MRS2500 (magenta) and

BPTU (yellow) bind to P2Y1R

Image courtesy of

Yekaterina Kadyshevskaya

Researchers say they have identified 2 disparate ligand-binding sites in the human P2Y1 receptor (P2Y1R), which plays a critical role in thrombosis.

Their research has provided a detailed molecular map of P2Y1R, a G protein-coupled receptor (GPCR), in complex with a nucleotide antagonist MRS2500 and a non-nucleotide antagonist BPTU.

The researchers believe their findings, published in Nature, could aid the development of new antithrombotic drugs.

Beili Wu, PhD, of the Shanghai Institute of Materia Medica in China, and her colleagues noted that the human purinergic receptors P2Y1R and P2Y12R play a major physiological role in adenosine 5′-diphosphate (ADP)-mediated platelet aggregation, an important component of thrombosis.

Although most of the available antithrombotic drugs act on P2Y12R, research has suggested that P2Y1R may be a promising antithrombotic drug target. In addition, P2Y1R inhibitors may offer a safety advantage over P2Y12R inhibitors by reducing the risk of bleeding. However, efforts to develop new drugs have been impeded by poor understanding of receptor-ligand interaction.

“The P2Y1R structures [we mapped] help us understand how this receptor and different types of experimental drugs interact at the molecular level and could enable further exploration to design new and safer antithrombotic drugs with reduced adverse effects,” Dr Wu said.

She and her colleagues found that the nucleotide ligand MRS2500 recognizes a binding site within the transmembrane bundle of P2Y1R. And it is different in shape and location from the nucleotide-binding site in P2Y12R.

“It is amazing to observe that 2 GPCRs recognize the same ligand in such different ways,” Dr Wu said. “The finding highlights the diversity of signal recognition mechanisms in GPCRs, and this is of great value to drug design for each receptor with high selectivity.”

The researchers also found that, instead of interacting within the transmembrane bundle, the non-nucleotide ligand BPTU binds to a pocket on the outer interface of P2Y1R embedded in the cell membrane.

This is the first structurally characterized, selective, and high-affinity GPCR ligand located entirely outside of the helical bundle, and it represents a new paradigm in ligand binding to alter signaling in GPCRs, according to the researchers.

The team believes this new understanding of the P2Y1R structure provides opportunities to broaden the scope of future GPCR drug discovery to target novel sites outside of the conventional GPCR ligand-binding pocket, which may improve drug selectivity and reduce side effects.

MRS2500 (magenta) and

BPTU (yellow) bind to P2Y1R

Image courtesy of

Yekaterina Kadyshevskaya

Researchers say they have identified 2 disparate ligand-binding sites in the human P2Y1 receptor (P2Y1R), which plays a critical role in thrombosis.

Their research has provided a detailed molecular map of P2Y1R, a G protein-coupled receptor (GPCR), in complex with a nucleotide antagonist MRS2500 and a non-nucleotide antagonist BPTU.

The researchers believe their findings, published in Nature, could aid the development of new antithrombotic drugs.

Beili Wu, PhD, of the Shanghai Institute of Materia Medica in China, and her colleagues noted that the human purinergic receptors P2Y1R and P2Y12R play a major physiological role in adenosine 5′-diphosphate (ADP)-mediated platelet aggregation, an important component of thrombosis.

Although most of the available antithrombotic drugs act on P2Y12R, research has suggested that P2Y1R may be a promising antithrombotic drug target. In addition, P2Y1R inhibitors may offer a safety advantage over P2Y12R inhibitors by reducing the risk of bleeding. However, efforts to develop new drugs have been impeded by poor understanding of receptor-ligand interaction.

“The P2Y1R structures [we mapped] help us understand how this receptor and different types of experimental drugs interact at the molecular level and could enable further exploration to design new and safer antithrombotic drugs with reduced adverse effects,” Dr Wu said.

She and her colleagues found that the nucleotide ligand MRS2500 recognizes a binding site within the transmembrane bundle of P2Y1R. And it is different in shape and location from the nucleotide-binding site in P2Y12R.

“It is amazing to observe that 2 GPCRs recognize the same ligand in such different ways,” Dr Wu said. “The finding highlights the diversity of signal recognition mechanisms in GPCRs, and this is of great value to drug design for each receptor with high selectivity.”

The researchers also found that, instead of interacting within the transmembrane bundle, the non-nucleotide ligand BPTU binds to a pocket on the outer interface of P2Y1R embedded in the cell membrane.

This is the first structurally characterized, selective, and high-affinity GPCR ligand located entirely outside of the helical bundle, and it represents a new paradigm in ligand binding to alter signaling in GPCRs, according to the researchers.

The team believes this new understanding of the P2Y1R structure provides opportunities to broaden the scope of future GPCR drug discovery to target novel sites outside of the conventional GPCR ligand-binding pocket, which may improve drug selectivity and reduce side effects.

MRS2500 (magenta) and

BPTU (yellow) bind to P2Y1R

Image courtesy of

Yekaterina Kadyshevskaya

Researchers say they have identified 2 disparate ligand-binding sites in the human P2Y1 receptor (P2Y1R), which plays a critical role in thrombosis.

Their research has provided a detailed molecular map of P2Y1R, a G protein-coupled receptor (GPCR), in complex with a nucleotide antagonist MRS2500 and a non-nucleotide antagonist BPTU.

The researchers believe their findings, published in Nature, could aid the development of new antithrombotic drugs.

Beili Wu, PhD, of the Shanghai Institute of Materia Medica in China, and her colleagues noted that the human purinergic receptors P2Y1R and P2Y12R play a major physiological role in adenosine 5′-diphosphate (ADP)-mediated platelet aggregation, an important component of thrombosis.

Although most of the available antithrombotic drugs act on P2Y12R, research has suggested that P2Y1R may be a promising antithrombotic drug target. In addition, P2Y1R inhibitors may offer a safety advantage over P2Y12R inhibitors by reducing the risk of bleeding. However, efforts to develop new drugs have been impeded by poor understanding of receptor-ligand interaction.

“The P2Y1R structures [we mapped] help us understand how this receptor and different types of experimental drugs interact at the molecular level and could enable further exploration to design new and safer antithrombotic drugs with reduced adverse effects,” Dr Wu said.

She and her colleagues found that the nucleotide ligand MRS2500 recognizes a binding site within the transmembrane bundle of P2Y1R. And it is different in shape and location from the nucleotide-binding site in P2Y12R.

“It is amazing to observe that 2 GPCRs recognize the same ligand in such different ways,” Dr Wu said. “The finding highlights the diversity of signal recognition mechanisms in GPCRs, and this is of great value to drug design for each receptor with high selectivity.”

The researchers also found that, instead of interacting within the transmembrane bundle, the non-nucleotide ligand BPTU binds to a pocket on the outer interface of P2Y1R embedded in the cell membrane.

This is the first structurally characterized, selective, and high-affinity GPCR ligand located entirely outside of the helical bundle, and it represents a new paradigm in ligand binding to alter signaling in GPCRs, according to the researchers.

The team believes this new understanding of the P2Y1R structure provides opportunities to broaden the scope of future GPCR drug discovery to target novel sites outside of the conventional GPCR ligand-binding pocket, which may improve drug selectivity and reduce side effects.

Vials of drug

Photo by Bill Branson

The US Food and Drug Administration (FDA) has strengthened an existing warning that serious, potentially fatal, allergic reactions can occur with the anemia drug Feraheme (ferumoxytol).

The FDA changed the drug’s prescribing information and approved a boxed warning detailing this risk.

The agency also added a new contraindication, which advises against the use of Feraheme in patients who have had an allergic reaction to any intravenous (IV) iron replacement product.

The FDA said it is continuing to monitor and evaluate the risk of serious allergic reactions with all IV iron products, and the agency will update the public as new information becomes available.

About Feraheme

Feraheme is an IV iron replacement product used to treat iron-deficiency anemia in patients with chronic kidney disease. Like other IV iron products, Feraheme may only be given where emergency personnel and equipment are immediately available to treat the potentially life-threatening allergic reactions that can occur with treatment.

All IV iron products carry a risk of potentially life-threatening allergic reactions. At the time of Feraheme’s approval in 2009, this risk was described in the “Warnings and Precautions” section of the drug label.

Since then, serious reactions, including deaths, have occurred, despite the proper use of therapies to treat these reactions and emergency resuscitation measures.

Serious reactions reported

In the initial clinical trials of Feraheme, conducted predominantly in patients with chronic kidney disease, serious hypersensitivity reactions were reported in 0.2% (3/1726) of patients receiving Feraheme.

