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New recommendations for pediatric AMKL
Image courtesy of St. Jude
Children’s Research Hospital
and Tina Motroni
Research has revealed genetic alterations that may prove useful for predicting treatment outcomes in pediatric patients with acute megakaryoblastic leukemia (AMKL) who do not have Down syndrome.
The study suggests that 3
genetic alterations can be used to identify high-risk patients who may benefit
from allogeneic stem cell transplant, and 1 alteration may identify
low-risk patients who require less chemotherapy than their peers.
Researchers said these findings, published in Nature Genetics, support revised diagnostic screening and treatment recommendations for pediatric AMKL.
“Because long-term survival for pediatric AMKL patients without Down syndrome is poor, just 14% to 34%, the standard recommendation by many pediatric oncologists has been to treat all patients with allogeneic stem cell transplantation during their first remission,” said study author Tanja Gruber, MD, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
“In this study, we identified several genetic alterations that are important predictors of treatment success. All newly identified pediatric AMKL patients without Down syndrome should be screened for these prognostic indicators at diagnosis. The results will help identify which patients need allogeneic stem cell transplants during their first remission and which do not.”
This study involved next-generation sequencing of the whole exome or RNA of 99 AMKL patients without Down syndrome (75 pediatric and 24 adult patients). Along with the sequencing data, researchers analyzed patients’ gene expression and long-term survival.
Results
The results showed that non-Down syndrome pediatric AMKL can be divided into 7 subgroups based on the underlying genetic alteration, pattern of gene expression, and treatment outcome.
The subgroups include the newly identified HOX subgroup. About 15% of the pediatric patients in this study were in the HOX subgroup, which is characterized by several different HOX fusion genes.
The researchers also identified cooperating mutations that help fuel AMKL in different subgroups. The cooperating mutations include changes in the RB1 gene and recurring mutations in the RAS and JAK pathways.
In addition, the study showed that 3 genetic alterations—CBFA2T3-GLIS2, KMT2A rearrangements, and NUP98-KDM5A—are associated with reduced survival in pediatric AMKL subtypes.
The researchers said patients with these alterations may benefit from allogeneic stem cell transplants, so non-Down syndrome pediatric AMKL patients should be screened for these alterations at diagnosis.
The team also recommended testing AMKL patients for mutations in the GATA1 gene. GATA1 mutations are a hallmark of AMKL in children with Down syndrome, who almost always survive the leukemia. In this study, AMKL patients with GATA1 mutations and no fusion gene had the same favorable outcomes.
“The results raise the possibility that pediatric AMKL patients without Down syndrome who have mutations in GATA1 may benefit from the same reduced chemotherapy used to treat the leukemia in patients with Down syndrome,” Dr Gruber said.
These revised diagnostic screening and treatment recommendations are being implemented at St. Jude.
This study also showed that adults with AMKL lacked recurrent fusion genes. The most common mutations found in the adult patients were in TP53 (21%), cohesin genes (17%), splicing factor genes (17%), ASXL genes (17%), and DNMT3A (13%). About 4% had GATA1 mutations. 
Image courtesy of St. Jude
Children’s Research Hospital
and Tina Motroni
Research has revealed genetic alterations that may prove useful for predicting treatment outcomes in pediatric patients with acute megakaryoblastic leukemia (AMKL) who do not have Down syndrome.
The study suggests that 3
genetic alterations can be used to identify high-risk patients who may benefit
from allogeneic stem cell transplant, and 1 alteration may identify
low-risk patients who require less chemotherapy than their peers.
Researchers said these findings, published in Nature Genetics, support revised diagnostic screening and treatment recommendations for pediatric AMKL.
“Because long-term survival for pediatric AMKL patients without Down syndrome is poor, just 14% to 34%, the standard recommendation by many pediatric oncologists has been to treat all patients with allogeneic stem cell transplantation during their first remission,” said study author Tanja Gruber, MD, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
“In this study, we identified several genetic alterations that are important predictors of treatment success. All newly identified pediatric AMKL patients without Down syndrome should be screened for these prognostic indicators at diagnosis. The results will help identify which patients need allogeneic stem cell transplants during their first remission and which do not.”
This study involved next-generation sequencing of the whole exome or RNA of 99 AMKL patients without Down syndrome (75 pediatric and 24 adult patients). Along with the sequencing data, researchers analyzed patients’ gene expression and long-term survival.
Results
The results showed that non-Down syndrome pediatric AMKL can be divided into 7 subgroups based on the underlying genetic alteration, pattern of gene expression, and treatment outcome.
The subgroups include the newly identified HOX subgroup. About 15% of the pediatric patients in this study were in the HOX subgroup, which is characterized by several different HOX fusion genes.
The researchers also identified cooperating mutations that help fuel AMKL in different subgroups. The cooperating mutations include changes in the RB1 gene and recurring mutations in the RAS and JAK pathways.
In addition, the study showed that 3 genetic alterations—CBFA2T3-GLIS2, KMT2A rearrangements, and NUP98-KDM5A—are associated with reduced survival in pediatric AMKL subtypes.
The researchers said patients with these alterations may benefit from allogeneic stem cell transplants, so non-Down syndrome pediatric AMKL patients should be screened for these alterations at diagnosis.
The team also recommended testing AMKL patients for mutations in the GATA1 gene. GATA1 mutations are a hallmark of AMKL in children with Down syndrome, who almost always survive the leukemia. In this study, AMKL patients with GATA1 mutations and no fusion gene had the same favorable outcomes.
“The results raise the possibility that pediatric AMKL patients without Down syndrome who have mutations in GATA1 may benefit from the same reduced chemotherapy used to treat the leukemia in patients with Down syndrome,” Dr Gruber said.
These revised diagnostic screening and treatment recommendations are being implemented at St. Jude.
This study also showed that adults with AMKL lacked recurrent fusion genes. The most common mutations found in the adult patients were in TP53 (21%), cohesin genes (17%), splicing factor genes (17%), ASXL genes (17%), and DNMT3A (13%). About 4% had GATA1 mutations.
Image courtesy of St. Jude
Children’s Research Hospital
and Tina Motroni
Research has revealed genetic alterations that may prove useful for predicting treatment outcomes in pediatric patients with acute megakaryoblastic leukemia (AMKL) who do not have Down syndrome.
The study suggests that 3
genetic alterations can be used to identify high-risk patients who may benefit
from allogeneic stem cell transplant, and 1 alteration may identify
low-risk patients who require less chemotherapy than their peers.
Researchers said these findings, published in Nature Genetics, support revised diagnostic screening and treatment recommendations for pediatric AMKL.
“Because long-term survival for pediatric AMKL patients without Down syndrome is poor, just 14% to 34%, the standard recommendation by many pediatric oncologists has been to treat all patients with allogeneic stem cell transplantation during their first remission,” said study author Tanja Gruber, MD, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
“In this study, we identified several genetic alterations that are important predictors of treatment success. All newly identified pediatric AMKL patients without Down syndrome should be screened for these prognostic indicators at diagnosis. The results will help identify which patients need allogeneic stem cell transplants during their first remission and which do not.”
This study involved next-generation sequencing of the whole exome or RNA of 99 AMKL patients without Down syndrome (75 pediatric and 24 adult patients). Along with the sequencing data, researchers analyzed patients’ gene expression and long-term survival.
Results
The results showed that non-Down syndrome pediatric AMKL can be divided into 7 subgroups based on the underlying genetic alteration, pattern of gene expression, and treatment outcome.
The subgroups include the newly identified HOX subgroup. About 15% of the pediatric patients in this study were in the HOX subgroup, which is characterized by several different HOX fusion genes.
The researchers also identified cooperating mutations that help fuel AMKL in different subgroups. The cooperating mutations include changes in the RB1 gene and recurring mutations in the RAS and JAK pathways.
In addition, the study showed that 3 genetic alterations—CBFA2T3-GLIS2, KMT2A rearrangements, and NUP98-KDM5A—are associated with reduced survival in pediatric AMKL subtypes.
The researchers said patients with these alterations may benefit from allogeneic stem cell transplants, so non-Down syndrome pediatric AMKL patients should be screened for these alterations at diagnosis.
The team also recommended testing AMKL patients for mutations in the GATA1 gene. GATA1 mutations are a hallmark of AMKL in children with Down syndrome, who almost always survive the leukemia. In this study, AMKL patients with GATA1 mutations and no fusion gene had the same favorable outcomes.
“The results raise the possibility that pediatric AMKL patients without Down syndrome who have mutations in GATA1 may benefit from the same reduced chemotherapy used to treat the leukemia in patients with Down syndrome,” Dr Gruber said.
These revised diagnostic screening and treatment recommendations are being implemented at St. Jude.
This study also showed that adults with AMKL lacked recurrent fusion genes. The most common mutations found in the adult patients were in TP53 (21%), cohesin genes (17%), splicing factor genes (17%), ASXL genes (17%), and DNMT3A (13%). About 4% had GATA1 mutations.
What Do Parasites Have to Do With Leukemia?
