BOSTON – A nonsteroidal anti-inflammatory drug and exercise may be enough to control active axial spondyloarthritis in some patients, suggest authors of draft guidelines on the management of patients with the condition.

The guidelines, not ready for prime time, have yet to be reviewed or endorsed by the American College of Rheumatology (ACR) and the Spondylitis Association of America, or the SpondyloArthritis Research and Treatment Network (SPARTAN), and are subject to change, emphasized Dr. Michael M. Ward, senior investigator at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS).

With that caveat in mind, Dr. Ward presented a sneak peek at the guidelines to a standing-room only crowd at the ACR annual meeting in Boston.

Some definitions

The guidelines offer recommendations on the management of patients with active and stable ankylosing spondylitis (AS) and axial spondyloarthropathies (axSpA) that are symptomatic but without radiographic evidence (nonradiographic, or nr-axSpA).

Active AS is defined as disease that causes symptoms at an unacceptably burdensome level as reported by the patient that are judged by the examining clinician to be caused by AS. The same definition also applies to nr-axSpA.

Stable disease is defined as either an asymptomatic state or symptoms that were previously bothersome but are currently at an acceptable level as reported by the patient. The patient had to have had bothersome symptoms for at least 6 months before entering the stable disease state. This definition is also applicable to stable nr-axSpA.

The investigators considered the best available evidence on the use of NSAIDs (running the gamut from aspirin to tolmetin), slow-acting antirheumatic agents such as methotrexate, glucocorticoids (prednisone and others), tumor necrosis factor (TNF) inhibitors, such as adalimumab, etanercept, and others), and non-TNF biologic agents (abatacept, rituximab, tocilizumab, and others).

Active AS

Dr. Ward presented a management flow tree for patients with active AS, starting with a strong recommendation for an NSAID, conditionally recommended to be used continuously. The authors felt, however, that there was not enough evidence to support the use of one NSAID over another. They also strongly recommended physical therapy, with less robust recommendations for active than for passive exercise and for exercises performed in water rather than on land. The latter recommendation is based on the fact that, although water-based exercises have been shown to be as good as or better than dry land exercises for relieving symptoms, water-based exercise may be impractical for many patients, Dr. Ward noted.

For patients whose disease remains active despite NSAIDs and exercise, the committee strongly recommends use of a tumor necrosis factor inhibitor (TNFi) (no specific agent preferred). If a patient on a TNFi has recurrent iritis, the guidelines have a conditional recommendation for the use of infliximab or adalimumab. For patients with inflammatory bowel disease (IBD), the authors conditionally recommend a TNFi monoclonal antibody as opposed to etanercept.

If the disease remains active on a TNFi, an alternative TNFi can be considered.

“For patients who have contraindications to TNF inhibitors, we considered the choice between adding a slow-acting drug such as sulfasalazine or pamidronate or treating with a non-TNF biologic. Of course, there are no head-to-head trials between those two options, so based on the indirect evidence that’s available, the committee voted for a conditional recommendation against the use of a non-TNF biologic in favor of a slow-acting drug in that setting,” Dr. Ward said.

If there are no contraindications to a TNF inhibitor, however, the committee strongly favored the use of a TNF inhibitor over a slow-acting agent, he emphasized.

For patients who have isolated sacroiliitis, peripheral arthritis, or enthesis, the committee provisionally recommends local injection of a glucocorticoid, with cautions to use infrequently and only if two or fewer joints are involved in peripheral arthritis, and avoidance of injection of the Achilles, patellar, or quadriceps tendons in patients with enthesitis.

For all patients, the guidelines half-heartedly recommend monitoring validated axSpA disease activity measures and C-reactive protein and erythrocyte sedimentation rate (ESR). The group also conditionally supported unsupervised back exercises, formal group or individual self-management education, and fall evaluation and counseling.

Committee members strongly felt that systemic glucocorticoids should not be used in patients with active axSpA, except in cases where a short-term course with quick taper may be helpful, such as in patients with peripheral flare, or during pregnancy or a concomitant IBD flare.

Stable AS

“For patients with stable ankylosing spondylitis who are on combination therapy, either combination therapy with NSAIDs and a TNF inhibitor, or a slow-acting drug and a TNF inhibitor, the committee voted against continuation of a combination in favor of TNF monotherapy. It’s a conditional recommendation, so there certainly would be situations where one would not want to do that, but in general the committee thought that was the preferable approach, balancing the benefits and potential risks of combination therapy against monotherapy in patients with stable AS,” Dr. Ward said.

The committee members strongly supported physical therapy in patients with stable AS and gave a conditional nod to monitoring, back exercises, group support, and fall counseling.

For patients with stable AS and advanced hip arthritis, hip replacement is strongly recommended. Recommendations for and against other special conditions include severe kyphosis (strongly against elective spine osteotomy except in specialized centers), acute iritis (strong support for an ophthalmology consultant), recurrent iritis (conditional support for at home use of a topical glucocorticoid under the supervision of an eye care provider, and use of infliximab or adalimumab over etanercept), and IBD (strong recommendation for TNFi monoclonals over etanercept and conditional endorsement of no preferred NSAID).

Active nr-axSpA

Recommendations for the treatment of nr-axSpA are essentially identical to those for treating active AS, Dr. Ward noted, except that in contrast to active AS, where the recommendation is strongly in favor of TNF inhibitors, the committee gave only a conditional recommendation for the use of a TNF inhibitor in this clinical situation.

Stable nr-axSpA

For patients with stable nr-axSpA, the recommendations are strongly in favor of NSAID use, with a conditional suggestion to use on demand. The recommendations also are conditionally against combination therapy with either an NSAID or slow-acting agent plus a TNF inhibitor, with a conditional approval for TNF inhibitor monotherapy instead. The committee strongly supported physical therapy for these patients and gave a lukewarm embrace of monitoring for disease activity, CRP, or ESR.

Dr. Ward noted that the guidelines are designed to help clinicians with treatment decisions for the typical patient with AS or nr-axSpA, and do not address the needs of all populations or all clinical circumstances or contingencies.

He also noted that for many of the questions the committee members tried to address, high-quality evidence was limited.

Dr. Ward did not mention a projected publication date for the guidelines. He had no relevant financial conflicts to disclose.

BOSTON – A nonsteroidal anti-inflammatory drug and exercise may be enough to control active axial spondyloarthritis in some patients, suggest authors of draft guidelines on the management of patients with the condition.

The guidelines, not ready for prime time, have yet to be reviewed or endorsed by the American College of Rheumatology (ACR) and the Spondylitis Association of America, or the SpondyloArthritis Research and Treatment Network (SPARTAN), and are subject to change, emphasized Dr. Michael M. Ward, senior investigator at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS).

With that caveat in mind, Dr. Ward presented a sneak peek at the guidelines to a standing-room only crowd at the ACR annual meeting in Boston.

Some definitions

The guidelines offer recommendations on the management of patients with active and stable ankylosing spondylitis (AS) and axial spondyloarthropathies (axSpA) that are symptomatic but without radiographic evidence (nonradiographic, or nr-axSpA).

Active AS is defined as disease that causes symptoms at an unacceptably burdensome level as reported by the patient that are judged by the examining clinician to be caused by AS. The same definition also applies to nr-axSpA.

Stable disease is defined as either an asymptomatic state or symptoms that were previously bothersome but are currently at an acceptable level as reported by the patient. The patient had to have had bothersome symptoms for at least 6 months before entering the stable disease state. This definition is also applicable to stable nr-axSpA.

The investigators considered the best available evidence on the use of NSAIDs (running the gamut from aspirin to tolmetin), slow-acting antirheumatic agents such as methotrexate, glucocorticoids (prednisone and others), tumor necrosis factor (TNF) inhibitors, such as adalimumab, etanercept, and others), and non-TNF biologic agents (abatacept, rituximab, tocilizumab, and others).

Active AS

Dr. Ward presented a management flow tree for patients with active AS, starting with a strong recommendation for an NSAID, conditionally recommended to be used continuously. The authors felt, however, that there was not enough evidence to support the use of one NSAID over another. They also strongly recommended physical therapy, with less robust recommendations for active than for passive exercise and for exercises performed in water rather than on land. The latter recommendation is based on the fact that, although water-based exercises have been shown to be as good as or better than dry land exercises for relieving symptoms, water-based exercise may be impractical for many patients, Dr. Ward noted.

For patients whose disease remains active despite NSAIDs and exercise, the committee strongly recommends use of a tumor necrosis factor inhibitor (TNFi) (no specific agent preferred). If a patient on a TNFi has recurrent iritis, the guidelines have a conditional recommendation for the use of infliximab or adalimumab. For patients with inflammatory bowel disease (IBD), the authors conditionally recommend a TNFi monoclonal antibody as opposed to etanercept.

If the disease remains active on a TNFi, an alternative TNFi can be considered.

“For patients who have contraindications to TNF inhibitors, we considered the choice between adding a slow-acting drug such as sulfasalazine or pamidronate or treating with a non-TNF biologic. Of course, there are no head-to-head trials between those two options, so based on the indirect evidence that’s available, the committee voted for a conditional recommendation against the use of a non-TNF biologic in favor of a slow-acting drug in that setting,” Dr. Ward said.

If there are no contraindications to a TNF inhibitor, however, the committee strongly favored the use of a TNF inhibitor over a slow-acting agent, he emphasized.

For patients who have isolated sacroiliitis, peripheral arthritis, or enthesis, the committee provisionally recommends local injection of a glucocorticoid, with cautions to use infrequently and only if two or fewer joints are involved in peripheral arthritis, and avoidance of injection of the Achilles, patellar, or quadriceps tendons in patients with enthesitis.

For all patients, the guidelines half-heartedly recommend monitoring validated axSpA disease activity measures and C-reactive protein and erythrocyte sedimentation rate (ESR). The group also conditionally supported unsupervised back exercises, formal group or individual self-management education, and fall evaluation and counseling.

Committee members strongly felt that systemic glucocorticoids should not be used in patients with active axSpA, except in cases where a short-term course with quick taper may be helpful, such as in patients with peripheral flare, or during pregnancy or a concomitant IBD flare.

Stable AS

“For patients with stable ankylosing spondylitis who are on combination therapy, either combination therapy with NSAIDs and a TNF inhibitor, or a slow-acting drug and a TNF inhibitor, the committee voted against continuation of a combination in favor of TNF monotherapy. It’s a conditional recommendation, so there certainly would be situations where one would not want to do that, but in general the committee thought that was the preferable approach, balancing the benefits and potential risks of combination therapy against monotherapy in patients with stable AS,” Dr. Ward said.

The committee members strongly supported physical therapy in patients with stable AS and gave a conditional nod to monitoring, back exercises, group support, and fall counseling.

For patients with stable AS and advanced hip arthritis, hip replacement is strongly recommended. Recommendations for and against other special conditions include severe kyphosis (strongly against elective spine osteotomy except in specialized centers), acute iritis (strong support for an ophthalmology consultant), recurrent iritis (conditional support for at home use of a topical glucocorticoid under the supervision of an eye care provider, and use of infliximab or adalimumab over etanercept), and IBD (strong recommendation for TNFi monoclonals over etanercept and conditional endorsement of no preferred NSAID).

Active nr-axSpA

Recommendations for the treatment of nr-axSpA are essentially identical to those for treating active AS, Dr. Ward noted, except that in contrast to active AS, where the recommendation is strongly in favor of TNF inhibitors, the committee gave only a conditional recommendation for the use of a TNF inhibitor in this clinical situation.

Stable nr-axSpA

For patients with stable nr-axSpA, the recommendations are strongly in favor of NSAID use, with a conditional suggestion to use on demand. The recommendations also are conditionally against combination therapy with either an NSAID or slow-acting agent plus a TNF inhibitor, with a conditional approval for TNF inhibitor monotherapy instead. The committee strongly supported physical therapy for these patients and gave a lukewarm embrace of monitoring for disease activity, CRP, or ESR.

Dr. Ward noted that the guidelines are designed to help clinicians with treatment decisions for the typical patient with AS or nr-axSpA, and do not address the needs of all populations or all clinical circumstances or contingencies.

He also noted that for many of the questions the committee members tried to address, high-quality evidence was limited.

Dr. Ward did not mention a projected publication date for the guidelines. He had no relevant financial conflicts to disclose.

BOSTON – A nonsteroidal anti-inflammatory drug and exercise may be enough to control active axial spondyloarthritis in some patients, suggest authors of draft guidelines on the management of patients with the condition.

The guidelines, not ready for prime time, have yet to be reviewed or endorsed by the American College of Rheumatology (ACR) and the Spondylitis Association of America, or the SpondyloArthritis Research and Treatment Network (SPARTAN), and are subject to change, emphasized Dr. Michael M. Ward, senior investigator at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS).

With that caveat in mind, Dr. Ward presented a sneak peek at the guidelines to a standing-room only crowd at the ACR annual meeting in Boston.

Some definitions

The guidelines offer recommendations on the management of patients with active and stable ankylosing spondylitis (AS) and axial spondyloarthropathies (axSpA) that are symptomatic but without radiographic evidence (nonradiographic, or nr-axSpA).

Active AS is defined as disease that causes symptoms at an unacceptably burdensome level as reported by the patient that are judged by the examining clinician to be caused by AS. The same definition also applies to nr-axSpA.

Stable disease is defined as either an asymptomatic state or symptoms that were previously bothersome but are currently at an acceptable level as reported by the patient. The patient had to have had bothersome symptoms for at least 6 months before entering the stable disease state. This definition is also applicable to stable nr-axSpA.

The investigators considered the best available evidence on the use of NSAIDs (running the gamut from aspirin to tolmetin), slow-acting antirheumatic agents such as methotrexate, glucocorticoids (prednisone and others), tumor necrosis factor (TNF) inhibitors, such as adalimumab, etanercept, and others), and non-TNF biologic agents (abatacept, rituximab, tocilizumab, and others).

Active AS

Dr. Ward presented a management flow tree for patients with active AS, starting with a strong recommendation for an NSAID, conditionally recommended to be used continuously. The authors felt, however, that there was not enough evidence to support the use of one NSAID over another. They also strongly recommended physical therapy, with less robust recommendations for active than for passive exercise and for exercises performed in water rather than on land. The latter recommendation is based on the fact that, although water-based exercises have been shown to be as good as or better than dry land exercises for relieving symptoms, water-based exercise may be impractical for many patients, Dr. Ward noted.

For patients whose disease remains active despite NSAIDs and exercise, the committee strongly recommends use of a tumor necrosis factor inhibitor (TNFi) (no specific agent preferred). If a patient on a TNFi has recurrent iritis, the guidelines have a conditional recommendation for the use of infliximab or adalimumab. For patients with inflammatory bowel disease (IBD), the authors conditionally recommend a TNFi monoclonal antibody as opposed to etanercept.

If the disease remains active on a TNFi, an alternative TNFi can be considered.

“For patients who have contraindications to TNF inhibitors, we considered the choice between adding a slow-acting drug such as sulfasalazine or pamidronate or treating with a non-TNF biologic. Of course, there are no head-to-head trials between those two options, so based on the indirect evidence that’s available, the committee voted for a conditional recommendation against the use of a non-TNF biologic in favor of a slow-acting drug in that setting,” Dr. Ward said.

If there are no contraindications to a TNF inhibitor, however, the committee strongly favored the use of a TNF inhibitor over a slow-acting agent, he emphasized.

For patients who have isolated sacroiliitis, peripheral arthritis, or enthesis, the committee provisionally recommends local injection of a glucocorticoid, with cautions to use infrequently and only if two or fewer joints are involved in peripheral arthritis, and avoidance of injection of the Achilles, patellar, or quadriceps tendons in patients with enthesitis.

For all patients, the guidelines half-heartedly recommend monitoring validated axSpA disease activity measures and C-reactive protein and erythrocyte sedimentation rate (ESR). The group also conditionally supported unsupervised back exercises, formal group or individual self-management education, and fall evaluation and counseling.

Committee members strongly felt that systemic glucocorticoids should not be used in patients with active axSpA, except in cases where a short-term course with quick taper may be helpful, such as in patients with peripheral flare, or during pregnancy or a concomitant IBD flare.

Stable AS

“For patients with stable ankylosing spondylitis who are on combination therapy, either combination therapy with NSAIDs and a TNF inhibitor, or a slow-acting drug and a TNF inhibitor, the committee voted against continuation of a combination in favor of TNF monotherapy. It’s a conditional recommendation, so there certainly would be situations where one would not want to do that, but in general the committee thought that was the preferable approach, balancing the benefits and potential risks of combination therapy against monotherapy in patients with stable AS,” Dr. Ward said.

The committee members strongly supported physical therapy in patients with stable AS and gave a conditional nod to monitoring, back exercises, group support, and fall counseling.

For patients with stable AS and advanced hip arthritis, hip replacement is strongly recommended. Recommendations for and against other special conditions include severe kyphosis (strongly against elective spine osteotomy except in specialized centers), acute iritis (strong support for an ophthalmology consultant), recurrent iritis (conditional support for at home use of a topical glucocorticoid under the supervision of an eye care provider, and use of infliximab or adalimumab over etanercept), and IBD (strong recommendation for TNFi monoclonals over etanercept and conditional endorsement of no preferred NSAID).

Active nr-axSpA

Recommendations for the treatment of nr-axSpA are essentially identical to those for treating active AS, Dr. Ward noted, except that in contrast to active AS, where the recommendation is strongly in favor of TNF inhibitors, the committee gave only a conditional recommendation for the use of a TNF inhibitor in this clinical situation.

Stable nr-axSpA

For patients with stable nr-axSpA, the recommendations are strongly in favor of NSAID use, with a conditional suggestion to use on demand. The recommendations also are conditionally against combination therapy with either an NSAID or slow-acting agent plus a TNF inhibitor, with a conditional approval for TNF inhibitor monotherapy instead. The committee strongly supported physical therapy for these patients and gave a lukewarm embrace of monitoring for disease activity, CRP, or ESR.

Dr. Ward noted that the guidelines are designed to help clinicians with treatment decisions for the typical patient with AS or nr-axSpA, and do not address the needs of all populations or all clinical circumstances or contingencies.

He also noted that for many of the questions the committee members tried to address, high-quality evidence was limited.

Dr. Ward did not mention a projected publication date for the guidelines. He had no relevant financial conflicts to disclose.

Daniel Pollyea, MD

Credit: University of Colorado

BARCELONA—An agent that inhibits isocitrate dehydrogenase (IDH) 1 shows the potential to transform therapy for certain patients with acute myeloid leukemia (AML), according to a speaker at the 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics.