Other adverse reactions potentially associated with hypersensitivity (eg, pruritus, rash, urticaria, or wheezing) were reported in 3.7% (63/1726) of these patients.

In other trials that did not include patients with chronic kidney disease, moderate to severe hypersensitivity reactions, including anaphylaxis, were reported in 2.6% (26/1014) of patients treated with Feraheme.

Since the approval of Feraheme on June 30, 2009, cases of serious hypersensitivity reactions, including death, have occurred.

A search of the FDA Adverse Event Reporting System database revealed 79 cases of anaphylactic reactions associated with Feraheme administration, reported from the time of approval to June 30, 2014. Of the 79 cases, 18 were fatal, despite immediate medical intervention and emergency resuscitation attempts.

The 79 patients ranged in age from 19 to 96 years. In nearly half of all cases, the anaphylactic reactions occurred with the first dose of Feraheme. For approximately 75% (60/79) of the cases, the reaction began during the infusion or within 5 minutes after administration was complete.

Frequently reported symptoms included cardiac arrest, hypotension, dyspnea, nausea, vomiting, and flushing. Of the 79 patients, 43% (34/79) had a medical history of drug allergy, and 24% had a history of multiple drug allergies.

Recommendations for administering Feraheme

Initial symptoms of fatal and serious hypersensitivity reactions associated with Feraheme may include hypotension, syncope, unresponsiveness, and cardiac/cardiorespiratory arrest, with or without signs of rash.

All IV iron products carry a risk of anaphylaxis, so these products should be administered only in patients who require IV iron therapy.

Feraheme is only approved for use in adults with iron-deficiency anemia in the setting of chronic kidney disease. The drug is contraindicated in patients with a history of hypersensitivity to Feraheme or any other IV iron product.

Only administer Feraheme and other IV iron products when personnel and therapies are immediately available for the treatment of anaphylaxis and other hypersensitivity reactions.

Patients with a history of multiple drug allergies may have a greater risk of anaphylaxis with parenteral iron products. Carefully consider the potential risks and benefits before administering Feraheme to these patients.

Feraheme should only be administered as an IV infusion in 50-200 mL of 0.9% sodium chloride or 5% dextrose over a minimum period of 15 minutes following dilution. Do not administer Feraheme by undiluted IV injection.

Closely monitor patients for signs and symptoms of hypersensitivity reactions, including monitoring blood pressure and pulse during administration and for at least 30 minutes following each infusion of Feraheme.

Elderly patients 65 years of age and older with multiple or serious comorbidities who experience hypersensitivity reactions, hypotension, or both following administration of Feraheme may have more severe outcomes.

Advise patients to immediately report any signs and symptoms of hypersensitivity that may develop during and following Feraheme administration, such as respiratory distress, hypotension, dizziness or lightheadedness, edema, rash, or itching. Advise patients to seek immediate medical attention if these signs and symptoms occur.

Allow at least 30 minutes between administration of Feraheme and administration of other medications that could potentially cause serious hypersensitivity reactions, hypotension, or both, such as chemotherapeutic agents or monoclonal antibodies.

Report adverse events involving Feraheme to the FDA’s MedWatch Program.

Vials of drug

Photo by Bill Branson

The US Food and Drug Administration (FDA) has strengthened an existing warning that serious, potentially fatal, allergic reactions can occur with the anemia drug Feraheme (ferumoxytol).

The FDA changed the drug’s prescribing information and approved a boxed warning detailing this risk.

The agency also added a new contraindication, which advises against the use of Feraheme in patients who have had an allergic reaction to any intravenous (IV) iron replacement product.

The FDA said it is continuing to monitor and evaluate the risk of serious allergic reactions with all IV iron products, and the agency will update the public as new information becomes available.

About Feraheme

Feraheme is an IV iron replacement product used to treat iron-deficiency anemia in patients with chronic kidney disease. Like other IV iron products, Feraheme may only be given where emergency personnel and equipment are immediately available to treat the potentially life-threatening allergic reactions that can occur with treatment.

All IV iron products carry a risk of potentially life-threatening allergic reactions. At the time of Feraheme’s approval in 2009, this risk was described in the “Warnings and Precautions” section of the drug label.

Since then, serious reactions, including deaths, have occurred, despite the proper use of therapies to treat these reactions and emergency resuscitation measures.

Serious reactions reported

In the initial clinical trials of Feraheme, conducted predominantly in patients with chronic kidney disease, serious hypersensitivity reactions were reported in 0.2% (3/1726) of patients receiving Feraheme.

Other adverse reactions potentially associated with hypersensitivity (eg, pruritus, rash, urticaria, or wheezing) were reported in 3.7% (63/1726) of these patients.

In other trials that did not include patients with chronic kidney disease, moderate to severe hypersensitivity reactions, including anaphylaxis, were reported in 2.6% (26/1014) of patients treated with Feraheme.

Since the approval of Feraheme on June 30, 2009, cases of serious hypersensitivity reactions, including death, have occurred.

A search of the FDA Adverse Event Reporting System database revealed 79 cases of anaphylactic reactions associated with Feraheme administration, reported from the time of approval to June 30, 2014. Of the 79 cases, 18 were fatal, despite immediate medical intervention and emergency resuscitation attempts.

The 79 patients ranged in age from 19 to 96 years. In nearly half of all cases, the anaphylactic reactions occurred with the first dose of Feraheme. For approximately 75% (60/79) of the cases, the reaction began during the infusion or within 5 minutes after administration was complete.

Frequently reported symptoms included cardiac arrest, hypotension, dyspnea, nausea, vomiting, and flushing. Of the 79 patients, 43% (34/79) had a medical history of drug allergy, and 24% had a history of multiple drug allergies.

Recommendations for administering Feraheme

Initial symptoms of fatal and serious hypersensitivity reactions associated with Feraheme may include hypotension, syncope, unresponsiveness, and cardiac/cardiorespiratory arrest, with or without signs of rash.

All IV iron products carry a risk of anaphylaxis, so these products should be administered only in patients who require IV iron therapy.

Feraheme is only approved for use in adults with iron-deficiency anemia in the setting of chronic kidney disease. The drug is contraindicated in patients with a history of hypersensitivity to Feraheme or any other IV iron product.

Only administer Feraheme and other IV iron products when personnel and therapies are immediately available for the treatment of anaphylaxis and other hypersensitivity reactions.

Patients with a history of multiple drug allergies may have a greater risk of anaphylaxis with parenteral iron products. Carefully consider the potential risks and benefits before administering Feraheme to these patients.

Feraheme should only be administered as an IV infusion in 50-200 mL of 0.9% sodium chloride or 5% dextrose over a minimum period of 15 minutes following dilution. Do not administer Feraheme by undiluted IV injection.

Closely monitor patients for signs and symptoms of hypersensitivity reactions, including monitoring blood pressure and pulse during administration and for at least 30 minutes following each infusion of Feraheme.

Elderly patients 65 years of age and older with multiple or serious comorbidities who experience hypersensitivity reactions, hypotension, or both following administration of Feraheme may have more severe outcomes.

Advise patients to immediately report any signs and symptoms of hypersensitivity that may develop during and following Feraheme administration, such as respiratory distress, hypotension, dizziness or lightheadedness, edema, rash, or itching. Advise patients to seek immediate medical attention if these signs and symptoms occur.

Allow at least 30 minutes between administration of Feraheme and administration of other medications that could potentially cause serious hypersensitivity reactions, hypotension, or both, such as chemotherapeutic agents or monoclonal antibodies.

Report adverse events involving Feraheme to the FDA’s MedWatch Program.

Vials of drug

Photo by Bill Branson

The US Food and Drug Administration (FDA) has strengthened an existing warning that serious, potentially fatal, allergic reactions can occur with the anemia drug Feraheme (ferumoxytol).

The FDA changed the drug’s prescribing information and approved a boxed warning detailing this risk.

The agency also added a new contraindication, which advises against the use of Feraheme in patients who have had an allergic reaction to any intravenous (IV) iron replacement product.

The FDA said it is continuing to monitor and evaluate the risk of serious allergic reactions with all IV iron products, and the agency will update the public as new information becomes available.

About Feraheme

Feraheme is an IV iron replacement product used to treat iron-deficiency anemia in patients with chronic kidney disease. Like other IV iron products, Feraheme may only be given where emergency personnel and equipment are immediately available to treat the potentially life-threatening allergic reactions that can occur with treatment.