Parasites have been shown to have both pro- and antitumor effects. Malaria parasites (Plasmodium spp) are among those known to have this possible “bidirectional role” in carcinogenesis, say researchers from Aix-Marseille Université in France. They reviewed the current thinking on whether malaria—a worldwide killer—can be useful in cancer prevention and treatment.
Positive relationships between malaria and virus-associated cancers are relatively well documented, the researchers say. Evidence suggests that malaria can alter immune responses by modulating both humoral and cell-mediated immunity. Plasmodium-related cancers are primarily lymphoproliferative, vulnerable to virus reactivation. Epstein-Barr virus (EBV), for example, has been observed in lymphatic and hematologic tumors such as Hodgkin disease and T cell lymphoma, and malaria can reactivate EBV.
In animal studies, malarial infection with Plasmodium berghei (P berghei) increased the rate of spontaneous leukemia. In one study, concurrent infection with P berghei increased the incidence of malignant lymphoma in mice injected with Moloney leukemogenic virus.
On the other hand, Plasmodium spp also produces proteins that demonstrate certain anti-oncogenic effects, they note. The researchers suggest that using proteins in cancer treatment should be explored, adding that it’s a “safer approach than the inoculation of wild type Plasmodium.” Positive parasite-induced effects against cancers of the hematopoietic and lymphoid tissues are mentioned only for 2 species and those only in a decades-old study. Based on current knowledge, the researchers say, the antitumor effects observed are attributable to modifications to the host immune response. Thus, their characteristics and locations within the host can be highly diverse.
All in all, the researchers conclude, the growing evidence is opening intriguing pathways for using one ill to cure another.
Source:
Faure E. Parasitology. 2016;143(14):1811-1823.
Parasites have been shown to have both pro- and antitumor effects. Malaria parasites (Plasmodium spp) are among those known to have this possible “bidirectional role” in carcinogenesis, say researchers from Aix-Marseille Université in France. They reviewed the current thinking on whether malaria—a worldwide killer—can be useful in cancer prevention and treatment.
Positive relationships between malaria and virus-associated cancers are relatively well documented, the researchers say. Evidence suggests that malaria can alter immune responses by modulating both humoral and cell-mediated immunity. Plasmodium-related cancers are primarily lymphoproliferative, vulnerable to virus reactivation. Epstein-Barr virus (EBV), for example, has been observed in lymphatic and hematologic tumors such as Hodgkin disease and T cell lymphoma, and malaria can reactivate EBV.
In animal studies, malarial infection with Plasmodium berghei (P berghei) increased the rate of spontaneous leukemia. In one study, concurrent infection with P berghei increased the incidence of malignant lymphoma in mice injected with Moloney leukemogenic virus.
On the other hand, Plasmodium spp also produces proteins that demonstrate certain anti-oncogenic effects, they note. The researchers suggest that using proteins in cancer treatment should be explored, adding that it’s a “safer approach than the inoculation of wild type Plasmodium.” Positive parasite-induced effects against cancers of the hematopoietic and lymphoid tissues are mentioned only for 2 species and those only in a decades-old study. Based on current knowledge, the researchers say, the antitumor effects observed are attributable to modifications to the host immune response. Thus, their characteristics and locations within the host can be highly diverse.
All in all, the researchers conclude, the growing evidence is opening intriguing pathways for using one ill to cure another.
Source:
Faure E. Parasitology. 2016;143(14):1811-1823.
Parasites have been shown to have both pro- and antitumor effects. Malaria parasites (Plasmodium spp) are among those known to have this possible “bidirectional role” in carcinogenesis, say researchers from Aix-Marseille Université in France. They reviewed the current thinking on whether malaria—a worldwide killer—can be useful in cancer prevention and treatment.
Positive relationships between malaria and virus-associated cancers are relatively well documented, the researchers say. Evidence suggests that malaria can alter immune responses by modulating both humoral and cell-mediated immunity. Plasmodium-related cancers are primarily lymphoproliferative, vulnerable to virus reactivation. Epstein-Barr virus (EBV), for example, has been observed in lymphatic and hematologic tumors such as Hodgkin disease and T cell lymphoma, and malaria can reactivate EBV.
In animal studies, malarial infection with Plasmodium berghei (P berghei) increased the rate of spontaneous leukemia. In one study, concurrent infection with P berghei increased the incidence of malignant lymphoma in mice injected with Moloney leukemogenic virus.
On the other hand, Plasmodium spp also produces proteins that demonstrate certain anti-oncogenic effects, they note. The researchers suggest that using proteins in cancer treatment should be explored, adding that it’s a “safer approach than the inoculation of wild type Plasmodium.” Positive parasite-induced effects against cancers of the hematopoietic and lymphoid tissues are mentioned only for 2 species and those only in a decades-old study. Based on current knowledge, the researchers say, the antitumor effects observed are attributable to modifications to the host immune response. Thus, their characteristics and locations within the host can be highly diverse.
All in all, the researchers conclude, the growing evidence is opening intriguing pathways for using one ill to cure another.
Source:
Faure E. Parasitology. 2016;143(14):1811-1823.
Treat Hypothyroid Conditions
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Founder, Metabolic Medicine Associates, King George, Va
Founder, Metabolic Medicine Associates, King George, Va
Founder, Metabolic Medicine Associates, King George, Va
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Finding the Sweet Spot: The Diabetic Kidney
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American Academy of Nephrology PAs, Oceanside, Calif
American Academy of Nephrology PAs, Oceanside, Calif
American Academy of Nephrology PAs, Oceanside, Calif
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Dabigatran has less bleeding than rivaroxaban in atrial fibrillation
Clinical question: Does dabigatran or rivaroxaban have more bleeding episodes?
Background: Alternatives to warfarin exist for stroke prevention in nonvalvular atrial fibrillation (AF). The RE-LY and ROCKET-AF trials demonstrated noninferiority to warfarin for both dabigatran (a direct thrombin inhibitor) and rivaroxaban (a factor Xa inhibitor), respectively. Although indirect comparisons have been done using data from these trials, direct, head-to-head comparisons are not available.
Study design: New-user cohort study.
Setting: Medicare beneficiaries 65 years or older with AF and a prescription for either dabigatran or rivaroxaban.
Intracranial hemorrhage and extracranial major bleeding events were significantly greater in the rivaroxaban group than the dabigatran group. There was no significant difference in thromboembolic stroke events.
Limitations include short treatment and follow-up times. Additionally, the study is not generalizable to younger populations.
Bottom line: In elderly patients with non-valvular AF, rivaroxaban was associated with more adverse bleeding events than dabigatran, with no difference in stroke prevention.
Citation: Graham DJ, Reichman ME, Wernecke M, et al. Stroke, bleeding, and mortality risks in elderly Medicare beneficiaries treated with dabigatran or rivaroxaban for nonvalvular atrial fibrillation. JAMA Intern Med. 2016;176:1662-71.
Dr. Graves is an assistant professor at the University of Utah School of Medicine and associate program director of quality and patient safety for the University of Utah Internal Medicine residency training program.
Clinical question: Does dabigatran or rivaroxaban have more bleeding episodes?
Background: Alternatives to warfarin exist for stroke prevention in nonvalvular atrial fibrillation (AF). The RE-LY and ROCKET-AF trials demonstrated noninferiority to warfarin for both dabigatran (a direct thrombin inhibitor) and rivaroxaban (a factor Xa inhibitor), respectively. Although indirect comparisons have been done using data from these trials, direct, head-to-head comparisons are not available.
Study design: New-user cohort study.
Setting: Medicare beneficiaries 65 years or older with AF and a prescription for either dabigatran or rivaroxaban.
Intracranial hemorrhage and extracranial major bleeding events were significantly greater in the rivaroxaban group than the dabigatran group. There was no significant difference in thromboembolic stroke events.
Limitations include short treatment and follow-up times. Additionally, the study is not generalizable to younger populations.
Bottom line: In elderly patients with non-valvular AF, rivaroxaban was associated with more adverse bleeding events than dabigatran, with no difference in stroke prevention.
Citation: Graham DJ, Reichman ME, Wernecke M, et al. Stroke, bleeding, and mortality risks in elderly Medicare beneficiaries treated with dabigatran or rivaroxaban for nonvalvular atrial fibrillation. JAMA Intern Med. 2016;176:1662-71.
Dr. Graves is an assistant professor at the University of Utah School of Medicine and associate program director of quality and patient safety for the University of Utah Internal Medicine residency training program.
Clinical question: Does dabigatran or rivaroxaban have more bleeding episodes?
Background: Alternatives to warfarin exist for stroke prevention in nonvalvular atrial fibrillation (AF). The RE-LY and ROCKET-AF trials demonstrated noninferiority to warfarin for both dabigatran (a direct thrombin inhibitor) and rivaroxaban (a factor Xa inhibitor), respectively. Although indirect comparisons have been done using data from these trials, direct, head-to-head comparisons are not available.
Study design: New-user cohort study.
Setting: Medicare beneficiaries 65 years or older with AF and a prescription for either dabigatran or rivaroxaban.
