Attendees at ASH 2014

SAN FRANCISCO—Multiple myeloma (MM) is driven to spread by only a subset of the myeloma cells within a patient’s body, according to research presented at the 2014 ASH Annual Meeting.

Attacking those cells with targeted drugs may degrade MM’s ability to spread throughout the bone marrow, study investigators said.

The team had used a mouse model of MM to track which of 15 subclones of myeloma cells spread beyond their initial site in the animals’ hind legs.

By labeling the different subgroups with fluorescent dyes, the researchers determined that just one of the subclones was responsible for disease metastasis.

They then compared the pattern of gene abnormalities in the initial myeloma tissue and the metastatic tumors. And they found that 238 genes were significantly less active in the latter group, comprising a gene signature of metastatic myeloma.

“Out of all the genes that were differently expressed in the 2 groups, we found 11 that played a functional role in metastasis and therefore may be drivers of the disease,” said study investigator Irene Ghobrial, MD, of the Dana-Farber Cancer Institute in Boston.

If future studies confirm that role, the genes may become targets for therapies that inhibit MM metastasis, she added.

Dr Ghobrial and her colleagues presented this research in a poster session at ASH (abstract 3370).

Attendees at ASH 2014

SAN FRANCISCO—Multiple myeloma (MM) is driven to spread by only a subset of the myeloma cells within a patient’s body, according to research presented at the 2014 ASH Annual Meeting.

Attacking those cells with targeted drugs may degrade MM’s ability to spread throughout the bone marrow, study investigators said.

The team had used a mouse model of MM to track which of 15 subclones of myeloma cells spread beyond their initial site in the animals’ hind legs.

By labeling the different subgroups with fluorescent dyes, the researchers determined that just one of the subclones was responsible for disease metastasis.

They then compared the pattern of gene abnormalities in the initial myeloma tissue and the metastatic tumors. And they found that 238 genes were significantly less active in the latter group, comprising a gene signature of metastatic myeloma.

“Out of all the genes that were differently expressed in the 2 groups, we found 11 that played a functional role in metastasis and therefore may be drivers of the disease,” said study investigator Irene Ghobrial, MD, of the Dana-Farber Cancer Institute in Boston.

If future studies confirm that role, the genes may become targets for therapies that inhibit MM metastasis, she added.

Dr Ghobrial and her colleagues presented this research in a poster session at ASH (abstract 3370).

Attendees at ASH 2014

SAN FRANCISCO—Multiple myeloma (MM) is driven to spread by only a subset of the myeloma cells within a patient’s body, according to research presented at the 2014 ASH Annual Meeting.

Attacking those cells with targeted drugs may degrade MM’s ability to spread throughout the bone marrow, study investigators said.

The team had used a mouse model of MM to track which of 15 subclones of myeloma cells spread beyond their initial site in the animals’ hind legs.

By labeling the different subgroups with fluorescent dyes, the researchers determined that just one of the subclones was responsible for disease metastasis.

They then compared the pattern of gene abnormalities in the initial myeloma tissue and the metastatic tumors. And they found that 238 genes were significantly less active in the latter group, comprising a gene signature of metastatic myeloma.

“Out of all the genes that were differently expressed in the 2 groups, we found 11 that played a functional role in metastasis and therefore may be drivers of the disease,” said study investigator Irene Ghobrial, MD, of the Dana-Farber Cancer Institute in Boston.

If future studies confirm that role, the genes may become targets for therapies that inhibit MM metastasis, she added.

Dr Ghobrial and her colleagues presented this research in a poster session at ASH (abstract 3370).

Chronic myeloid leukemia cells

PHILADELPHIA—New research suggests that stiffness in the extracellular matrix (ECM) can predict how leukemias will respond to therapy.

Using a 3D model, investigators demonstrated that ECM stiffness can affect treatment response in both chronic and acute myeloid leukemia.

The researchers believe that correcting for the matrix effect could give hematologists a new tool for personalizing leukemia treatment.

The team presented this research at the 2014 ASCB/IFCB meeting (poster 429).

Jae-Won Shin, PhD, and David Mooney, PhD, both of Harvard University, knew that myeloid leukemia subtypes are defined by distinct genetic mutations and the activation of known signaling pathways.

But the investigators wanted to see if changes in matrix stiffness played a part in cancer cell proliferation and if myeloid leukemia subtypes could be sorted out by their responses.

The researchers built a 3D hydrogel system with tunable stiffness and attempted to evaluate how relative stiffness of the surrounding ECM affected the resistance of human myeloid leukemias to chemotherapeutic drugs.

They found, for example, that chronic myeloid leukemias (CMLs) grown in their viscous 3D gel system were more resistant to the tyrosine kinase inhibitor imatinib than those cultured in a rigid matrix.

Using this and other data from their variable ECM system, the team screened libraries of small-molecule drugs, identifying a subset of drugs they say are more likely to be effective against CML, regardless of the surrounding matrix.

By correcting for the matrix effect, Drs Shin and Mooney believe their novel approach to drug screening could more precisely tailor chemotherapy to a patient’s individual malignancy.

The investigators’ 3D hydrogel system allowed them to vary the stiffness of the matrix and uncover different growth patterns, which they used to profile different leukemia subtypes.

They also looked at a cellular signaling pathway, protein kinase B (AKT), known to be involved in mechanotransduction and therefore sensitive to stiffness in different leukemia subtypes.

They discovered that CML cells in the 3D hydrogel were resistant to an AKT inhibitor, while acute myeloid leukemia cells grown in the same conditions were responsive to the drug, supporting their idea that a tunable matrix system could be a way to sort out leukemia subtypes by drug resistance.

Chronic myeloid leukemia cells

PHILADELPHIA—New research suggests that stiffness in the extracellular matrix (ECM) can predict how leukemias will respond to therapy.

Using a 3D model, investigators demonstrated that ECM stiffness can affect treatment response in both chronic and acute myeloid leukemia.

The researchers believe that correcting for the matrix effect could give hematologists a new tool for personalizing leukemia treatment.

The team presented this research at the 2014 ASCB/IFCB meeting (poster 429).

Jae-Won Shin, PhD, and David Mooney, PhD, both of Harvard University, knew that myeloid leukemia subtypes are defined by distinct genetic mutations and the activation of known signaling pathways.

But the investigators wanted to see if changes in matrix stiffness played a part in cancer cell proliferation and if myeloid leukemia subtypes could be sorted out by their responses.

The researchers built a 3D hydrogel system with tunable stiffness and attempted to evaluate how relative stiffness of the surrounding ECM affected the resistance of human myeloid leukemias to chemotherapeutic drugs.

They found, for example, that chronic myeloid leukemias (CMLs) grown in their viscous 3D gel system were more resistant to the tyrosine kinase inhibitor imatinib than those cultured in a rigid matrix.

Using this and other data from their variable ECM system, the team screened libraries of small-molecule drugs, identifying a subset of drugs they say are more likely to be effective against CML, regardless of the surrounding matrix.

By correcting for the matrix effect, Drs Shin and Mooney believe their novel approach to drug screening could more precisely tailor chemotherapy to a patient’s individual malignancy.

The investigators’ 3D hydrogel system allowed them to vary the stiffness of the matrix and uncover different growth patterns, which they used to profile different leukemia subtypes.

They also looked at a cellular signaling pathway, protein kinase B (AKT), known to be involved in mechanotransduction and therefore sensitive to stiffness in different leukemia subtypes.

They discovered that CML cells in the 3D hydrogel were resistant to an AKT inhibitor, while acute myeloid leukemia cells grown in the same conditions were responsive to the drug, supporting their idea that a tunable matrix system could be a way to sort out leukemia subtypes by drug resistance.

Chronic myeloid leukemia cells

PHILADELPHIA—New research suggests that stiffness in the extracellular matrix (ECM) can predict how leukemias will respond to therapy.

Using a 3D model, investigators demonstrated that ECM stiffness can affect treatment response in both chronic and acute myeloid leukemia.

The researchers believe that correcting for the matrix effect could give hematologists a new tool for personalizing leukemia treatment.

The team presented this research at the 2014 ASCB/IFCB meeting (poster 429).

Jae-Won Shin, PhD, and David Mooney, PhD, both of Harvard University, knew that myeloid leukemia subtypes are defined by distinct genetic mutations and the activation of known signaling pathways.

But the investigators wanted to see if changes in matrix stiffness played a part in cancer cell proliferation and if myeloid leukemia subtypes could be sorted out by their responses.

The researchers built a 3D hydrogel system with tunable stiffness and attempted to evaluate how relative stiffness of the surrounding ECM affected the resistance of human myeloid leukemias to chemotherapeutic drugs.

They found, for example, that chronic myeloid leukemias (CMLs) grown in their viscous 3D gel system were more resistant to the tyrosine kinase inhibitor imatinib than those cultured in a rigid matrix.

Using this and other data from their variable ECM system, the team screened libraries of small-molecule drugs, identifying a subset of drugs they say are more likely to be effective against CML, regardless of the surrounding matrix.

By correcting for the matrix effect, Drs Shin and Mooney believe their novel approach to drug screening could more precisely tailor chemotherapy to a patient’s individual malignancy.

The investigators’ 3D hydrogel system allowed them to vary the stiffness of the matrix and uncover different growth patterns, which they used to profile different leukemia subtypes.

They also looked at a cellular signaling pathway, protein kinase B (AKT), known to be involved in mechanotransduction and therefore sensitive to stiffness in different leukemia subtypes.

They discovered that CML cells in the 3D hydrogel were resistant to an AKT inhibitor, while acute myeloid leukemia cells grown in the same conditions were responsive to the drug, supporting their idea that a tunable matrix system could be a way to sort out leukemia subtypes by drug resistance.

If you’re stumped about what to tell patients who ask you if they should be adding supplemental vitamin D to their diet, you’re not alone.

Speaker after speaker at a public conference on vitamin D sponsored by the National Institutes of Health acknowledged that there is general disagreement among well-respected scientists and medical organizations not only about recommended intakes, but about whether supplementation of vitamin D (25-hydroxyvitamin D) has any impact on ailments ranging from depression and nonspecific pain to hypertension and fall prevention.

“Most people agree that at least in high-risk individuals with osteoporosis, vitamin D has an impact on bone and skeletal health, but maybe not in those who are asymptomatic and in healthy individuals as a preventive tool,” said Dr. Clifford J. Rosen, director of clinical and translational research and a senior scientist at Maine Medical Center Research Institute, Scarborough, Me. “There seems to be growing evidence that in high-risk individuals, or in those who repeatedly fall, vitamin D may have an impact, particularly in those with very-low levels of 25-D.”

Other relationships lack conclusive randomized control data, although there are strong observational data for vitamin D’s role in preventing type 2 diabetes. Dr. Rosen is one of the investigators in a National Institute of Diabetes and Digestive and Kidney Diseases–funded clinical trial known as D2D: a study of 4,000 IU of vitamin D vs. placebo in high-risk individuals with obesity and prediabetes. The primary outcome is time to onset of type 2 diabetes. “Currently, that [trial is] in its second year and is about 30% recruited,” said Dr. Rosen, who is also a member of the FDA Advisory Panel on Endocrinologic and Metabolic Drugs. “One of the biggest obstacles to recruitment has been the constant use of vitamin D by people being screened. [They say] ‘Why should I go into a clinical trial when I’m taking vitamin D, and my doctor tells me that it will prevent diabetes?’”

The potential benefit of vitamin D intake on reducing the risk for developing cardiovascular disease, cancer, and stroke is being investigated in the NIH-funded VITAL trial. Clinicians involved in this project have enrolled more than 28,000 men and women with no prior history of these illnesses, investigating the impact of taking vitamin D3 supplements (2,000 IU/day) or omega 3 fatty acids (1 G/day).

In the meantime, current vitamin D guidance and conclusions differ among leading medical organizations. For example, the American Geriatrics Society (AGS) recommends a daily dose of 4,000 IU for fall prevention in elderly individuals. This differs from the daily dose for adults recommended by the Endocrine Society (1,500-2,000 IU), Institute of Medicine (an average requirement of 400 IU and 600-800 IU meeting the greatest need), the United States Preventive Services Task Force (600-800 IU as a fall-prevention strategy), the Standing Committee of European Doctors (600-800 IU), and the National Osteoporosis Foundation (400-1,000 IU). “How do we reconcile vitamin D intake with vitamin D levels?” asked Dr. Rosen, who is also a professor of medicine at Tufts University. “This is one of the hallmarks of the questions or problems we have, or the lack of consistency of data. We know that intakes do not reflect serum 25-D levels to a great extent.”

In addition, the terminology for serum 25-D is not clear. “Is it a deficiency? Is it a disease? What does that mean?” he asked. “More importantly, we don’t really understand what vitamin D insufficiency is. Is it a disease? Not a disease? Is it inadequate intake?”

The definition of optimal 25-D is also a matter of debate, he continued. “What’s the upper level? What does pharmacological treatment mean with respect to long-term outcomes. What is the tolerable upper limit? What is the potentially toxic limit?”

A lack of consensus also exists regarding one’s risk of vitamin D deficiency. For example, the AGS puts this risk at less than 30 ng/mL, the Endocrine Society at less than 20 ng/mL, and the Institute of Medicine at less than 12 ng/mL. “We have a lot of inconsistency in the data,” Dr. Rosen concluded. “There’s not unanimity in recommendations, even among so-called experts.”

During the same session, Dr. Peter Millard presented findings from a national analysis of vitamin D level testing in adult patients conducted from January 2013 to September 2014. The sample, drawn from Athenahealth integrated electronic health records (EHRs), included more than 6,000 internists and family physicians and 2,000 nonphysician clinicians, translating into an estimated 900,000 patient encounters per month. During that time period 4%-5% of all adult patient encounters were associated with a vitamin D test ordered.

“Curiously, the Sunbelt states of Arizona and Nevada have a high testing rate, in the 8.5%-10.7% range,” said Dr. Millard, a family physician who practices at Seaport Community Health Center in Belfast, Me. “Perhaps it’s because of snowbirds coming down from Canada to get tested. I don’t know. There are certainly lots of retirees in those two states. There are also high levels of testing in Illinois, Maryland, Rhode Island, and Delaware. I don’t have a hypothesis as to why there are variations, but that’s about 10% of all encounters associated with a vitamin D test in those states, which seems like quite a high number.”

The greatest proportion of tests occurred in patients over the age of 65 (39%) years, and about 70% of all vitamin D tests were conducted in females.

Fewer than 0.1% of tests were associated with a diagnosis of osteoporosis. The most common diagnoses associated with ordering of a vitamin D test were depression and falls. “This was particularly true in the elderly group, where falls became much more important, and depression slightly less,” Dr. Millard said. He noted that the EHR findings “don’t answer many questions but clearly the cost for [vitamin D] testing itself is significant. The amount of time my colleagues are spending doing tests and interpreting tests for patients [and] deciding what to do about those results is very considerable. In the long run, the research to resolve these issues may not be anywhere near as expensive as continuing to do what we’re doing now.”

Dr. Rosen and Dr. Millard reporting having no financial disclosures.

[email protected]

On Twitter @dougbrunk

If you’re stumped about what to tell patients who ask you if they should be adding supplemental vitamin D to their diet, you’re not alone.

Speaker after speaker at a public conference on vitamin D sponsored by the National Institutes of Health acknowledged that there is general disagreement among well-respected scientists and medical organizations not only about recommended intakes, but about whether supplementation of vitamin D (25-hydroxyvitamin D) has any impact on ailments ranging from depression and nonspecific pain to hypertension and fall prevention.

“Most people agree that at least in high-risk individuals with osteoporosis, vitamin D has an impact on bone and skeletal health, but maybe not in those who are asymptomatic and in healthy individuals as a preventive tool,” said Dr. Clifford J. Rosen, director of clinical and translational research and a senior scientist at Maine Medical Center Research Institute, Scarborough, Me. “There seems to be growing evidence that in high-risk individuals, or in those who repeatedly fall, vitamin D may have an impact, particularly in those with very-low levels of 25-D.”

Other relationships lack conclusive randomized control data, although there are strong observational data for vitamin D’s role in preventing type 2 diabetes. Dr. Rosen is one of the investigators in a National Institute of Diabetes and Digestive and Kidney Diseases–funded clinical trial known as D2D: a study of 4,000 IU of vitamin D vs. placebo in high-risk individuals with obesity and prediabetes. The primary outcome is time to onset of type 2 diabetes. “Currently, that [trial is] in its second year and is about 30% recruited,” said Dr. Rosen, who is also a member of the FDA Advisory Panel on Endocrinologic and Metabolic Drugs. “One of the biggest obstacles to recruitment has been the constant use of vitamin D by people being screened. [They say] ‘Why should I go into a clinical trial when I’m taking vitamin D, and my doctor tells me that it will prevent diabetes?’”

The potential benefit of vitamin D intake on reducing the risk for developing cardiovascular disease, cancer, and stroke is being investigated in the NIH-funded VITAL trial. Clinicians involved in this project have enrolled more than 28,000 men and women with no prior history of these illnesses, investigating the impact of taking vitamin D3 supplements (2,000 IU/day) or omega 3 fatty acids (1 G/day).

In the meantime, current vitamin D guidance and conclusions differ among leading medical organizations. For example, the American Geriatrics Society (AGS) recommends a daily dose of 4,000 IU for fall prevention in elderly individuals. This differs from the daily dose for adults recommended by the Endocrine Society (1,500-2,000 IU), Institute of Medicine (an average requirement of 400 IU and 600-800 IU meeting the greatest need), the United States Preventive Services Task Force (600-800 IU as a fall-prevention strategy), the Standing Committee of European Doctors (600-800 IU), and the National Osteoporosis Foundation (400-1,000 IU). “How do we reconcile vitamin D intake with vitamin D levels?” asked Dr. Rosen, who is also a professor of medicine at Tufts University. “This is one of the hallmarks of the questions or problems we have, or the lack of consistency of data. We know that intakes do not reflect serum 25-D levels to a great extent.”

In addition, the terminology for serum 25-D is not clear. “Is it a deficiency? Is it a disease? What does that mean?” he asked. “More importantly, we don’t really understand what vitamin D insufficiency is. Is it a disease? Not a disease? Is it inadequate intake?”

The definition of optimal 25-D is also a matter of debate, he continued. “What’s the upper level? What does pharmacological treatment mean with respect to long-term outcomes. What is the tolerable upper limit? What is the potentially toxic limit?”

A lack of consensus also exists regarding one’s risk of vitamin D deficiency. For example, the AGS puts this risk at less than 30 ng/mL, the Endocrine Society at less than 20 ng/mL, and the Institute of Medicine at less than 12 ng/mL. “We have a lot of inconsistency in the data,” Dr. Rosen concluded. “There’s not unanimity in recommendations, even among so-called experts.”

During the same session, Dr. Peter Millard presented findings from a national analysis of vitamin D level testing in adult patients conducted from January 2013 to September 2014. The sample, drawn from Athenahealth integrated electronic health records (EHRs), included more than 6,000 internists and family physicians and 2,000 nonphysician clinicians, translating into an estimated 900,000 patient encounters per month. During that time period 4%-5% of all adult patient encounters were associated with a vitamin D test ordered.

“Curiously, the Sunbelt states of Arizona and Nevada have a high testing rate, in the 8.5%-10.7% range,” said Dr. Millard, a family physician who practices at Seaport Community Health Center in Belfast, Me. “Perhaps it’s because of snowbirds coming down from Canada to get tested. I don’t know. There are certainly lots of retirees in those two states. There are also high levels of testing in Illinois, Maryland, Rhode Island, and Delaware. I don’t have a hypothesis as to why there are variations, but that’s about 10% of all encounters associated with a vitamin D test in those states, which seems like quite a high number.”

The greatest proportion of tests occurred in patients over the age of 65 (39%) years, and about 70% of all vitamin D tests were conducted in females.

Fewer than 0.1% of tests were associated with a diagnosis of osteoporosis. The most common diagnoses associated with ordering of a vitamin D test were depression and falls. “This was particularly true in the elderly group, where falls became much more important, and depression slightly less,” Dr. Millard said. He noted that the EHR findings “don’t answer many questions but clearly the cost for [vitamin D] testing itself is significant. The amount of time my colleagues are spending doing tests and interpreting tests for patients [and] deciding what to do about those results is very considerable. In the long run, the research to resolve these issues may not be anywhere near as expensive as continuing to do what we’re doing now.”

Dr. Rosen and Dr. Millard reporting having no financial disclosures.

[email protected]

On Twitter @dougbrunk

If you’re stumped about what to tell patients who ask you if they should be adding supplemental vitamin D to their diet, you’re not alone.

Speaker after speaker at a public conference on vitamin D sponsored by the National Institutes of Health acknowledged that there is general disagreement among well-respected scientists and medical organizations not only about recommended intakes, but about whether supplementation of vitamin D (25-hydroxyvitamin D) has any impact on ailments ranging from depression and nonspecific pain to hypertension and fall prevention.

“Most people agree that at least in high-risk individuals with osteoporosis, vitamin D has an impact on bone and skeletal health, but maybe not in those who are asymptomatic and in healthy individuals as a preventive tool,” said Dr. Clifford J. Rosen, director of clinical and translational research and a senior scientist at Maine Medical Center Research Institute, Scarborough, Me. “There seems to be growing evidence that in high-risk individuals, or in those who repeatedly fall, vitamin D may have an impact, particularly in those with very-low levels of 25-D.”

Other relationships lack conclusive randomized control data, although there are strong observational data for vitamin D’s role in preventing type 2 diabetes. Dr. Rosen is one of the investigators in a National Institute of Diabetes and Digestive and Kidney Diseases–funded clinical trial known as D2D: a study of 4,000 IU of vitamin D vs. placebo in high-risk individuals with obesity and prediabetes. The primary outcome is time to onset of type 2 diabetes. “Currently, that [trial is] in its second year and is about 30% recruited,” said Dr. Rosen, who is also a member of the FDA Advisory Panel on Endocrinologic and Metabolic Drugs. “One of the biggest obstacles to recruitment has been the constant use of vitamin D by people being screened. [They say] ‘Why should I go into a clinical trial when I’m taking vitamin D, and my doctor tells me that it will prevent diabetes?’”

The potential benefit of vitamin D intake on reducing the risk for developing cardiovascular disease, cancer, and stroke is being investigated in the NIH-funded VITAL trial. Clinicians involved in this project have enrolled more than 28,000 men and women with no prior history of these illnesses, investigating the impact of taking vitamin D3 supplements (2,000 IU/day) or omega 3 fatty acids (1 G/day).

In the meantime, current vitamin D guidance and conclusions differ among leading medical organizations. For example, the American Geriatrics Society (AGS) recommends a daily dose of 4,000 IU for fall prevention in elderly individuals. This differs from the daily dose for adults recommended by the Endocrine Society (1,500-2,000 IU), Institute of Medicine (an average requirement of 400 IU and 600-800 IU meeting the greatest need), the United States Preventive Services Task Force (600-800 IU as a fall-prevention strategy), the Standing Committee of European Doctors (600-800 IU), and the National Osteoporosis Foundation (400-1,000 IU). “How do we reconcile vitamin D intake with vitamin D levels?” asked Dr. Rosen, who is also a professor of medicine at Tufts University. “This is one of the hallmarks of the questions or problems we have, or the lack of consistency of data. We know that intakes do not reflect serum 25-D levels to a great extent.”