All IV iron products carry a risk of potentially life-threatening allergic reactions. At the time of Feraheme’s approval in 2009, this risk was described in the “Warnings and Precautions” section of the drug label.

Since then, serious reactions, including deaths, have occurred, despite the proper use of therapies to treat these reactions and emergency resuscitation measures.

Serious reactions reported

In the initial clinical trials of Feraheme, conducted predominantly in patients with chronic kidney disease, serious hypersensitivity reactions were reported in 0.2% (3/1726) of patients receiving Feraheme.

Other adverse reactions potentially associated with hypersensitivity (eg, pruritus, rash, urticaria, or wheezing) were reported in 3.7% (63/1726) of these patients.

In other trials that did not include patients with chronic kidney disease, moderate to severe hypersensitivity reactions, including anaphylaxis, were reported in 2.6% (26/1014) of patients treated with Feraheme.

Since the approval of Feraheme on June 30, 2009, cases of serious hypersensitivity reactions, including death, have occurred.

A search of the FDA Adverse Event Reporting System database revealed 79 cases of anaphylactic reactions associated with Feraheme administration, reported from the time of approval to June 30, 2014. Of the 79 cases, 18 were fatal, despite immediate medical intervention and emergency resuscitation attempts.

The 79 patients ranged in age from 19 to 96 years. In nearly half of all cases, the anaphylactic reactions occurred with the first dose of Feraheme. For approximately 75% (60/79) of the cases, the reaction began during the infusion or within 5 minutes after administration was complete.

Frequently reported symptoms included cardiac arrest, hypotension, dyspnea, nausea, vomiting, and flushing. Of the 79 patients, 43% (34/79) had a medical history of drug allergy, and 24% had a history of multiple drug allergies.

Recommendations for administering Feraheme

Initial symptoms of fatal and serious hypersensitivity reactions associated with Feraheme may include hypotension, syncope, unresponsiveness, and cardiac/cardiorespiratory arrest, with or without signs of rash.

All IV iron products carry a risk of anaphylaxis, so these products should be administered only in patients who require IV iron therapy.

Feraheme is only approved for use in adults with iron-deficiency anemia in the setting of chronic kidney disease. The drug is contraindicated in patients with a history of hypersensitivity to Feraheme or any other IV iron product.

Only administer Feraheme and other IV iron products when personnel and therapies are immediately available for the treatment of anaphylaxis and other hypersensitivity reactions.

Patients with a history of multiple drug allergies may have a greater risk of anaphylaxis with parenteral iron products. Carefully consider the potential risks and benefits before administering Feraheme to these patients.

Feraheme should only be administered as an IV infusion in 50-200 mL of 0.9% sodium chloride or 5% dextrose over a minimum period of 15 minutes following dilution. Do not administer Feraheme by undiluted IV injection.

Closely monitor patients for signs and symptoms of hypersensitivity reactions, including monitoring blood pressure and pulse during administration and for at least 30 minutes following each infusion of Feraheme.

Elderly patients 65 years of age and older with multiple or serious comorbidities who experience hypersensitivity reactions, hypotension, or both following administration of Feraheme may have more severe outcomes.

Advise patients to immediately report any signs and symptoms of hypersensitivity that may develop during and following Feraheme administration, such as respiratory distress, hypotension, dizziness or lightheadedness, edema, rash, or itching. Advise patients to seek immediate medical attention if these signs and symptoms occur.

Allow at least 30 minutes between administration of Feraheme and administration of other medications that could potentially cause serious hypersensitivity reactions, hypotension, or both, such as chemotherapeutic agents or monoclonal antibodies.

Report adverse events involving Feraheme to the FDA’s MedWatch Program.

Fatih Uckun, MD, PhD

Photo courtesy of Dr Uckun

An engineered protein can enhance the effects of radiation and even overcome radiation resistance to treat B-precursor acute lymphoblastic leukemia (ALL), according to research published in EBioMedicine.

The protein, CD19L-sTRAIL, is a fusion of the CD19 ligand protein, which seeks out and binds to leukemia cells, with soluble TRAIL, a protein that can amplify the potency of radiation if it can be anchored on the membrane of leukemia cells.

Researchers found that CD19L-sTRAIL augmented the potency of radiation therapy even against the most aggressive and radiation-resistant forms of leukemia.

“Even very low doses of radiation were highly effective in mice challenged with aggressive human leukemia cells, when it was combined with [CD19L-sTRAIL],” said Fatih M. Uckun, MD, PhD, of The Saban Research Institute of Children’s Hospital Los Angeles in California.

“Due to its ability to selectively anchor to the surface of leukemia cells via its CD19L portion, CD19L-sTRAIL was 100,000-fold more potent than sTRAIL and consistently killed aggressive leukemia cells taken directly from children with ALL—not only in the test tube but also in mice.”

The researchers found that a combination of low-dose total body irradiation (TBI) and CD19L-sTRAIL greatly improved event-free survival (EFS) in mice that had received a typically fatal dose of cells from a patient with relapsed B-precursor ALL.

The median EFS for mice treated with CD19L-sTRAIL plus low-dose TBI was 72 days, which was significantly longer than the EFS for untreated control mice (17 days, P<0.0001), mice that received TBI alone (64 days, P=0.0014), mice that received CD19L-sTRAIL alone (20 days, P=0.0022), and mice that received a combination of vincristine, dexamethasone, and PEG-asparaginase (17 days, P=0.0033).

Dr Uckun and his colleagues noted that none of the mice that received CD19L-sTRAIL and TBI experienced a toxic death or signs of treatment-related toxicity.

The team also found that TBI plus CD19L-sTRAIL improved progression-free survival (PFS) in CD22ΔE12xBCR-ABL double transgenic mice with radiation-resistant, advanced stage, CD19+ murine B-precursor ALL with lymphomatous features.

The mean PFS was 24.0 ± 4.0 days for mice that received CD19L-sTRAIL plus TBI, which was significantly longer than the PFS for control mice (0 ± 0 days, P<0.0001), mice that received CD19L-sTRAIL alone (3.4 ± 0.9 days, P=0.0003), and mice that received TBI alone (9.0 ± 4.6 days, P=0.020).

Based on these results, Dr Uckun and his colleagues believe that incorporating CD19L-sTRAIL into the pre-transplant TBI regimens of patients with very high-risk B-precursor ALL could improve survival after hematopoietic stem cell transplant.

“We are hopeful that the knowledge gained from this study will open a new range of effective treatment opportunities for children with recurrent leukemia,” Dr Uckun said.

Fatih Uckun, MD, PhD

Photo courtesy of Dr Uckun

An engineered protein can enhance the effects of radiation and even overcome radiation resistance to treat B-precursor acute lymphoblastic leukemia (ALL), according to research published in EBioMedicine.

The protein, CD19L-sTRAIL, is a fusion of the CD19 ligand protein, which seeks out and binds to leukemia cells, with soluble TRAIL, a protein that can amplify the potency of radiation if it can be anchored on the membrane of leukemia cells.

Researchers found that CD19L-sTRAIL augmented the potency of radiation therapy even against the most aggressive and radiation-resistant forms of leukemia.

“Even very low doses of radiation were highly effective in mice challenged with aggressive human leukemia cells, when it was combined with [CD19L-sTRAIL],” said Fatih M. Uckun, MD, PhD, of The Saban Research Institute of Children’s Hospital Los Angeles in California.

“Due to its ability to selectively anchor to the surface of leukemia cells via its CD19L portion, CD19L-sTRAIL was 100,000-fold more potent than sTRAIL and consistently killed aggressive leukemia cells taken directly from children with ALL—not only in the test tube but also in mice.”

The researchers found that a combination of low-dose total body irradiation (TBI) and CD19L-sTRAIL greatly improved event-free survival (EFS) in mice that had received a typically fatal dose of cells from a patient with relapsed B-precursor ALL.

The median EFS for mice treated with CD19L-sTRAIL plus low-dose TBI was 72 days, which was significantly longer than the EFS for untreated control mice (17 days, P<0.0001), mice that received TBI alone (64 days, P=0.0014), mice that received CD19L-sTRAIL alone (20 days, P=0.0022), and mice that received a combination of vincristine, dexamethasone, and PEG-asparaginase (17 days, P=0.0033).

Dr Uckun and his colleagues noted that none of the mice that received CD19L-sTRAIL and TBI experienced a toxic death or signs of treatment-related toxicity.

The team also found that TBI plus CD19L-sTRAIL improved progression-free survival (PFS) in CD22ΔE12xBCR-ABL double transgenic mice with radiation-resistant, advanced stage, CD19+ murine B-precursor ALL with lymphomatous features.