The drug, known as AG-120, demonstrated clinical activity and was considered to be well-tolerated in a phase 1 study of patients with advanced, IDH1 mutant-positive AML.

Daniel Pollyea, MD, of the University of Colorado School of Medicine in Aurora, presented data on AG-120 at the symposium as abstract LBA1. The research was sponsored by Agios Pharmaceuticals, makers of AG-120.

“This is the first study in humans of an inhibitor of mutant IDH1 and the first demonstration of clinical activity of AG-120 in AML patients whose cancers have the IDH1 mutation,” Dr Pollyea said. “Although the data are early, we are encouraged to see evidence of clinical activity, as the primary objectives of phase 1 studies are to determine safety and tolerability.”

Dr Pollyea noted that mutations in IDH1 lead to a cascade of metabolic events that contribute to malignancy. Mutant IDH1 produces an excess amount of 2-hydroxyglutarate (2-HG), which prevents cells from maturing into normal, functioning cells, and this leads to malignancy.

In this study, the researchers found that AG-120 reduced 2-HG levels in diseased cells to normal levels, allowing them to mature into normal cells.

The trial included 17 patients with relapsed and/or refractory AML, who had received a median of 2 prior treatments. Patients were scheduled to

receive AG-120 in 1 of 4 dose groups: 100 mg twice a day, 300 mg once a day, 500 mg once a day, and 800 mg once a day over continuous 28-day cycles.

Fourteen patients were evaluable for response, and 7 responded. Four patients achieved a complete response, 2 had a complete response in the marrow, and 1 had a partial response.

Responses occurred at all the dose levels tested. In the 4 patients who achieved a complete response, there was early evidence of durability, ranging from 15 days to 5 months. All responding patients remain on AG-120, and 1 patient with stable disease remains on the drug.

“AML is a devastating disease that has historically been very difficult to treat, and these findings suggest that AG-120 has the potential to transform therapy for patients with IDH1-mutant positive AML,” Dr Pollyea said.

He and his colleagues also found that AG-120 was generally well-tolerated. The majority of adverse events were grade 1 and 2. The most common of these were nausea, fatigue, and dyspnea.

Eight patients experienced serious adverse events, but these were primarily related to disease progression.

One patient experienced a dose-limiting toxicity of asymptomatic grade 3 QT prolongation at the highest dose tested to date, which improved to grade 1 with dose reduction. This patient is in complete remission and remains on AG-120.

The maximum-tolerated dose of AG-120 has not been reached.

There were 6 patient deaths, all unrelated to AG-120. Five deaths occurred after patients discontinued treatment due to progressive disease, and 1 patient died due to disease-related intracranial hemorrhage while on treatment.

Dr Pollyea and his colleagues are continuing this study with the aim of fully understanding the safety of the drug, determining the maximum-tolerated dose, and assessing its efficacy in treating AML and myelodysplastic syndromes.

Daniel Pollyea, MD

Credit: University of Colorado

BARCELONA—An agent that inhibits isocitrate dehydrogenase (IDH) 1 shows the potential to transform therapy for certain patients with acute myeloid leukemia (AML), according to a speaker at the 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics.

The drug, known as AG-120, demonstrated clinical activity and was considered to be well-tolerated in a phase 1 study of patients with advanced, IDH1 mutant-positive AML.

Daniel Pollyea, MD, of the University of Colorado School of Medicine in Aurora, presented data on AG-120 at the symposium as abstract LBA1. The research was sponsored by Agios Pharmaceuticals, makers of AG-120.

“This is the first study in humans of an inhibitor of mutant IDH1 and the first demonstration of clinical activity of AG-120 in AML patients whose cancers have the IDH1 mutation,” Dr Pollyea said. “Although the data are early, we are encouraged to see evidence of clinical activity, as the primary objectives of phase 1 studies are to determine safety and tolerability.”

Dr Pollyea noted that mutations in IDH1 lead to a cascade of metabolic events that contribute to malignancy. Mutant IDH1 produces an excess amount of 2-hydroxyglutarate (2-HG), which prevents cells from maturing into normal, functioning cells, and this leads to malignancy.

In this study, the researchers found that AG-120 reduced 2-HG levels in diseased cells to normal levels, allowing them to mature into normal cells.

The trial included 17 patients with relapsed and/or refractory AML, who had received a median of 2 prior treatments. Patients were scheduled to

receive AG-120 in 1 of 4 dose groups: 100 mg twice a day, 300 mg once a day, 500 mg once a day, and 800 mg once a day over continuous 28-day cycles.

Fourteen patients were evaluable for response, and 7 responded. Four patients achieved a complete response, 2 had a complete response in the marrow, and 1 had a partial response.

Responses occurred at all the dose levels tested. In the 4 patients who achieved a complete response, there was early evidence of durability, ranging from 15 days to 5 months. All responding patients remain on AG-120, and 1 patient with stable disease remains on the drug.

“AML is a devastating disease that has historically been very difficult to treat, and these findings suggest that AG-120 has the potential to transform therapy for patients with IDH1-mutant positive AML,” Dr Pollyea said.

He and his colleagues also found that AG-120 was generally well-tolerated. The majority of adverse events were grade 1 and 2. The most common of these were nausea, fatigue, and dyspnea.

Eight patients experienced serious adverse events, but these were primarily related to disease progression.

One patient experienced a dose-limiting toxicity of asymptomatic grade 3 QT prolongation at the highest dose tested to date, which improved to grade 1 with dose reduction. This patient is in complete remission and remains on AG-120.

The maximum-tolerated dose of AG-120 has not been reached.

There were 6 patient deaths, all unrelated to AG-120. Five deaths occurred after patients discontinued treatment due to progressive disease, and 1 patient died due to disease-related intracranial hemorrhage while on treatment.

Dr Pollyea and his colleagues are continuing this study with the aim of fully understanding the safety of the drug, determining the maximum-tolerated dose, and assessing its efficacy in treating AML and myelodysplastic syndromes.

Daniel Pollyea, MD

Credit: University of Colorado

BARCELONA—An agent that inhibits isocitrate dehydrogenase (IDH) 1 shows the potential to transform therapy for certain patients with acute myeloid leukemia (AML), according to a speaker at the 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics.

The drug, known as AG-120, demonstrated clinical activity and was considered to be well-tolerated in a phase 1 study of patients with advanced, IDH1 mutant-positive AML.

Daniel Pollyea, MD, of the University of Colorado School of Medicine in Aurora, presented data on AG-120 at the symposium as abstract LBA1. The research was sponsored by Agios Pharmaceuticals, makers of AG-120.

“This is the first study in humans of an inhibitor of mutant IDH1 and the first demonstration of clinical activity of AG-120 in AML patients whose cancers have the IDH1 mutation,” Dr Pollyea said. “Although the data are early, we are encouraged to see evidence of clinical activity, as the primary objectives of phase 1 studies are to determine safety and tolerability.”

Dr Pollyea noted that mutations in IDH1 lead to a cascade of metabolic events that contribute to malignancy. Mutant IDH1 produces an excess amount of 2-hydroxyglutarate (2-HG), which prevents cells from maturing into normal, functioning cells, and this leads to malignancy.

In this study, the researchers found that AG-120 reduced 2-HG levels in diseased cells to normal levels, allowing them to mature into normal cells.

The trial included 17 patients with relapsed and/or refractory AML, who had received a median of 2 prior treatments. Patients were scheduled to

receive AG-120 in 1 of 4 dose groups: 100 mg twice a day, 300 mg once a day, 500 mg once a day, and 800 mg once a day over continuous 28-day cycles.

Fourteen patients were evaluable for response, and 7 responded. Four patients achieved a complete response, 2 had a complete response in the marrow, and 1 had a partial response.

Responses occurred at all the dose levels tested. In the 4 patients who achieved a complete response, there was early evidence of durability, ranging from 15 days to 5 months. All responding patients remain on AG-120, and 1 patient with stable disease remains on the drug.

“AML is a devastating disease that has historically been very difficult to treat, and these findings suggest that AG-120 has the potential to transform therapy for patients with IDH1-mutant positive AML,” Dr Pollyea said.

He and his colleagues also found that AG-120 was generally well-tolerated. The majority of adverse events were grade 1 and 2. The most common of these were nausea, fatigue, and dyspnea.

Eight patients experienced serious adverse events, but these were primarily related to disease progression.

One patient experienced a dose-limiting toxicity of asymptomatic grade 3 QT prolongation at the highest dose tested to date, which improved to grade 1 with dose reduction. This patient is in complete remission and remains on AG-120.

The maximum-tolerated dose of AG-120 has not been reached.

There were 6 patient deaths, all unrelated to AG-120. Five deaths occurred after patients discontinued treatment due to progressive disease, and 1 patient died due to disease-related intracranial hemorrhage while on treatment.

Dr Pollyea and his colleagues are continuing this study with the aim of fully understanding the safety of the drug, determining the maximum-tolerated dose, and assessing its efficacy in treating AML and myelodysplastic syndromes.

Lab mice

Credit: Aaron Logan

Scientists have long known that mice are not perfect models for studying conditions in humans, but new research reveals why certain processes and systems in

mice are so different from those in humans.

As part of the mouse ENCODE project, researchers discovered that a significant number of mouse genes do not behave like their human counterparts.

This suggests scientists will need to rethink at least some roles of the lab mouse as a model organism.

“There are a substantial number of mouse genes that are regulated in ways different from similar genes in humans,” said Bing Ren, PhD, of the University of California, San Diego.

“The differences are not random. They are clustered along certain pathways, such as in genes regulating the immune system.”

The findings, part of a series of related papers being published in Nature, Science, and other journals (see below), are derived from the ongoing mouse ENCODE (Encyclopedia of DNA Elements) project.

This multi-institution effort was launched in 2007 to build a comprehensive list of functional elements of the mouse genome. It complements the earlier human ENCODE project, which published its functional catalogue in 2012.

“Both the original human and mouse genome projects gave us the sequence of genetic letters that comprise each organism but no idea how they worked or worked together to create and sustain life,” Dr Ren said.

“The human ENCODE project was designed to answer some of those questions. The mouse ENCODE project is its complement. It’s intended to provide scientists with comprehensive annotation of what mouse genes do, information that may ultimately be used for human therapeutic purposes.”

Only half of human genomic DNA aligns to mouse genomic DNA. But protein-coding genes, which provide the actionable instructions to build a living organism, are more strongly conserved across the two species.

Mice and humans share approximately 70% of the same protein-coding gene sequences, though these genes constitute just 1.5% of their respective genomes.

Dr Ren said scientists had assumed that significant conservation would occur at the deeper level of gene regulation as well, that similar genes in humans and mice would be expressed in similar ways.

Using the same high throughput technologies applied in the human ENCODE project, he and his colleagues analyzed 100 different mouse cell types and tissues.

They found that, while much conservation did exist, the expression profiles of some distinct biological pathways in mouse samples diverged considerably from human samples.

Put another way, core genomic programs were largely conserved between the species, but genes and their underlying regulatory programs had changed significantly over time. Each species had evolved to find different ways to do some of the same things.

The findings are not entirely unexpected. Dr Ren said previous studies had documented rapidly evolving transcription factors in a handful of cell types and model organisms, but the ability to more systematically discern how humans and mice differ in genomic function marks an important milestone.

“One benefit is that, while mice have proved to be substantially different than humans in some ways, we now have a better idea of where exactly they are different, where we will need to take into account those differences, perhaps finding or developing a better model, and where the mouse continues to be a very good model indeed,” Dr Ren concluded.

Visit the following links for the mouse ENCODE papers published yesterday in Nature and Science:

A comparative encyclopedia of DNA elements in the mouse genome

Conservation of trans-acting circuitry during mammalian regulatory evolution

Principles of regulatory information conservation between mouse and human

Topologically associating domains are stable units of replication-timing regulation

Mouse regulatory DNA landscapes reveal global principles of cis-regulatory evolution

Related studies are set to appear in PNAS, Genome Research, Genome Biology, Nature Communications, and Blood.

Lab mice

Credit: Aaron Logan

Scientists have long known that mice are not perfect models for studying conditions in humans, but new research reveals why certain processes and systems in

mice are so different from those in humans.

As part of the mouse ENCODE project, researchers discovered that a significant number of mouse genes do not behave like their human counterparts.

This suggests scientists will need to rethink at least some roles of the lab mouse as a model organism.

“There are a substantial number of mouse genes that are regulated in ways different from similar genes in humans,” said Bing Ren, PhD, of the University of California, San Diego.

“The differences are not random. They are clustered along certain pathways, such as in genes regulating the immune system.”

The findings, part of a series of related papers being published in Nature, Science, and other journals (see below), are derived from the ongoing mouse ENCODE (Encyclopedia of DNA Elements) project.

This multi-institution effort was launched in 2007 to build a comprehensive list of functional elements of the mouse genome. It complements the earlier human ENCODE project, which published its functional catalogue in 2012.

“Both the original human and mouse genome projects gave us the sequence of genetic letters that comprise each organism but no idea how they worked or worked together to create and sustain life,” Dr Ren said.

“The human ENCODE project was designed to answer some of those questions. The mouse ENCODE project is its complement. It’s intended to provide scientists with comprehensive annotation of what mouse genes do, information that may ultimately be used for human therapeutic purposes.”

Only half of human genomic DNA aligns to mouse genomic DNA. But protein-coding genes, which provide the actionable instructions to build a living organism, are more strongly conserved across the two species.

Mice and humans share approximately 70% of the same protein-coding gene sequences, though these genes constitute just 1.5% of their respective genomes.

Dr Ren said scientists had assumed that significant conservation would occur at the deeper level of gene regulation as well, that similar genes in humans and mice would be expressed in similar ways.

Using the same high throughput technologies applied in the human ENCODE project, he and his colleagues analyzed 100 different mouse cell types and tissues.

They found that, while much conservation did exist, the expression profiles of some distinct biological pathways in mouse samples diverged considerably from human samples.

Put another way, core genomic programs were largely conserved between the species, but genes and their underlying regulatory programs had changed significantly over time. Each species had evolved to find different ways to do some of the same things.

The findings are not entirely unexpected. Dr Ren said previous studies had documented rapidly evolving transcription factors in a handful of cell types and model organisms, but the ability to more systematically discern how humans and mice differ in genomic function marks an important milestone.

“One benefit is that, while mice have proved to be substantially different than humans in some ways, we now have a better idea of where exactly they are different, where we will need to take into account those differences, perhaps finding or developing a better model, and where the mouse continues to be a very good model indeed,” Dr Ren concluded.

Visit the following links for the mouse ENCODE papers published yesterday in Nature and Science:

A comparative encyclopedia of DNA elements in the mouse genome

Conservation of trans-acting circuitry during mammalian regulatory evolution

Principles of regulatory information conservation between mouse and human

Topologically associating domains are stable units of replication-timing regulation

Mouse regulatory DNA landscapes reveal global principles of cis-regulatory evolution

Related studies are set to appear in PNAS, Genome Research, Genome Biology, Nature Communications, and Blood.

Lab mice

Credit: Aaron Logan

Scientists have long known that mice are not perfect models for studying conditions in humans, but new research reveals why certain processes and systems in

mice are so different from those in humans.

As part of the mouse ENCODE project, researchers discovered that a significant number of mouse genes do not behave like their human counterparts.

This suggests scientists will need to rethink at least some roles of the lab mouse as a model organism.

“There are a substantial number of mouse genes that are regulated in ways different from similar genes in humans,” said Bing Ren, PhD, of the University of California, San Diego.

“The differences are not random. They are clustered along certain pathways, such as in genes regulating the immune system.”

The findings, part of a series of related papers being published in Nature, Science, and other journals (see below), are derived from the ongoing mouse ENCODE (Encyclopedia of DNA Elements) project.

This multi-institution effort was launched in 2007 to build a comprehensive list of functional elements of the mouse genome. It complements the earlier human ENCODE project, which published its functional catalogue in 2012.

“Both the original human and mouse genome projects gave us the sequence of genetic letters that comprise each organism but no idea how they worked or worked together to create and sustain life,” Dr Ren said.

“The human ENCODE project was designed to answer some of those questions. The mouse ENCODE project is its complement. It’s intended to provide scientists with comprehensive annotation of what mouse genes do, information that may ultimately be used for human therapeutic purposes.”

Only half of human genomic DNA aligns to mouse genomic DNA. But protein-coding genes, which provide the actionable instructions to build a living organism, are more strongly conserved across the two species.

Mice and humans share approximately 70% of the same protein-coding gene sequences, though these genes constitute just 1.5% of their respective genomes.

Dr Ren said scientists had assumed that significant conservation would occur at the deeper level of gene regulation as well, that similar genes in humans and mice would be expressed in similar ways.

Using the same high throughput technologies applied in the human ENCODE project, he and his colleagues analyzed 100 different mouse cell types and tissues.

They found that, while much conservation did exist, the expression profiles of some distinct biological pathways in mouse samples diverged considerably from human samples.

Put another way, core genomic programs were largely conserved between the species, but genes and their underlying regulatory programs had changed significantly over time. Each species had evolved to find different ways to do some of the same things.

The findings are not entirely unexpected. Dr Ren said previous studies had documented rapidly evolving transcription factors in a handful of cell types and model organisms, but the ability to more systematically discern how humans and mice differ in genomic function marks an important milestone.

“One benefit is that, while mice have proved to be substantially different than humans in some ways, we now have a better idea of where exactly they are different, where we will need to take into account those differences, perhaps finding or developing a better model, and where the mouse continues to be a very good model indeed,” Dr Ren concluded.

Visit the following links for the mouse ENCODE papers published yesterday in Nature and Science:

A comparative encyclopedia of DNA elements in the mouse genome

Conservation of trans-acting circuitry during mammalian regulatory evolution

Principles of regulatory information conservation between mouse and human

Topologically associating domains are stable units of replication-timing regulation

Mouse regulatory DNA landscapes reveal global principles of cis-regulatory evolution

Related studies are set to appear in PNAS, Genome Research, Genome Biology, Nature Communications, and Blood.

Benzodiazepines are regularly used to treat anxiety, insomnia, and depression. Guidelines advise only short-term benzodiazepine use for elderly patients, but long-term treatment is still common. According to researchers from the University of Montreal in Canada and the University of Bordeaux in France, long-term dosing can do more harm than good for patients at risk for Alzheimer disease. Previous research has established that long-term benzodiazepine use can have deleterious effects on memory and cognition, say the researchers.

