Hematopoietic stem cells in the bone marrow

New research suggests the classical yet contested “tree” model of hematopoiesis is accurate.

In this model, the tree trunk is composed of hematopoietic stem cells (HSCs), and the branches consist of various progenitor cells that give rise to a number of distinct cell types.

Because previous research raised doubts about this model, investigators set out to track hematopoiesis more effectively than ever before.

The team used a “random generator” to label HSCs with genetic barcodes, and this allowed them to trace which cell types arise from an HSC.

Hans-Reimer Rodewald, PhD, of the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) in Heidelberg, and his colleagues described this research in Nature.

“Genetic barcodes have been developed and applied before, but they were based on methods that can also change cellular properties,” Dr Rodewald said. “Our barcodes are different. They can be induced tissue-specifically and directly in the genome of mice–without influencing the animals’ physiological development.”

The basis of the new technology is the Cre/loxP system that is used to rearrange or remove specially labeled DNA segments.

The investigators bred mice whose genomes exhibit the basic elements of the barcode. At a selected site, where no genes are encoded, it contains 9 DNA fragments from a plant called Arabidopsis thaliana. These elements are flanked by 10 genetic cutting sites called IoxP sites.

By administering a pharmacological agent, the matching molecular scissors, called “Cre,” can be activated in the animals’ HSCs. Then, code elements are randomly rearranged or cut out.

“This genetic, random DNA barcode generator can generate up to 1.8 million genetic barcodes, and we can identify the codes that arise only once in an experiment,” said study author Thomas Höfer, PhD, also of DKFZ.

When these specially labeled HSCs divide and mature, the barcodes are preserved.

The investigators performed comprehensive barcode analyses in order to trace an individual blood cell back to the HSC from which it originated.

These analyses revealed 2 large developmental branches “growing” from the HSC “tree trunk.” In one branch, T cells and B cells develop. In the other, red blood cells and other white blood cells, such as granulocytes and monocytes, form.

“Our findings show that the classical model of a hierarchical developmental tree that starts from multipotent stem cells holds true for hematopoiesis,” Dr Rodewald said.

He and his colleagues believe their genetic barcode system can be used for purposes other than studying blood cell development. In the future, it might be used for experimentally tracing the origin of leukemias and other cancers.

Hematopoietic stem cells in the bone marrow

New research suggests the classical yet contested “tree” model of hematopoiesis is accurate.

In this model, the tree trunk is composed of hematopoietic stem cells (HSCs), and the branches consist of various progenitor cells that give rise to a number of distinct cell types.

Because previous research raised doubts about this model, investigators set out to track hematopoiesis more effectively than ever before.

The team used a “random generator” to label HSCs with genetic barcodes, and this allowed them to trace which cell types arise from an HSC.

Hans-Reimer Rodewald, PhD, of the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) in Heidelberg, and his colleagues described this research in Nature.

“Genetic barcodes have been developed and applied before, but they were based on methods that can also change cellular properties,” Dr Rodewald said. “Our barcodes are different. They can be induced tissue-specifically and directly in the genome of mice–without influencing the animals’ physiological development.”

The basis of the new technology is the Cre/loxP system that is used to rearrange or remove specially labeled DNA segments.

The investigators bred mice whose genomes exhibit the basic elements of the barcode. At a selected site, where no genes are encoded, it contains 9 DNA fragments from a plant called Arabidopsis thaliana. These elements are flanked by 10 genetic cutting sites called IoxP sites.

By administering a pharmacological agent, the matching molecular scissors, called “Cre,” can be activated in the animals’ HSCs. Then, code elements are randomly rearranged or cut out.

“This genetic, random DNA barcode generator can generate up to 1.8 million genetic barcodes, and we can identify the codes that arise only once in an experiment,” said study author Thomas Höfer, PhD, also of DKFZ.

When these specially labeled HSCs divide and mature, the barcodes are preserved.

The investigators performed comprehensive barcode analyses in order to trace an individual blood cell back to the HSC from which it originated.

These analyses revealed 2 large developmental branches “growing” from the HSC “tree trunk.” In one branch, T cells and B cells develop. In the other, red blood cells and other white blood cells, such as granulocytes and monocytes, form.

“Our findings show that the classical model of a hierarchical developmental tree that starts from multipotent stem cells holds true for hematopoiesis,” Dr Rodewald said.

He and his colleagues believe their genetic barcode system can be used for purposes other than studying blood cell development. In the future, it might be used for experimentally tracing the origin of leukemias and other cancers.

Hematopoietic stem cells in the bone marrow

New research suggests the classical yet contested “tree” model of hematopoiesis is accurate.

In this model, the tree trunk is composed of hematopoietic stem cells (HSCs), and the branches consist of various progenitor cells that give rise to a number of distinct cell types.

Because previous research raised doubts about this model, investigators set out to track hematopoiesis more effectively than ever before.

The team used a “random generator” to label HSCs with genetic barcodes, and this allowed them to trace which cell types arise from an HSC.

Hans-Reimer Rodewald, PhD, of the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) in Heidelberg, and his colleagues described this research in Nature.

“Genetic barcodes have been developed and applied before, but they were based on methods that can also change cellular properties,” Dr Rodewald said. “Our barcodes are different. They can be induced tissue-specifically and directly in the genome of mice–without influencing the animals’ physiological development.”

The basis of the new technology is the Cre/loxP system that is used to rearrange or remove specially labeled DNA segments.

The investigators bred mice whose genomes exhibit the basic elements of the barcode. At a selected site, where no genes are encoded, it contains 9 DNA fragments from a plant called Arabidopsis thaliana. These elements are flanked by 10 genetic cutting sites called IoxP sites.

By administering a pharmacological agent, the matching molecular scissors, called “Cre,” can be activated in the animals’ HSCs. Then, code elements are randomly rearranged or cut out.

“This genetic, random DNA barcode generator can generate up to 1.8 million genetic barcodes, and we can identify the codes that arise only once in an experiment,” said study author Thomas Höfer, PhD, also of DKFZ.

When these specially labeled HSCs divide and mature, the barcodes are preserved.

The investigators performed comprehensive barcode analyses in order to trace an individual blood cell back to the HSC from which it originated.

These analyses revealed 2 large developmental branches “growing” from the HSC “tree trunk.” In one branch, T cells and B cells develop. In the other, red blood cells and other white blood cells, such as granulocytes and monocytes, form.

“Our findings show that the classical model of a hierarchical developmental tree that starts from multipotent stem cells holds true for hematopoiesis,” Dr Rodewald said.

He and his colleagues believe their genetic barcode system can be used for purposes other than studying blood cell development. In the future, it might be used for experimentally tracing the origin of leukemias and other cancers.

Image by Ed Uthman

An investigational antibody has demonstrated activity against acute myeloid leukemia (AML), multiple myeloma (MM), and non-Hodgkin lymphoma (NHL), according to researchers.

PF-06747143 is a humanized CXCR4 immunoglobulin G1 (IgG1) antibody that binds to CXCR4 and inhibits both CXCL12-mediated signaling pathways and cell migration.

Whether given alone or in combination with chemotherapy, PF-06747143 demonstrated efficacy in mouse models of NHL, MM, and AML.

Treatment involving PF-06747143—alone or in combination—eradicated more cancer cells than did standard treatment options.

These results were published in Blood Advances. The research was sponsored by Pfizer, Inc., the company developing PF-06747143.

“One of the major limitations we see in treating blood cancers is the failure to clear cancer cells from the bone marrow,” said study author Flavia Pernasetti, PhD, of Pfizer Oncology Research and Development.

“Because the bone marrow allows the cancer cells to flourish, removing these cells is an essential step in treating these malignancies effectively.”

With this goal in mind, Dr Pernasetti and her colleagues looked to the mechanisms that control the movement of cells into the bone marrow (BM) in the first place—the chemokine receptor CXCR4 and its ligand CXCL12.

The researchers created PF-06747143, which attacks and kills cancer cells directly but also removes cancer cells from the BM so they can be killed by other treatments.

Results in NHL

The researchers first tested PF-06747143 in an NHL Ramos xenograft model. Mice received PF-06747143 or a control IgG1 antibody at 10 mg/kg on days 1 and 8.

PF-06747143 significantly inhibited tumor growth compared to the control antibody (P<0.0001). Seventy percent of PF-06747143-treated mice had tumor volumes below their initial size at the end of the study.

PF-06747143 produced a dose-dependent response that was sustained until the end of the study, even after treatment was stopped.

Results in MM

The researchers tested PF-06747143 in a disseminated MM model, in which the OPM2-Luc tumor cells were implanted intravenously and migrated spontaneously to the BM.