In addition, the terminology for serum 25-D is not clear. “Is it a deficiency? Is it a disease? What does that mean?” he asked. “More importantly, we don’t really understand what vitamin D insufficiency is. Is it a disease? Not a disease? Is it inadequate intake?”

The definition of optimal 25-D is also a matter of debate, he continued. “What’s the upper level? What does pharmacological treatment mean with respect to long-term outcomes. What is the tolerable upper limit? What is the potentially toxic limit?”

A lack of consensus also exists regarding one’s risk of vitamin D deficiency. For example, the AGS puts this risk at less than 30 ng/mL, the Endocrine Society at less than 20 ng/mL, and the Institute of Medicine at less than 12 ng/mL. “We have a lot of inconsistency in the data,” Dr. Rosen concluded. “There’s not unanimity in recommendations, even among so-called experts.”

During the same session, Dr. Peter Millard presented findings from a national analysis of vitamin D level testing in adult patients conducted from January 2013 to September 2014. The sample, drawn from Athenahealth integrated electronic health records (EHRs), included more than 6,000 internists and family physicians and 2,000 nonphysician clinicians, translating into an estimated 900,000 patient encounters per month. During that time period 4%-5% of all adult patient encounters were associated with a vitamin D test ordered.

“Curiously, the Sunbelt states of Arizona and Nevada have a high testing rate, in the 8.5%-10.7% range,” said Dr. Millard, a family physician who practices at Seaport Community Health Center in Belfast, Me. “Perhaps it’s because of snowbirds coming down from Canada to get tested. I don’t know. There are certainly lots of retirees in those two states. There are also high levels of testing in Illinois, Maryland, Rhode Island, and Delaware. I don’t have a hypothesis as to why there are variations, but that’s about 10% of all encounters associated with a vitamin D test in those states, which seems like quite a high number.”

The greatest proportion of tests occurred in patients over the age of 65 (39%) years, and about 70% of all vitamin D tests were conducted in females.

Fewer than 0.1% of tests were associated with a diagnosis of osteoporosis. The most common diagnoses associated with ordering of a vitamin D test were depression and falls. “This was particularly true in the elderly group, where falls became much more important, and depression slightly less,” Dr. Millard said. He noted that the EHR findings “don’t answer many questions but clearly the cost for [vitamin D] testing itself is significant. The amount of time my colleagues are spending doing tests and interpreting tests for patients [and] deciding what to do about those results is very considerable. In the long run, the research to resolve these issues may not be anywhere near as expensive as continuing to do what we’re doing now.”

Dr. Rosen and Dr. Millard reporting having no financial disclosures.

[email protected]

On Twitter @dougbrunk

SAN FRANCISCO – Adding a kinase inhibitor to a standard regimen for acute myeloid leukemia can prolong event-free and relapse-free survival in young adult patients, but the effect on overall survival is still unclear, investigators reported.

In a randomized controlled trial, 3-year event-free survival (EFS), the primary endpoint, was 40% among patients treated with chemotherapy and sorafenib (Nexavar), compared with 22% for patients treated with chemotherapy and a placebo (P = .013). The median EFS was 21 months and 9 months, respectively, reported Dr. Christoph Röllig of University Hospital in Dresden, Germany.

Relapse-free survival (RFS) at 3 years was 56% in the sorafenib-treated group, compared with 38% in the placebo group (P = .017). The median RFS was not reached in the sorafenib group, vs. 23 months in the placebo group, Dr. Röllig reported at the annual meeting of the American Society of Hematology.

“These data constitute the first randomized evidence that actually kinase inhibitors work in AML. What we judge is that, according to evidence-based medicine principles, a comparatory trial would be desirable in order to establish sorafenib in AML treatment,” he said at a briefing prior to his presentation of the data in a plenary session.

Dr. Röllig and colleagues in 25 centers enrolled patients from 18 to 60 years with newly diagnosed AML. Of the 276 enrolled, 267 went on to receive study treatment: 134 were assigned to sorafenib and 133 to placebo. The study drug was given along a chemotherapy regimen consisting of two cycles of induction with daunorubicin and cytarabine followed by three cycles of high-dose cytarabine consolidation. Patients who did not have a response after the first cycle of daunorubicin induction underwent a second induction attempt with cytarabine and mitoxantrone.

The assigned study medication was given on days 10-19 of induction cycles one and two, from day 8 of each consolidation cycle until 3 days before the start of the next consolidation cycle, and as maintenance for 12 months after the end of consolidation.

As noted before, EFS in an intention-to-treat analysis censored for stem-cell therapy favored the sorafenib-treated patients, as did RFS. In addition, there was evidence to suggest a benefit trend toward prolonged RFS and overall survival with sorafenib among patients positive for the FLT3-ITD mutation, which has been shown to be sensitive to kinase inhibitors.

Patients in the sorafenib arm had significantly more episodes of fever, bleeding events, and the hand-foot syndrome, but there were no significant differences in other adverse events, Dr. Röllig said.

In an interview, he said that the investigators chose sorafenib because of its good track record and its efficacy against multiple kinases. His center is also involved in clinical trials exploring whether a different kinase inhibitor, quizartinib, has similar or better efficacy against AML.

The study was supported by Bayer. Dr. Röllig reported having no relevant disclosures.

SAN FRANCISCO – Adding a kinase inhibitor to a standard regimen for acute myeloid leukemia can prolong event-free and relapse-free survival in young adult patients, but the effect on overall survival is still unclear, investigators reported.

In a randomized controlled trial, 3-year event-free survival (EFS), the primary endpoint, was 40% among patients treated with chemotherapy and sorafenib (Nexavar), compared with 22% for patients treated with chemotherapy and a placebo (P = .013). The median EFS was 21 months and 9 months, respectively, reported Dr. Christoph Röllig of University Hospital in Dresden, Germany.

Relapse-free survival (RFS) at 3 years was 56% in the sorafenib-treated group, compared with 38% in the placebo group (P = .017). The median RFS was not reached in the sorafenib group, vs. 23 months in the placebo group, Dr. Röllig reported at the annual meeting of the American Society of Hematology.

“These data constitute the first randomized evidence that actually kinase inhibitors work in AML. What we judge is that, according to evidence-based medicine principles, a comparatory trial would be desirable in order to establish sorafenib in AML treatment,” he said at a briefing prior to his presentation of the data in a plenary session.

Dr. Röllig and colleagues in 25 centers enrolled patients from 18 to 60 years with newly diagnosed AML. Of the 276 enrolled, 267 went on to receive study treatment: 134 were assigned to sorafenib and 133 to placebo. The study drug was given along a chemotherapy regimen consisting of two cycles of induction with daunorubicin and cytarabine followed by three cycles of high-dose cytarabine consolidation. Patients who did not have a response after the first cycle of daunorubicin induction underwent a second induction attempt with cytarabine and mitoxantrone.

The assigned study medication was given on days 10-19 of induction cycles one and two, from day 8 of each consolidation cycle until 3 days before the start of the next consolidation cycle, and as maintenance for 12 months after the end of consolidation.

As noted before, EFS in an intention-to-treat analysis censored for stem-cell therapy favored the sorafenib-treated patients, as did RFS. In addition, there was evidence to suggest a benefit trend toward prolonged RFS and overall survival with sorafenib among patients positive for the FLT3-ITD mutation, which has been shown to be sensitive to kinase inhibitors.

Patients in the sorafenib arm had significantly more episodes of fever, bleeding events, and the hand-foot syndrome, but there were no significant differences in other adverse events, Dr. Röllig said.

In an interview, he said that the investigators chose sorafenib because of its good track record and its efficacy against multiple kinases. His center is also involved in clinical trials exploring whether a different kinase inhibitor, quizartinib, has similar or better efficacy against AML.

The study was supported by Bayer. Dr. Röllig reported having no relevant disclosures.

SAN FRANCISCO – Adding a kinase inhibitor to a standard regimen for acute myeloid leukemia can prolong event-free and relapse-free survival in young adult patients, but the effect on overall survival is still unclear, investigators reported.

In a randomized controlled trial, 3-year event-free survival (EFS), the primary endpoint, was 40% among patients treated with chemotherapy and sorafenib (Nexavar), compared with 22% for patients treated with chemotherapy and a placebo (P = .013). The median EFS was 21 months and 9 months, respectively, reported Dr. Christoph Röllig of University Hospital in Dresden, Germany.

Relapse-free survival (RFS) at 3 years was 56% in the sorafenib-treated group, compared with 38% in the placebo group (P = .017). The median RFS was not reached in the sorafenib group, vs. 23 months in the placebo group, Dr. Röllig reported at the annual meeting of the American Society of Hematology.

“These data constitute the first randomized evidence that actually kinase inhibitors work in AML. What we judge is that, according to evidence-based medicine principles, a comparatory trial would be desirable in order to establish sorafenib in AML treatment,” he said at a briefing prior to his presentation of the data in a plenary session.

Dr. Röllig and colleagues in 25 centers enrolled patients from 18 to 60 years with newly diagnosed AML. Of the 276 enrolled, 267 went on to receive study treatment: 134 were assigned to sorafenib and 133 to placebo. The study drug was given along a chemotherapy regimen consisting of two cycles of induction with daunorubicin and cytarabine followed by three cycles of high-dose cytarabine consolidation. Patients who did not have a response after the first cycle of daunorubicin induction underwent a second induction attempt with cytarabine and mitoxantrone.

The assigned study medication was given on days 10-19 of induction cycles one and two, from day 8 of each consolidation cycle until 3 days before the start of the next consolidation cycle, and as maintenance for 12 months after the end of consolidation.

As noted before, EFS in an intention-to-treat analysis censored for stem-cell therapy favored the sorafenib-treated patients, as did RFS. In addition, there was evidence to suggest a benefit trend toward prolonged RFS and overall survival with sorafenib among patients positive for the FLT3-ITD mutation, which has been shown to be sensitive to kinase inhibitors.

Patients in the sorafenib arm had significantly more episodes of fever, bleeding events, and the hand-foot syndrome, but there were no significant differences in other adverse events, Dr. Röllig said.

In an interview, he said that the investigators chose sorafenib because of its good track record and its efficacy against multiple kinases. His center is also involved in clinical trials exploring whether a different kinase inhibitor, quizartinib, has similar or better efficacy against AML.

The study was supported by Bayer. Dr. Röllig reported having no relevant disclosures.

Carcinoma of the lung is the most common lethal form of cancer in both men and women worldwide.¹ It accounts for more deaths than the next 3 most common cancers combined. In 2012, 160,000 Americans are estimated to have died from lung cancer.¹ Lung cancer is known to have a high metastatic potential for the brain, bones, adrenal glands, lungs, and liver.² Orthopedic manifestations frequently include bony metastasis, most commonly the vertebrae (42%), ribs (20%), and pelvis (18%).³ Acral metastatic disease is defined as metastasis distal to the elbow or the knee. Bony acral metastases from lung carcinoma to the upper and lower extremities are extremely uncommon, accounting for only 1% each of total bone metastases from carcinoma of the lung.³ Metastases to the bones of the hand are even rarer. Only 0.1% of metastatic disease from any type of carcinoma or sarcoma manifests as metastasis in the hand.⁴ There are only a few reports in the literature of soft-tissue or muscular metastasis to the hand from a carcinoma. Of these cases, the majority are caused by metastatic lung carcinoma.^5-9 There are no reports in the literature of metastatic disease of squamous cell origin affecting the soft tissues of the hand.

We present a case of a man with known metastatic squamous cell carcinoma of the lung who presented with acral soft-tissue metastatic disease. This report highlights a rare clinical scenario that has not been reported in the literature. The report also emphasizes a rare but important consideration for clinicians who encounter acral soft-tissue lesions in patients with a history of a primary carcinoma. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 56-year-old man presented with right-sided pleuritic flank pain, along with a 30-lb weight loss over a 6-month period. A computed tomographic scan revealed a 5.58×3.7-cm cavitary lesion in the right lower lobe with abutment of the posterior chest wall (Figure 1). He underwent biopsy and staging, and was found to be T3N1, with biopsy-proven well-differentiated bronchogenic squamous cell carcinoma. The patient then underwent right lower and middle lobectomy with concomitant en-bloc resection of the posterior portion of ribs 7 to 11, along with mediastinal lymph-node dissection with negative margins. After surgery, he was treated with 4 cycles of adjuvant chemotherapy with cisplatin and docetaxel.

Six months after surgery, the patient began to complain of right-hand pain isolated to the thenar eminence. He also described swelling and significant pain with active or passive movement of the thumb and with relatively mild-to-moderate palpation of the area. The patient reported that the functioning of his thumb deteriorated rapidly over the course of about 1 month. On physical examination, he was neurovascularly intact with no apparent deficit in sensation of his right hand. There was no erythema or overlying skin changes. His right thenar eminence was mildly enlarged as compared with the left, and a firm, focal mass was readily palpated. Range of motion at the metacarpophalangeal joint of the thumb and index finger was limited because of pain. Thumb opposition was markedly limited. After a detailed history and physical examination, we were concerned about possible deep space infection, old hematoma, or possible metastatic disease. Magnetic resonance imaging (MRI) was ordered to evaluate the palpable mass.

Radiographically, localized soft-tissue swelling was present on the palmar surface of the hand obliquely overlying the index finger metacarpal (Figures 2, 3). On MRI, the lesion measured approximately 1.8×3.3 cm and was isointense to slightly hyperintense diffusely with central hyperintensity on T1 images (Figure 4). On T2 and short tau inversion recovery images, the lesion was more strikingly hyperintense and infiltrative in appearance (Figure 5). Postcontrast images showed avid enhancement peripherally, with central nonenhancement consistent with necrosis in the adductor pollicis.

We performed a biopsy of the lesion with the aid of immediate adequacy by fine needle aspiration cytology. We saw mitotically active malignant cells with large nuclei, high nuclear-to-cytoplasmic ratios, nucleoli, and dense cytoplasm, suggesting a metastatic squamous cell carcinoma. Because infection was part of the differential, it is pertinent to note that there was no significant inflammatory infiltrate. The core biopsy was consistent with metastatic lung cancer (Figure 6).

Discussion

This patient presented an interesting diagnostic challenge, particularly because of his previous malignancy. The differential diagnosis of acute onset thenar pain without history of trauma would include encompassing soft-tissue abscess, osteomyelitis, and infectious myositis. Soft-tissue hematoma is also in the differential for this patient, especially given the malignancy. Bony metastasis should be considered in this patient given the propensity of lung carcinoma to metastasize to bone. The location would certainly be atypical, with metastasis to the bones of the forearm or hand representing only 0.1% of all metastasis of any type of primary carcinoma or sarcoma.⁴ Primary bone or soft-tissue sarcoma should also be considered. Some authors have also suggested that necrosis, peritumoral edema-like signal, and lobulation are more common with skeletal muscle metastasis than with a primary sarcoma.¹⁰ In this case, the degree of surrounding postcontrast enhancement made simple muscle tear with hematoma unlikely, despite the  presence of increased T1 signal. The lack of evidence for localized infection and the presence of a firm focal mass on physical examination made tumor more likely than infection.        

Acrometastasis

Metastatic disease distal to the elbow and knee is very rare; specifically, metastatic disease of the hands or feet accounts for approximately 0.1% of all metastases.⁴ Carcinoma of the lung accounts for 44% to 47% of all acrometastasis.^11,12 When hand acrometastasis is considered, the right hand accounts for 55% of bony cases, likely because of hand dominance, although approximately 10% of patients had bilateral acral metastatic disease.¹² The underlying mechanism of acrometastasis remains unclear; however, some authors have postulated that it may result from an increase in vascularity or a trauma to the affected extremity.^12,13 Flynn and colleagues¹² reviewed the literature and reported a total of 257 cases of acral metastasis to the hand; they found that the median age at presentation was 58 years. Men were more than twice as likely to be affected when compared with women. Most commonly, the primary malignancies were in the lung (44%), kidney (12%), and breast (10%). The authors also reported less common cases of acral metastasis with primary malignancies located in the stomach, liver, rectum, prostate, and colon. Most commonly, these metastases were found in the distal phalynx, followed by the metacarpals, proximal phalynx, and middle phalynx.¹²

Soft-Tissue Metastasis

Skeletal muscle metastasis occurs in 0.8% to 17.5% of metastatic neoplasms.^14-17 Studies in lung cancer patients have also revealed a low prevalence of muscular metastasis (0% to 0.8%).¹⁶ The rarity of muscular metastatic disease has been attributed to local inhibition of tumor survival secondary to muscle contraction, increased diffusing capacity of enzymes and immune cells, and extreme variability in blood flow and pH, lactate, and oxygen concentration. Skeletal muscular metastases most commonly arise from the lung, kidneys, colon, or melanoma.¹⁶ In a recent large series of more than 1400 patients imaged for soft-tissue masses, 2.5% were metastatic.¹⁸ There are only 2 reports of soft-tissue metastatic disease involving the hand: one from a patient with a thyroid carcinoma and the other from a patient with a lung adenocarcinoma.¹⁸ Soft-tissue metastatic disease from squamous cell carcinoma distal to the wrist has never been reported in the literature.  

Acral Soft-Tissue Metastasis

A review from 2012 found 264 cases of skeletal muscle metastasis from 151 articles.⁶ Only 2 (0.75%) of these patients, as reported above, had a soft-tissue metastasis distal to the wrist.^6,17

Conclusion

We report the first known case of a soft-tissue metastasis distal to the wrist from a primary bronchogenic squamous cell carcinoma. This report highlights the extremely uncommon presentation of soft-tissue acral metastatic disease of a bronchogenic squamous cell carcinoma of the lung. Although exceedingly rare, oncologists and physicians who manage pathology of the hand should consider metastatic disease when evaluating a patient with complaints of hand pain and a soft-tissue mass, especially in a patient with a known primary malignancy.

Carcinoma of the lung is the most common lethal form of cancer in both men and women worldwide.¹ It accounts for more deaths than the next 3 most common cancers combined. In 2012, 160,000 Americans are estimated to have died from lung cancer.¹ Lung cancer is known to have a high metastatic potential for the brain, bones, adrenal glands, lungs, and liver.² Orthopedic manifestations frequently include bony metastasis, most commonly the vertebrae (42%), ribs (20%), and pelvis (18%).³ Acral metastatic disease is defined as metastasis distal to the elbow or the knee. Bony acral metastases from lung carcinoma to the upper and lower extremities are extremely uncommon, accounting for only 1% each of total bone metastases from carcinoma of the lung.³ Metastases to the bones of the hand are even rarer. Only 0.1% of metastatic disease from any type of carcinoma or sarcoma manifests as metastasis in the hand.⁴ There are only a few reports in the literature of soft-tissue or muscular metastasis to the hand from a carcinoma. Of these cases, the majority are caused by metastatic lung carcinoma.^5-9 There are no reports in the literature of metastatic disease of squamous cell origin affecting the soft tissues of the hand.

We present a case of a man with known metastatic squamous cell carcinoma of the lung who presented with acral soft-tissue metastatic disease. This report highlights a rare clinical scenario that has not been reported in the literature. The report also emphasizes a rare but important consideration for clinicians who encounter acral soft-tissue lesions in patients with a history of a primary carcinoma. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 56-year-old man presented with right-sided pleuritic flank pain, along with a 30-lb weight loss over a 6-month period. A computed tomographic scan revealed a 5.58×3.7-cm cavitary lesion in the right lower lobe with abutment of the posterior chest wall (Figure 1). He underwent biopsy and staging, and was found to be T3N1, with biopsy-proven well-differentiated bronchogenic squamous cell carcinoma. The patient then underwent right lower and middle lobectomy with concomitant en-bloc resection of the posterior portion of ribs 7 to 11, along with mediastinal lymph-node dissection with negative margins. After surgery, he was treated with 4 cycles of adjuvant chemotherapy with cisplatin and docetaxel.

Six months after surgery, the patient began to complain of right-hand pain isolated to the thenar eminence. He also described swelling and significant pain with active or passive movement of the thumb and with relatively mild-to-moderate palpation of the area. The patient reported that the functioning of his thumb deteriorated rapidly over the course of about 1 month. On physical examination, he was neurovascularly intact with no apparent deficit in sensation of his right hand. There was no erythema or overlying skin changes. His right thenar eminence was mildly enlarged as compared with the left, and a firm, focal mass was readily palpated. Range of motion at the metacarpophalangeal joint of the thumb and index finger was limited because of pain. Thumb opposition was markedly limited. After a detailed history and physical examination, we were concerned about possible deep space infection, old hematoma, or possible metastatic disease. Magnetic resonance imaging (MRI) was ordered to evaluate the palpable mass.

Radiographically, localized soft-tissue swelling was present on the palmar surface of the hand obliquely overlying the index finger metacarpal (Figures 2, 3). On MRI, the lesion measured approximately 1.8×3.3 cm and was isointense to slightly hyperintense diffusely with central hyperintensity on T1 images (Figure 4). On T2 and short tau inversion recovery images, the lesion was more strikingly hyperintense and infiltrative in appearance (Figure 5). Postcontrast images showed avid enhancement peripherally, with central nonenhancement consistent with necrosis in the adductor pollicis.

We performed a biopsy of the lesion with the aid of immediate adequacy by fine needle aspiration cytology. We saw mitotically active malignant cells with large nuclei, high nuclear-to-cytoplasmic ratios, nucleoli, and dense cytoplasm, suggesting a metastatic squamous cell carcinoma. Because infection was part of the differential, it is pertinent to note that there was no significant inflammatory infiltrate. The core biopsy was consistent with metastatic lung cancer (Figure 6).

Discussion

This patient presented an interesting diagnostic challenge, particularly because of his previous malignancy. The differential diagnosis of acute onset thenar pain without history of trauma would include encompassing soft-tissue abscess, osteomyelitis, and infectious myositis. Soft-tissue hematoma is also in the differential for this patient, especially given the malignancy. Bony metastasis should be considered in this patient given the propensity of lung carcinoma to metastasize to bone. The location would certainly be atypical, with metastasis to the bones of the forearm or hand representing only 0.1% of all metastasis of any type of primary carcinoma or sarcoma.⁴ Primary bone or soft-tissue sarcoma should also be considered. Some authors have also suggested that necrosis, peritumoral edema-like signal, and lobulation are more common with skeletal muscle metastasis than with a primary sarcoma.¹⁰ In this case, the degree of surrounding postcontrast enhancement made simple muscle tear with hematoma unlikely, despite the  presence of increased T1 signal. The lack of evidence for localized infection and the presence of a firm focal mass on physical examination made tumor more likely than infection.        

