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Antithrombotics no deterrent for emergent lap appendectomy
HOUSTON – Few studies have looked at the risk of irreversible antithrombotic therapy in patients who need emergent or urgent laparoscopic appendectomy, but a new study showed that the operation poses no significantly greater risk for such patients, compared with people who are not on antithrombotics.
The study’s findings do not apply to all patients on anticoagulation, specifically those on new novel oral anticoagulants (NOACs), said Christopher Pearcy, MD, of Methodist Dallas Medical Center.
NOAC agents include dabigatran, rivaroxaban, and apixaban.
Appendicitis is the third most common indication for abdominal surgery in the elderly, Dr. Pearcy noted, and their mortality rates are eight times greater than those of younger patients. However, these patients often proceed to operation with minimal workup, “given that laparoscopic appendectomy is a relatively benign procedure,” he said at the annual meeting of the Society of American Gastrointestinal and Endoscopic Surgeons.
The retrospective study evaluated two groups of 195 patients who had urgent or emergent laparoscopic appendectomy at three centers from 2010 to 2014. One group was on irreversible antithrombotic therapy, and the other served as controls.
The primary outcomes were blood loss, transfusion requirement, and mortality. Secondary outcomes were duration of operation, length of hospital stay, rates of infections, complications, and 30-day readmissions.
“Compared with controls, we didn’t find any significant difference in any outcome whatsoever after laparoscopic appendectomy in patients on prehospital antithrombotic therapy,” Dr. Pearcy said.
Specifically, average estimated blood loss was 18 cc in controls vs. 22 cc in patients on antithrombotics, and mortality was 0% in the former vs. 1% in the latter. Patients on antithrombotics had a lower rate of complications: 3% vs. 11%.
Dr. Pearcy discussed a case of a 70-year-old man with acute appendicitis. He had a history of coronary artery disease, hypertension, hyperlipidemia, type 2 diabetes, and stroke, and was taking clopidogrel and aspirin daily.
“Is it safe to proceed with surgery given this patient’s irreversible antithrombotic therapy? We would say yes,” he said.
Dr. Pearcy reported having no financial disclosures.
HOUSTON – Few studies have looked at the risk of irreversible antithrombotic therapy in patients who need emergent or urgent laparoscopic appendectomy, but a new study showed that the operation poses no significantly greater risk for such patients, compared with people who are not on antithrombotics.
The study’s findings do not apply to all patients on anticoagulation, specifically those on new novel oral anticoagulants (NOACs), said Christopher Pearcy, MD, of Methodist Dallas Medical Center.
NOAC agents include dabigatran, rivaroxaban, and apixaban.
Appendicitis is the third most common indication for abdominal surgery in the elderly, Dr. Pearcy noted, and their mortality rates are eight times greater than those of younger patients. However, these patients often proceed to operation with minimal workup, “given that laparoscopic appendectomy is a relatively benign procedure,” he said at the annual meeting of the Society of American Gastrointestinal and Endoscopic Surgeons.
The retrospective study evaluated two groups of 195 patients who had urgent or emergent laparoscopic appendectomy at three centers from 2010 to 2014. One group was on irreversible antithrombotic therapy, and the other served as controls.
The primary outcomes were blood loss, transfusion requirement, and mortality. Secondary outcomes were duration of operation, length of hospital stay, rates of infections, complications, and 30-day readmissions.
“Compared with controls, we didn’t find any significant difference in any outcome whatsoever after laparoscopic appendectomy in patients on prehospital antithrombotic therapy,” Dr. Pearcy said.
Specifically, average estimated blood loss was 18 cc in controls vs. 22 cc in patients on antithrombotics, and mortality was 0% in the former vs. 1% in the latter. Patients on antithrombotics had a lower rate of complications: 3% vs. 11%.
Dr. Pearcy discussed a case of a 70-year-old man with acute appendicitis. He had a history of coronary artery disease, hypertension, hyperlipidemia, type 2 diabetes, and stroke, and was taking clopidogrel and aspirin daily.
“Is it safe to proceed with surgery given this patient’s irreversible antithrombotic therapy? We would say yes,” he said.
Dr. Pearcy reported having no financial disclosures.
HOUSTON – Few studies have looked at the risk of irreversible antithrombotic therapy in patients who need emergent or urgent laparoscopic appendectomy, but a new study showed that the operation poses no significantly greater risk for such patients, compared with people who are not on antithrombotics.
The study’s findings do not apply to all patients on anticoagulation, specifically those on new novel oral anticoagulants (NOACs), said Christopher Pearcy, MD, of Methodist Dallas Medical Center.
NOAC agents include dabigatran, rivaroxaban, and apixaban.
Appendicitis is the third most common indication for abdominal surgery in the elderly, Dr. Pearcy noted, and their mortality rates are eight times greater than those of younger patients. However, these patients often proceed to operation with minimal workup, “given that laparoscopic appendectomy is a relatively benign procedure,” he said at the annual meeting of the Society of American Gastrointestinal and Endoscopic Surgeons.
The retrospective study evaluated two groups of 195 patients who had urgent or emergent laparoscopic appendectomy at three centers from 2010 to 2014. One group was on irreversible antithrombotic therapy, and the other served as controls.
The primary outcomes were blood loss, transfusion requirement, and mortality. Secondary outcomes were duration of operation, length of hospital stay, rates of infections, complications, and 30-day readmissions.
“Compared with controls, we didn’t find any significant difference in any outcome whatsoever after laparoscopic appendectomy in patients on prehospital antithrombotic therapy,” Dr. Pearcy said.
Specifically, average estimated blood loss was 18 cc in controls vs. 22 cc in patients on antithrombotics, and mortality was 0% in the former vs. 1% in the latter. Patients on antithrombotics had a lower rate of complications: 3% vs. 11%.
Dr. Pearcy discussed a case of a 70-year-old man with acute appendicitis. He had a history of coronary artery disease, hypertension, hyperlipidemia, type 2 diabetes, and stroke, and was taking clopidogrel and aspirin daily.
“Is it safe to proceed with surgery given this patient’s irreversible antithrombotic therapy? We would say yes,” he said.
Dr. Pearcy reported having no financial disclosures.
AT SAGES 2017
Key clinical point: Emergent laparoscopic appendectomy poses no significant risk for patients on irreversible antithrombotic therapy.
Major finding: Average estimated blood loss was 18 cc in controls vs. 22 cc in patients on antithrombotics, and mortality was 0% vs. 1%, respectively.
Data source: A retrospective study of 390 patients who had urgent or emergent laparoscopic appendectomy at three centers from 2010 to 2014.
Disclosures: Dr. Pearcy reported having no financial disclosures.
CRT-D beneficial in mild HF with ejection fraction above 30%
WASHINGTON – Patients with mild heart failure symptoms, left bundle branch block, and a left ventricular ejection fraction of 31% to 44% who received cardiac resynchronization therapy with a built-in defibrillator experienced a significant reduction in all-cause mortality, compared with those randomized to an implantable cardioverter-defibrillator alone during 7 years of follow-up.
These results from a new MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy) long-term follow-up substudy “suggest that patients with a relatively preserved ejection fraction greater than 30% benefit from CRT-D [cardiac resynchronization therapy defibrillator] and could potentially be considered for this therapy,” said Katherine Vermilye, MD, at the annual meeting of the American College of Cardiology.
In a subsequent publication, the MADIT-CRT investigators reported that, with extension of follow-up to 7 years, CRT-D also provided a significant benefit in terms of all-cause mortality in addition to the reduced rate of heart failure events (N Engl J Med. 2014 May 1;370[18]:1694-701).
However, even though an LVEF of 30% or less was a requirement for participation in MADIT-CRT, it turned out that, when the initial screening echocardiograms were eventually analyzed in a central core laboratory, one-third of study participants actually had a baseline LVEF of 31% to 44%, with the majority of excessive values being in the 31%-35% range.
Dr. Vermilye, of the University of Rochester in New York, presented a post hoc analysis of long-term outcomes in the subgroup having a baseline LVEF greater than 30%. They totaled 450 of 1,224 MADIT-CRT participants with left bundle branch block. They were significantly older and more likely to be female than the 824 subjects with an LVEF of 30% or less. They also had a shorter QRS duration – an average of 160 ms, versus 165 ms in patients with an LVEF of 30% or lower – and a smaller baseline left ventricular end systolic volume of 151 mL, compared with 196 mL in patients with a lower LVEF.