Earlier studies could not prove a connection between the drugs and dementia, because they did not have sufficient power, follow-up was too short, or because of other methodologic limitations. To counter those earlier limitations, the researchers designed their study to assess benzodiazepine treatments initiated > 5 years before the diagnosis of Alzheimer disease or dementia, when prescriptions were less likely to be motivated by prodromes.

The researchers used an administrative claims database with a long follow-up period to look at the potential dose-effect relationship. They defined exposure by 3 criteria: “ever use” (≥ 1 claim for a benzodiazepine from 5 to 10 years before the index date); cumulative dose (≤ 3 months, 3 to 6 months, or > 6 months [long-term use]); and drug elimination half-life (short- [< 20 hours] or long-acting benzodiazepines). The researchers matched 1,796 patients with 7,184 controls and followed them for ≥ 6 years before the index date.

The risk of Alzheimer disease, the study revealed, increased by 43% to 51% among people who had used benzodiazepines in the past: 894 (49.8%) people with Alzheimer disease had used benzodiazepines at some point, compared with 2,873 controls (40%). Short-term use did not differ between the 2 groups. Long-term use was more common among people with Alzheimer disease, the researchers found: 32.9% of those with Alzheimer disease compared with 21.8% of those in the control group.

Risk of Alzheimer disease increased when long-acting benzodiazepines were used. Because there is no prevention or cure for Alzheimer disease, the researchers urge focusing on duration of benzodiazepine use and other modifiable risk factors.

Source
Billioti de Gage S, Moride Y, Ducruet T, et al. BMJ. 2014;349:g5205.
doi: 10.1136/bmj.g5205.

Benzodiazepines are regularly used to treat anxiety, insomnia, and depression. Guidelines advise only short-term benzodiazepine use for elderly patients, but long-term treatment is still common. According to researchers from the University of Montreal in Canada and the University of Bordeaux in France, long-term dosing can do more harm than good for patients at risk for Alzheimer disease. Previous research has established that long-term benzodiazepine use can have deleterious effects on memory and cognition, say the researchers.

Earlier studies could not prove a connection between the drugs and dementia, because they did not have sufficient power, follow-up was too short, or because of other methodologic limitations. To counter those earlier limitations, the researchers designed their study to assess benzodiazepine treatments initiated > 5 years before the diagnosis of Alzheimer disease or dementia, when prescriptions were less likely to be motivated by prodromes.

The researchers used an administrative claims database with a long follow-up period to look at the potential dose-effect relationship. They defined exposure by 3 criteria: “ever use” (≥ 1 claim for a benzodiazepine from 5 to 10 years before the index date); cumulative dose (≤ 3 months, 3 to 6 months, or > 6 months [long-term use]); and drug elimination half-life (short- [< 20 hours] or long-acting benzodiazepines). The researchers matched 1,796 patients with 7,184 controls and followed them for ≥ 6 years before the index date.

The risk of Alzheimer disease, the study revealed, increased by 43% to 51% among people who had used benzodiazepines in the past: 894 (49.8%) people with Alzheimer disease had used benzodiazepines at some point, compared with 2,873 controls (40%). Short-term use did not differ between the 2 groups. Long-term use was more common among people with Alzheimer disease, the researchers found: 32.9% of those with Alzheimer disease compared with 21.8% of those in the control group.

Risk of Alzheimer disease increased when long-acting benzodiazepines were used. Because there is no prevention or cure for Alzheimer disease, the researchers urge focusing on duration of benzodiazepine use and other modifiable risk factors.

Source
Billioti de Gage S, Moride Y, Ducruet T, et al. BMJ. 2014;349:g5205.
doi: 10.1136/bmj.g5205.

Benzodiazepines are regularly used to treat anxiety, insomnia, and depression. Guidelines advise only short-term benzodiazepine use for elderly patients, but long-term treatment is still common. According to researchers from the University of Montreal in Canada and the University of Bordeaux in France, long-term dosing can do more harm than good for patients at risk for Alzheimer disease. Previous research has established that long-term benzodiazepine use can have deleterious effects on memory and cognition, say the researchers.

Earlier studies could not prove a connection between the drugs and dementia, because they did not have sufficient power, follow-up was too short, or because of other methodologic limitations. To counter those earlier limitations, the researchers designed their study to assess benzodiazepine treatments initiated > 5 years before the diagnosis of Alzheimer disease or dementia, when prescriptions were less likely to be motivated by prodromes.

The researchers used an administrative claims database with a long follow-up period to look at the potential dose-effect relationship. They defined exposure by 3 criteria: “ever use” (≥ 1 claim for a benzodiazepine from 5 to 10 years before the index date); cumulative dose (≤ 3 months, 3 to 6 months, or > 6 months [long-term use]); and drug elimination half-life (short- [< 20 hours] or long-acting benzodiazepines). The researchers matched 1,796 patients with 7,184 controls and followed them for ≥ 6 years before the index date.

The risk of Alzheimer disease, the study revealed, increased by 43% to 51% among people who had used benzodiazepines in the past: 894 (49.8%) people with Alzheimer disease had used benzodiazepines at some point, compared with 2,873 controls (40%). Short-term use did not differ between the 2 groups. Long-term use was more common among people with Alzheimer disease, the researchers found: 32.9% of those with Alzheimer disease compared with 21.8% of those in the control group.

Risk of Alzheimer disease increased when long-acting benzodiazepines were used. Because there is no prevention or cure for Alzheimer disease, the researchers urge focusing on duration of benzodiazepine use and other modifiable risk factors.

Source
Billioti de Gage S, Moride Y, Ducruet T, et al. BMJ. 2014;349:g5205.
doi: 10.1136/bmj.g5205.

Herman Eisen, MD

Photo courtesy of MIT

Herman Eisen, MD, a respected immunologist, has died at the age of 96.

Over a 70-year career, Dr Eisen contributed a great deal to his own field and other fields of research.

He published work describing affinity maturation, clarified the basis for certain allergic reactions, and provided new insight into multiple myeloma and other cancers.

Dr Eisen was a professor emeritus of biology at the Massachusetts Institute of Technology (MIT) and a founding member of the MIT Center for Cancer Research (now the Koch Institute for Integrative Cancer Research).

He joined MIT in 1973 and retired in 1989, but only in the official sense. As a professor emeritus, he maintained an active lab and continued to research, publish, and advise students and postdocs at MIT until his passing.

Early years

Born in 1918 in Brooklyn, New York, Dr Eisen developed a keen interest in science at an early age, when a high school chemistry class helped frame his perception of the world as a collection of atoms and molecules.

Dr Eisen began premedical studies at New York University (NYU) in 1934, but halfway through his undergraduate career, he developed tuberculosis and left school. Though this kept him out of school for one year, the illness sparked a curiosity about the immune system that would endure for the rest of his life.

Dr Eisen returned to NYU to complete his bachelor’s degree, then enrolled at the university’s medical school. He graduated with an MD in 1943 and then worked as an assistant in the pathology department at the Columbia University College of Physicians and Surgeons before going back to NYU for his residency.

Research interests

Dr Eisen had a strong interest in basic science research, particularly in trying to better understand the body’s immune system. Though career options for physician-scientists had historically been limited, the federal government began to increase its funding of biomedical research through the National Institutes of Health (NIH) following World War II.

Seizing these new opportunities, Dr Eisen became one of the first recipients of an NIH fellowship, which supported his research on sulfonamide-induced antibodies at NYU. These investigations helped him and colleague Fred Karush, PhD, determine the number of antigen-binding sites on antibodies.

After his 2-year NIH fellowship, Dr Eisen worked briefly at the Sloan Kettering Institute before returning once again to NYU as a faculty member.

Inspired by the work of his recently deceased role model, Karl Landsteiner, MD, Dr Eisen studied immune reactions of the skin. In doing so, he clarified the basis for certain allergic responses and showed that only those chemicals capable of forming covalent bonds to skin proteins could cause a characteristic itchy rash.

In 1955, Washington University in St Louis recruited Dr Eisen to join the faculty of its School of Medicine. There, he served as dermatologist-in-chief for 5 years before moving to the Department of Microbiology to serve as chair.

While at Washington University, Dr Eisen published groundbreaking research in which he described affinity maturation: the process by which activated B cells produce antibodies with an increasingly higher affinity for invading pathogens after infection. This process is fundamental to the development of potent immune responses.

“Our understanding of affinity maturation begins with Herman’s papers,” said Arup K. Chakraborty, PhD, director of MIT’s Institute for Medical Engineering and Science.

“Understanding this evolutionary process is critical for vaccine design, and affinity maturation is also mimicked in countless academic laboratories and companies to design antibody-based therapies.”

Cancer research

In response to the National Cancer Act of 1971, MIT tasked Nobel Prize-winning biology professor Salvador Luria, MD, with establishing and leading a new MIT Center for Cancer Research. Wanting to include cancer immunology as a focus of this new center, Dr Luria approached Dr Eisen about joining as a founding faculty member.

Dr Eisen accepted the role and arrived at MIT in 1973 as a professor in the Department of Biology. He brought his immunology expertise to MIT’s new cancer center to study how cancer cells evade the body’s natural immune response.

Much of his work focused on studying myeloma tumors in mice and screening their associated proteins. He found that if he used myeloma proteins from one mouse to immunize other mice from the same strain, they were resistant when challenged with cancer cells.

Dr Eisen and his lab went on to study how CD8 T cells develop into cytotoxic T cells and long-lived memory T cells. Therapeutic vaccines that exploit CD8 responses have not yet been developed for humans.

Dr Eisen was working to understand and overcome the barriers to creating effective CD8 vaccines, and his research on the subject was of particular importance to the advancement of cancer immunology.

“Herman’s lifelong pursuit of science, even to the very last day of his life, has been an inspiration to many of us,” said Jianzhu Chen, PhD, of the Koch Institute. “He was a great human being with a great attitude and a clear mind. He will be missed greatly.”

Other colleagues remember Dr Eisen not only as a respected immunologist, but as a hardworking collaborator and a man of integrity. He continued to be an active scientist and had been working with Dr Chakraborty on a paper until his passing.

“Herman was a giant in the field of immunology, with many seminal discoveries,” Dr Chakraborty said. “He was also the kindest and most generous and moral person I have known. Until the end, he was working on scientific problems with junior colleagues and students who benefited from his wisdom. I am lucky to have worked with this great scientist and wonderful human being.”

Dr Eisen was elected to the American Academy of Arts and Sciences in 1965, the National Academy of Sciences in 1969, and the Institute of Medicine of the National Academies in 1974.

He received numerous other awards and honors throughout his career, including the Behring-Heidelberger Award from the American Association of Immunologists, an Outstanding Investigator Award from the National Cancer Institute, and the Lifetime Service Award from the American Association of Immunologists, of which he served as president from 1968 to 1969.

Dr Eisen passed away on November 2. He is survived by his wife Natalie and their children, Ellen, Jane, Jim, Tom, and Matthew, as well as 12 grandchildren.

Herman Eisen, MD

Photo courtesy of MIT

Herman Eisen, MD, a respected immunologist, has died at the age of 96.

Over a 70-year career, Dr Eisen contributed a great deal to his own field and other fields of research.

He published work describing affinity maturation, clarified the basis for certain allergic reactions, and provided new insight into multiple myeloma and other cancers.

Dr Eisen was a professor emeritus of biology at the Massachusetts Institute of Technology (MIT) and a founding member of the MIT Center for Cancer Research (now the Koch Institute for Integrative Cancer Research).

He joined MIT in 1973 and retired in 1989, but only in the official sense. As a professor emeritus, he maintained an active lab and continued to research, publish, and advise students and postdocs at MIT until his passing.

Early years

Born in 1918 in Brooklyn, New York, Dr Eisen developed a keen interest in science at an early age, when a high school chemistry class helped frame his perception of the world as a collection of atoms and molecules.

Dr Eisen began premedical studies at New York University (NYU) in 1934, but halfway through his undergraduate career, he developed tuberculosis and left school. Though this kept him out of school for one year, the illness sparked a curiosity about the immune system that would endure for the rest of his life.

Dr Eisen returned to NYU to complete his bachelor’s degree, then enrolled at the university’s medical school. He graduated with an MD in 1943 and then worked as an assistant in the pathology department at the Columbia University College of Physicians and Surgeons before going back to NYU for his residency.

Research interests

Dr Eisen had a strong interest in basic science research, particularly in trying to better understand the body’s immune system. Though career options for physician-scientists had historically been limited, the federal government began to increase its funding of biomedical research through the National Institutes of Health (NIH) following World War II.

Seizing these new opportunities, Dr Eisen became one of the first recipients of an NIH fellowship, which supported his research on sulfonamide-induced antibodies at NYU. These investigations helped him and colleague Fred Karush, PhD, determine the number of antigen-binding sites on antibodies.

After his 2-year NIH fellowship, Dr Eisen worked briefly at the Sloan Kettering Institute before returning once again to NYU as a faculty member.

Inspired by the work of his recently deceased role model, Karl Landsteiner, MD, Dr Eisen studied immune reactions of the skin. In doing so, he clarified the basis for certain allergic responses and showed that only those chemicals capable of forming covalent bonds to skin proteins could cause a characteristic itchy rash.

In 1955, Washington University in St Louis recruited Dr Eisen to join the faculty of its School of Medicine. There, he served as dermatologist-in-chief for 5 years before moving to the Department of Microbiology to serve as chair.

While at Washington University, Dr Eisen published groundbreaking research in which he described affinity maturation: the process by which activated B cells produce antibodies with an increasingly higher affinity for invading pathogens after infection. This process is fundamental to the development of potent immune responses.

“Our understanding of affinity maturation begins with Herman’s papers,” said Arup K. Chakraborty, PhD, director of MIT’s Institute for Medical Engineering and Science.

“Understanding this evolutionary process is critical for vaccine design, and affinity maturation is also mimicked in countless academic laboratories and companies to design antibody-based therapies.”

Cancer research

In response to the National Cancer Act of 1971, MIT tasked Nobel Prize-winning biology professor Salvador Luria, MD, with establishing and leading a new MIT Center for Cancer Research. Wanting to include cancer immunology as a focus of this new center, Dr Luria approached Dr Eisen about joining as a founding faculty member.

Dr Eisen accepted the role and arrived at MIT in 1973 as a professor in the Department of Biology. He brought his immunology expertise to MIT’s new cancer center to study how cancer cells evade the body’s natural immune response.

Much of his work focused on studying myeloma tumors in mice and screening their associated proteins. He found that if he used myeloma proteins from one mouse to immunize other mice from the same strain, they were resistant when challenged with cancer cells.

Dr Eisen and his lab went on to study how CD8 T cells develop into cytotoxic T cells and long-lived memory T cells. Therapeutic vaccines that exploit CD8 responses have not yet been developed for humans.

Dr Eisen was working to understand and overcome the barriers to creating effective CD8 vaccines, and his research on the subject was of particular importance to the advancement of cancer immunology.

“Herman’s lifelong pursuit of science, even to the very last day of his life, has been an inspiration to many of us,” said Jianzhu Chen, PhD, of the Koch Institute. “He was a great human being with a great attitude and a clear mind. He will be missed greatly.”

Other colleagues remember Dr Eisen not only as a respected immunologist, but as a hardworking collaborator and a man of integrity. He continued to be an active scientist and had been working with Dr Chakraborty on a paper until his passing.

“Herman was a giant in the field of immunology, with many seminal discoveries,” Dr Chakraborty said. “He was also the kindest and most generous and moral person I have known. Until the end, he was working on scientific problems with junior colleagues and students who benefited from his wisdom. I am lucky to have worked with this great scientist and wonderful human being.”

Dr Eisen was elected to the American Academy of Arts and Sciences in 1965, the National Academy of Sciences in 1969, and the Institute of Medicine of the National Academies in 1974.

He received numerous other awards and honors throughout his career, including the Behring-Heidelberger Award from the American Association of Immunologists, an Outstanding Investigator Award from the National Cancer Institute, and the Lifetime Service Award from the American Association of Immunologists, of which he served as president from 1968 to 1969.

Dr Eisen passed away on November 2. He is survived by his wife Natalie and their children, Ellen, Jane, Jim, Tom, and Matthew, as well as 12 grandchildren.

Herman Eisen, MD

Photo courtesy of MIT

Herman Eisen, MD, a respected immunologist, has died at the age of 96.

Over a 70-year career, Dr Eisen contributed a great deal to his own field and other fields of research.

He published work describing affinity maturation, clarified the basis for certain allergic reactions, and provided new insight into multiple myeloma and other cancers.

Dr Eisen was a professor emeritus of biology at the Massachusetts Institute of Technology (MIT) and a founding member of the MIT Center for Cancer Research (now the Koch Institute for Integrative Cancer Research).

He joined MIT in 1973 and retired in 1989, but only in the official sense. As a professor emeritus, he maintained an active lab and continued to research, publish, and advise students and postdocs at MIT until his passing.

Early years

Born in 1918 in Brooklyn, New York, Dr Eisen developed a keen interest in science at an early age, when a high school chemistry class helped frame his perception of the world as a collection of atoms and molecules.

Dr Eisen began premedical studies at New York University (NYU) in 1934, but halfway through his undergraduate career, he developed tuberculosis and left school. Though this kept him out of school for one year, the illness sparked a curiosity about the immune system that would endure for the rest of his life.

Dr Eisen returned to NYU to complete his bachelor’s degree, then enrolled at the university’s medical school. He graduated with an MD in 1943 and then worked as an assistant in the pathology department at the Columbia University College of Physicians and Surgeons before going back to NYU for his residency.

Research interests

Dr Eisen had a strong interest in basic science research, particularly in trying to better understand the body’s immune system. Though career options for physician-scientists had historically been limited, the federal government began to increase its funding of biomedical research through the National Institutes of Health (NIH) following World War II.

Seizing these new opportunities, Dr Eisen became one of the first recipients of an NIH fellowship, which supported his research on sulfonamide-induced antibodies at NYU. These investigations helped him and colleague Fred Karush, PhD, determine the number of antigen-binding sites on antibodies.

After his 2-year NIH fellowship, Dr Eisen worked briefly at the Sloan Kettering Institute before returning once again to NYU as a faculty member.

Inspired by the work of his recently deceased role model, Karl Landsteiner, MD, Dr Eisen studied immune reactions of the skin. In doing so, he clarified the basis for certain allergic responses and showed that only those chemicals capable of forming covalent bonds to skin proteins could cause a characteristic itchy rash.

In 1955, Washington University in St Louis recruited Dr Eisen to join the faculty of its School of Medicine. There, he served as dermatologist-in-chief for 5 years before moving to the Department of Microbiology to serve as chair.