Mice received PF-06747143 or IgG1 control at 10 mg/kg weekly for 5 doses. Other mice received melphalan at 1 mg/kg twice a week for a total of 4 cycles.

On day 30, PF-06747143 had significantly inhibited BM tumor growth compared to the control antibody or melphalan (P<0.0001).

PF-06747143-treated mice also had a significant survival benefit. The median survival was 33.5 days for mice that received the control antibody and 36 days for mice treated with melphalan. However, there were no deaths in the PF-06747143-treated mice by day 50, which marked the end of the study (P<0.0001).

The researchers also tested PF-06747143 at a lower dose (1 mg/kg weekly for a total of 7 doses), both alone and in combination with bortezomib (0.5 mg/kg twice a week for a total of 4 cycles).

The median survival was 34 days in the control mice, 44 days in mice that received bortezomib alone, and 47 days in mice that received PF-06747143 alone. However, there were no deaths in the combination arm at day 51, which was the end of the study (P<0.0003).

Results in AML

The researchers tested PF-06747143 in an AML disseminated tumor model using MV4-11 cells.

They compared PF-06747143 (given at 0.1, 1, or 10 mg/kg weekly for 4 doses) to the chemotherapeutic agent daunorubicin (2 mg/kg on days 1, 3, and 5), the FLT3 inhibitor crenolanib (7.5 mg/kg twice a day, on days 11-15 and 25-29), and a control IgG1 antibody (10 mg/kg weekly for 4 doses).

PF-06747143 (at 10 mg/kg), daunorubicin, and crenolanib all significantly reduced the number of tumor cells in the peripheral blood and BM when compared with the control antibody (P<0.05).

PF-06746143 treatment (at 10 mg/kg) reduced the number of AML cells in the BM by 95.9%, while daunorubicin reduced them by 84.5% and crenolanib by 80.5%.

The median survival was 36 days for mice that received PF-06747143 at 0.1 mg/kg, 41 days for mice that received the control antibody, 47 days for mice that received PF-06747143 at 1 mg/kg, and 63 days for mice that received PF-06747143 at 10 mg/kg.

The researchers also found that PF-06747143 had a “strong combinatorial effect” with daunorubicin and cytarabine in a chemotherapy-resistant model of AML. The team noted that only 36% of BM cells are positive for CXCR4 in this model.

Treatment with PF-06747143 alone reduced the percentage of AML cells in the BM to 80%, combination daunorubicin and cytarabine reduced it to 27%, and combination PF-06747143, daunorubicin, and cytarabine reduced the percentage of AML cells in the BM to 0.3%.

“Our preliminary preclinical results are encouraging,” Dr Pernasetti said, “and we are very excited to see how our antibody fares in clinical testing.”

PF-06747143 is currently being evaluated in a phase 1 trial of AML patients.

Image by Ed Uthman

An investigational antibody has demonstrated activity against acute myeloid leukemia (AML), multiple myeloma (MM), and non-Hodgkin lymphoma (NHL), according to researchers.

PF-06747143 is a humanized CXCR4 immunoglobulin G1 (IgG1) antibody that binds to CXCR4 and inhibits both CXCL12-mediated signaling pathways and cell migration.

Whether given alone or in combination with chemotherapy, PF-06747143 demonstrated efficacy in mouse models of NHL, MM, and AML.

Treatment involving PF-06747143—alone or in combination—eradicated more cancer cells than did standard treatment options.

These results were published in Blood Advances. The research was sponsored by Pfizer, Inc., the company developing PF-06747143.

“One of the major limitations we see in treating blood cancers is the failure to clear cancer cells from the bone marrow,” said study author Flavia Pernasetti, PhD, of Pfizer Oncology Research and Development.

“Because the bone marrow allows the cancer cells to flourish, removing these cells is an essential step in treating these malignancies effectively.”

With this goal in mind, Dr Pernasetti and her colleagues looked to the mechanisms that control the movement of cells into the bone marrow (BM) in the first place—the chemokine receptor CXCR4 and its ligand CXCL12.

The researchers created PF-06747143, which attacks and kills cancer cells directly but also removes cancer cells from the BM so they can be killed by other treatments.

Results in NHL

The researchers first tested PF-06747143 in an NHL Ramos xenograft model. Mice received PF-06747143 or a control IgG1 antibody at 10 mg/kg on days 1 and 8.

PF-06747143 significantly inhibited tumor growth compared to the control antibody (P<0.0001). Seventy percent of PF-06747143-treated mice had tumor volumes below their initial size at the end of the study.

PF-06747143 produced a dose-dependent response that was sustained until the end of the study, even after treatment was stopped.

Results in MM

The researchers tested PF-06747143 in a disseminated MM model, in which the OPM2-Luc tumor cells were implanted intravenously and migrated spontaneously to the BM.

Mice received PF-06747143 or IgG1 control at 10 mg/kg weekly for 5 doses. Other mice received melphalan at 1 mg/kg twice a week for a total of 4 cycles.

On day 30, PF-06747143 had significantly inhibited BM tumor growth compared to the control antibody or melphalan (P<0.0001).

PF-06747143-treated mice also had a significant survival benefit. The median survival was 33.5 days for mice that received the control antibody and 36 days for mice treated with melphalan. However, there were no deaths in the PF-06747143-treated mice by day 50, which marked the end of the study (P<0.0001).

The researchers also tested PF-06747143 at a lower dose (1 mg/kg weekly for a total of 7 doses), both alone and in combination with bortezomib (0.5 mg/kg twice a week for a total of 4 cycles).

The median survival was 34 days in the control mice, 44 days in mice that received bortezomib alone, and 47 days in mice that received PF-06747143 alone. However, there were no deaths in the combination arm at day 51, which was the end of the study (P<0.0003).

Results in AML

The researchers tested PF-06747143 in an AML disseminated tumor model using MV4-11 cells.

They compared PF-06747143 (given at 0.1, 1, or 10 mg/kg weekly for 4 doses) to the chemotherapeutic agent daunorubicin (2 mg/kg on days 1, 3, and 5), the FLT3 inhibitor crenolanib (7.5 mg/kg twice a day, on days 11-15 and 25-29), and a control IgG1 antibody (10 mg/kg weekly for 4 doses).

PF-06747143 (at 10 mg/kg), daunorubicin, and crenolanib all significantly reduced the number of tumor cells in the peripheral blood and BM when compared with the control antibody (P<0.05).

PF-06746143 treatment (at 10 mg/kg) reduced the number of AML cells in the BM by 95.9%, while daunorubicin reduced them by 84.5% and crenolanib by 80.5%.

The median survival was 36 days for mice that received PF-06747143 at 0.1 mg/kg, 41 days for mice that received the control antibody, 47 days for mice that received PF-06747143 at 1 mg/kg, and 63 days for mice that received PF-06747143 at 10 mg/kg.

The researchers also found that PF-06747143 had a “strong combinatorial effect” with daunorubicin and cytarabine in a chemotherapy-resistant model of AML. The team noted that only 36% of BM cells are positive for CXCR4 in this model.

Treatment with PF-06747143 alone reduced the percentage of AML cells in the BM to 80%, combination daunorubicin and cytarabine reduced it to 27%, and combination PF-06747143, daunorubicin, and cytarabine reduced the percentage of AML cells in the BM to 0.3%.

“Our preliminary preclinical results are encouraging,” Dr Pernasetti said, “and we are very excited to see how our antibody fares in clinical testing.”

PF-06747143 is currently being evaluated in a phase 1 trial of AML patients.

Image by Ed Uthman

An investigational antibody has demonstrated activity against acute myeloid leukemia (AML), multiple myeloma (MM), and non-Hodgkin lymphoma (NHL), according to researchers.

PF-06747143 is a humanized CXCR4 immunoglobulin G1 (IgG1) antibody that binds to CXCR4 and inhibits both CXCL12-mediated signaling pathways and cell migration.

Whether given alone or in combination with chemotherapy, PF-06747143 demonstrated efficacy in mouse models of NHL, MM, and AML.

Treatment involving PF-06747143—alone or in combination—eradicated more cancer cells than did standard treatment options.

These results were published in Blood Advances. The research was sponsored by Pfizer, Inc., the company developing PF-06747143.

“One of the major limitations we see in treating blood cancers is the failure to clear cancer cells from the bone marrow,” said study author Flavia Pernasetti, PhD, of Pfizer Oncology Research and Development.

“Because the bone marrow allows the cancer cells to flourish, removing these cells is an essential step in treating these malignancies effectively.”

With this goal in mind, Dr Pernasetti and her colleagues looked to the mechanisms that control the movement of cells into the bone marrow (BM) in the first place—the chemokine receptor CXCR4 and its ligand CXCL12.