In a multivariate Cox regression analysis adjusted for potential confounders, CRT-D in patients with a baseline LVEF greater than 30% was associated with a 54% reduction in the risk of all-cause mortality at 7 years of follow-up, compared with receipt of an ICD-only device and with a smaller yet significant 31% reduction in risk in those with an LVEF of 30% or less. Worsening heart failure events were reduced by 64% in patients with a baseline LVEF greater than 30% who received CRT-D, compared with ICD-only, and by 54% in those with a lower baseline LVEF.
The reduction in all-cause mortality seen with CRT-D was confined to patients who were high responders to CRT as defined echocardiographically by at least a 35% change in left ventricular end systolic volume 1 year post implantation. They had an 85% reduction in the risk of death during 7 years of follow-up with CRT-D if their baseline LVEF was greater than 30% and a 58% relative risk reduction if their LVEF was 30% or less.
In contrast, CRT-D brought a significantly reduced risk of heart failure events regardless of whether a patient was a low or high responder, although the magnitude of benefit was greater in the high responders. Among patients with a baseline LVEF greater than 30%, CRT-D low responders had a 52% reduction in risk of heart failure events, compared with ICD recipients, while CRT-D high responders had an 81% relative risk reduction. Similarly, in patients with a baseline LVEF of 30% or less, CRT-D low responders had 48% reduction in heart failure events and high responders had a 79% risk reduction, compared with the ICD-only group.
Because this is a post hoc analysis, these new MADIT-CRT findings require validation in future studies, Dr. Vermilye observed.
MADIT-CRT was supported by Boston Scientific. Dr.. Vermilye reported having no financial conflicts.
The authors demonstrate the benefit of cardiac resynchronization therapy in patients with a defibrillator. The reduction in mortality at 5 years was greater in high responders to CRT-D, although overall mortality was significantly reduced in all comers.
The authors demonstrate the benefit of cardiac resynchronization therapy in patients with a defibrillator. The reduction in mortality at 5 years was greater in high responders to CRT-D, although overall mortality was significantly reduced in all comers.
The authors demonstrate the benefit of cardiac resynchronization therapy in patients with a defibrillator. The reduction in mortality at 5 years was greater in high responders to CRT-D, although overall mortality was significantly reduced in all comers.
WASHINGTON – Patients with mild heart failure symptoms, left bundle branch block, and a left ventricular ejection fraction of 31% to 44% who received cardiac resynchronization therapy with a built-in defibrillator experienced a significant reduction in all-cause mortality, compared with those randomized to an implantable cardioverter-defibrillator alone during 7 years of follow-up.
These results from a new MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy) long-term follow-up substudy “suggest that patients with a relatively preserved ejection fraction greater than 30% benefit from CRT-D [cardiac resynchronization therapy defibrillator] and could potentially be considered for this therapy,” said Katherine Vermilye, MD, at the annual meeting of the American College of Cardiology.
In a subsequent publication, the MADIT-CRT investigators reported that, with extension of follow-up to 7 years, CRT-D also provided a significant benefit in terms of all-cause mortality in addition to the reduced rate of heart failure events (N Engl J Med. 2014 May 1;370[18]:1694-701).
However, even though an LVEF of 30% or less was a requirement for participation in MADIT-CRT, it turned out that, when the initial screening echocardiograms were eventually analyzed in a central core laboratory, one-third of study participants actually had a baseline LVEF of 31% to 44%, with the majority of excessive values being in the 31%-35% range.
Dr. Vermilye, of the University of Rochester in New York, presented a post hoc analysis of long-term outcomes in the subgroup having a baseline LVEF greater than 30%. They totaled 450 of 1,224 MADIT-CRT participants with left bundle branch block. They were significantly older and more likely to be female than the 824 subjects with an LVEF of 30% or less. They also had a shorter QRS duration – an average of 160 ms, versus 165 ms in patients with an LVEF of 30% or lower – and a smaller baseline left ventricular end systolic volume of 151 mL, compared with 196 mL in patients with a lower LVEF.
In a multivariate Cox regression analysis adjusted for potential confounders, CRT-D in patients with a baseline LVEF greater than 30% was associated with a 54% reduction in the risk of all-cause mortality at 7 years of follow-up, compared with receipt of an ICD-only device and with a smaller yet significant 31% reduction in risk in those with an LVEF of 30% or less. Worsening heart failure events were reduced by 64% in patients with a baseline LVEF greater than 30% who received CRT-D, compared with ICD-only, and by 54% in those with a lower baseline LVEF.
The reduction in all-cause mortality seen with CRT-D was confined to patients who were high responders to CRT as defined echocardiographically by at least a 35% change in left ventricular end systolic volume 1 year post implantation. They had an 85% reduction in the risk of death during 7 years of follow-up with CRT-D if their baseline LVEF was greater than 30% and a 58% relative risk reduction if their LVEF was 30% or less.
In contrast, CRT-D brought a significantly reduced risk of heart failure events regardless of whether a patient was a low or high responder, although the magnitude of benefit was greater in the high responders. Among patients with a baseline LVEF greater than 30%, CRT-D low responders had a 52% reduction in risk of heart failure events, compared with ICD recipients, while CRT-D high responders had an 81% relative risk reduction. Similarly, in patients with a baseline LVEF of 30% or less, CRT-D low responders had 48% reduction in heart failure events and high responders had a 79% risk reduction, compared with the ICD-only group.
Because this is a post hoc analysis, these new MADIT-CRT findings require validation in future studies, Dr. Vermilye observed.
MADIT-CRT was supported by Boston Scientific. Dr.. Vermilye reported having no financial conflicts.
WASHINGTON – Patients with mild heart failure symptoms, left bundle branch block, and a left ventricular ejection fraction of 31% to 44% who received cardiac resynchronization therapy with a built-in defibrillator experienced a significant reduction in all-cause mortality, compared with those randomized to an implantable cardioverter-defibrillator alone during 7 years of follow-up.
These results from a new MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy) long-term follow-up substudy “suggest that patients with a relatively preserved ejection fraction greater than 30% benefit from CRT-D [cardiac resynchronization therapy defibrillator] and could potentially be considered for this therapy,” said Katherine Vermilye, MD, at the annual meeting of the American College of Cardiology.
In a subsequent publication, the MADIT-CRT investigators reported that, with extension of follow-up to 7 years, CRT-D also provided a significant benefit in terms of all-cause mortality in addition to the reduced rate of heart failure events (N Engl J Med. 2014 May 1;370[18]:1694-701).
However, even though an LVEF of 30% or less was a requirement for participation in MADIT-CRT, it turned out that, when the initial screening echocardiograms were eventually analyzed in a central core laboratory, one-third of study participants actually had a baseline LVEF of 31% to 44%, with the majority of excessive values being in the 31%-35% range.
Dr. Vermilye, of the University of Rochester in New York, presented a post hoc analysis of long-term outcomes in the subgroup having a baseline LVEF greater than 30%. They totaled 450 of 1,224 MADIT-CRT participants with left bundle branch block. They were significantly older and more likely to be female than the 824 subjects with an LVEF of 30% or less. They also had a shorter QRS duration – an average of 160 ms, versus 165 ms in patients with an LVEF of 30% or lower – and a smaller baseline left ventricular end systolic volume of 151 mL, compared with 196 mL in patients with a lower LVEF.
In a multivariate Cox regression analysis adjusted for potential confounders, CRT-D in patients with a baseline LVEF greater than 30% was associated with a 54% reduction in the risk of all-cause mortality at 7 years of follow-up, compared with receipt of an ICD-only device and with a smaller yet significant 31% reduction in risk in those with an LVEF of 30% or less. Worsening heart failure events were reduced by 64% in patients with a baseline LVEF greater than 30% who received CRT-D, compared with ICD-only, and by 54% in those with a lower baseline LVEF.