While at Washington University, Dr Eisen published groundbreaking research in which he described affinity maturation: the process by which activated B cells produce antibodies with an increasingly higher affinity for invading pathogens after infection. This process is fundamental to the development of potent immune responses.

“Our understanding of affinity maturation begins with Herman’s papers,” said Arup K. Chakraborty, PhD, director of MIT’s Institute for Medical Engineering and Science.

“Understanding this evolutionary process is critical for vaccine design, and affinity maturation is also mimicked in countless academic laboratories and companies to design antibody-based therapies.”

Cancer research

In response to the National Cancer Act of 1971, MIT tasked Nobel Prize-winning biology professor Salvador Luria, MD, with establishing and leading a new MIT Center for Cancer Research. Wanting to include cancer immunology as a focus of this new center, Dr Luria approached Dr Eisen about joining as a founding faculty member.

Dr Eisen accepted the role and arrived at MIT in 1973 as a professor in the Department of Biology. He brought his immunology expertise to MIT’s new cancer center to study how cancer cells evade the body’s natural immune response.

Much of his work focused on studying myeloma tumors in mice and screening their associated proteins. He found that if he used myeloma proteins from one mouse to immunize other mice from the same strain, they were resistant when challenged with cancer cells.

Dr Eisen and his lab went on to study how CD8 T cells develop into cytotoxic T cells and long-lived memory T cells. Therapeutic vaccines that exploit CD8 responses have not yet been developed for humans.

Dr Eisen was working to understand and overcome the barriers to creating effective CD8 vaccines, and his research on the subject was of particular importance to the advancement of cancer immunology.

“Herman’s lifelong pursuit of science, even to the very last day of his life, has been an inspiration to many of us,” said Jianzhu Chen, PhD, of the Koch Institute. “He was a great human being with a great attitude and a clear mind. He will be missed greatly.”

Other colleagues remember Dr Eisen not only as a respected immunologist, but as a hardworking collaborator and a man of integrity. He continued to be an active scientist and had been working with Dr Chakraborty on a paper until his passing.

“Herman was a giant in the field of immunology, with many seminal discoveries,” Dr Chakraborty said. “He was also the kindest and most generous and moral person I have known. Until the end, he was working on scientific problems with junior colleagues and students who benefited from his wisdom. I am lucky to have worked with this great scientist and wonderful human being.”

Dr Eisen was elected to the American Academy of Arts and Sciences in 1965, the National Academy of Sciences in 1969, and the Institute of Medicine of the National Academies in 1974.

He received numerous other awards and honors throughout his career, including the Behring-Heidelberger Award from the American Association of Immunologists, an Outstanding Investigator Award from the National Cancer Institute, and the Lifetime Service Award from the American Association of Immunologists, of which he served as president from 1968 to 1969.

Dr Eisen passed away on November 2. He is survived by his wife Natalie and their children, Ellen, Jane, Jim, Tom, and Matthew, as well as 12 grandchildren.

CML cells

Credit: UCSD School of Medicine

By analyzing structural changes that occur during Abl kinase activation, researchers have gained new insight into this process.

The team discovered a mechanism that links the allosteric regulation of the SH2 domain to two critical phosphorylation events.

As allosteric SH2-kinase domain interactions have proven essential for leukemogenesis caused by Bcr-Abl, the researchers believe this finding has implications for treating chronic myeloid leukemia (CML).

Oliver Hantschel, PhD, of the École polytechnique fédérale de Lausanne (EPFL) in Lausanne, Switzerland, and his colleagues described this work in Nature Communications.

The team made small, strategic mutations to Abl kinase that caused its 3D structure to change. Then, they tested each mutant version of the enzyme to see if its function would change.

The researchers built on previous studies showing that Abl kinase is indirectly controlled by the SH2 region. Normally, the SH2 region regulates the activation loop by opening and closing it. But under the Philadelphia chromosome translocation, that regulation is lost.

The team discovered that when the Philadelphia mutation takes effect, the SH2 region changes the Abl activation loop to a fully open conformation. This enables the trans-autophosphorylation of the activation loop and requires prior phosphorylation of the SH2-kinase linker.

This discovery provides the first-ever picture of the molecular events surrounding the hyperactivity of Abl kinase, the researchers said.

They also found that by disrupting the SH2-kinase interaction, it’s possible to modulate the activity of Abl kinase, which could potentially stop the growth of leukemia.

Since the SH2 region is common to other kinases, the researchers think it’s likely the effect could extend to malignancies other than CML as well, particularly those characterized by abnormal kinase activity.

Finally, the team expects this approach could overcome the problem of drug resistance in CML, as it might offer an alternative way to inhibit Abl kinase, and mutations of rapidly growing cancer cells may be less likely to occur.

CML cells

Credit: UCSD School of Medicine

By analyzing structural changes that occur during Abl kinase activation, researchers have gained new insight into this process.

The team discovered a mechanism that links the allosteric regulation of the SH2 domain to two critical phosphorylation events.

As allosteric SH2-kinase domain interactions have proven essential for leukemogenesis caused by Bcr-Abl, the researchers believe this finding has implications for treating chronic myeloid leukemia (CML).

Oliver Hantschel, PhD, of the École polytechnique fédérale de Lausanne (EPFL) in Lausanne, Switzerland, and his colleagues described this work in Nature Communications.

The team made small, strategic mutations to Abl kinase that caused its 3D structure to change. Then, they tested each mutant version of the enzyme to see if its function would change.

The researchers built on previous studies showing that Abl kinase is indirectly controlled by the SH2 region. Normally, the SH2 region regulates the activation loop by opening and closing it. But under the Philadelphia chromosome translocation, that regulation is lost.

The team discovered that when the Philadelphia mutation takes effect, the SH2 region changes the Abl activation loop to a fully open conformation. This enables the trans-autophosphorylation of the activation loop and requires prior phosphorylation of the SH2-kinase linker.

This discovery provides the first-ever picture of the molecular events surrounding the hyperactivity of Abl kinase, the researchers said.

They also found that by disrupting the SH2-kinase interaction, it’s possible to modulate the activity of Abl kinase, which could potentially stop the growth of leukemia.

Since the SH2 region is common to other kinases, the researchers think it’s likely the effect could extend to malignancies other than CML as well, particularly those characterized by abnormal kinase activity.

Finally, the team expects this approach could overcome the problem of drug resistance in CML, as it might offer an alternative way to inhibit Abl kinase, and mutations of rapidly growing cancer cells may be less likely to occur.

CML cells

Credit: UCSD School of Medicine

By analyzing structural changes that occur during Abl kinase activation, researchers have gained new insight into this process.

The team discovered a mechanism that links the allosteric regulation of the SH2 domain to two critical phosphorylation events.

As allosteric SH2-kinase domain interactions have proven essential for leukemogenesis caused by Bcr-Abl, the researchers believe this finding has implications for treating chronic myeloid leukemia (CML).

Oliver Hantschel, PhD, of the École polytechnique fédérale de Lausanne (EPFL) in Lausanne, Switzerland, and his colleagues described this work in Nature Communications.

The team made small, strategic mutations to Abl kinase that caused its 3D structure to change. Then, they tested each mutant version of the enzyme to see if its function would change.

The researchers built on previous studies showing that Abl kinase is indirectly controlled by the SH2 region. Normally, the SH2 region regulates the activation loop by opening and closing it. But under the Philadelphia chromosome translocation, that regulation is lost.

The team discovered that when the Philadelphia mutation takes effect, the SH2 region changes the Abl activation loop to a fully open conformation. This enables the trans-autophosphorylation of the activation loop and requires prior phosphorylation of the SH2-kinase linker.

This discovery provides the first-ever picture of the molecular events surrounding the hyperactivity of Abl kinase, the researchers said.

They also found that by disrupting the SH2-kinase interaction, it’s possible to modulate the activity of Abl kinase, which could potentially stop the growth of leukemia.

Since the SH2 region is common to other kinases, the researchers think it’s likely the effect could extend to malignancies other than CML as well, particularly those characterized by abnormal kinase activity.

Finally, the team expects this approach could overcome the problem of drug resistance in CML, as it might offer an alternative way to inhibit Abl kinase, and mutations of rapidly growing cancer cells may be less likely to occur.

Midfoot (Lisfranc) joint injuries are uncommon in the general population, with a reported incidence ranging from 1 per 50,000 to 1 per 60,000 per year.^1,2 The majority of these midfoot injuries result from high-velocity direct trauma involving severe disruption of the tarsometatarsal joint.^1-6 Most of the literature on Lisfranc injuries are based on cohorts that include trauma patients. On the other hand, low-velocity indirect injuries of the tarsometatarsal joint have also been associated with midfoot or Lisfranc sprains.⁷ These injuries are even less extensively studied in athletes, who may sustain them from torsion or the shoe–surface interface.⁸

Foot and ankle injuries are among the most common injuries in athletes and represent 16% to 22% of all sports injuries.⁹ Although midfoot sprains are not common in the general population, sporting activities appear to result in a higher rate of midfoot injury, especially in elite athletes. In fact, midfoot sprains comprise the second most common athlete injury to the foot, after metatarsophalangeal joint injuries.¹⁰ Football players are especially prone to midfoot sprains; incidence is 4% per year, with offensive linemen sustaining 29.2% of midfoot sprains.¹⁰ The most common mechanism of injury is an axial longitudinal force while the foot is plantarflexed and slightly rotated.^11,12

There is a paucity of literature detailing the impact of midfoot injuries on football players.^8,10,13 A study of 23 collegiate football players found that they may have initially underwent a long period of acute disability but had very minor long-term complaints resulting in residual functional disability.¹⁰ However, there are no case series detailing the impact of midfoot sprains on professional football players for whom delayed return to sport can potentially have a devastating impact on a career in terms of both acute- and long-term disability.

We conducted a study to further define the mechanism of injury, diagnosis, treatment, and outcomes among National Football League (NFL) players with midfoot sprains. In addition, we aimed to provide a qualitative analysis of diagnostic and treatment algorithms being used by NFL team physicians in their management of midfoot sprains in these high-level contact athletes.

Materials and Methods

We evaluated midfoot sprains in NFL players in 2 specific phases. In phase 1, we retrospectively reviewed prospectively collected data involving midfoot sprains in professional players from a single NFL team over a 15-year period. In phase 2, we collated diagnostic and treatment algorithms for midfoot sprains among all 32 NFL team physicians by means of a structured questionnaire. Institutional review board approval was obtained for this study at the investigators’ institution.

In phase 1, a NFL team injury database was reviewed for midfoot sprains that had been prospectively entered by a team-certified athletic trainer after consultation with the head orthopedic team physician. All injury and diagnostic modalities and treatments were then analyzed. These included player position, foot and ankle protective gear (none, tape, brace, or unknown), playing surface (grass, AstroTurf, FieldTurf, or unknown), field condition (normal, wet, hard, or unknown), onset of injury (acute, chronic, or unknown), place of injury (game or practice), time of injury in game or practice (first quarter, second quarter, third quarter, fourth quarter, or unknown), type of play (collision, tackled, tackling, blocked, blocking, running/cutting, kicking, or unknown), and mechanism of injury (direct, torsion, shearing, or unknown).

Once the diagnosis was confirmed by physical examination and radiographic findings, midfoot sprain treatment was initiated based on the following algorithm protocols. Nondisplaced sprains were treated with a period of immobilization in a cam walker with progression to weight-bearing as tolerated (grade 1). Once asymptomatic, rehabilitation was initiated, including range of motion, strengthening, and proprioception, and gradual return to play as tolerated. Injuries with subtle diastasis (2-5 mm) were typically treated with nonoperative management in the same manner as the nondisplaced sprain protocol (grade 2); however, signs of gross instability indicated the potential requirement for surgical management. Some of these injuries underwent stress-testing to determine if there was gross instability. If the injury had subtle diastasis with instability or frank (>5 mm) displacement (grade 3), then surgical management was performed with closed versus open reduction and internal fixation (ORIF). The postoperative course included no weight-bearing for 4 to 6 weeks followed by partial weight-bearing for an additional 4 to 6 weeks. After approximately 8 to 12 postoperative weeks, screw removal was performed followed by progression to full weight-bearing and a comprehensive rehabilitation program, including range of motion, strengthening, proprioception, and gradual return to play. Return to play was allowed when the athlete was asymptomatic and had normal range of motion and strength. Time lost from participation was then recorded based on the dates of injury and return to play.

To further elucidate long-term postinjury playing status, we then gathered information from the www.NFL.com historical and current player databases as previously described by Shah and colleagues.¹⁴ From this website, we documented the number of regular-season and postseason games as well as the number of seasons before and after the injury. To be included in the series, the athlete had to have been on the active roster for an NFL franchise at the time of injury. Successful return to play was defined as actual return to play in regular season or postseason NFL games after the midfoot sprain.

In phase 2, a structured electronic questionnaire was sent to all 32 NFL team physicians. The questionnaire was compiled to gather information relating to current diagnostic, treatment, and outcome algorithms in the management of midfoot sprains involving professional football players. Each questionnaire was sent by e-mail to all survey participants and included an embedded link to a secure online survey resource (REDCap Survey Software Version 1.3.9; Vanderbilt University, Nashville, Tennessee). Once the electronic questionnaire was completed by each NFL team physician, results were exported in spreadsheet format for descriptive data analysis.

The retrospective case series and NFL team physician survey data were then analyzed. A descriptive analysis was performed for all variables, including means and minimum–maximum range for quantitative variables as well as frequencies and percentages for qualitative variables. Depending on injury severity, an independent-sample t test with corresponding P values was also calculated for time lost from participation.

Results

The retrospective review of the prospectively collected NFL injury database revealed there were 15 midfoot sprains during the study period. A statistical and descriptive analysis was performed for all study parameters, including player, field, injury, and outcome-specific data. For player, field, and injury-specific data, the results are summarized in the Table.

All grade 1 midfoot sprains (7 nondisplaced) and grade 2 midfoot sprains (5 with subtle diastasis and no instability) were treated with nonoperative management. The 12 players were allowed to return to play without the need for subsequent surgery within the same season. In the evaluation of return to play, based on the severity of the midfoot sprain, there was a statistically significant (P = .047) difference in mean (SD) time lost from participation between the grade 1 sprain group, 3.1 (1.9) days, and the grade 2 sprain group, 36 (26.1) days. Overall, nonoperative treatment of either grade 1 or grade 2 midfoot sprains resulted in a mean of 11.7 days of time lost from participation. In 1 patient with a grade 2 midfoot sprain, the injury occurred toward the end of the season, and the patient was not able to return to play during the remaining 42 days of the season. However, this patient returned to play the next season and had no residual problems.

Three grade 3 injuries (midfoot sprains with frank displacement) required surgical management with ORIF. One patient returned to play the same season, in 73 days; however, the other 2 patients had injuries toward the end of the season (29 and 77 days remaining) and were not able to return to play the same season. However, both these patients returned to play the next season and had no persistent problems. In terms of complications within the same season, there were no recurrent injuries reported after successful return to play.

When evaluating long-term postinjury playing status, we found that 11 (92%) of the 12 NFL players who had nonoperative treatment successfully returned to play. The only player who did not return to an NFL regular season or postseason game was an active-roster NFL player who never actually played in an NFL game before or after his midfoot sprain injury. Our series of NFL players played on average 1.9 years (range, 0-7 years) before the midfoot injury and 5.5 years (range, 0-14 years) after the midfoot injury. In terms of NFL regular-season and postseason games played, our cohort of NFL players played on average 24.0 games (range, 0-80 games) before the midfoot injury and 77.7 games (range, 0-226 games) after the midfoot injury. In fact, 10 of the 12 NFL players (83%) who had nonoperative treatment played more games and seasons after their midfoot injury.

The surveys from phase 2 were completed by all 32 NFL team physicians. When evaluating the severity of midfoot sprains, 63% of the NFL team physicians perform stress-view radiographs. To ascertain NFL team physicians’ management decisions, we evaluated midfoot sprain results according to injury severity, including amount of diastasis.

When managing midfoot sprains with no diastasis, 94% of the team physicians use immobilization, including 27 with a cam walker and 2 with a cast; however, 2 physicians (6%) use only ankle taping or an Ace bandage. Initial weight-bearing status varies among the NFL team physicians, but most (78%) choose to protect the player, including 17 non-weight-bearing, 8 partial weight-bearing, and 7 weight-bearing as tolerated. Most physicians ideally progress players to full weight-bearing by 3 weeks (12% immediately, 12% by week 1, 41% by week 2, 16% by week 3, and 19% from 4-6 weeks).

In the management of midfoot sprains with subtle diastasis, there is variation in treatment modes among the NFL team physicians, with 53% using nonoperative management (34% cam walker, 19% cast) and 47% suggesting operative management. Regardless of treatment, most physicians (97%) maintain initial non-weight-bearing restrictions. In fact, only 1 physician first recommended partial weight-bearing, which corresponded to initial treatment in a cam walker.

In terms of midfoot sprains with frank diastasis, 94% of the NFL team physicians indicated surgical management is warranted, with only 2 physicians (6%) recommending initial nonoperative management with a cam walker. Regardless of treatment, all the physicians (100%) implemented initial non-weight-bearing restrictions. Once surgical treatment was recommended, the preferred fixation method was ORIF using screws (94%) as opposed to closed reduction and internal fixation with percutaneous Kirschner wires (6%). Most of the physicians (59%) do not allow return to play until midfoot hardware is removed; however, 38% allow full participation with contact, and 3% allow partial participation with no contact. Removal of midfoot fixation is an important factor for most of the physicians before considering return to play, and 69% recommend hardware removal after 11 weeks. However, the specific timeline for hardware removal varied among these physicians, with 28% opting for removal at 11 to 12 weeks, 16% at 13 to 14 weeks, 12.5% at 7 to 8 weeks, 12.5% at 15 to 16 weeks, 12.5% at more than 16 weeks, 12.5% never, and 6% at 9 to 10 weeks.

The midfoot sprain treatment protocol (nonoperative vs operative management) based on injury severity was an important factor in considering return-to-play guidelines. When evaluating time lost from participation because of midfoot sprains, most of the NFL team physicians anticipated a period of 5 to 8 weeks when considering nonoperative management (56%) and more than 17 weeks after operative management (53%). In evaluating nonoperative management protocols, return-to-play guidelines were relatively expeditious, with 56% of the physicians estimating from 5 to 8 weeks, 22% from 1 to 4 weeks, 13% from 9 to 12 weeks, 6% from 13 to 16 weeks, and 3% longer than 20 weeks. In comparison to nonoperative management, return-to-play guidelines for operative management were prolonged, with 53% of the physicians estimating more than 20 weeks, 25% from 17 to 20 weeks, 13% from 13 to 16 weeks, and 9% from 9 to 12 weeks.