Acrometastasis

Metastatic disease distal to the elbow and knee is very rare; specifically, metastatic disease of the hands or feet accounts for approximately 0.1% of all metastases.⁴ Carcinoma of the lung accounts for 44% to 47% of all acrometastasis.^11,12 When hand acrometastasis is considered, the right hand accounts for 55% of bony cases, likely because of hand dominance, although approximately 10% of patients had bilateral acral metastatic disease.¹² The underlying mechanism of acrometastasis remains unclear; however, some authors have postulated that it may result from an increase in vascularity or a trauma to the affected extremity.^12,13 Flynn and colleagues¹² reviewed the literature and reported a total of 257 cases of acral metastasis to the hand; they found that the median age at presentation was 58 years. Men were more than twice as likely to be affected when compared with women. Most commonly, the primary malignancies were in the lung (44%), kidney (12%), and breast (10%). The authors also reported less common cases of acral metastasis with primary malignancies located in the stomach, liver, rectum, prostate, and colon. Most commonly, these metastases were found in the distal phalynx, followed by the metacarpals, proximal phalynx, and middle phalynx.¹²

Soft-Tissue Metastasis

Skeletal muscle metastasis occurs in 0.8% to 17.5% of metastatic neoplasms.^14-17 Studies in lung cancer patients have also revealed a low prevalence of muscular metastasis (0% to 0.8%).¹⁶ The rarity of muscular metastatic disease has been attributed to local inhibition of tumor survival secondary to muscle contraction, increased diffusing capacity of enzymes and immune cells, and extreme variability in blood flow and pH, lactate, and oxygen concentration. Skeletal muscular metastases most commonly arise from the lung, kidneys, colon, or melanoma.¹⁶ In a recent large series of more than 1400 patients imaged for soft-tissue masses, 2.5% were metastatic.¹⁸ There are only 2 reports of soft-tissue metastatic disease involving the hand: one from a patient with a thyroid carcinoma and the other from a patient with a lung adenocarcinoma.¹⁸ Soft-tissue metastatic disease from squamous cell carcinoma distal to the wrist has never been reported in the literature.  

Acral Soft-Tissue Metastasis

A review from 2012 found 264 cases of skeletal muscle metastasis from 151 articles.⁶ Only 2 (0.75%) of these patients, as reported above, had a soft-tissue metastasis distal to the wrist.^6,17

Conclusion

We report the first known case of a soft-tissue metastasis distal to the wrist from a primary bronchogenic squamous cell carcinoma. This report highlights the extremely uncommon presentation of soft-tissue acral metastatic disease of a bronchogenic squamous cell carcinoma of the lung. Although exceedingly rare, oncologists and physicians who manage pathology of the hand should consider metastatic disease when evaluating a patient with complaints of hand pain and a soft-tissue mass, especially in a patient with a known primary malignancy.

Carcinoma of the lung is the most common lethal form of cancer in both men and women worldwide.¹ It accounts for more deaths than the next 3 most common cancers combined. In 2012, 160,000 Americans are estimated to have died from lung cancer.¹ Lung cancer is known to have a high metastatic potential for the brain, bones, adrenal glands, lungs, and liver.² Orthopedic manifestations frequently include bony metastasis, most commonly the vertebrae (42%), ribs (20%), and pelvis (18%).³ Acral metastatic disease is defined as metastasis distal to the elbow or the knee. Bony acral metastases from lung carcinoma to the upper and lower extremities are extremely uncommon, accounting for only 1% each of total bone metastases from carcinoma of the lung.³ Metastases to the bones of the hand are even rarer. Only 0.1% of metastatic disease from any type of carcinoma or sarcoma manifests as metastasis in the hand.⁴ There are only a few reports in the literature of soft-tissue or muscular metastasis to the hand from a carcinoma. Of these cases, the majority are caused by metastatic lung carcinoma.^5-9 There are no reports in the literature of metastatic disease of squamous cell origin affecting the soft tissues of the hand.

We present a case of a man with known metastatic squamous cell carcinoma of the lung who presented with acral soft-tissue metastatic disease. This report highlights a rare clinical scenario that has not been reported in the literature. The report also emphasizes a rare but important consideration for clinicians who encounter acral soft-tissue lesions in patients with a history of a primary carcinoma. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 56-year-old man presented with right-sided pleuritic flank pain, along with a 30-lb weight loss over a 6-month period. A computed tomographic scan revealed a 5.58×3.7-cm cavitary lesion in the right lower lobe with abutment of the posterior chest wall (Figure 1). He underwent biopsy and staging, and was found to be T3N1, with biopsy-proven well-differentiated bronchogenic squamous cell carcinoma. The patient then underwent right lower and middle lobectomy with concomitant en-bloc resection of the posterior portion of ribs 7 to 11, along with mediastinal lymph-node dissection with negative margins. After surgery, he was treated with 4 cycles of adjuvant chemotherapy with cisplatin and docetaxel.

Six months after surgery, the patient began to complain of right-hand pain isolated to the thenar eminence. He also described swelling and significant pain with active or passive movement of the thumb and with relatively mild-to-moderate palpation of the area. The patient reported that the functioning of his thumb deteriorated rapidly over the course of about 1 month. On physical examination, he was neurovascularly intact with no apparent deficit in sensation of his right hand. There was no erythema or overlying skin changes. His right thenar eminence was mildly enlarged as compared with the left, and a firm, focal mass was readily palpated. Range of motion at the metacarpophalangeal joint of the thumb and index finger was limited because of pain. Thumb opposition was markedly limited. After a detailed history and physical examination, we were concerned about possible deep space infection, old hematoma, or possible metastatic disease. Magnetic resonance imaging (MRI) was ordered to evaluate the palpable mass.

Radiographically, localized soft-tissue swelling was present on the palmar surface of the hand obliquely overlying the index finger metacarpal (Figures 2, 3). On MRI, the lesion measured approximately 1.8×3.3 cm and was isointense to slightly hyperintense diffusely with central hyperintensity on T1 images (Figure 4). On T2 and short tau inversion recovery images, the lesion was more strikingly hyperintense and infiltrative in appearance (Figure 5). Postcontrast images showed avid enhancement peripherally, with central nonenhancement consistent with necrosis in the adductor pollicis.

We performed a biopsy of the lesion with the aid of immediate adequacy by fine needle aspiration cytology. We saw mitotically active malignant cells with large nuclei, high nuclear-to-cytoplasmic ratios, nucleoli, and dense cytoplasm, suggesting a metastatic squamous cell carcinoma. Because infection was part of the differential, it is pertinent to note that there was no significant inflammatory infiltrate. The core biopsy was consistent with metastatic lung cancer (Figure 6).

Discussion

This patient presented an interesting diagnostic challenge, particularly because of his previous malignancy. The differential diagnosis of acute onset thenar pain without history of trauma would include encompassing soft-tissue abscess, osteomyelitis, and infectious myositis. Soft-tissue hematoma is also in the differential for this patient, especially given the malignancy. Bony metastasis should be considered in this patient given the propensity of lung carcinoma to metastasize to bone. The location would certainly be atypical, with metastasis to the bones of the forearm or hand representing only 0.1% of all metastasis of any type of primary carcinoma or sarcoma.⁴ Primary bone or soft-tissue sarcoma should also be considered. Some authors have also suggested that necrosis, peritumoral edema-like signal, and lobulation are more common with skeletal muscle metastasis than with a primary sarcoma.¹⁰ In this case, the degree of surrounding postcontrast enhancement made simple muscle tear with hematoma unlikely, despite the  presence of increased T1 signal. The lack of evidence for localized infection and the presence of a firm focal mass on physical examination made tumor more likely than infection.        

Acrometastasis

Metastatic disease distal to the elbow and knee is very rare; specifically, metastatic disease of the hands or feet accounts for approximately 0.1% of all metastases.⁴ Carcinoma of the lung accounts for 44% to 47% of all acrometastasis.^11,12 When hand acrometastasis is considered, the right hand accounts for 55% of bony cases, likely because of hand dominance, although approximately 10% of patients had bilateral acral metastatic disease.¹² The underlying mechanism of acrometastasis remains unclear; however, some authors have postulated that it may result from an increase in vascularity or a trauma to the affected extremity.^12,13 Flynn and colleagues¹² reviewed the literature and reported a total of 257 cases of acral metastasis to the hand; they found that the median age at presentation was 58 years. Men were more than twice as likely to be affected when compared with women. Most commonly, the primary malignancies were in the lung (44%), kidney (12%), and breast (10%). The authors also reported less common cases of acral metastasis with primary malignancies located in the stomach, liver, rectum, prostate, and colon. Most commonly, these metastases were found in the distal phalynx, followed by the metacarpals, proximal phalynx, and middle phalynx.¹²

Soft-Tissue Metastasis

Skeletal muscle metastasis occurs in 0.8% to 17.5% of metastatic neoplasms.^14-17 Studies in lung cancer patients have also revealed a low prevalence of muscular metastasis (0% to 0.8%).¹⁶ The rarity of muscular metastatic disease has been attributed to local inhibition of tumor survival secondary to muscle contraction, increased diffusing capacity of enzymes and immune cells, and extreme variability in blood flow and pH, lactate, and oxygen concentration. Skeletal muscular metastases most commonly arise from the lung, kidneys, colon, or melanoma.¹⁶ In a recent large series of more than 1400 patients imaged for soft-tissue masses, 2.5% were metastatic.¹⁸ There are only 2 reports of soft-tissue metastatic disease involving the hand: one from a patient with a thyroid carcinoma and the other from a patient with a lung adenocarcinoma.¹⁸ Soft-tissue metastatic disease from squamous cell carcinoma distal to the wrist has never been reported in the literature.  

Acral Soft-Tissue Metastasis

A review from 2012 found 264 cases of skeletal muscle metastasis from 151 articles.⁶ Only 2 (0.75%) of these patients, as reported above, had a soft-tissue metastasis distal to the wrist.^6,17

Conclusion

We report the first known case of a soft-tissue metastasis distal to the wrist from a primary bronchogenic squamous cell carcinoma. This report highlights the extremely uncommon presentation of soft-tissue acral metastatic disease of a bronchogenic squamous cell carcinoma of the lung. Although exceedingly rare, oncologists and physicians who manage pathology of the hand should consider metastatic disease when evaluating a patient with complaints of hand pain and a soft-tissue mass, especially in a patient with a known primary malignancy.

Hip arthroscopy has experienced a dramatic increase in popularity, largely resulting from improvements in techniques and technology.^1,2 As with any procedure, there are complications associated with arthroscopy of the hip. These include neurapraxia, iatrogenic cartilage and labral injuries, postoperative bleeding, perineal skin necrosis, infection, intra-articular instrument breakage, intra-abdominal fluid extravasation, avascular necrosis, and femoral neck fracture.^1-4 Many of these have been attributed to the expected learning curve seen with any new procedure, and are less likely to occur as surgeons become more familiar with the procedure.¹ One rare but serious complication is anterior dislocation of the hip.^5-7

We present a patient who experienced an anterior hip dislocation and instability after hip arthroscopy, and was successfully treated with an anterior capsuloligamentous reconstruction. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

An otherwise healthy 37-year-old woman presented to our clinic with a 6-month history of right groin pain and an occasional popping sensation during activity, which was unresponsive to hip-specific physical therapy. On physical examination, she was 5 ft 10 in tall, weighed 150 lbs, and appeared in excellent physical condition. She had no signs of systemic ligamentous laxity. She had an otherwise normal musculoskeletal, neurologic, and vascular examination in her bilateral lower extremities. She had a mild antalgic gait on the right leg.

The affected right hip could be flexed painfully to 120º, extended to 0º, adducted 20º, and abducted 45º. At 90º of flexion, her right hip could be externally rotated 30º and internally rotated 20º. Internal rotation during hip flexion beyond 90º caused sharp pain in the groin. Her normal left hip could be flexed to 120º, extended to 0º, adducted 30º, and abducted 60º. At 90º of flexion, her left hip could be externally rotated 50º and internally rotated 30º. She had negative Ober tests bilaterally but had tenderness along the right iliotibial band. She had negative Patrick and Gaenslen tests bilaterally. She had no tenderness in the area of either greater trochanter. 

Imaging evaluation included plain radiographs and a magnetic resonance arthrogram (MRA) of the right hip. The plain radiographs showed signs of femoroacetabular impingement, but no joint space narrowing, no dysplasia, and no retroversion of the acetabulum (Figures 1A, 1B). The MRA showed a degenerative peripheral tear of the anterosuperior labrum without significant cartilage wear (Figure 2).

Based upon her findings on physical examination and imaging, we recommended arthroscopic treatment of her right hip pathology. Thirteen months after initial presentation, we performed a right hip arthroscopy with the patient in the supine position. Through modified anterior and anterolateral portals, we used electrocautery to perform a capsulotomy from the 9 o’clock to 12 o’clock positions. A central compartment diagnostic arthroscopy showed mild degenerative fraying of the labrum from the 9 o’clock to 12 o’clock positions without signs of detachment. There was grade III chondral fraying near the articular margin in that same arc. The femoral articular cartilage appeared normal, as did the ligamentum teres. We used a shaver to gently débride the torn labrum down to stable tissue. The frayed cartilage on the acetabulum was also gently débrided.

Traction was released and the hip was flexed. Minimal capsular release and débridement were performed for adequate visualization of the peripheral compartment. A diagnostic examination revealed a significant cam-type impingement lesion from the 12 o’clock to 6 o’clock positions. We performed a femoral neck resection, with a proximal-distal dimension of 15 mm and a depth of 7 mm. A dynamic fluoroscopic examination of the hip joint showed no signs of impingement. In accordance with our standard protocol, the anterior capsulotomy was not repaired.

Postoperatively, the patient was instructed to perform toe-touch weight-bearing with crutches for 2 weeks and to advance to full weight-bearing over the next 2 weeks. She did not use a hip orthosis. She was also advised to avoid combined hip extension/external rotation maneuvers for the first 4 weeks. She took part in a formal hip-specific physical therapy program for a total of 12 weeks. She was seen in clinic at 2, 6, and 12 weeks postoperatively and appeared to have had a typical, uneventful course. We advised her to gradually return to normal activities as tolerated at the 12-week visit.

Four months after the procedure, the patient returned to our clinic for evaluation after a right hip dislocation. Two days prior, she was at a school function with her child and experienced sudden pain and inability to bear weight after she extended and externally rotated her right hip in a low-energy manner. She was taken to an emergency room and found to have an anterior dislocation of the right hip (Figure 3), which was concentrically reduced under anesthesia.

Upon questioning, she reported having had feelings of mild instability of the right hip during demanding activities (jogging, yoga) after sustaining a low-energy fall 1 month prior to her dislocation. On examination, she had significant apprehension about the right hip during gentle external rotation maneuvers. An MRA 2 weeks after the dislocation showed a large defect of the anterosuperior capsuloligamentous complex measuring 4 cm from medial to lateral and 2.5 cm superior to inferior (Figure 4). No loose bodies, chondral injuries, or recurrent tears of the labrum were seen. Typical postoperative changes were observed at the femoral head-neck junction.

Initially, we recommended nonoperative management with 6 weeks of toe-touch weight-bearing and strict avoidance of hip extension–external rotation maneuvers. No hip orthosis was used. After this period, the patient advanced to full weight-bearing and continued in hip-specific physical therapy. Despite continued therapy and avoidance of provocative maneuvers, the patient reported persistent feelings of right hip instability with significant apprehension during extension and external rotation of the right hip. A repeat MRA 4 months after the hip dislocation showed a persistent defect in the anterosuperior capsuloligamentous complex and no signs of avascular necrosis. After 6 months of conservative treatment, we recommended an open capsulorrhaphy of the right hip with autograft iliotibial band reconstruction of the iliofemoral ligament and capsule.

Six months after the dislocation, the patient underwent the recommended procedure. After induction of general anesthesia, she was placed in the supine position on a standard operating table. A Smith-Petersen approach was used to visualize the anterior hip structures. During deep dissection, we observed a large defect, measuring 2.5×4 cm (Figure 5A), in the anterior hip capsule, with only a thin pseudocapsule covering the femoral head. Extensive mobilization of the anterior capsule was unsuccessful.

The decision was made to harvest a graft from the patient’s ipsilateral iliotibial band. A skin incision was made over the iliotibial band in the distal midthigh region, and a 2.5×4-cm graft was harvested from the central portion of the iliotibial band. An arthrotomy was performed on the hip joint (Figure 5B). The labrum appeared healthy without recurrent tearing or fraying, and other than focal thinning on the superior acetabulum, the cartilage appeared healthy. A double-loaded anchor was placed in the supra-acetabular region, and the sutures were passed through the graft. Then, No. 2 nonabsorbable sutures were sequentially placed between the capsular remnant and the graft medially, inferiorly, and laterally. The graft was placed into position (Figure 5C) and the sutures were tied (Figure 5D).

Postoperatively, the patient was allowed toe-touch weight-bearing for 6 weeks, with strict avoidance of extension–external rotation maneuvers. She participated in a 12-week course of physical therapy with gradual advancement of activities. About a year after the capsulorrhaphy, she was able to resume all previous activities with only occasional low-level discomfort. She returned to the clinic 16 months after the capsulorrhaphy complaining of increased pain with long-distance running but denied feelings of instability. We performed an intra-articular hip injection under ultrasound guidance, which provided 100% relief of her symptoms. We obtained an MRA to evaluate for any recurrent capsular or labral injury (Figure 6). The previous anterosuperior capsular defect was not visible, and no signs of recurrent labral or cartilage injury were seen.

Discussion

With the increasing popularity of hip arthroscopy, more complications are being reported as well, including postoperative hip instability. Three separate cases of anterior hip instability have been published in the past several years.^5-7

Ranawat and colleagues⁵ were the first to report a case of postoperative anterior hip dislocation after arthroscopy. Their patient was a 52-year-old woman with right hip pain and generalized ligamentous laxity. Her preoperative radiographs showed no evidence of degenerative changes, dysplasia, or femoroacetabular impingement. An MRA showed a peripheral tear of the anterosuperior labrum. At arthroscopy, her right hip was easily distracted 2 to 3 cm with what they described as “minimal traction.” A small 1- to 2-cm capsulotomy was performed about the anterior portal. A detached labral tear was identified and repaired with an anchor, and no rim resection was performed. To improve visualization of the peripheral compartment, they extended the previous capsulotomy 1 to 2 cm and débrided the edges. A cam-type lesion was identified and resected. Lastly, they performed an anterior capsular plication, specifically including the iliofemoral ligament. Postoperatively, the patient wore a hip orthosis for 6 weeks to prevent extension and external rotation of the hip as well as a foot brace at night for 3 weeks. The patient was allowed to partially bear weight for the first 6 weeks with use of crutches. Approximately 2 months postoperatively, she slipped and fell down a short flight of stairs. She was diagnosed with an anterior hip dislocation. After successful closed reduction, she was treated conservatively with the same regimen used earlier. She remained symptomatic over the next several months with signs of instability and apprehension, and she eventually underwent a repeat hip arthroscopy. A 1- to 2-cm tear of the anterior capsule and iliofemoral ligament was treated with a revision arthroscopic capsular plication. A postoperative regimen similar to that used at the index procedure was instituted and, at most recent follow-up, she was found to have occasional pain without instability.

Matsuda⁶ reported a case of acute iatrogenic hip dislocation after arthroscopic surgery. His patient was a 39-year-old woman with a mildly retroverted acetabulum leading to impingement about the hip. She had no signs of generalized ligamentous laxity. A hip arthroscopy in the lateral position was performed, with no comment about the extent of the capsulotomy. During the procedure, about 5 mm of anterosuperior acetabulum were removed as part of arthroscopic rim trimming for treatment of the pincer lesion. A femoral osteochondroplasty was also performed (unspecified size) to restore more normal anterolateral offset. One confounding factor was that supranormal hip distraction was needed for 20 minutes to aid in removal of a metallic piece from a radiofrequency ablator, which inadvertently detached. The patient experienced an anterior hip dislocation in the recovery room and was found to be unstable during closed reduction under general anesthesia. A mini-open capsular repair was performed, which showed a 1×1.5-cm defect in the anterolateral capsule. After closure of the defect, the hip was found to be stable under fluoroscopic examination. Postoperatively, the patient was allowed to perform partial weight-bearing in a hip-knee-ankle-foot orthosis for 2 months and then a flexible hip brace for 1 month. At 15-month follow-up, her hip was stable and she was pain-free.

Benali and Katthagen⁷ highlighted the significant contribution of the labrum to hip stability in a dysplastic hip. Their patient was a 49-year-old woman with mild hip dysplasia and a degenerative bucket-handle tear of the ventrolateral labrum. The patient underwent a near-complete labral resection and rim trimming at an outside institution. The patient began full weight-bearing at 3 weeks postoperatively and noticed considerable groin and back pain (no hip orthosis use was mentioned). After failed treatment for suspected lumbar pathology, she was referred to the authors’ clinic for further evaluation. Plain radiographs showed subluxation of the left hip with degenerative changes. The patient had an uneventful left total hip arthroplasty (THA).

After reviewing the 3 reported cases of hip instability after arthroscopy, we suggest that surgeons fully recognize and appreciate the delicate balance of stability and motion provided by the static and dynamic stabilizers of the hip joint, and be cognizant of potential imbalance created by surgical intervention.^8,9 Postarthroscopic hip instability appears to be multifactorial in nature, because all of the reported cases detailed different factors, both patient- and surgeon-related, contributing to instability.

Ranawat and colleagues⁵ identified several factors that may have contributed to the anterior hip dislocation sustained by their patient, including the patient’s generalized ligamentous laxity, performance of a capsulectomy (with repair of iliofemoral ligament), and a traumatic fall. Benali and Katthagen⁷ (although they did not perform the index procedure) described the disastrous complication of overzealous labral resection and rim trimming in a patient with hip dysplasia. Matsuda⁶ performed a labral resection and rim trimming, an extended (unspecified size) capsulotomy, and also used supranormal traction for 20 minutes to remove an iatrogenic foreign body. Surgeons performing hip arthroscopies should be aware of all these factors, because many are directly controlled by the surgeon.

The only factor we feel may have contributed to hip instability in our patient was the performance of a capsulotomy without closure. Our patient was an otherwise healthy woman with no signs of ligamentous laxity, hip dysplasia, or retroversion of the acetabulum. We did not perform a labral resection or rim trimming. We use modified anterior and anterolateral portals, and electrocautery to connect the portals. This typically leads to a release of a thin strip (less than 5 mm wide) of 3 cm of capsule. Based upon findings at rare second-look arthroscopy for recurrent symptoms, Dr. Guanche has observed that the capsulotomy from the initial procedure heals with normal-appearing tissue. Also, during peripheral compartment arthroscopy, we do not routinely release the iliofemoral ligament, and the orbicular ligament is left intact. Instead, we prefer to flex the hip and débride only enough capsular tissue to allow for adequate visualization. 