The reduction in all-cause mortality seen with CRT-D was confined to patients who were high responders to CRT as defined echocardiographically by at least a 35% change in left ventricular end systolic volume 1 year post implantation. They had an 85% reduction in the risk of death during 7 years of follow-up with CRT-D if their baseline LVEF was greater than 30% and a 58% relative risk reduction if their LVEF was 30% or less.
In contrast, CRT-D brought a significantly reduced risk of heart failure events regardless of whether a patient was a low or high responder, although the magnitude of benefit was greater in the high responders. Among patients with a baseline LVEF greater than 30%, CRT-D low responders had a 52% reduction in risk of heart failure events, compared with ICD recipients, while CRT-D high responders had an 81% relative risk reduction. Similarly, in patients with a baseline LVEF of 30% or less, CRT-D low responders had 48% reduction in heart failure events and high responders had a 79% risk reduction, compared with the ICD-only group.
Because this is a post hoc analysis, these new MADIT-CRT findings require validation in future studies, Dr. Vermilye observed.
MADIT-CRT was supported by Boston Scientific. Dr.. Vermilye reported having no financial conflicts.
AT ACC 2017
Key clinical point:
Major finding: The risk of all-cause mortality was reduced by 54% with CRT-D as compared with an ICD alone in MADIT-CRT participants with a baseline LVEF greater than 30% and by 31% in those with an LVEF of 30% or lower.
Data source: An analysis of 7-year rates of all-cause mortality and worsening heart failure events in 1,224 MADIT-CRT participants with left bundle branch block, 450 of whom had a baseline LVEF greater than 30%.
Disclosures: The MADIT-CRT study was supported by Boston Scientific. The presenter reported having no financial conflicts.
Genomic Variation May Reveal ‘Biological Pathway’ to Obesity
African-Americans have the highest age-adjusted rates of obesity in the U.S. Now, an NIH study is offering clues to why that is.
Researchers from the National Human Genome Research Institute (NHGRI), University of Lagos, University of Nigeria, Kwame Nkumrah University of Science and Technology, University of Ghana, and University of Maryland collaborated in a study and found about 1 % of West Africans, African-Americans, and others of African ancestry carry a genomic variant that increases their risk of obesity. People with the genomic differences were about 6 pounds heavier than those without the variant.
This is the first study to use a Genome-Wide Association Study (GWAS) to investigate the genomic basis of obesity in continental Africans. Most previous studies on obesity using a GWAS have examined people of European ancestry. Those studies would not have found the genomic variant for the African descendants which is absent in Europeans and Asians. “We wanted to close this unacceptable gap in genomics research,” said Charles Rotimi, PhD, chief of NHGRI’s Metabolic, Cardiovascular and Inflammatory Disease Genomics Branch and director of the NIH Center for Research on Genomics and Global Health.
“By studying people of West Africa, the ancestral home of most African-Americans, and replicating our results in a large group of African-Americans,” said Ayo Doumatey, PhD, study co-lead and CRGGH staff scientist, “we are providing new insights into biological pathways for obesity that have not been previously explored.”
African-Americans have the highest age-adjusted rates of obesity in the U.S. Now, an NIH study is offering clues to why that is.
Researchers from the National Human Genome Research Institute (NHGRI), University of Lagos, University of Nigeria, Kwame Nkumrah University of Science and Technology, University of Ghana, and University of Maryland collaborated in a study and found about 1 % of West Africans, African-Americans, and others of African ancestry carry a genomic variant that increases their risk of obesity. People with the genomic differences were about 6 pounds heavier than those without the variant.
This is the first study to use a Genome-Wide Association Study (GWAS) to investigate the genomic basis of obesity in continental Africans. Most previous studies on obesity using a GWAS have examined people of European ancestry. Those studies would not have found the genomic variant for the African descendants which is absent in Europeans and Asians. “We wanted to close this unacceptable gap in genomics research,” said Charles Rotimi, PhD, chief of NHGRI’s Metabolic, Cardiovascular and Inflammatory Disease Genomics Branch and director of the NIH Center for Research on Genomics and Global Health.
“By studying people of West Africa, the ancestral home of most African-Americans, and replicating our results in a large group of African-Americans,” said Ayo Doumatey, PhD, study co-lead and CRGGH staff scientist, “we are providing new insights into biological pathways for obesity that have not been previously explored.”
African-Americans have the highest age-adjusted rates of obesity in the U.S. Now, an NIH study is offering clues to why that is.
Researchers from the National Human Genome Research Institute (NHGRI), University of Lagos, University of Nigeria, Kwame Nkumrah University of Science and Technology, University of Ghana, and University of Maryland collaborated in a study and found about 1 % of West Africans, African-Americans, and others of African ancestry carry a genomic variant that increases their risk of obesity. People with the genomic differences were about 6 pounds heavier than those without the variant.
This is the first study to use a Genome-Wide Association Study (GWAS) to investigate the genomic basis of obesity in continental Africans. Most previous studies on obesity using a GWAS have examined people of European ancestry. Those studies would not have found the genomic variant for the African descendants which is absent in Europeans and Asians. “We wanted to close this unacceptable gap in genomics research,” said Charles Rotimi, PhD, chief of NHGRI’s Metabolic, Cardiovascular and Inflammatory Disease Genomics Branch and director of the NIH Center for Research on Genomics and Global Health.
“By studying people of West Africa, the ancestral home of most African-Americans, and replicating our results in a large group of African-Americans,” said Ayo Doumatey, PhD, study co-lead and CRGGH staff scientist, “we are providing new insights into biological pathways for obesity that have not been previously explored.”
Role of TET2 in hematologic malignancies
New research appears to explain how TET2 mutations increase the risk of hematologic malignancies.
In studying mouse models and patient samples, researchers found evidence to suggest that loss of TET2 opens the door for mutations that drive lymphoid and myeloid malignancies.
The researchers said loss of TET2 leads to hypermutagenicity in hematopoietic stem and progenitor cells (HSPCs), and although TET2-deficient HSPCs are likely not malignant, the higher mutation rates in these cells may result in additional driver mutations in TET2 target genes over time.
“If you lose TET2, it’s not a malignant state per se,” said Mingjiang Xu, MD, PhD, of the University of Miami Miller School of Medicine in Florida.
“But it’s creating a situation for other mutations to happen, leading to all types of blood cancer.”
Dr Xu and his colleagues reported these findings in Nature Communications.
The researchers found that Tet2-knockout mice developed spontaneous, lethal hematologic malignancies. Most (92%) developed myeloid malignancies, but 3.5% developed T-cell malignancies, and 4.5% developed B-cell malignancies.
In sequencing tumor and non-tumor cells from the Tet2-knockout mice, the researchers observed that loss of Tet2 leads to hypermutagenicity in HSPCs.
The team identified 190 genes with recurrent single-nucleotide variants. This included genes that are recurrently altered in human hematologic malignancies—Apc, Nf1, Flt3, Cbl, Notch1, and Mll2.
The researchers also analyzed samples from patients with acute myeloid leukemia, myeloproliferative neoplasms, and myelodysplastic syndromes.
The team found that patients with TET2 mutations had “significantly more mutational events than patients with wild-type TET2.” And TET2 mutations were associated with subclonal events in APC, NF1, ASXL1, CBL, and ZRSR2, among other genes.
These findings suggest that targeting TET2 could potentially prevent the development of hematologic malignancies.
The researchers noted that TET2 mutations occur in healthy elderly individuals with clonal hematopoiesis, and these individuals would be ideal candidates for a preventive therapy targeting TET2.
“We are developing a method to target TET2,” Dr Xu said. “If we target that population [with TET2 mutations] for early therapy, we could potentially prevent those downstream mutations from happening.” 
New research appears to explain how TET2 mutations increase the risk of hematologic malignancies.
In studying mouse models and patient samples, researchers found evidence to suggest that loss of TET2 opens the door for mutations that drive lymphoid and myeloid malignancies.
The researchers said loss of TET2 leads to hypermutagenicity in hematopoietic stem and progenitor cells (HSPCs), and although TET2-deficient HSPCs are likely not malignant, the higher mutation rates in these cells may result in additional driver mutations in TET2 target genes over time.
“If you lose TET2, it’s not a malignant state per se,” said Mingjiang Xu, MD, PhD, of the University of Miami Miller School of Medicine in Florida.
“But it’s creating a situation for other mutations to happen, leading to all types of blood cancer.”