The researchers created PF-06747143, which attacks and kills cancer cells directly but also removes cancer cells from the BM so they can be killed by other treatments.

Results in NHL

The researchers first tested PF-06747143 in an NHL Ramos xenograft model. Mice received PF-06747143 or a control IgG1 antibody at 10 mg/kg on days 1 and 8.

PF-06747143 significantly inhibited tumor growth compared to the control antibody (P<0.0001). Seventy percent of PF-06747143-treated mice had tumor volumes below their initial size at the end of the study.

PF-06747143 produced a dose-dependent response that was sustained until the end of the study, even after treatment was stopped.

Results in MM

The researchers tested PF-06747143 in a disseminated MM model, in which the OPM2-Luc tumor cells were implanted intravenously and migrated spontaneously to the BM.

Mice received PF-06747143 or IgG1 control at 10 mg/kg weekly for 5 doses. Other mice received melphalan at 1 mg/kg twice a week for a total of 4 cycles.

On day 30, PF-06747143 had significantly inhibited BM tumor growth compared to the control antibody or melphalan (P<0.0001).

PF-06747143-treated mice also had a significant survival benefit. The median survival was 33.5 days for mice that received the control antibody and 36 days for mice treated with melphalan. However, there were no deaths in the PF-06747143-treated mice by day 50, which marked the end of the study (P<0.0001).

The researchers also tested PF-06747143 at a lower dose (1 mg/kg weekly for a total of 7 doses), both alone and in combination with bortezomib (0.5 mg/kg twice a week for a total of 4 cycles).

The median survival was 34 days in the control mice, 44 days in mice that received bortezomib alone, and 47 days in mice that received PF-06747143 alone. However, there were no deaths in the combination arm at day 51, which was the end of the study (P<0.0003).

Results in AML

The researchers tested PF-06747143 in an AML disseminated tumor model using MV4-11 cells.

They compared PF-06747143 (given at 0.1, 1, or 10 mg/kg weekly for 4 doses) to the chemotherapeutic agent daunorubicin (2 mg/kg on days 1, 3, and 5), the FLT3 inhibitor crenolanib (7.5 mg/kg twice a day, on days 11-15 and 25-29), and a control IgG1 antibody (10 mg/kg weekly for 4 doses).

PF-06747143 (at 10 mg/kg), daunorubicin, and crenolanib all significantly reduced the number of tumor cells in the peripheral blood and BM when compared with the control antibody (P<0.05).

PF-06746143 treatment (at 10 mg/kg) reduced the number of AML cells in the BM by 95.9%, while daunorubicin reduced them by 84.5% and crenolanib by 80.5%.

The median survival was 36 days for mice that received PF-06747143 at 0.1 mg/kg, 41 days for mice that received the control antibody, 47 days for mice that received PF-06747143 at 1 mg/kg, and 63 days for mice that received PF-06747143 at 10 mg/kg.

The researchers also found that PF-06747143 had a “strong combinatorial effect” with daunorubicin and cytarabine in a chemotherapy-resistant model of AML. The team noted that only 36% of BM cells are positive for CXCR4 in this model.

Treatment with PF-06747143 alone reduced the percentage of AML cells in the BM to 80%, combination daunorubicin and cytarabine reduced it to 27%, and combination PF-06747143, daunorubicin, and cytarabine reduced the percentage of AML cells in the BM to 0.3%.

“Our preliminary preclinical results are encouraging,” Dr Pernasetti said, “and we are very excited to see how our antibody fares in clinical testing.”

PF-06747143 is currently being evaluated in a phase 1 trial of AML patients.

AML cells

The US Food and Drug Administration (FDA) has granted orphan drug designation to SY-1425 for the treatment of acute myeloid leukemia (AML).

SY-1425 is an oral, first-in-class, selective retinoic acid receptor alpha (RARα) agonist. It is currently under investigation in a phase 2 trial of patients with AML and myelodysplastic syndromes (MDS).

“We believe that SY-1425 may provide a meaningful benefit for subsets of AML patients whose disease is driven by abnormally high expression of the RARA or IRF8 genes,” said David A. Roth, MD, chief medical officer at Syros Pharmaceuticals, the company developing SY-1425.

“Receiving orphan drug designation is an important regulatory milestone in the development of SY-1425. We’re pleased with the continued progress of the ongoing phase 2 clinical trial, and we look forward to presenting initial clinical data in the fourth quarter of this year.”

Using its gene control platform, Syros discovered subsets of AML and MDS patients with super-enhancers associated with RARA or IRF8. These super-enhancers are believed to drive overexpression of the RARA or IRF8 genes, locking cells in an immature, undifferentiated, and proliferative state and leading to disease.

In preclinical studies, SY-1425 promoted differentiation of AML cells with high RARA or IRF8 expression and inhibited tumor growth and prolonged survival in patient-derived xenograft models of AML with high RARA expression.

In the ongoing phase 2 trial, researchers are assessing the safety and efficacy of SY-1425 as a single agent in 4 AML and MDS patient populations, as well as SY-1425 in combination with azacitidine in newly diagnosed AML patients who are not suitable candidates for standard chemotherapy.

All patients are prospectively selected using biomarkers for high expression of RARA or IRF8. Additional details about the trial can be found at https://clinicaltrials.gov/ct2/show/NCT02807558.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

AML cells

The US Food and Drug Administration (FDA) has granted orphan drug designation to SY-1425 for the treatment of acute myeloid leukemia (AML).

SY-1425 is an oral, first-in-class, selective retinoic acid receptor alpha (RARα) agonist. It is currently under investigation in a phase 2 trial of patients with AML and myelodysplastic syndromes (MDS).

“We believe that SY-1425 may provide a meaningful benefit for subsets of AML patients whose disease is driven by abnormally high expression of the RARA or IRF8 genes,” said David A. Roth, MD, chief medical officer at Syros Pharmaceuticals, the company developing SY-1425.

“Receiving orphan drug designation is an important regulatory milestone in the development of SY-1425. We’re pleased with the continued progress of the ongoing phase 2 clinical trial, and we look forward to presenting initial clinical data in the fourth quarter of this year.”

Using its gene control platform, Syros discovered subsets of AML and MDS patients with super-enhancers associated with RARA or IRF8. These super-enhancers are believed to drive overexpression of the RARA or IRF8 genes, locking cells in an immature, undifferentiated, and proliferative state and leading to disease.

In preclinical studies, SY-1425 promoted differentiation of AML cells with high RARA or IRF8 expression and inhibited tumor growth and prolonged survival in patient-derived xenograft models of AML with high RARA expression.

In the ongoing phase 2 trial, researchers are assessing the safety and efficacy of SY-1425 as a single agent in 4 AML and MDS patient populations, as well as SY-1425 in combination with azacitidine in newly diagnosed AML patients who are not suitable candidates for standard chemotherapy.

All patients are prospectively selected using biomarkers for high expression of RARA or IRF8. Additional details about the trial can be found at https://clinicaltrials.gov/ct2/show/NCT02807558.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

AML cells

The US Food and Drug Administration (FDA) has granted orphan drug designation to SY-1425 for the treatment of acute myeloid leukemia (AML).

SY-1425 is an oral, first-in-class, selective retinoic acid receptor alpha (RARα) agonist. It is currently under investigation in a phase 2 trial of patients with AML and myelodysplastic syndromes (MDS).

“We believe that SY-1425 may provide a meaningful benefit for subsets of AML patients whose disease is driven by abnormally high expression of the RARA or IRF8 genes,” said David A. Roth, MD, chief medical officer at Syros Pharmaceuticals, the company developing SY-1425.

“Receiving orphan drug designation is an important regulatory milestone in the development of SY-1425. We’re pleased with the continued progress of the ongoing phase 2 clinical trial, and we look forward to presenting initial clinical data in the fourth quarter of this year.”

Using its gene control platform, Syros discovered subsets of AML and MDS patients with super-enhancers associated with RARA or IRF8. These super-enhancers are believed to drive overexpression of the RARA or IRF8 genes, locking cells in an immature, undifferentiated, and proliferative state and leading to disease.

In preclinical studies, SY-1425 promoted differentiation of AML cells with high RARA or IRF8 expression and inhibited tumor growth and prolonged survival in patient-derived xenograft models of AML with high RARA expression.

In the ongoing phase 2 trial, researchers are assessing the safety and efficacy of SY-1425 as a single agent in 4 AML and MDS patient populations, as well as SY-1425 in combination with azacitidine in newly diagnosed AML patients who are not suitable candidates for standard chemotherapy.