Discussion

Lisfranc and midfoot injuries remain a controversial topic in sports medicine. Several authors have argued that anatomical reduction of the tarsometatarsal joint in the setting of a Lisfranc injury yields optimal outcomes.^15,16 Some studies have also suggested that purely ligamentous Lisfranc injuries may be more of a problem than bony injuries, which may have the benefit of osseous healing.^15,17 Anatomical reduction can minimize the potential for arch collapse by maintaining the normal tarsometatarsal relationship. However, there are no long-term data to determine how midfoot arthrosis is affected by ORIF, which typically involves hardware traversing joints. Some have even argued that primary tarsometatarsal arthrodesis should be the treatment of choice, as the midfoot has limited native motion, and successful arthrodesis eliminates the potential for midfoot arthrosis.^17,18 However, we are unaware of any studies that have routinely performed arthrodesis in an athletic population.

The majority of studies on midfoot injuries have evaluated individuals involved in traumatic accidents, most commonly motor vehicle collisions. The present study suggests there may be a subset of injuries in athletes that have yet to be adequately studied. Anecdotally, the NFL team physicians surveyed in our study suggested that midfoot sprains with no or subtle displacement may be treated with nonoperative measures while yielding satisfactory clinical outcomes. These results have been quantified in return-to-play status. Our subset of athletes from an NFL team corroborates these findings, even though the series was small (15 patients). Our survey results also suggest there is considerable variation in the “optimal” management plan among the physicians treating these elite athletes. Most would agree that the nondisplaced injuries can be managed conservatively and that the severely displaced injuries should be managed operatively, but the natural history of those injuries with subtle diastasis remains unclear. When operative intervention is implemented, hardware removal versus retention must also be considered when allowing for return to play. Although one would assume that motion-related hardware failure would be possible at the tarsometatarsal joints, this concept has yet to be clearly defined in the literature.

The present study also demonstrates that most athletes with these midfoot injuries can return to play at the elite NFL level, as evidenced by their short- and long-term return to play. However, it was not possible to differentiate the specific return-to-play level related to preinjury performance level. Furthermore, this relatively short-term NFL career follow-up study was not able to elucidate the long-term consequences of these injuries. In fact, arch collapse and acquired flatfoot deformity could eventually result from this injury, and long-term outcomes would be of particular interest in patients who have subtle diastasis and who are treated nonoperatively.

Although previous studies have supported operative management for Lisfranc injuries involving subtle diastasis, more than half of the NFL team physicians surveyed in this study use nonoperative treatment for these injuries.¹⁹ Future studies should evaluate stress-imaging to define the effect of stability or latent diastasis on long-term outcomes. Nonetheless, the present study demonstrates that a large cohort of NFL team physicians supports nonoperative management for these Lisfranc injuries with subtle diastasis, even in elite athletes. Additional prospective studies are needed to provide a more rigorous injury evaluation and closer follow-up, including subjective and objective outcomes, to further define the indications for management options for midfoot sprains in this population of contact athletes.

Midfoot (Lisfranc) joint injuries are uncommon in the general population, with a reported incidence ranging from 1 per 50,000 to 1 per 60,000 per year.^1,2 The majority of these midfoot injuries result from high-velocity direct trauma involving severe disruption of the tarsometatarsal joint.^1-6 Most of the literature on Lisfranc injuries are based on cohorts that include trauma patients. On the other hand, low-velocity indirect injuries of the tarsometatarsal joint have also been associated with midfoot or Lisfranc sprains.⁷ These injuries are even less extensively studied in athletes, who may sustain them from torsion or the shoe–surface interface.⁸

Foot and ankle injuries are among the most common injuries in athletes and represent 16% to 22% of all sports injuries.⁹ Although midfoot sprains are not common in the general population, sporting activities appear to result in a higher rate of midfoot injury, especially in elite athletes. In fact, midfoot sprains comprise the second most common athlete injury to the foot, after metatarsophalangeal joint injuries.¹⁰ Football players are especially prone to midfoot sprains; incidence is 4% per year, with offensive linemen sustaining 29.2% of midfoot sprains.¹⁰ The most common mechanism of injury is an axial longitudinal force while the foot is plantarflexed and slightly rotated.^11,12

There is a paucity of literature detailing the impact of midfoot injuries on football players.^8,10,13 A study of 23 collegiate football players found that they may have initially underwent a long period of acute disability but had very minor long-term complaints resulting in residual functional disability.¹⁰ However, there are no case series detailing the impact of midfoot sprains on professional football players for whom delayed return to sport can potentially have a devastating impact on a career in terms of both acute- and long-term disability.

We conducted a study to further define the mechanism of injury, diagnosis, treatment, and outcomes among National Football League (NFL) players with midfoot sprains. In addition, we aimed to provide a qualitative analysis of diagnostic and treatment algorithms being used by NFL team physicians in their management of midfoot sprains in these high-level contact athletes.

Materials and Methods

We evaluated midfoot sprains in NFL players in 2 specific phases. In phase 1, we retrospectively reviewed prospectively collected data involving midfoot sprains in professional players from a single NFL team over a 15-year period. In phase 2, we collated diagnostic and treatment algorithms for midfoot sprains among all 32 NFL team physicians by means of a structured questionnaire. Institutional review board approval was obtained for this study at the investigators’ institution.

In phase 1, a NFL team injury database was reviewed for midfoot sprains that had been prospectively entered by a team-certified athletic trainer after consultation with the head orthopedic team physician. All injury and diagnostic modalities and treatments were then analyzed. These included player position, foot and ankle protective gear (none, tape, brace, or unknown), playing surface (grass, AstroTurf, FieldTurf, or unknown), field condition (normal, wet, hard, or unknown), onset of injury (acute, chronic, or unknown), place of injury (game or practice), time of injury in game or practice (first quarter, second quarter, third quarter, fourth quarter, or unknown), type of play (collision, tackled, tackling, blocked, blocking, running/cutting, kicking, or unknown), and mechanism of injury (direct, torsion, shearing, or unknown).

Once the diagnosis was confirmed by physical examination and radiographic findings, midfoot sprain treatment was initiated based on the following algorithm protocols. Nondisplaced sprains were treated with a period of immobilization in a cam walker with progression to weight-bearing as tolerated (grade 1). Once asymptomatic, rehabilitation was initiated, including range of motion, strengthening, and proprioception, and gradual return to play as tolerated. Injuries with subtle diastasis (2-5 mm) were typically treated with nonoperative management in the same manner as the nondisplaced sprain protocol (grade 2); however, signs of gross instability indicated the potential requirement for surgical management. Some of these injuries underwent stress-testing to determine if there was gross instability. If the injury had subtle diastasis with instability or frank (>5 mm) displacement (grade 3), then surgical management was performed with closed versus open reduction and internal fixation (ORIF). The postoperative course included no weight-bearing for 4 to 6 weeks followed by partial weight-bearing for an additional 4 to 6 weeks. After approximately 8 to 12 postoperative weeks, screw removal was performed followed by progression to full weight-bearing and a comprehensive rehabilitation program, including range of motion, strengthening, proprioception, and gradual return to play. Return to play was allowed when the athlete was asymptomatic and had normal range of motion and strength. Time lost from participation was then recorded based on the dates of injury and return to play.

To further elucidate long-term postinjury playing status, we then gathered information from the www.NFL.com historical and current player databases as previously described by Shah and colleagues.¹⁴ From this website, we documented the number of regular-season and postseason games as well as the number of seasons before and after the injury. To be included in the series, the athlete had to have been on the active roster for an NFL franchise at the time of injury. Successful return to play was defined as actual return to play in regular season or postseason NFL games after the midfoot sprain.

In phase 2, a structured electronic questionnaire was sent to all 32 NFL team physicians. The questionnaire was compiled to gather information relating to current diagnostic, treatment, and outcome algorithms in the management of midfoot sprains involving professional football players. Each questionnaire was sent by e-mail to all survey participants and included an embedded link to a secure online survey resource (REDCap Survey Software Version 1.3.9; Vanderbilt University, Nashville, Tennessee). Once the electronic questionnaire was completed by each NFL team physician, results were exported in spreadsheet format for descriptive data analysis.

The retrospective case series and NFL team physician survey data were then analyzed. A descriptive analysis was performed for all variables, including means and minimum–maximum range for quantitative variables as well as frequencies and percentages for qualitative variables. Depending on injury severity, an independent-sample t test with corresponding P values was also calculated for time lost from participation.

Results

The retrospective review of the prospectively collected NFL injury database revealed there were 15 midfoot sprains during the study period. A statistical and descriptive analysis was performed for all study parameters, including player, field, injury, and outcome-specific data. For player, field, and injury-specific data, the results are summarized in the Table.

All grade 1 midfoot sprains (7 nondisplaced) and grade 2 midfoot sprains (5 with subtle diastasis and no instability) were treated with nonoperative management. The 12 players were allowed to return to play without the need for subsequent surgery within the same season. In the evaluation of return to play, based on the severity of the midfoot sprain, there was a statistically significant (P = .047) difference in mean (SD) time lost from participation between the grade 1 sprain group, 3.1 (1.9) days, and the grade 2 sprain group, 36 (26.1) days. Overall, nonoperative treatment of either grade 1 or grade 2 midfoot sprains resulted in a mean of 11.7 days of time lost from participation. In 1 patient with a grade 2 midfoot sprain, the injury occurred toward the end of the season, and the patient was not able to return to play during the remaining 42 days of the season. However, this patient returned to play the next season and had no residual problems.

Three grade 3 injuries (midfoot sprains with frank displacement) required surgical management with ORIF. One patient returned to play the same season, in 73 days; however, the other 2 patients had injuries toward the end of the season (29 and 77 days remaining) and were not able to return to play the same season. However, both these patients returned to play the next season and had no persistent problems. In terms of complications within the same season, there were no recurrent injuries reported after successful return to play.

When evaluating long-term postinjury playing status, we found that 11 (92%) of the 12 NFL players who had nonoperative treatment successfully returned to play. The only player who did not return to an NFL regular season or postseason game was an active-roster NFL player who never actually played in an NFL game before or after his midfoot sprain injury. Our series of NFL players played on average 1.9 years (range, 0-7 years) before the midfoot injury and 5.5 years (range, 0-14 years) after the midfoot injury. In terms of NFL regular-season and postseason games played, our cohort of NFL players played on average 24.0 games (range, 0-80 games) before the midfoot injury and 77.7 games (range, 0-226 games) after the midfoot injury. In fact, 10 of the 12 NFL players (83%) who had nonoperative treatment played more games and seasons after their midfoot injury.

The surveys from phase 2 were completed by all 32 NFL team physicians. When evaluating the severity of midfoot sprains, 63% of the NFL team physicians perform stress-view radiographs. To ascertain NFL team physicians’ management decisions, we evaluated midfoot sprain results according to injury severity, including amount of diastasis.

When managing midfoot sprains with no diastasis, 94% of the team physicians use immobilization, including 27 with a cam walker and 2 with a cast; however, 2 physicians (6%) use only ankle taping or an Ace bandage. Initial weight-bearing status varies among the NFL team physicians, but most (78%) choose to protect the player, including 17 non-weight-bearing, 8 partial weight-bearing, and 7 weight-bearing as tolerated. Most physicians ideally progress players to full weight-bearing by 3 weeks (12% immediately, 12% by week 1, 41% by week 2, 16% by week 3, and 19% from 4-6 weeks).

In the management of midfoot sprains with subtle diastasis, there is variation in treatment modes among the NFL team physicians, with 53% using nonoperative management (34% cam walker, 19% cast) and 47% suggesting operative management. Regardless of treatment, most physicians (97%) maintain initial non-weight-bearing restrictions. In fact, only 1 physician first recommended partial weight-bearing, which corresponded to initial treatment in a cam walker.

In terms of midfoot sprains with frank diastasis, 94% of the NFL team physicians indicated surgical management is warranted, with only 2 physicians (6%) recommending initial nonoperative management with a cam walker. Regardless of treatment, all the physicians (100%) implemented initial non-weight-bearing restrictions. Once surgical treatment was recommended, the preferred fixation method was ORIF using screws (94%) as opposed to closed reduction and internal fixation with percutaneous Kirschner wires (6%). Most of the physicians (59%) do not allow return to play until midfoot hardware is removed; however, 38% allow full participation with contact, and 3% allow partial participation with no contact. Removal of midfoot fixation is an important factor for most of the physicians before considering return to play, and 69% recommend hardware removal after 11 weeks. However, the specific timeline for hardware removal varied among these physicians, with 28% opting for removal at 11 to 12 weeks, 16% at 13 to 14 weeks, 12.5% at 7 to 8 weeks, 12.5% at 15 to 16 weeks, 12.5% at more than 16 weeks, 12.5% never, and 6% at 9 to 10 weeks.

The midfoot sprain treatment protocol (nonoperative vs operative management) based on injury severity was an important factor in considering return-to-play guidelines. When evaluating time lost from participation because of midfoot sprains, most of the NFL team physicians anticipated a period of 5 to 8 weeks when considering nonoperative management (56%) and more than 17 weeks after operative management (53%). In evaluating nonoperative management protocols, return-to-play guidelines were relatively expeditious, with 56% of the physicians estimating from 5 to 8 weeks, 22% from 1 to 4 weeks, 13% from 9 to 12 weeks, 6% from 13 to 16 weeks, and 3% longer than 20 weeks. In comparison to nonoperative management, return-to-play guidelines for operative management were prolonged, with 53% of the physicians estimating more than 20 weeks, 25% from 17 to 20 weeks, 13% from 13 to 16 weeks, and 9% from 9 to 12 weeks.

Discussion

Lisfranc and midfoot injuries remain a controversial topic in sports medicine. Several authors have argued that anatomical reduction of the tarsometatarsal joint in the setting of a Lisfranc injury yields optimal outcomes.^15,16 Some studies have also suggested that purely ligamentous Lisfranc injuries may be more of a problem than bony injuries, which may have the benefit of osseous healing.^15,17 Anatomical reduction can minimize the potential for arch collapse by maintaining the normal tarsometatarsal relationship. However, there are no long-term data to determine how midfoot arthrosis is affected by ORIF, which typically involves hardware traversing joints. Some have even argued that primary tarsometatarsal arthrodesis should be the treatment of choice, as the midfoot has limited native motion, and successful arthrodesis eliminates the potential for midfoot arthrosis.^17,18 However, we are unaware of any studies that have routinely performed arthrodesis in an athletic population.

The majority of studies on midfoot injuries have evaluated individuals involved in traumatic accidents, most commonly motor vehicle collisions. The present study suggests there may be a subset of injuries in athletes that have yet to be adequately studied. Anecdotally, the NFL team physicians surveyed in our study suggested that midfoot sprains with no or subtle displacement may be treated with nonoperative measures while yielding satisfactory clinical outcomes. These results have been quantified in return-to-play status. Our subset of athletes from an NFL team corroborates these findings, even though the series was small (15 patients). Our survey results also suggest there is considerable variation in the “optimal” management plan among the physicians treating these elite athletes. Most would agree that the nondisplaced injuries can be managed conservatively and that the severely displaced injuries should be managed operatively, but the natural history of those injuries with subtle diastasis remains unclear. When operative intervention is implemented, hardware removal versus retention must also be considered when allowing for return to play. Although one would assume that motion-related hardware failure would be possible at the tarsometatarsal joints, this concept has yet to be clearly defined in the literature.

The present study also demonstrates that most athletes with these midfoot injuries can return to play at the elite NFL level, as evidenced by their short- and long-term return to play. However, it was not possible to differentiate the specific return-to-play level related to preinjury performance level. Furthermore, this relatively short-term NFL career follow-up study was not able to elucidate the long-term consequences of these injuries. In fact, arch collapse and acquired flatfoot deformity could eventually result from this injury, and long-term outcomes would be of particular interest in patients who have subtle diastasis and who are treated nonoperatively.

Although previous studies have supported operative management for Lisfranc injuries involving subtle diastasis, more than half of the NFL team physicians surveyed in this study use nonoperative treatment for these injuries.¹⁹ Future studies should evaluate stress-imaging to define the effect of stability or latent diastasis on long-term outcomes. Nonetheless, the present study demonstrates that a large cohort of NFL team physicians supports nonoperative management for these Lisfranc injuries with subtle diastasis, even in elite athletes. Additional prospective studies are needed to provide a more rigorous injury evaluation and closer follow-up, including subjective and objective outcomes, to further define the indications for management options for midfoot sprains in this population of contact athletes.

Midfoot (Lisfranc) joint injuries are uncommon in the general population, with a reported incidence ranging from 1 per 50,000 to 1 per 60,000 per year.^1,2 The majority of these midfoot injuries result from high-velocity direct trauma involving severe disruption of the tarsometatarsal joint.^1-6 Most of the literature on Lisfranc injuries are based on cohorts that include trauma patients. On the other hand, low-velocity indirect injuries of the tarsometatarsal joint have also been associated with midfoot or Lisfranc sprains.⁷ These injuries are even less extensively studied in athletes, who may sustain them from torsion or the shoe–surface interface.⁸

Foot and ankle injuries are among the most common injuries in athletes and represent 16% to 22% of all sports injuries.⁹ Although midfoot sprains are not common in the general population, sporting activities appear to result in a higher rate of midfoot injury, especially in elite athletes. In fact, midfoot sprains comprise the second most common athlete injury to the foot, after metatarsophalangeal joint injuries.¹⁰ Football players are especially prone to midfoot sprains; incidence is 4% per year, with offensive linemen sustaining 29.2% of midfoot sprains.¹⁰ The most common mechanism of injury is an axial longitudinal force while the foot is plantarflexed and slightly rotated.^11,12

There is a paucity of literature detailing the impact of midfoot injuries on football players.^8,10,13 A study of 23 collegiate football players found that they may have initially underwent a long period of acute disability but had very minor long-term complaints resulting in residual functional disability.¹⁰ However, there are no case series detailing the impact of midfoot sprains on professional football players for whom delayed return to sport can potentially have a devastating impact on a career in terms of both acute- and long-term disability.

We conducted a study to further define the mechanism of injury, diagnosis, treatment, and outcomes among National Football League (NFL) players with midfoot sprains. In addition, we aimed to provide a qualitative analysis of diagnostic and treatment algorithms being used by NFL team physicians in their management of midfoot sprains in these high-level contact athletes.