Intracranial hemorrhage and extracranial major bleeding events were significantly greater in the rivaroxaban group than the dabigatran group. There was no significant difference in thromboembolic stroke events.
Limitations include short treatment and follow-up times. Additionally, the study is not generalizable to younger populations.
Bottom line: In elderly patients with non-valvular AF, rivaroxaban was associated with more adverse bleeding events than dabigatran, with no difference in stroke prevention.
Citation: Graham DJ, Reichman ME, Wernecke M, et al. Stroke, bleeding, and mortality risks in elderly Medicare beneficiaries treated with dabigatran or rivaroxaban for nonvalvular atrial fibrillation. JAMA Intern Med. 2016;176:1662-71.
Dr. Graves is an assistant professor at the University of Utah School of Medicine and associate program director of quality and patient safety for the University of Utah Internal Medicine residency training program.
Unique microbiota mix found in guts of T1D patients
potentially offering early insight into possible links between the disease and gut germs.
The findings by an Italian team don’t confirm any connection between bacteria in the digestive system and diabetes. Still, “this study is probably the best example to date in the literature of inflammatory events happening in the gut that are correlated with type 1 diabetes,” said Aleksandar Kostic, PhD, of the department of microbiology and immunobiology at Harvard Medical School, Boston, who conducts similar research.
At issue: What role, if any, does the gut play in the development of type 1 diabetes (T1D)? Scientists already believe that the gut microbiome directly affects metabolism and the development of type 2 diabetes, according to Dr. Kostic. But T1D is an autoimmune disease, not a metabolic one, he said, “and the mechanisms are very different. For type 1, we don’t know a whole lot. We’re in the very early days.”
Still, “there’s a theory that inflammatory stimulus in the gut that is somehow partially responsible for causing T1D. The idea is that the microbiome is less diverse, which means that it loses its integrity in some way and loses the ability to crowd out inflammatory organisms,” he said in an interview.
For the new study, researchers led by scientists at Milan’s IRCCS San Raffaele Scientific Institute measured inflammation and the microbiome in the duodenal mucosa of 19 patients with T1D, 19 with celiac disease, and 16 healthy controls. They reported their findings online Jan. 19 (J Clin Endocrinol Metab. 2017. doi: 10.1210/jc.2016-3222).
The researchers found a unique inflammation profile through an analysis of gene expression in the patients with T1D. They called it a “peculiar signature” that’s notable for increased numbers of infiltration from the monocyte/macrophage lineage.
“In T1D patients, we didn’t observe any correlation between gene expression and [hemoglobin A1c] level, duration of diabetes, presence of secondary complications or the reason that led to endoscopy, indicating that gene expression was not influenced by these variables,” the researchers write.
They also found a “specific microbiota composition” featuring a reduction in the role of Proteobacteria and an increase in Firmicutes; this was unique to the T1D patients. Bacteroidetes “showed a trend to reduction” in both T1D and celiac patients compared to the controls.
“The expression of genes specific for T1D inflammation was associated with the abundance of specific bacteria in duodenum,” the researchers added.
Elena Barengolts, MD, of the division of endocrinology, diabetes, and metabolism at the University of Illinois, Chicago, who’s familiar with the study, said it appears to be valid. However, the methods used have limited powers to define specific types of bacteria, making it difficult to know if the germs in question are “bad” or “good,” she said in an interview.
For his part, Dr. Kostic said the findings are “really neat” and consistent with previous findings regarding the role of the gut microbiome and T1D. He pointed to a study he led that found less-diverse microbiomes in the guts of Finnish infants with T1D (Cell Host Microbe. 2015 Feb 11;17[2]:260-73).
As a result, the gut microbiome is “functionally capable of doing fewer things, and the community gets overrun by certain pathogens,” he said. “We saw that a lot of organisms were capable of promoting inflammation in the gut.”
Dr. Kostic, Dr. Barengolts, and the study authors report no relevant disclosures.
potentially offering early insight into possible links between the disease and gut germs.
The findings by an Italian team don’t confirm any connection between bacteria in the digestive system and diabetes. Still, “this study is probably the best example to date in the literature of inflammatory events happening in the gut that are correlated with type 1 diabetes,” said Aleksandar Kostic, PhD, of the department of microbiology and immunobiology at Harvard Medical School, Boston, who conducts similar research.
At issue: What role, if any, does the gut play in the development of type 1 diabetes (T1D)? Scientists already believe that the gut microbiome directly affects metabolism and the development of type 2 diabetes, according to Dr. Kostic. But T1D is an autoimmune disease, not a metabolic one, he said, “and the mechanisms are very different. For type 1, we don’t know a whole lot. We’re in the very early days.”
Still, “there’s a theory that inflammatory stimulus in the gut that is somehow partially responsible for causing T1D. The idea is that the microbiome is less diverse, which means that it loses its integrity in some way and loses the ability to crowd out inflammatory organisms,” he said in an interview.
For the new study, researchers led by scientists at Milan’s IRCCS San Raffaele Scientific Institute measured inflammation and the microbiome in the duodenal mucosa of 19 patients with T1D, 19 with celiac disease, and 16 healthy controls. They reported their findings online Jan. 19 (J Clin Endocrinol Metab. 2017. doi: 10.1210/jc.2016-3222).
The researchers found a unique inflammation profile through an analysis of gene expression in the patients with T1D. They called it a “peculiar signature” that’s notable for increased numbers of infiltration from the monocyte/macrophage lineage.
“In T1D patients, we didn’t observe any correlation between gene expression and [hemoglobin A1c] level, duration of diabetes, presence of secondary complications or the reason that led to endoscopy, indicating that gene expression was not influenced by these variables,” the researchers write.
They also found a “specific microbiota composition” featuring a reduction in the role of Proteobacteria and an increase in Firmicutes; this was unique to the T1D patients. Bacteroidetes “showed a trend to reduction” in both T1D and celiac patients compared to the controls.
“The expression of genes specific for T1D inflammation was associated with the abundance of specific bacteria in duodenum,” the researchers added.
Elena Barengolts, MD, of the division of endocrinology, diabetes, and metabolism at the University of Illinois, Chicago, who’s familiar with the study, said it appears to be valid. However, the methods used have limited powers to define specific types of bacteria, making it difficult to know if the germs in question are “bad” or “good,” she said in an interview.
For his part, Dr. Kostic said the findings are “really neat” and consistent with previous findings regarding the role of the gut microbiome and T1D. He pointed to a study he led that found less-diverse microbiomes in the guts of Finnish infants with T1D (Cell Host Microbe. 2015 Feb 11;17[2]:260-73).
As a result, the gut microbiome is “functionally capable of doing fewer things, and the community gets overrun by certain pathogens,” he said. “We saw that a lot of organisms were capable of promoting inflammation in the gut.”
Dr. Kostic, Dr. Barengolts, and the study authors report no relevant disclosures.
potentially offering early insight into possible links between the disease and gut germs.
The findings by an Italian team don’t confirm any connection between bacteria in the digestive system and diabetes. Still, “this study is probably the best example to date in the literature of inflammatory events happening in the gut that are correlated with type 1 diabetes,” said Aleksandar Kostic, PhD, of the department of microbiology and immunobiology at Harvard Medical School, Boston, who conducts similar research.
At issue: What role, if any, does the gut play in the development of type 1 diabetes (T1D)? Scientists already believe that the gut microbiome directly affects metabolism and the development of type 2 diabetes, according to Dr. Kostic. But T1D is an autoimmune disease, not a metabolic one, he said, “and the mechanisms are very different. For type 1, we don’t know a whole lot. We’re in the very early days.”
Still, “there’s a theory that inflammatory stimulus in the gut that is somehow partially responsible for causing T1D. The idea is that the microbiome is less diverse, which means that it loses its integrity in some way and loses the ability to crowd out inflammatory organisms,” he said in an interview.
For the new study, researchers led by scientists at Milan’s IRCCS San Raffaele Scientific Institute measured inflammation and the microbiome in the duodenal mucosa of 19 patients with T1D, 19 with celiac disease, and 16 healthy controls. They reported their findings online Jan. 19 (J Clin Endocrinol Metab. 2017. doi: 10.1210/jc.2016-3222).
The researchers found a unique inflammation profile through an analysis of gene expression in the patients with T1D. They called it a “peculiar signature” that’s notable for increased numbers of infiltration from the monocyte/macrophage lineage.
“In T1D patients, we didn’t observe any correlation between gene expression and [hemoglobin A1c] level, duration of diabetes, presence of secondary complications or the reason that led to endoscopy, indicating that gene expression was not influenced by these variables,” the researchers write.
They also found a “specific microbiota composition” featuring a reduction in the role of Proteobacteria and an increase in Firmicutes; this was unique to the T1D patients. Bacteroidetes “showed a trend to reduction” in both T1D and celiac patients compared to the controls.
“The expression of genes specific for T1D inflammation was associated with the abundance of specific bacteria in duodenum,” the researchers added.
