biopsy (over all physically reasonable sampling variability).
The estimates suggested that MRI liver iron measurements (R2 and R2*) are more accurate than a physically realizable liver biopsy (which has a sampling error of 10% or higher).
For R2, the standard deviation of ICE was 44.8% at 12 weeks, 14.8% at 24 weeks, and 7.4% at 48 weeks. For R2*, the standard deviation was 22.9% at 12 weeks, 9.3% at 24 weeks, and 5.7% at 48 weeks.
For a biopsy with a sampling error of 0%, the standard deviation of ICE was 25.9% at 12 weeks, 12.8% at 24 weeks, and 6.7% at 48 weeks. For a biopsy with a sampling error of 10%, it was 32.8%, 16.5%, and 8.7%, respectively.
For a biopsy with a sampling error of 20%, the standard deviation of ICE was 49.1% at 12 weeks, 24.9% at 24 weeks, and 13% at 48 weeks. For a biopsy with a sampling error of 30%, it was 68.1%, 34.5%, and 18%, respectively. And for a biopsy with a sampling error of 40%, it was 88.1%, 44.6%, and 23.2%, respectively.
In practice, the accuracy of MRI compared to liver biopsy is likely even greater than these estimates suggest, Dr Wood said.
Magnetic resonance imaging (MRI) should be the gold standard for measuring liver iron concentration (LIC) in patients receiving ongoing transfusion therapy, according to a group of researchers.
The team found evidence suggesting that liver MRI is more accurate than liver biopsy in determining total body iron balance in patients with sickle cell disease and other disorders requiring regular blood transfusions.
The findings have been published in Magnetic Resonance Imaging.
“Measuring total body iron using MRI is safer and less painful than biopsy,” said study author John Wood, MD, PhD, of Children’s Hospital Los Angeles in California.
“In this study, we’ve demonstrated that it is also more accurate. MRI should be recognized as the new gold standard for determining iron accumulation in the body.”
Dr Wood and his colleagues came to this conclusion after analyzing data from 49 patients who were undergoing treatment with deferitazole, an experimental chelating agent.
The team looked at the amount of iron the patients were receiving by transfusion and the amount of chelating agent they consumed, providing insights into the expected changes in iron levels at 12, 24, and 48 weeks after the start of deferitazole.
To compare MRI and liver biopsy, the researchers used serial estimates of iron chelation efficiency (ICE) calculated by R2 and R2* MRI LIC estimates as well as by simulated liver biopsy (over all physically reasonable sampling variability).
The estimates suggested that MRI liver iron measurements (R2 and R2*) are more accurate than a physically realizable liver biopsy (which has a sampling error of 10% or higher).
For R2, the standard deviation of ICE was 44.8% at 12 weeks, 14.8% at 24 weeks, and 7.4% at 48 weeks. For R2*, the standard deviation was 22.9% at 12 weeks, 9.3% at 24 weeks, and 5.7% at 48 weeks.
For a biopsy with a sampling error of 0%, the standard deviation of ICE was 25.9% at 12 weeks, 12.8% at 24 weeks, and 6.7% at 48 weeks. For a biopsy with a sampling error of 10%, it was 32.8%, 16.5%, and 8.7%, respectively.
For a biopsy with a sampling error of 20%, the standard deviation of ICE was 49.1% at 12 weeks, 24.9% at 24 weeks, and 13% at 48 weeks. For a biopsy with a sampling error of 30%, it was 68.1%, 34.5%, and 18%, respectively. And for a biopsy with a sampling error of 40%, it was 88.1%, 44.6%, and 23.2%, respectively.
In practice, the accuracy of MRI compared to liver biopsy is likely even greater than these estimates suggest, Dr Wood said.
Magnetic resonance imaging (MRI) should be the gold standard for measuring liver iron concentration (LIC) in patients receiving ongoing transfusion therapy, according to a group of researchers.
The team found evidence suggesting that liver MRI is more accurate than liver biopsy in determining total body iron balance in patients with sickle cell disease and other disorders requiring regular blood transfusions.
The findings have been published in Magnetic Resonance Imaging.
“Measuring total body iron using MRI is safer and less painful than biopsy,” said study author John Wood, MD, PhD, of Children’s Hospital Los Angeles in California.
“In this study, we’ve demonstrated that it is also more accurate. MRI should be recognized as the new gold standard for determining iron accumulation in the body.”
Dr Wood and his colleagues came to this conclusion after analyzing data from 49 patients who were undergoing treatment with deferitazole, an experimental chelating agent.
The team looked at the amount of iron the patients were receiving by transfusion and the amount of chelating agent they consumed, providing insights into the expected changes in iron levels at 12, 24, and 48 weeks after the start of deferitazole.
To compare MRI and liver biopsy, the researchers used serial estimates of iron chelation efficiency (ICE) calculated by R2 and R2* MRI LIC estimates as well as by simulated liver biopsy (over all physically reasonable sampling variability).
The estimates suggested that MRI liver iron measurements (R2 and R2*) are more accurate than a physically realizable liver biopsy (which has a sampling error of 10% or higher).
For R2, the standard deviation of ICE was 44.8% at 12 weeks, 14.8% at 24 weeks, and 7.4% at 48 weeks. For R2*, the standard deviation was 22.9% at 12 weeks, 9.3% at 24 weeks, and 5.7% at 48 weeks.
For a biopsy with a sampling error of 0%, the standard deviation of ICE was 25.9% at 12 weeks, 12.8% at 24 weeks, and 6.7% at 48 weeks. For a biopsy with a sampling error of 10%, it was 32.8%, 16.5%, and 8.7%, respectively.
For a biopsy with a sampling error of 20%, the standard deviation of ICE was 49.1% at 12 weeks, 24.9% at 24 weeks, and 13% at 48 weeks. For a biopsy with a sampling error of 30%, it was 68.1%, 34.5%, and 18%, respectively. And for a biopsy with a sampling error of 40%, it was 88.1%, 44.6%, and 23.2%, respectively.
In practice, the accuracy of MRI compared to liver biopsy is likely even greater than these estimates suggest, Dr Wood said.
Study supports sequential MRD monitoring in certain patients
Photo by Chad McNeeley
Based on results of a prospective study, investigators are advocating sequential minimal residual disease (MRD) monitoring in pediatric patients with acute lymphoblastic leukemia (ALL) who have detectable MRD after remission induction therapy.
The researchers said their findings show that MRD levels during remission induction treatment have important therapeutic indications, even in the context of MRD-guided therapy, as patients with higher MRD levels have worse outcomes.
Ching-Hon Pui, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues described the findings in The Lancet Oncology.
The team analyzed 498 pediatric patients newly diagnosed with ALL, 492 of whom (99%) attained a complete remission following induction therapy and 491 of whom were monitored for MRD.
The researchers first estimated patients’ risk of relapse according to baseline clinical and laboratory features, provisionally classifying them as having a low, standard, or high risk of relapse.
But the investigators also took MRD levels into consideration. They measured MRD on days 19 and 46 of remission induction, on week 7 of maintenance treatment, and on weeks 17, 48, and 120 (the end of treatment).
The team found that 10-year event-free survival (EFS) was significantly worse for patients with 1% or greater MRD levels on day 19, regardless of their initial risk assessment. Ten-year EFS was 64.1% in these patients, compared to 90.7% in patients with lower or no detectable MRD (P<0.001).
Thirteen percent of patients who were deemed low-risk initially and 28% of patients deemed standard-risk initially had 1% or higher MRD levels on day 19. And these levels were associated with worse 10-year EFS.
In the provisional low-risk group, EFS was 69.2% in the high-MRD patients and 95.5% in the low-MRD patients (P<0.001). And in the provisional standard-risk group, 10-year EFS was 65.1% and 82.9%, respectively (P=0.01).
MRD levels at day 46 also appeared to have a bearing on EFS. For patients in the provisional low-risk group who had 1% or higher MRD on day 19 but became MRD-negative on day 46, 10-year EFS was 88.9%, compared to 59.2% for other provisionally low-risk patients who had detectable MRD on day 46 (P=0.02).
MRD levels on days 19 and 46 led to the reclassification of 50 patients from low-risk to a higher risk group that warranted more intensive therapy. The researchers credited the change with boosting survival.