Little has been published on capsulotomy closure after hip arthroscopy, and no consensus exists. Our standard practice is to not close the capsulotomy, which accords with the practice of other surgeons.⁹ There is concern, however, that extensive capsulotomy leading to injury or disruption of the iliofemoral ligament may cause anterior hip instability, driving other prominent hip arthroscopists to routinely close the capsulotomy.^9,10 Myers and colleagues¹⁰ published a recent biomechanical study on the role of the labrum and the capsular ligaments in hip stability. They concluded that the iliofemoral ligament plays a significant role in limiting external rotation and anterior translation of the femoral head, and recommended closure of the capsulotomy after arthroscopy. Of note, Dr. Guanche has performed more than 1500 hip arthroscopic procedures in the past 5 years, and we are aware of only 2 patients who have sustained anterior hip dislocations, in spite of our not closing the capsulotomy defect. This highlights an important clinical question in need of further investigation.

Our case also raises questions about the ideal postoperative regimen after standard hip arthroscopy. Although we do not routinely prescribe hip orthoses for our patients, others do.⁵ We are unaware of any proven benefit to the standard use of hip orthoses, and are concerned over the possible lack of patient compliance and of adequate restraint. We prefer to educate our patients on avoiding the “at-risk” position of hip extension and external rotation and to counsel them on gradual return to activities. Studies are needed to determine the role of these devices in hip arthroscopy, as well as the ideal postoperative activity regimen.

Our patient failed 6 months of conservative treatment after her dislocation and continued to have feelings of hip instability even during light activities. As a result of this failure and given an anatomical defect in the anterior capsuloligamentous complex, we decided our patient would be best treated with reconstruction of the defect. We did not think a revision capsular plication, as done by Ranawat and colleagues,⁵ was a reasonable option for our patient because of a large defect in the capsular tissue. Even in smaller defects, plication could potentially lead to overtightening of the capsule and subsequent overconstraint of the joint. Also, plication of defects may place excessive strain on the suture, which may fail if the repair is even mildly stressed.

Recurrent anterior hip dislocations, although rare in their own right, are much more common after THA than after hip arthroscopy.¹¹ Fujishiro and colleagues¹² described a similar technique to ours developed to treat a patient with recurrent anterior hip instability from anterior capsular insufficiency after multiple revision THA procedures. They used a Leeds-Keio artificial ligament to reconstruct the iliofemoral ligament, and this successfully treated their patient’s instability.

Conclusion

We believe this is the first report of recurrent instability after hip arthroscopy, necessitating reconstruction of the anterior capsuloligamentous complex. This case shows that reconstruction of the iliofemoral ligament with iliotibial band autograft is safe, restores hip stability without compromising function, and should be considered by any hip arthroscopist encountering a similar scenario. It also highlights the importance of the capsuloligamentous complex surrounding the hip joint for its stability and the need for further research to better delineate the indications for capsular repair/closure after capsulotomy.

Hip arthroscopy has experienced a dramatic increase in popularity, largely resulting from improvements in techniques and technology.^1,2 As with any procedure, there are complications associated with arthroscopy of the hip. These include neurapraxia, iatrogenic cartilage and labral injuries, postoperative bleeding, perineal skin necrosis, infection, intra-articular instrument breakage, intra-abdominal fluid extravasation, avascular necrosis, and femoral neck fracture.^1-4 Many of these have been attributed to the expected learning curve seen with any new procedure, and are less likely to occur as surgeons become more familiar with the procedure.¹ One rare but serious complication is anterior dislocation of the hip.^5-7

We present a patient who experienced an anterior hip dislocation and instability after hip arthroscopy, and was successfully treated with an anterior capsuloligamentous reconstruction. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

An otherwise healthy 37-year-old woman presented to our clinic with a 6-month history of right groin pain and an occasional popping sensation during activity, which was unresponsive to hip-specific physical therapy. On physical examination, she was 5 ft 10 in tall, weighed 150 lbs, and appeared in excellent physical condition. She had no signs of systemic ligamentous laxity. She had an otherwise normal musculoskeletal, neurologic, and vascular examination in her bilateral lower extremities. She had a mild antalgic gait on the right leg.

The affected right hip could be flexed painfully to 120º, extended to 0º, adducted 20º, and abducted 45º. At 90º of flexion, her right hip could be externally rotated 30º and internally rotated 20º. Internal rotation during hip flexion beyond 90º caused sharp pain in the groin. Her normal left hip could be flexed to 120º, extended to 0º, adducted 30º, and abducted 60º. At 90º of flexion, her left hip could be externally rotated 50º and internally rotated 30º. She had negative Ober tests bilaterally but had tenderness along the right iliotibial band. She had negative Patrick and Gaenslen tests bilaterally. She had no tenderness in the area of either greater trochanter. 

Imaging evaluation included plain radiographs and a magnetic resonance arthrogram (MRA) of the right hip. The plain radiographs showed signs of femoroacetabular impingement, but no joint space narrowing, no dysplasia, and no retroversion of the acetabulum (Figures 1A, 1B). The MRA showed a degenerative peripheral tear of the anterosuperior labrum without significant cartilage wear (Figure 2).

Based upon her findings on physical examination and imaging, we recommended arthroscopic treatment of her right hip pathology. Thirteen months after initial presentation, we performed a right hip arthroscopy with the patient in the supine position. Through modified anterior and anterolateral portals, we used electrocautery to perform a capsulotomy from the 9 o’clock to 12 o’clock positions. A central compartment diagnostic arthroscopy showed mild degenerative fraying of the labrum from the 9 o’clock to 12 o’clock positions without signs of detachment. There was grade III chondral fraying near the articular margin in that same arc. The femoral articular cartilage appeared normal, as did the ligamentum teres. We used a shaver to gently débride the torn labrum down to stable tissue. The frayed cartilage on the acetabulum was also gently débrided.

Traction was released and the hip was flexed. Minimal capsular release and débridement were performed for adequate visualization of the peripheral compartment. A diagnostic examination revealed a significant cam-type impingement lesion from the 12 o’clock to 6 o’clock positions. We performed a femoral neck resection, with a proximal-distal dimension of 15 mm and a depth of 7 mm. A dynamic fluoroscopic examination of the hip joint showed no signs of impingement. In accordance with our standard protocol, the anterior capsulotomy was not repaired.

Postoperatively, the patient was instructed to perform toe-touch weight-bearing with crutches for 2 weeks and to advance to full weight-bearing over the next 2 weeks. She did not use a hip orthosis. She was also advised to avoid combined hip extension/external rotation maneuvers for the first 4 weeks. She took part in a formal hip-specific physical therapy program for a total of 12 weeks. She was seen in clinic at 2, 6, and 12 weeks postoperatively and appeared to have had a typical, uneventful course. We advised her to gradually return to normal activities as tolerated at the 12-week visit.

Four months after the procedure, the patient returned to our clinic for evaluation after a right hip dislocation. Two days prior, she was at a school function with her child and experienced sudden pain and inability to bear weight after she extended and externally rotated her right hip in a low-energy manner. She was taken to an emergency room and found to have an anterior dislocation of the right hip (Figure 3), which was concentrically reduced under anesthesia.

Upon questioning, she reported having had feelings of mild instability of the right hip during demanding activities (jogging, yoga) after sustaining a low-energy fall 1 month prior to her dislocation. On examination, she had significant apprehension about the right hip during gentle external rotation maneuvers. An MRA 2 weeks after the dislocation showed a large defect of the anterosuperior capsuloligamentous complex measuring 4 cm from medial to lateral and 2.5 cm superior to inferior (Figure 4). No loose bodies, chondral injuries, or recurrent tears of the labrum were seen. Typical postoperative changes were observed at the femoral head-neck junction.

Initially, we recommended nonoperative management with 6 weeks of toe-touch weight-bearing and strict avoidance of hip extension–external rotation maneuvers. No hip orthosis was used. After this period, the patient advanced to full weight-bearing and continued in hip-specific physical therapy. Despite continued therapy and avoidance of provocative maneuvers, the patient reported persistent feelings of right hip instability with significant apprehension during extension and external rotation of the right hip. A repeat MRA 4 months after the hip dislocation showed a persistent defect in the anterosuperior capsuloligamentous complex and no signs of avascular necrosis. After 6 months of conservative treatment, we recommended an open capsulorrhaphy of the right hip with autograft iliotibial band reconstruction of the iliofemoral ligament and capsule.

Six months after the dislocation, the patient underwent the recommended procedure. After induction of general anesthesia, she was placed in the supine position on a standard operating table. A Smith-Petersen approach was used to visualize the anterior hip structures. During deep dissection, we observed a large defect, measuring 2.5×4 cm (Figure 5A), in the anterior hip capsule, with only a thin pseudocapsule covering the femoral head. Extensive mobilization of the anterior capsule was unsuccessful.

The decision was made to harvest a graft from the patient’s ipsilateral iliotibial band. A skin incision was made over the iliotibial band in the distal midthigh region, and a 2.5×4-cm graft was harvested from the central portion of the iliotibial band. An arthrotomy was performed on the hip joint (Figure 5B). The labrum appeared healthy without recurrent tearing or fraying, and other than focal thinning on the superior acetabulum, the cartilage appeared healthy. A double-loaded anchor was placed in the supra-acetabular region, and the sutures were passed through the graft. Then, No. 2 nonabsorbable sutures were sequentially placed between the capsular remnant and the graft medially, inferiorly, and laterally. The graft was placed into position (Figure 5C) and the sutures were tied (Figure 5D).

Postoperatively, the patient was allowed toe-touch weight-bearing for 6 weeks, with strict avoidance of extension–external rotation maneuvers. She participated in a 12-week course of physical therapy with gradual advancement of activities. About a year after the capsulorrhaphy, she was able to resume all previous activities with only occasional low-level discomfort. She returned to the clinic 16 months after the capsulorrhaphy complaining of increased pain with long-distance running but denied feelings of instability. We performed an intra-articular hip injection under ultrasound guidance, which provided 100% relief of her symptoms. We obtained an MRA to evaluate for any recurrent capsular or labral injury (Figure 6). The previous anterosuperior capsular defect was not visible, and no signs of recurrent labral or cartilage injury were seen.

Discussion

With the increasing popularity of hip arthroscopy, more complications are being reported as well, including postoperative hip instability. Three separate cases of anterior hip instability have been published in the past several years.^5-7

Ranawat and colleagues⁵ were the first to report a case of postoperative anterior hip dislocation after arthroscopy. Their patient was a 52-year-old woman with right hip pain and generalized ligamentous laxity. Her preoperative radiographs showed no evidence of degenerative changes, dysplasia, or femoroacetabular impingement. An MRA showed a peripheral tear of the anterosuperior labrum. At arthroscopy, her right hip was easily distracted 2 to 3 cm with what they described as “minimal traction.” A small 1- to 2-cm capsulotomy was performed about the anterior portal. A detached labral tear was identified and repaired with an anchor, and no rim resection was performed. To improve visualization of the peripheral compartment, they extended the previous capsulotomy 1 to 2 cm and débrided the edges. A cam-type lesion was identified and resected. Lastly, they performed an anterior capsular plication, specifically including the iliofemoral ligament. Postoperatively, the patient wore a hip orthosis for 6 weeks to prevent extension and external rotation of the hip as well as a foot brace at night for 3 weeks. The patient was allowed to partially bear weight for the first 6 weeks with use of crutches. Approximately 2 months postoperatively, she slipped and fell down a short flight of stairs. She was diagnosed with an anterior hip dislocation. After successful closed reduction, she was treated conservatively with the same regimen used earlier. She remained symptomatic over the next several months with signs of instability and apprehension, and she eventually underwent a repeat hip arthroscopy. A 1- to 2-cm tear of the anterior capsule and iliofemoral ligament was treated with a revision arthroscopic capsular plication. A postoperative regimen similar to that used at the index procedure was instituted and, at most recent follow-up, she was found to have occasional pain without instability.

Matsuda⁶ reported a case of acute iatrogenic hip dislocation after arthroscopic surgery. His patient was a 39-year-old woman with a mildly retroverted acetabulum leading to impingement about the hip. She had no signs of generalized ligamentous laxity. A hip arthroscopy in the lateral position was performed, with no comment about the extent of the capsulotomy. During the procedure, about 5 mm of anterosuperior acetabulum were removed as part of arthroscopic rim trimming for treatment of the pincer lesion. A femoral osteochondroplasty was also performed (unspecified size) to restore more normal anterolateral offset. One confounding factor was that supranormal hip distraction was needed for 20 minutes to aid in removal of a metallic piece from a radiofrequency ablator, which inadvertently detached. The patient experienced an anterior hip dislocation in the recovery room and was found to be unstable during closed reduction under general anesthesia. A mini-open capsular repair was performed, which showed a 1×1.5-cm defect in the anterolateral capsule. After closure of the defect, the hip was found to be stable under fluoroscopic examination. Postoperatively, the patient was allowed to perform partial weight-bearing in a hip-knee-ankle-foot orthosis for 2 months and then a flexible hip brace for 1 month. At 15-month follow-up, her hip was stable and she was pain-free.

Benali and Katthagen⁷ highlighted the significant contribution of the labrum to hip stability in a dysplastic hip. Their patient was a 49-year-old woman with mild hip dysplasia and a degenerative bucket-handle tear of the ventrolateral labrum. The patient underwent a near-complete labral resection and rim trimming at an outside institution. The patient began full weight-bearing at 3 weeks postoperatively and noticed considerable groin and back pain (no hip orthosis use was mentioned). After failed treatment for suspected lumbar pathology, she was referred to the authors’ clinic for further evaluation. Plain radiographs showed subluxation of the left hip with degenerative changes. The patient had an uneventful left total hip arthroplasty (THA).

After reviewing the 3 reported cases of hip instability after arthroscopy, we suggest that surgeons fully recognize and appreciate the delicate balance of stability and motion provided by the static and dynamic stabilizers of the hip joint, and be cognizant of potential imbalance created by surgical intervention.^8,9 Postarthroscopic hip instability appears to be multifactorial in nature, because all of the reported cases detailed different factors, both patient- and surgeon-related, contributing to instability.

Ranawat and colleagues⁵ identified several factors that may have contributed to the anterior hip dislocation sustained by their patient, including the patient’s generalized ligamentous laxity, performance of a capsulectomy (with repair of iliofemoral ligament), and a traumatic fall. Benali and Katthagen⁷ (although they did not perform the index procedure) described the disastrous complication of overzealous labral resection and rim trimming in a patient with hip dysplasia. Matsuda⁶ performed a labral resection and rim trimming, an extended (unspecified size) capsulotomy, and also used supranormal traction for 20 minutes to remove an iatrogenic foreign body. Surgeons performing hip arthroscopies should be aware of all these factors, because many are directly controlled by the surgeon.

The only factor we feel may have contributed to hip instability in our patient was the performance of a capsulotomy without closure. Our patient was an otherwise healthy woman with no signs of ligamentous laxity, hip dysplasia, or retroversion of the acetabulum. We did not perform a labral resection or rim trimming. We use modified anterior and anterolateral portals, and electrocautery to connect the portals. This typically leads to a release of a thin strip (less than 5 mm wide) of 3 cm of capsule. Based upon findings at rare second-look arthroscopy for recurrent symptoms, Dr. Guanche has observed that the capsulotomy from the initial procedure heals with normal-appearing tissue. Also, during peripheral compartment arthroscopy, we do not routinely release the iliofemoral ligament, and the orbicular ligament is left intact. Instead, we prefer to flex the hip and débride only enough capsular tissue to allow for adequate visualization. 

Little has been published on capsulotomy closure after hip arthroscopy, and no consensus exists. Our standard practice is to not close the capsulotomy, which accords with the practice of other surgeons.⁹ There is concern, however, that extensive capsulotomy leading to injury or disruption of the iliofemoral ligament may cause anterior hip instability, driving other prominent hip arthroscopists to routinely close the capsulotomy.^9,10 Myers and colleagues¹⁰ published a recent biomechanical study on the role of the labrum and the capsular ligaments in hip stability. They concluded that the iliofemoral ligament plays a significant role in limiting external rotation and anterior translation of the femoral head, and recommended closure of the capsulotomy after arthroscopy. Of note, Dr. Guanche has performed more than 1500 hip arthroscopic procedures in the past 5 years, and we are aware of only 2 patients who have sustained anterior hip dislocations, in spite of our not closing the capsulotomy defect. This highlights an important clinical question in need of further investigation.

Our case also raises questions about the ideal postoperative regimen after standard hip arthroscopy. Although we do not routinely prescribe hip orthoses for our patients, others do.⁵ We are unaware of any proven benefit to the standard use of hip orthoses, and are concerned over the possible lack of patient compliance and of adequate restraint. We prefer to educate our patients on avoiding the “at-risk” position of hip extension and external rotation and to counsel them on gradual return to activities. Studies are needed to determine the role of these devices in hip arthroscopy, as well as the ideal postoperative activity regimen.

Our patient failed 6 months of conservative treatment after her dislocation and continued to have feelings of hip instability even during light activities. As a result of this failure and given an anatomical defect in the anterior capsuloligamentous complex, we decided our patient would be best treated with reconstruction of the defect. We did not think a revision capsular plication, as done by Ranawat and colleagues,⁵ was a reasonable option for our patient because of a large defect in the capsular tissue. Even in smaller defects, plication could potentially lead to overtightening of the capsule and subsequent overconstraint of the joint. Also, plication of defects may place excessive strain on the suture, which may fail if the repair is even mildly stressed.

Recurrent anterior hip dislocations, although rare in their own right, are much more common after THA than after hip arthroscopy.¹¹ Fujishiro and colleagues¹² described a similar technique to ours developed to treat a patient with recurrent anterior hip instability from anterior capsular insufficiency after multiple revision THA procedures. They used a Leeds-Keio artificial ligament to reconstruct the iliofemoral ligament, and this successfully treated their patient’s instability.

Conclusion

We believe this is the first report of recurrent instability after hip arthroscopy, necessitating reconstruction of the anterior capsuloligamentous complex. This case shows that reconstruction of the iliofemoral ligament with iliotibial band autograft is safe, restores hip stability without compromising function, and should be considered by any hip arthroscopist encountering a similar scenario. It also highlights the importance of the capsuloligamentous complex surrounding the hip joint for its stability and the need for further research to better delineate the indications for capsular repair/closure after capsulotomy.

Hip arthroscopy has experienced a dramatic increase in popularity, largely resulting from improvements in techniques and technology.^1,2 As with any procedure, there are complications associated with arthroscopy of the hip. These include neurapraxia, iatrogenic cartilage and labral injuries, postoperative bleeding, perineal skin necrosis, infection, intra-articular instrument breakage, intra-abdominal fluid extravasation, avascular necrosis, and femoral neck fracture.^1-4 Many of these have been attributed to the expected learning curve seen with any new procedure, and are less likely to occur as surgeons become more familiar with the procedure.¹ One rare but serious complication is anterior dislocation of the hip.^5-7

We present a patient who experienced an anterior hip dislocation and instability after hip arthroscopy, and was successfully treated with an anterior capsuloligamentous reconstruction. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

An otherwise healthy 37-year-old woman presented to our clinic with a 6-month history of right groin pain and an occasional popping sensation during activity, which was unresponsive to hip-specific physical therapy. On physical examination, she was 5 ft 10 in tall, weighed 150 lbs, and appeared in excellent physical condition. She had no signs of systemic ligamentous laxity. She had an otherwise normal musculoskeletal, neurologic, and vascular examination in her bilateral lower extremities. She had a mild antalgic gait on the right leg.

The affected right hip could be flexed painfully to 120º, extended to 0º, adducted 20º, and abducted 45º. At 90º of flexion, her right hip could be externally rotated 30º and internally rotated 20º. Internal rotation during hip flexion beyond 90º caused sharp pain in the groin. Her normal left hip could be flexed to 120º, extended to 0º, adducted 30º, and abducted 60º. At 90º of flexion, her left hip could be externally rotated 50º and internally rotated 30º. She had negative Ober tests bilaterally but had tenderness along the right iliotibial band. She had negative Patrick and Gaenslen tests bilaterally. She had no tenderness in the area of either greater trochanter. 

Imaging evaluation included plain radiographs and a magnetic resonance arthrogram (MRA) of the right hip. The plain radiographs showed signs of femoroacetabular impingement, but no joint space narrowing, no dysplasia, and no retroversion of the acetabulum (Figures 1A, 1B). The MRA showed a degenerative peripheral tear of the anterosuperior labrum without significant cartilage wear (Figure 2).

Based upon her findings on physical examination and imaging, we recommended arthroscopic treatment of her right hip pathology. Thirteen months after initial presentation, we performed a right hip arthroscopy with the patient in the supine position. Through modified anterior and anterolateral portals, we used electrocautery to perform a capsulotomy from the 9 o’clock to 12 o’clock positions. A central compartment diagnostic arthroscopy showed mild degenerative fraying of the labrum from the 9 o’clock to 12 o’clock positions without signs of detachment. There was grade III chondral fraying near the articular margin in that same arc. The femoral articular cartilage appeared normal, as did the ligamentum teres. We used a shaver to gently débride the torn labrum down to stable tissue. The frayed cartilage on the acetabulum was also gently débrided.

Traction was released and the hip was flexed. Minimal capsular release and débridement were performed for adequate visualization of the peripheral compartment. A diagnostic examination revealed a significant cam-type impingement lesion from the 12 o’clock to 6 o’clock positions. We performed a femoral neck resection, with a proximal-distal dimension of 15 mm and a depth of 7 mm. A dynamic fluoroscopic examination of the hip joint showed no signs of impingement. In accordance with our standard protocol, the anterior capsulotomy was not repaired.

Postoperatively, the patient was instructed to perform toe-touch weight-bearing with crutches for 2 weeks and to advance to full weight-bearing over the next 2 weeks. She did not use a hip orthosis. She was also advised to avoid combined hip extension/external rotation maneuvers for the first 4 weeks. She took part in a formal hip-specific physical therapy program for a total of 12 weeks. She was seen in clinic at 2, 6, and 12 weeks postoperatively and appeared to have had a typical, uneventful course. We advised her to gradually return to normal activities as tolerated at the 12-week visit.

Four months after the procedure, the patient returned to our clinic for evaluation after a right hip dislocation. Two days prior, she was at a school function with her child and experienced sudden pain and inability to bear weight after she extended and externally rotated her right hip in a low-energy manner. She was taken to an emergency room and found to have an anterior dislocation of the right hip (Figure 3), which was concentrically reduced under anesthesia.

Upon questioning, she reported having had feelings of mild instability of the right hip during demanding activities (jogging, yoga) after sustaining a low-energy fall 1 month prior to her dislocation. On examination, she had significant apprehension about the right hip during gentle external rotation maneuvers. An MRA 2 weeks after the dislocation showed a large defect of the anterosuperior capsuloligamentous complex measuring 4 cm from medial to lateral and 2.5 cm superior to inferior (Figure 4). No loose bodies, chondral injuries, or recurrent tears of the labrum were seen. Typical postoperative changes were observed at the femoral head-neck junction.