The mean PFS was 24.0 ± 4.0 days for mice that received CD19L-sTRAIL plus TBI, which was significantly longer than the PFS for control mice (0 ± 0 days, P<0.0001), mice that received CD19L-sTRAIL alone (3.4 ± 0.9 days, P=0.0003), and mice that received TBI alone (9.0 ± 4.6 days, P=0.020).

Based on these results, Dr Uckun and his colleagues believe that incorporating CD19L-sTRAIL into the pre-transplant TBI regimens of patients with very high-risk B-precursor ALL could improve survival after hematopoietic stem cell transplant.

“We are hopeful that the knowledge gained from this study will open a new range of effective treatment opportunities for children with recurrent leukemia,” Dr Uckun said.

Fatih Uckun, MD, PhD

Photo courtesy of Dr Uckun

An engineered protein can enhance the effects of radiation and even overcome radiation resistance to treat B-precursor acute lymphoblastic leukemia (ALL), according to research published in EBioMedicine.

The protein, CD19L-sTRAIL, is a fusion of the CD19 ligand protein, which seeks out and binds to leukemia cells, with soluble TRAIL, a protein that can amplify the potency of radiation if it can be anchored on the membrane of leukemia cells.

Researchers found that CD19L-sTRAIL augmented the potency of radiation therapy even against the most aggressive and radiation-resistant forms of leukemia.

“Even very low doses of radiation were highly effective in mice challenged with aggressive human leukemia cells, when it was combined with [CD19L-sTRAIL],” said Fatih M. Uckun, MD, PhD, of The Saban Research Institute of Children’s Hospital Los Angeles in California.

“Due to its ability to selectively anchor to the surface of leukemia cells via its CD19L portion, CD19L-sTRAIL was 100,000-fold more potent than sTRAIL and consistently killed aggressive leukemia cells taken directly from children with ALL—not only in the test tube but also in mice.”

The researchers found that a combination of low-dose total body irradiation (TBI) and CD19L-sTRAIL greatly improved event-free survival (EFS) in mice that had received a typically fatal dose of cells from a patient with relapsed B-precursor ALL.

The median EFS for mice treated with CD19L-sTRAIL plus low-dose TBI was 72 days, which was significantly longer than the EFS for untreated control mice (17 days, P<0.0001), mice that received TBI alone (64 days, P=0.0014), mice that received CD19L-sTRAIL alone (20 days, P=0.0022), and mice that received a combination of vincristine, dexamethasone, and PEG-asparaginase (17 days, P=0.0033).

Dr Uckun and his colleagues noted that none of the mice that received CD19L-sTRAIL and TBI experienced a toxic death or signs of treatment-related toxicity.

The team also found that TBI plus CD19L-sTRAIL improved progression-free survival (PFS) in CD22ΔE12xBCR-ABL double transgenic mice with radiation-resistant, advanced stage, CD19+ murine B-precursor ALL with lymphomatous features.

The mean PFS was 24.0 ± 4.0 days for mice that received CD19L-sTRAIL plus TBI, which was significantly longer than the PFS for control mice (0 ± 0 days, P<0.0001), mice that received CD19L-sTRAIL alone (3.4 ± 0.9 days, P=0.0003), and mice that received TBI alone (9.0 ± 4.6 days, P=0.020).

Based on these results, Dr Uckun and his colleagues believe that incorporating CD19L-sTRAIL into the pre-transplant TBI regimens of patients with very high-risk B-precursor ALL could improve survival after hematopoietic stem cell transplant.

“We are hopeful that the knowledge gained from this study will open a new range of effective treatment opportunities for children with recurrent leukemia,” Dr Uckun said.

In this video, diffuse complex endometrial hyperplasia is identified using a vaginoscopic approach with a 1.9-mm diagnostic rigid hysteroscope. The posterior fornix of the vagina is filled with saline until the cervix is elevated with the fluid and the cervical os is identified. The cervical canal is entered and gentle rotational movement and hydrodistension allows the canal to be traversed into the uterine cavity. 

Video provided by Amy L. Garcia, MD

Vidyard Video

Read Dr. Garcia’s “Update on minimally invasive gynecology” (April 2015)

In this video, diffuse complex endometrial hyperplasia is identified using a vaginoscopic approach with a 1.9-mm diagnostic rigid hysteroscope. The posterior fornix of the vagina is filled with saline until the cervix is elevated with the fluid and the cervical os is identified. The cervical canal is entered and gentle rotational movement and hydrodistension allows the canal to be traversed into the uterine cavity. 

Video provided by Amy L. Garcia, MD

Vidyard Video

Read Dr. Garcia’s “Update on minimally invasive gynecology” (April 2015)

In this video, diffuse complex endometrial hyperplasia is identified using a vaginoscopic approach with a 1.9-mm diagnostic rigid hysteroscope. The posterior fornix of the vagina is filled with saline until the cervix is elevated with the fluid and the cervical os is identified. The cervical canal is entered and gentle rotational movement and hydrodistension allows the canal to be traversed into the uterine cavity. 

Video provided by Amy L. Garcia, MD

Vidyard Video

Read Dr. Garcia’s “Update on minimally invasive gynecology” (April 2015)

The relationship between parents and pediatricians is unique. More than any other field of medicine, there is a level of trust that develops because of the consistent and ongoing interaction for several years. But as the child grows older and enters the adolescent years, the relationship shifts from catering to the desires of the parent to the needs of the child.

When a strong relationship is established, the transition of trust is usually easy, and parents are very comfortable and welcoming of an independent relationship between the physician and the child. But there are many issues that come up in adolescence that may be very difficult for a child to discuss with the parent despite having a good relationship, putting the physician directly in the middle.

The issue of minor consent is complex, and because it differs from state to state, it becomes even more complex. Of course, the best approach is to have a conversation with the parent to determine their views on various issues and ask for consent to address them should their child present to you for treatment, but new patients present, and time to establish a relationship is not always possible. The American Academy of Pediatrics statement on treatment of adolescents requires that every attempt is made to encourage inclusion of the parent in any decision making.

Understanding the laws that govern the state in which you practice is imperative. The state policies and laws can be found at www.Guttmacher.org. Although there has not been a physician held liable for nonnegligent care given to a minor who gave consent, it is important for parents to understand what their child can consent to or against. It also is important for the physician to be explicitly clear as to what their limitations are by law.

A minor status is defined by age under 18 years of age. An emancipated minor is someone who attained legal adulthood because of marriage, military service, or living separately from parents and managing one’s financial affairs (Understanding Legal Aspects of Care, in “Adolescent Health Care: A Practical Guide,” 5th ed [Philadelphia Lippincott Williams & Wilkins, 2008]). These laws are very clear and do not usually cause much confusion. Where the situation becomes very grey is in the case of the mature minor. This category is recognized in some states as an exception to the rules requiring parental consent for medical care (Int. J. Gynaecol. Obstet. 1998;63:295-300). The mature minor is defined as being at least 14 years old, having the ability to understand risk and benefits, and having the ability to provide informed consent. But this requires a subjective assessment of the adolescent, which could be argued by the parent.

Minors can consent to contraceptive services in most states. In 1977, the Supreme Court ruled that the right to privacy protects a minor’s access to nonprescriptive contraception, and although prescribed contraception is not included, it is generally considered to be included (Med. Clin. North Am, 1990; 74:1097-112). It is important to note that a pharmacist under the Pharmacist Conscience Clause, in some states, can refuse to fill the prescription without parental consent at their discretion (Arch. Pediatr. Adolesc. Med. 2003;157:361-5). Although this not a common issue, it may present a larger issue if the patient requested confidentiality.

Diagnosis and treatment of sexually transmitted disease also can be done with the consent of a minor, but the age of the patient, usually greater than 14 years, is required in most states. A careful assessment must be done for abuse regardless of whether the minor admitted to consensual sex or not. The laws regarding statutory rape are clearly defined state to state and may present a larger problem if disputed by the parent.

Elective abortion is always a topic of debate. States require at least one parent to consent when a minor is seeking an abortion, but a minor also can seek a judicial bypass, which is a request from a minor to not have parental consent for an abortion if they believe that notification will bring harm to the minor. Conversely, an adolescent also can refuse to consent to an abortion that the parent requests.

Immunizations also can be given with the consent of the minor, but extra precaution should be given to documentation of clear explanation of risk and benefits. Despite there being no federal law requiring parental consent, some states do require it, and it is prudent to obtain it.