“This analysis shows that MRD-directed therapy clearly contributed to the unprecedented high rates of long-term survival that patients in this study achieved,” Dr Pui said. “MRD proved to be a powerful way to identify high-risk patients who needed more intensive therapy and helped us avoid over-treatment of low-risk patients by reducing their exposure to chemotherapy.”
Still, MRD assessments at days 19 and 46 were not perfect predictors of patient outcomes. Of the patients who were MRD negative after remission induction, MRD re-emerged in 6 patients—4 of the 382 patients studied on week 7, 1 of the 448 studied at week 17, and 1 of the 437 studied at week 48. All but 1 of these patients died despite additional treatment.
On the other hand, relapse occurred in 2 of the 11 patients who had decreasing MRD levels between the end of induction and week 7 of maintenance therapy and were treated with chemotherapy alone.
Taking these results together, the investigators concluded that measuring MRD at days 19 and 46 was sufficient to guide the treatment of most pediatric ALL patients. However, MRD measurements should continue to guide treatment for patients with detectable MRD on day 46.
Photo by Chad McNeeley
Based on results of a prospective study, investigators are advocating sequential minimal residual disease (MRD) monitoring in pediatric patients with acute lymphoblastic leukemia (ALL) who have detectable MRD after remission induction therapy.
The researchers said their findings show that MRD levels during remission induction treatment have important therapeutic indications, even in the context of MRD-guided therapy, as patients with higher MRD levels have worse outcomes.
Ching-Hon Pui, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues described the findings in The Lancet Oncology.
The team analyzed 498 pediatric patients newly diagnosed with ALL, 492 of whom (99%) attained a complete remission following induction therapy and 491 of whom were monitored for MRD.
The researchers first estimated patients’ risk of relapse according to baseline clinical and laboratory features, provisionally classifying them as having a low, standard, or high risk of relapse.
But the investigators also took MRD levels into consideration. They measured MRD on days 19 and 46 of remission induction, on week 7 of maintenance treatment, and on weeks 17, 48, and 120 (the end of treatment).
The team found that 10-year event-free survival (EFS) was significantly worse for patients with 1% or greater MRD levels on day 19, regardless of their initial risk assessment. Ten-year EFS was 64.1% in these patients, compared to 90.7% in patients with lower or no detectable MRD (P<0.001).
Thirteen percent of patients who were deemed low-risk initially and 28% of patients deemed standard-risk initially had 1% or higher MRD levels on day 19. And these levels were associated with worse 10-year EFS.
In the provisional low-risk group, EFS was 69.2% in the high-MRD patients and 95.5% in the low-MRD patients (P<0.001). And in the provisional standard-risk group, 10-year EFS was 65.1% and 82.9%, respectively (P=0.01).
MRD levels at day 46 also appeared to have a bearing on EFS. For patients in the provisional low-risk group who had 1% or higher MRD on day 19 but became MRD-negative on day 46, 10-year EFS was 88.9%, compared to 59.2% for other provisionally low-risk patients who had detectable MRD on day 46 (P=0.02).
MRD levels on days 19 and 46 led to the reclassification of 50 patients from low-risk to a higher risk group that warranted more intensive therapy. The researchers credited the change with boosting survival.
“This analysis shows that MRD-directed therapy clearly contributed to the unprecedented high rates of long-term survival that patients in this study achieved,” Dr Pui said. “MRD proved to be a powerful way to identify high-risk patients who needed more intensive therapy and helped us avoid over-treatment of low-risk patients by reducing their exposure to chemotherapy.”
Still, MRD assessments at days 19 and 46 were not perfect predictors of patient outcomes. Of the patients who were MRD negative after remission induction, MRD re-emerged in 6 patients—4 of the 382 patients studied on week 7, 1 of the 448 studied at week 17, and 1 of the 437 studied at week 48. All but 1 of these patients died despite additional treatment.
On the other hand, relapse occurred in 2 of the 11 patients who had decreasing MRD levels between the end of induction and week 7 of maintenance therapy and were treated with chemotherapy alone.
Taking these results together, the investigators concluded that measuring MRD at days 19 and 46 was sufficient to guide the treatment of most pediatric ALL patients. However, MRD measurements should continue to guide treatment for patients with detectable MRD on day 46.
Photo by Chad McNeeley
Based on results of a prospective study, investigators are advocating sequential minimal residual disease (MRD) monitoring in pediatric patients with acute lymphoblastic leukemia (ALL) who have detectable MRD after remission induction therapy.
The researchers said their findings show that MRD levels during remission induction treatment have important therapeutic indications, even in the context of MRD-guided therapy, as patients with higher MRD levels have worse outcomes.
Ching-Hon Pui, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues described the findings in The Lancet Oncology.
The team analyzed 498 pediatric patients newly diagnosed with ALL, 492 of whom (99%) attained a complete remission following induction therapy and 491 of whom were monitored for MRD.
The researchers first estimated patients’ risk of relapse according to baseline clinical and laboratory features, provisionally classifying them as having a low, standard, or high risk of relapse.
But the investigators also took MRD levels into consideration. They measured MRD on days 19 and 46 of remission induction, on week 7 of maintenance treatment, and on weeks 17, 48, and 120 (the end of treatment).
The team found that 10-year event-free survival (EFS) was significantly worse for patients with 1% or greater MRD levels on day 19, regardless of their initial risk assessment. Ten-year EFS was 64.1% in these patients, compared to 90.7% in patients with lower or no detectable MRD (P<0.001).
Thirteen percent of patients who were deemed low-risk initially and 28% of patients deemed standard-risk initially had 1% or higher MRD levels on day 19. And these levels were associated with worse 10-year EFS.
In the provisional low-risk group, EFS was 69.2% in the high-MRD patients and 95.5% in the low-MRD patients (P<0.001). And in the provisional standard-risk group, 10-year EFS was 65.1% and 82.9%, respectively (P=0.01).
MRD levels at day 46 also appeared to have a bearing on EFS. For patients in the provisional low-risk group who had 1% or higher MRD on day 19 but became MRD-negative on day 46, 10-year EFS was 88.9%, compared to 59.2% for other provisionally low-risk patients who had detectable MRD on day 46 (P=0.02).
MRD levels on days 19 and 46 led to the reclassification of 50 patients from low-risk to a higher risk group that warranted more intensive therapy. The researchers credited the change with boosting survival.
“This analysis shows that MRD-directed therapy clearly contributed to the unprecedented high rates of long-term survival that patients in this study achieved,” Dr Pui said. “MRD proved to be a powerful way to identify high-risk patients who needed more intensive therapy and helped us avoid over-treatment of low-risk patients by reducing their exposure to chemotherapy.”
Still, MRD assessments at days 19 and 46 were not perfect predictors of patient outcomes. Of the patients who were MRD negative after remission induction, MRD re-emerged in 6 patients—4 of the 382 patients studied on week 7, 1 of the 448 studied at week 17, and 1 of the 437 studied at week 48. All but 1 of these patients died despite additional treatment.
On the other hand, relapse occurred in 2 of the 11 patients who had decreasing MRD levels between the end of induction and week 7 of maintenance therapy and were treated with chemotherapy alone.
Taking these results together, the investigators concluded that measuring MRD at days 19 and 46 was sufficient to guide the treatment of most pediatric ALL patients. However, MRD measurements should continue to guide treatment for patients with detectable MRD on day 46.
Discovery may aid malaria vaccine development
a red blood cell
Image courtesy of St. Jude
Children’s Research Hospital
Researchers say they have made a major advance in the quest toward a viable malaria vaccine—by uncovering a strategy the immune system employs to protect against malaria infection.
The team discovered how antibodies work in partnership with complement proteins to block Plasmodium falciparum infection.
And they believe this finding will aid the development of vaccine candidates that are already under investigation.
“We have known that antibodies on their own are not highly effective at blocking malaria, so they must be getting help from other parts of the immune system,” said James Beeson, MBBS, PhD, of the Burnet Institute in Melbourne, Victoria, Australia.
“This new research provides evidence that complement plays a key role in antibody-mediated immunity to blood-stage replication of Plasmodium falciparum malaria in humans.”
Dr Beeson and his colleagues described their research in Immunity.
The team found that acquired and vaccine-induced human antibodies recruited complement to block red blood cell infection and blood-stage replication of P falciparum.
Without complement, many of the antibodies were not functional, and P falciparum merozoites invaded red blood cells. But when the antibodies interacted with complement factors, they were able to prevent invasion and lyse merozoites.