Initially, we recommended nonoperative management with 6 weeks of toe-touch weight-bearing and strict avoidance of hip extension–external rotation maneuvers. No hip orthosis was used. After this period, the patient advanced to full weight-bearing and continued in hip-specific physical therapy. Despite continued therapy and avoidance of provocative maneuvers, the patient reported persistent feelings of right hip instability with significant apprehension during extension and external rotation of the right hip. A repeat MRA 4 months after the hip dislocation showed a persistent defect in the anterosuperior capsuloligamentous complex and no signs of avascular necrosis. After 6 months of conservative treatment, we recommended an open capsulorrhaphy of the right hip with autograft iliotibial band reconstruction of the iliofemoral ligament and capsule.

Six months after the dislocation, the patient underwent the recommended procedure. After induction of general anesthesia, she was placed in the supine position on a standard operating table. A Smith-Petersen approach was used to visualize the anterior hip structures. During deep dissection, we observed a large defect, measuring 2.5×4 cm (Figure 5A), in the anterior hip capsule, with only a thin pseudocapsule covering the femoral head. Extensive mobilization of the anterior capsule was unsuccessful.

The decision was made to harvest a graft from the patient’s ipsilateral iliotibial band. A skin incision was made over the iliotibial band in the distal midthigh region, and a 2.5×4-cm graft was harvested from the central portion of the iliotibial band. An arthrotomy was performed on the hip joint (Figure 5B). The labrum appeared healthy without recurrent tearing or fraying, and other than focal thinning on the superior acetabulum, the cartilage appeared healthy. A double-loaded anchor was placed in the supra-acetabular region, and the sutures were passed through the graft. Then, No. 2 nonabsorbable sutures were sequentially placed between the capsular remnant and the graft medially, inferiorly, and laterally. The graft was placed into position (Figure 5C) and the sutures were tied (Figure 5D).

Postoperatively, the patient was allowed toe-touch weight-bearing for 6 weeks, with strict avoidance of extension–external rotation maneuvers. She participated in a 12-week course of physical therapy with gradual advancement of activities. About a year after the capsulorrhaphy, she was able to resume all previous activities with only occasional low-level discomfort. She returned to the clinic 16 months after the capsulorrhaphy complaining of increased pain with long-distance running but denied feelings of instability. We performed an intra-articular hip injection under ultrasound guidance, which provided 100% relief of her symptoms. We obtained an MRA to evaluate for any recurrent capsular or labral injury (Figure 6). The previous anterosuperior capsular defect was not visible, and no signs of recurrent labral or cartilage injury were seen.

Discussion

With the increasing popularity of hip arthroscopy, more complications are being reported as well, including postoperative hip instability. Three separate cases of anterior hip instability have been published in the past several years.^5-7

Ranawat and colleagues⁵ were the first to report a case of postoperative anterior hip dislocation after arthroscopy. Their patient was a 52-year-old woman with right hip pain and generalized ligamentous laxity. Her preoperative radiographs showed no evidence of degenerative changes, dysplasia, or femoroacetabular impingement. An MRA showed a peripheral tear of the anterosuperior labrum. At arthroscopy, her right hip was easily distracted 2 to 3 cm with what they described as “minimal traction.” A small 1- to 2-cm capsulotomy was performed about the anterior portal. A detached labral tear was identified and repaired with an anchor, and no rim resection was performed. To improve visualization of the peripheral compartment, they extended the previous capsulotomy 1 to 2 cm and débrided the edges. A cam-type lesion was identified and resected. Lastly, they performed an anterior capsular plication, specifically including the iliofemoral ligament. Postoperatively, the patient wore a hip orthosis for 6 weeks to prevent extension and external rotation of the hip as well as a foot brace at night for 3 weeks. The patient was allowed to partially bear weight for the first 6 weeks with use of crutches. Approximately 2 months postoperatively, she slipped and fell down a short flight of stairs. She was diagnosed with an anterior hip dislocation. After successful closed reduction, she was treated conservatively with the same regimen used earlier. She remained symptomatic over the next several months with signs of instability and apprehension, and she eventually underwent a repeat hip arthroscopy. A 1- to 2-cm tear of the anterior capsule and iliofemoral ligament was treated with a revision arthroscopic capsular plication. A postoperative regimen similar to that used at the index procedure was instituted and, at most recent follow-up, she was found to have occasional pain without instability.

Matsuda⁶ reported a case of acute iatrogenic hip dislocation after arthroscopic surgery. His patient was a 39-year-old woman with a mildly retroverted acetabulum leading to impingement about the hip. She had no signs of generalized ligamentous laxity. A hip arthroscopy in the lateral position was performed, with no comment about the extent of the capsulotomy. During the procedure, about 5 mm of anterosuperior acetabulum were removed as part of arthroscopic rim trimming for treatment of the pincer lesion. A femoral osteochondroplasty was also performed (unspecified size) to restore more normal anterolateral offset. One confounding factor was that supranormal hip distraction was needed for 20 minutes to aid in removal of a metallic piece from a radiofrequency ablator, which inadvertently detached. The patient experienced an anterior hip dislocation in the recovery room and was found to be unstable during closed reduction under general anesthesia. A mini-open capsular repair was performed, which showed a 1×1.5-cm defect in the anterolateral capsule. After closure of the defect, the hip was found to be stable under fluoroscopic examination. Postoperatively, the patient was allowed to perform partial weight-bearing in a hip-knee-ankle-foot orthosis for 2 months and then a flexible hip brace for 1 month. At 15-month follow-up, her hip was stable and she was pain-free.

Benali and Katthagen⁷ highlighted the significant contribution of the labrum to hip stability in a dysplastic hip. Their patient was a 49-year-old woman with mild hip dysplasia and a degenerative bucket-handle tear of the ventrolateral labrum. The patient underwent a near-complete labral resection and rim trimming at an outside institution. The patient began full weight-bearing at 3 weeks postoperatively and noticed considerable groin and back pain (no hip orthosis use was mentioned). After failed treatment for suspected lumbar pathology, she was referred to the authors’ clinic for further evaluation. Plain radiographs showed subluxation of the left hip with degenerative changes. The patient had an uneventful left total hip arthroplasty (THA).

After reviewing the 3 reported cases of hip instability after arthroscopy, we suggest that surgeons fully recognize and appreciate the delicate balance of stability and motion provided by the static and dynamic stabilizers of the hip joint, and be cognizant of potential imbalance created by surgical intervention.^8,9 Postarthroscopic hip instability appears to be multifactorial in nature, because all of the reported cases detailed different factors, both patient- and surgeon-related, contributing to instability.

Ranawat and colleagues⁵ identified several factors that may have contributed to the anterior hip dislocation sustained by their patient, including the patient’s generalized ligamentous laxity, performance of a capsulectomy (with repair of iliofemoral ligament), and a traumatic fall. Benali and Katthagen⁷ (although they did not perform the index procedure) described the disastrous complication of overzealous labral resection and rim trimming in a patient with hip dysplasia. Matsuda⁶ performed a labral resection and rim trimming, an extended (unspecified size) capsulotomy, and also used supranormal traction for 20 minutes to remove an iatrogenic foreign body. Surgeons performing hip arthroscopies should be aware of all these factors, because many are directly controlled by the surgeon.

The only factor we feel may have contributed to hip instability in our patient was the performance of a capsulotomy without closure. Our patient was an otherwise healthy woman with no signs of ligamentous laxity, hip dysplasia, or retroversion of the acetabulum. We did not perform a labral resection or rim trimming. We use modified anterior and anterolateral portals, and electrocautery to connect the portals. This typically leads to a release of a thin strip (less than 5 mm wide) of 3 cm of capsule. Based upon findings at rare second-look arthroscopy for recurrent symptoms, Dr. Guanche has observed that the capsulotomy from the initial procedure heals with normal-appearing tissue. Also, during peripheral compartment arthroscopy, we do not routinely release the iliofemoral ligament, and the orbicular ligament is left intact. Instead, we prefer to flex the hip and débride only enough capsular tissue to allow for adequate visualization. 

Little has been published on capsulotomy closure after hip arthroscopy, and no consensus exists. Our standard practice is to not close the capsulotomy, which accords with the practice of other surgeons.⁹ There is concern, however, that extensive capsulotomy leading to injury or disruption of the iliofemoral ligament may cause anterior hip instability, driving other prominent hip arthroscopists to routinely close the capsulotomy.^9,10 Myers and colleagues¹⁰ published a recent biomechanical study on the role of the labrum and the capsular ligaments in hip stability. They concluded that the iliofemoral ligament plays a significant role in limiting external rotation and anterior translation of the femoral head, and recommended closure of the capsulotomy after arthroscopy. Of note, Dr. Guanche has performed more than 1500 hip arthroscopic procedures in the past 5 years, and we are aware of only 2 patients who have sustained anterior hip dislocations, in spite of our not closing the capsulotomy defect. This highlights an important clinical question in need of further investigation.

Our case also raises questions about the ideal postoperative regimen after standard hip arthroscopy. Although we do not routinely prescribe hip orthoses for our patients, others do.⁵ We are unaware of any proven benefit to the standard use of hip orthoses, and are concerned over the possible lack of patient compliance and of adequate restraint. We prefer to educate our patients on avoiding the “at-risk” position of hip extension and external rotation and to counsel them on gradual return to activities. Studies are needed to determine the role of these devices in hip arthroscopy, as well as the ideal postoperative activity regimen.

Our patient failed 6 months of conservative treatment after her dislocation and continued to have feelings of hip instability even during light activities. As a result of this failure and given an anatomical defect in the anterior capsuloligamentous complex, we decided our patient would be best treated with reconstruction of the defect. We did not think a revision capsular plication, as done by Ranawat and colleagues,⁵ was a reasonable option for our patient because of a large defect in the capsular tissue. Even in smaller defects, plication could potentially lead to overtightening of the capsule and subsequent overconstraint of the joint. Also, plication of defects may place excessive strain on the suture, which may fail if the repair is even mildly stressed.

Recurrent anterior hip dislocations, although rare in their own right, are much more common after THA than after hip arthroscopy.¹¹ Fujishiro and colleagues¹² described a similar technique to ours developed to treat a patient with recurrent anterior hip instability from anterior capsular insufficiency after multiple revision THA procedures. They used a Leeds-Keio artificial ligament to reconstruct the iliofemoral ligament, and this successfully treated their patient’s instability.

Conclusion

We believe this is the first report of recurrent instability after hip arthroscopy, necessitating reconstruction of the anterior capsuloligamentous complex. This case shows that reconstruction of the iliofemoral ligament with iliotibial band autograft is safe, restores hip stability without compromising function, and should be considered by any hip arthroscopist encountering a similar scenario. It also highlights the importance of the capsuloligamentous complex surrounding the hip joint for its stability and the need for further research to better delineate the indications for capsular repair/closure after capsulotomy.

SAN FRANCISCO– Teens and young adults don’t like being treated like children, but they should make an exception when it comes to acute lymphoblastic leukemia therapy, because pediatric ALL regimens are associated with significantly better event-free and overall survival among patients with ALL from the ages of 16 to 40 years.

Those findings come from a clinical trial 14 years in the making, in which 296 adolescents and young adults (AYA) with ALL were treated with an intensive pediatric chemotherapy combination regiment rather than a less-intensive adult regimen. At 2-year follow-up, the rate of overall survival (OS) was 78%, with the median overall survival not yet reached, and the event-free survival (EFS) rate was 66%, reported Dr. Wendy Stock from the University of Chicago Medical Center.

In contrast, EFS rates among AYA treated with adult regimens have historically ranged from 35-40%, Dr. Stock said at a press briefing at the annual meeting of the American Society of Hematology.

“These data really started 14 years ago at this ASH meeting when we presented data showing that young adults ages 16 to 20 who were treated on adult cooperative group studies in the United States fared much worse than the same age group who were treated on pediatric studies,” she said.

In 2008, Dr. Stock and her colleagues published a study (Blood 2008;112:1646-54) showing that AYAs treated under Children’s Cancer Group (CCG) protocols had an overall survival rate at 7 years of 67% and an EFS rate of 63%. In contrast, AYAs treated under Cancer and Leukemia Group B (CALGB) protocols had an OS of 46% and EFS of only 34%. The risk for worse outcomes was approximately twofold among adolescents treated with adult regimens, compared with those treated with pediatric regimens. The findings were similar in studies from France, the United Kingdom, and the Netherlands, Dr. Stock noted.

The investigators determined at that time that, under the CCG regimens, the teen and young adult patients received earlier and more intensive central nervous system prophylaxis and higher doses of nonmyelosuppressive drugs, especially glucocorticoids, vincristine, and pegylated asparignase, while those on the CALGB regimens received higher doses of myelosuppressive agents such as anthracyclines.

Because their original findings came from a retrospective study, the investigators decided to launch a prospective study,US Intergroup trial C10403, designed to evaluate outcomes among patients with ALL from the ages of 16-40 years when they were treated with a pediatric regimen by adult hematologists/oncologists in the cooperative group setting.

A total of 296 eligible patients with a median age of 25 years were enrolled. The patients had newly diagnosed ALL of T-cell or B-cell lineage; patients with Burkitt’s type ALL or ALL positive for the Philadelphia chromosome were excluded. The patients were treated with a regimen identical to the Capizzi methotrexate arm of the Children’s Oncology Group AALL0232 study. The regimen consisted of four intensive courses: remission induction, remission consolidation, interim maintenance and delayed intensification, and prolonged maintenance therapy. Patients who had an M2 marrow response after remission induction (more than 5% but less than 25% lymphoblasts) received an extended remission induction course of therapy.

As noted before, the EFS rate was 66% and the median EFS duration was 59 months. The 2-year overall survival rate was 79%. EFS rates were similar between patients with B-cell lineage (65%) and T-cell lineage (68%) ALL, and there were no significant differences in EFS or OS by sex or by age.

There were five (2%) treatment-related deaths during protocol therapy, including two cases of liver failure, both occurring during induction; two infections (one in the induction phase and one in the consolidation phase); and one ventricular arrhythmia (during induction). Treatment toxicities in general were similar to those seen in the standard therapy of the COG AALL0232 trial, although patients in the current study had an increase in risk for thrombosis and early hyperbilirubinemia.

“Our outcomes are similar to other prospective international studies which apply pediatric regimens to the young adult population of acute lymphoblastic leukemia,” Dr. Stock said.

In analyses of biological factors that affect outcome, the investigators found that white blood cell counts above 30,000/uL were associated with worse EFS and OS, and that the presence of a BCR-ABL1-like signature and overexpression of the gene CRLF2 were common and associated with significantly worse survival.

The investigators plan to use the study as a basis for future studies incorporating target antibodies and kinase inhibitors in an attempt to improve survival further by eradicating minimal residual disease, Dr. Stock said.

SAN FRANCISCO– Teens and young adults don’t like being treated like children, but they should make an exception when it comes to acute lymphoblastic leukemia therapy, because pediatric ALL regimens are associated with significantly better event-free and overall survival among patients with ALL from the ages of 16 to 40 years.

Those findings come from a clinical trial 14 years in the making, in which 296 adolescents and young adults (AYA) with ALL were treated with an intensive pediatric chemotherapy combination regiment rather than a less-intensive adult regimen. At 2-year follow-up, the rate of overall survival (OS) was 78%, with the median overall survival not yet reached, and the event-free survival (EFS) rate was 66%, reported Dr. Wendy Stock from the University of Chicago Medical Center.

In contrast, EFS rates among AYA treated with adult regimens have historically ranged from 35-40%, Dr. Stock said at a press briefing at the annual meeting of the American Society of Hematology.

“These data really started 14 years ago at this ASH meeting when we presented data showing that young adults ages 16 to 20 who were treated on adult cooperative group studies in the United States fared much worse than the same age group who were treated on pediatric studies,” she said.

In 2008, Dr. Stock and her colleagues published a study (Blood 2008;112:1646-54) showing that AYAs treated under Children’s Cancer Group (CCG) protocols had an overall survival rate at 7 years of 67% and an EFS rate of 63%. In contrast, AYAs treated under Cancer and Leukemia Group B (CALGB) protocols had an OS of 46% and EFS of only 34%. The risk for worse outcomes was approximately twofold among adolescents treated with adult regimens, compared with those treated with pediatric regimens. The findings were similar in studies from France, the United Kingdom, and the Netherlands, Dr. Stock noted.

The investigators determined at that time that, under the CCG regimens, the teen and young adult patients received earlier and more intensive central nervous system prophylaxis and higher doses of nonmyelosuppressive drugs, especially glucocorticoids, vincristine, and pegylated asparignase, while those on the CALGB regimens received higher doses of myelosuppressive agents such as anthracyclines.

Because their original findings came from a retrospective study, the investigators decided to launch a prospective study,US Intergroup trial C10403, designed to evaluate outcomes among patients with ALL from the ages of 16-40 years when they were treated with a pediatric regimen by adult hematologists/oncologists in the cooperative group setting.

A total of 296 eligible patients with a median age of 25 years were enrolled. The patients had newly diagnosed ALL of T-cell or B-cell lineage; patients with Burkitt’s type ALL or ALL positive for the Philadelphia chromosome were excluded. The patients were treated with a regimen identical to the Capizzi methotrexate arm of the Children’s Oncology Group AALL0232 study. The regimen consisted of four intensive courses: remission induction, remission consolidation, interim maintenance and delayed intensification, and prolonged maintenance therapy. Patients who had an M2 marrow response after remission induction (more than 5% but less than 25% lymphoblasts) received an extended remission induction course of therapy.

As noted before, the EFS rate was 66% and the median EFS duration was 59 months. The 2-year overall survival rate was 79%. EFS rates were similar between patients with B-cell lineage (65%) and T-cell lineage (68%) ALL, and there were no significant differences in EFS or OS by sex or by age.

There were five (2%) treatment-related deaths during protocol therapy, including two cases of liver failure, both occurring during induction; two infections (one in the induction phase and one in the consolidation phase); and one ventricular arrhythmia (during induction). Treatment toxicities in general were similar to those seen in the standard therapy of the COG AALL0232 trial, although patients in the current study had an increase in risk for thrombosis and early hyperbilirubinemia.

“Our outcomes are similar to other prospective international studies which apply pediatric regimens to the young adult population of acute lymphoblastic leukemia,” Dr. Stock said.

In analyses of biological factors that affect outcome, the investigators found that white blood cell counts above 30,000/uL were associated with worse EFS and OS, and that the presence of a BCR-ABL1-like signature and overexpression of the gene CRLF2 were common and associated with significantly worse survival.

The investigators plan to use the study as a basis for future studies incorporating target antibodies and kinase inhibitors in an attempt to improve survival further by eradicating minimal residual disease, Dr. Stock said.

SAN FRANCISCO– Teens and young adults don’t like being treated like children, but they should make an exception when it comes to acute lymphoblastic leukemia therapy, because pediatric ALL regimens are associated with significantly better event-free and overall survival among patients with ALL from the ages of 16 to 40 years.

Those findings come from a clinical trial 14 years in the making, in which 296 adolescents and young adults (AYA) with ALL were treated with an intensive pediatric chemotherapy combination regiment rather than a less-intensive adult regimen. At 2-year follow-up, the rate of overall survival (OS) was 78%, with the median overall survival not yet reached, and the event-free survival (EFS) rate was 66%, reported Dr. Wendy Stock from the University of Chicago Medical Center.

In contrast, EFS rates among AYA treated with adult regimens have historically ranged from 35-40%, Dr. Stock said at a press briefing at the annual meeting of the American Society of Hematology.

“These data really started 14 years ago at this ASH meeting when we presented data showing that young adults ages 16 to 20 who were treated on adult cooperative group studies in the United States fared much worse than the same age group who were treated on pediatric studies,” she said.

In 2008, Dr. Stock and her colleagues published a study (Blood 2008;112:1646-54) showing that AYAs treated under Children’s Cancer Group (CCG) protocols had an overall survival rate at 7 years of 67% and an EFS rate of 63%. In contrast, AYAs treated under Cancer and Leukemia Group B (CALGB) protocols had an OS of 46% and EFS of only 34%. The risk for worse outcomes was approximately twofold among adolescents treated with adult regimens, compared with those treated with pediatric regimens. The findings were similar in studies from France, the United Kingdom, and the Netherlands, Dr. Stock noted.

The investigators determined at that time that, under the CCG regimens, the teen and young adult patients received earlier and more intensive central nervous system prophylaxis and higher doses of nonmyelosuppressive drugs, especially glucocorticoids, vincristine, and pegylated asparignase, while those on the CALGB regimens received higher doses of myelosuppressive agents such as anthracyclines.

Because their original findings came from a retrospective study, the investigators decided to launch a prospective study,US Intergroup trial C10403, designed to evaluate outcomes among patients with ALL from the ages of 16-40 years when they were treated with a pediatric regimen by adult hematologists/oncologists in the cooperative group setting.

A total of 296 eligible patients with a median age of 25 years were enrolled. The patients had newly diagnosed ALL of T-cell or B-cell lineage; patients with Burkitt’s type ALL or ALL positive for the Philadelphia chromosome were excluded. The patients were treated with a regimen identical to the Capizzi methotrexate arm of the Children’s Oncology Group AALL0232 study. The regimen consisted of four intensive courses: remission induction, remission consolidation, interim maintenance and delayed intensification, and prolonged maintenance therapy. Patients who had an M2 marrow response after remission induction (more than 5% but less than 25% lymphoblasts) received an extended remission induction course of therapy.

As noted before, the EFS rate was 66% and the median EFS duration was 59 months. The 2-year overall survival rate was 79%. EFS rates were similar between patients with B-cell lineage (65%) and T-cell lineage (68%) ALL, and there were no significant differences in EFS or OS by sex or by age.

There were five (2%) treatment-related deaths during protocol therapy, including two cases of liver failure, both occurring during induction; two infections (one in the induction phase and one in the consolidation phase); and one ventricular arrhythmia (during induction). Treatment toxicities in general were similar to those seen in the standard therapy of the COG AALL0232 trial, although patients in the current study had an increase in risk for thrombosis and early hyperbilirubinemia.

“Our outcomes are similar to other prospective international studies which apply pediatric regimens to the young adult population of acute lymphoblastic leukemia,” Dr. Stock said.

In analyses of biological factors that affect outcome, the investigators found that white blood cell counts above 30,000/uL were associated with worse EFS and OS, and that the presence of a BCR-ABL1-like signature and overexpression of the gene CRLF2 were common and associated with significantly worse survival.

The investigators plan to use the study as a basis for future studies incorporating target antibodies and kinase inhibitors in an attempt to improve survival further by eradicating minimal residual disease, Dr. Stock said.