Elena Barengolts, MD, of the division of endocrinology, diabetes, and metabolism at the University of Illinois, Chicago, who’s familiar with the study, said it appears to be valid. However, the methods used have limited powers to define specific types of bacteria, making it difficult to know if the germs in question are “bad” or “good,” she said in an interview.
For his part, Dr. Kostic said the findings are “really neat” and consistent with previous findings regarding the role of the gut microbiome and T1D. He pointed to a study he led that found less-diverse microbiomes in the guts of Finnish infants with T1D (Cell Host Microbe. 2015 Feb 11;17[2]:260-73).
As a result, the gut microbiome is “functionally capable of doing fewer things, and the community gets overrun by certain pathogens,” he said. “We saw that a lot of organisms were capable of promoting inflammation in the gut.”
Dr. Kostic, Dr. Barengolts, and the study authors report no relevant disclosures.
FROM THE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
Key clinical point: Patients with type 1 diabetes (T1D) show signs of unique inflammation and microbiota in the duodenal mucosa, compared with controls and celiac patients.
Major finding: T1D patients had a “peculiar” inflammation signature and a unique microbiota composition, and there’s a sign of a link between inflammation and bacteria levels.
Data source: An analysis of 19 patients with T1D, 19 with celiac disease, and 16 healthy controls.
Disclosures: The study was supported by institutional funds, and the authors report no relevant disclosures.
Experts say don’t SPRINT to adopt low blood pressure target
NEW ORLEANS – The key message of the SPRINT trial – that aggressive antihypertensive therapy to a target systolic blood pressure (SBP) of less than 120 mm Hg reduces all-cause mortality, compared with a target SBP under 140 mm Hg – is not broadly applicable as a routine strategy in managing hypertension, experts declared at the American Heart Association scientific sessions.
“My concern is that the patients in the SPRINT trial ended up being highly selected for having a strong ability to achieve and tolerate being at systolic blood pressure levels that we generally don’t see in a lot of treated hypertensives today in this country,” cautioned Peter M. Okin, MD, of Columbia University, New York.
It will be interesting to see how Dr. Okin’s opinion, which is shared by many leading cardiologists, is addressed in new hypertension treatment guidelines from the American College of Cardiology and the American Heart Association. The guidelines are anticipated in March.
Dr. Okin presented a secondary analysis of the earlier landmark LIFE (Losartan Intervention for Endpoint Reduction in Hypertension) trial that’s diametrically at odds with the main finding in SPRINT (the Systolic Blood Pressure Intervention Trial): namely, in LIFE (Lancet. 2002 Mar 23;359[9311]:1004-10), all-cause mortality during follow-up was heavily dependent upon baseline blood pressure.
Among LIFE participants with a baseline SBP below 164 mm Hg, achievement of an average on-treatment SBP below 142 mm Hg was associated with a 40% reduction in all-cause mortality more than 4 years of follow-up, compared with those with an achieved SBP of 152 mm Hg or more. In contrast, LIFE subjects whose baseline SBP was greater than 164 mm Hg actually had a 32% increase in all-cause mortality if their achieved SBP was less than 142 mm Hg, compared with those whose average on-treatment SBP was 152 mm Hg or higher.
How to account for the disparate results of LIFE and SPRINT?
SPRINT (N Engl J Med. 2015 Nov 26; 373:2103-16) enrolled nondiabetic patients aged 50 years or older who had an SBP of 130 mm Hg or more and high cardiovascular risk, with a 10-year Framingham Risk Score greater than 15%. But because the SBP threshold for entry was set so low, at 130 mm Hg, roughly half of SPRINT participants had baseline SBP levels that were already at or below the standard treatment target of 140 mm Hg. For those patients, getting to roughly 120 mm Hg on treatment wasn’t all that big a stretch in terms of the magnitude of blood pressure reduction, Dr. Okin said.
“Our analysis doesn’t invalidate SPRINT in any way, shape, or fashion. It just gives us some pause for thought,” he added.
His post-hoc analysis of LIFE was restricted to the 7,998 participants without diabetes at baseline, since SPRINT excluded diabetics from enrollment.
Audience comments were split between cardiologists who consider SPRINT a game-changer in the treatment of hypertension and those who, like Dr. Okin, have reservations. Among those reservations was the unexpected and difficult-to-explain finding that aggressive SBP lowering didn’t reduce the risk of stroke, compared with less-intensive SBP lowering, unlike the case in other clinical trials and epidemiologic studies in hypertension. Also, audience members took issue with the fact that blood pressure measurements in SPRINT weren’t done in the standard office measurement way employed in other major trials. Instead, SPRINT relied upon automated blood pressure monitoring of a patient alone in a room, which several cardiologists in the audience thought might have skewed the study results, since automated measurements tend to run lower.
Elsewhere at the AHA meeting, former AHA president Clyde W. Yancy, MD, offered a cautionary note regarding SPRINT.
“I think it’s important that we emphasize to this audience that SPRINT is looking at a very select patient population that probably describes only 15% of those with hypertension, specifically those with very high cardiovascular disease risk profiles. So we have to be very careful when we take the blood pressure targets that were identified in SPRINT and try to extrapolate those to other populations,” said Dr. Yancy, professor of medicine and chief of cardiology at Northwestern University, Chicago.
Dr. Okin reported having no financial conflicts of interest.
NEW ORLEANS – The key message of the SPRINT trial – that aggressive antihypertensive therapy to a target systolic blood pressure (SBP) of less than 120 mm Hg reduces all-cause mortality, compared with a target SBP under 140 mm Hg – is not broadly applicable as a routine strategy in managing hypertension, experts declared at the American Heart Association scientific sessions.
“My concern is that the patients in the SPRINT trial ended up being highly selected for having a strong ability to achieve and tolerate being at systolic blood pressure levels that we generally don’t see in a lot of treated hypertensives today in this country,” cautioned Peter M. Okin, MD, of Columbia University, New York.
It will be interesting to see how Dr. Okin’s opinion, which is shared by many leading cardiologists, is addressed in new hypertension treatment guidelines from the American College of Cardiology and the American Heart Association. The guidelines are anticipated in March.
Dr. Okin presented a secondary analysis of the earlier landmark LIFE (Losartan Intervention for Endpoint Reduction in Hypertension) trial that’s diametrically at odds with the main finding in SPRINT (the Systolic Blood Pressure Intervention Trial): namely, in LIFE (Lancet. 2002 Mar 23;359[9311]:1004-10), all-cause mortality during follow-up was heavily dependent upon baseline blood pressure.
Among LIFE participants with a baseline SBP below 164 mm Hg, achievement of an average on-treatment SBP below 142 mm Hg was associated with a 40% reduction in all-cause mortality more than 4 years of follow-up, compared with those with an achieved SBP of 152 mm Hg or more. In contrast, LIFE subjects whose baseline SBP was greater than 164 mm Hg actually had a 32% increase in all-cause mortality if their achieved SBP was less than 142 mm Hg, compared with those whose average on-treatment SBP was 152 mm Hg or higher.
How to account for the disparate results of LIFE and SPRINT?
SPRINT (N Engl J Med. 2015 Nov 26; 373:2103-16) enrolled nondiabetic patients aged 50 years or older who had an SBP of 130 mm Hg or more and high cardiovascular risk, with a 10-year Framingham Risk Score greater than 15%. But because the SBP threshold for entry was set so low, at 130 mm Hg, roughly half of SPRINT participants had baseline SBP levels that were already at or below the standard treatment target of 140 mm Hg. For those patients, getting to roughly 120 mm Hg on treatment wasn’t all that big a stretch in terms of the magnitude of blood pressure reduction, Dr. Okin said.
“Our analysis doesn’t invalidate SPRINT in any way, shape, or fashion. It just gives us some pause for thought,” he added.
His post-hoc analysis of LIFE was restricted to the 7,998 participants without diabetes at baseline, since SPRINT excluded diabetics from enrollment.
Audience comments were split between cardiologists who consider SPRINT a game-changer in the treatment of hypertension and those who, like Dr. Okin, have reservations. Among those reservations was the unexpected and difficult-to-explain finding that aggressive SBP lowering didn’t reduce the risk of stroke, compared with less-intensive SBP lowering, unlike the case in other clinical trials and epidemiologic studies in hypertension. Also, audience members took issue with the fact that blood pressure measurements in SPRINT weren’t done in the standard office measurement way employed in other major trials. Instead, SPRINT relied upon automated blood pressure monitoring of a patient alone in a room, which several cardiologists in the audience thought might have skewed the study results, since automated measurements tend to run lower.
Elsewhere at the AHA meeting, former AHA president Clyde W. Yancy, MD, offered a cautionary note regarding SPRINT.
“I think it’s important that we emphasize to this audience that SPRINT is looking at a very select patient population that probably describes only 15% of those with hypertension, specifically those with very high cardiovascular disease risk profiles. So we have to be very careful when we take the blood pressure targets that were identified in SPRINT and try to extrapolate those to other populations,” said Dr. Yancy, professor of medicine and chief of cardiology at Northwestern University, Chicago.
Dr. Okin reported having no financial conflicts of interest.