Further investigation revealed that inhibitory activity was mediated predominately by C1q fixation, and merozoite surface proteins (MSPs) 1 and 2 were major targets of antibody-mediated complement-dependent (Ab-C’) inhibition.
To examine the importance of antibody-mediated complement fixation in acquired immunity to malaria, the researchers tested antibodies for C1q fixation in 206 children (ages 5 to 14) living in a malaria-endemic region.
This revealed that complement fixation was strongly associated with protection from clinical malaria and high-density parasitemia.
The researchers also investigated whether Ab-C′ inhibitory activity could be induced by human immunization with a candidate MSP vaccine. They studied 10 immunoglobulin G (IgG) samples from a phase 1 trial of the MSP2-C1 vaccine.
Eight of the IgG samples showed substantial inhibition in normal serum, but not in heat-inactivated serum, which suggests vaccination induced Ab-C’ inhibition. The researchers did not observe inhibition in IgG from pre-vaccinated individuals or placebo-vaccinated samples.
The team said this suggests that MSP2 antibodies induced by vaccination can inhibit P falciparum invasion via Ab-C’ inhibition.
“We have shown that it is possible to effectively generate this protective immune response by immunizing humans with a candidate vaccine,” Dr Beeson said, noting that this “may prove a valuable strategy to prevent the devastating effects of malaria.”
a red blood cell
Image courtesy of St. Jude
Children’s Research Hospital
Researchers say they have made a major advance in the quest toward a viable malaria vaccine—by uncovering a strategy the immune system employs to protect against malaria infection.
The team discovered how antibodies work in partnership with complement proteins to block Plasmodium falciparum infection.
And they believe this finding will aid the development of vaccine candidates that are already under investigation.
“We have known that antibodies on their own are not highly effective at blocking malaria, so they must be getting help from other parts of the immune system,” said James Beeson, MBBS, PhD, of the Burnet Institute in Melbourne, Victoria, Australia.
“This new research provides evidence that complement plays a key role in antibody-mediated immunity to blood-stage replication of Plasmodium falciparum malaria in humans.”
Dr Beeson and his colleagues described their research in Immunity.
The team found that acquired and vaccine-induced human antibodies recruited complement to block red blood cell infection and blood-stage replication of P falciparum.
Without complement, many of the antibodies were not functional, and P falciparum merozoites invaded red blood cells. But when the antibodies interacted with complement factors, they were able to prevent invasion and lyse merozoites.
Further investigation revealed that inhibitory activity was mediated predominately by C1q fixation, and merozoite surface proteins (MSPs) 1 and 2 were major targets of antibody-mediated complement-dependent (Ab-C’) inhibition.
To examine the importance of antibody-mediated complement fixation in acquired immunity to malaria, the researchers tested antibodies for C1q fixation in 206 children (ages 5 to 14) living in a malaria-endemic region.
This revealed that complement fixation was strongly associated with protection from clinical malaria and high-density parasitemia.
The researchers also investigated whether Ab-C′ inhibitory activity could be induced by human immunization with a candidate MSP vaccine. They studied 10 immunoglobulin G (IgG) samples from a phase 1 trial of the MSP2-C1 vaccine.
Eight of the IgG samples showed substantial inhibition in normal serum, but not in heat-inactivated serum, which suggests vaccination induced Ab-C’ inhibition. The researchers did not observe inhibition in IgG from pre-vaccinated individuals or placebo-vaccinated samples.
The team said this suggests that MSP2 antibodies induced by vaccination can inhibit P falciparum invasion via Ab-C’ inhibition.
“We have shown that it is possible to effectively generate this protective immune response by immunizing humans with a candidate vaccine,” Dr Beeson said, noting that this “may prove a valuable strategy to prevent the devastating effects of malaria.”
a red blood cell
Image courtesy of St. Jude
Children’s Research Hospital
Researchers say they have made a major advance in the quest toward a viable malaria vaccine—by uncovering a strategy the immune system employs to protect against malaria infection.
The team discovered how antibodies work in partnership with complement proteins to block Plasmodium falciparum infection.
And they believe this finding will aid the development of vaccine candidates that are already under investigation.
“We have known that antibodies on their own are not highly effective at blocking malaria, so they must be getting help from other parts of the immune system,” said James Beeson, MBBS, PhD, of the Burnet Institute in Melbourne, Victoria, Australia.
“This new research provides evidence that complement plays a key role in antibody-mediated immunity to blood-stage replication of Plasmodium falciparum malaria in humans.”
Dr Beeson and his colleagues described their research in Immunity.
The team found that acquired and vaccine-induced human antibodies recruited complement to block red blood cell infection and blood-stage replication of P falciparum.
Without complement, many of the antibodies were not functional, and P falciparum merozoites invaded red blood cells. But when the antibodies interacted with complement factors, they were able to prevent invasion and lyse merozoites.
Further investigation revealed that inhibitory activity was mediated predominately by C1q fixation, and merozoite surface proteins (MSPs) 1 and 2 were major targets of antibody-mediated complement-dependent (Ab-C’) inhibition.
To examine the importance of antibody-mediated complement fixation in acquired immunity to malaria, the researchers tested antibodies for C1q fixation in 206 children (ages 5 to 14) living in a malaria-endemic region.
This revealed that complement fixation was strongly associated with protection from clinical malaria and high-density parasitemia.
The researchers also investigated whether Ab-C′ inhibitory activity could be induced by human immunization with a candidate MSP vaccine. They studied 10 immunoglobulin G (IgG) samples from a phase 1 trial of the MSP2-C1 vaccine.
Eight of the IgG samples showed substantial inhibition in normal serum, but not in heat-inactivated serum, which suggests vaccination induced Ab-C’ inhibition. The researchers did not observe inhibition in IgG from pre-vaccinated individuals or placebo-vaccinated samples.
The team said this suggests that MSP2 antibodies induced by vaccination can inhibit P falciparum invasion via Ab-C’ inhibition.
“We have shown that it is possible to effectively generate this protective immune response by immunizing humans with a candidate vaccine,” Dr Beeson said, noting that this “may prove a valuable strategy to prevent the devastating effects of malaria.”
Topical TXA decreases use of blood transfusions
Photo by Daniel Gay
Using topical tranexamic acid (TXA) in patients undergoing primary total hip and knee arthroplasty can reduce the need for blood transfusions, according to a study published in The Journal of Arthroplasty.
Topical TXA reduced the transfusion rate by 12%, thereby reducing transfusion costs.
Topical TXA also enabled about 9% more patients to be discharged to their homes rather than a skilled nursing facility, and it did not affect the rate of complications.
“Historically, with hip or knee replacement, there was a 25% to 30% chance of a blood transfusion,” said study author John Froehlich, MD, of The Miriam Hospital in Providence, Rhode Island.
“We realized that this high frequency of transfusions was associated with longer hospital stays and a higher risk of infections, which we are always working to avoid. Tranexamic acid has been around for 30 years, but because there was concern about the danger of administering it intravenously, we opted to inject it in the joints. We found it to be effective in reducing ongoing blood loss and the subsequent need for transfusion, and we have now standardized the practice.”
TXA is a synthetic derivative of the amino acid lysine that produces antifibrinolytic activity by competitively inhibiting lysine binding sites on plasminogen molecules. TXA helps the body stabilize blood clot formation, thereby reducing bleeding at surgical sites.
Most protocols of TXA in total joint arthroplasty have involved intravenous delivery. However, studies have indicated that topical injection may provide advantages, such as potentially reduced costs with a single injection, surgeon control, and localization and concentration of the drug more precisely at the surgical site.
“As the evidence for topical TXA grew, our arthroplasty surgeons started adopting topical TXA for total joint arthroplasty,” Dr Froehlich said.
He and his colleagues studied topical TXA in patients undergoing primary hip or knee arthroplasty by 5 surgeons from March 2012 to March 2013. Of the 591 consecutive patients, 311 received topical TXA, and 280 served as controls.
The researchers found that topical TXA reduced the proportion of red blood cell units transfused by 18%, from 28.6% to 10.6% (P<0.001). The drug also reduce the number of patients who required transfusions by 12%, from 17.5% to 5.5% (P<0.001).
On, the other hand, there was no significant difference between the TXA and control groups with regard to tourniquet time, operative time, time in the operating room, or the length of hospital stay.