The tibia is the most commonly fractured long bone in adults, and tibial malunions occur in up to 60% of these patients.^1,2 Persistent tibial malalignment, particularly varus alignment, negatively alters gait and joint kinematics, leading to altered weight-bearing forces across the knee and ankle joints. These altered forces may lead to osteoarthritis.^3-8

Several studies have identified a relationship between extent of tibial malalignment and changes in joint reaction forces.^3,5-7,9-13 Puno and colleagues¹⁴ developed a mathematical model to better define the changes in neighboring joints relative to the pattern of the tibia malalignment. Not surprisingly, their work showed that, with distal tibial malunions, altered stress concentrations were realized at the ankle joint, and more proximal tibial deformities led to larger alterations in the joint stresses at the knee. More recently, van der Schoot and colleagues⁸ found a high prevalence of ipsilateral ankle osteoarthritis with tibial malalignment of 5° or more, and Greenwood and colleagues¹⁵ showed a higher incidence of knee pain, lower limb osteoarthritis, and disability in patients with previous tibia fractures. Given these findings, it would seem that correction of tibial malalignment would lead to normative lower extremity joint kinematic values, joint reaction forces, and overall quality of life (QOL).

The ability to ambulate has been recognized as an important milestone in functional recovery after lower extremity injury.^2,16,17 Gait analysis, assessment of joint kinematics, and QOL and health status questionnaires can provide information to evaluate rehabilitation protocols, treatment algorithms, and surgical outcomes. Recently, these measures have been used to assess patients recovering from acetabular fractures, femoral shaft fractures, and calcaneal fractures.^4,11,17-24 However, no study has used these measures to assess the benefits of surgical correction of malaligned tibias.

We conducted a study to determine improvement in gait, joint kinematics, and patients’ perceptions of overall well-being after surgical correction of tibial malunions. The null hypothesis was that correction of tibial malunion would have no effect on gait, joint kinematics, or patients’ perceptions of function and QOL.

Materials and Methods

This prospective double-time-point study, which was approved by the Institutional Review Board of Washington University/Barnes-Jewish Hospital, evaluated 11 consecutive patients with a varus tibial malunion treated by a single surgeon between September 2003 and January 2006. All patients were treated using a technique that included oblique osteotomy and open reduction and internal fixation (ORIF) or osteotomy and intramedullary nailing. Study inclusion criteria were age 18 years or older; symptomatic varus malunion of the tibia of 10º or more; absence of a developmental or pathologic process leading to the fracture and subsequent deformity; no neurologic deficit of either lower extremity or contralateral lower extremity deformity; and ability to ambulate 9 meters with or without use of an assistive device.

The 11 patients (6 men, 5 women) who met these criteria enrolled in the study. Mean age was 53 years (range, 43-68 years). Eight malunions involved the left tibia. The mechanisms of injury were motor vehicle crash (6 patients), fall from a great height (3), being struck by a motor vehicle (1), and gunshot (1). Mean time from injury to corrective surgery was 16.9 years (range, 1-34 years). Before surgery, each patient had a thorough physical examination, with plain radiographs, including anteroposterior (AP), lateral, and oblique views, obtained to assess degree of limb malalignment. Patients completed the Short Form-36 (SF-36) and the Musculoskeletal Function Assessment (MFA) and underwent joint kinematics and gait analysis. Five malunions were located in the mid-diaphysis of the tibia, 3 in the proximal third, and 2 in the distal third of the tibial shaft. One patient had posttraumatic deformity involving the proximal and the mid-diaphysis (Table 1). After surgery, each patient was followed at regular intervals in the surgeon’s private office. Minimum follow-up was 7 months (mean, 11 months; range 7-17 months). At follow-up, radiographs were obtained, and each patient completed the SF-36 and the MFA and underwent joint kinematics and gait analysis.

We obtained preoperative AP and lateral radiographs of the malaligned and contralateral normal tibias for each patient. Angular deformity was determined in the sagittal and coronal planes to determine location and magnitude of the deformity. Specifically, on each AP and lateral radiograph, a line was drawn the length of the tibia proximal and distal to the area of the deformity. The angle generated by the intersection of these lines on the AP and lateral radiographs was then plotted on a grid to determine the precise plane and magnitude of the deformity (Table 2).^1,12 Clinically, relevant rotational deformity of the involved limb was assessed by physical examination, and the results were compared with those of the contralateral limb. Owing to the lack of considerable rotational deformity in any of these 11 patients, we did not obtain computed tomography scans for further assessment of rotation.

Perioperative intravenous antibiotics were administered: 2 g cefazolin 30 minutes before incision and 1 g every 8 hours for 24 hours after surgery. A pneumatic tourniquet was placed on the proximal thigh, and the entire leg was prepared and draped in a sterile fashion. The limb was elevated and exsanguinated with an Esmark bandage and the tourniquet raised to 250 mm Hg. With fluoroscopy, the site of the tibial deformity was identified. Generally, an incision was made centered over the apex of the deformity and one fingerbreadth lateral to the palpable tibial crest. In most cases, the anterolateral aspect of the tibia was exposed while minimizing soft-tissue and periosteal stripping. The plane of the maximum deformity was identified with both direct visualization and fluoroscopy. The osteotomy was performed with an oscillating saw, and in each case a fibular osteotomy was also performed. Malalignment was corrected using a combination of manual manipulation and femoral distractor.^25,26 Intraoperative biplanar radiographs were compared with our preoperative plan and with reversed images of the contralateral tibia to assess correction of the deformity. If lengthening was required, in addition to the tibial osteotomy, a corticotomy was created, and a circular external fixator applied and distraction osteogenesis performed.

We maintained the limbs in a short-leg splint for about 10 days after surgery and then initiated active-assisted range of motion of neighboring joints. Patients were maintained on toe-touch weight-bearing for the initial 6 weeks and were then advanced to partial weight-bearing (23 kg). Physical therapy for lower extremity strengthening and gait training was started 6 weeks after surgery. Three months after surgery, patients were advanced to weight-bearing as tolerated and were allowed to return to their activities of daily living without restrictions if radiographs and clinical examination were consistent with healing of the osteotomy.

Each patient was examined and radiographs obtained at regular intervals (2, 6, and 12 weeks and then about every 3 months) after surgery until healing. Bone union was determined by history and physical examination with pain-free weight-bearing without use of assistive devices and by return of functional use of the extremity. Radiographic union was considered to have occurred when bridging trabeculae were present across the osteotomy and there was no loosening or failure of the implants. Occasionally, if there were questions regarding healing, a musculoskeletal radiologist was consulted. Acceptable tibia alignment was defined as alignment of less than 5° varus or less than 10° valgus in the coronal plane and less than 15° procurvatum or recurvatum in the sagittal plane. Immediate postoperative radiographs and most recent radiographs were used to determine the final amount of angular correction.²⁷

Two patients subsequently required secondary operative procedures. One had varus collapse through the regenerate, and the other developed a nonunion of the osteotomy site and required exchange intramedullary nailing. In each case, the final assessment was done after the patient had healed after the second surgery and had fully recovered.

Perceived Functional Assessment

The MFA is a 100-item self-administered QOL questionnaire designed to assess self-perception of physical, psychological, and social well-being in patients with a musculoskeletal injury or condition. The MFA provides a summary score and separate score for each of 10 functional domains. The lower the score, the better the patient’s perception of function. Validated and published norms are available.^20,28-30

Perceived Health Status

The Short Form-36 is a 36-item multipurpose self-administered health survey questionnaire. The SF-36, which assesses overall health status, provides a Physical Component Score (PCS) and a Mental Component Score (MCS). The higher the score, the better the patient’s perception of function. Validated and published norms are available.³¹

Gait Analysis

Video data from a 6-camera high-resolution system (Motion Analysis, Santa Rosa, California) were used to assess gait. A set of 3 reflective surface markers was placed on each of 4 areas: trunk, thighs, legs, and feet.^18,19 The patient walked barefoot along a 9-meter walkway, and video data were collected during the middle 2 meters. For each patient, data from 4 to 7 trials were collected. Computerized software produced data describing the averaged joint angle as a function of the gait cycle for each of the 3 principal planes of the body. Specific points in the gait cycle were analyzed. Variables included maximum knee varus in stance phase; maximum knee valgus in swing; maximum knee flexion in stance and swing; minimum knee flexion in stance; maximum ankle inversion in terminal stance; maximum ankle eversion in stance; maximum ankle dorsiflexion in stance and swing; and maximum ankle plantarflexion at takeoff. In addition to the lower extremity joint kinematics, angular measurements, basic gait measurements of step length, stride length, cadence, and speed were also recorded.

Statistical Analysis

Paired t tests were used to determine if significant changes occurred as a consequence of the surgery for the outcome variables (P < .05). Normative gait data were used to assess the quality of any changes that occurred in the variables, but no statistical analysis was performed to determine significant differences.¹⁸

Results

All 11 patients had clinical and radiographic evidence of healing and deformity correction at most recent follow-up. Nine patients (82%) healed after the index procedure. Mean total angular correction in the coronal plane was 21° (range, 14° varus to 7° valgus), and mean total angular correction in the sagittal plane was 9° (range, 21° recurvatum to 15° procurvatum) (Table 2).

For the group, mean preoperative MFA score was 39 (SD, 18; range, 10-69), and mean postoperative MFA score was 28 (SD, 14; range, 8-53). Patients reported the most improvement in 2 domains: In Leisure, mean (SD) preoperative score was 8 (2), and mean postoperative score was 5 (2); in Emotional, mean preoperative score was 5 (2), and mean postoperative score was 4 (1). The other domains were not significantly different between the 2 assessments.

 On the SF-36, mean (SD) PCS significantly (P < .05) improved from 32 (8) to 43 (9). Mean (SD) MCS showed little change: preoperative, 46 (16); postoperative, 48 (13). The PCS subcategories that showed the most improvement were Physical Function, mean (SD) preoperative, 26 (20), to postoperative, 52 (26); Role of Physical Health, preoperative, 18 (24), to postoperative, 60 (41); and Bodily Pain, preoperative, 39 (27), to 58 (18).

The results from the preoperative and postoperative gait analysis showed no significant differences for the ankle, knee, and hip variables during swing phase (Table 3). In an analysis of the changes in joint kinematics during stance, maximum hip adduction (increased) and maximum knee varus (decreased) on the operative side were significantly improved toward normative values as a consequence of the surgery (Table 3). The other kinematic stance variables were not significantly different. No significant changes were observed in stance time, step length, stride length, cadence, or speed as a consequence of the surgery (Table 4).

Discussion

Correction of malaligned tibias leads to improved limb alignment and patients’ perceptions of functional abilities and health but had a limited effect on joint kinematics and gait. In a group of like patients, we used common techniques to realign malunited tibias and validated instruments to measure functional outcome, health status, joint kinematics, and gait. The goals of this study were to evaluate changes in perceived function and health status and changes in joint kinematics and gait as a result of correction of a posttraumatic limb deformity.

Other investigators have reported outcomes of treating symptomatic malunions,³² nonunions,²⁴ and leg-length discrepancies.³³ In these reports, correction of deformity improved patient satisfaction and function, though objective means of assessment were infrequently used. Good results were reported with use of a dome-shaped supramalleolar osteotomy for the correction of tibial malunion.³² In this study, supramalleolar osteotomy was performed on 8 patients for correction of a malunited tibia. Postoperative assessment included subjective assessment of pain, limp, appearance, instability, and activity. Of these 8 patients, 7 reported overall symptomatic improvement after healing, and the 1 who lost the deformity correction remained symptomatic. Significant improvement in overall health has been reported after successful treatment of tibia nonunions.²⁴ The investigators used the SF-36 to assess patients who underwent treatment for a tibial nonunion. Analysis of these patients’ results showed a significant improvement in physical and mental functioning after healing. In addition, improved gait symmetry was reported in patients successfully treated for leg-length discrepancies.³³ Unfortunately, how improvement in gait related to overall patient function was not assessed. In the present study, we used stringent objective and subjective validated instruments to assess changes in joint gait kinematics and functional outcome before and after treatment of a tibial malunion. In general, our results are consistent with published results and indicate that realignment of tibial malunions improves patients’ perceptions of function. Our results also indicate improvements toward normative values in maximal hip adduction and knee varus, thus confirming the efficacy of the surgery from a functional perspective. Unfortunately, we did not show significant improvements in the remaining joint kinematics measurements or temporal gait parameters.

It is not entirely clear whether tibial malalignment leads to degenerative changes of the ipsilateral knee and/or ankle and what role this might play in functioning. In a retrospective analysis of 92 patients, angular deformity within 15° of normal alignment did not lead to ankle arthrosis.⁹ Milner and colleagues⁴ found that, though varus malunion of the tibia may lead to arthrosis of the medial compartment of the knee, other factors were more important in causing arthrosis of the ankle.

Wu and colleagues³⁴ used tibial osteotomies in New Zealand white rabbits to investigate cartilage and bone changes of the knee after creation of varus or valgus tibial deformities. Thirty-four weeks after osteotomy, rabbits with up to 30° of deformity had severe cartilage changes with osteophytes, fibrillation, derangement of cell columns, and associated increased subchondral bone density of the knees. Cadaveric studies have also shown increased contact pressures within the knees and ankles with ever increasing amounts of tibial deformity.^6,10 In each cadaveric study, malalignment in the distal third of the tibia caused the largest changes in the ankle, and changes in the alignment in the proximal third caused the largest changes in the knee.

Consistent with these animal and cadaveric studies are several retrospective clinical studies that have correlated tibial malalignment (particularly varus) with development of knee and ankle arthrosis.^3,5,8 Kettelkamp and colleagues³ found a direct correlation between magnitude of deformity and length of time with development of knee arthrosis. These findings have led many to recommend that surgeons try to restore tibial alignment to as near normal as possible to reduce the likelihood of arthrosis after tibia fracture. We found significant improvement toward normative values for maximum hip adduction (increased) and tibial varus (decreased) after surgery. These improvements would shift the weight-bearing forces back to the central part of the knee and therefore more uniformly distribute weight-bearing forces.

Posttraumatic arthrosis that develops after fracture is thought to result from increased joint pressures and possibly factors related to the injury. Although surgical correction of tibial alignment is unlikely to reverse these cartilage changes, it may restore joint pressure symmetry and “offload” compromised compartments. Offloading of already degenerative compartments may explain our patients’ improved perceptions of function and overall health status.

There were several limitations to our study. First, plain radiographs of malaligned and uninjured tibia and fibula were used, and these do not allow complete assessment of the weight-bearing access of the limb. Our patients, however, had isolated tibia fractures, which involved a normal limb before injury, so any alterations in joint kinematics, gait, or function would likely be the result of the fracture. Another limitation of our study is its nonrandomized design. However, the patients reflect the typical heterogeneous trauma patient population, who typically develop tibial malunions and seek correction. Another limitation was the lack of a treatment protocol regarding exact surgical technique and implants used to stabilize the osteotomies. In general, the patients were treated similarly, and their preoperative and postoperative assessments were exactly the same, as was their state-of-the-art joint kinematics and gait analysis, combined with the use of previously validated outcome measures. In addition, the lack of improvement in gait could have resulted from postoperative physical therapy that focused on joint mobilization and muscle strengthening and not on correction of abnormal gait parameters noted on preoperative gait analysis. Despite the potential limitations of the study, surgical correction of these symptomatic tibial malunions resulted in significant improvement in functional outcome and improved joint kinematics on the operative side.

Conclusion

Significant effort should be made to restore and maintain near-anatomical tibial alignment until a tibia fracture is healed. In patients who develop a symptomatic tibial malunion, surgical correction should be undertaken with the intent to restore normal limb alignment and improve joint kinematics, function, and overall health status.

The tibia is the most commonly fractured long bone in adults, and tibial malunions occur in up to 60% of these patients.^1,2 Persistent tibial malalignment, particularly varus alignment, negatively alters gait and joint kinematics, leading to altered weight-bearing forces across the knee and ankle joints. These altered forces may lead to osteoarthritis.^3-8

Several studies have identified a relationship between extent of tibial malalignment and changes in joint reaction forces.^3,5-7,9-13 Puno and colleagues¹⁴ developed a mathematical model to better define the changes in neighboring joints relative to the pattern of the tibia malalignment. Not surprisingly, their work showed that, with distal tibial malunions, altered stress concentrations were realized at the ankle joint, and more proximal tibial deformities led to larger alterations in the joint stresses at the knee. More recently, van der Schoot and colleagues⁸ found a high prevalence of ipsilateral ankle osteoarthritis with tibial malalignment of 5° or more, and Greenwood and colleagues¹⁵ showed a higher incidence of knee pain, lower limb osteoarthritis, and disability in patients with previous tibia fractures. Given these findings, it would seem that correction of tibial malalignment would lead to normative lower extremity joint kinematic values, joint reaction forces, and overall quality of life (QOL).

The ability to ambulate has been recognized as an important milestone in functional recovery after lower extremity injury.^2,16,17 Gait analysis, assessment of joint kinematics, and QOL and health status questionnaires can provide information to evaluate rehabilitation protocols, treatment algorithms, and surgical outcomes. Recently, these measures have been used to assess patients recovering from acetabular fractures, femoral shaft fractures, and calcaneal fractures.^4,11,17-24 However, no study has used these measures to assess the benefits of surgical correction of malaligned tibias.

We conducted a study to determine improvement in gait, joint kinematics, and patients’ perceptions of overall well-being after surgical correction of tibial malunions. The null hypothesis was that correction of tibial malunion would have no effect on gait, joint kinematics, or patients’ perceptions of function and QOL.

Materials and Methods

This prospective double-time-point study, which was approved by the Institutional Review Board of Washington University/Barnes-Jewish Hospital, evaluated 11 consecutive patients with a varus tibial malunion treated by a single surgeon between September 2003 and January 2006. All patients were treated using a technique that included oblique osteotomy and open reduction and internal fixation (ORIF) or osteotomy and intramedullary nailing. Study inclusion criteria were age 18 years or older; symptomatic varus malunion of the tibia of 10º or more; absence of a developmental or pathologic process leading to the fracture and subsequent deformity; no neurologic deficit of either lower extremity or contralateral lower extremity deformity; and ability to ambulate 9 meters with or without use of an assistive device.

The 11 patients (6 men, 5 women) who met these criteria enrolled in the study. Mean age was 53 years (range, 43-68 years). Eight malunions involved the left tibia. The mechanisms of injury were motor vehicle crash (6 patients), fall from a great height (3), being struck by a motor vehicle (1), and gunshot (1). Mean time from injury to corrective surgery was 16.9 years (range, 1-34 years). Before surgery, each patient had a thorough physical examination, with plain radiographs, including anteroposterior (AP), lateral, and oblique views, obtained to assess degree of limb malalignment. Patients completed the Short Form-36 (SF-36) and the Musculoskeletal Function Assessment (MFA) and underwent joint kinematics and gait analysis. Five malunions were located in the mid-diaphysis of the tibia, 3 in the proximal third, and 2 in the distal third of the tibial shaft. One patient had posttraumatic deformity involving the proximal and the mid-diaphysis (Table 1). After surgery, each patient was followed at regular intervals in the surgeon’s private office. Minimum follow-up was 7 months (mean, 11 months; range 7-17 months). At follow-up, radiographs were obtained, and each patient completed the SF-36 and the MFA and underwent joint kinematics and gait analysis.

We obtained preoperative AP and lateral radiographs of the malaligned and contralateral normal tibias for each patient. Angular deformity was determined in the sagittal and coronal planes to determine location and magnitude of the deformity. Specifically, on each AP and lateral radiograph, a line was drawn the length of the tibia proximal and distal to the area of the deformity. The angle generated by the intersection of these lines on the AP and lateral radiographs was then plotted on a grid to determine the precise plane and magnitude of the deformity (Table 2).^1,12 Clinically, relevant rotational deformity of the involved limb was assessed by physical examination, and the results were compared with those of the contralateral limb. Owing to the lack of considerable rotational deformity in any of these 11 patients, we did not obtain computed tomography scans for further assessment of rotation.

Perioperative intravenous antibiotics were administered: 2 g cefazolin 30 minutes before incision and 1 g every 8 hours for 24 hours after surgery. A pneumatic tourniquet was placed on the proximal thigh, and the entire leg was prepared and draped in a sterile fashion. The limb was elevated and exsanguinated with an Esmark bandage and the tourniquet raised to 250 mm Hg. With fluoroscopy, the site of the tibial deformity was identified. Generally, an incision was made centered over the apex of the deformity and one fingerbreadth lateral to the palpable tibial crest. In most cases, the anterolateral aspect of the tibia was exposed while minimizing soft-tissue and periosteal stripping. The plane of the maximum deformity was identified with both direct visualization and fluoroscopy. The osteotomy was performed with an oscillating saw, and in each case a fibular osteotomy was also performed. Malalignment was corrected using a combination of manual manipulation and femoral distractor.^25,26 Intraoperative biplanar radiographs were compared with our preoperative plan and with reversed images of the contralateral tibia to assess correction of the deformity. If lengthening was required, in addition to the tibial osteotomy, a corticotomy was created, and a circular external fixator applied and distraction osteogenesis performed.

We maintained the limbs in a short-leg splint for about 10 days after surgery and then initiated active-assisted range of motion of neighboring joints. Patients were maintained on toe-touch weight-bearing for the initial 6 weeks and were then advanced to partial weight-bearing (23 kg). Physical therapy for lower extremity strengthening and gait training was started 6 weeks after surgery. Three months after surgery, patients were advanced to weight-bearing as tolerated and were allowed to return to their activities of daily living without restrictions if radiographs and clinical examination were consistent with healing of the osteotomy.

Each patient was examined and radiographs obtained at regular intervals (2, 6, and 12 weeks and then about every 3 months) after surgery until healing. Bone union was determined by history and physical examination with pain-free weight-bearing without use of assistive devices and by return of functional use of the extremity. Radiographic union was considered to have occurred when bridging trabeculae were present across the osteotomy and there was no loosening or failure of the implants. Occasionally, if there were questions regarding healing, a musculoskeletal radiologist was consulted. Acceptable tibia alignment was defined as alignment of less than 5° varus or less than 10° valgus in the coronal plane and less than 15° procurvatum or recurvatum in the sagittal plane. Immediate postoperative radiographs and most recent radiographs were used to determine the final amount of angular correction.²⁷

Two patients subsequently required secondary operative procedures. One had varus collapse through the regenerate, and the other developed a nonunion of the osteotomy site and required exchange intramedullary nailing. In each case, the final assessment was done after the patient had healed after the second surgery and had fully recovered.