Dr Xu and his colleagues reported these findings in Nature Communications.
The researchers found that Tet2-knockout mice developed spontaneous, lethal hematologic malignancies. Most (92%) developed myeloid malignancies, but 3.5% developed T-cell malignancies, and 4.5% developed B-cell malignancies.
In sequencing tumor and non-tumor cells from the Tet2-knockout mice, the researchers observed that loss of Tet2 leads to hypermutagenicity in HSPCs.
The team identified 190 genes with recurrent single-nucleotide variants. This included genes that are recurrently altered in human hematologic malignancies—Apc, Nf1, Flt3, Cbl, Notch1, and Mll2.
The researchers also analyzed samples from patients with acute myeloid leukemia, myeloproliferative neoplasms, and myelodysplastic syndromes.
The team found that patients with TET2 mutations had “significantly more mutational events than patients with wild-type TET2.” And TET2 mutations were associated with subclonal events in APC, NF1, ASXL1, CBL, and ZRSR2, among other genes.
These findings suggest that targeting TET2 could potentially prevent the development of hematologic malignancies.
The researchers noted that TET2 mutations occur in healthy elderly individuals with clonal hematopoiesis, and these individuals would be ideal candidates for a preventive therapy targeting TET2.
“We are developing a method to target TET2,” Dr Xu said. “If we target that population [with TET2 mutations] for early therapy, we could potentially prevent those downstream mutations from happening.”
New research appears to explain how TET2 mutations increase the risk of hematologic malignancies.
In studying mouse models and patient samples, researchers found evidence to suggest that loss of TET2 opens the door for mutations that drive lymphoid and myeloid malignancies.
The researchers said loss of TET2 leads to hypermutagenicity in hematopoietic stem and progenitor cells (HSPCs), and although TET2-deficient HSPCs are likely not malignant, the higher mutation rates in these cells may result in additional driver mutations in TET2 target genes over time.
“If you lose TET2, it’s not a malignant state per se,” said Mingjiang Xu, MD, PhD, of the University of Miami Miller School of Medicine in Florida.
“But it’s creating a situation for other mutations to happen, leading to all types of blood cancer.”
Dr Xu and his colleagues reported these findings in Nature Communications.
The researchers found that Tet2-knockout mice developed spontaneous, lethal hematologic malignancies. Most (92%) developed myeloid malignancies, but 3.5% developed T-cell malignancies, and 4.5% developed B-cell malignancies.
In sequencing tumor and non-tumor cells from the Tet2-knockout mice, the researchers observed that loss of Tet2 leads to hypermutagenicity in HSPCs.
The team identified 190 genes with recurrent single-nucleotide variants. This included genes that are recurrently altered in human hematologic malignancies—Apc, Nf1, Flt3, Cbl, Notch1, and Mll2.
The researchers also analyzed samples from patients with acute myeloid leukemia, myeloproliferative neoplasms, and myelodysplastic syndromes.
The team found that patients with TET2 mutations had “significantly more mutational events than patients with wild-type TET2.” And TET2 mutations were associated with subclonal events in APC, NF1, ASXL1, CBL, and ZRSR2, among other genes.
These findings suggest that targeting TET2 could potentially prevent the development of hematologic malignancies.
The researchers noted that TET2 mutations occur in healthy elderly individuals with clonal hematopoiesis, and these individuals would be ideal candidates for a preventive therapy targeting TET2.
“We are developing a method to target TET2,” Dr Xu said. “If we target that population [with TET2 mutations] for early therapy, we could potentially prevent those downstream mutations from happening.”
Drug receives fast track designation for follicular lymphoma
The US Food and Drug Administration (FDA) has granted fast track designation to the EZH2 inhibitor tazemetostat as a treatment for relapsed or refractory follicular lymphoma, with or without EZH2-activating mutations.
The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.
Through the fast track program, a product may be eligible for priority review.
In addition, the company developing the product may be allowed to submit sections of the new drug application or biologic license application on a rolling basis as data become available.
Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.
Tazemetostat also has fast track designation from the FDA as a treatment for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) with EZH2-activating mutations.
Tazemetostat is under investigation as monotherapy and in combination with other agents as a treatment for multiple cancers.
Results from a phase 1 study suggested tazemetostat can produce durable responses in patients with advanced non-Hodgkin lymphomas, including follicular lymphoma and DLBCL. The study was presented at the 2015 ASH Annual Meeting.
Tazemetostat is currently under investigation in a phase 2 trial of adults with relapsed or refractory DLBCL or follicular lymphoma.
Interim efficacy and safety data from this study are scheduled to be presented at the International Conference on Malignant Lymphoma (ICML) in Lugano, Switzerland, on June 14, 2017, at 2:00 pm CET.
Tazemetostat is being developed by Epizyme, Inc.
The US Food and Drug Administration (FDA) has granted fast track designation to the EZH2 inhibitor tazemetostat as a treatment for relapsed or refractory follicular lymphoma, with or without EZH2-activating mutations.
The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.
Through the fast track program, a product may be eligible for priority review.
In addition, the company developing the product may be allowed to submit sections of the new drug application or biologic license application on a rolling basis as data become available.
Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.
Tazemetostat also has fast track designation from the FDA as a treatment for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) with EZH2-activating mutations.
Tazemetostat is under investigation as monotherapy and in combination with other agents as a treatment for multiple cancers.
Results from a phase 1 study suggested tazemetostat can produce durable responses in patients with advanced non-Hodgkin lymphomas, including follicular lymphoma and DLBCL. The study was presented at the 2015 ASH Annual Meeting.
Tazemetostat is currently under investigation in a phase 2 trial of adults with relapsed or refractory DLBCL or follicular lymphoma.
Interim efficacy and safety data from this study are scheduled to be presented at the International Conference on Malignant Lymphoma (ICML) in Lugano, Switzerland, on June 14, 2017, at 2:00 pm CET.
Tazemetostat is being developed by Epizyme, Inc.
The US Food and Drug Administration (FDA) has granted fast track designation to the EZH2 inhibitor tazemetostat as a treatment for relapsed or refractory follicular lymphoma, with or without EZH2-activating mutations.
The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.
Through the fast track program, a product may be eligible for priority review.
In addition, the company developing the product may be allowed to submit sections of the new drug application or biologic license application on a rolling basis as data become available.
Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.
Tazemetostat also has fast track designation from the FDA as a treatment for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) with EZH2-activating mutations.
Tazemetostat is under investigation as monotherapy and in combination with other agents as a treatment for multiple cancers.
Results from a phase 1 study suggested tazemetostat can produce durable responses in patients with advanced non-Hodgkin lymphomas, including follicular lymphoma and DLBCL. The study was presented at the 2015 ASH Annual Meeting.
Tazemetostat is currently under investigation in a phase 2 trial of adults with relapsed or refractory DLBCL or follicular lymphoma.
Interim efficacy and safety data from this study are scheduled to be presented at the International Conference on Malignant Lymphoma (ICML) in Lugano, Switzerland, on June 14, 2017, at 2:00 pm CET.
Tazemetostat is being developed by Epizyme, Inc.
Treatment granted PRIME designation for hemophilia B
The European Medicines Agency (EMA) has granted AMT-060 access to the agency’s PRIority MEdicines (PRIME) program.
AMT-060 is an investigational gene therapy intended for the treatment of patients with severe hemophilia B.
The goal of the EMA’s PRIME program is to accelerate the development of therapies that may offer a major advantage over existing treatments or benefit patients with no treatment options.
Through PRIME, the EMA offers early and enhanced support to developers in order to optimize development plans and speed regulatory evaluations to potentially bring therapies to patients more quickly.
To be accepted for PRIME, a therapy must demonstrate the potential to benefit patients with unmet medical need through early clinical or nonclinical data.
About AMT-060
AMT-060 consists of a codon-optimized wild-type factor IX (FIX) gene cassette, the LP1 liver promoter, and an AAV5 viral vector manufactured by uniQure using its proprietary insect cell-based technology platform. UniQure is the company developing AMT-060.
The EMA’s decision to grant AMT-060 access to the PRIME program is based on results from an ongoing phase 1/2 study. Updated data from this study were presented at the 2016 ASH Annual Meeting (abstract 2314).