Still, more patients in the TXA arm than in the control arm were able to go home rather than to a subacute nursing facility—71.4% and 62.1%, respectively (P<0.02).
And TXA conferred a cost benefit based solely on the rate of transfusion reduction. The researchers’ cost analysis revealed a net savings of $8372.66 per 100 patients treated, which amounted to $83.73 per patient.
“[Topical TXA] reduces transfusion rates, increases home disposition, and reduces cost in primary hip and knee arthroplasty,” said study author Lee Rubin, MD, of The Miriam Hospital.
“[W]e have now developed a simple, standardized, and cost-effective protocol for the use of topical TXA during total joint replacement that can be immediately used by any surgeon around the world to improve patient care.”
Photo by Daniel Gay
Using topical tranexamic acid (TXA) in patients undergoing primary total hip and knee arthroplasty can reduce the need for blood transfusions, according to a study published in The Journal of Arthroplasty.
Topical TXA reduced the transfusion rate by 12%, thereby reducing transfusion costs.
Topical TXA also enabled about 9% more patients to be discharged to their homes rather than a skilled nursing facility, and it did not affect the rate of complications.
“Historically, with hip or knee replacement, there was a 25% to 30% chance of a blood transfusion,” said study author John Froehlich, MD, of The Miriam Hospital in Providence, Rhode Island.
“We realized that this high frequency of transfusions was associated with longer hospital stays and a higher risk of infections, which we are always working to avoid. Tranexamic acid has been around for 30 years, but because there was concern about the danger of administering it intravenously, we opted to inject it in the joints. We found it to be effective in reducing ongoing blood loss and the subsequent need for transfusion, and we have now standardized the practice.”
TXA is a synthetic derivative of the amino acid lysine that produces antifibrinolytic activity by competitively inhibiting lysine binding sites on plasminogen molecules. TXA helps the body stabilize blood clot formation, thereby reducing bleeding at surgical sites.
Most protocols of TXA in total joint arthroplasty have involved intravenous delivery. However, studies have indicated that topical injection may provide advantages, such as potentially reduced costs with a single injection, surgeon control, and localization and concentration of the drug more precisely at the surgical site.
“As the evidence for topical TXA grew, our arthroplasty surgeons started adopting topical TXA for total joint arthroplasty,” Dr Froehlich said.
He and his colleagues studied topical TXA in patients undergoing primary hip or knee arthroplasty by 5 surgeons from March 2012 to March 2013. Of the 591 consecutive patients, 311 received topical TXA, and 280 served as controls.
The researchers found that topical TXA reduced the proportion of red blood cell units transfused by 18%, from 28.6% to 10.6% (P<0.001). The drug also reduce the number of patients who required transfusions by 12%, from 17.5% to 5.5% (P<0.001).
On, the other hand, there was no significant difference between the TXA and control groups with regard to tourniquet time, operative time, time in the operating room, or the length of hospital stay.
Still, more patients in the TXA arm than in the control arm were able to go home rather than to a subacute nursing facility—71.4% and 62.1%, respectively (P<0.02).
And TXA conferred a cost benefit based solely on the rate of transfusion reduction. The researchers’ cost analysis revealed a net savings of $8372.66 per 100 patients treated, which amounted to $83.73 per patient.
“[Topical TXA] reduces transfusion rates, increases home disposition, and reduces cost in primary hip and knee arthroplasty,” said study author Lee Rubin, MD, of The Miriam Hospital.
“[W]e have now developed a simple, standardized, and cost-effective protocol for the use of topical TXA during total joint replacement that can be immediately used by any surgeon around the world to improve patient care.”
Photo by Daniel Gay
Using topical tranexamic acid (TXA) in patients undergoing primary total hip and knee arthroplasty can reduce the need for blood transfusions, according to a study published in The Journal of Arthroplasty.
Topical TXA reduced the transfusion rate by 12%, thereby reducing transfusion costs.
Topical TXA also enabled about 9% more patients to be discharged to their homes rather than a skilled nursing facility, and it did not affect the rate of complications.
“Historically, with hip or knee replacement, there was a 25% to 30% chance of a blood transfusion,” said study author John Froehlich, MD, of The Miriam Hospital in Providence, Rhode Island.
“We realized that this high frequency of transfusions was associated with longer hospital stays and a higher risk of infections, which we are always working to avoid. Tranexamic acid has been around for 30 years, but because there was concern about the danger of administering it intravenously, we opted to inject it in the joints. We found it to be effective in reducing ongoing blood loss and the subsequent need for transfusion, and we have now standardized the practice.”
TXA is a synthetic derivative of the amino acid lysine that produces antifibrinolytic activity by competitively inhibiting lysine binding sites on plasminogen molecules. TXA helps the body stabilize blood clot formation, thereby reducing bleeding at surgical sites.
Most protocols of TXA in total joint arthroplasty have involved intravenous delivery. However, studies have indicated that topical injection may provide advantages, such as potentially reduced costs with a single injection, surgeon control, and localization and concentration of the drug more precisely at the surgical site.
“As the evidence for topical TXA grew, our arthroplasty surgeons started adopting topical TXA for total joint arthroplasty,” Dr Froehlich said.
He and his colleagues studied topical TXA in patients undergoing primary hip or knee arthroplasty by 5 surgeons from March 2012 to March 2013. Of the 591 consecutive patients, 311 received topical TXA, and 280 served as controls.
The researchers found that topical TXA reduced the proportion of red blood cell units transfused by 18%, from 28.6% to 10.6% (P<0.001). The drug also reduce the number of patients who required transfusions by 12%, from 17.5% to 5.5% (P<0.001).
On, the other hand, there was no significant difference between the TXA and control groups with regard to tourniquet time, operative time, time in the operating room, or the length of hospital stay.
Still, more patients in the TXA arm than in the control arm were able to go home rather than to a subacute nursing facility—71.4% and 62.1%, respectively (P<0.02).
And TXA conferred a cost benefit based solely on the rate of transfusion reduction. The researchers’ cost analysis revealed a net savings of $8372.66 per 100 patients treated, which amounted to $83.73 per patient.
“[Topical TXA] reduces transfusion rates, increases home disposition, and reduces cost in primary hip and knee arthroplasty,” said study author Lee Rubin, MD, of The Miriam Hospital.
“[W]e have now developed a simple, standardized, and cost-effective protocol for the use of topical TXA during total joint replacement that can be immediately used by any surgeon around the world to improve patient care.”
Team discovers how cerebral malaria kills children
at Queen Elizabeth Hospital
Photo by Jim Peck
After grant money brought magnetic resonance imaging (MRI) to a hospital in Africa, researchers were able to uncover the cause of death in children with cerebral malaria.
MRI scans revealed that, in some children, the brain can become so swollen that it is forced out through the bottom of the skull and compresses the brain stem. This pressure causes the children to stop breathing and die.
The researchers reported these findings in NEJM.
“Because we know now that the brain swelling is what causes death, we can work to find new treatments,” said study author Terrie Taylor, DO, of Michigan State University in East Lansing.
“The next step is to identify what’s causing the swelling and then develop treatments targeting those causes. It’s also possible that using ventilators to keep the children breathing until the swelling subsides might save lives, but ventilators are few and far between in Africa at the moment.”
Scans reveal brain swelling
In 2008, GE Healthcare provided a $1 million MRI to the Queen Elizabeth Hospital in Blantyre, Malawi, where Dr Taylor spends 6 months of every year treating and studying children with malaria.
Dr Taylor and her colleagues used the MRI to view brain images from hundreds of children with cerebral malaria, comparing findings in those who died to those who survived.
The team imaged 168 children with cerebral malaria (as defined by the World Health Organization). Fifteen percent (25/168) of the children died. And 84% of these children (21/25) had evidence of severe brain swelling at admission.
In contrast, the researchers found evidence of severe brain swelling in 27% (39/143) of children who survived. And serial MRI scans revealed decreasing brain volume in the survivors who initially had brain swelling.
“We found that survivors’ brains were either never swollen or decreased in size after 2 to 3 days,” Dr Taylor said. “This was a triumphant moment. I wanted to say to the parasite, ‘Ha! You never thought we’d get an MRI, did you?’”
at Queen Elizabeth Hospital
Photo by Jim Peck
After grant money brought magnetic resonance imaging (MRI) to a hospital in Africa, researchers were able to uncover the cause of death in children with cerebral malaria.