Perceived Functional Assessment

The MFA is a 100-item self-administered QOL questionnaire designed to assess self-perception of physical, psychological, and social well-being in patients with a musculoskeletal injury or condition. The MFA provides a summary score and separate score for each of 10 functional domains. The lower the score, the better the patient’s perception of function. Validated and published norms are available.^20,28-30

Perceived Health Status

The Short Form-36 is a 36-item multipurpose self-administered health survey questionnaire. The SF-36, which assesses overall health status, provides a Physical Component Score (PCS) and a Mental Component Score (MCS). The higher the score, the better the patient’s perception of function. Validated and published norms are available.³¹

Gait Analysis

Video data from a 6-camera high-resolution system (Motion Analysis, Santa Rosa, California) were used to assess gait. A set of 3 reflective surface markers was placed on each of 4 areas: trunk, thighs, legs, and feet.^18,19 The patient walked barefoot along a 9-meter walkway, and video data were collected during the middle 2 meters. For each patient, data from 4 to 7 trials were collected. Computerized software produced data describing the averaged joint angle as a function of the gait cycle for each of the 3 principal planes of the body. Specific points in the gait cycle were analyzed. Variables included maximum knee varus in stance phase; maximum knee valgus in swing; maximum knee flexion in stance and swing; minimum knee flexion in stance; maximum ankle inversion in terminal stance; maximum ankle eversion in stance; maximum ankle dorsiflexion in stance and swing; and maximum ankle plantarflexion at takeoff. In addition to the lower extremity joint kinematics, angular measurements, basic gait measurements of step length, stride length, cadence, and speed were also recorded.

Statistical Analysis

Paired t tests were used to determine if significant changes occurred as a consequence of the surgery for the outcome variables (P < .05). Normative gait data were used to assess the quality of any changes that occurred in the variables, but no statistical analysis was performed to determine significant differences.¹⁸

Results

All 11 patients had clinical and radiographic evidence of healing and deformity correction at most recent follow-up. Nine patients (82%) healed after the index procedure. Mean total angular correction in the coronal plane was 21° (range, 14° varus to 7° valgus), and mean total angular correction in the sagittal plane was 9° (range, 21° recurvatum to 15° procurvatum) (Table 2).

For the group, mean preoperative MFA score was 39 (SD, 18; range, 10-69), and mean postoperative MFA score was 28 (SD, 14; range, 8-53). Patients reported the most improvement in 2 domains: In Leisure, mean (SD) preoperative score was 8 (2), and mean postoperative score was 5 (2); in Emotional, mean preoperative score was 5 (2), and mean postoperative score was 4 (1). The other domains were not significantly different between the 2 assessments.

 On the SF-36, mean (SD) PCS significantly (P < .05) improved from 32 (8) to 43 (9). Mean (SD) MCS showed little change: preoperative, 46 (16); postoperative, 48 (13). The PCS subcategories that showed the most improvement were Physical Function, mean (SD) preoperative, 26 (20), to postoperative, 52 (26); Role of Physical Health, preoperative, 18 (24), to postoperative, 60 (41); and Bodily Pain, preoperative, 39 (27), to 58 (18).

The results from the preoperative and postoperative gait analysis showed no significant differences for the ankle, knee, and hip variables during swing phase (Table 3). In an analysis of the changes in joint kinematics during stance, maximum hip adduction (increased) and maximum knee varus (decreased) on the operative side were significantly improved toward normative values as a consequence of the surgery (Table 3). The other kinematic stance variables were not significantly different. No significant changes were observed in stance time, step length, stride length, cadence, or speed as a consequence of the surgery (Table 4).

Discussion

Correction of malaligned tibias leads to improved limb alignment and patients’ perceptions of functional abilities and health but had a limited effect on joint kinematics and gait. In a group of like patients, we used common techniques to realign malunited tibias and validated instruments to measure functional outcome, health status, joint kinematics, and gait. The goals of this study were to evaluate changes in perceived function and health status and changes in joint kinematics and gait as a result of correction of a posttraumatic limb deformity.

Other investigators have reported outcomes of treating symptomatic malunions,³² nonunions,²⁴ and leg-length discrepancies.³³ In these reports, correction of deformity improved patient satisfaction and function, though objective means of assessment were infrequently used. Good results were reported with use of a dome-shaped supramalleolar osteotomy for the correction of tibial malunion.³² In this study, supramalleolar osteotomy was performed on 8 patients for correction of a malunited tibia. Postoperative assessment included subjective assessment of pain, limp, appearance, instability, and activity. Of these 8 patients, 7 reported overall symptomatic improvement after healing, and the 1 who lost the deformity correction remained symptomatic. Significant improvement in overall health has been reported after successful treatment of tibia nonunions.²⁴ The investigators used the SF-36 to assess patients who underwent treatment for a tibial nonunion. Analysis of these patients’ results showed a significant improvement in physical and mental functioning after healing. In addition, improved gait symmetry was reported in patients successfully treated for leg-length discrepancies.³³ Unfortunately, how improvement in gait related to overall patient function was not assessed. In the present study, we used stringent objective and subjective validated instruments to assess changes in joint gait kinematics and functional outcome before and after treatment of a tibial malunion. In general, our results are consistent with published results and indicate that realignment of tibial malunions improves patients’ perceptions of function. Our results also indicate improvements toward normative values in maximal hip adduction and knee varus, thus confirming the efficacy of the surgery from a functional perspective. Unfortunately, we did not show significant improvements in the remaining joint kinematics measurements or temporal gait parameters.

It is not entirely clear whether tibial malalignment leads to degenerative changes of the ipsilateral knee and/or ankle and what role this might play in functioning. In a retrospective analysis of 92 patients, angular deformity within 15° of normal alignment did not lead to ankle arthrosis.⁹ Milner and colleagues⁴ found that, though varus malunion of the tibia may lead to arthrosis of the medial compartment of the knee, other factors were more important in causing arthrosis of the ankle.

Wu and colleagues³⁴ used tibial osteotomies in New Zealand white rabbits to investigate cartilage and bone changes of the knee after creation of varus or valgus tibial deformities. Thirty-four weeks after osteotomy, rabbits with up to 30° of deformity had severe cartilage changes with osteophytes, fibrillation, derangement of cell columns, and associated increased subchondral bone density of the knees. Cadaveric studies have also shown increased contact pressures within the knees and ankles with ever increasing amounts of tibial deformity.^6,10 In each cadaveric study, malalignment in the distal third of the tibia caused the largest changes in the ankle, and changes in the alignment in the proximal third caused the largest changes in the knee.

Consistent with these animal and cadaveric studies are several retrospective clinical studies that have correlated tibial malalignment (particularly varus) with development of knee and ankle arthrosis.^3,5,8 Kettelkamp and colleagues³ found a direct correlation between magnitude of deformity and length of time with development of knee arthrosis. These findings have led many to recommend that surgeons try to restore tibial alignment to as near normal as possible to reduce the likelihood of arthrosis after tibia fracture. We found significant improvement toward normative values for maximum hip adduction (increased) and tibial varus (decreased) after surgery. These improvements would shift the weight-bearing forces back to the central part of the knee and therefore more uniformly distribute weight-bearing forces.

Posttraumatic arthrosis that develops after fracture is thought to result from increased joint pressures and possibly factors related to the injury. Although surgical correction of tibial alignment is unlikely to reverse these cartilage changes, it may restore joint pressure symmetry and “offload” compromised compartments. Offloading of already degenerative compartments may explain our patients’ improved perceptions of function and overall health status.

There were several limitations to our study. First, plain radiographs of malaligned and uninjured tibia and fibula were used, and these do not allow complete assessment of the weight-bearing access of the limb. Our patients, however, had isolated tibia fractures, which involved a normal limb before injury, so any alterations in joint kinematics, gait, or function would likely be the result of the fracture. Another limitation of our study is its nonrandomized design. However, the patients reflect the typical heterogeneous trauma patient population, who typically develop tibial malunions and seek correction. Another limitation was the lack of a treatment protocol regarding exact surgical technique and implants used to stabilize the osteotomies. In general, the patients were treated similarly, and their preoperative and postoperative assessments were exactly the same, as was their state-of-the-art joint kinematics and gait analysis, combined with the use of previously validated outcome measures. In addition, the lack of improvement in gait could have resulted from postoperative physical therapy that focused on joint mobilization and muscle strengthening and not on correction of abnormal gait parameters noted on preoperative gait analysis. Despite the potential limitations of the study, surgical correction of these symptomatic tibial malunions resulted in significant improvement in functional outcome and improved joint kinematics on the operative side.

Conclusion

Significant effort should be made to restore and maintain near-anatomical tibial alignment until a tibia fracture is healed. In patients who develop a symptomatic tibial malunion, surgical correction should be undertaken with the intent to restore normal limb alignment and improve joint kinematics, function, and overall health status.

The tibia is the most commonly fractured long bone in adults, and tibial malunions occur in up to 60% of these patients.^1,2 Persistent tibial malalignment, particularly varus alignment, negatively alters gait and joint kinematics, leading to altered weight-bearing forces across the knee and ankle joints. These altered forces may lead to osteoarthritis.^3-8

Several studies have identified a relationship between extent of tibial malalignment and changes in joint reaction forces.^3,5-7,9-13 Puno and colleagues¹⁴ developed a mathematical model to better define the changes in neighboring joints relative to the pattern of the tibia malalignment. Not surprisingly, their work showed that, with distal tibial malunions, altered stress concentrations were realized at the ankle joint, and more proximal tibial deformities led to larger alterations in the joint stresses at the knee. More recently, van der Schoot and colleagues⁸ found a high prevalence of ipsilateral ankle osteoarthritis with tibial malalignment of 5° or more, and Greenwood and colleagues¹⁵ showed a higher incidence of knee pain, lower limb osteoarthritis, and disability in patients with previous tibia fractures. Given these findings, it would seem that correction of tibial malalignment would lead to normative lower extremity joint kinematic values, joint reaction forces, and overall quality of life (QOL).

The ability to ambulate has been recognized as an important milestone in functional recovery after lower extremity injury.^2,16,17 Gait analysis, assessment of joint kinematics, and QOL and health status questionnaires can provide information to evaluate rehabilitation protocols, treatment algorithms, and surgical outcomes. Recently, these measures have been used to assess patients recovering from acetabular fractures, femoral shaft fractures, and calcaneal fractures.^4,11,17-24 However, no study has used these measures to assess the benefits of surgical correction of malaligned tibias.

We conducted a study to determine improvement in gait, joint kinematics, and patients’ perceptions of overall well-being after surgical correction of tibial malunions. The null hypothesis was that correction of tibial malunion would have no effect on gait, joint kinematics, or patients’ perceptions of function and QOL.

Materials and Methods

This prospective double-time-point study, which was approved by the Institutional Review Board of Washington University/Barnes-Jewish Hospital, evaluated 11 consecutive patients with a varus tibial malunion treated by a single surgeon between September 2003 and January 2006. All patients were treated using a technique that included oblique osteotomy and open reduction and internal fixation (ORIF) or osteotomy and intramedullary nailing. Study inclusion criteria were age 18 years or older; symptomatic varus malunion of the tibia of 10º or more; absence of a developmental or pathologic process leading to the fracture and subsequent deformity; no neurologic deficit of either lower extremity or contralateral lower extremity deformity; and ability to ambulate 9 meters with or without use of an assistive device.

The 11 patients (6 men, 5 women) who met these criteria enrolled in the study. Mean age was 53 years (range, 43-68 years). Eight malunions involved the left tibia. The mechanisms of injury were motor vehicle crash (6 patients), fall from a great height (3), being struck by a motor vehicle (1), and gunshot (1). Mean time from injury to corrective surgery was 16.9 years (range, 1-34 years). Before surgery, each patient had a thorough physical examination, with plain radiographs, including anteroposterior (AP), lateral, and oblique views, obtained to assess degree of limb malalignment. Patients completed the Short Form-36 (SF-36) and the Musculoskeletal Function Assessment (MFA) and underwent joint kinematics and gait analysis. Five malunions were located in the mid-diaphysis of the tibia, 3 in the proximal third, and 2 in the distal third of the tibial shaft. One patient had posttraumatic deformity involving the proximal and the mid-diaphysis (Table 1). After surgery, each patient was followed at regular intervals in the surgeon’s private office. Minimum follow-up was 7 months (mean, 11 months; range 7-17 months). At follow-up, radiographs were obtained, and each patient completed the SF-36 and the MFA and underwent joint kinematics and gait analysis.

We obtained preoperative AP and lateral radiographs of the malaligned and contralateral normal tibias for each patient. Angular deformity was determined in the sagittal and coronal planes to determine location and magnitude of the deformity. Specifically, on each AP and lateral radiograph, a line was drawn the length of the tibia proximal and distal to the area of the deformity. The angle generated by the intersection of these lines on the AP and lateral radiographs was then plotted on a grid to determine the precise plane and magnitude of the deformity (Table 2).^1,12 Clinically, relevant rotational deformity of the involved limb was assessed by physical examination, and the results were compared with those of the contralateral limb. Owing to the lack of considerable rotational deformity in any of these 11 patients, we did not obtain computed tomography scans for further assessment of rotation.

Perioperative intravenous antibiotics were administered: 2 g cefazolin 30 minutes before incision and 1 g every 8 hours for 24 hours after surgery. A pneumatic tourniquet was placed on the proximal thigh, and the entire leg was prepared and draped in a sterile fashion. The limb was elevated and exsanguinated with an Esmark bandage and the tourniquet raised to 250 mm Hg. With fluoroscopy, the site of the tibial deformity was identified. Generally, an incision was made centered over the apex of the deformity and one fingerbreadth lateral to the palpable tibial crest. In most cases, the anterolateral aspect of the tibia was exposed while minimizing soft-tissue and periosteal stripping. The plane of the maximum deformity was identified with both direct visualization and fluoroscopy. The osteotomy was performed with an oscillating saw, and in each case a fibular osteotomy was also performed. Malalignment was corrected using a combination of manual manipulation and femoral distractor.^25,26 Intraoperative biplanar radiographs were compared with our preoperative plan and with reversed images of the contralateral tibia to assess correction of the deformity. If lengthening was required, in addition to the tibial osteotomy, a corticotomy was created, and a circular external fixator applied and distraction osteogenesis performed.

We maintained the limbs in a short-leg splint for about 10 days after surgery and then initiated active-assisted range of motion of neighboring joints. Patients were maintained on toe-touch weight-bearing for the initial 6 weeks and were then advanced to partial weight-bearing (23 kg). Physical therapy for lower extremity strengthening and gait training was started 6 weeks after surgery. Three months after surgery, patients were advanced to weight-bearing as tolerated and were allowed to return to their activities of daily living without restrictions if radiographs and clinical examination were consistent with healing of the osteotomy.

Each patient was examined and radiographs obtained at regular intervals (2, 6, and 12 weeks and then about every 3 months) after surgery until healing. Bone union was determined by history and physical examination with pain-free weight-bearing without use of assistive devices and by return of functional use of the extremity. Radiographic union was considered to have occurred when bridging trabeculae were present across the osteotomy and there was no loosening or failure of the implants. Occasionally, if there were questions regarding healing, a musculoskeletal radiologist was consulted. Acceptable tibia alignment was defined as alignment of less than 5° varus or less than 10° valgus in the coronal plane and less than 15° procurvatum or recurvatum in the sagittal plane. Immediate postoperative radiographs and most recent radiographs were used to determine the final amount of angular correction.²⁷

Two patients subsequently required secondary operative procedures. One had varus collapse through the regenerate, and the other developed a nonunion of the osteotomy site and required exchange intramedullary nailing. In each case, the final assessment was done after the patient had healed after the second surgery and had fully recovered.

Perceived Functional Assessment

The MFA is a 100-item self-administered QOL questionnaire designed to assess self-perception of physical, psychological, and social well-being in patients with a musculoskeletal injury or condition. The MFA provides a summary score and separate score for each of 10 functional domains. The lower the score, the better the patient’s perception of function. Validated and published norms are available.^20,28-30

Perceived Health Status

The Short Form-36 is a 36-item multipurpose self-administered health survey questionnaire. The SF-36, which assesses overall health status, provides a Physical Component Score (PCS) and a Mental Component Score (MCS). The higher the score, the better the patient’s perception of function. Validated and published norms are available.³¹

Gait Analysis

Video data from a 6-camera high-resolution system (Motion Analysis, Santa Rosa, California) were used to assess gait. A set of 3 reflective surface markers was placed on each of 4 areas: trunk, thighs, legs, and feet.^18,19 The patient walked barefoot along a 9-meter walkway, and video data were collected during the middle 2 meters. For each patient, data from 4 to 7 trials were collected. Computerized software produced data describing the averaged joint angle as a function of the gait cycle for each of the 3 principal planes of the body. Specific points in the gait cycle were analyzed. Variables included maximum knee varus in stance phase; maximum knee valgus in swing; maximum knee flexion in stance and swing; minimum knee flexion in stance; maximum ankle inversion in terminal stance; maximum ankle eversion in stance; maximum ankle dorsiflexion in stance and swing; and maximum ankle plantarflexion at takeoff. In addition to the lower extremity joint kinematics, angular measurements, basic gait measurements of step length, stride length, cadence, and speed were also recorded.

Statistical Analysis

Paired t tests were used to determine if significant changes occurred as a consequence of the surgery for the outcome variables (P < .05). Normative gait data were used to assess the quality of any changes that occurred in the variables, but no statistical analysis was performed to determine significant differences.¹⁸

Results

All 11 patients had clinical and radiographic evidence of healing and deformity correction at most recent follow-up. Nine patients (82%) healed after the index procedure. Mean total angular correction in the coronal plane was 21° (range, 14° varus to 7° valgus), and mean total angular correction in the sagittal plane was 9° (range, 21° recurvatum to 15° procurvatum) (Table 2).

For the group, mean preoperative MFA score was 39 (SD, 18; range, 10-69), and mean postoperative MFA score was 28 (SD, 14; range, 8-53). Patients reported the most improvement in 2 domains: In Leisure, mean (SD) preoperative score was 8 (2), and mean postoperative score was 5 (2); in Emotional, mean preoperative score was 5 (2), and mean postoperative score was 4 (1). The other domains were not significantly different between the 2 assessments.

 On the SF-36, mean (SD) PCS significantly (P < .05) improved from 32 (8) to 43 (9). Mean (SD) MCS showed little change: preoperative, 46 (16); postoperative, 48 (13). The PCS subcategories that showed the most improvement were Physical Function, mean (SD) preoperative, 26 (20), to postoperative, 52 (26); Role of Physical Health, preoperative, 18 (24), to postoperative, 60 (41); and Bodily Pain, preoperative, 39 (27), to 58 (18).

The results from the preoperative and postoperative gait analysis showed no significant differences for the ankle, knee, and hip variables during swing phase (Table 3). In an analysis of the changes in joint kinematics during stance, maximum hip adduction (increased) and maximum knee varus (decreased) on the operative side were significantly improved toward normative values as a consequence of the surgery (Table 3). The other kinematic stance variables were not significantly different. No significant changes were observed in stance time, step length, stride length, cadence, or speed as a consequence of the surgery (Table 4).

Discussion

Correction of malaligned tibias leads to improved limb alignment and patients’ perceptions of functional abilities and health but had a limited effect on joint kinematics and gait. In a group of like patients, we used common techniques to realign malunited tibias and validated instruments to measure functional outcome, health status, joint kinematics, and gait. The goals of this study were to evaluate changes in perceived function and health status and changes in joint kinematics and gait as a result of correction of a posttraumatic limb deformity.

Other investigators have reported outcomes of treating symptomatic malunions,³² nonunions,²⁴ and leg-length discrepancies.³³ In these reports, correction of deformity improved patient satisfaction and function, though objective means of assessment were infrequently used. Good results were reported with use of a dome-shaped supramalleolar osteotomy for the correction of tibial malunion.³² In this study, supramalleolar osteotomy was performed on 8 patients for correction of a malunited tibia. Postoperative assessment included subjective assessment of pain, limp, appearance, instability, and activity. Of these 8 patients, 7 reported overall symptomatic improvement after healing, and the 1 who lost the deformity correction remained symptomatic. Significant improvement in overall health has been reported after successful treatment of tibia nonunions.²⁴ The investigators used the SF-36 to assess patients who underwent treatment for a tibial nonunion. Analysis of these patients’ results showed a significant improvement in physical and mental functioning after healing. In addition, improved gait symmetry was reported in patients successfully treated for leg-length discrepancies.³³ Unfortunately, how improvement in gait related to overall patient function was not assessed. In the present study, we used stringent objective and subjective validated instruments to assess changes in joint gait kinematics and functional outcome before and after treatment of a tibial malunion. In general, our results are consistent with published results and indicate that realignment of tibial malunions improves patients’ perceptions of function. Our results also indicate improvements toward normative values in maximal hip adduction and knee varus, thus confirming the efficacy of the surgery from a functional perspective. Unfortunately, we did not show significant improvements in the remaining joint kinematics measurements or temporal gait parameters.

It is not entirely clear whether tibial malalignment leads to degenerative changes of the ipsilateral knee and/or ankle and what role this might play in functioning. In a retrospective analysis of 92 patients, angular deformity within 15° of normal alignment did not lead to ankle arthrosis.⁹ Milner and colleagues⁴ found that, though varus malunion of the tibia may lead to arthrosis of the medial compartment of the knee, other factors were more important in causing arthrosis of the ankle.

Wu and colleagues³⁴ used tibial osteotomies in New Zealand white rabbits to investigate cartilage and bone changes of the knee after creation of varus or valgus tibial deformities. Thirty-four weeks after osteotomy, rabbits with up to 30° of deformity had severe cartilage changes with osteophytes, fibrillation, derangement of cell columns, and associated increased subchondral bone density of the knees. Cadaveric studies have also shown increased contact pressures within the knees and ankles with ever increasing amounts of tibial deformity.^6,10 In each cadaveric study, malalignment in the distal third of the tibia caused the largest changes in the ankle, and changes in the alignment in the proximal third caused the largest changes in the knee.

Consistent with these animal and cadaveric studies are several retrospective clinical studies that have correlated tibial malalignment (particularly varus) with development of knee and ankle arthrosis.^3,5,8 Kettelkamp and colleagues³ found a direct correlation between magnitude of deformity and length of time with development of knee arthrosis. These findings have led many to recommend that surgeons try to restore tibial alignment to as near normal as possible to reduce the likelihood of arthrosis after tibia fracture. We found significant improvement toward normative values for maximum hip adduction (increased) and tibial varus (decreased) after surgery. These improvements would shift the weight-bearing forces back to the central part of the knee and therefore more uniformly distribute weight-bearing forces.

Posttraumatic arthrosis that develops after fracture is thought to result from increased joint pressures and possibly factors related to the injury. Although surgical correction of tibial alignment is unlikely to reverse these cartilage changes, it may restore joint pressure symmetry and “offload” compromised compartments. Offloading of already degenerative compartments may explain our patients’ improved perceptions of function and overall health status.

There were several limitations to our study. First, plain radiographs of malaligned and uninjured tibia and fibula were used, and these do not allow complete assessment of the weight-bearing access of the limb. Our patients, however, had isolated tibia fractures, which involved a normal limb before injury, so any alterations in joint kinematics, gait, or function would likely be the result of the fracture. Another limitation of our study is its nonrandomized design. However, the patients reflect the typical heterogeneous trauma patient population, who typically develop tibial malunions and seek correction. Another limitation was the lack of a treatment protocol regarding exact surgical technique and implants used to stabilize the osteotomies. In general, the patients were treated similarly, and their preoperative and postoperative assessments were exactly the same, as was their state-of-the-art joint kinematics and gait analysis, combined with the use of previously validated outcome measures. In addition, the lack of improvement in gait could have resulted from postoperative physical therapy that focused on joint mobilization and muscle strengthening and not on correction of abnormal gait parameters noted on preoperative gait analysis. Despite the potential limitations of the study, surgical correction of these symptomatic tibial malunions resulted in significant improvement in functional outcome and improved joint kinematics on the operative side.