The presentation included data on 10 patients. All patients had severe or moderately severe hemophilia at baseline, including documented FIX levels less than 1% to 2% of normal, and required chronic infusions of prophylactic or on-demand FIX therapy at the time of enrollment.
Each patient received a 1-time, 30-minute, intravenous dose of AMT-060, without the use of corticosteroids. Five patients received AMT-060 at 5 x 1012 gc/kg, and 5 received AMT-060 at 2 x 1013 gc/kg.
Patients in the low-dose cohort were followed for up to 52 weeks, and those in the higher-dose cohort were followed for up to 31 weeks.
Data from the higher-dose cohort showed a dose response with improvement in disease state in all 5 patients. Four patients who previously required prophylactic FIX therapy were able to stop this therapy.
As of the data cutoff date, 1 unconfirmed spontaneous bleed had been reported during an aggregate of 94 weeks of follow-up after the discontinuation of prophylaxis.
Researchers previously reported that 4 patients in the low-dose cohort were able to discontinue prophylactic therapy. The 1 patient who remained on prophylaxis sustained an improved disease phenotype and also required materially less FIX concentrate after treatment with AMT-060.
According to uniQure, all 5 patients in the low-dose cohort maintained “constant and clinically meaningful” levels of FIX activity for up to 52 weeks post-treatment. In fact, there were no spontaneous bleeds in these patients in the last 14 weeks of observation.
uniQure also said AMT-060 was well-tolerated, and there have been no severe adverse events.
Three patients (2 in the higher-dose cohort and 1 previously reported from the low-dose cohort) experienced mild, asymptomatic elevations of alanine aminotransferase and received a tapering course of corticosteroids per protocol.
These temporary alanine aminotransferase elevations were not associated with any loss of endogenous FIX activity or T-cell response to the AAV5 capsid.
None of the patients in either cohort have developed inhibitory antibodies against FIX, and none of the patients screened tested positive for anti-AAV5 antibodies.
The European Medicines Agency (EMA) has granted AMT-060 access to the agency’s PRIority MEdicines (PRIME) program.
AMT-060 is an investigational gene therapy intended for the treatment of patients with severe hemophilia B.
The goal of the EMA’s PRIME program is to accelerate the development of therapies that may offer a major advantage over existing treatments or benefit patients with no treatment options.
Through PRIME, the EMA offers early and enhanced support to developers in order to optimize development plans and speed regulatory evaluations to potentially bring therapies to patients more quickly.
To be accepted for PRIME, a therapy must demonstrate the potential to benefit patients with unmet medical need through early clinical or nonclinical data.
About AMT-060
AMT-060 consists of a codon-optimized wild-type factor IX (FIX) gene cassette, the LP1 liver promoter, and an AAV5 viral vector manufactured by uniQure using its proprietary insect cell-based technology platform. UniQure is the company developing AMT-060.
The EMA’s decision to grant AMT-060 access to the PRIME program is based on results from an ongoing phase 1/2 study. Updated data from this study were presented at the 2016 ASH Annual Meeting (abstract 2314).
The presentation included data on 10 patients. All patients had severe or moderately severe hemophilia at baseline, including documented FIX levels less than 1% to 2% of normal, and required chronic infusions of prophylactic or on-demand FIX therapy at the time of enrollment.
Each patient received a 1-time, 30-minute, intravenous dose of AMT-060, without the use of corticosteroids. Five patients received AMT-060 at 5 x 1012 gc/kg, and 5 received AMT-060 at 2 x 1013 gc/kg.
Patients in the low-dose cohort were followed for up to 52 weeks, and those in the higher-dose cohort were followed for up to 31 weeks.
Data from the higher-dose cohort showed a dose response with improvement in disease state in all 5 patients. Four patients who previously required prophylactic FIX therapy were able to stop this therapy.
As of the data cutoff date, 1 unconfirmed spontaneous bleed had been reported during an aggregate of 94 weeks of follow-up after the discontinuation of prophylaxis.
Researchers previously reported that 4 patients in the low-dose cohort were able to discontinue prophylactic therapy. The 1 patient who remained on prophylaxis sustained an improved disease phenotype and also required materially less FIX concentrate after treatment with AMT-060.
According to uniQure, all 5 patients in the low-dose cohort maintained “constant and clinically meaningful” levels of FIX activity for up to 52 weeks post-treatment. In fact, there were no spontaneous bleeds in these patients in the last 14 weeks of observation.
uniQure also said AMT-060 was well-tolerated, and there have been no severe adverse events.
Three patients (2 in the higher-dose cohort and 1 previously reported from the low-dose cohort) experienced mild, asymptomatic elevations of alanine aminotransferase and received a tapering course of corticosteroids per protocol.
These temporary alanine aminotransferase elevations were not associated with any loss of endogenous FIX activity or T-cell response to the AAV5 capsid.
None of the patients in either cohort have developed inhibitory antibodies against FIX, and none of the patients screened tested positive for anti-AAV5 antibodies.
The European Medicines Agency (EMA) has granted AMT-060 access to the agency’s PRIority MEdicines (PRIME) program.
AMT-060 is an investigational gene therapy intended for the treatment of patients with severe hemophilia B.
The goal of the EMA’s PRIME program is to accelerate the development of therapies that may offer a major advantage over existing treatments or benefit patients with no treatment options.
Through PRIME, the EMA offers early and enhanced support to developers in order to optimize development plans and speed regulatory evaluations to potentially bring therapies to patients more quickly.
To be accepted for PRIME, a therapy must demonstrate the potential to benefit patients with unmet medical need through early clinical or nonclinical data.
About AMT-060
AMT-060 consists of a codon-optimized wild-type factor IX (FIX) gene cassette, the LP1 liver promoter, and an AAV5 viral vector manufactured by uniQure using its proprietary insect cell-based technology platform. UniQure is the company developing AMT-060.
The EMA’s decision to grant AMT-060 access to the PRIME program is based on results from an ongoing phase 1/2 study. Updated data from this study were presented at the 2016 ASH Annual Meeting (abstract 2314).
The presentation included data on 10 patients. All patients had severe or moderately severe hemophilia at baseline, including documented FIX levels less than 1% to 2% of normal, and required chronic infusions of prophylactic or on-demand FIX therapy at the time of enrollment.
Each patient received a 1-time, 30-minute, intravenous dose of AMT-060, without the use of corticosteroids. Five patients received AMT-060 at 5 x 1012 gc/kg, and 5 received AMT-060 at 2 x 1013 gc/kg.
Patients in the low-dose cohort were followed for up to 52 weeks, and those in the higher-dose cohort were followed for up to 31 weeks.
Data from the higher-dose cohort showed a dose response with improvement in disease state in all 5 patients. Four patients who previously required prophylactic FIX therapy were able to stop this therapy.
As of the data cutoff date, 1 unconfirmed spontaneous bleed had been reported during an aggregate of 94 weeks of follow-up after the discontinuation of prophylaxis.
Researchers previously reported that 4 patients in the low-dose cohort were able to discontinue prophylactic therapy. The 1 patient who remained on prophylaxis sustained an improved disease phenotype and also required materially less FIX concentrate after treatment with AMT-060.
According to uniQure, all 5 patients in the low-dose cohort maintained “constant and clinically meaningful” levels of FIX activity for up to 52 weeks post-treatment. In fact, there were no spontaneous bleeds in these patients in the last 14 weeks of observation.
uniQure also said AMT-060 was well-tolerated, and there have been no severe adverse events.
Three patients (2 in the higher-dose cohort and 1 previously reported from the low-dose cohort) experienced mild, asymptomatic elevations of alanine aminotransferase and received a tapering course of corticosteroids per protocol.
These temporary alanine aminotransferase elevations were not associated with any loss of endogenous FIX activity or T-cell response to the AAV5 capsid.
None of the patients in either cohort have developed inhibitory antibodies against FIX, and none of the patients screened tested positive for anti-AAV5 antibodies.
FDA issues warnings about illegal ‘anticancer’ products
The US Food and Drug Administration (FDA) has posted warning letters addressed to 14 US-based companies illegally selling more than 65 products.
The companies are fraudulently claiming that these products prevent, diagnose, treat, or cure cancer.