MRI scans revealed that, in some children, the brain can become so swollen that it is forced out through the bottom of the skull and compresses the brain stem. This pressure causes the children to stop breathing and die.
The researchers reported these findings in NEJM.
“Because we know now that the brain swelling is what causes death, we can work to find new treatments,” said study author Terrie Taylor, DO, of Michigan State University in East Lansing.
“The next step is to identify what’s causing the swelling and then develop treatments targeting those causes. It’s also possible that using ventilators to keep the children breathing until the swelling subsides might save lives, but ventilators are few and far between in Africa at the moment.”
Scans reveal brain swelling
In 2008, GE Healthcare provided a $1 million MRI to the Queen Elizabeth Hospital in Blantyre, Malawi, where Dr Taylor spends 6 months of every year treating and studying children with malaria.
Dr Taylor and her colleagues used the MRI to view brain images from hundreds of children with cerebral malaria, comparing findings in those who died to those who survived.
The team imaged 168 children with cerebral malaria (as defined by the World Health Organization). Fifteen percent (25/168) of the children died. And 84% of these children (21/25) had evidence of severe brain swelling at admission.
In contrast, the researchers found evidence of severe brain swelling in 27% (39/143) of children who survived. And serial MRI scans revealed decreasing brain volume in the survivors who initially had brain swelling.
“We found that survivors’ brains were either never swollen or decreased in size after 2 to 3 days,” Dr Taylor said. “This was a triumphant moment. I wanted to say to the parasite, ‘Ha! You never thought we’d get an MRI, did you?’”
at Queen Elizabeth Hospital
Photo by Jim Peck
After grant money brought magnetic resonance imaging (MRI) to a hospital in Africa, researchers were able to uncover the cause of death in children with cerebral malaria.
MRI scans revealed that, in some children, the brain can become so swollen that it is forced out through the bottom of the skull and compresses the brain stem. This pressure causes the children to stop breathing and die.
The researchers reported these findings in NEJM.
“Because we know now that the brain swelling is what causes death, we can work to find new treatments,” said study author Terrie Taylor, DO, of Michigan State University in East Lansing.
“The next step is to identify what’s causing the swelling and then develop treatments targeting those causes. It’s also possible that using ventilators to keep the children breathing until the swelling subsides might save lives, but ventilators are few and far between in Africa at the moment.”
Scans reveal brain swelling
In 2008, GE Healthcare provided a $1 million MRI to the Queen Elizabeth Hospital in Blantyre, Malawi, where Dr Taylor spends 6 months of every year treating and studying children with malaria.
Dr Taylor and her colleagues used the MRI to view brain images from hundreds of children with cerebral malaria, comparing findings in those who died to those who survived.
The team imaged 168 children with cerebral malaria (as defined by the World Health Organization). Fifteen percent (25/168) of the children died. And 84% of these children (21/25) had evidence of severe brain swelling at admission.
In contrast, the researchers found evidence of severe brain swelling in 27% (39/143) of children who survived. And serial MRI scans revealed decreasing brain volume in the survivors who initially had brain swelling.
“We found that survivors’ brains were either never swollen or decreased in size after 2 to 3 days,” Dr Taylor said. “This was a triumphant moment. I wanted to say to the parasite, ‘Ha! You never thought we’d get an MRI, did you?’”
Group traces clonal evolution of B-ALL
In tracing the clonal evolution of B-cell acute lymphoblastic leukemia (B-ALL) from diagnosis to relapse, researchers discovered that clonal diversity is comparable in both states.
They also identified mutations associated with B-ALL relapse and found that clonal survival is not dependent upon mutation burden.
In most of the cases the researchers analyzed, a single, minor clone survived therapy, acquired additional mutations, and drove disease relapse.
Jinghui Zhang, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and her colleagues recounted these findings in Nature Communications.
The researchers performed deep, whole-exome sequencing on cell samples from 20 young patients (ages 2 to 19) with relapsed B-ALL. The samples were collected at diagnosis, remission, and relapse.
“[W]e wanted to find out the underlying mechanism leading to cancer relapse,” Dr Zhang said. “When the cancer recurs, is it a completely different cancer, or is it an extension, or change, arising from pre-existing cancer?”
The researchers were able to detect the mutations in both the “rising” and “falling” clones—those that survive therapy and those that don’t—at the different disease stages and pinpoint the mutations that drove the leukemia.
Seven genes were highly likely to be mutated in relapsed disease—NT5C2, CREBBP, WHSC1, TP53, USH2A, NRAS, and IKZF1.
The researchers also characterized how diverse those mutations were at diagnosis and relapse. They found that B-ALL cells were mutating just as wildly and diversely in one phase of disease as in the other.
“This finding was interesting, because most people think that the clone that has the most mutations is more likely to survive therapy and evolve, but that doesn’t seem to be the case,” Dr Zhang said.
In most cases, relapse was driven by a minor subclone that had survived therapy and was present at an extremely low level. The researchers said this finding suggests a need to change the way we assess patients after treatment to determine the likelihood of relapse.
“When we are analyzing for the level of minimum residual disease in monitoring remission in patients, we should not only pay attention to the mutations in the predominant clone,” Dr Zhang said. “We should also be tracking what kinds of mutations exist in the minor subclones.”
In tracing the clonal evolution of B-cell acute lymphoblastic leukemia (B-ALL) from diagnosis to relapse, researchers discovered that clonal diversity is comparable in both states.
They also identified mutations associated with B-ALL relapse and found that clonal survival is not dependent upon mutation burden.
In most of the cases the researchers analyzed, a single, minor clone survived therapy, acquired additional mutations, and drove disease relapse.
Jinghui Zhang, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and her colleagues recounted these findings in Nature Communications.
The researchers performed deep, whole-exome sequencing on cell samples from 20 young patients (ages 2 to 19) with relapsed B-ALL. The samples were collected at diagnosis, remission, and relapse.
“[W]e wanted to find out the underlying mechanism leading to cancer relapse,” Dr Zhang said. “When the cancer recurs, is it a completely different cancer, or is it an extension, or change, arising from pre-existing cancer?”
The researchers were able to detect the mutations in both the “rising” and “falling” clones—those that survive therapy and those that don’t—at the different disease stages and pinpoint the mutations that drove the leukemia.
Seven genes were highly likely to be mutated in relapsed disease—NT5C2, CREBBP, WHSC1, TP53, USH2A, NRAS, and IKZF1.
The researchers also characterized how diverse those mutations were at diagnosis and relapse. They found that B-ALL cells were mutating just as wildly and diversely in one phase of disease as in the other.
“This finding was interesting, because most people think that the clone that has the most mutations is more likely to survive therapy and evolve, but that doesn’t seem to be the case,” Dr Zhang said.
In most cases, relapse was driven by a minor subclone that had survived therapy and was present at an extremely low level. The researchers said this finding suggests a need to change the way we assess patients after treatment to determine the likelihood of relapse.
“When we are analyzing for the level of minimum residual disease in monitoring remission in patients, we should not only pay attention to the mutations in the predominant clone,” Dr Zhang said. “We should also be tracking what kinds of mutations exist in the minor subclones.”
In tracing the clonal evolution of B-cell acute lymphoblastic leukemia (B-ALL) from diagnosis to relapse, researchers discovered that clonal diversity is comparable in both states.
They also identified mutations associated with B-ALL relapse and found that clonal survival is not dependent upon mutation burden.
In most of the cases the researchers analyzed, a single, minor clone survived therapy, acquired additional mutations, and drove disease relapse.
Jinghui Zhang, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and her colleagues recounted these findings in Nature Communications.
The researchers performed deep, whole-exome sequencing on cell samples from 20 young patients (ages 2 to 19) with relapsed B-ALL. The samples were collected at diagnosis, remission, and relapse.
“[W]e wanted to find out the underlying mechanism leading to cancer relapse,” Dr Zhang said. “When the cancer recurs, is it a completely different cancer, or is it an extension, or change, arising from pre-existing cancer?”
The researchers were able to detect the mutations in both the “rising” and “falling” clones—those that survive therapy and those that don’t—at the different disease stages and pinpoint the mutations that drove the leukemia.
Seven genes were highly likely to be mutated in relapsed disease—NT5C2, CREBBP, WHSC1, TP53, USH2A, NRAS, and IKZF1.