NEW ORLEANS – The key message of the SPRINT trial – that aggressive antihypertensive therapy to a target systolic blood pressure (SBP) of less than 120 mm Hg reduces all-cause mortality, compared with a target SBP under 140 mm Hg – is not broadly applicable as a routine strategy in managing hypertension, experts declared at the American Heart Association scientific sessions.
“My concern is that the patients in the SPRINT trial ended up being highly selected for having a strong ability to achieve and tolerate being at systolic blood pressure levels that we generally don’t see in a lot of treated hypertensives today in this country,” cautioned Peter M. Okin, MD, of Columbia University, New York.
It will be interesting to see how Dr. Okin’s opinion, which is shared by many leading cardiologists, is addressed in new hypertension treatment guidelines from the American College of Cardiology and the American Heart Association. The guidelines are anticipated in March.
Dr. Okin presented a secondary analysis of the earlier landmark LIFE (Losartan Intervention for Endpoint Reduction in Hypertension) trial that’s diametrically at odds with the main finding in SPRINT (the Systolic Blood Pressure Intervention Trial): namely, in LIFE (Lancet. 2002 Mar 23;359[9311]:1004-10), all-cause mortality during follow-up was heavily dependent upon baseline blood pressure.
Among LIFE participants with a baseline SBP below 164 mm Hg, achievement of an average on-treatment SBP below 142 mm Hg was associated with a 40% reduction in all-cause mortality more than 4 years of follow-up, compared with those with an achieved SBP of 152 mm Hg or more. In contrast, LIFE subjects whose baseline SBP was greater than 164 mm Hg actually had a 32% increase in all-cause mortality if their achieved SBP was less than 142 mm Hg, compared with those whose average on-treatment SBP was 152 mm Hg or higher.
How to account for the disparate results of LIFE and SPRINT?
SPRINT (N Engl J Med. 2015 Nov 26; 373:2103-16) enrolled nondiabetic patients aged 50 years or older who had an SBP of 130 mm Hg or more and high cardiovascular risk, with a 10-year Framingham Risk Score greater than 15%. But because the SBP threshold for entry was set so low, at 130 mm Hg, roughly half of SPRINT participants had baseline SBP levels that were already at or below the standard treatment target of 140 mm Hg. For those patients, getting to roughly 120 mm Hg on treatment wasn’t all that big a stretch in terms of the magnitude of blood pressure reduction, Dr. Okin said.
“Our analysis doesn’t invalidate SPRINT in any way, shape, or fashion. It just gives us some pause for thought,” he added.
His post-hoc analysis of LIFE was restricted to the 7,998 participants without diabetes at baseline, since SPRINT excluded diabetics from enrollment.
Audience comments were split between cardiologists who consider SPRINT a game-changer in the treatment of hypertension and those who, like Dr. Okin, have reservations. Among those reservations was the unexpected and difficult-to-explain finding that aggressive SBP lowering didn’t reduce the risk of stroke, compared with less-intensive SBP lowering, unlike the case in other clinical trials and epidemiologic studies in hypertension. Also, audience members took issue with the fact that blood pressure measurements in SPRINT weren’t done in the standard office measurement way employed in other major trials. Instead, SPRINT relied upon automated blood pressure monitoring of a patient alone in a room, which several cardiologists in the audience thought might have skewed the study results, since automated measurements tend to run lower.
Elsewhere at the AHA meeting, former AHA president Clyde W. Yancy, MD, offered a cautionary note regarding SPRINT.
“I think it’s important that we emphasize to this audience that SPRINT is looking at a very select patient population that probably describes only 15% of those with hypertension, specifically those with very high cardiovascular disease risk profiles. So we have to be very careful when we take the blood pressure targets that were identified in SPRINT and try to extrapolate those to other populations,” said Dr. Yancy, professor of medicine and chief of cardiology at Northwestern University, Chicago.
Dr. Okin reported having no financial conflicts of interest.
EXPERT ANALYSIS FROM THE AHA SCIENTIFIC SESSIONS
Deferring RT for brain mets in EGFR-mutated NSCLC shortens survival
Deferring radiotherapy to administer epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) first doesn’t prolong overall survival, it shortens survival in patients who have brain metastases of EGFR-mutated non–small-cell lung cancer (NSCLC), according to a report in the Journal of Clinical Oncology.
Upfront therapy using EGFR TKIs such as erlotinib has been proposed as a way to avoid radiotherapy altogether in this patient population, or to at least defer it and any related toxicities until intracranial disease progresses, said William J. Magnuson, MD, of Yale University, New Haven, Conn., and his associates.
To assess the advantages and disadvantages of upfront EGFR TKIs vs. initial radiotherapy, the researchers pooled survival data for 351 patients treated at six academic medical centers during 2008-2015. A total of 131 (37%) received upfront EGFR TKIs followed by stereotactic radiosurgery or whole-brain radiotherapy when the brain metastases progressed, 120 (34%) received whole-brain radiotherapy followed by EGFR TKIs, and 100 (29%) received stereotactic radiosurgery followed by EGFR TKIs. These patients were followed for a median of 22 months.
Median overall survival was 25 months for upfront EGFR TKIs, compared with 30 months for initial whole-brain radiotherapy and 46 months for initial stereotactic radiosurgery. At 2 years, overall survival rates for the three study groups were 51%, 62%, and 78%, respectively. Both forms of initial radiotherapy were associated with improved overall survival relative to EGFR TKIs, with a hazard ratio of 0.39 for stereotactic radiosurgery and a hazard ratio of 0.70 for whole-brain irradiation.
This survival advantage was even more pronounced in the subgroup of patients who had more favorable prognostic features at baseline. These patients had a median overall survival of 64 months if they received radiotherapy followed by EGFR TKIs, compared with only 32 months if EGFR TKIs were taken before radiotherapy, the investigators said (J Clin Oncol. 2017 Jan 23. doi: 10.1200/JCO.2016.69.7144).
These findings have the potential to change clinical practice, but prospective randomized data to confirm the results are urgently needed. “Until such a study is conducted and published, the standard-of-care treatment of newly diagnosed brain metastases should remain stereotactic radiosurgery followed by systemic therapy,” Dr. Magnuson and his associates said.
No funding source was cited for this study. Dr. Magnuson reported having no relevant financial disclosures; his associates reported having ties to numerous industry sources.
The findings of Magnuson et al. suggest that initial brain radiotherapy, especially stereotactic radiosurgery, is critical for patients who have EGFR-mutated NSCLC with brain metastases.
However, prospective studies are needed to confirm these results, and outcomes other than survival – including quality of life and neurocognitive function – must be addressed. The authors were unable to assess these outcomes in their pooled retrospective analysis.
In addition, potentially synergetic cognitive toxicities caused by combined or sequential therapies are still unclear, and are especially important for patients who do achieve long-term survival.
Lin Zhou, MD, and associates are at West China Hospital and Sichuan University, Chengdu, China. Dr. Zhou reported having no relevant financial disclosures; one of Dr. Zhou’s associates reported having ties to AstraZeneca. Hoffman-La Roche, Eli Lilly, Pfizer, Elekta, and Varian Medical Systems. Dr. Zhou and associates made these remarks in an editorial accompanying Dr. Magnuson’s report (J Clin Oncol. 2017 Jan 23. doi: 10.1200/JCO.2016.71.5706).
The findings of Magnuson et al. suggest that initial brain radiotherapy, especially stereotactic radiosurgery, is critical for patients who have EGFR-mutated NSCLC with brain metastases.
However, prospective studies are needed to confirm these results, and outcomes other than survival – including quality of life and neurocognitive function – must be addressed. The authors were unable to assess these outcomes in their pooled retrospective analysis.
In addition, potentially synergetic cognitive toxicities caused by combined or sequential therapies are still unclear, and are especially important for patients who do achieve long-term survival.
Lin Zhou, MD, and associates are at West China Hospital and Sichuan University, Chengdu, China. Dr. Zhou reported having no relevant financial disclosures; one of Dr. Zhou’s associates reported having ties to AstraZeneca. Hoffman-La Roche, Eli Lilly, Pfizer, Elekta, and Varian Medical Systems. Dr. Zhou and associates made these remarks in an editorial accompanying Dr. Magnuson’s report (J Clin Oncol. 2017 Jan 23. doi: 10.1200/JCO.2016.71.5706).
The findings of Magnuson et al. suggest that initial brain radiotherapy, especially stereotactic radiosurgery, is critical for patients who have EGFR-mutated NSCLC with brain metastases.
However, prospective studies are needed to confirm these results, and outcomes other than survival – including quality of life and neurocognitive function – must be addressed. The authors were unable to assess these outcomes in their pooled retrospective analysis.
In addition, potentially synergetic cognitive toxicities caused by combined or sequential therapies are still unclear, and are especially important for patients who do achieve long-term survival.
Lin Zhou, MD, and associates are at West China Hospital and Sichuan University, Chengdu, China. Dr. Zhou reported having no relevant financial disclosures; one of Dr. Zhou’s associates reported having ties to AstraZeneca. Hoffman-La Roche, Eli Lilly, Pfizer, Elekta, and Varian Medical Systems. Dr. Zhou and associates made these remarks in an editorial accompanying Dr. Magnuson’s report (J Clin Oncol. 2017 Jan 23. doi: 10.1200/JCO.2016.71.5706).