The products are being marketed and sold without FDA approval, most commonly on websites and social media platforms.
“Consumers should not use these or similar unproven products because they may be unsafe and could prevent a person from seeking an appropriate and potentially life-saving cancer diagnosis or treatment,” said Douglas W. Stearn, director of the Office of Enforcement and Import Operations in the FDA’s Office of Regulatory Affairs.
“We encourage people to remain vigilant whether online or in a store, and avoid purchasing products marketed to treat cancer without any proof they will work. Patients should consult a healthcare professional about proper prevention, diagnosis, and treatment of cancer.”
It is a violation of the Federal Food, Drug and Cosmetic Act to market and sell products that claim to prevent, diagnose, treat, mitigate, or cure diseases without first demonstrating to the FDA that they are safe and effective for their labeled uses.
The illegally sold products cited in the FDA’s warning letters include a variety of product types, such as pills, topical creams, ointments, oils, drops, syrups, teas, and diagnostics (such as thermography devices).
They include products marketed for use by humans or pets that make illegal, unproven claims regarding preventing, reversing, or curing cancer; killing/inhibiting cancer cells or tumors; or other similar anticancer claims.
The FDA has requested responses from the 14 companies stating how the violations will be corrected. Failure to correct the violations promptly may result in legal action, including product seizure, injunction, and/or criminal prosecution.
As part of the FDA’s effort to protect consumers from cancer health fraud, the FDA has issued more than 90 warning letters in the past 10 years to companies marketing hundreds of fraudulent cancer-related products on websites, social media, and in stores.
Although many of these companies have stopped selling the products or making fraudulent claims, numerous unsafe and unapproved products continue to be sold directly to consumers due, in part, to the ease with which companies can move their marketing operations to new websites.
The FDA continues to monitor and take action against companies promoting and selling unproven treatments in an effort to minimize the potential dangers to consumers and to educate consumers about the risks.
The FDA encourages healthcare professionals and consumers to report adverse reactions associated with these or similar products to the FDA’s MedWatch program.
The US Food and Drug Administration (FDA) has posted warning letters addressed to 14 US-based companies illegally selling more than 65 products.
The companies are fraudulently claiming that these products prevent, diagnose, treat, or cure cancer.
The products are being marketed and sold without FDA approval, most commonly on websites and social media platforms.
“Consumers should not use these or similar unproven products because they may be unsafe and could prevent a person from seeking an appropriate and potentially life-saving cancer diagnosis or treatment,” said Douglas W. Stearn, director of the Office of Enforcement and Import Operations in the FDA’s Office of Regulatory Affairs.
“We encourage people to remain vigilant whether online or in a store, and avoid purchasing products marketed to treat cancer without any proof they will work. Patients should consult a healthcare professional about proper prevention, diagnosis, and treatment of cancer.”
It is a violation of the Federal Food, Drug and Cosmetic Act to market and sell products that claim to prevent, diagnose, treat, mitigate, or cure diseases without first demonstrating to the FDA that they are safe and effective for their labeled uses.
The illegally sold products cited in the FDA’s warning letters include a variety of product types, such as pills, topical creams, ointments, oils, drops, syrups, teas, and diagnostics (such as thermography devices).
They include products marketed for use by humans or pets that make illegal, unproven claims regarding preventing, reversing, or curing cancer; killing/inhibiting cancer cells or tumors; or other similar anticancer claims.
The FDA has requested responses from the 14 companies stating how the violations will be corrected. Failure to correct the violations promptly may result in legal action, including product seizure, injunction, and/or criminal prosecution.
As part of the FDA’s effort to protect consumers from cancer health fraud, the FDA has issued more than 90 warning letters in the past 10 years to companies marketing hundreds of fraudulent cancer-related products on websites, social media, and in stores.
Although many of these companies have stopped selling the products or making fraudulent claims, numerous unsafe and unapproved products continue to be sold directly to consumers due, in part, to the ease with which companies can move their marketing operations to new websites.
The FDA continues to monitor and take action against companies promoting and selling unproven treatments in an effort to minimize the potential dangers to consumers and to educate consumers about the risks.
The FDA encourages healthcare professionals and consumers to report adverse reactions associated with these or similar products to the FDA’s MedWatch program.
The US Food and Drug Administration (FDA) has posted warning letters addressed to 14 US-based companies illegally selling more than 65 products.
The companies are fraudulently claiming that these products prevent, diagnose, treat, or cure cancer.
The products are being marketed and sold without FDA approval, most commonly on websites and social media platforms.
“Consumers should not use these or similar unproven products because they may be unsafe and could prevent a person from seeking an appropriate and potentially life-saving cancer diagnosis or treatment,” said Douglas W. Stearn, director of the Office of Enforcement and Import Operations in the FDA’s Office of Regulatory Affairs.
“We encourage people to remain vigilant whether online or in a store, and avoid purchasing products marketed to treat cancer without any proof they will work. Patients should consult a healthcare professional about proper prevention, diagnosis, and treatment of cancer.”
It is a violation of the Federal Food, Drug and Cosmetic Act to market and sell products that claim to prevent, diagnose, treat, mitigate, or cure diseases without first demonstrating to the FDA that they are safe and effective for their labeled uses.
The illegally sold products cited in the FDA’s warning letters include a variety of product types, such as pills, topical creams, ointments, oils, drops, syrups, teas, and diagnostics (such as thermography devices).
They include products marketed for use by humans or pets that make illegal, unproven claims regarding preventing, reversing, or curing cancer; killing/inhibiting cancer cells or tumors; or other similar anticancer claims.
The FDA has requested responses from the 14 companies stating how the violations will be corrected. Failure to correct the violations promptly may result in legal action, including product seizure, injunction, and/or criminal prosecution.
As part of the FDA’s effort to protect consumers from cancer health fraud, the FDA has issued more than 90 warning letters in the past 10 years to companies marketing hundreds of fraudulent cancer-related products on websites, social media, and in stores.
Although many of these companies have stopped selling the products or making fraudulent claims, numerous unsafe and unapproved products continue to be sold directly to consumers due, in part, to the ease with which companies can move their marketing operations to new websites.
The FDA continues to monitor and take action against companies promoting and selling unproven treatments in an effort to minimize the potential dangers to consumers and to educate consumers about the risks.
The FDA encourages healthcare professionals and consumers to report adverse reactions associated with these or similar products to the FDA’s MedWatch program.
Use of second-generation antidepressants in older adults is associated with increased hospitalization with hyponatremia
Clinical Question: Is there an increased risk of hyponatremia for older patients who are taking a second-generation antidepressant?
Background: Mood and anxiety disorders affect about one in eight older adults, and second-generation antidepressants are frequently recommended for treatment. A potential adverse effect of these agents is hyponatremia, which can lead to serious sequelae. The aim of this study was to investigate the 30-day risk for hospitalization with hyponatremia in older adults who were newly started on a second-generation antidepressant.
Setting: Ontario, Canada.
Synopsis: Multiple databases were utilized to obtain vital statistics and demographic information, diagnoses, prescriptions, and serum sodium measurements to establish a cohort population. One group of 172,552 was newly prescribed a second-generation antidepressant. A second control group of 297,501 was established in which patients were not prescribed antidepressants. Greedy matching was used to match each user to a nonuser based on similar characteristics of age, sex, evidence of mood disorder, chronic kidney disease, congestive heart failure, or diuretic use. After matching, 138,246 patients remained in each group and were nearly identical for all 10 0 measured characteristics. The primary outcome was that, compared with nonuse, second-generation antidepressant use was associated with higher 30-day risk of hospitalization with hyponatremia (relative risk, 5.46; 95% CI, 4.32-6.91). The secondary outcome showed that, compared with non-use, second-generation antidepressant use was associated with higher 30-day risk for hospitalization with concomitant hyponatremia and delirium (RR, 4.00; 95% CI, 1.74 - 9.16). Additionally, tests for specificity and temporality were employed.
Bottom Line: A robust association between second-generation antidepressant use and hospitalization with hyponatremia was determined in the large population-based cohort study.
Citation: Gandhi S, Shariff SZ, Al-Jaishi A, et al. “Second-generation antidepressants and hyponatremia risk: a population-based cohort study of older adults.” Am J Kidney Dis. 2017 Jan;69(1):87-96.