The researchers also characterized how diverse those mutations were at diagnosis and relapse. They found that B-ALL cells were mutating just as wildly and diversely in one phase of disease as in the other.
“This finding was interesting, because most people think that the clone that has the most mutations is more likely to survive therapy and evolve, but that doesn’t seem to be the case,” Dr Zhang said.
In most cases, relapse was driven by a minor subclone that had survived therapy and was present at an extremely low level. The researchers said this finding suggests a need to change the way we assess patients after treatment to determine the likelihood of relapse.
“When we are analyzing for the level of minimum residual disease in monitoring remission in patients, we should not only pay attention to the mutations in the predominant clone,” Dr Zhang said. “We should also be tracking what kinds of mutations exist in the minor subclones.”
Malaria interventions prove insufficient
Photo by James Gathany
Current malaria interventions are failing to control the disease in high-transmission areas of sub-Saharan Africa, according to research published in The American Journal of Tropical Medicine & Hygiene.
A 2-year surveillance study revealed that the incidence of malaria in rural Uganda is high and continues to rise.
Researchers said this study offers the most accurate, comprehensive, and up-to-date measurement of the malaria disease burden in Uganda.
“Our findings suggest that current efforts at controlling malaria may not be as effective as previously believed in high-transmission areas, where the disease is the biggest threat,” said Grant Dorsey, MD, PhD, of the University of California, San Francisco.
“It’s important to tell the less happy story that we have not yet seen advances in more rural areas, including at least 2 sites in Uganda, where transmission has been historically high.”
To reach an accurate assessment of the malaria incidence in Uganda, Dr Dorsey and his colleagues gathered comprehensive surveillance data over 24 months, from August 2011 to September 2013.
Ultimately, the team evaluated 703 children between the ages of 6 months and 10 years. The children were randomly selected from 3 areas of Uganda with differing malaria characteristics.
The researchers found the incidence of malaria infection decreased in the relatively low-transmission, peri-urban Walukuba area during the study period—from an average of 0.51 to 0.31 episodes of malaria per person per year (P=0.001).
However, the incidence increased in the 2 rural areas. Episodes of malaria per person per year rose from an average of 0.97 to 1.93 (P<0.001) in the moderate-transmission area of Kihihi and rose from an average of 2.33 to 3.30 (P<0.001) in Nagongera, a high-transmission rural area near the southeastern border with Kenya.
Throughout the study period, families were provided with bednets and had access to 24-hour medical care free of charge at a designated study clinic for episodes of fever. The children were also routinely tested for malaria every 3 months, whether they had symptoms or not.
In addition, the researchers collected mosquito specimens monthly from light traps that were strategically placed in each house to estimate the percentages of malaria-carrying mosquitoes in the study areas.
Healthcare workers provided over 2500 treatments for malaria over the course of the study.
“Children in our study experienced a significantly high rate of infection, and that rate increased in the 2 rural areas,” Dr Dorsey said. “Based on prior data, our higher transmission sites are very likely to be representative of most of Uganda and perhaps of most other rural areas in sub-Saharan Africa as well.”
The researchers said these results suggest a need to further scale up campaigns to distribute insecticide-treated bednets and spray homes with insecticides. And high-transmission countries like Uganda may also require new interventions, such as using malaria drugs for prevention and controlling mosquito larvae, in order to match the malaria reduction successes seen elsewhere in the world.
In a related editorial, Steven Meshnick, MD, PhD, of the University of North Carolina, Chapel Hill, wrote, “The real take-home message of this study may be that malaria control in Africa requires sustained and consistent efforts over much more than 2 years.”
Photo by James Gathany
Current malaria interventions are failing to control the disease in high-transmission areas of sub-Saharan Africa, according to research published in The American Journal of Tropical Medicine & Hygiene.
A 2-year surveillance study revealed that the incidence of malaria in rural Uganda is high and continues to rise.
Researchers said this study offers the most accurate, comprehensive, and up-to-date measurement of the malaria disease burden in Uganda.
“Our findings suggest that current efforts at controlling malaria may not be as effective as previously believed in high-transmission areas, where the disease is the biggest threat,” said Grant Dorsey, MD, PhD, of the University of California, San Francisco.
“It’s important to tell the less happy story that we have not yet seen advances in more rural areas, including at least 2 sites in Uganda, where transmission has been historically high.”
To reach an accurate assessment of the malaria incidence in Uganda, Dr Dorsey and his colleagues gathered comprehensive surveillance data over 24 months, from August 2011 to September 2013.
Ultimately, the team evaluated 703 children between the ages of 6 months and 10 years. The children were randomly selected from 3 areas of Uganda with differing malaria characteristics.
The researchers found the incidence of malaria infection decreased in the relatively low-transmission, peri-urban Walukuba area during the study period—from an average of 0.51 to 0.31 episodes of malaria per person per year (P=0.001).
However, the incidence increased in the 2 rural areas. Episodes of malaria per person per year rose from an average of 0.97 to 1.93 (P<0.001) in the moderate-transmission area of Kihihi and rose from an average of 2.33 to 3.30 (P<0.001) in Nagongera, a high-transmission rural area near the southeastern border with Kenya.
Throughout the study period, families were provided with bednets and had access to 24-hour medical care free of charge at a designated study clinic for episodes of fever. The children were also routinely tested for malaria every 3 months, whether they had symptoms or not.
In addition, the researchers collected mosquito specimens monthly from light traps that were strategically placed in each house to estimate the percentages of malaria-carrying mosquitoes in the study areas.
Healthcare workers provided over 2500 treatments for malaria over the course of the study.
“Children in our study experienced a significantly high rate of infection, and that rate increased in the 2 rural areas,” Dr Dorsey said. “Based on prior data, our higher transmission sites are very likely to be representative of most of Uganda and perhaps of most other rural areas in sub-Saharan Africa as well.”
The researchers said these results suggest a need to further scale up campaigns to distribute insecticide-treated bednets and spray homes with insecticides. And high-transmission countries like Uganda may also require new interventions, such as using malaria drugs for prevention and controlling mosquito larvae, in order to match the malaria reduction successes seen elsewhere in the world.
In a related editorial, Steven Meshnick, MD, PhD, of the University of North Carolina, Chapel Hill, wrote, “The real take-home message of this study may be that malaria control in Africa requires sustained and consistent efforts over much more than 2 years.”
Photo by James Gathany
Current malaria interventions are failing to control the disease in high-transmission areas of sub-Saharan Africa, according to research published in The American Journal of Tropical Medicine & Hygiene.
A 2-year surveillance study revealed that the incidence of malaria in rural Uganda is high and continues to rise.
Researchers said this study offers the most accurate, comprehensive, and up-to-date measurement of the malaria disease burden in Uganda.
“Our findings suggest that current efforts at controlling malaria may not be as effective as previously believed in high-transmission areas, where the disease is the biggest threat,” said Grant Dorsey, MD, PhD, of the University of California, San Francisco.
“It’s important to tell the less happy story that we have not yet seen advances in more rural areas, including at least 2 sites in Uganda, where transmission has been historically high.”
To reach an accurate assessment of the malaria incidence in Uganda, Dr Dorsey and his colleagues gathered comprehensive surveillance data over 24 months, from August 2011 to September 2013.
Ultimately, the team evaluated 703 children between the ages of 6 months and 10 years. The children were randomly selected from 3 areas of Uganda with differing malaria characteristics.
The researchers found the incidence of malaria infection decreased in the relatively low-transmission, peri-urban Walukuba area during the study period—from an average of 0.51 to 0.31 episodes of malaria per person per year (P=0.001).
However, the incidence increased in the 2 rural areas. Episodes of malaria per person per year rose from an average of 0.97 to 1.93 (P<0.001) in the moderate-transmission area of Kihihi and rose from an average of 2.33 to 3.30 (P<0.001) in Nagongera, a high-transmission rural area near the southeastern border with Kenya.
Throughout the study period, families were provided with bednets and had access to 24-hour medical care free of charge at a designated study clinic for episodes of fever. The children were also routinely tested for malaria every 3 months, whether they had symptoms or not.
In addition, the researchers collected mosquito specimens monthly from light traps that were strategically placed in each house to estimate the percentages of malaria-carrying mosquitoes in the study areas.
Healthcare workers provided over 2500 treatments for malaria over the course of the study.