Deferring radiotherapy to administer epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) first doesn’t prolong overall survival, it shortens survival in patients who have brain metastases of EGFR-mutated non–small-cell lung cancer (NSCLC), according to a report in the Journal of Clinical Oncology.
Upfront therapy using EGFR TKIs such as erlotinib has been proposed as a way to avoid radiotherapy altogether in this patient population, or to at least defer it and any related toxicities until intracranial disease progresses, said William J. Magnuson, MD, of Yale University, New Haven, Conn., and his associates.
To assess the advantages and disadvantages of upfront EGFR TKIs vs. initial radiotherapy, the researchers pooled survival data for 351 patients treated at six academic medical centers during 2008-2015. A total of 131 (37%) received upfront EGFR TKIs followed by stereotactic radiosurgery or whole-brain radiotherapy when the brain metastases progressed, 120 (34%) received whole-brain radiotherapy followed by EGFR TKIs, and 100 (29%) received stereotactic radiosurgery followed by EGFR TKIs. These patients were followed for a median of 22 months.
Median overall survival was 25 months for upfront EGFR TKIs, compared with 30 months for initial whole-brain radiotherapy and 46 months for initial stereotactic radiosurgery. At 2 years, overall survival rates for the three study groups were 51%, 62%, and 78%, respectively. Both forms of initial radiotherapy were associated with improved overall survival relative to EGFR TKIs, with a hazard ratio of 0.39 for stereotactic radiosurgery and a hazard ratio of 0.70 for whole-brain irradiation.
This survival advantage was even more pronounced in the subgroup of patients who had more favorable prognostic features at baseline. These patients had a median overall survival of 64 months if they received radiotherapy followed by EGFR TKIs, compared with only 32 months if EGFR TKIs were taken before radiotherapy, the investigators said (J Clin Oncol. 2017 Jan 23. doi: 10.1200/JCO.2016.69.7144).
These findings have the potential to change clinical practice, but prospective randomized data to confirm the results are urgently needed. “Until such a study is conducted and published, the standard-of-care treatment of newly diagnosed brain metastases should remain stereotactic radiosurgery followed by systemic therapy,” Dr. Magnuson and his associates said.
No funding source was cited for this study. Dr. Magnuson reported having no relevant financial disclosures; his associates reported having ties to numerous industry sources.
Deferring radiotherapy to administer epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) first doesn’t prolong overall survival, it shortens survival in patients who have brain metastases of EGFR-mutated non–small-cell lung cancer (NSCLC), according to a report in the Journal of Clinical Oncology.
Upfront therapy using EGFR TKIs such as erlotinib has been proposed as a way to avoid radiotherapy altogether in this patient population, or to at least defer it and any related toxicities until intracranial disease progresses, said William J. Magnuson, MD, of Yale University, New Haven, Conn., and his associates.
To assess the advantages and disadvantages of upfront EGFR TKIs vs. initial radiotherapy, the researchers pooled survival data for 351 patients treated at six academic medical centers during 2008-2015. A total of 131 (37%) received upfront EGFR TKIs followed by stereotactic radiosurgery or whole-brain radiotherapy when the brain metastases progressed, 120 (34%) received whole-brain radiotherapy followed by EGFR TKIs, and 100 (29%) received stereotactic radiosurgery followed by EGFR TKIs. These patients were followed for a median of 22 months.
Median overall survival was 25 months for upfront EGFR TKIs, compared with 30 months for initial whole-brain radiotherapy and 46 months for initial stereotactic radiosurgery. At 2 years, overall survival rates for the three study groups were 51%, 62%, and 78%, respectively. Both forms of initial radiotherapy were associated with improved overall survival relative to EGFR TKIs, with a hazard ratio of 0.39 for stereotactic radiosurgery and a hazard ratio of 0.70 for whole-brain irradiation.
This survival advantage was even more pronounced in the subgroup of patients who had more favorable prognostic features at baseline. These patients had a median overall survival of 64 months if they received radiotherapy followed by EGFR TKIs, compared with only 32 months if EGFR TKIs were taken before radiotherapy, the investigators said (J Clin Oncol. 2017 Jan 23. doi: 10.1200/JCO.2016.69.7144).
These findings have the potential to change clinical practice, but prospective randomized data to confirm the results are urgently needed. “Until such a study is conducted and published, the standard-of-care treatment of newly diagnosed brain metastases should remain stereotactic radiosurgery followed by systemic therapy,” Dr. Magnuson and his associates said.
No funding source was cited for this study. Dr. Magnuson reported having no relevant financial disclosures; his associates reported having ties to numerous industry sources.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: Deferring radiotherapy to administer EGFR tyrosine kinase inhibitors first doesn’t prolong overall survival, it shortens survival in patients who have brain metastases of EGFR-mutated non–small-cell lung cancer.
Major finding: At 2 years, overall survival rates were 51% with upfront EGFR TKIs, 62% with initial whole-brain radiotherapy, and 78% with stereotactic radiosurgery.
Data source: A retrospective multicenter pooled analysis of survival data for 351 patients with NSCLC brain metastases followed for a median of 22 months.
Disclosures: No funding source was cited for this study. Dr. Magnuson reported having no relevant financial disclosures; his associates reported having ties to numerous industry sources.
Cardiac events after NSCLC radiotherapy occur early
Cardiac events are “relatively common,” affecting 23% of patients, and occur earlier than previously thought following radiotherapy for non–small-cell lung cancer (NSCLC), according to a report in the Journal of Clinical Oncology.
Radiation-associated cardiac toxicity has long been recognized in patients treated for other thoracic cancers, but the conventional wisdom has been that it isn’t a consideration in patients with stage III NSCLC because “there are few long-term survivors to experience toxicity, given the typically long latency of radiotherapy-associated heart injury and the poor prognosis” of this cancer. However, the findings “challenge the perception that minimizing heart dose is not important in the treatment of patients with stage III NSCLC,” said Kyle Wang, MD, of University of North Carolina Hospitals, Chapel Hill, and his associates.
“Our data support minimization of heart radiation exposure whenever possible to doses lower than commonly recommended in patients with stage III NSCLC, to reduce risks of [cardiac] toxicity,” they noted.
Dr. Wang and his associates performed a retrospective post hoc analysis of data pooled from six prospective phase I and II trials that the University of North Carolina was involved in between 1996 and 2009. The studies assessed both dose-escalated radiotherapy and various chemotherapeutic regimens in 112 patients who were followed for a median of 8.8 years (range, 2.3-17.3 years). All the patients received induction chemotherapy, 90% received concurrent chemotherapy, and 25% received consolidation chemotherapy.
A total of 26 patients (23%) had at least one symptomatic cardiac event following radiotherapy: pericardial effusion (7 patients), MI (5 patients), unstable angina (3 patients), pericarditis (2 patients), significant arrhythmia (12 patients), and heart failure (1 patient). After the data were adjusted to account for competing risks of death, the 2-year rate of symptomatic cardiac toxicity was 10% and the 4-year rate was 18%. The first adverse cardiac event occurred at a median of 26 months (range, 1-84 months).
The risk of cardiac toxicities rose with increasing radiation exposure: At 2 years, the rate of cardiac events was 4% for those exposed to less than 10 Gy, 7% for those exposed to 10-20 Gy, and 21% for those exposed to greater than 20 Gy. At 4 years, those rates were 4%, 13%, and 41%, respectively. Patients whose hearts were exposed to greater than 20 Gy had a significantly higher rate of cardiac events than did those exposed to less than 10 Gy (HR, 5.47) or to 10-20 Gy (HR, 2.76).
Even though the prognosis may be poor in patients with stage III NSCLC, “they generally receive higher heart doses and may also have more comorbidities and smoking history, thus increasing risk and perhaps shortening the latency between radiotherapy and resultant heart disease,” Dr. Wang and his associates said (J Clin Oncol. 2017 Jan 23 [doi: 10.1200/JCO.2016.70.0229]).
“In our opinion, tumor coverage should rarely be compromised to meet a heart dose constraint. However, it would be reasonable to try to limit heart mean dose to less than 20 Gy (lower if possible) on the basis of the high event rate we observed in patients exceeding this dose (21% at 2 years and 41% at 4 years). Sophisticated radiation treatment planning techniques (e.g., [intensity-modulated radiation therapy]) and charged-particle therapy with protons or carbon ions may provide increased flexibility to generate more conformal treatment plans and reduce heart dose, which could potentially improve the clinical outcomes in patients with stage III NSCLC,” they added.
This is the first report to clearly associate radiation doses with clinically significant cardiac events in patients with locally advanced NSCLC treated with modern radiotherapy techniques, and it suggests that these events happen much earlier than conventionally believed.
Perhaps cardiac risk didn’t matter so much when, historically, the life expectancy of this patient population was only 2 years. But given the improvements in survival over the last 2 decades, together with the findings of Wang et al., the era of indiscriminate irradiation to the heart should end.