Dr. Kim is clinical assistant professor in the division of hospital medicine, Loyola University Chicago, Maywood, Ill.
Clinical Question: Is there an increased risk of hyponatremia for older patients who are taking a second-generation antidepressant?
Background: Mood and anxiety disorders affect about one in eight older adults, and second-generation antidepressants are frequently recommended for treatment. A potential adverse effect of these agents is hyponatremia, which can lead to serious sequelae. The aim of this study was to investigate the 30-day risk for hospitalization with hyponatremia in older adults who were newly started on a second-generation antidepressant.
Setting: Ontario, Canada.
Synopsis: Multiple databases were utilized to obtain vital statistics and demographic information, diagnoses, prescriptions, and serum sodium measurements to establish a cohort population. One group of 172,552 was newly prescribed a second-generation antidepressant. A second control group of 297,501 was established in which patients were not prescribed antidepressants. Greedy matching was used to match each user to a nonuser based on similar characteristics of age, sex, evidence of mood disorder, chronic kidney disease, congestive heart failure, or diuretic use. After matching, 138,246 patients remained in each group and were nearly identical for all 10 0 measured characteristics. The primary outcome was that, compared with nonuse, second-generation antidepressant use was associated with higher 30-day risk of hospitalization with hyponatremia (relative risk, 5.46; 95% CI, 4.32-6.91). The secondary outcome showed that, compared with non-use, second-generation antidepressant use was associated with higher 30-day risk for hospitalization with concomitant hyponatremia and delirium (RR, 4.00; 95% CI, 1.74 - 9.16). Additionally, tests for specificity and temporality were employed.
Bottom Line: A robust association between second-generation antidepressant use and hospitalization with hyponatremia was determined in the large population-based cohort study.
Citation: Gandhi S, Shariff SZ, Al-Jaishi A, et al. “Second-generation antidepressants and hyponatremia risk: a population-based cohort study of older adults.” Am J Kidney Dis. 2017 Jan;69(1):87-96.
Dr. Kim is clinical assistant professor in the division of hospital medicine, Loyola University Chicago, Maywood, Ill.
Clinical Question: Is there an increased risk of hyponatremia for older patients who are taking a second-generation antidepressant?
Background: Mood and anxiety disorders affect about one in eight older adults, and second-generation antidepressants are frequently recommended for treatment. A potential adverse effect of these agents is hyponatremia, which can lead to serious sequelae. The aim of this study was to investigate the 30-day risk for hospitalization with hyponatremia in older adults who were newly started on a second-generation antidepressant.
Setting: Ontario, Canada.
Synopsis: Multiple databases were utilized to obtain vital statistics and demographic information, diagnoses, prescriptions, and serum sodium measurements to establish a cohort population. One group of 172,552 was newly prescribed a second-generation antidepressant. A second control group of 297,501 was established in which patients were not prescribed antidepressants. Greedy matching was used to match each user to a nonuser based on similar characteristics of age, sex, evidence of mood disorder, chronic kidney disease, congestive heart failure, or diuretic use. After matching, 138,246 patients remained in each group and were nearly identical for all 10 0 measured characteristics. The primary outcome was that, compared with nonuse, second-generation antidepressant use was associated with higher 30-day risk of hospitalization with hyponatremia (relative risk, 5.46; 95% CI, 4.32-6.91). The secondary outcome showed that, compared with non-use, second-generation antidepressant use was associated with higher 30-day risk for hospitalization with concomitant hyponatremia and delirium (RR, 4.00; 95% CI, 1.74 - 9.16). Additionally, tests for specificity and temporality were employed.
Bottom Line: A robust association between second-generation antidepressant use and hospitalization with hyponatremia was determined in the large population-based cohort study.
Citation: Gandhi S, Shariff SZ, Al-Jaishi A, et al. “Second-generation antidepressants and hyponatremia risk: a population-based cohort study of older adults.” Am J Kidney Dis. 2017 Jan;69(1):87-96.
Dr. Kim is clinical assistant professor in the division of hospital medicine, Loyola University Chicago, Maywood, Ill.
FDA issues warning to companies selling illegal cancer treatments
The Food and Drug Administration has issued a warning to 14 U.S. companies that are illegally selling more than 65 products purported to prevent, diagnose, treat, or cure cancer, according to an FDA safety alert.
Product types include pills, topical creams, ointments, oils, drops, syrups, teas, and diagnostic tools. The affected products are usually sold online or through social media.
Find the full safety alert on the FDA website.
The Food and Drug Administration has issued a warning to 14 U.S. companies that are illegally selling more than 65 products purported to prevent, diagnose, treat, or cure cancer, according to an FDA safety alert.
Product types include pills, topical creams, ointments, oils, drops, syrups, teas, and diagnostic tools. The affected products are usually sold online or through social media.
Find the full safety alert on the FDA website.
The Food and Drug Administration has issued a warning to 14 U.S. companies that are illegally selling more than 65 products purported to prevent, diagnose, treat, or cure cancer, according to an FDA safety alert.
Product types include pills, topical creams, ointments, oils, drops, syrups, teas, and diagnostic tools. The affected products are usually sold online or through social media.
Find the full safety alert on the FDA website.
MDS genetic analysis identifies allogeneic HSCT candidates
NEW YORK – Genetic mutation analysis of patients with myelodysplastic syndrome (MDS) may have a useful role in routine practice based on recent reports that showed clear links between certain gene mutations and the outcomes of patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT).
Two reports published in 2017 helped strengthen the case for routine mutation analysis in distinguishing patients with MDS or myeloproliferative neoplasms (MDN) who are very likely to have just a brief response to allogeneic HSCT from similar patients who seem likely to have several years of overall survival following transplantation.
Allogeneic HSCT is the only potentially curative procedure for patients with MDS or MDN. Although an increasing number of these patients undergo transplantation, clinicians need to choose the patients they select for the treatment carefully. “Molecular testing is playing an increasing role in selecting the best candidates,” Dr. Zeidan said.
The largest reported genetic study of allogeneic HSCT in MDS patients involved 1,514 patients entered into a U.S.-based dataset during 2005-2015. Testing identified at least one mutation in 1,196 (79%) of these patients.
Analysis of data from these patients found a disparate pattern of posttransplant survival that appeared to link with gene mutations and other risk factors. The highest risk patients were those with a mutation in their TP53 gene, found in 289 patients (19% of the 1,514 tested) who had a median overall survival (OS) of 0.7 years and a 3-year OS of 20% (New Engl J Med. 2017 Feb 9;376[6]:536-47).
Among patients without a TP53 mutation, OS depended on age, with the best survival seen among patients less than 40 years old. Patients in this subgroup who also had no other high-risk features – no therapy-related MDS, a platelet level of at least 30 x 109 at the time of transplantation, and bone marrow blasts less than 15% at diagnosis – had the best OS, 82% at 3-years of follow-up. The studied cohort included 116 patients (8%) who fell into this low-risk, best-outcome category, the optimal population for receiving an allogeneic HSCT, Dr. Zeidan said. Another 98 patients (6%) who had at least one of these high risk feature had a median OS of 2.6 years and a 3-year OS of 49%.
Additional gene mutations further subdivided the older patients in the study, those at least 40 years old, into various risk subgroups. Older patients with a mutation in a ras-pathway gene had a 0.9 year median OS and a 3-year OS of 30%. This subgroup included 129 patients (9%). Among older patients with no mutation in the ras-pathway gene, mutations in the JAK2 gene also linked with worse survival, a median OS of 0.5 years and a 3-year OS of 28% of a subgroup with 28 patients (2%). The largest subgroup in the study was older patients with no mutations in the TP53, JAK2, or ras-pathway genes, a subgroup with 854 patients (56%), who had a median OS of 2.3 years and a 3-year OS of 46%.
The second recent report was a Japanese study of 797 MDS patients who underwent genetic testing and received an allogeneic HSCT through the Japan Marrow Donor Program. The investigators found identifiable mutations in 617 patients (77%) and documented that patients with a TP53 or ras-pathway mutation had a “dismal prognosis” when associated with a complex karyotype and myelodysplastic or myeloproliferative neoplasms. However, among patients with a mutated TP53 gene or complex karyotype alone, long-term survival following transplantation appeared possible (Blood. 2017. doi: org/10.1182/blood-2016-12-754796.