All patients are prospectively selected using biomarkers for high expression of RARA or IRF8. Additional details about the trial can be found at https://clinicaltrials.gov/ct2/show/NCT02807558.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Body mass index z scores fall short for tracking children with severe obesity, based on data from nearly 7,000 children in the Bogalusa Heart Study.

The current parameters used in the Centers for Disease Control and Prevention growth charts for children with high body mass index (BMI) “can result in estimates that differ substantially from those that are observed and constrains the maximum BMI z that is attainable at a given sex and age,” wrote David S. Freedman, PhD, of the Centers for Disease Control and Prevention in Atlanta, and Gerald S. Berenson, MD, of Louisiana State University Health Sciences Center, New Orleans, (Pediatrics. 2017;140:e20171072).

The BMI adjusted z score (BMIaz) or the BMI expressed as a percentage of the 95th percentile (%BMI_p95) “will provide more accurate information on body size over time among children with very high BMIs,” they said.

iStockphoto

Body mass index z scores fall short for tracking children with severe obesity, based on data from nearly 7,000 children in the Bogalusa Heart Study.

The current parameters used in the Centers for Disease Control and Prevention growth charts for children with high body mass index (BMI) “can result in estimates that differ substantially from those that are observed and constrains the maximum BMI z that is attainable at a given sex and age,” wrote David S. Freedman, PhD, of the Centers for Disease Control and Prevention in Atlanta, and Gerald S. Berenson, MD, of Louisiana State University Health Sciences Center, New Orleans, (Pediatrics. 2017;140:e20171072).

The BMI adjusted z score (BMIaz) or the BMI expressed as a percentage of the 95th percentile (%BMI_p95) “will provide more accurate information on body size over time among children with very high BMIs,” they said.

iStockphoto

Body mass index z scores fall short for tracking children with severe obesity, based on data from nearly 7,000 children in the Bogalusa Heart Study.

The current parameters used in the Centers for Disease Control and Prevention growth charts for children with high body mass index (BMI) “can result in estimates that differ substantially from those that are observed and constrains the maximum BMI z that is attainable at a given sex and age,” wrote David S. Freedman, PhD, of the Centers for Disease Control and Prevention in Atlanta, and Gerald S. Berenson, MD, of Louisiana State University Health Sciences Center, New Orleans, (Pediatrics. 2017;140:e20171072).

The BMI adjusted z score (BMIaz) or the BMI expressed as a percentage of the 95th percentile (%BMI_p95) “will provide more accurate information on body size over time among children with very high BMIs,” they said.

iStockphoto

Rates of phlebitis associated with peripheral venous catheters (PVC) ranged from less than 1% to 34% depending on which assessment tool researchers used in a large cross-sectional study.

Rates also varied within individual instruments because they included several possible case definitions, Katarina Göransson, PhD, and her associates reported in Lancet Haematology. “We find it concerning that our study shows variation of the proportion of PVCs causing phlebitis both within and across the instruments investigated,” they wrote. “How to best measure phlebitis outcomes is still unclear, since no universally accepted instrument exists that has had rigorous testing. From a work environment and patient safety perspective, clinical staff engaged in PVC management should be aware of the absence of adequately validated instruments for phlebitis assessment.”

There are many tools to measure PVC-related phlebitis, but no consensus on which to use, and past studies have reported rates of anywhere from 2% to 62%. Hypothesizing that instrument variability contributed to this discrepancy, the researchers tested 17 instruments in 1,032 patients who had 1,175 PVCs placed at 12 inpatient units in Sweden. Eight tools used clinical definitions, seven used severity rating systems, and two used scoring systems (Lancet Haematol. 2017 doi: 10.1016/S2352-3026[17]30122-9).

Rates of PVC-induced phlebitis reached 12% (137 cases) when the researchers used case definition tools, up to 31% when they used scoring systems (P less than .0001), and up to 34% when they used severity rating systems (P less than .0001, compared with the 12% rate). “The proportion within instruments ranged from less than 1% to 28%,” they added. “We [also] identified face validity issues, such as use of indistinct or complex measurements and inconsistent measurements or definitions.”

The investigators did not perform a systematic review to identify these instruments, and they did not necessarily use the most recent versions, they noted. Nevertheless, the findings have direct implications for hospital quality control measures, which require using a single validated instrument over time to generate meaningful results, they said. Hence, the investigators recommended developing a joint research program to develop reliable measures of PVC-related adverse events and better support clinicians who are trying to decide whether to remove PVCs.

The investigators reported having no funding sources and no competing interests.

[email protected]

Rates of phlebitis associated with peripheral venous catheters (PVC) ranged from less than 1% to 34% depending on which assessment tool researchers used in a large cross-sectional study.

Rates also varied within individual instruments because they included several possible case definitions, Katarina Göransson, PhD, and her associates reported in Lancet Haematology. “We find it concerning that our study shows variation of the proportion of PVCs causing phlebitis both within and across the instruments investigated,” they wrote. “How to best measure phlebitis outcomes is still unclear, since no universally accepted instrument exists that has had rigorous testing. From a work environment and patient safety perspective, clinical staff engaged in PVC management should be aware of the absence of adequately validated instruments for phlebitis assessment.”

There are many tools to measure PVC-related phlebitis, but no consensus on which to use, and past studies have reported rates of anywhere from 2% to 62%. Hypothesizing that instrument variability contributed to this discrepancy, the researchers tested 17 instruments in 1,032 patients who had 1,175 PVCs placed at 12 inpatient units in Sweden. Eight tools used clinical definitions, seven used severity rating systems, and two used scoring systems (Lancet Haematol. 2017 doi: 10.1016/S2352-3026[17]30122-9).

Rates of PVC-induced phlebitis reached 12% (137 cases) when the researchers used case definition tools, up to 31% when they used scoring systems (P less than .0001), and up to 34% when they used severity rating systems (P less than .0001, compared with the 12% rate). “The proportion within instruments ranged from less than 1% to 28%,” they added. “We [also] identified face validity issues, such as use of indistinct or complex measurements and inconsistent measurements or definitions.”

The investigators did not perform a systematic review to identify these instruments, and they did not necessarily use the most recent versions, they noted. Nevertheless, the findings have direct implications for hospital quality control measures, which require using a single validated instrument over time to generate meaningful results, they said. Hence, the investigators recommended developing a joint research program to develop reliable measures of PVC-related adverse events and better support clinicians who are trying to decide whether to remove PVCs.

The investigators reported having no funding sources and no competing interests.

[email protected]

Rates of phlebitis associated with peripheral venous catheters (PVC) ranged from less than 1% to 34% depending on which assessment tool researchers used in a large cross-sectional study.

Rates also varied within individual instruments because they included several possible case definitions, Katarina Göransson, PhD, and her associates reported in Lancet Haematology. “We find it concerning that our study shows variation of the proportion of PVCs causing phlebitis both within and across the instruments investigated,” they wrote. “How to best measure phlebitis outcomes is still unclear, since no universally accepted instrument exists that has had rigorous testing. From a work environment and patient safety perspective, clinical staff engaged in PVC management should be aware of the absence of adequately validated instruments for phlebitis assessment.”

There are many tools to measure PVC-related phlebitis, but no consensus on which to use, and past studies have reported rates of anywhere from 2% to 62%. Hypothesizing that instrument variability contributed to this discrepancy, the researchers tested 17 instruments in 1,032 patients who had 1,175 PVCs placed at 12 inpatient units in Sweden. Eight tools used clinical definitions, seven used severity rating systems, and two used scoring systems (Lancet Haematol. 2017 doi: 10.1016/S2352-3026[17]30122-9).

Rates of PVC-induced phlebitis reached 12% (137 cases) when the researchers used case definition tools, up to 31% when they used scoring systems (P less than .0001), and up to 34% when they used severity rating systems (P less than .0001, compared with the 12% rate). “The proportion within instruments ranged from less than 1% to 28%,” they added. “We [also] identified face validity issues, such as use of indistinct or complex measurements and inconsistent measurements or definitions.”

The investigators did not perform a systematic review to identify these instruments, and they did not necessarily use the most recent versions, they noted. Nevertheless, the findings have direct implications for hospital quality control measures, which require using a single validated instrument over time to generate meaningful results, they said. Hence, the investigators recommended developing a joint research program to develop reliable measures of PVC-related adverse events and better support clinicians who are trying to decide whether to remove PVCs.

The investigators reported having no funding sources and no competing interests.

[email protected]

Tighter blood pressure control is not linked to cognitive decline among older adults and may instead be associated with preservation of cognitive function, according to a new analysis.

Further, the cognitive benefits of tighter control are even more pronounced among black patients.

American Heart Association

[email protected]

Tighter blood pressure control is not linked to cognitive decline among older adults and may instead be associated with preservation of cognitive function, according to a new analysis.