Parents don’t often realize the limitations of their ability to prevent or demand treatment. So although the abortion itself falls outside the scope of care of a pediatrician, educating parents on the laws can help them navigate the situation better. Parents also may request drug, sexually transmitted infection, or pregnancy testing without the knowledge of the minor. Whether it is done is left to the discretion of the physician but the AAP advises that this only be done as a rare exception (Pediatrics 2007;119:627-30).

Now a larger consideration for physicians is financial liability. Parents are not obligated to pay for treatment and procedures for which they did not consent. The financial responsibility falls on the minor who requested it. Obviously, this could be costly for the facility, and therefore a decision has to be made to either disrupt continuity of care and refer to an outside facility or absorb the cost. This can be a challenging decision. Disclosing to the minor that payment sent through the insurance might unintentionally breach the confidentiality of the treatment is also an important consideration if the minor’s desire is to keep the parent uninformed.

The issue of consent to treatment when it comes to minors is multifaceted. Maintaining the trust of the parent and gaining the trust of the adolescent is tricky when the lines of communication between them are limited. Establishing early a relationship of trust with the parent to advise and treat the child appropriately in the event he or she does present with complex issues will settle many of the issues. More importantly, as pediatricians our goal is to establish a relationship with the adolescent so that he or she knows where to go to get good sound advice and treatment to ensure good health and prevent avoidable consequences.

Dr. Pearce is a pediatrician in Frankfort, Ill. E-mail her at [email protected]. Scan this QR code to view similar columns or go to pediatricnews.com.

The relationship between parents and pediatricians is unique. More than any other field of medicine, there is a level of trust that develops because of the consistent and ongoing interaction for several years. But as the child grows older and enters the adolescent years, the relationship shifts from catering to the desires of the parent to the needs of the child.

When a strong relationship is established, the transition of trust is usually easy, and parents are very comfortable and welcoming of an independent relationship between the physician and the child. But there are many issues that come up in adolescence that may be very difficult for a child to discuss with the parent despite having a good relationship, putting the physician directly in the middle.

The issue of minor consent is complex, and because it differs from state to state, it becomes even more complex. Of course, the best approach is to have a conversation with the parent to determine their views on various issues and ask for consent to address them should their child present to you for treatment, but new patients present, and time to establish a relationship is not always possible. The American Academy of Pediatrics statement on treatment of adolescents requires that every attempt is made to encourage inclusion of the parent in any decision making.

Understanding the laws that govern the state in which you practice is imperative. The state policies and laws can be found at www.Guttmacher.org. Although there has not been a physician held liable for nonnegligent care given to a minor who gave consent, it is important for parents to understand what their child can consent to or against. It also is important for the physician to be explicitly clear as to what their limitations are by law.

A minor status is defined by age under 18 years of age. An emancipated minor is someone who attained legal adulthood because of marriage, military service, or living separately from parents and managing one’s financial affairs (Understanding Legal Aspects of Care, in “Adolescent Health Care: A Practical Guide,” 5th ed [Philadelphia Lippincott Williams & Wilkins, 2008]). These laws are very clear and do not usually cause much confusion. Where the situation becomes very grey is in the case of the mature minor. This category is recognized in some states as an exception to the rules requiring parental consent for medical care (Int. J. Gynaecol. Obstet. 1998;63:295-300). The mature minor is defined as being at least 14 years old, having the ability to understand risk and benefits, and having the ability to provide informed consent. But this requires a subjective assessment of the adolescent, which could be argued by the parent.

Minors can consent to contraceptive services in most states. In 1977, the Supreme Court ruled that the right to privacy protects a minor’s access to nonprescriptive contraception, and although prescribed contraception is not included, it is generally considered to be included (Med. Clin. North Am, 1990; 74:1097-112). It is important to note that a pharmacist under the Pharmacist Conscience Clause, in some states, can refuse to fill the prescription without parental consent at their discretion (Arch. Pediatr. Adolesc. Med. 2003;157:361-5). Although this not a common issue, it may present a larger issue if the patient requested confidentiality.

Diagnosis and treatment of sexually transmitted disease also can be done with the consent of a minor, but the age of the patient, usually greater than 14 years, is required in most states. A careful assessment must be done for abuse regardless of whether the minor admitted to consensual sex or not. The laws regarding statutory rape are clearly defined state to state and may present a larger problem if disputed by the parent.

Elective abortion is always a topic of debate. States require at least one parent to consent when a minor is seeking an abortion, but a minor also can seek a judicial bypass, which is a request from a minor to not have parental consent for an abortion if they believe that notification will bring harm to the minor. Conversely, an adolescent also can refuse to consent to an abortion that the parent requests.

Immunizations also can be given with the consent of the minor, but extra precaution should be given to documentation of clear explanation of risk and benefits. Despite there being no federal law requiring parental consent, some states do require it, and it is prudent to obtain it.

Parents don’t often realize the limitations of their ability to prevent or demand treatment. So although the abortion itself falls outside the scope of care of a pediatrician, educating parents on the laws can help them navigate the situation better. Parents also may request drug, sexually transmitted infection, or pregnancy testing without the knowledge of the minor. Whether it is done is left to the discretion of the physician but the AAP advises that this only be done as a rare exception (Pediatrics 2007;119:627-30).

Now a larger consideration for physicians is financial liability. Parents are not obligated to pay for treatment and procedures for which they did not consent. The financial responsibility falls on the minor who requested it. Obviously, this could be costly for the facility, and therefore a decision has to be made to either disrupt continuity of care and refer to an outside facility or absorb the cost. This can be a challenging decision. Disclosing to the minor that payment sent through the insurance might unintentionally breach the confidentiality of the treatment is also an important consideration if the minor’s desire is to keep the parent uninformed.

The issue of consent to treatment when it comes to minors is multifaceted. Maintaining the trust of the parent and gaining the trust of the adolescent is tricky when the lines of communication between them are limited. Establishing early a relationship of trust with the parent to advise and treat the child appropriately in the event he or she does present with complex issues will settle many of the issues. More importantly, as pediatricians our goal is to establish a relationship with the adolescent so that he or she knows where to go to get good sound advice and treatment to ensure good health and prevent avoidable consequences.

Dr. Pearce is a pediatrician in Frankfort, Ill. E-mail her at [email protected]. Scan this QR code to view similar columns or go to pediatricnews.com.

The relationship between parents and pediatricians is unique. More than any other field of medicine, there is a level of trust that develops because of the consistent and ongoing interaction for several years. But as the child grows older and enters the adolescent years, the relationship shifts from catering to the desires of the parent to the needs of the child.

When a strong relationship is established, the transition of trust is usually easy, and parents are very comfortable and welcoming of an independent relationship between the physician and the child. But there are many issues that come up in adolescence that may be very difficult for a child to discuss with the parent despite having a good relationship, putting the physician directly in the middle.

The issue of minor consent is complex, and because it differs from state to state, it becomes even more complex. Of course, the best approach is to have a conversation with the parent to determine their views on various issues and ask for consent to address them should their child present to you for treatment, but new patients present, and time to establish a relationship is not always possible. The American Academy of Pediatrics statement on treatment of adolescents requires that every attempt is made to encourage inclusion of the parent in any decision making.

Understanding the laws that govern the state in which you practice is imperative. The state policies and laws can be found at www.Guttmacher.org. Although there has not been a physician held liable for nonnegligent care given to a minor who gave consent, it is important for parents to understand what their child can consent to or against. It also is important for the physician to be explicitly clear as to what their limitations are by law.

A minor status is defined by age under 18 years of age. An emancipated minor is someone who attained legal adulthood because of marriage, military service, or living separately from parents and managing one’s financial affairs (Understanding Legal Aspects of Care, in “Adolescent Health Care: A Practical Guide,” 5th ed [Philadelphia Lippincott Williams & Wilkins, 2008]). These laws are very clear and do not usually cause much confusion. Where the situation becomes very grey is in the case of the mature minor. This category is recognized in some states as an exception to the rules requiring parental consent for medical care (Int. J. Gynaecol. Obstet. 1998;63:295-300). The mature minor is defined as being at least 14 years old, having the ability to understand risk and benefits, and having the ability to provide informed consent. But this requires a subjective assessment of the adolescent, which could be argued by the parent.

Minors can consent to contraceptive services in most states. In 1977, the Supreme Court ruled that the right to privacy protects a minor’s access to nonprescriptive contraception, and although prescribed contraception is not included, it is generally considered to be included (Med. Clin. North Am, 1990; 74:1097-112). It is important to note that a pharmacist under the Pharmacist Conscience Clause, in some states, can refuse to fill the prescription without parental consent at their discretion (Arch. Pediatr. Adolesc. Med. 2003;157:361-5). Although this not a common issue, it may present a larger issue if the patient requested confidentiality.