Charles B. Simone II, MD, is at the University of Maryland Medical Center, Baltimore. He reported having no relevant financial disclosures. Dr. Simone made these remarks in an editorial accompanying Dr. Wang’s report (J Clin Oncol. 2017 January 23 [doi: 10.1200/JCO.2016.71.5581]).
This is the first report to clearly associate radiation doses with clinically significant cardiac events in patients with locally advanced NSCLC treated with modern radiotherapy techniques, and it suggests that these events happen much earlier than conventionally believed.
Perhaps cardiac risk didn’t matter so much when, historically, the life expectancy of this patient population was only 2 years. But given the improvements in survival over the last 2 decades, together with the findings of Wang et al., the era of indiscriminate irradiation to the heart should end.
Charles B. Simone II, MD, is at the University of Maryland Medical Center, Baltimore. He reported having no relevant financial disclosures. Dr. Simone made these remarks in an editorial accompanying Dr. Wang’s report (J Clin Oncol. 2017 January 23 [doi: 10.1200/JCO.2016.71.5581]).
This is the first report to clearly associate radiation doses with clinically significant cardiac events in patients with locally advanced NSCLC treated with modern radiotherapy techniques, and it suggests that these events happen much earlier than conventionally believed.
Perhaps cardiac risk didn’t matter so much when, historically, the life expectancy of this patient population was only 2 years. But given the improvements in survival over the last 2 decades, together with the findings of Wang et al., the era of indiscriminate irradiation to the heart should end.
Charles B. Simone II, MD, is at the University of Maryland Medical Center, Baltimore. He reported having no relevant financial disclosures. Dr. Simone made these remarks in an editorial accompanying Dr. Wang’s report (J Clin Oncol. 2017 January 23 [doi: 10.1200/JCO.2016.71.5581]).
Cardiac events are “relatively common,” affecting 23% of patients, and occur earlier than previously thought following radiotherapy for non–small-cell lung cancer (NSCLC), according to a report in the Journal of Clinical Oncology.
Radiation-associated cardiac toxicity has long been recognized in patients treated for other thoracic cancers, but the conventional wisdom has been that it isn’t a consideration in patients with stage III NSCLC because “there are few long-term survivors to experience toxicity, given the typically long latency of radiotherapy-associated heart injury and the poor prognosis” of this cancer. However, the findings “challenge the perception that minimizing heart dose is not important in the treatment of patients with stage III NSCLC,” said Kyle Wang, MD, of University of North Carolina Hospitals, Chapel Hill, and his associates.
“Our data support minimization of heart radiation exposure whenever possible to doses lower than commonly recommended in patients with stage III NSCLC, to reduce risks of [cardiac] toxicity,” they noted.
Dr. Wang and his associates performed a retrospective post hoc analysis of data pooled from six prospective phase I and II trials that the University of North Carolina was involved in between 1996 and 2009. The studies assessed both dose-escalated radiotherapy and various chemotherapeutic regimens in 112 patients who were followed for a median of 8.8 years (range, 2.3-17.3 years). All the patients received induction chemotherapy, 90% received concurrent chemotherapy, and 25% received consolidation chemotherapy.
A total of 26 patients (23%) had at least one symptomatic cardiac event following radiotherapy: pericardial effusion (7 patients), MI (5 patients), unstable angina (3 patients), pericarditis (2 patients), significant arrhythmia (12 patients), and heart failure (1 patient). After the data were adjusted to account for competing risks of death, the 2-year rate of symptomatic cardiac toxicity was 10% and the 4-year rate was 18%. The first adverse cardiac event occurred at a median of 26 months (range, 1-84 months).
The risk of cardiac toxicities rose with increasing radiation exposure: At 2 years, the rate of cardiac events was 4% for those exposed to less than 10 Gy, 7% for those exposed to 10-20 Gy, and 21% for those exposed to greater than 20 Gy. At 4 years, those rates were 4%, 13%, and 41%, respectively. Patients whose hearts were exposed to greater than 20 Gy had a significantly higher rate of cardiac events than did those exposed to less than 10 Gy (HR, 5.47) or to 10-20 Gy (HR, 2.76).
Even though the prognosis may be poor in patients with stage III NSCLC, “they generally receive higher heart doses and may also have more comorbidities and smoking history, thus increasing risk and perhaps shortening the latency between radiotherapy and resultant heart disease,” Dr. Wang and his associates said (J Clin Oncol. 2017 Jan 23 [doi: 10.1200/JCO.2016.70.0229]).
“In our opinion, tumor coverage should rarely be compromised to meet a heart dose constraint. However, it would be reasonable to try to limit heart mean dose to less than 20 Gy (lower if possible) on the basis of the high event rate we observed in patients exceeding this dose (21% at 2 years and 41% at 4 years). Sophisticated radiation treatment planning techniques (e.g., [intensity-modulated radiation therapy]) and charged-particle therapy with protons or carbon ions may provide increased flexibility to generate more conformal treatment plans and reduce heart dose, which could potentially improve the clinical outcomes in patients with stage III NSCLC,” they added.
Cardiac events are “relatively common,” affecting 23% of patients, and occur earlier than previously thought following radiotherapy for non–small-cell lung cancer (NSCLC), according to a report in the Journal of Clinical Oncology.
Radiation-associated cardiac toxicity has long been recognized in patients treated for other thoracic cancers, but the conventional wisdom has been that it isn’t a consideration in patients with stage III NSCLC because “there are few long-term survivors to experience toxicity, given the typically long latency of radiotherapy-associated heart injury and the poor prognosis” of this cancer. However, the findings “challenge the perception that minimizing heart dose is not important in the treatment of patients with stage III NSCLC,” said Kyle Wang, MD, of University of North Carolina Hospitals, Chapel Hill, and his associates.
“Our data support minimization of heart radiation exposure whenever possible to doses lower than commonly recommended in patients with stage III NSCLC, to reduce risks of [cardiac] toxicity,” they noted.
Dr. Wang and his associates performed a retrospective post hoc analysis of data pooled from six prospective phase I and II trials that the University of North Carolina was involved in between 1996 and 2009. The studies assessed both dose-escalated radiotherapy and various chemotherapeutic regimens in 112 patients who were followed for a median of 8.8 years (range, 2.3-17.3 years). All the patients received induction chemotherapy, 90% received concurrent chemotherapy, and 25% received consolidation chemotherapy.
A total of 26 patients (23%) had at least one symptomatic cardiac event following radiotherapy: pericardial effusion (7 patients), MI (5 patients), unstable angina (3 patients), pericarditis (2 patients), significant arrhythmia (12 patients), and heart failure (1 patient). After the data were adjusted to account for competing risks of death, the 2-year rate of symptomatic cardiac toxicity was 10% and the 4-year rate was 18%. The first adverse cardiac event occurred at a median of 26 months (range, 1-84 months).
The risk of cardiac toxicities rose with increasing radiation exposure: At 2 years, the rate of cardiac events was 4% for those exposed to less than 10 Gy, 7% for those exposed to 10-20 Gy, and 21% for those exposed to greater than 20 Gy. At 4 years, those rates were 4%, 13%, and 41%, respectively. Patients whose hearts were exposed to greater than 20 Gy had a significantly higher rate of cardiac events than did those exposed to less than 10 Gy (HR, 5.47) or to 10-20 Gy (HR, 2.76).
Even though the prognosis may be poor in patients with stage III NSCLC, “they generally receive higher heart doses and may also have more comorbidities and smoking history, thus increasing risk and perhaps shortening the latency between radiotherapy and resultant heart disease,” Dr. Wang and his associates said (J Clin Oncol. 2017 Jan 23 [doi: 10.1200/JCO.2016.70.0229]).
“In our opinion, tumor coverage should rarely be compromised to meet a heart dose constraint. However, it would be reasonable to try to limit heart mean dose to less than 20 Gy (lower if possible) on the basis of the high event rate we observed in patients exceeding this dose (21% at 2 years and 41% at 4 years). Sophisticated radiation treatment planning techniques (e.g., [intensity-modulated radiation therapy]) and charged-particle therapy with protons or carbon ions may provide increased flexibility to generate more conformal treatment plans and reduce heart dose, which could potentially improve the clinical outcomes in patients with stage III NSCLC,” they added.
FROM JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: Cardiac events are “relatively common” and occur earlier than previously thought following radiotherapy for NSCLC.
Major finding: Following radiotherapy, 26 of 112 patients (23%) had at least one symptomatic cardiac event: pericardial effusion (7 patients), MI (5 patients), unstable angina (3 patients), pericarditis (2 patients), significant arrhythmia (12 patients), and heart failure (1 patient).
Data source: A retrospective post hoc analysis of data from six phase I and II trials involving 112 patients who received radiotherapy for stage-III NSCLC during 1996-2009.
Disclosures: This study was supported in part by the National Institutes of Health. Dr. Wang reported having no relevant financial disclosures; his associates disclosed ties to La Jolla Pharmaceutical, Vision RT, Medtronic, Novartis, Elekta, Morphomics, Accuray, and Varian Medical Systems.