Further, the cognitive benefits of tighter control are even more pronounced among black patients.

American Heart Association

[email protected]

Tighter blood pressure control is not linked to cognitive decline among older adults and may instead be associated with preservation of cognitive function, according to a new analysis.

Further, the cognitive benefits of tighter control are even more pronounced among black patients.

American Heart Association

[email protected]

The recent approval of L-glutamine, marketed as Endari, to reduce the acute complications of sickle cell disease in adult and pediatric patients 5 years of age and older is discussed in the Drug Information Soundcast in Clinical Oncology (DISCO) from a Food and Drug Adminstration podcast series that provides information about new product approvals, emerging safety information for cancer treatments, and other current topics in cancer drug development.

The basis for the approval was discussed in our coverage of the FDA’s Oncologic Drugs Advisory Committee meeting.

This episode of DISCO is hosted by Sanjeeve Bala, MD, and was developed by Abhilasha Nair, MD; Dr. Bala; Kathy M. Robie Suh, MD; Ann T. Farrell, MD; Kirsten B. Goldberg, and Richard Pazdur, MD. All are with the FDA’s Oncology Center of Excellence and the Office of Hematology and Oncology Products. Steven Jackson of the FDA’s Division of Drug Information was the sound producer.

The recent approval of L-glutamine, marketed as Endari, to reduce the acute complications of sickle cell disease in adult and pediatric patients 5 years of age and older is discussed in the Drug Information Soundcast in Clinical Oncology (DISCO) from a Food and Drug Adminstration podcast series that provides information about new product approvals, emerging safety information for cancer treatments, and other current topics in cancer drug development.

The basis for the approval was discussed in our coverage of the FDA’s Oncologic Drugs Advisory Committee meeting.

This episode of DISCO is hosted by Sanjeeve Bala, MD, and was developed by Abhilasha Nair, MD; Dr. Bala; Kathy M. Robie Suh, MD; Ann T. Farrell, MD; Kirsten B. Goldberg, and Richard Pazdur, MD. All are with the FDA’s Oncology Center of Excellence and the Office of Hematology and Oncology Products. Steven Jackson of the FDA’s Division of Drug Information was the sound producer.

The recent approval of L-glutamine, marketed as Endari, to reduce the acute complications of sickle cell disease in adult and pediatric patients 5 years of age and older is discussed in the Drug Information Soundcast in Clinical Oncology (DISCO) from a Food and Drug Adminstration podcast series that provides information about new product approvals, emerging safety information for cancer treatments, and other current topics in cancer drug development.

The basis for the approval was discussed in our coverage of the FDA’s Oncologic Drugs Advisory Committee meeting.

This episode of DISCO is hosted by Sanjeeve Bala, MD, and was developed by Abhilasha Nair, MD; Dr. Bala; Kathy M. Robie Suh, MD; Ann T. Farrell, MD; Kirsten B. Goldberg, and Richard Pazdur, MD. All are with the FDA’s Oncology Center of Excellence and the Office of Hematology and Oncology Products. Steven Jackson of the FDA’s Division of Drug Information was the sound producer.

MADRID – Acute lobar nephronia needs to be considered in children with high fever, abdominal pain, and markedly elevated acute-phase reactants, even if their urinalysis and ultrasound results are negative, Paula Sanchez-Marcos, MD, reported at the annual meeting of the European Society for Paediatric Infectious Diseases.

Zoonar RF/Thinkstock

[email protected]
 

MADRID – Acute lobar nephronia needs to be considered in children with high fever, abdominal pain, and markedly elevated acute-phase reactants, even if their urinalysis and ultrasound results are negative, Paula Sanchez-Marcos, MD, reported at the annual meeting of the European Society for Paediatric Infectious Diseases.

Zoonar RF/Thinkstock

[email protected]
 

MADRID – Acute lobar nephronia needs to be considered in children with high fever, abdominal pain, and markedly elevated acute-phase reactants, even if their urinalysis and ultrasound results are negative, Paula Sanchez-Marcos, MD, reported at the annual meeting of the European Society for Paediatric Infectious Diseases.

Zoonar RF/Thinkstock

[email protected]
 

The Diagnosis: Incontinentia Pigmenti

The infant's mother was noted to have diffuse hypopigmented patches over the trunk, arms, and legs (present since adolescence) with whorled cicatricial alopecia of the vertex scalp and peg-shaped teeth (Figure). Together, these findings suggested incontinentia pigmenti (IP), which the mother revealed she had been diagnosed with in childhood. The infant's characteristic lesions in the setting of her mother's diagnosed genodermatosis confirmed the diagnosis of IP.

Incontinentia pigmenti is an X-linked dominant disorder that presents with many classic dermatologic, dental, neurologic, and ophthalmologic findings. The causative mutation occurs in IKBKG/NEMO (inhibitor of κ polypeptide gene enhancer in B-cells, kinase γ/nuclear factor-κB essential modulator) gene on Xq28, disabling the resultant protein that normally protects cells from tumor necrosis factor family-induced apoptosis.¹ Incontinentia pigmenti usually is lethal in males and causes an unbalanced X-inactivation in surviving female IP patients. Occurring at a rate of 1.2 per 100,000 births,² IP typically presents in female infants with skin lesions patterned along Blaschko lines that evolve in 4 stages over a lifetime.³ Stage I, presenting in the neonatal period, manifests as vesiculobullous eruptions on the limbs and scalp. Stages II to IV vary in duration from months to years and are comprised of a verrucous stage, a hyperpigmented stage, and a hypopigmented stage, respectively.³ All stages of IP can overlap and coexist. 

The vesiculobullous findings in infants with IP may be mistakenly attributed to other diseases with prominent vesicular or bullous components including herpes simplex virus, epidermolysis bullosa, and infantile acropustulosis. With neonatal herpes simplex virus infection, vesicular skin or mucocutaneous lesions occur 9 to 11 days after birth and can be confirmed by specimen culture or qualitative polymerase chain reaction, while stage I of IP appears within the first 6 to 8 weeks of life and can be present at birth.⁴ The hallmark of epidermolysis bullosa, caused by mutations in keratins 5 and 14, is blistering erosions of the skin in response to frictional stress,¹ thus these lesions do not follow Blaschko lines. Infantile acropustulosis, a nonheritable vesiculopustular eruption of the hands and feet, rarely occurs in the immediate newborn period; it most often appears in the 3- to 6-month age range with recurrent eruptions at 3- to 4-week intervals.⁵ Focal dermal hypoplasia is another X-linked dominant disorder with blaschkolinear findings at birth that presents with pink or red, angular, atrophic macules, in contrast to the bullous lesions of IP.⁶

Incontinentia pigmenti may encompass a wide range of systemic symptoms in addition to the classic dermatologic findings. Notably, central nervous system defects are concurrent in up to 40% of IP cases, with seizures, mental retardation, and spastic paresis being the most common sequelae.⁷ Teeth defects, seen in 35% of patients, include delayed primary dentition and peg-shaped teeth. Many patients will experience ophthalmologic defects including vision problems (16%) and retinopathy (15%).⁷

The cutaneous eruptions of IP may be treated with topical corticosteroids or topical tacrolimus, and vesicles should be left intact and monitored for signs of infection.^8,9 Seizures, if present, should be treated with anticonvulsants, and regular neuropsychiatric monitoring and physical rehabilitation may be warranted. Patients should be regularly monitored for retinopathy beginning at the time of diagnosis. Retinal fibrovascular proliferation is treated with xenon laser photocoagulation to reduce the high risk for retinal detachment in this population.^10,11 Older and younger at-risk relatives must be evaluated by genetic testing or thorough physical examination to clarify their disease status and determine the need for additional genetic counseling.

The Diagnosis: Incontinentia Pigmenti

The infant's mother was noted to have diffuse hypopigmented patches over the trunk, arms, and legs (present since adolescence) with whorled cicatricial alopecia of the vertex scalp and peg-shaped teeth (Figure). Together, these findings suggested incontinentia pigmenti (IP), which the mother revealed she had been diagnosed with in childhood. The infant's characteristic lesions in the setting of her mother's diagnosed genodermatosis confirmed the diagnosis of IP.