Diagnosis and treatment of sexually transmitted disease also can be done with the consent of a minor, but the age of the patient, usually greater than 14 years, is required in most states. A careful assessment must be done for abuse regardless of whether the minor admitted to consensual sex or not. The laws regarding statutory rape are clearly defined state to state and may present a larger problem if disputed by the parent.

Elective abortion is always a topic of debate. States require at least one parent to consent when a minor is seeking an abortion, but a minor also can seek a judicial bypass, which is a request from a minor to not have parental consent for an abortion if they believe that notification will bring harm to the minor. Conversely, an adolescent also can refuse to consent to an abortion that the parent requests.

Immunizations also can be given with the consent of the minor, but extra precaution should be given to documentation of clear explanation of risk and benefits. Despite there being no federal law requiring parental consent, some states do require it, and it is prudent to obtain it.

Parents don’t often realize the limitations of their ability to prevent or demand treatment. So although the abortion itself falls outside the scope of care of a pediatrician, educating parents on the laws can help them navigate the situation better. Parents also may request drug, sexually transmitted infection, or pregnancy testing without the knowledge of the minor. Whether it is done is left to the discretion of the physician but the AAP advises that this only be done as a rare exception (Pediatrics 2007;119:627-30).

Now a larger consideration for physicians is financial liability. Parents are not obligated to pay for treatment and procedures for which they did not consent. The financial responsibility falls on the minor who requested it. Obviously, this could be costly for the facility, and therefore a decision has to be made to either disrupt continuity of care and refer to an outside facility or absorb the cost. This can be a challenging decision. Disclosing to the minor that payment sent through the insurance might unintentionally breach the confidentiality of the treatment is also an important consideration if the minor’s desire is to keep the parent uninformed.

The issue of consent to treatment when it comes to minors is multifaceted. Maintaining the trust of the parent and gaining the trust of the adolescent is tricky when the lines of communication between them are limited. Establishing early a relationship of trust with the parent to advise and treat the child appropriately in the event he or she does present with complex issues will settle many of the issues. More importantly, as pediatricians our goal is to establish a relationship with the adolescent so that he or she knows where to go to get good sound advice and treatment to ensure good health and prevent avoidable consequences.

Dr. Pearce is a pediatrician in Frankfort, Ill. E-mail her at [email protected]. Scan this QR code to view similar columns or go to pediatricnews.com.

Day Two highlights from HM15, the Society of Hospital Medicine’s (SHM) annual meeting in National Harbor, Md., just outside Washington, D.C.

Day Two highlights from HM15, the Society of Hospital Medicine’s (SHM) annual meeting in National Harbor, Md., just outside Washington, D.C.

Day Two highlights from HM15, the Society of Hospital Medicine’s (SHM) annual meeting in National Harbor, Md., just outside Washington, D.C.

A month ago the American Board of Internal Medicine sent a letter to diplomates saying they “got it wrong,” referring to the process of maintenance of certification or MOC, that the board required. They acknowledged that “parts of the new program are not meeting the needs of physicians like yourself.” Some of the things they proposed include changing the content of the Internal Medicine recertification exam to be “more reflective of what physicians in practice are doing,” with a promise that subspecialty recertification exams will follow suit. They also talk about “new and more flexible ways ... to demonstrate ... medical knowledge,” likely making room for the continuing medical education or CME credits that state licensures require.

While the letter was evidence that physician grievances were being heard, it was widely criticized for not having gone far enough. Questions remained about the financial and time cost of certification, the relevance of the exam, and the motivation of the board.

Well, the ABIM has written us again. Except it’s still not saying much. They simply say that they have been listening to feedback, and they list some points about what they’ve been hearing and are presumably going to take into consideration. In summary, they are recognizing that the while we all agree that we need a way for physicians to keep up on their medical knowledge, there is “a shared sense that defining ‘keeping up’ is the work of the whole community, including physicians, specialty societies, patient groups, and health care institutions.”

They proceed to outline what they’ve heard and will presumably consider, including the suggestion that the recertification exam be eliminated completely, and that CME units count toward recertification. Like I said, they didn’t say much. But this is promising. Particularly telling is the part where they acknowledge that the job of defining ‘keeping up’ does not fall solely on, as a friend put it, people that sit in their ivory towers and are removed from the daily grind of patient care.

Apropos of all this, I recently got my first 10 points toward MOC by taking a 30-question exam posted by the American College of Rheumatology. Each question comes with a list of references that you can review should you need or want to. To my great surprise, one of the references was in German. So what does that tell you about the people writing the questions and the process they use? What does that tell you about the validity of the questions as a measure of my competence and ability to treat people?

Exams like the boards are a measure of test-taking skills and retention, neither one of which is a true measure of what a capable, competent physician should be. The ABIM is imposing on us an onerous and ill-conceived tool, one that most physicians agree is irrelevant. I am glad this conversation is happening, because frankly the process was enough to make me want to quit being a doctor.

Dr. Chan practices rheumatology in Pawtucket, R.I.

A month ago the American Board of Internal Medicine sent a letter to diplomates saying they “got it wrong,” referring to the process of maintenance of certification or MOC, that the board required. They acknowledged that “parts of the new program are not meeting the needs of physicians like yourself.” Some of the things they proposed include changing the content of the Internal Medicine recertification exam to be “more reflective of what physicians in practice are doing,” with a promise that subspecialty recertification exams will follow suit. They also talk about “new and more flexible ways ... to demonstrate ... medical knowledge,” likely making room for the continuing medical education or CME credits that state licensures require.

While the letter was evidence that physician grievances were being heard, it was widely criticized for not having gone far enough. Questions remained about the financial and time cost of certification, the relevance of the exam, and the motivation of the board.

Well, the ABIM has written us again. Except it’s still not saying much. They simply say that they have been listening to feedback, and they list some points about what they’ve been hearing and are presumably going to take into consideration. In summary, they are recognizing that the while we all agree that we need a way for physicians to keep up on their medical knowledge, there is “a shared sense that defining ‘keeping up’ is the work of the whole community, including physicians, specialty societies, patient groups, and health care institutions.”

They proceed to outline what they’ve heard and will presumably consider, including the suggestion that the recertification exam be eliminated completely, and that CME units count toward recertification. Like I said, they didn’t say much. But this is promising. Particularly telling is the part where they acknowledge that the job of defining ‘keeping up’ does not fall solely on, as a friend put it, people that sit in their ivory towers and are removed from the daily grind of patient care.

Apropos of all this, I recently got my first 10 points toward MOC by taking a 30-question exam posted by the American College of Rheumatology. Each question comes with a list of references that you can review should you need or want to. To my great surprise, one of the references was in German. So what does that tell you about the people writing the questions and the process they use? What does that tell you about the validity of the questions as a measure of my competence and ability to treat people?

Exams like the boards are a measure of test-taking skills and retention, neither one of which is a true measure of what a capable, competent physician should be. The ABIM is imposing on us an onerous and ill-conceived tool, one that most physicians agree is irrelevant. I am glad this conversation is happening, because frankly the process was enough to make me want to quit being a doctor.

Dr. Chan practices rheumatology in Pawtucket, R.I.

A month ago the American Board of Internal Medicine sent a letter to diplomates saying they “got it wrong,” referring to the process of maintenance of certification or MOC, that the board required. They acknowledged that “parts of the new program are not meeting the needs of physicians like yourself.” Some of the things they proposed include changing the content of the Internal Medicine recertification exam to be “more reflective of what physicians in practice are doing,” with a promise that subspecialty recertification exams will follow suit. They also talk about “new and more flexible ways ... to demonstrate ... medical knowledge,” likely making room for the continuing medical education or CME credits that state licensures require.

While the letter was evidence that physician grievances were being heard, it was widely criticized for not having gone far enough. Questions remained about the financial and time cost of certification, the relevance of the exam, and the motivation of the board.

Well, the ABIM has written us again. Except it’s still not saying much. They simply say that they have been listening to feedback, and they list some points about what they’ve been hearing and are presumably going to take into consideration. In summary, they are recognizing that the while we all agree that we need a way for physicians to keep up on their medical knowledge, there is “a shared sense that defining ‘keeping up’ is the work of the whole community, including physicians, specialty societies, patient groups, and health care institutions.”

They proceed to outline what they’ve heard and will presumably consider, including the suggestion that the recertification exam be eliminated completely, and that CME units count toward recertification. Like I said, they didn’t say much. But this is promising. Particularly telling is the part where they acknowledge that the job of defining ‘keeping up’ does not fall solely on, as a friend put it, people that sit in their ivory towers and are removed from the daily grind of patient care.