Judge blocks Aetna-Humana merger
A federal judge has blocked a megamerger between health insurance giants Aetna and Humana, ruling that the consolidation would violate antitrust laws and reduce competition.
In a Jan. 23 decision, Judge John D. Bates of the U.S. District Court for the District of Columbia denied Aetna’s $37 billion plan to purchase Humana, following a month-long trial that began in early December. The court was unpersuaded that the efficiencies generated by the merger would be “sufficient to mitigate the anticompetitive effects for consumers in the challenged markets,” Judge Bates said in his opinion.
The U.S. Department of Justice, which challenged the merger, called the ruling a victory for patients, particularly seniors and working families.
“Competition spurs health insurers to offer higher quality and more affordable health insurance to seniors who choose Medicare Advantage plans and to low-income families and individuals who purchase insurance from public exchanges,” Brent Snyder, deputy assistant attorney general, said in a statement. “Aetna attempted to buy a formidable rival, Humana, instead of competing independently to win customers. Millions of consumers have benefited from competition between Aetna and Humana, and will continue to benefit because of today’s decision to block this merger.”
The Department of Justice, eight states, and the District of Columbia sued Aetna and Humana after an investigation into their proposed July 2015 merger. The government argued that the companies compete head-to-head in the Medicare Advantage and public exchange markets, and that such competition would be lost following the merger to the significant detriment of patients. Aetna and Humana argued their proposed merger would not substantially lessen competition because of the government’s regulatory authority over Medicare Advantage, the threat of entry by new competitors, and the defendants’ proposed divestiture of a portion of their Medicare Advantage business to insurer Molina Healthcare. The insurers also asserted that no current competition between the two companies exists in the 17 complaint counties because Aetna has decided not to compete in those counties in 2017. Judge Bates disagreed.
“The merger would likely substantially lessen competition in the market for individual Medicare Advantage in all 364 complaint counties,” Judge Bates said in his opinion. “This conclusion is based on identification of the proper product market, the overwhelming market concentration figures generated by the merger, and the considerable evidence of valuable head-to-head competition between Aetna and Humana, which the merger would eliminate. The companies’ rebuttal arguments are unpersuasive.”
The American Medical Association praised the ruling.
“Elderly patients were the big winners today as a federal court imposed an injunction on Aetna’s $37 billion acquisition of Humana,” AMA president Andrew W. Gurman, MD, said in a statement. “Aetna’s strategy to eliminate head-to-head competition with rival Humana posed a clear and present threat to the quality, accessibility, and affordability of health care for millions of seniors. The AMA applauds the extraordinarily well-documented, comprehensive, fact-based ruling of U.S. District Judge John D. Bates, which acknowledged that meaningful action was needed to preserve competition and protect high-quality medical care from unprecedented market power that Aetna would acquire from the merger deal.”
Another ruling is expected soon in the $48 billion planned merger between Anthem and Cigna, which is also being challenged by the Justice department. A trial in that case wrapped up in late December in front of U.S. District Court for the District of Columbia Judge Amy Berman.
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On Twitter @legal_med
A federal judge has blocked a megamerger between health insurance giants Aetna and Humana, ruling that the consolidation would violate antitrust laws and reduce competition.
In a Jan. 23 decision, Judge John D. Bates of the U.S. District Court for the District of Columbia denied Aetna’s $37 billion plan to purchase Humana, following a month-long trial that began in early December. The court was unpersuaded that the efficiencies generated by the merger would be “sufficient to mitigate the anticompetitive effects for consumers in the challenged markets,” Judge Bates said in his opinion.
The U.S. Department of Justice, which challenged the merger, called the ruling a victory for patients, particularly seniors and working families.
“Competition spurs health insurers to offer higher quality and more affordable health insurance to seniors who choose Medicare Advantage plans and to low-income families and individuals who purchase insurance from public exchanges,” Brent Snyder, deputy assistant attorney general, said in a statement. “Aetna attempted to buy a formidable rival, Humana, instead of competing independently to win customers. Millions of consumers have benefited from competition between Aetna and Humana, and will continue to benefit because of today’s decision to block this merger.”
The Department of Justice, eight states, and the District of Columbia sued Aetna and Humana after an investigation into their proposed July 2015 merger. The government argued that the companies compete head-to-head in the Medicare Advantage and public exchange markets, and that such competition would be lost following the merger to the significant detriment of patients. Aetna and Humana argued their proposed merger would not substantially lessen competition because of the government’s regulatory authority over Medicare Advantage, the threat of entry by new competitors, and the defendants’ proposed divestiture of a portion of their Medicare Advantage business to insurer Molina Healthcare. The insurers also asserted that no current competition between the two companies exists in the 17 complaint counties because Aetna has decided not to compete in those counties in 2017. Judge Bates disagreed.
“The merger would likely substantially lessen competition in the market for individual Medicare Advantage in all 364 complaint counties,” Judge Bates said in his opinion. “This conclusion is based on identification of the proper product market, the overwhelming market concentration figures generated by the merger, and the considerable evidence of valuable head-to-head competition between Aetna and Humana, which the merger would eliminate. The companies’ rebuttal arguments are unpersuasive.”
The American Medical Association praised the ruling.
“Elderly patients were the big winners today as a federal court imposed an injunction on Aetna’s $37 billion acquisition of Humana,” AMA president Andrew W. Gurman, MD, said in a statement. “Aetna’s strategy to eliminate head-to-head competition with rival Humana posed a clear and present threat to the quality, accessibility, and affordability of health care for millions of seniors. The AMA applauds the extraordinarily well-documented, comprehensive, fact-based ruling of U.S. District Judge John D. Bates, which acknowledged that meaningful action was needed to preserve competition and protect high-quality medical care from unprecedented market power that Aetna would acquire from the merger deal.”
Another ruling is expected soon in the $48 billion planned merger between Anthem and Cigna, which is also being challenged by the Justice department. A trial in that case wrapped up in late December in front of U.S. District Court for the District of Columbia Judge Amy Berman.
[email protected]
On Twitter @legal_med
A federal judge has blocked a megamerger between health insurance giants Aetna and Humana, ruling that the consolidation would violate antitrust laws and reduce competition.
In a Jan. 23 decision, Judge John D. Bates of the U.S. District Court for the District of Columbia denied Aetna’s $37 billion plan to purchase Humana, following a month-long trial that began in early December. The court was unpersuaded that the efficiencies generated by the merger would be “sufficient to mitigate the anticompetitive effects for consumers in the challenged markets,” Judge Bates said in his opinion.
The U.S. Department of Justice, which challenged the merger, called the ruling a victory for patients, particularly seniors and working families.
“Competition spurs health insurers to offer higher quality and more affordable health insurance to seniors who choose Medicare Advantage plans and to low-income families and individuals who purchase insurance from public exchanges,” Brent Snyder, deputy assistant attorney general, said in a statement. “Aetna attempted to buy a formidable rival, Humana, instead of competing independently to win customers. Millions of consumers have benefited from competition between Aetna and Humana, and will continue to benefit because of today’s decision to block this merger.”
The Department of Justice, eight states, and the District of Columbia sued Aetna and Humana after an investigation into their proposed July 2015 merger. The government argued that the companies compete head-to-head in the Medicare Advantage and public exchange markets, and that such competition would be lost following the merger to the significant detriment of patients. Aetna and Humana argued their proposed merger would not substantially lessen competition because of the government’s regulatory authority over Medicare Advantage, the threat of entry by new competitors, and the defendants’ proposed divestiture of a portion of their Medicare Advantage business to insurer Molina Healthcare. The insurers also asserted that no current competition between the two companies exists in the 17 complaint counties because Aetna has decided not to compete in those counties in 2017. Judge Bates disagreed.
“The merger would likely substantially lessen competition in the market for individual Medicare Advantage in all 364 complaint counties,” Judge Bates said in his opinion. “This conclusion is based on identification of the proper product market, the overwhelming market concentration figures generated by the merger, and the considerable evidence of valuable head-to-head competition between Aetna and Humana, which the merger would eliminate. The companies’ rebuttal arguments are unpersuasive.”
The American Medical Association praised the ruling.
“Elderly patients were the big winners today as a federal court imposed an injunction on Aetna’s $37 billion acquisition of Humana,” AMA president Andrew W. Gurman, MD, said in a statement. “Aetna’s strategy to eliminate head-to-head competition with rival Humana posed a clear and present threat to the quality, accessibility, and affordability of health care for millions of seniors. The AMA applauds the extraordinarily well-documented, comprehensive, fact-based ruling of U.S. District Judge John D. Bates, which acknowledged that meaningful action was needed to preserve competition and protect high-quality medical care from unprecedented market power that Aetna would acquire from the merger deal.”
Another ruling is expected soon in the $48 billion planned merger between Anthem and Cigna, which is also being challenged by the Justice department. A trial in that case wrapped up in late December in front of U.S. District Court for the District of Columbia Judge Amy Berman.
[email protected]
On Twitter @legal_med