Incontinentia pigmenti is an X-linked dominant disorder that presents with many classic dermatologic, dental, neurologic, and ophthalmologic findings. The causative mutation occurs in IKBKG/NEMO (inhibitor of κ polypeptide gene enhancer in B-cells, kinase γ/nuclear factor-κB essential modulator) gene on Xq28, disabling the resultant protein that normally protects cells from tumor necrosis factor family-induced apoptosis.¹ Incontinentia pigmenti usually is lethal in males and causes an unbalanced X-inactivation in surviving female IP patients. Occurring at a rate of 1.2 per 100,000 births,² IP typically presents in female infants with skin lesions patterned along Blaschko lines that evolve in 4 stages over a lifetime.³ Stage I, presenting in the neonatal period, manifests as vesiculobullous eruptions on the limbs and scalp. Stages II to IV vary in duration from months to years and are comprised of a verrucous stage, a hyperpigmented stage, and a hypopigmented stage, respectively.³ All stages of IP can overlap and coexist. 

The vesiculobullous findings in infants with IP may be mistakenly attributed to other diseases with prominent vesicular or bullous components including herpes simplex virus, epidermolysis bullosa, and infantile acropustulosis. With neonatal herpes simplex virus infection, vesicular skin or mucocutaneous lesions occur 9 to 11 days after birth and can be confirmed by specimen culture or qualitative polymerase chain reaction, while stage I of IP appears within the first 6 to 8 weeks of life and can be present at birth.⁴ The hallmark of epidermolysis bullosa, caused by mutations in keratins 5 and 14, is blistering erosions of the skin in response to frictional stress,¹ thus these lesions do not follow Blaschko lines. Infantile acropustulosis, a nonheritable vesiculopustular eruption of the hands and feet, rarely occurs in the immediate newborn period; it most often appears in the 3- to 6-month age range with recurrent eruptions at 3- to 4-week intervals.⁵ Focal dermal hypoplasia is another X-linked dominant disorder with blaschkolinear findings at birth that presents with pink or red, angular, atrophic macules, in contrast to the bullous lesions of IP.⁶

Incontinentia pigmenti may encompass a wide range of systemic symptoms in addition to the classic dermatologic findings. Notably, central nervous system defects are concurrent in up to 40% of IP cases, with seizures, mental retardation, and spastic paresis being the most common sequelae.⁷ Teeth defects, seen in 35% of patients, include delayed primary dentition and peg-shaped teeth. Many patients will experience ophthalmologic defects including vision problems (16%) and retinopathy (15%).⁷

The cutaneous eruptions of IP may be treated with topical corticosteroids or topical tacrolimus, and vesicles should be left intact and monitored for signs of infection.^8,9 Seizures, if present, should be treated with anticonvulsants, and regular neuropsychiatric monitoring and physical rehabilitation may be warranted. Patients should be regularly monitored for retinopathy beginning at the time of diagnosis. Retinal fibrovascular proliferation is treated with xenon laser photocoagulation to reduce the high risk for retinal detachment in this population.^10,11 Older and younger at-risk relatives must be evaluated by genetic testing or thorough physical examination to clarify their disease status and determine the need for additional genetic counseling.

The Diagnosis: Incontinentia Pigmenti

The infant's mother was noted to have diffuse hypopigmented patches over the trunk, arms, and legs (present since adolescence) with whorled cicatricial alopecia of the vertex scalp and peg-shaped teeth (Figure). Together, these findings suggested incontinentia pigmenti (IP), which the mother revealed she had been diagnosed with in childhood. The infant's characteristic lesions in the setting of her mother's diagnosed genodermatosis confirmed the diagnosis of IP.

Incontinentia pigmenti is an X-linked dominant disorder that presents with many classic dermatologic, dental, neurologic, and ophthalmologic findings. The causative mutation occurs in IKBKG/NEMO (inhibitor of κ polypeptide gene enhancer in B-cells, kinase γ/nuclear factor-κB essential modulator) gene on Xq28, disabling the resultant protein that normally protects cells from tumor necrosis factor family-induced apoptosis.¹ Incontinentia pigmenti usually is lethal in males and causes an unbalanced X-inactivation in surviving female IP patients. Occurring at a rate of 1.2 per 100,000 births,² IP typically presents in female infants with skin lesions patterned along Blaschko lines that evolve in 4 stages over a lifetime.³ Stage I, presenting in the neonatal period, manifests as vesiculobullous eruptions on the limbs and scalp. Stages II to IV vary in duration from months to years and are comprised of a verrucous stage, a hyperpigmented stage, and a hypopigmented stage, respectively.³ All stages of IP can overlap and coexist. 

The vesiculobullous findings in infants with IP may be mistakenly attributed to other diseases with prominent vesicular or bullous components including herpes simplex virus, epidermolysis bullosa, and infantile acropustulosis. With neonatal herpes simplex virus infection, vesicular skin or mucocutaneous lesions occur 9 to 11 days after birth and can be confirmed by specimen culture or qualitative polymerase chain reaction, while stage I of IP appears within the first 6 to 8 weeks of life and can be present at birth.⁴ The hallmark of epidermolysis bullosa, caused by mutations in keratins 5 and 14, is blistering erosions of the skin in response to frictional stress,¹ thus these lesions do not follow Blaschko lines. Infantile acropustulosis, a nonheritable vesiculopustular eruption of the hands and feet, rarely occurs in the immediate newborn period; it most often appears in the 3- to 6-month age range with recurrent eruptions at 3- to 4-week intervals.⁵ Focal dermal hypoplasia is another X-linked dominant disorder with blaschkolinear findings at birth that presents with pink or red, angular, atrophic macules, in contrast to the bullous lesions of IP.⁶

Incontinentia pigmenti may encompass a wide range of systemic symptoms in addition to the classic dermatologic findings. Notably, central nervous system defects are concurrent in up to 40% of IP cases, with seizures, mental retardation, and spastic paresis being the most common sequelae.⁷ Teeth defects, seen in 35% of patients, include delayed primary dentition and peg-shaped teeth. Many patients will experience ophthalmologic defects including vision problems (16%) and retinopathy (15%).⁷

The cutaneous eruptions of IP may be treated with topical corticosteroids or topical tacrolimus, and vesicles should be left intact and monitored for signs of infection.^8,9 Seizures, if present, should be treated with anticonvulsants, and regular neuropsychiatric monitoring and physical rehabilitation may be warranted. Patients should be regularly monitored for retinopathy beginning at the time of diagnosis. Retinal fibrovascular proliferation is treated with xenon laser photocoagulation to reduce the high risk for retinal detachment in this population.^10,11 Older and younger at-risk relatives must be evaluated by genetic testing or thorough physical examination to clarify their disease status and determine the need for additional genetic counseling.

This article exhibits key pediatric dermatology pearls garnered at the 2017 Annual Meeting of the American Academy of Dermatology (AAD) in Orlando, Florida (March 3–7, 2017). Highlights from both the Society for Pediatric Dermatology pre-AAD meeting (March 2, 2017) and the AAD general meeting sessions are included. This discussion is intended to help maximize care of our pediatric patients in dermatology and present high-yield take-home points from the AAD that can be readily transferred to our patient care.

“New Tools for Your Therapeutic Toolbox” by Erin Mathes, MD (University of California, San Francisco)

During this lecture at the Society for Pediatric Dermatology meeting, Dr. Mathes discussed a randomized controlled trial that took place in 2014 in both the United States and the United Kingdom to assess skin barrier enhancement to reduce the incidence of atopic dermatitis (AD) in 124 high-risk infants.¹ The high-risk infants had either a parent or sibling with physician-diagnosed AD, asthma, or rhinitis, or a first-degree relative with an aforementioned condition. Full-body emollient therapy was applied at least once daily within 3 weeks of birth for 6 months, while the control arm did not use emollient. Parents were allowed to choose from the following emollients: sunflower seed oil, moisturizing cream, or ointment. The primary outcome was the incidence of AD at 6 months. The authors found a 43% incidence of AD in the control group compared to 22% in the emollient group, amounting to a relative risk reduction of approximately 50%.¹

Emollients in AD are hypothesized to help through the enhanced barrier function and decreased penetration of irritant substances and allergens. This study is vital given the ease of use of emollients and the foreseeable substantial impact on reduced health care costs associated with the decreased incidence of AD.

Take-Home Point
Full-body emollient therapy within 3 weeks of birth may reduce the incidence of AD in high-risk infants.

Dr. Mathes also discussed the novel topical phosphodiesterase 4 inhibitor crisaborole and its emerging role in AD. She reviewed the results of a large phase 3 trial of crisaborole therapy for patients aged 2 years or older with mild to moderate AD.² Crisaborole ointment was applied twice daily for 28 days. The primary outcome measured was an investigator static global assessment score of clear or almost clear, which is a score for AD based on the degree of erythema, presence of oozing and crusting, and presence of induration or papulation. Overall, 32.8% of patients treated with crisaborole achieved success compared to 25.4% of vehicle-treated patients. The control patients were still given a vehicle to apply, which can function as therapy to help repair the barrier of AD and thus theoretically reduced the percentage gap between patients who met success with and without crisaborole therapy. Furthermore, only 4% of patients reported adverse effects such as burning and stinging with application of crisaborole in contrast to topical calcineurin inhibitors, which can elicit symptoms up to 50% of the time.² In summary, this lecture reviewed the first new topical treatment for AD in 15 years.