Materials and Methods

We evaluated midfoot sprains in NFL players in 2 specific phases. In phase 1, we retrospectively reviewed prospectively collected data involving midfoot sprains in professional players from a single NFL team over a 15-year period. In phase 2, we collated diagnostic and treatment algorithms for midfoot sprains among all 32 NFL team physicians by means of a structured questionnaire. Institutional review board approval was obtained for this study at the investigators’ institution.

In phase 1, a NFL team injury database was reviewed for midfoot sprains that had been prospectively entered by a team-certified athletic trainer after consultation with the head orthopedic team physician. All injury and diagnostic modalities and treatments were then analyzed. These included player position, foot and ankle protective gear (none, tape, brace, or unknown), playing surface (grass, AstroTurf, FieldTurf, or unknown), field condition (normal, wet, hard, or unknown), onset of injury (acute, chronic, or unknown), place of injury (game or practice), time of injury in game or practice (first quarter, second quarter, third quarter, fourth quarter, or unknown), type of play (collision, tackled, tackling, blocked, blocking, running/cutting, kicking, or unknown), and mechanism of injury (direct, torsion, shearing, or unknown).

Once the diagnosis was confirmed by physical examination and radiographic findings, midfoot sprain treatment was initiated based on the following algorithm protocols. Nondisplaced sprains were treated with a period of immobilization in a cam walker with progression to weight-bearing as tolerated (grade 1). Once asymptomatic, rehabilitation was initiated, including range of motion, strengthening, and proprioception, and gradual return to play as tolerated. Injuries with subtle diastasis (2-5 mm) were typically treated with nonoperative management in the same manner as the nondisplaced sprain protocol (grade 2); however, signs of gross instability indicated the potential requirement for surgical management. Some of these injuries underwent stress-testing to determine if there was gross instability. If the injury had subtle diastasis with instability or frank (>5 mm) displacement (grade 3), then surgical management was performed with closed versus open reduction and internal fixation (ORIF). The postoperative course included no weight-bearing for 4 to 6 weeks followed by partial weight-bearing for an additional 4 to 6 weeks. After approximately 8 to 12 postoperative weeks, screw removal was performed followed by progression to full weight-bearing and a comprehensive rehabilitation program, including range of motion, strengthening, proprioception, and gradual return to play. Return to play was allowed when the athlete was asymptomatic and had normal range of motion and strength. Time lost from participation was then recorded based on the dates of injury and return to play.

To further elucidate long-term postinjury playing status, we then gathered information from the www.NFL.com historical and current player databases as previously described by Shah and colleagues.¹⁴ From this website, we documented the number of regular-season and postseason games as well as the number of seasons before and after the injury. To be included in the series, the athlete had to have been on the active roster for an NFL franchise at the time of injury. Successful return to play was defined as actual return to play in regular season or postseason NFL games after the midfoot sprain.

In phase 2, a structured electronic questionnaire was sent to all 32 NFL team physicians. The questionnaire was compiled to gather information relating to current diagnostic, treatment, and outcome algorithms in the management of midfoot sprains involving professional football players. Each questionnaire was sent by e-mail to all survey participants and included an embedded link to a secure online survey resource (REDCap Survey Software Version 1.3.9; Vanderbilt University, Nashville, Tennessee). Once the electronic questionnaire was completed by each NFL team physician, results were exported in spreadsheet format for descriptive data analysis.

The retrospective case series and NFL team physician survey data were then analyzed. A descriptive analysis was performed for all variables, including means and minimum–maximum range for quantitative variables as well as frequencies and percentages for qualitative variables. Depending on injury severity, an independent-sample t test with corresponding P values was also calculated for time lost from participation.

Results

The retrospective review of the prospectively collected NFL injury database revealed there were 15 midfoot sprains during the study period. A statistical and descriptive analysis was performed for all study parameters, including player, field, injury, and outcome-specific data. For player, field, and injury-specific data, the results are summarized in the Table.

All grade 1 midfoot sprains (7 nondisplaced) and grade 2 midfoot sprains (5 with subtle diastasis and no instability) were treated with nonoperative management. The 12 players were allowed to return to play without the need for subsequent surgery within the same season. In the evaluation of return to play, based on the severity of the midfoot sprain, there was a statistically significant (P = .047) difference in mean (SD) time lost from participation between the grade 1 sprain group, 3.1 (1.9) days, and the grade 2 sprain group, 36 (26.1) days. Overall, nonoperative treatment of either grade 1 or grade 2 midfoot sprains resulted in a mean of 11.7 days of time lost from participation. In 1 patient with a grade 2 midfoot sprain, the injury occurred toward the end of the season, and the patient was not able to return to play during the remaining 42 days of the season. However, this patient returned to play the next season and had no residual problems.

Three grade 3 injuries (midfoot sprains with frank displacement) required surgical management with ORIF. One patient returned to play the same season, in 73 days; however, the other 2 patients had injuries toward the end of the season (29 and 77 days remaining) and were not able to return to play the same season. However, both these patients returned to play the next season and had no persistent problems. In terms of complications within the same season, there were no recurrent injuries reported after successful return to play.

When evaluating long-term postinjury playing status, we found that 11 (92%) of the 12 NFL players who had nonoperative treatment successfully returned to play. The only player who did not return to an NFL regular season or postseason game was an active-roster NFL player who never actually played in an NFL game before or after his midfoot sprain injury. Our series of NFL players played on average 1.9 years (range, 0-7 years) before the midfoot injury and 5.5 years (range, 0-14 years) after the midfoot injury. In terms of NFL regular-season and postseason games played, our cohort of NFL players played on average 24.0 games (range, 0-80 games) before the midfoot injury and 77.7 games (range, 0-226 games) after the midfoot injury. In fact, 10 of the 12 NFL players (83%) who had nonoperative treatment played more games and seasons after their midfoot injury.

The surveys from phase 2 were completed by all 32 NFL team physicians. When evaluating the severity of midfoot sprains, 63% of the NFL team physicians perform stress-view radiographs. To ascertain NFL team physicians’ management decisions, we evaluated midfoot sprain results according to injury severity, including amount of diastasis.

When managing midfoot sprains with no diastasis, 94% of the team physicians use immobilization, including 27 with a cam walker and 2 with a cast; however, 2 physicians (6%) use only ankle taping or an Ace bandage. Initial weight-bearing status varies among the NFL team physicians, but most (78%) choose to protect the player, including 17 non-weight-bearing, 8 partial weight-bearing, and 7 weight-bearing as tolerated. Most physicians ideally progress players to full weight-bearing by 3 weeks (12% immediately, 12% by week 1, 41% by week 2, 16% by week 3, and 19% from 4-6 weeks).

In the management of midfoot sprains with subtle diastasis, there is variation in treatment modes among the NFL team physicians, with 53% using nonoperative management (34% cam walker, 19% cast) and 47% suggesting operative management. Regardless of treatment, most physicians (97%) maintain initial non-weight-bearing restrictions. In fact, only 1 physician first recommended partial weight-bearing, which corresponded to initial treatment in a cam walker.

In terms of midfoot sprains with frank diastasis, 94% of the NFL team physicians indicated surgical management is warranted, with only 2 physicians (6%) recommending initial nonoperative management with a cam walker. Regardless of treatment, all the physicians (100%) implemented initial non-weight-bearing restrictions. Once surgical treatment was recommended, the preferred fixation method was ORIF using screws (94%) as opposed to closed reduction and internal fixation with percutaneous Kirschner wires (6%). Most of the physicians (59%) do not allow return to play until midfoot hardware is removed; however, 38% allow full participation with contact, and 3% allow partial participation with no contact. Removal of midfoot fixation is an important factor for most of the physicians before considering return to play, and 69% recommend hardware removal after 11 weeks. However, the specific timeline for hardware removal varied among these physicians, with 28% opting for removal at 11 to 12 weeks, 16% at 13 to 14 weeks, 12.5% at 7 to 8 weeks, 12.5% at 15 to 16 weeks, 12.5% at more than 16 weeks, 12.5% never, and 6% at 9 to 10 weeks.

The midfoot sprain treatment protocol (nonoperative vs operative management) based on injury severity was an important factor in considering return-to-play guidelines. When evaluating time lost from participation because of midfoot sprains, most of the NFL team physicians anticipated a period of 5 to 8 weeks when considering nonoperative management (56%) and more than 17 weeks after operative management (53%). In evaluating nonoperative management protocols, return-to-play guidelines were relatively expeditious, with 56% of the physicians estimating from 5 to 8 weeks, 22% from 1 to 4 weeks, 13% from 9 to 12 weeks, 6% from 13 to 16 weeks, and 3% longer than 20 weeks. In comparison to nonoperative management, return-to-play guidelines for operative management were prolonged, with 53% of the physicians estimating more than 20 weeks, 25% from 17 to 20 weeks, 13% from 13 to 16 weeks, and 9% from 9 to 12 weeks.

Discussion

Lisfranc and midfoot injuries remain a controversial topic in sports medicine. Several authors have argued that anatomical reduction of the tarsometatarsal joint in the setting of a Lisfranc injury yields optimal outcomes.^15,16 Some studies have also suggested that purely ligamentous Lisfranc injuries may be more of a problem than bony injuries, which may have the benefit of osseous healing.^15,17 Anatomical reduction can minimize the potential for arch collapse by maintaining the normal tarsometatarsal relationship. However, there are no long-term data to determine how midfoot arthrosis is affected by ORIF, which typically involves hardware traversing joints. Some have even argued that primary tarsometatarsal arthrodesis should be the treatment of choice, as the midfoot has limited native motion, and successful arthrodesis eliminates the potential for midfoot arthrosis.^17,18 However, we are unaware of any studies that have routinely performed arthrodesis in an athletic population.

The majority of studies on midfoot injuries have evaluated individuals involved in traumatic accidents, most commonly motor vehicle collisions. The present study suggests there may be a subset of injuries in athletes that have yet to be adequately studied. Anecdotally, the NFL team physicians surveyed in our study suggested that midfoot sprains with no or subtle displacement may be treated with nonoperative measures while yielding satisfactory clinical outcomes. These results have been quantified in return-to-play status. Our subset of athletes from an NFL team corroborates these findings, even though the series was small (15 patients). Our survey results also suggest there is considerable variation in the “optimal” management plan among the physicians treating these elite athletes. Most would agree that the nondisplaced injuries can be managed conservatively and that the severely displaced injuries should be managed operatively, but the natural history of those injuries with subtle diastasis remains unclear. When operative intervention is implemented, hardware removal versus retention must also be considered when allowing for return to play. Although one would assume that motion-related hardware failure would be possible at the tarsometatarsal joints, this concept has yet to be clearly defined in the literature.

The present study also demonstrates that most athletes with these midfoot injuries can return to play at the elite NFL level, as evidenced by their short- and long-term return to play. However, it was not possible to differentiate the specific return-to-play level related to preinjury performance level. Furthermore, this relatively short-term NFL career follow-up study was not able to elucidate the long-term consequences of these injuries. In fact, arch collapse and acquired flatfoot deformity could eventually result from this injury, and long-term outcomes would be of particular interest in patients who have subtle diastasis and who are treated nonoperatively.

Although previous studies have supported operative management for Lisfranc injuries involving subtle diastasis, more than half of the NFL team physicians surveyed in this study use nonoperative treatment for these injuries.¹⁹ Future studies should evaluate stress-imaging to define the effect of stability or latent diastasis on long-term outcomes. Nonetheless, the present study demonstrates that a large cohort of NFL team physicians supports nonoperative management for these Lisfranc injuries with subtle diastasis, even in elite athletes. Additional prospective studies are needed to provide a more rigorous injury evaluation and closer follow-up, including subjective and objective outcomes, to further define the indications for management options for midfoot sprains in this population of contact athletes.

U.S. military veterans living in rural areas who engage in evidence-based psychotherapy and telemedicine-based collaborative care can significantly increase their chances of improving outcomes related to posttraumatic stress disorder, according to a new study.

“Although psychotherapy and pharmacotherapy treatments for PTSD have proven to be efficacious in randomized clinical trials and have been disseminated widely by the [Veterans Health Administration], stigma and geographic barriers often prevent rural veterans from engaging in these evidence-based treatments,” says the study, published in JAMA (2014 Nov. 19 [doi.101001/jamapsychiatry.2014.1575]) and led by John C. Fortney, Ph.D., of the University of Washington’s department of psychiatry and behavioral sciences in Seattle, and his associates.

In a pragmatic, randomized effectiveness trial, Dr. Fortney and his associates recruited outpatients from 11 Department of Veterans Affairs (VA) community-based outpatient clinics (CBOCs) in predominantly rural areas of the United States over the course of 22 months. A total of 265 patients completed baseline interviews and randomization after meeting eligibility criteria, which consisted of meeting diagnostic standards for PTSD; having no medical history of schizophrenia, bipolar disorder, substance dependence, or hearing impairment; having a telephone; not having a life-threatening illness; and lacking capacity to consent.

© Dron - Fotolia.com

The 265 subjects were randomized into one of two groups: those receiving usual care (UC), or those receiving the Telemedicine Outreach for PTSD (TOP) treatment developed by the investigators. Patients were mostly unemployed, middle-aged men with severe PTSD symptoms and “other mental health coexisting illnesses,” according to a press release.

Subjects in the UC group received certain health care services, such as psychotropic medications for PTSD prescribed by psychiatrists, evidence-based psychotherapy for PTSD delivered by psychologists or social workers, supportive PTSD-focused therapy delivered by psychologists or social workers (individual and group), and supportive therapy delivered by social workers (individual and group), among others. Subjects in the TOP group, however, received the attention of telephone nurse care managers, including PTSD symptom monitoring and medication regimen adherence monitoring and promotion. In addition, those in the TOP group received access to a telephone pharmacist and telepsychologist.

Subjects were enrolled in a series of 12 cognitive processing therapy sessions for the duration of the study, from Nov. 23, 2009, through Sept. 28, 2011, and attendance was taken at each session. After the sessions concluded, subjects were then followed up on for 12 months.

During that follow-up period after treatments ended, patients who received TOP had significantly larger decreases in Posttraumatic Diagnostic Scale (PDS) scores (from 35.0 to 29.1), compared with those from the UC group (from 33.5 to 32.1) at 6 months (beta = −3.81; P = .002) and 12 months (beta = −2.49; P = .04). At 12 months, TOP subjects also had significantly larger decreases in PDS scores (from 35.0 to 30.1), compared with those who received UC (from 33.5 to 29.1) .

Subjects who attended at least eight cognitive processing therapy sessions were more likely to improve their PDS scores (beta = −3.86 [95% confidence interval, −7.19 to −0.54]; P = .02). However, the authors noted that there were “no significant group differences in the number of PTSD medications prescribed and adherence to medication regimens” was not significant.

“This trial introduces a promising model for managing PTSD in a treatment-resistant population,” Dr. Fortney and his associates wrote. “Findings suggest that telemedicine-based collaborative care can successfully engage this population in evidence-based psychotherapy for PTSD, thereby improving clinical outcomes.”

Among the study limitations cited by the investigators is that the PDS was administered to assess PTSD, rather than the Clinician-Administered PTSD Scale, which is the reference standard.

The authors reported no relevant financial conflicts of interest.

[email protected]

U.S. military veterans living in rural areas who engage in evidence-based psychotherapy and telemedicine-based collaborative care can significantly increase their chances of improving outcomes related to posttraumatic stress disorder, according to a new study.

“Although psychotherapy and pharmacotherapy treatments for PTSD have proven to be efficacious in randomized clinical trials and have been disseminated widely by the [Veterans Health Administration], stigma and geographic barriers often prevent rural veterans from engaging in these evidence-based treatments,” says the study, published in JAMA (2014 Nov. 19 [doi.101001/jamapsychiatry.2014.1575]) and led by John C. Fortney, Ph.D., of the University of Washington’s department of psychiatry and behavioral sciences in Seattle, and his associates.

In a pragmatic, randomized effectiveness trial, Dr. Fortney and his associates recruited outpatients from 11 Department of Veterans Affairs (VA) community-based outpatient clinics (CBOCs) in predominantly rural areas of the United States over the course of 22 months. A total of 265 patients completed baseline interviews and randomization after meeting eligibility criteria, which consisted of meeting diagnostic standards for PTSD; having no medical history of schizophrenia, bipolar disorder, substance dependence, or hearing impairment; having a telephone; not having a life-threatening illness; and lacking capacity to consent.

© Dron - Fotolia.com

The 265 subjects were randomized into one of two groups: those receiving usual care (UC), or those receiving the Telemedicine Outreach for PTSD (TOP) treatment developed by the investigators. Patients were mostly unemployed, middle-aged men with severe PTSD symptoms and “other mental health coexisting illnesses,” according to a press release.

Subjects in the UC group received certain health care services, such as psychotropic medications for PTSD prescribed by psychiatrists, evidence-based psychotherapy for PTSD delivered by psychologists or social workers, supportive PTSD-focused therapy delivered by psychologists or social workers (individual and group), and supportive therapy delivered by social workers (individual and group), among others. Subjects in the TOP group, however, received the attention of telephone nurse care managers, including PTSD symptom monitoring and medication regimen adherence monitoring and promotion. In addition, those in the TOP group received access to a telephone pharmacist and telepsychologist.

Subjects were enrolled in a series of 12 cognitive processing therapy sessions for the duration of the study, from Nov. 23, 2009, through Sept. 28, 2011, and attendance was taken at each session. After the sessions concluded, subjects were then followed up on for 12 months.

During that follow-up period after treatments ended, patients who received TOP had significantly larger decreases in Posttraumatic Diagnostic Scale (PDS) scores (from 35.0 to 29.1), compared with those from the UC group (from 33.5 to 32.1) at 6 months (beta = −3.81; P = .002) and 12 months (beta = −2.49; P = .04). At 12 months, TOP subjects also had significantly larger decreases in PDS scores (from 35.0 to 30.1), compared with those who received UC (from 33.5 to 29.1) .

Subjects who attended at least eight cognitive processing therapy sessions were more likely to improve their PDS scores (beta = −3.86 [95% confidence interval, −7.19 to −0.54]; P = .02). However, the authors noted that there were “no significant group differences in the number of PTSD medications prescribed and adherence to medication regimens” was not significant.

“This trial introduces a promising model for managing PTSD in a treatment-resistant population,” Dr. Fortney and his associates wrote. “Findings suggest that telemedicine-based collaborative care can successfully engage this population in evidence-based psychotherapy for PTSD, thereby improving clinical outcomes.”