“Children in our study experienced a significantly high rate of infection, and that rate increased in the 2 rural areas,” Dr Dorsey said. “Based on prior data, our higher transmission sites are very likely to be representative of most of Uganda and perhaps of most other rural areas in sub-Saharan Africa as well.”
The researchers said these results suggest a need to further scale up campaigns to distribute insecticide-treated bednets and spray homes with insecticides. And high-transmission countries like Uganda may also require new interventions, such as using malaria drugs for prevention and controlling mosquito larvae, in order to match the malaria reduction successes seen elsewhere in the world.
In a related editorial, Steven Meshnick, MD, PhD, of the University of North Carolina, Chapel Hill, wrote, “The real take-home message of this study may be that malaria control in Africa requires sustained and consistent efforts over much more than 2 years.”
Drug appears feasible for hard-to-treat myelofibrosis
myelofibrosis
Results of a phase 2 study suggest the JAK2/FLT3 inhibitor pacritinib is a feasible treatment option for patients with myelofibrosis who cannot receive or do not respond well to standard therapies.
The drug reduced patients’ spleen volume and improved disease-related symptoms without causing clinically significant myelosuppression.
And pacritinib was considered well-tolerated, even in patients with disease-related anemia and thrombocytopenia.
“Currently, myelofibrosis patients with anemia and thrombocytopenia have limited treatment options for splenomegaly and constitutional symptoms, and
these data show that pacritinib has potential to help patients that are sub-optimally managed on currently available treatments,” said study author Rami S. Komrokji, MD, of the Moffitt Cancer Center in Tampa, Florida.
Dr Komrokji and his colleagues reported these results in Blood. The study was sponsored by CTI Biopharma, the company developing pacritinib.
The researchers evaluated the safety and efficacy of pacritinib in myelofibrosis patients who had clinical splenomegaly that was poorly controlled with standard therapies or who were newly diagnosed with intermediate- or high-risk disease and not considered candidates for standard therapy.
Patients were allowed to enroll irrespective of their degree of thrombocytopenia or anemia. At study entry, 40% of patients had hemoglobin levels below 10 g/dL, and 43% had platelet counts less than 100,000/µL.
A total of 35 patients were enrolled and treated with pacritinib administered at 400 mg once daily in 28-day cycles. The patients’ median age was 69 years.
The primary endpoint was assessment of the spleen response rate, defined as the proportion of subjects achieving 35% or greater reduction in spleen volume from baseline up to week 24, measured by MRI or CT.
A secondary endpoint was the proportion of patients with a 50% or greater reduction in spleen size as determined by physical exam.
The researchers also assessed the proportion of patients with a 50% or greater reduction in total symptom score, which included symptoms of abdominal pain,
bone pain, early satiety, fatigue, inactivity, night sweats, and pruritus, from baseline up to week 24.
Results showed that 30.8% of the evaluable patients (8/26) had a 35% or greater reduction in spleen volume by CT or MRI scan, with 42% of patients reaching a
35% or greater reduction by the end of treatment.
In addition, 42.4% of evaluable patients (14/33) achieved a 50% or greater reduction in spleen size by physical exam. And 48.4% of evaluable patients (15/31) achieved a 50% or greater reduction in total symptom score.
The most common treatment-emergent adverse events were grade 1-2 diarrhea (69%) and nausea (49%). Anemia and thrombocytopenia adverse events were reported in 12 (34.3%) and 8 (22.9%) patients, respectively.
Nine patients (26%) stopped taking pacritinib due to adverse events, but 3 of the events were deemed unrelated to the drug.
There were 5 deaths, 3 of which were due to serious adverse events. Of those, 1 (subdural hematoma) was considered possibly related to pacritinib treatment.
myelofibrosis
Results of a phase 2 study suggest the JAK2/FLT3 inhibitor pacritinib is a feasible treatment option for patients with myelofibrosis who cannot receive or do not respond well to standard therapies.
The drug reduced patients’ spleen volume and improved disease-related symptoms without causing clinically significant myelosuppression.
And pacritinib was considered well-tolerated, even in patients with disease-related anemia and thrombocytopenia.
“Currently, myelofibrosis patients with anemia and thrombocytopenia have limited treatment options for splenomegaly and constitutional symptoms, and
these data show that pacritinib has potential to help patients that are sub-optimally managed on currently available treatments,” said study author Rami S. Komrokji, MD, of the Moffitt Cancer Center in Tampa, Florida.
Dr Komrokji and his colleagues reported these results in Blood. The study was sponsored by CTI Biopharma, the company developing pacritinib.
The researchers evaluated the safety and efficacy of pacritinib in myelofibrosis patients who had clinical splenomegaly that was poorly controlled with standard therapies or who were newly diagnosed with intermediate- or high-risk disease and not considered candidates for standard therapy.
Patients were allowed to enroll irrespective of their degree of thrombocytopenia or anemia. At study entry, 40% of patients had hemoglobin levels below 10 g/dL, and 43% had platelet counts less than 100,000/µL.
A total of 35 patients were enrolled and treated with pacritinib administered at 400 mg once daily in 28-day cycles. The patients’ median age was 69 years.
The primary endpoint was assessment of the spleen response rate, defined as the proportion of subjects achieving 35% or greater reduction in spleen volume from baseline up to week 24, measured by MRI or CT.
A secondary endpoint was the proportion of patients with a 50% or greater reduction in spleen size as determined by physical exam.
The researchers also assessed the proportion of patients with a 50% or greater reduction in total symptom score, which included symptoms of abdominal pain,
bone pain, early satiety, fatigue, inactivity, night sweats, and pruritus, from baseline up to week 24.
Results showed that 30.8% of the evaluable patients (8/26) had a 35% or greater reduction in spleen volume by CT or MRI scan, with 42% of patients reaching a
35% or greater reduction by the end of treatment.
In addition, 42.4% of evaluable patients (14/33) achieved a 50% or greater reduction in spleen size by physical exam. And 48.4% of evaluable patients (15/31) achieved a 50% or greater reduction in total symptom score.
The most common treatment-emergent adverse events were grade 1-2 diarrhea (69%) and nausea (49%). Anemia and thrombocytopenia adverse events were reported in 12 (34.3%) and 8 (22.9%) patients, respectively.
Nine patients (26%) stopped taking pacritinib due to adverse events, but 3 of the events were deemed unrelated to the drug.
There were 5 deaths, 3 of which were due to serious adverse events. Of those, 1 (subdural hematoma) was considered possibly related to pacritinib treatment.
myelofibrosis
Results of a phase 2 study suggest the JAK2/FLT3 inhibitor pacritinib is a feasible treatment option for patients with myelofibrosis who cannot receive or do not respond well to standard therapies.
The drug reduced patients’ spleen volume and improved disease-related symptoms without causing clinically significant myelosuppression.
And pacritinib was considered well-tolerated, even in patients with disease-related anemia and thrombocytopenia.
“Currently, myelofibrosis patients with anemia and thrombocytopenia have limited treatment options for splenomegaly and constitutional symptoms, and
these data show that pacritinib has potential to help patients that are sub-optimally managed on currently available treatments,” said study author Rami S. Komrokji, MD, of the Moffitt Cancer Center in Tampa, Florida.
Dr Komrokji and his colleagues reported these results in Blood. The study was sponsored by CTI Biopharma, the company developing pacritinib.
The researchers evaluated the safety and efficacy of pacritinib in myelofibrosis patients who had clinical splenomegaly that was poorly controlled with standard therapies or who were newly diagnosed with intermediate- or high-risk disease and not considered candidates for standard therapy.
Patients were allowed to enroll irrespective of their degree of thrombocytopenia or anemia. At study entry, 40% of patients had hemoglobin levels below 10 g/dL, and 43% had platelet counts less than 100,000/µL.
A total of 35 patients were enrolled and treated with pacritinib administered at 400 mg once daily in 28-day cycles. The patients’ median age was 69 years.
The primary endpoint was assessment of the spleen response rate, defined as the proportion of subjects achieving 35% or greater reduction in spleen volume from baseline up to week 24, measured by MRI or CT.
A secondary endpoint was the proportion of patients with a 50% or greater reduction in spleen size as determined by physical exam.
The researchers also assessed the proportion of patients with a 50% or greater reduction in total symptom score, which included symptoms of abdominal pain,
bone pain, early satiety, fatigue, inactivity, night sweats, and pruritus, from baseline up to week 24.