Take-Home Point
Crisaborole ointment is a novel topical phosphodiesterase 4 inhibitor approved for mild to moderate AD in patients 2 years of age and older.

“The Truth About Pediatric Contact Dermatitis” by Sharon Jacob, MD (Loma Linda University, California)

In this session, Dr. Jacob discussed how she approaches pediatric patients with suspected contact dermatitis and elaborated on the common allergens unique to this patient population. Furthermore, she explained the substantial role of nickel in pediatric contact dermatitis, citing a study performed in Denmark and the United States, which tested 212 toys for nickel using the dimethylglyoxime test and found that 34.4% of toys did in fact release nickel.³ Additional studies have shown that nickel released from children’s toys is deposited on the skin, even with short contact times such as 30 minutes on one or more occasions within 2 weeks.^3,4 She is currently evaluating the presence of nickel in locales frequented by children such as schools, libraries, and supermarkets. Interestingly, she anecdotally found that a pediatric eczematous eruption in a spiralized distribution of the legs can be attributed to the presence of nickel in school chairs, and the morphology is secondary to children wrapping their legs around the chairs. In conclusion, she reiterated that nickel continues to be the top allergen among pediatric patients, and states that additional allergens for patch testing in this population are unique to their adult counterparts.

Take-Home Point
Nickel is an ubiquitous allergen for pediatric contact dermatitis; additionally, the list of allergens for patch testing should be tailored to this patient population.

“When to Image, When to Sedate” by Annette Wagner, MD (Northwestern Medicine, Chicago, Illinois)

This lecture was a 3-part discussion on the safety of general anesthesia in children, when to image children, and when sedation may be worth the risk. Dr. Wagner shared her pearls for when children younger than 3 years may benefit from dermatologic procedures that involve general anesthesia. Large congenital lesions of the scalp or face that require tissue expansion or multiple stages may be best performed at a younger age due to the flexibility of the infant scalp, providing the best outcome. Additional considerations include a questionable malignant diagnosis in which a punch biopsy is not enough, rapidly growing facial lesions, Spitz nevi of the face, congenital lesions with no available therapy, and nonhealing refractory lesions causing severe pain. The general rule proposed was intervention for single procedures lasting less than 1 hour that otherwise would result in a worse outcome if postponed. Finally, she concluded to always advocate for your patient, to wait if the outcome will be the same regardless of timing, and to be frank about not knowing the risks of general anesthesia in this population. The resource, SmartTots (http://smarttots.org) provides current consensus statements and ongoing research on the use and safety of general anesthesia in children.

Take-Home Point
General sedation may be considered for short pediatric procedures that will result in a worse outcome if postponed.

“Highlights From the Pediatric Literature” by Katherine Marks, DO (Geisinger, Danville and Wilkes-Barre, Pennsylvania)

Dr. Marks discussed numerous emerging pediatric dermatology articles. One article looked at 40 infants with proliferating infantile hemangiomas (IHs) who had timolol gel 0.5% applied twice daily.⁵ The primary outcomes were the urinary excretion and serum levels of timolol as well as the clinical response to therapy measured by a visual analog scale at monthly visits. A urinalysis collected 3 to 4 hours after timolol application was found to be positive in 83% (20/24) of the tested patients; the first 3 positive infants were then sent to have their serum timolol levels drawn and also were found to be positive, though substantially small levels (median, 0.16 ng/mL). The 3 patients tested had small IHs on the face with no ulceration. None of these patients experienced adverse effects and all of the IHs significantly (P<.001) improved with therapy. The authors stated that even though the absorption was minimal, it is wise to be cognizant about the use of timolol in certain patient demographics such as preterm or young infants with large ulcerating IHs.⁵

Take-Home Point
Systemic absorption with topical timolol occurs, albeit substantially small; be judicious about giving this medication in select patient populations with ulcerated hemangiomas.

Acknowledgment
The author thanks the presenters for their review and contributions to this article.

This article exhibits key pediatric dermatology pearls garnered at the 2017 Annual Meeting of the American Academy of Dermatology (AAD) in Orlando, Florida (March 3–7, 2017). Highlights from both the Society for Pediatric Dermatology pre-AAD meeting (March 2, 2017) and the AAD general meeting sessions are included. This discussion is intended to help maximize care of our pediatric patients in dermatology and present high-yield take-home points from the AAD that can be readily transferred to our patient care.

“New Tools for Your Therapeutic Toolbox” by Erin Mathes, MD (University of California, San Francisco)

During this lecture at the Society for Pediatric Dermatology meeting, Dr. Mathes discussed a randomized controlled trial that took place in 2014 in both the United States and the United Kingdom to assess skin barrier enhancement to reduce the incidence of atopic dermatitis (AD) in 124 high-risk infants.¹ The high-risk infants had either a parent or sibling with physician-diagnosed AD, asthma, or rhinitis, or a first-degree relative with an aforementioned condition. Full-body emollient therapy was applied at least once daily within 3 weeks of birth for 6 months, while the control arm did not use emollient. Parents were allowed to choose from the following emollients: sunflower seed oil, moisturizing cream, or ointment. The primary outcome was the incidence of AD at 6 months. The authors found a 43% incidence of AD in the control group compared to 22% in the emollient group, amounting to a relative risk reduction of approximately 50%.¹

Emollients in AD are hypothesized to help through the enhanced barrier function and decreased penetration of irritant substances and allergens. This study is vital given the ease of use of emollients and the foreseeable substantial impact on reduced health care costs associated with the decreased incidence of AD.

Take-Home Point
Full-body emollient therapy within 3 weeks of birth may reduce the incidence of AD in high-risk infants.

Dr. Mathes also discussed the novel topical phosphodiesterase 4 inhibitor crisaborole and its emerging role in AD. She reviewed the results of a large phase 3 trial of crisaborole therapy for patients aged 2 years or older with mild to moderate AD.² Crisaborole ointment was applied twice daily for 28 days. The primary outcome measured was an investigator static global assessment score of clear or almost clear, which is a score for AD based on the degree of erythema, presence of oozing and crusting, and presence of induration or papulation. Overall, 32.8% of patients treated with crisaborole achieved success compared to 25.4% of vehicle-treated patients. The control patients were still given a vehicle to apply, which can function as therapy to help repair the barrier of AD and thus theoretically reduced the percentage gap between patients who met success with and without crisaborole therapy. Furthermore, only 4% of patients reported adverse effects such as burning and stinging with application of crisaborole in contrast to topical calcineurin inhibitors, which can elicit symptoms up to 50% of the time.² In summary, this lecture reviewed the first new topical treatment for AD in 15 years.

Take-Home Point
Crisaborole ointment is a novel topical phosphodiesterase 4 inhibitor approved for mild to moderate AD in patients 2 years of age and older.

“The Truth About Pediatric Contact Dermatitis” by Sharon Jacob, MD (Loma Linda University, California)

In this session, Dr. Jacob discussed how she approaches pediatric patients with suspected contact dermatitis and elaborated on the common allergens unique to this patient population. Furthermore, she explained the substantial role of nickel in pediatric contact dermatitis, citing a study performed in Denmark and the United States, which tested 212 toys for nickel using the dimethylglyoxime test and found that 34.4% of toys did in fact release nickel.³ Additional studies have shown that nickel released from children’s toys is deposited on the skin, even with short contact times such as 30 minutes on one or more occasions within 2 weeks.^3,4 She is currently evaluating the presence of nickel in locales frequented by children such as schools, libraries, and supermarkets. Interestingly, she anecdotally found that a pediatric eczematous eruption in a spiralized distribution of the legs can be attributed to the presence of nickel in school chairs, and the morphology is secondary to children wrapping their legs around the chairs. In conclusion, she reiterated that nickel continues to be the top allergen among pediatric patients, and states that additional allergens for patch testing in this population are unique to their adult counterparts.

Take-Home Point
Nickel is an ubiquitous allergen for pediatric contact dermatitis; additionally, the list of allergens for patch testing should be tailored to this patient population.