Among the study limitations cited by the investigators is that the PDS was administered to assess PTSD, rather than the Clinician-Administered PTSD Scale, which is the reference standard.

The authors reported no relevant financial conflicts of interest.

[email protected]

U.S. military veterans living in rural areas who engage in evidence-based psychotherapy and telemedicine-based collaborative care can significantly increase their chances of improving outcomes related to posttraumatic stress disorder, according to a new study.

“Although psychotherapy and pharmacotherapy treatments for PTSD have proven to be efficacious in randomized clinical trials and have been disseminated widely by the [Veterans Health Administration], stigma and geographic barriers often prevent rural veterans from engaging in these evidence-based treatments,” says the study, published in JAMA (2014 Nov. 19 [doi.101001/jamapsychiatry.2014.1575]) and led by John C. Fortney, Ph.D., of the University of Washington’s department of psychiatry and behavioral sciences in Seattle, and his associates.

In a pragmatic, randomized effectiveness trial, Dr. Fortney and his associates recruited outpatients from 11 Department of Veterans Affairs (VA) community-based outpatient clinics (CBOCs) in predominantly rural areas of the United States over the course of 22 months. A total of 265 patients completed baseline interviews and randomization after meeting eligibility criteria, which consisted of meeting diagnostic standards for PTSD; having no medical history of schizophrenia, bipolar disorder, substance dependence, or hearing impairment; having a telephone; not having a life-threatening illness; and lacking capacity to consent.

© Dron - Fotolia.com

The 265 subjects were randomized into one of two groups: those receiving usual care (UC), or those receiving the Telemedicine Outreach for PTSD (TOP) treatment developed by the investigators. Patients were mostly unemployed, middle-aged men with severe PTSD symptoms and “other mental health coexisting illnesses,” according to a press release.

Subjects in the UC group received certain health care services, such as psychotropic medications for PTSD prescribed by psychiatrists, evidence-based psychotherapy for PTSD delivered by psychologists or social workers, supportive PTSD-focused therapy delivered by psychologists or social workers (individual and group), and supportive therapy delivered by social workers (individual and group), among others. Subjects in the TOP group, however, received the attention of telephone nurse care managers, including PTSD symptom monitoring and medication regimen adherence monitoring and promotion. In addition, those in the TOP group received access to a telephone pharmacist and telepsychologist.

Subjects were enrolled in a series of 12 cognitive processing therapy sessions for the duration of the study, from Nov. 23, 2009, through Sept. 28, 2011, and attendance was taken at each session. After the sessions concluded, subjects were then followed up on for 12 months.

During that follow-up period after treatments ended, patients who received TOP had significantly larger decreases in Posttraumatic Diagnostic Scale (PDS) scores (from 35.0 to 29.1), compared with those from the UC group (from 33.5 to 32.1) at 6 months (beta = −3.81; P = .002) and 12 months (beta = −2.49; P = .04). At 12 months, TOP subjects also had significantly larger decreases in PDS scores (from 35.0 to 30.1), compared with those who received UC (from 33.5 to 29.1) .

Subjects who attended at least eight cognitive processing therapy sessions were more likely to improve their PDS scores (beta = −3.86 [95% confidence interval, −7.19 to −0.54]; P = .02). However, the authors noted that there were “no significant group differences in the number of PTSD medications prescribed and adherence to medication regimens” was not significant.

“This trial introduces a promising model for managing PTSD in a treatment-resistant population,” Dr. Fortney and his associates wrote. “Findings suggest that telemedicine-based collaborative care can successfully engage this population in evidence-based psychotherapy for PTSD, thereby improving clinical outcomes.”

Among the study limitations cited by the investigators is that the PDS was administered to assess PTSD, rather than the Clinician-Administered PTSD Scale, which is the reference standard.

The authors reported no relevant financial conflicts of interest.

[email protected]

With the first cases described in 1977, ischiofemoral impingement (IFI) is a relatively recently discovered and less known potential cause of hip pain caused by compression on the quadratus femoris muscle (QFM).^1-10 These first patients, who were treated with surgical excision of the lesser trochanter, experienced symptom improvement in all 3 cases.^5,7 The most widely accepted diagnostic criteria use a combination of clinical and imaging findings.^1-10 Criteria most often cited in the literature include isolated edema-like signal in the QFM on magnetic resonance imaging (MRI) and ipsilateral hip pain without a known cause, such as recent trauma or infection.^4,5 All studies describe QFM compression occurring as the muscle passes between the lesser trochanter of the femur and the origin of the ischial tuberosity/hamstring tendons.^1-10

Several authors have sought to improve diagnostic accuracy by providing various measurements to quantify the probability of impingement.^5,7,9 Although groups have proposed different thresholds, our institution currently uses values reported by Tosun and colleagues⁵ because theirs is the most robust sample size to date and included 50 patients with IFI.^7,9 Although 5 different measurements were proposed, 2 are more commonly cited. The first is the ischiofemoral space (IFS), which is the most narrow distance between the cortex of the lesser trochanter and the cortex of the ischial tuberosity. This space should normally be greater than 1.8 cm.⁵ The second measurement is called the quadratus femoris space (QFS) and is the most narrow distance between the hamstring tendons and either the iliopsoas tendon or the cortex of the lesser trochanter. The QFS should normally be greater than 1.0 cm.⁵ However, because these measurements may depend on the hip position during imaging, full-range-of-motion (FROM) MRI may increase diagnostic yield. At our institution, patients are usually imaged supine in neutral position (with respect to internal or external rotation).

In this article, we briefly review IFI, provide an example of how FROM MRI can improve diagnostic accuracy, describe our FROM protocol, and propose an expanded definition of the impingement criteria. The patient provided written informed consent for print and electronic publication of the case details and images.  

Full–Range-of-Motion MRI Technique

A 58-year-old woman with no surgical history or diagnosed inflammatory arthropathy presented to the department of physical medicine and rehabilitation with left-buttock pain radiating down the left thigh. Despite nonsurgical management with nonsteroidal anti-inflammatory medication, exercise therapy, use of a transcutaneous electrical nerve stimulator unit, and oral corticosteroid therapy, the pain continued. The patient was referred for MRI, and routine static imaging of the pelvis was performed. Although edema-like signal was present in both QFMs (Figure 1), left more than right, the measurement of the QFS and IFS did not meet all criteria for narrowing as described in previous studies. On the symptomatic left side, the IFS measured 1.5 cm and the QFS measured 1.4 cm (Figure 2). On the same side, the distance between the cortex of the greater trochanter and the cortex of the ischial tuberosity, proposed adapted IFS, measured 1.4 cm, and the distance between the cortex of the greater trochanter and the hamstring tendons origin, proposed adapted QFS, measured 1.1 cm (Figure 3). However, because of the isolated QFM edema, refractory buttock and thigh pain, and exclusion of other diagnoses (such as labral tear, bone marrow edema/stress reaction in the hip, or MRI findings of sciatic neuropathy), we determined that the patient needed evaluation of the QFS and the IFS through a full range of motion. The patient returned for the FROM MRI 16 days after the initial static MRI.

Our FROM MRI was performed on a Magnetom Skyra 3 Tesla magnet (Seimens Healthcare Global, Munich, Germany), using a body array 18-channel coil and a table spine coil. In a supine position, the patient’s imaging started with the hip in extension, adduction, and approximately 20º of internal rotation. During imaging acquisition, the patient was maintained in adduction and extension while the hip was passively externally rotated (Figure 3). A technologist assisted the patient in maintaining the position through a 60º arc of external rotation, while an axial-gradient echo sequence was used to obtain sequential images through the entire arc. Selected parameters are listed in the Table. Acquisition of the arc of motion in the axial plane requires approximately 3 minutes per hip to generate between 8 and 10 images.

With the patient’s hip in internal rotation, narrowing between the ischium or hamstring tendons and the lesser trochanter did not meet all of the criteria described by Tosun and colleagues⁵ or Torriani and colleagues.⁷ However, when the patient shifted into external rotation, the distance between the ischial tuberosity and the greater trochanter, and between the hamstring tendons origin and the greater trochanter, significantly narrowed. The adapted IFS decreased from 3.4 cm to 1.5 cm, and the adapted QFS decreased from 3.2 cm to 0.9 cm, accounting for a 54% and 72% reduction of the adapted IFS and QFS, respectively, with maximum external rotation (Figures 4, 5).

Discussion

While femoroacetabular impingement is a widely recognized and sometimes surgically treated syndrome, IFI may be overlooked as a cause of hip pain. Although IFI is traditionally described as mass effect on the QFM by the ischium/hamstring tendons origin and the lesser trochanter, we propose expansion of this criteria to include narrowing resulting from the greater trochanter in external rotation as a potential source of impingement. By use of FROM MRI, we adapted measurements previously described for IFI to evaluate for compression of the QFM by adjacent osseous and tendinous structures throughout the full range of internal/external hip rotation. In this case, FROM imaging provided evidence of possible anatomical narrowing caused by the greater trochanter, in addition to that caused by the lesser trochanter. Given that impingement may be caused by either the greater or lesser trochanters, it is prudent to perform FROM MRI in evaluating patients with suspected IFI. If FROM imaging is not feasible, static imaging in both maximal internal and external rotation may allow for better assessment. There have been no large studies conducted to assess the normal interval between the ischial tuberosity/hamstring origins and the greater trochanter.

The purpose of this report is to call attention to a source of impingement that may be undetected with static MRI, possibly leading to a missed diagnosis. While we believe this to be the first reported example of impingement involving the greater trochanter, larger studies should be conducted to explore this possible source of impingement. Information about the incidence of greater trochanteric impingement could lead to changes in our understanding of this syndrome and its management.

With the first cases described in 1977, ischiofemoral impingement (IFI) is a relatively recently discovered and less known potential cause of hip pain caused by compression on the quadratus femoris muscle (QFM).^1-10 These first patients, who were treated with surgical excision of the lesser trochanter, experienced symptom improvement in all 3 cases.^5,7 The most widely accepted diagnostic criteria use a combination of clinical and imaging findings.^1-10 Criteria most often cited in the literature include isolated edema-like signal in the QFM on magnetic resonance imaging (MRI) and ipsilateral hip pain without a known cause, such as recent trauma or infection.^4,5 All studies describe QFM compression occurring as the muscle passes between the lesser trochanter of the femur and the origin of the ischial tuberosity/hamstring tendons.^1-10

Several authors have sought to improve diagnostic accuracy by providing various measurements to quantify the probability of impingement.^5,7,9 Although groups have proposed different thresholds, our institution currently uses values reported by Tosun and colleagues⁵ because theirs is the most robust sample size to date and included 50 patients with IFI.^7,9 Although 5 different measurements were proposed, 2 are more commonly cited. The first is the ischiofemoral space (IFS), which is the most narrow distance between the cortex of the lesser trochanter and the cortex of the ischial tuberosity. This space should normally be greater than 1.8 cm.⁵ The second measurement is called the quadratus femoris space (QFS) and is the most narrow distance between the hamstring tendons and either the iliopsoas tendon or the cortex of the lesser trochanter. The QFS should normally be greater than 1.0 cm.⁵ However, because these measurements may depend on the hip position during imaging, full-range-of-motion (FROM) MRI may increase diagnostic yield. At our institution, patients are usually imaged supine in neutral position (with respect to internal or external rotation).

In this article, we briefly review IFI, provide an example of how FROM MRI can improve diagnostic accuracy, describe our FROM protocol, and propose an expanded definition of the impingement criteria. The patient provided written informed consent for print and electronic publication of the case details and images.  

Full–Range-of-Motion MRI Technique

A 58-year-old woman with no surgical history or diagnosed inflammatory arthropathy presented to the department of physical medicine and rehabilitation with left-buttock pain radiating down the left thigh. Despite nonsurgical management with nonsteroidal anti-inflammatory medication, exercise therapy, use of a transcutaneous electrical nerve stimulator unit, and oral corticosteroid therapy, the pain continued. The patient was referred for MRI, and routine static imaging of the pelvis was performed. Although edema-like signal was present in both QFMs (Figure 1), left more than right, the measurement of the QFS and IFS did not meet all criteria for narrowing as described in previous studies. On the symptomatic left side, the IFS measured 1.5 cm and the QFS measured 1.4 cm (Figure 2). On the same side, the distance between the cortex of the greater trochanter and the cortex of the ischial tuberosity, proposed adapted IFS, measured 1.4 cm, and the distance between the cortex of the greater trochanter and the hamstring tendons origin, proposed adapted QFS, measured 1.1 cm (Figure 3). However, because of the isolated QFM edema, refractory buttock and thigh pain, and exclusion of other diagnoses (such as labral tear, bone marrow edema/stress reaction in the hip, or MRI findings of sciatic neuropathy), we determined that the patient needed evaluation of the QFS and the IFS through a full range of motion. The patient returned for the FROM MRI 16 days after the initial static MRI.

Our FROM MRI was performed on a Magnetom Skyra 3 Tesla magnet (Seimens Healthcare Global, Munich, Germany), using a body array 18-channel coil and a table spine coil. In a supine position, the patient’s imaging started with the hip in extension, adduction, and approximately 20º of internal rotation. During imaging acquisition, the patient was maintained in adduction and extension while the hip was passively externally rotated (Figure 3). A technologist assisted the patient in maintaining the position through a 60º arc of external rotation, while an axial-gradient echo sequence was used to obtain sequential images through the entire arc. Selected parameters are listed in the Table. Acquisition of the arc of motion in the axial plane requires approximately 3 minutes per hip to generate between 8 and 10 images.

With the patient’s hip in internal rotation, narrowing between the ischium or hamstring tendons and the lesser trochanter did not meet all of the criteria described by Tosun and colleagues⁵ or Torriani and colleagues.⁷ However, when the patient shifted into external rotation, the distance between the ischial tuberosity and the greater trochanter, and between the hamstring tendons origin and the greater trochanter, significantly narrowed. The adapted IFS decreased from 3.4 cm to 1.5 cm, and the adapted QFS decreased from 3.2 cm to 0.9 cm, accounting for a 54% and 72% reduction of the adapted IFS and QFS, respectively, with maximum external rotation (Figures 4, 5).

Discussion

While femoroacetabular impingement is a widely recognized and sometimes surgically treated syndrome, IFI may be overlooked as a cause of hip pain. Although IFI is traditionally described as mass effect on the QFM by the ischium/hamstring tendons origin and the lesser trochanter, we propose expansion of this criteria to include narrowing resulting from the greater trochanter in external rotation as a potential source of impingement. By use of FROM MRI, we adapted measurements previously described for IFI to evaluate for compression of the QFM by adjacent osseous and tendinous structures throughout the full range of internal/external hip rotation. In this case, FROM imaging provided evidence of possible anatomical narrowing caused by the greater trochanter, in addition to that caused by the lesser trochanter. Given that impingement may be caused by either the greater or lesser trochanters, it is prudent to perform FROM MRI in evaluating patients with suspected IFI. If FROM imaging is not feasible, static imaging in both maximal internal and external rotation may allow for better assessment. There have been no large studies conducted to assess the normal interval between the ischial tuberosity/hamstring origins and the greater trochanter.

The purpose of this report is to call attention to a source of impingement that may be undetected with static MRI, possibly leading to a missed diagnosis. While we believe this to be the first reported example of impingement involving the greater trochanter, larger studies should be conducted to explore this possible source of impingement. Information about the incidence of greater trochanteric impingement could lead to changes in our understanding of this syndrome and its management.

With the first cases described in 1977, ischiofemoral impingement (IFI) is a relatively recently discovered and less known potential cause of hip pain caused by compression on the quadratus femoris muscle (QFM).^1-10 These first patients, who were treated with surgical excision of the lesser trochanter, experienced symptom improvement in all 3 cases.^5,7 The most widely accepted diagnostic criteria use a combination of clinical and imaging findings.^1-10 Criteria most often cited in the literature include isolated edema-like signal in the QFM on magnetic resonance imaging (MRI) and ipsilateral hip pain without a known cause, such as recent trauma or infection.^4,5 All studies describe QFM compression occurring as the muscle passes between the lesser trochanter of the femur and the origin of the ischial tuberosity/hamstring tendons.^1-10

Several authors have sought to improve diagnostic accuracy by providing various measurements to quantify the probability of impingement.^5,7,9 Although groups have proposed different thresholds, our institution currently uses values reported by Tosun and colleagues⁵ because theirs is the most robust sample size to date and included 50 patients with IFI.^7,9 Although 5 different measurements were proposed, 2 are more commonly cited. The first is the ischiofemoral space (IFS), which is the most narrow distance between the cortex of the lesser trochanter and the cortex of the ischial tuberosity. This space should normally be greater than 1.8 cm.⁵ The second measurement is called the quadratus femoris space (QFS) and is the most narrow distance between the hamstring tendons and either the iliopsoas tendon or the cortex of the lesser trochanter. The QFS should normally be greater than 1.0 cm.⁵ However, because these measurements may depend on the hip position during imaging, full-range-of-motion (FROM) MRI may increase diagnostic yield. At our institution, patients are usually imaged supine in neutral position (with respect to internal or external rotation).

In this article, we briefly review IFI, provide an example of how FROM MRI can improve diagnostic accuracy, describe our FROM protocol, and propose an expanded definition of the impingement criteria. The patient provided written informed consent for print and electronic publication of the case details and images.  

Full–Range-of-Motion MRI Technique

A 58-year-old woman with no surgical history or diagnosed inflammatory arthropathy presented to the department of physical medicine and rehabilitation with left-buttock pain radiating down the left thigh. Despite nonsurgical management with nonsteroidal anti-inflammatory medication, exercise therapy, use of a transcutaneous electrical nerve stimulator unit, and oral corticosteroid therapy, the pain continued. The patient was referred for MRI, and routine static imaging of the pelvis was performed. Although edema-like signal was present in both QFMs (Figure 1), left more than right, the measurement of the QFS and IFS did not meet all criteria for narrowing as described in previous studies. On the symptomatic left side, the IFS measured 1.5 cm and the QFS measured 1.4 cm (Figure 2). On the same side, the distance between the cortex of the greater trochanter and the cortex of the ischial tuberosity, proposed adapted IFS, measured 1.4 cm, and the distance between the cortex of the greater trochanter and the hamstring tendons origin, proposed adapted QFS, measured 1.1 cm (Figure 3). However, because of the isolated QFM edema, refractory buttock and thigh pain, and exclusion of other diagnoses (such as labral tear, bone marrow edema/stress reaction in the hip, or MRI findings of sciatic neuropathy), we determined that the patient needed evaluation of the QFS and the IFS through a full range of motion. The patient returned for the FROM MRI 16 days after the initial static MRI.