Results showed that 30.8% of the evaluable patients (8/26) had a 35% or greater reduction in spleen volume by CT or MRI scan, with 42% of patients reaching a
35% or greater reduction by the end of treatment.
In addition, 42.4% of evaluable patients (14/33) achieved a 50% or greater reduction in spleen size by physical exam. And 48.4% of evaluable patients (15/31) achieved a 50% or greater reduction in total symptom score.
The most common treatment-emergent adverse events were grade 1-2 diarrhea (69%) and nausea (49%). Anemia and thrombocytopenia adverse events were reported in 12 (34.3%) and 8 (22.9%) patients, respectively.
Nine patients (26%) stopped taking pacritinib due to adverse events, but 3 of the events were deemed unrelated to the drug.
There were 5 deaths, 3 of which were due to serious adverse events. Of those, 1 (subdural hematoma) was considered possibly related to pacritinib treatment.
Experts urge review of global sepsis guidelines
Investigators are calling for a global review of guidelines used to diagnose sepsis, after a study showed that 1 in 8 patients with infections severe enough to necessitate admission to an intensive care unit did not meet current diagnostic criteria.
The researchers identified 109,663 patients with possible sepsis who had infection and organ failure. However, more than 13,000 patients from this group did not meet the classic criteria used to diagnose sepsis.
“To be diagnosed with sepsis, a patient must be thought to have an infection and exhibit at least 2 of the following criteria: abnormal body temperature or white blood cell count, high heart rate, high respiratory rate, or low carbon dioxide level in the blood,” said Maija Kaukonen, MD, PhD, of Monash University in Melbourne, Victoria, Australia.
“But our study found that many patients—for example, the elderly or those on medications that affect heart rate or the immune system—may not meet the classic criteria to diagnose sepsis, despite having severe infections and organ failure. If we continue to use these criteria, we may miss the opportunity to identify many critically ill patients with sepsis.”
The study was published in NEJM.
The investigators studied 1,171,797 patients from 172 intensive care units in New Zealand and Australia.
The team identified patients with infection and organ failure and categorized them according to whether they had signs meeting 2 or more systemic inflammatory response syndrome (SIRS) criteria (SIRS-positive severe sepsis) or less than 2 SIRS criteria (SIRS-negative severe sepsis).
Of the 109,663 patients who had infection and organ failure, 96,385 (87.9%) had SIRS-positive severe sepsis and 13,278 (12.1%) had SIRS-negative severe sepsis.
Over 14 years, the 2 patient groups had similar characteristics and changes in mortality. Mortality decreased from 36.1% (829/2296) to 18.3% (2037/11,119) in the SIRS-positive group (P<0.001) and from 27.7% (100/361) to 9.3% (122/1315) in the SIRS-negative group (P<0.001).
This similarity between the groups remained after the researchers adjusted their analysis for baseline characteristics. In both groups, the odds ratio was 0.96 (P=0.12).
The investigators also noted that, in the adjusted analysis, mortality increased linearly with each additional SIRS criterion (P<0.001), without any transitional increase in risk at a threshold of 2 SIRS criteria.
Rinaldo Bellomo, MD, PhD, also of Monash University, conceived this study. He said that although the classic definition of sepsis has been widely used throughout the world, he believed that, after 20 years, it was time for it to be reviewed.
“There are clear signs from this study that if we continue to use these criteria, we may fail to identify septic patients and, therefore, potentially delay their treatment,” he said.
Investigators are calling for a global review of guidelines used to diagnose sepsis, after a study showed that 1 in 8 patients with infections severe enough to necessitate admission to an intensive care unit did not meet current diagnostic criteria.
The researchers identified 109,663 patients with possible sepsis who had infection and organ failure. However, more than 13,000 patients from this group did not meet the classic criteria used to diagnose sepsis.
“To be diagnosed with sepsis, a patient must be thought to have an infection and exhibit at least 2 of the following criteria: abnormal body temperature or white blood cell count, high heart rate, high respiratory rate, or low carbon dioxide level in the blood,” said Maija Kaukonen, MD, PhD, of Monash University in Melbourne, Victoria, Australia.
“But our study found that many patients—for example, the elderly or those on medications that affect heart rate or the immune system—may not meet the classic criteria to diagnose sepsis, despite having severe infections and organ failure. If we continue to use these criteria, we may miss the opportunity to identify many critically ill patients with sepsis.”
The study was published in NEJM.
The investigators studied 1,171,797 patients from 172 intensive care units in New Zealand and Australia.
The team identified patients with infection and organ failure and categorized them according to whether they had signs meeting 2 or more systemic inflammatory response syndrome (SIRS) criteria (SIRS-positive severe sepsis) or less than 2 SIRS criteria (SIRS-negative severe sepsis).
Of the 109,663 patients who had infection and organ failure, 96,385 (87.9%) had SIRS-positive severe sepsis and 13,278 (12.1%) had SIRS-negative severe sepsis.
Over 14 years, the 2 patient groups had similar characteristics and changes in mortality. Mortality decreased from 36.1% (829/2296) to 18.3% (2037/11,119) in the SIRS-positive group (P<0.001) and from 27.7% (100/361) to 9.3% (122/1315) in the SIRS-negative group (P<0.001).
This similarity between the groups remained after the researchers adjusted their analysis for baseline characteristics. In both groups, the odds ratio was 0.96 (P=0.12).
The investigators also noted that, in the adjusted analysis, mortality increased linearly with each additional SIRS criterion (P<0.001), without any transitional increase in risk at a threshold of 2 SIRS criteria.
Rinaldo Bellomo, MD, PhD, also of Monash University, conceived this study. He said that although the classic definition of sepsis has been widely used throughout the world, he believed that, after 20 years, it was time for it to be reviewed.
“There are clear signs from this study that if we continue to use these criteria, we may fail to identify septic patients and, therefore, potentially delay their treatment,” he said.
Investigators are calling for a global review of guidelines used to diagnose sepsis, after a study showed that 1 in 8 patients with infections severe enough to necessitate admission to an intensive care unit did not meet current diagnostic criteria.
The researchers identified 109,663 patients with possible sepsis who had infection and organ failure. However, more than 13,000 patients from this group did not meet the classic criteria used to diagnose sepsis.
“To be diagnosed with sepsis, a patient must be thought to have an infection and exhibit at least 2 of the following criteria: abnormal body temperature or white blood cell count, high heart rate, high respiratory rate, or low carbon dioxide level in the blood,” said Maija Kaukonen, MD, PhD, of Monash University in Melbourne, Victoria, Australia.
“But our study found that many patients—for example, the elderly or those on medications that affect heart rate or the immune system—may not meet the classic criteria to diagnose sepsis, despite having severe infections and organ failure. If we continue to use these criteria, we may miss the opportunity to identify many critically ill patients with sepsis.”
The study was published in NEJM.
The investigators studied 1,171,797 patients from 172 intensive care units in New Zealand and Australia.
The team identified patients with infection and organ failure and categorized them according to whether they had signs meeting 2 or more systemic inflammatory response syndrome (SIRS) criteria (SIRS-positive severe sepsis) or less than 2 SIRS criteria (SIRS-negative severe sepsis).
Of the 109,663 patients who had infection and organ failure, 96,385 (87.9%) had SIRS-positive severe sepsis and 13,278 (12.1%) had SIRS-negative severe sepsis.
Over 14 years, the 2 patient groups had similar characteristics and changes in mortality. Mortality decreased from 36.1% (829/2296) to 18.3% (2037/11,119) in the SIRS-positive group (P<0.001) and from 27.7% (100/361) to 9.3% (122/1315) in the SIRS-negative group (P<0.001).
This similarity between the groups remained after the researchers adjusted their analysis for baseline characteristics. In both groups, the odds ratio was 0.96 (P=0.12).
The investigators also noted that, in the adjusted analysis, mortality increased linearly with each additional SIRS criterion (P<0.001), without any transitional increase in risk at a threshold of 2 SIRS criteria.
Rinaldo Bellomo, MD, PhD, also of Monash University, conceived this study. He said that although the classic definition of sepsis has been widely used throughout the world, he believed that, after 20 years, it was time for it to be reviewed.
“There are clear signs from this study that if we continue to use these criteria, we may fail to identify septic patients and, therefore, potentially delay their treatment,” he said.