“When to Image, When to Sedate” by Annette Wagner, MD (Northwestern Medicine, Chicago, Illinois)

This lecture was a 3-part discussion on the safety of general anesthesia in children, when to image children, and when sedation may be worth the risk. Dr. Wagner shared her pearls for when children younger than 3 years may benefit from dermatologic procedures that involve general anesthesia. Large congenital lesions of the scalp or face that require tissue expansion or multiple stages may be best performed at a younger age due to the flexibility of the infant scalp, providing the best outcome. Additional considerations include a questionable malignant diagnosis in which a punch biopsy is not enough, rapidly growing facial lesions, Spitz nevi of the face, congenital lesions with no available therapy, and nonhealing refractory lesions causing severe pain. The general rule proposed was intervention for single procedures lasting less than 1 hour that otherwise would result in a worse outcome if postponed. Finally, she concluded to always advocate for your patient, to wait if the outcome will be the same regardless of timing, and to be frank about not knowing the risks of general anesthesia in this population. The resource, SmartTots (http://smarttots.org) provides current consensus statements and ongoing research on the use and safety of general anesthesia in children.

Take-Home Point
General sedation may be considered for short pediatric procedures that will result in a worse outcome if postponed.

“Highlights From the Pediatric Literature” by Katherine Marks, DO (Geisinger, Danville and Wilkes-Barre, Pennsylvania)

Dr. Marks discussed numerous emerging pediatric dermatology articles. One article looked at 40 infants with proliferating infantile hemangiomas (IHs) who had timolol gel 0.5% applied twice daily.⁵ The primary outcomes were the urinary excretion and serum levels of timolol as well as the clinical response to therapy measured by a visual analog scale at monthly visits. A urinalysis collected 3 to 4 hours after timolol application was found to be positive in 83% (20/24) of the tested patients; the first 3 positive infants were then sent to have their serum timolol levels drawn and also were found to be positive, though substantially small levels (median, 0.16 ng/mL). The 3 patients tested had small IHs on the face with no ulceration. None of these patients experienced adverse effects and all of the IHs significantly (P<.001) improved with therapy. The authors stated that even though the absorption was minimal, it is wise to be cognizant about the use of timolol in certain patient demographics such as preterm or young infants with large ulcerating IHs.⁵

Take-Home Point
Systemic absorption with topical timolol occurs, albeit substantially small; be judicious about giving this medication in select patient populations with ulcerated hemangiomas.

Acknowledgment
The author thanks the presenters for their review and contributions to this article.

This article exhibits key pediatric dermatology pearls garnered at the 2017 Annual Meeting of the American Academy of Dermatology (AAD) in Orlando, Florida (March 3–7, 2017). Highlights from both the Society for Pediatric Dermatology pre-AAD meeting (March 2, 2017) and the AAD general meeting sessions are included. This discussion is intended to help maximize care of our pediatric patients in dermatology and present high-yield take-home points from the AAD that can be readily transferred to our patient care.

“New Tools for Your Therapeutic Toolbox” by Erin Mathes, MD (University of California, San Francisco)

During this lecture at the Society for Pediatric Dermatology meeting, Dr. Mathes discussed a randomized controlled trial that took place in 2014 in both the United States and the United Kingdom to assess skin barrier enhancement to reduce the incidence of atopic dermatitis (AD) in 124 high-risk infants.¹ The high-risk infants had either a parent or sibling with physician-diagnosed AD, asthma, or rhinitis, or a first-degree relative with an aforementioned condition. Full-body emollient therapy was applied at least once daily within 3 weeks of birth for 6 months, while the control arm did not use emollient. Parents were allowed to choose from the following emollients: sunflower seed oil, moisturizing cream, or ointment. The primary outcome was the incidence of AD at 6 months. The authors found a 43% incidence of AD in the control group compared to 22% in the emollient group, amounting to a relative risk reduction of approximately 50%.¹

Emollients in AD are hypothesized to help through the enhanced barrier function and decreased penetration of irritant substances and allergens. This study is vital given the ease of use of emollients and the foreseeable substantial impact on reduced health care costs associated with the decreased incidence of AD.

Take-Home Point
Full-body emollient therapy within 3 weeks of birth may reduce the incidence of AD in high-risk infants.

Dr. Mathes also discussed the novel topical phosphodiesterase 4 inhibitor crisaborole and its emerging role in AD. She reviewed the results of a large phase 3 trial of crisaborole therapy for patients aged 2 years or older with mild to moderate AD.² Crisaborole ointment was applied twice daily for 28 days. The primary outcome measured was an investigator static global assessment score of clear or almost clear, which is a score for AD based on the degree of erythema, presence of oozing and crusting, and presence of induration or papulation. Overall, 32.8% of patients treated with crisaborole achieved success compared to 25.4% of vehicle-treated patients. The control patients were still given a vehicle to apply, which can function as therapy to help repair the barrier of AD and thus theoretically reduced the percentage gap between patients who met success with and without crisaborole therapy. Furthermore, only 4% of patients reported adverse effects such as burning and stinging with application of crisaborole in contrast to topical calcineurin inhibitors, which can elicit symptoms up to 50% of the time.² In summary, this lecture reviewed the first new topical treatment for AD in 15 years.

Take-Home Point
Crisaborole ointment is a novel topical phosphodiesterase 4 inhibitor approved for mild to moderate AD in patients 2 years of age and older.

“The Truth About Pediatric Contact Dermatitis” by Sharon Jacob, MD (Loma Linda University, California)

In this session, Dr. Jacob discussed how she approaches pediatric patients with suspected contact dermatitis and elaborated on the common allergens unique to this patient population. Furthermore, she explained the substantial role of nickel in pediatric contact dermatitis, citing a study performed in Denmark and the United States, which tested 212 toys for nickel using the dimethylglyoxime test and found that 34.4% of toys did in fact release nickel.³ Additional studies have shown that nickel released from children’s toys is deposited on the skin, even with short contact times such as 30 minutes on one or more occasions within 2 weeks.^3,4 She is currently evaluating the presence of nickel in locales frequented by children such as schools, libraries, and supermarkets. Interestingly, she anecdotally found that a pediatric eczematous eruption in a spiralized distribution of the legs can be attributed to the presence of nickel in school chairs, and the morphology is secondary to children wrapping their legs around the chairs. In conclusion, she reiterated that nickel continues to be the top allergen among pediatric patients, and states that additional allergens for patch testing in this population are unique to their adult counterparts.

Take-Home Point
Nickel is an ubiquitous allergen for pediatric contact dermatitis; additionally, the list of allergens for patch testing should be tailored to this patient population.

“When to Image, When to Sedate” by Annette Wagner, MD (Northwestern Medicine, Chicago, Illinois)

This lecture was a 3-part discussion on the safety of general anesthesia in children, when to image children, and when sedation may be worth the risk. Dr. Wagner shared her pearls for when children younger than 3 years may benefit from dermatologic procedures that involve general anesthesia. Large congenital lesions of the scalp or face that require tissue expansion or multiple stages may be best performed at a younger age due to the flexibility of the infant scalp, providing the best outcome. Additional considerations include a questionable malignant diagnosis in which a punch biopsy is not enough, rapidly growing facial lesions, Spitz nevi of the face, congenital lesions with no available therapy, and nonhealing refractory lesions causing severe pain. The general rule proposed was intervention for single procedures lasting less than 1 hour that otherwise would result in a worse outcome if postponed. Finally, she concluded to always advocate for your patient, to wait if the outcome will be the same regardless of timing, and to be frank about not knowing the risks of general anesthesia in this population. The resource, SmartTots (http://smarttots.org) provides current consensus statements and ongoing research on the use and safety of general anesthesia in children.

Take-Home Point
General sedation may be considered for short pediatric procedures that will result in a worse outcome if postponed.

“Highlights From the Pediatric Literature” by Katherine Marks, DO (Geisinger, Danville and Wilkes-Barre, Pennsylvania)

Dr. Marks discussed numerous emerging pediatric dermatology articles. One article looked at 40 infants with proliferating infantile hemangiomas (IHs) who had timolol gel 0.5% applied twice daily.⁵ The primary outcomes were the urinary excretion and serum levels of timolol as well as the clinical response to therapy measured by a visual analog scale at monthly visits. A urinalysis collected 3 to 4 hours after timolol application was found to be positive in 83% (20/24) of the tested patients; the first 3 positive infants were then sent to have their serum timolol levels drawn and also were found to be positive, though substantially small levels (median, 0.16 ng/mL). The 3 patients tested had small IHs on the face with no ulceration. None of these patients experienced adverse effects and all of the IHs significantly (P<.001) improved with therapy. The authors stated that even though the absorption was minimal, it is wise to be cognizant about the use of timolol in certain patient demographics such as preterm or young infants with large ulcerating IHs.⁵

Take-Home Point
Systemic absorption with topical timolol occurs, albeit substantially small; be judicious about giving this medication in select patient populations with ulcerated hemangiomas.

Acknowledgment
The author thanks the presenters for their review and contributions to this article.