Apropos of all this, I recently got my first 10 points toward MOC by taking a 30-question exam posted by the American College of Rheumatology. Each question comes with a list of references that you can review should you need or want to. To my great surprise, one of the references was in German. So what does that tell you about the people writing the questions and the process they use? What does that tell you about the validity of the questions as a measure of my competence and ability to treat people?

Exams like the boards are a measure of test-taking skills and retention, neither one of which is a true measure of what a capable, competent physician should be. The ABIM is imposing on us an onerous and ill-conceived tool, one that most physicians agree is irrelevant. I am glad this conversation is happening, because frankly the process was enough to make me want to quit being a doctor.

Dr. Chan practices rheumatology in Pawtucket, R.I.

SAN DIEGO – Maintenance of long-term weight loss in obese or overweight individuals with atrial fibrillation was associated with nearly a sixfold greater likelihood of freedom from recurrent AF during nearly 5 years of active follow-up in the LEGACY study.

“The effect was dose dependent. The most important finding is that 46% of patients with at least a 10% weight loss were free from AF without the use of drugs or ablation procedures through nearly 5 years, versus 22% of those with 3%-9% weight loss, and just 13% with less than a 3% weight loss,” Dr. Rajeev K. Pathak said at the annual meeting of the American College of Cardiology.

Nick Piegari/Frontline Medical News

LEGACY (Long-Term Effect of Goal-Directed Weight Management in an Atrial Fibrillation Cohort: A Long-Term Follow-Up Study) included 355 overweight or obese participants with paroxsymal or persistent AF who were offered the chance to participate in a dedicated weight-loss clinic. Regular participation in this clinic proved to be a key factor in losing weight, keeping it off, and reducing AF burden; the more frequently patients attended the quarterly sessions the better the outcomes, noted Dr. Pathak, a cardiologist and electrophysiology fellow at the University of Adelaide (Australia).

Of the 355 participants, 135 lost at least 10% of their body weight, 103 had a 3%-9% drop in body weight, and 117 had less than a 3% loss or a weight gain.

Year-by-year weight trends had a significant impact on outcome. The 141 patients with linear weight loss had a 76% AF-free rate with or without the use of drugs or ablation, compared with a 59% in the 179 patients with weight fluctuations and the 38% rate in those with no loss or a weight gain. Atrial fibrillation status was assessed by 7-day Holter monitoring at least annually.

Weight fluctuation – defined as a 1% or greater change in weight between two consecutive annual follow-ups – dampened the benefits conferred by weight loss. Patients who experienced more than a 5% weight fluctuation were 2.2-fold more likely to experience AF recurrence than were those without weight fluctuation.

Patients with a sustained 10% weight loss were 5.6-fold more likely to achieve long-term freedom from AF than were patients with lesser or no weight loss. The goal was 10% weight loss rather than a body mass index of 25 kg/m² or less because once AF patients get down to a BMI below 27 kg/m² the incremental benefit of each additional 1 BMI point in terms of freedom from AF becomes much smaller, said Dr. Pathak.

Weight loss also showed a dose-dependent effect on various cardiovascular risk factors. For example, mean systolic blood pressure fell by 18 mm Hg in subjects with at least a 10% weight loss, by 10 mm Hg with a 3%-9% loss, and by 7 mm Hg with a lesser weight loss. Triglycerides, LDL cholesterol, and glycemic control improved in similar fashion. In addition, weight loss showed beneficial effects on cardiac structure, with dose-dependent reductions in left atrial volume indexed for body surface area as well as interventricular septal thickness, Dr. Pathak continued.

He described the weight loss clinic as a “very simple” structured motivational and goal-directed program with face-to-face counseling.

“We have one patient, one physician, no props. We sit with the patient, discuss areas we can improve, then we devise a low-carb, low-fat, high-protein diet in consultation with the patient. Patients maintain a lifestyle journal where they log their meals and exercise. We prescribe at least 200 minutes of moderate-intensity activity per week. Eating is a behavioral pattern, and we have found this approach to be a very effective behavioral tool. Because the plan is developed in consultation with the patient, we’ve found patients tend to adhere to what they have planned,” he explained.

Discussant Dr. Bernard J. Gersh praised LEGACY as “a really wonderful study – very important.

“There are years of epidemiologic evidence suggesting that obesity contributes in a major way to the epidemic of atrial fibrillation, and you’ve taken it a step further,” added Dr. Gersh, professor of medicine at the Mayo Clinic in Rochester, Minn.

Playing devil’s advocate, he asked whether the observed reduction in AF might have nothing to do with weight loss, but could be explained simply by LEGACY perhaps having enrolled a highly compliant group of patients who agreed to attend a clinic and were more willing to take their medications.

Dr. Pathak rejected the compliance factor as an explanation for the results. He noted that while cardiovascular risk factors improved with greater weight loss, the need for antihypertensive, lipid-lowering, and antiarrhythmic medications decreased.

“The effect can’t possibly be due to increased compliance with medications, but rather it’s a true effect of the weight loss itself. So I think this is a true clinical effect and not an epiphenomenon,” he replied.

Dr. Pathak added that he and his coinvestigators are organizing a randomized controlled confirmatory study.

Dr. Prediman K. Shah, who chaired a press conference where the LEGACY study was highlighted, said the study provided him with one of the major take-home lessons from ACC 15.

“We can argue about the mechanism of atrial fibrillation till kingdom come, but the fact is that the association is very strong that weight loss is associated with a reduced burden of atrial fibrillation, and with a very robust magnitude of benefit. That’s one of the messages that I’ll take home with me from this meeting: The next time I see my fat patient with atrial fibrillation, I’m putting him on a weight-reducing diet as the first approach,” declared Dr. Shah, professor of medicine at UCLA and director of the Oppenheimer Atherosclerosis Research Center at Cedars-Sinai Medical Center in Los Angeles.

Dr. Pathak reported having no financial conflicts regarding this study, which was supported by university funds.

Simultaneously with Dr. Pathak’s presentation at ACC 15, the LEGACY study was published online (J. Am. Coll. Cardiol. 2015 [doi: 10.1016/j.jacc.2015.03.002])

[email protected]

SAN DIEGO – Maintenance of long-term weight loss in obese or overweight individuals with atrial fibrillation was associated with nearly a sixfold greater likelihood of freedom from recurrent AF during nearly 5 years of active follow-up in the LEGACY study.

“The effect was dose dependent. The most important finding is that 46% of patients with at least a 10% weight loss were free from AF without the use of drugs or ablation procedures through nearly 5 years, versus 22% of those with 3%-9% weight loss, and just 13% with less than a 3% weight loss,” Dr. Rajeev K. Pathak said at the annual meeting of the American College of Cardiology.

Nick Piegari/Frontline Medical News

LEGACY (Long-Term Effect of Goal-Directed Weight Management in an Atrial Fibrillation Cohort: A Long-Term Follow-Up Study) included 355 overweight or obese participants with paroxsymal or persistent AF who were offered the chance to participate in a dedicated weight-loss clinic. Regular participation in this clinic proved to be a key factor in losing weight, keeping it off, and reducing AF burden; the more frequently patients attended the quarterly sessions the better the outcomes, noted Dr. Pathak, a cardiologist and electrophysiology fellow at the University of Adelaide (Australia).

Of the 355 participants, 135 lost at least 10% of their body weight, 103 had a 3%-9% drop in body weight, and 117 had less than a 3% loss or a weight gain.

Year-by-year weight trends had a significant impact on outcome. The 141 patients with linear weight loss had a 76% AF-free rate with or without the use of drugs or ablation, compared with a 59% in the 179 patients with weight fluctuations and the 38% rate in those with no loss or a weight gain. Atrial fibrillation status was assessed by 7-day Holter monitoring at least annually.

Weight fluctuation – defined as a 1% or greater change in weight between two consecutive annual follow-ups – dampened the benefits conferred by weight loss. Patients who experienced more than a 5% weight fluctuation were 2.2-fold more likely to experience AF recurrence than were those without weight fluctuation.

Patients with a sustained 10% weight loss were 5.6-fold more likely to achieve long-term freedom from AF than were patients with lesser or no weight loss. The goal was 10% weight loss rather than a body mass index of 25 kg/m² or less because once AF patients get down to a BMI below 27 kg/m² the incremental benefit of each additional 1 BMI point in terms of freedom from AF becomes much smaller, said Dr. Pathak.