Our FROM MRI was performed on a Magnetom Skyra 3 Tesla magnet (Seimens Healthcare Global, Munich, Germany), using a body array 18-channel coil and a table spine coil. In a supine position, the patient’s imaging started with the hip in extension, adduction, and approximately 20º of internal rotation. During imaging acquisition, the patient was maintained in adduction and extension while the hip was passively externally rotated (Figure 3). A technologist assisted the patient in maintaining the position through a 60º arc of external rotation, while an axial-gradient echo sequence was used to obtain sequential images through the entire arc. Selected parameters are listed in the Table. Acquisition of the arc of motion in the axial plane requires approximately 3 minutes per hip to generate between 8 and 10 images.

With the patient’s hip in internal rotation, narrowing between the ischium or hamstring tendons and the lesser trochanter did not meet all of the criteria described by Tosun and colleagues⁵ or Torriani and colleagues.⁷ However, when the patient shifted into external rotation, the distance between the ischial tuberosity and the greater trochanter, and between the hamstring tendons origin and the greater trochanter, significantly narrowed. The adapted IFS decreased from 3.4 cm to 1.5 cm, and the adapted QFS decreased from 3.2 cm to 0.9 cm, accounting for a 54% and 72% reduction of the adapted IFS and QFS, respectively, with maximum external rotation (Figures 4, 5).

Discussion

While femoroacetabular impingement is a widely recognized and sometimes surgically treated syndrome, IFI may be overlooked as a cause of hip pain. Although IFI is traditionally described as mass effect on the QFM by the ischium/hamstring tendons origin and the lesser trochanter, we propose expansion of this criteria to include narrowing resulting from the greater trochanter in external rotation as a potential source of impingement. By use of FROM MRI, we adapted measurements previously described for IFI to evaluate for compression of the QFM by adjacent osseous and tendinous structures throughout the full range of internal/external hip rotation. In this case, FROM imaging provided evidence of possible anatomical narrowing caused by the greater trochanter, in addition to that caused by the lesser trochanter. Given that impingement may be caused by either the greater or lesser trochanters, it is prudent to perform FROM MRI in evaluating patients with suspected IFI. If FROM imaging is not feasible, static imaging in both maximal internal and external rotation may allow for better assessment. There have been no large studies conducted to assess the normal interval between the ischial tuberosity/hamstring origins and the greater trochanter.

The purpose of this report is to call attention to a source of impingement that may be undetected with static MRI, possibly leading to a missed diagnosis. While we believe this to be the first reported example of impingement involving the greater trochanter, larger studies should be conducted to explore this possible source of impingement. Information about the incidence of greater trochanteric impingement could lead to changes in our understanding of this syndrome and its management.

Preventable medical errors rank as the third most common cause of death in the United States after heart disease and cancer.¹ They are responsible for 400,000 deaths each year (over 1095 per day) and another 10,000 serious complications resulting from medical errors each day.¹ That is the equivalent of two 747 airliner midair crashes per day. The economic cost to our nation is $1 trillion per year.¹

On July 17, 2014, the US Senate Subcommittee on Primary Health and Aging met to address this crisis. Participants included senators and John James, PhD, Founder, Patient Safety America, Houston, Texas; Ashish Jha, MD, MPH, Professor of Health Policy and Management, Harvard School of Public Health, Boston, Massachusetts; Tejal Gandhi, MD, MPH, President, National Patient Safety Foundation, and Associate Professor of Medicine, Harvard Medical School, Boston, Massachusetts; Peter Pronovost, MD, PhD, Senior Vice President for Patient Safety and Quality, and Director of the Armstrong Institute for Patient Safety and Quality, Johns Hopkins Medicine, Baltimore, Maryland; Joanne Disch, PhD, RN, Professor ad Honorem, University of Minnesota School of Nursing, Minneapolis, Minnesota; and Lisa McGiffert, Director, Safe Patient Project, Consumers Union, Austin, Texas. While each speaker suggested various strategies for improving patient safety, they all agreed that information technology is not living up to our expectations for meeting this need. They also agreed that health care has become increasingly “high tech and low touch,” and, as a result, the medical community is leveraging neither technology nor the knowledge accrued from individual patient/physician interactions to improve patient safety and outcomes.¹

Last year my mother had a spinal fusion. The surgery was a success by all measures. Two days after she was discharged home, she became weak and was unable to walk. She went to the emergency room, where it was noted that she was severely hyponatremic, weak, and experiencing severe back pain. For the next 36 hours she was not seen by a physician or physician assistant (PA), as the PA who admitted her to the hospital had not notified the “team” that she was admitted. My father, who is a vascular surgeon, notified her spine surgeon, who came to see her. Her hyponatremia was markedly worse, and she was transferred to the intensive care unit (ICU). She continued to decline and was started on hypertonic intravenous (IV) saline. Over the next several days her hyponatremia improved, and she was transferred out of the ICU but continued to have pain. The spine surgeon examined her several times, and imaging showed no evidence of epidural bleeding, infection, or misplaced hardware.

Over the next several days, I was informed by family members that the nurses were “keeping the pain in check” with IV narcotics and that my mom was heavily sedated most of the time. My dad later informed me that she had a foot drop on the left, and the next day another family member told me the foot drop was on the right. My dad and stepbrother each assured me that they were right. When my mom could talk, she told me how weak she was and that sometimes it was her right leg and other times her left. She was seen by a neurologist on 6 out of the next 10 days and underwent 3 computed tomography scans and magnetic resonance imaging, and the neurologist assured us that she had not had a stroke. On a Friday evening, I called my mom, who was progressively short of breath, and she told me that she felt weaker and weaker each day. The “foot drop,” which was now bilateral according to the neurologist, was from “not using it while she was in the ICU.”

My mom, who is an artist, commented that she was having trouble using her hands now and unable to hold a cup. I called the physician on call, who assured me that she was taking care of my mom’s blood pressure (which was labile for the first time ever; she had no history of hypertension) and her pain score was a 5. I explained that I knew that she was not “looking to play mystery diagnosis with an orthopedic surgeon 500 miles away, but I think my mom has Guillain-Barré syndrome.” Fortunately, the doctor said, “Oh my god, I think you’re right.” Monday morning, her diagnosis was confirmed and she has made a remarkable recovery. So how is it that she could be seen by a neurologist and a team of nurses, doctors, therapists, and resident staff and no one made a diagnosis? Certainly contributing factors include a system of multiple medical teams with frequent turnovers and a desire to consult others but no real “quarterback” who was looking at the overall care in a responsible and critical way. A thorough history and physical examination, rather than a multitude of expensive and unnecessary imaging studies, could certainly have led to a quicker diagnosis and avoidance of a protracted hospital stay and rehabilitation.

To be sure, there are many factors that lead to delays in diagnosis. The reliance on advanced imaging, the lack of a simple physical examination, and the lack of critical thinking played prominently in the failure to make a diagnosis in my mom’s case. Some would argue that we need information technology (IT) systems that will allow us to better diagnose and treat patients. They believe that with electronic medical records (EMRs) data points will be entered and a diagnosis will be made. Major corporations like IBM and GE are working to make this a reality. Although Watson (the artificially intelligent computer system created by IBM) may be able to win on Jeopardy and may move the needle forward to improving patient care, 2 things are certain: (1) Appropriate data will need to be input by people, and (2) without critical thinking, the appropriate data can’t be entered or interpreted correctly. 

The fact remains that EMR has fallen short of expectations. We have more data at our fingertips but this has not translated into a significant improvement in patient safety. The human factor remains critical. Even though industry and health care workers strive to innovate and merge technological advances with improved patient outcomes, technology will continue to fall short of expectations without the input of critical thinking. There are things that computers and technological advances can do that people can’t, and there are things that people can do that computers can’t.

We cannot become a profession reliant on technology to substitute for critical thinking, and we cannot become a profession that doesn’t recognize what technology can bring to us and our patients. Like a railroad track that needs 2 parallel tracks to move trains, we must continue to build on 2 tracks: innovation and critical thinking. ◾

Preventable medical errors rank as the third most common cause of death in the United States after heart disease and cancer.¹ They are responsible for 400,000 deaths each year (over 1095 per day) and another 10,000 serious complications resulting from medical errors each day.¹ That is the equivalent of two 747 airliner midair crashes per day. The economic cost to our nation is $1 trillion per year.¹

On July 17, 2014, the US Senate Subcommittee on Primary Health and Aging met to address this crisis. Participants included senators and John James, PhD, Founder, Patient Safety America, Houston, Texas; Ashish Jha, MD, MPH, Professor of Health Policy and Management, Harvard School of Public Health, Boston, Massachusetts; Tejal Gandhi, MD, MPH, President, National Patient Safety Foundation, and Associate Professor of Medicine, Harvard Medical School, Boston, Massachusetts; Peter Pronovost, MD, PhD, Senior Vice President for Patient Safety and Quality, and Director of the Armstrong Institute for Patient Safety and Quality, Johns Hopkins Medicine, Baltimore, Maryland; Joanne Disch, PhD, RN, Professor ad Honorem, University of Minnesota School of Nursing, Minneapolis, Minnesota; and Lisa McGiffert, Director, Safe Patient Project, Consumers Union, Austin, Texas. While each speaker suggested various strategies for improving patient safety, they all agreed that information technology is not living up to our expectations for meeting this need. They also agreed that health care has become increasingly “high tech and low touch,” and, as a result, the medical community is leveraging neither technology nor the knowledge accrued from individual patient/physician interactions to improve patient safety and outcomes.¹

Last year my mother had a spinal fusion. The surgery was a success by all measures. Two days after she was discharged home, she became weak and was unable to walk. She went to the emergency room, where it was noted that she was severely hyponatremic, weak, and experiencing severe back pain. For the next 36 hours she was not seen by a physician or physician assistant (PA), as the PA who admitted her to the hospital had not notified the “team” that she was admitted. My father, who is a vascular surgeon, notified her spine surgeon, who came to see her. Her hyponatremia was markedly worse, and she was transferred to the intensive care unit (ICU). She continued to decline and was started on hypertonic intravenous (IV) saline. Over the next several days her hyponatremia improved, and she was transferred out of the ICU but continued to have pain. The spine surgeon examined her several times, and imaging showed no evidence of epidural bleeding, infection, or misplaced hardware.

Over the next several days, I was informed by family members that the nurses were “keeping the pain in check” with IV narcotics and that my mom was heavily sedated most of the time. My dad later informed me that she had a foot drop on the left, and the next day another family member told me the foot drop was on the right. My dad and stepbrother each assured me that they were right. When my mom could talk, she told me how weak she was and that sometimes it was her right leg and other times her left. She was seen by a neurologist on 6 out of the next 10 days and underwent 3 computed tomography scans and magnetic resonance imaging, and the neurologist assured us that she had not had a stroke. On a Friday evening, I called my mom, who was progressively short of breath, and she told me that she felt weaker and weaker each day. The “foot drop,” which was now bilateral according to the neurologist, was from “not using it while she was in the ICU.”

My mom, who is an artist, commented that she was having trouble using her hands now and unable to hold a cup. I called the physician on call, who assured me that she was taking care of my mom’s blood pressure (which was labile for the first time ever; she had no history of hypertension) and her pain score was a 5. I explained that I knew that she was not “looking to play mystery diagnosis with an orthopedic surgeon 500 miles away, but I think my mom has Guillain-Barré syndrome.” Fortunately, the doctor said, “Oh my god, I think you’re right.” Monday morning, her diagnosis was confirmed and she has made a remarkable recovery. So how is it that she could be seen by a neurologist and a team of nurses, doctors, therapists, and resident staff and no one made a diagnosis? Certainly contributing factors include a system of multiple medical teams with frequent turnovers and a desire to consult others but no real “quarterback” who was looking at the overall care in a responsible and critical way. A thorough history and physical examination, rather than a multitude of expensive and unnecessary imaging studies, could certainly have led to a quicker diagnosis and avoidance of a protracted hospital stay and rehabilitation.

To be sure, there are many factors that lead to delays in diagnosis. The reliance on advanced imaging, the lack of a simple physical examination, and the lack of critical thinking played prominently in the failure to make a diagnosis in my mom’s case. Some would argue that we need information technology (IT) systems that will allow us to better diagnose and treat patients. They believe that with electronic medical records (EMRs) data points will be entered and a diagnosis will be made. Major corporations like IBM and GE are working to make this a reality. Although Watson (the artificially intelligent computer system created by IBM) may be able to win on Jeopardy and may move the needle forward to improving patient care, 2 things are certain: (1) Appropriate data will need to be input by people, and (2) without critical thinking, the appropriate data can’t be entered or interpreted correctly. 

The fact remains that EMR has fallen short of expectations. We have more data at our fingertips but this has not translated into a significant improvement in patient safety. The human factor remains critical. Even though industry and health care workers strive to innovate and merge technological advances with improved patient outcomes, technology will continue to fall short of expectations without the input of critical thinking. There are things that computers and technological advances can do that people can’t, and there are things that people can do that computers can’t.

We cannot become a profession reliant on technology to substitute for critical thinking, and we cannot become a profession that doesn’t recognize what technology can bring to us and our patients. Like a railroad track that needs 2 parallel tracks to move trains, we must continue to build on 2 tracks: innovation and critical thinking. ◾

Preventable medical errors rank as the third most common cause of death in the United States after heart disease and cancer.¹ They are responsible for 400,000 deaths each year (over 1095 per day) and another 10,000 serious complications resulting from medical errors each day.¹ That is the equivalent of two 747 airliner midair crashes per day. The economic cost to our nation is $1 trillion per year.¹

On July 17, 2014, the US Senate Subcommittee on Primary Health and Aging met to address this crisis. Participants included senators and John James, PhD, Founder, Patient Safety America, Houston, Texas; Ashish Jha, MD, MPH, Professor of Health Policy and Management, Harvard School of Public Health, Boston, Massachusetts; Tejal Gandhi, MD, MPH, President, National Patient Safety Foundation, and Associate Professor of Medicine, Harvard Medical School, Boston, Massachusetts; Peter Pronovost, MD, PhD, Senior Vice President for Patient Safety and Quality, and Director of the Armstrong Institute for Patient Safety and Quality, Johns Hopkins Medicine, Baltimore, Maryland; Joanne Disch, PhD, RN, Professor ad Honorem, University of Minnesota School of Nursing, Minneapolis, Minnesota; and Lisa McGiffert, Director, Safe Patient Project, Consumers Union, Austin, Texas. While each speaker suggested various strategies for improving patient safety, they all agreed that information technology is not living up to our expectations for meeting this need. They also agreed that health care has become increasingly “high tech and low touch,” and, as a result, the medical community is leveraging neither technology nor the knowledge accrued from individual patient/physician interactions to improve patient safety and outcomes.¹

Last year my mother had a spinal fusion. The surgery was a success by all measures. Two days after she was discharged home, she became weak and was unable to walk. She went to the emergency room, where it was noted that she was severely hyponatremic, weak, and experiencing severe back pain. For the next 36 hours she was not seen by a physician or physician assistant (PA), as the PA who admitted her to the hospital had not notified the “team” that she was admitted. My father, who is a vascular surgeon, notified her spine surgeon, who came to see her. Her hyponatremia was markedly worse, and she was transferred to the intensive care unit (ICU). She continued to decline and was started on hypertonic intravenous (IV) saline. Over the next several days her hyponatremia improved, and she was transferred out of the ICU but continued to have pain. The spine surgeon examined her several times, and imaging showed no evidence of epidural bleeding, infection, or misplaced hardware.

Over the next several days, I was informed by family members that the nurses were “keeping the pain in check” with IV narcotics and that my mom was heavily sedated most of the time. My dad later informed me that she had a foot drop on the left, and the next day another family member told me the foot drop was on the right. My dad and stepbrother each assured me that they were right. When my mom could talk, she told me how weak she was and that sometimes it was her right leg and other times her left. She was seen by a neurologist on 6 out of the next 10 days and underwent 3 computed tomography scans and magnetic resonance imaging, and the neurologist assured us that she had not had a stroke. On a Friday evening, I called my mom, who was progressively short of breath, and she told me that she felt weaker and weaker each day. The “foot drop,” which was now bilateral according to the neurologist, was from “not using it while she was in the ICU.”

My mom, who is an artist, commented that she was having trouble using her hands now and unable to hold a cup. I called the physician on call, who assured me that she was taking care of my mom’s blood pressure (which was labile for the first time ever; she had no history of hypertension) and her pain score was a 5. I explained that I knew that she was not “looking to play mystery diagnosis with an orthopedic surgeon 500 miles away, but I think my mom has Guillain-Barré syndrome.” Fortunately, the doctor said, “Oh my god, I think you’re right.” Monday morning, her diagnosis was confirmed and she has made a remarkable recovery. So how is it that she could be seen by a neurologist and a team of nurses, doctors, therapists, and resident staff and no one made a diagnosis? Certainly contributing factors include a system of multiple medical teams with frequent turnovers and a desire to consult others but no real “quarterback” who was looking at the overall care in a responsible and critical way. A thorough history and physical examination, rather than a multitude of expensive and unnecessary imaging studies, could certainly have led to a quicker diagnosis and avoidance of a protracted hospital stay and rehabilitation.

To be sure, there are many factors that lead to delays in diagnosis. The reliance on advanced imaging, the lack of a simple physical examination, and the lack of critical thinking played prominently in the failure to make a diagnosis in my mom’s case. Some would argue that we need information technology (IT) systems that will allow us to better diagnose and treat patients. They believe that with electronic medical records (EMRs) data points will be entered and a diagnosis will be made. Major corporations like IBM and GE are working to make this a reality. Although Watson (the artificially intelligent computer system created by IBM) may be able to win on Jeopardy and may move the needle forward to improving patient care, 2 things are certain: (1) Appropriate data will need to be input by people, and (2) without critical thinking, the appropriate data can’t be entered or interpreted correctly. 

The fact remains that EMR has fallen short of expectations. We have more data at our fingertips but this has not translated into a significant improvement in patient safety. The human factor remains critical. Even though industry and health care workers strive to innovate and merge technological advances with improved patient outcomes, technology will continue to fall short of expectations without the input of critical thinking. There are things that computers and technological advances can do that people can’t, and there are things that people can do that computers can’t.

We cannot become a profession reliant on technology to substitute for critical thinking, and we cannot become a profession that doesn’t recognize what technology can bring to us and our patients. Like a railroad track that needs 2 parallel tracks to move trains, we must continue to build on 2 tracks: innovation and critical thinking. ◾