Two smaller, earlier studies (J Clin Oncol. 2014 Sept 1;32[25]:2691-8; J Clin Oncol. 2016 Oct 20;34[30]:2627-37) also implicated mutations in the TET2, DNMT3A, ASXL1, and RUNX1 genes as identifying MDS patients with worse OS following allogeneic HSCT, Dr. Zeidan noted, but the combination of a TP53 gene mutation and a complex karyotype appears to confer the worst prognosis of all. Patients with mutations in more than one of these genes fared much worse than those with single mutations.
Dr. Zeidan had no relevant disclosures.
[email protected]
On Twitter @mitchelzoler
NEW YORK – Genetic mutation analysis of patients with myelodysplastic syndrome (MDS) may have a useful role in routine practice based on recent reports that showed clear links between certain gene mutations and the outcomes of patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT).
Two reports published in 2017 helped strengthen the case for routine mutation analysis in distinguishing patients with MDS or myeloproliferative neoplasms (MDN) who are very likely to have just a brief response to allogeneic HSCT from similar patients who seem likely to have several years of overall survival following transplantation.
Allogeneic HSCT is the only potentially curative procedure for patients with MDS or MDN. Although an increasing number of these patients undergo transplantation, clinicians need to choose the patients they select for the treatment carefully. “Molecular testing is playing an increasing role in selecting the best candidates,” Dr. Zeidan said.
The largest reported genetic study of allogeneic HSCT in MDS patients involved 1,514 patients entered into a U.S.-based dataset during 2005-2015. Testing identified at least one mutation in 1,196 (79%) of these patients.
Analysis of data from these patients found a disparate pattern of posttransplant survival that appeared to link with gene mutations and other risk factors. The highest risk patients were those with a mutation in their TP53 gene, found in 289 patients (19% of the 1,514 tested) who had a median overall survival (OS) of 0.7 years and a 3-year OS of 20% (New Engl J Med. 2017 Feb 9;376[6]:536-47).
Among patients without a TP53 mutation, OS depended on age, with the best survival seen among patients less than 40 years old. Patients in this subgroup who also had no other high-risk features – no therapy-related MDS, a platelet level of at least 30 x 109 at the time of transplantation, and bone marrow blasts less than 15% at diagnosis – had the best OS, 82% at 3-years of follow-up. The studied cohort included 116 patients (8%) who fell into this low-risk, best-outcome category, the optimal population for receiving an allogeneic HSCT, Dr. Zeidan said. Another 98 patients (6%) who had at least one of these high risk feature had a median OS of 2.6 years and a 3-year OS of 49%.
Additional gene mutations further subdivided the older patients in the study, those at least 40 years old, into various risk subgroups. Older patients with a mutation in a ras-pathway gene had a 0.9 year median OS and a 3-year OS of 30%. This subgroup included 129 patients (9%). Among older patients with no mutation in the ras-pathway gene, mutations in the JAK2 gene also linked with worse survival, a median OS of 0.5 years and a 3-year OS of 28% of a subgroup with 28 patients (2%). The largest subgroup in the study was older patients with no mutations in the TP53, JAK2, or ras-pathway genes, a subgroup with 854 patients (56%), who had a median OS of 2.3 years and a 3-year OS of 46%.
The second recent report was a Japanese study of 797 MDS patients who underwent genetic testing and received an allogeneic HSCT through the Japan Marrow Donor Program. The investigators found identifiable mutations in 617 patients (77%) and documented that patients with a TP53 or ras-pathway mutation had a “dismal prognosis” when associated with a complex karyotype and myelodysplastic or myeloproliferative neoplasms. However, among patients with a mutated TP53 gene or complex karyotype alone, long-term survival following transplantation appeared possible (Blood. 2017. doi: org/10.1182/blood-2016-12-754796.
Two smaller, earlier studies (J Clin Oncol. 2014 Sept 1;32[25]:2691-8; J Clin Oncol. 2016 Oct 20;34[30]:2627-37) also implicated mutations in the TET2, DNMT3A, ASXL1, and RUNX1 genes as identifying MDS patients with worse OS following allogeneic HSCT, Dr. Zeidan noted, but the combination of a TP53 gene mutation and a complex karyotype appears to confer the worst prognosis of all. Patients with mutations in more than one of these genes fared much worse than those with single mutations.
Dr. Zeidan had no relevant disclosures.
[email protected]
On Twitter @mitchelzoler
NEW YORK – Genetic mutation analysis of patients with myelodysplastic syndrome (MDS) may have a useful role in routine practice based on recent reports that showed clear links between certain gene mutations and the outcomes of patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT).
Two reports published in 2017 helped strengthen the case for routine mutation analysis in distinguishing patients with MDS or myeloproliferative neoplasms (MDN) who are very likely to have just a brief response to allogeneic HSCT from similar patients who seem likely to have several years of overall survival following transplantation.
Allogeneic HSCT is the only potentially curative procedure for patients with MDS or MDN. Although an increasing number of these patients undergo transplantation, clinicians need to choose the patients they select for the treatment carefully. “Molecular testing is playing an increasing role in selecting the best candidates,” Dr. Zeidan said.
The largest reported genetic study of allogeneic HSCT in MDS patients involved 1,514 patients entered into a U.S.-based dataset during 2005-2015. Testing identified at least one mutation in 1,196 (79%) of these patients.
Analysis of data from these patients found a disparate pattern of posttransplant survival that appeared to link with gene mutations and other risk factors. The highest risk patients were those with a mutation in their TP53 gene, found in 289 patients (19% of the 1,514 tested) who had a median overall survival (OS) of 0.7 years and a 3-year OS of 20% (New Engl J Med. 2017 Feb 9;376[6]:536-47).
Among patients without a TP53 mutation, OS depended on age, with the best survival seen among patients less than 40 years old. Patients in this subgroup who also had no other high-risk features – no therapy-related MDS, a platelet level of at least 30 x 109 at the time of transplantation, and bone marrow blasts less than 15% at diagnosis – had the best OS, 82% at 3-years of follow-up. The studied cohort included 116 patients (8%) who fell into this low-risk, best-outcome category, the optimal population for receiving an allogeneic HSCT, Dr. Zeidan said. Another 98 patients (6%) who had at least one of these high risk feature had a median OS of 2.6 years and a 3-year OS of 49%.
Additional gene mutations further subdivided the older patients in the study, those at least 40 years old, into various risk subgroups. Older patients with a mutation in a ras-pathway gene had a 0.9 year median OS and a 3-year OS of 30%. This subgroup included 129 patients (9%). Among older patients with no mutation in the ras-pathway gene, mutations in the JAK2 gene also linked with worse survival, a median OS of 0.5 years and a 3-year OS of 28% of a subgroup with 28 patients (2%). The largest subgroup in the study was older patients with no mutations in the TP53, JAK2, or ras-pathway genes, a subgroup with 854 patients (56%), who had a median OS of 2.3 years and a 3-year OS of 46%.
The second recent report was a Japanese study of 797 MDS patients who underwent genetic testing and received an allogeneic HSCT through the Japan Marrow Donor Program. The investigators found identifiable mutations in 617 patients (77%) and documented that patients with a TP53 or ras-pathway mutation had a “dismal prognosis” when associated with a complex karyotype and myelodysplastic or myeloproliferative neoplasms. However, among patients with a mutated TP53 gene or complex karyotype alone, long-term survival following transplantation appeared possible (Blood. 2017. doi: org/10.1182/blood-2016-12-754796.
Two smaller, earlier studies (J Clin Oncol. 2014 Sept 1;32[25]:2691-8; J Clin Oncol. 2016 Oct 20;34[30]:2627-37) also implicated mutations in the TET2, DNMT3A, ASXL1, and RUNX1 genes as identifying MDS patients with worse OS following allogeneic HSCT, Dr. Zeidan noted, but the combination of a TP53 gene mutation and a complex karyotype appears to confer the worst prognosis of all. Patients with mutations in more than one of these genes fared much worse than those with single mutations.
Dr. Zeidan had no relevant disclosures.
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