Weight loss also showed a dose-dependent effect on various cardiovascular risk factors. For example, mean systolic blood pressure fell by 18 mm Hg in subjects with at least a 10% weight loss, by 10 mm Hg with a 3%-9% loss, and by 7 mm Hg with a lesser weight loss. Triglycerides, LDL cholesterol, and glycemic control improved in similar fashion. In addition, weight loss showed beneficial effects on cardiac structure, with dose-dependent reductions in left atrial volume indexed for body surface area as well as interventricular septal thickness, Dr. Pathak continued.

He described the weight loss clinic as a “very simple” structured motivational and goal-directed program with face-to-face counseling.

“We have one patient, one physician, no props. We sit with the patient, discuss areas we can improve, then we devise a low-carb, low-fat, high-protein diet in consultation with the patient. Patients maintain a lifestyle journal where they log their meals and exercise. We prescribe at least 200 minutes of moderate-intensity activity per week. Eating is a behavioral pattern, and we have found this approach to be a very effective behavioral tool. Because the plan is developed in consultation with the patient, we’ve found patients tend to adhere to what they have planned,” he explained.

Discussant Dr. Bernard J. Gersh praised LEGACY as “a really wonderful study – very important.

“There are years of epidemiologic evidence suggesting that obesity contributes in a major way to the epidemic of atrial fibrillation, and you’ve taken it a step further,” added Dr. Gersh, professor of medicine at the Mayo Clinic in Rochester, Minn.

Playing devil’s advocate, he asked whether the observed reduction in AF might have nothing to do with weight loss, but could be explained simply by LEGACY perhaps having enrolled a highly compliant group of patients who agreed to attend a clinic and were more willing to take their medications.

Dr. Pathak rejected the compliance factor as an explanation for the results. He noted that while cardiovascular risk factors improved with greater weight loss, the need for antihypertensive, lipid-lowering, and antiarrhythmic medications decreased.

“The effect can’t possibly be due to increased compliance with medications, but rather it’s a true effect of the weight loss itself. So I think this is a true clinical effect and not an epiphenomenon,” he replied.

Dr. Pathak added that he and his coinvestigators are organizing a randomized controlled confirmatory study.

Dr. Prediman K. Shah, who chaired a press conference where the LEGACY study was highlighted, said the study provided him with one of the major take-home lessons from ACC 15.

“We can argue about the mechanism of atrial fibrillation till kingdom come, but the fact is that the association is very strong that weight loss is associated with a reduced burden of atrial fibrillation, and with a very robust magnitude of benefit. That’s one of the messages that I’ll take home with me from this meeting: The next time I see my fat patient with atrial fibrillation, I’m putting him on a weight-reducing diet as the first approach,” declared Dr. Shah, professor of medicine at UCLA and director of the Oppenheimer Atherosclerosis Research Center at Cedars-Sinai Medical Center in Los Angeles.

Dr. Pathak reported having no financial conflicts regarding this study, which was supported by university funds.

Simultaneously with Dr. Pathak’s presentation at ACC 15, the LEGACY study was published online (J. Am. Coll. Cardiol. 2015 [doi: 10.1016/j.jacc.2015.03.002])

[email protected]

SAN DIEGO – Maintenance of long-term weight loss in obese or overweight individuals with atrial fibrillation was associated with nearly a sixfold greater likelihood of freedom from recurrent AF during nearly 5 years of active follow-up in the LEGACY study.

“The effect was dose dependent. The most important finding is that 46% of patients with at least a 10% weight loss were free from AF without the use of drugs or ablation procedures through nearly 5 years, versus 22% of those with 3%-9% weight loss, and just 13% with less than a 3% weight loss,” Dr. Rajeev K. Pathak said at the annual meeting of the American College of Cardiology.

Nick Piegari/Frontline Medical News

LEGACY (Long-Term Effect of Goal-Directed Weight Management in an Atrial Fibrillation Cohort: A Long-Term Follow-Up Study) included 355 overweight or obese participants with paroxsymal or persistent AF who were offered the chance to participate in a dedicated weight-loss clinic. Regular participation in this clinic proved to be a key factor in losing weight, keeping it off, and reducing AF burden; the more frequently patients attended the quarterly sessions the better the outcomes, noted Dr. Pathak, a cardiologist and electrophysiology fellow at the University of Adelaide (Australia).

Of the 355 participants, 135 lost at least 10% of their body weight, 103 had a 3%-9% drop in body weight, and 117 had less than a 3% loss or a weight gain.

Year-by-year weight trends had a significant impact on outcome. The 141 patients with linear weight loss had a 76% AF-free rate with or without the use of drugs or ablation, compared with a 59% in the 179 patients with weight fluctuations and the 38% rate in those with no loss or a weight gain. Atrial fibrillation status was assessed by 7-day Holter monitoring at least annually.

Weight fluctuation – defined as a 1% or greater change in weight between two consecutive annual follow-ups – dampened the benefits conferred by weight loss. Patients who experienced more than a 5% weight fluctuation were 2.2-fold more likely to experience AF recurrence than were those without weight fluctuation.

Patients with a sustained 10% weight loss were 5.6-fold more likely to achieve long-term freedom from AF than were patients with lesser or no weight loss. The goal was 10% weight loss rather than a body mass index of 25 kg/m² or less because once AF patients get down to a BMI below 27 kg/m² the incremental benefit of each additional 1 BMI point in terms of freedom from AF becomes much smaller, said Dr. Pathak.

Weight loss also showed a dose-dependent effect on various cardiovascular risk factors. For example, mean systolic blood pressure fell by 18 mm Hg in subjects with at least a 10% weight loss, by 10 mm Hg with a 3%-9% loss, and by 7 mm Hg with a lesser weight loss. Triglycerides, LDL cholesterol, and glycemic control improved in similar fashion. In addition, weight loss showed beneficial effects on cardiac structure, with dose-dependent reductions in left atrial volume indexed for body surface area as well as interventricular septal thickness, Dr. Pathak continued.

He described the weight loss clinic as a “very simple” structured motivational and goal-directed program with face-to-face counseling.

“We have one patient, one physician, no props. We sit with the patient, discuss areas we can improve, then we devise a low-carb, low-fat, high-protein diet in consultation with the patient. Patients maintain a lifestyle journal where they log their meals and exercise. We prescribe at least 200 minutes of moderate-intensity activity per week. Eating is a behavioral pattern, and we have found this approach to be a very effective behavioral tool. Because the plan is developed in consultation with the patient, we’ve found patients tend to adhere to what they have planned,” he explained.

Discussant Dr. Bernard J. Gersh praised LEGACY as “a really wonderful study – very important.

“There are years of epidemiologic evidence suggesting that obesity contributes in a major way to the epidemic of atrial fibrillation, and you’ve taken it a step further,” added Dr. Gersh, professor of medicine at the Mayo Clinic in Rochester, Minn.

Playing devil’s advocate, he asked whether the observed reduction in AF might have nothing to do with weight loss, but could be explained simply by LEGACY perhaps having enrolled a highly compliant group of patients who agreed to attend a clinic and were more willing to take their medications.

Dr. Pathak rejected the compliance factor as an explanation for the results. He noted that while cardiovascular risk factors improved with greater weight loss, the need for antihypertensive, lipid-lowering, and antiarrhythmic medications decreased.

“The effect can’t possibly be due to increased compliance with medications, but rather it’s a true effect of the weight loss itself. So I think this is a true clinical effect and not an epiphenomenon,” he replied.

Dr. Pathak added that he and his coinvestigators are organizing a randomized controlled confirmatory study.

Dr. Prediman K. Shah, who chaired a press conference where the LEGACY study was highlighted, said the study provided him with one of the major take-home lessons from ACC 15.

“We can argue about the mechanism of atrial fibrillation till kingdom come, but the fact is that the association is very strong that weight loss is associated with a reduced burden of atrial fibrillation, and with a very robust magnitude of benefit. That’s one of the messages that I’ll take home with me from this meeting: The next time I see my fat patient with atrial fibrillation, I’m putting him on a weight-reducing diet as the first approach,” declared Dr. Shah, professor of medicine at UCLA and director of the Oppenheimer Atherosclerosis Research Center at Cedars-Sinai Medical Center in Los Angeles.

Dr. Pathak reported having no financial conflicts regarding this study, which was supported by university funds.

Simultaneously with Dr. Pathak’s presentation at ACC 15, the LEGACY study was published online (J. Am. Coll. Cardiol. 2015 [doi: 10.1016/j.jacc.2015.03.002])

[email protected]