Conclusion

Significant effort should be made to restore and maintain near-anatomical tibial alignment until a tibia fracture is healed. In patients who develop a symptomatic tibial malunion, surgical correction should be undertaken with the intent to restore normal limb alignment and improve joint kinematics, function, and overall health status.

SAN FRANCISCO—Trial results suggest a 3-drug regimen could represent a new standard of care for relapsed multiple myeloma (MM), according to a speaker at the 2014 ASH Annual Meeting.

In the phase 3 ASPIRE trial, patients who received combination carfilzomib, lenalidomide, and dexamethasone (KRd) had superior progression-free survival compared to patients who received only lenalidomide and dexamethasone (Rd).

There was a trend toward improved overall survival with KRd as well.

Patients who received KRd did experience more adverse events (AEs), but fewer patients discontinued treatment due to AEs in the KRd arm than in the Rd arm.

Keith Stewart, MBChB, of the Mayo Clinic in Arizona, presented these results at the meeting as abstract 79. The data were published in The New England Journal of Medicine as well. The trial was sponsored by Onyx Pharmaceuticals, Inc., the company developing carfilzomib.

ASPIRE included 792 patients with relapsed MM who had received 1 to 3 prior treatment regimens. Patients were randomized to treatment with KRd (n=396) or Rd (n=396), and baseline characteristics were similar between the arms.

“There was a slight preponderance of patients over the age of 65 in the Rd arm of the trial,” Dr Stewart noted. “Conversely, there were more patients on the Rd arm of the trial who had lower-risk cytogenetics.”

“Patients were also well-balanced for baseline exposure to prior therapies. Prior therapies included transplant in 55% of patients, bortezomib in two-thirds of patients, and lenalidomide in 20% of patients—again, equal in both arms of the trial.”

All patients received a standard dosing schedule of lenalidomide (25 mg on days 1-21) and low-dose dexamethasone (40 mg on days 1, 8, 15, and 22).

Patients in the KRd arm also received carfilzomib (20 mg/m² on days 1 and 2 of cycle 1 and 27 mg/m² thereafter). They received a 10-minute infusion of the drug on days 1, 2, 8, 9, 15, and 16. Carfilzomib was not given on days 8 and 9 in cycles 13 to 18 and not administered beyond 18 cycles.

‘Unprecedented’ results

The study’s primary endpoint was progression-free survival. And results showed progression-free survival was significantly longer in the KRd arm than in the Rd arm—26.3 months and 17.6 months, respectively (hazard ratio=0.69; P<0.0001).

“Progression-free survival was significantly improved by 8.7 months with KRd,” Dr Stewart noted. “In a phase 3 clinical trial setting, this is unprecedented.”

“In all prespecified subgroups, the advantage of KRd in progression-free survival was maintained. That includes age, international staging system, and prior exposure to either bortezomib or lenalidomide, or both drugs.”

The secondary endpoints of the trial were overall survival, overall response rate, duration of response, health-related quality of life, and safety.

The data for median overall survival are not yet mature based on the prespecified statistical boundary at the interim analysis (P=0.005). However, there was a trend in favor of KRd (hazard ratio, 0.79; P=0.018).

The overall response rate was 87.1% with KRd and 66.7% with Rd (P<0.0001), and the complete response rates were 14.1% and 4.3%, respectively (P<0.001). The median duration of response was 28.6 months and 21.2 months, respectively.

In addition, KRd improved global health-related quality of life compared with Rd over 18 cycles of treatment (P=0.0001).

‘Reassuring’ toxicity data

“In the discussion of adverse events,” Dr Stewart said, “it’s important to note that the median treatment duration was 88 weeks with KRd and 57 weeks with Rd.”

Most patients in each arm experienced at least one AE—96.9% in the KRd arm and 97.2% in the RD arm.

In the KRd arm, 7.7% of patients died while still on treatment or within 30 days of receiving their last dose of treatment, as did 8.5% of patients in the Rd arm. The percentage of deaths attributable to AEs was 6.9% in both arms.

The rates of treatment discontinuation were 69.9% in the KRd arm and 77.9% in the Rd arm. More patients discontinued treatment due to disease progression—39.8% in the KRd arm and 50.1% in the Rd arm—than to AEs—15.3% in the KRd arm and 17.7% in the Rd arm.

The most common grade 3 or higher hematologic treatment-emergent AEs (in the KRd and Rd arms, respectively) were neutropenia (29.6% vs 26.5%), anemia (17.9% vs 17.2%), and thrombocytopenia (16.6% vs 12.3%).

The most common grade 3 or higher nonhematologic treatment-emergent AEs (in the KRd and Rd arms, respectively) were hypokalemia (9.4% vs 4.9%), fatigue (7.7% vs 6.4%), and diarrhea (3.8% vs 4.1%).

Other treatment-emergent AEs of any grade (in the KRd and Rd arms, respectively) included dyspnea (19.4% vs 14.9%), hypertension (14.3% vs 6.9%), acute renal failure (8.4% vs 7.2%), cardiac failure (6.4% vs 4.1%), ischemic heart disease (5.9% vs 4.6%), and peripheral neuropathy (17.1% vs 17.0%).

“The results [are] very reassuring with respect to cardiac and renal events, which were reported at rates consistent with, or even lower than, those reported in prior studies of single-agent carfilzomib or more heavily pretreated patients,” Dr Stewart said.

“Based on the results of this phase 3 trial, I think it’s fair to say that KRd could represent a new standard of care in relapsed multiple myeloma.”

SAN FRANCISCO—Trial results suggest a 3-drug regimen could represent a new standard of care for relapsed multiple myeloma (MM), according to a speaker at the 2014 ASH Annual Meeting.

In the phase 3 ASPIRE trial, patients who received combination carfilzomib, lenalidomide, and dexamethasone (KRd) had superior progression-free survival compared to patients who received only lenalidomide and dexamethasone (Rd).

There was a trend toward improved overall survival with KRd as well.

Patients who received KRd did experience more adverse events (AEs), but fewer patients discontinued treatment due to AEs in the KRd arm than in the Rd arm.

Keith Stewart, MBChB, of the Mayo Clinic in Arizona, presented these results at the meeting as abstract 79. The data were published in The New England Journal of Medicine as well. The trial was sponsored by Onyx Pharmaceuticals, Inc., the company developing carfilzomib.

ASPIRE included 792 patients with relapsed MM who had received 1 to 3 prior treatment regimens. Patients were randomized to treatment with KRd (n=396) or Rd (n=396), and baseline characteristics were similar between the arms.

“There was a slight preponderance of patients over the age of 65 in the Rd arm of the trial,” Dr Stewart noted. “Conversely, there were more patients on the Rd arm of the trial who had lower-risk cytogenetics.”

“Patients were also well-balanced for baseline exposure to prior therapies. Prior therapies included transplant in 55% of patients, bortezomib in two-thirds of patients, and lenalidomide in 20% of patients—again, equal in both arms of the trial.”

All patients received a standard dosing schedule of lenalidomide (25 mg on days 1-21) and low-dose dexamethasone (40 mg on days 1, 8, 15, and 22).

Patients in the KRd arm also received carfilzomib (20 mg/m² on days 1 and 2 of cycle 1 and 27 mg/m² thereafter). They received a 10-minute infusion of the drug on days 1, 2, 8, 9, 15, and 16. Carfilzomib was not given on days 8 and 9 in cycles 13 to 18 and not administered beyond 18 cycles.

‘Unprecedented’ results

The study’s primary endpoint was progression-free survival. And results showed progression-free survival was significantly longer in the KRd arm than in the Rd arm—26.3 months and 17.6 months, respectively (hazard ratio=0.69; P<0.0001).

“Progression-free survival was significantly improved by 8.7 months with KRd,” Dr Stewart noted. “In a phase 3 clinical trial setting, this is unprecedented.”

“In all prespecified subgroups, the advantage of KRd in progression-free survival was maintained. That includes age, international staging system, and prior exposure to either bortezomib or lenalidomide, or both drugs.”

The secondary endpoints of the trial were overall survival, overall response rate, duration of response, health-related quality of life, and safety.

The data for median overall survival are not yet mature based on the prespecified statistical boundary at the interim analysis (P=0.005). However, there was a trend in favor of KRd (hazard ratio, 0.79; P=0.018).

The overall response rate was 87.1% with KRd and 66.7% with Rd (P<0.0001), and the complete response rates were 14.1% and 4.3%, respectively (P<0.001). The median duration of response was 28.6 months and 21.2 months, respectively.

In addition, KRd improved global health-related quality of life compared with Rd over 18 cycles of treatment (P=0.0001).

‘Reassuring’ toxicity data

“In the discussion of adverse events,” Dr Stewart said, “it’s important to note that the median treatment duration was 88 weeks with KRd and 57 weeks with Rd.”

Most patients in each arm experienced at least one AE—96.9% in the KRd arm and 97.2% in the RD arm.

In the KRd arm, 7.7% of patients died while still on treatment or within 30 days of receiving their last dose of treatment, as did 8.5% of patients in the Rd arm. The percentage of deaths attributable to AEs was 6.9% in both arms.

The rates of treatment discontinuation were 69.9% in the KRd arm and 77.9% in the Rd arm. More patients discontinued treatment due to disease progression—39.8% in the KRd arm and 50.1% in the Rd arm—than to AEs—15.3% in the KRd arm and 17.7% in the Rd arm.

The most common grade 3 or higher hematologic treatment-emergent AEs (in the KRd and Rd arms, respectively) were neutropenia (29.6% vs 26.5%), anemia (17.9% vs 17.2%), and thrombocytopenia (16.6% vs 12.3%).

The most common grade 3 or higher nonhematologic treatment-emergent AEs (in the KRd and Rd arms, respectively) were hypokalemia (9.4% vs 4.9%), fatigue (7.7% vs 6.4%), and diarrhea (3.8% vs 4.1%).

Other treatment-emergent AEs of any grade (in the KRd and Rd arms, respectively) included dyspnea (19.4% vs 14.9%), hypertension (14.3% vs 6.9%), acute renal failure (8.4% vs 7.2%), cardiac failure (6.4% vs 4.1%), ischemic heart disease (5.9% vs 4.6%), and peripheral neuropathy (17.1% vs 17.0%).

“The results [are] very reassuring with respect to cardiac and renal events, which were reported at rates consistent with, or even lower than, those reported in prior studies of single-agent carfilzomib or more heavily pretreated patients,” Dr Stewart said.

“Based on the results of this phase 3 trial, I think it’s fair to say that KRd could represent a new standard of care in relapsed multiple myeloma.”

SAN FRANCISCO—Trial results suggest a 3-drug regimen could represent a new standard of care for relapsed multiple myeloma (MM), according to a speaker at the 2014 ASH Annual Meeting.

In the phase 3 ASPIRE trial, patients who received combination carfilzomib, lenalidomide, and dexamethasone (KRd) had superior progression-free survival compared to patients who received only lenalidomide and dexamethasone (Rd).

There was a trend toward improved overall survival with KRd as well.

Patients who received KRd did experience more adverse events (AEs), but fewer patients discontinued treatment due to AEs in the KRd arm than in the Rd arm.

Keith Stewart, MBChB, of the Mayo Clinic in Arizona, presented these results at the meeting as abstract 79. The data were published in The New England Journal of Medicine as well. The trial was sponsored by Onyx Pharmaceuticals, Inc., the company developing carfilzomib.

ASPIRE included 792 patients with relapsed MM who had received 1 to 3 prior treatment regimens. Patients were randomized to treatment with KRd (n=396) or Rd (n=396), and baseline characteristics were similar between the arms.

“There was a slight preponderance of patients over the age of 65 in the Rd arm of the trial,” Dr Stewart noted. “Conversely, there were more patients on the Rd arm of the trial who had lower-risk cytogenetics.”

“Patients were also well-balanced for baseline exposure to prior therapies. Prior therapies included transplant in 55% of patients, bortezomib in two-thirds of patients, and lenalidomide in 20% of patients—again, equal in both arms of the trial.”

All patients received a standard dosing schedule of lenalidomide (25 mg on days 1-21) and low-dose dexamethasone (40 mg on days 1, 8, 15, and 22).

Patients in the KRd arm also received carfilzomib (20 mg/m² on days 1 and 2 of cycle 1 and 27 mg/m² thereafter). They received a 10-minute infusion of the drug on days 1, 2, 8, 9, 15, and 16. Carfilzomib was not given on days 8 and 9 in cycles 13 to 18 and not administered beyond 18 cycles.

‘Unprecedented’ results

The study’s primary endpoint was progression-free survival. And results showed progression-free survival was significantly longer in the KRd arm than in the Rd arm—26.3 months and 17.6 months, respectively (hazard ratio=0.69; P<0.0001).

“Progression-free survival was significantly improved by 8.7 months with KRd,” Dr Stewart noted. “In a phase 3 clinical trial setting, this is unprecedented.”

“In all prespecified subgroups, the advantage of KRd in progression-free survival was maintained. That includes age, international staging system, and prior exposure to either bortezomib or lenalidomide, or both drugs.”

The secondary endpoints of the trial were overall survival, overall response rate, duration of response, health-related quality of life, and safety.

The data for median overall survival are not yet mature based on the prespecified statistical boundary at the interim analysis (P=0.005). However, there was a trend in favor of KRd (hazard ratio, 0.79; P=0.018).

The overall response rate was 87.1% with KRd and 66.7% with Rd (P<0.0001), and the complete response rates were 14.1% and 4.3%, respectively (P<0.001). The median duration of response was 28.6 months and 21.2 months, respectively.

In addition, KRd improved global health-related quality of life compared with Rd over 18 cycles of treatment (P=0.0001).

‘Reassuring’ toxicity data

“In the discussion of adverse events,” Dr Stewart said, “it’s important to note that the median treatment duration was 88 weeks with KRd and 57 weeks with Rd.”

Most patients in each arm experienced at least one AE—96.9% in the KRd arm and 97.2% in the RD arm.

In the KRd arm, 7.7% of patients died while still on treatment or within 30 days of receiving their last dose of treatment, as did 8.5% of patients in the Rd arm. The percentage of deaths attributable to AEs was 6.9% in both arms.

The rates of treatment discontinuation were 69.9% in the KRd arm and 77.9% in the Rd arm. More patients discontinued treatment due to disease progression—39.8% in the KRd arm and 50.1% in the Rd arm—than to AEs—15.3% in the KRd arm and 17.7% in the Rd arm.

The most common grade 3 or higher hematologic treatment-emergent AEs (in the KRd and Rd arms, respectively) were neutropenia (29.6% vs 26.5%), anemia (17.9% vs 17.2%), and thrombocytopenia (16.6% vs 12.3%).

The most common grade 3 or higher nonhematologic treatment-emergent AEs (in the KRd and Rd arms, respectively) were hypokalemia (9.4% vs 4.9%), fatigue (7.7% vs 6.4%), and diarrhea (3.8% vs 4.1%).

Other treatment-emergent AEs of any grade (in the KRd and Rd arms, respectively) included dyspnea (19.4% vs 14.9%), hypertension (14.3% vs 6.9%), acute renal failure (8.4% vs 7.2%), cardiac failure (6.4% vs 4.1%), ischemic heart disease (5.9% vs 4.6%), and peripheral neuropathy (17.1% vs 17.0%).

“The results [are] very reassuring with respect to cardiac and renal events, which were reported at rates consistent with, or even lower than, those reported in prior studies of single-agent carfilzomib or more heavily pretreated patients,” Dr Stewart said.

“Based on the results of this phase 3 trial, I think it’s fair to say that KRd could represent a new standard of care in relapsed multiple myeloma.”

Lab mouse

Researchers say they have discovered why patients with chronic lymphocytic leukemia (CLL) often relapse.

Using a mouse model, the team demonstrated that crosstalk between leukemic cells and a group of stromal cells in the spleen is crucial for tumor growth.

The group also found a way to prevent leukemic cell proliferation and stop the cells from entering the spleen, thereby identifying new targets for future therapies in CLL.

Kristina Heinig, of Max Delbrück Center for Molecular Medicine in Berlin, Germany, and her colleagues reported these findings in Cancer Discovery.

The team theorized that the processes that normally regulate the migration of B lymphocytes into the B-cell follicle are also the reason for the migration of leukemia cells into the lymphoid organs. Hence, within the B-cell follicle, the survival and growth of malignant B cells may depend on the contact of leukemia cells with follicular dendritic cells (FDCs).

The researchers validated this theory with their mouse model. They found the chemokine CXCL13 and its receptor, CXCR5, on the surface of the leukemia cells are needed to ensure that leukemia cells can reach the spleen. With the aid of this homing receptor, the cancer cells are lured into the B-cell follicle of the spleen, where the FDCs secrete CXCL13.

When the researchers blocked CXCR5 in the mice, the leukemia cells could no longer migrate into the stromal cell niche and proliferated much more slowly.

In a second step, the group studied the consequences of the interaction between malignant B cells and the FDCs in the B-cell follicle. They found the close contact between the leukemia cells and the FDC network stimulates the cancer cells to increasingly produce another signaling substance, lymphotoxin.

The lymphotoxin binds to the lymphotoxin-beta receptor on the FDCs, which then increasingly secrete CXCL13. This creates a positive feedback loop because CXCL13 plays a major role in the recruitment of leukemia cells in the B-cell follicles.

The FDCs also provide growth factors that promote the proliferation of leukemia cells in the stromal niche.

When the researchers inhibited the binding of the lymphotoxin to the lymphotoxin-beta receptor on the FDCs with an immunologically active substance, they were able to end this ping-pong match between leukemia cells and the FDCs and dramatically reduce tumor growth.

The team thus identified two different targets that may complement the chemotherapy currently used to treat CLL. The first is blocking the chemokine/homing receptor CXCR5 on the leukemia cells, which prevents the cancer cells from lodging in the B-cell follicle.

The second is blocking the lymphotoxin-beta receptor on the FDCs so the reciprocal crosstalk between the leukemia cells and the FDCs is interrupted and tumor development is reduced.

From the results of their study, the researchers infer that chemotherapies already in clinical use combined with immune therapies that interrupt the crosstalk between leukemia cells and the FDCs may be beneficial.

This combination could prevent the residual leukemia cells that have escaped chemotherapy or radiation therapy from recovering in the stromal cell niche and from triggering a relapse.

Lab mouse

Researchers say they have discovered why patients with chronic lymphocytic leukemia (CLL) often relapse.

Using a mouse model, the team demonstrated that crosstalk between leukemic cells and a group of stromal cells in the spleen is crucial for tumor growth.

The group also found a way to prevent leukemic cell proliferation and stop the cells from entering the spleen, thereby identifying new targets for future therapies in CLL.

Kristina Heinig, of Max Delbrück Center for Molecular Medicine in Berlin, Germany, and her colleagues reported these findings in Cancer Discovery.

The team theorized that the processes that normally regulate the migration of B lymphocytes into the B-cell follicle are also the reason for the migration of leukemia cells into the lymphoid organs. Hence, within the B-cell follicle, the survival and growth of malignant B cells may depend on the contact of leukemia cells with follicular dendritic cells (FDCs).

The researchers validated this theory with their mouse model. They found the chemokine CXCL13 and its receptor, CXCR5, on the surface of the leukemia cells are needed to ensure that leukemia cells can reach the spleen. With the aid of this homing receptor, the cancer cells are lured into the B-cell follicle of the spleen, where the FDCs secrete CXCL13.

When the researchers blocked CXCR5 in the mice, the leukemia cells could no longer migrate into the stromal cell niche and proliferated much more slowly.

In a second step, the group studied the consequences of the interaction between malignant B cells and the FDCs in the B-cell follicle. They found the close contact between the leukemia cells and the FDC network stimulates the cancer cells to increasingly produce another signaling substance, lymphotoxin.

The lymphotoxin binds to the lymphotoxin-beta receptor on the FDCs, which then increasingly secrete CXCL13. This creates a positive feedback loop because CXCL13 plays a major role in the recruitment of leukemia cells in the B-cell follicles.

The FDCs also provide growth factors that promote the proliferation of leukemia cells in the stromal niche.

When the researchers inhibited the binding of the lymphotoxin to the lymphotoxin-beta receptor on the FDCs with an immunologically active substance, they were able to end this ping-pong match between leukemia cells and the FDCs and dramatically reduce tumor growth.

The team thus identified two different targets that may complement the chemotherapy currently used to treat CLL. The first is blocking the chemokine/homing receptor CXCR5 on the leukemia cells, which prevents the cancer cells from lodging in the B-cell follicle.

The second is blocking the lymphotoxin-beta receptor on the FDCs so the reciprocal crosstalk between the leukemia cells and the FDCs is interrupted and tumor development is reduced.

From the results of their study, the researchers infer that chemotherapies already in clinical use combined with immune therapies that interrupt the crosstalk between leukemia cells and the FDCs may be beneficial.

This combination could prevent the residual leukemia cells that have escaped chemotherapy or radiation therapy from recovering in the stromal cell niche and from triggering a relapse.

Lab mouse

Researchers say they have discovered why patients with chronic lymphocytic leukemia (CLL) often relapse.

Using a mouse model, the team demonstrated that crosstalk between leukemic cells and a group of stromal cells in the spleen is crucial for tumor growth.

The group also found a way to prevent leukemic cell proliferation and stop the cells from entering the spleen, thereby identifying new targets for future therapies in CLL.

Kristina Heinig, of Max Delbrück Center for Molecular Medicine in Berlin, Germany, and her colleagues reported these findings in Cancer Discovery.

The team theorized that the processes that normally regulate the migration of B lymphocytes into the B-cell follicle are also the reason for the migration of leukemia cells into the lymphoid organs. Hence, within the B-cell follicle, the survival and growth of malignant B cells may depend on the contact of leukemia cells with follicular dendritic cells (FDCs).

The researchers validated this theory with their mouse model. They found the chemokine CXCL13 and its receptor, CXCR5, on the surface of the leukemia cells are needed to ensure that leukemia cells can reach the spleen. With the aid of this homing receptor, the cancer cells are lured into the B-cell follicle of the spleen, where the FDCs secrete CXCL13.

When the researchers blocked CXCR5 in the mice, the leukemia cells could no longer migrate into the stromal cell niche and proliferated much more slowly.

In a second step, the group studied the consequences of the interaction between malignant B cells and the FDCs in the B-cell follicle. They found the close contact between the leukemia cells and the FDC network stimulates the cancer cells to increasingly produce another signaling substance, lymphotoxin.

The lymphotoxin binds to the lymphotoxin-beta receptor on the FDCs, which then increasingly secrete CXCL13. This creates a positive feedback loop because CXCL13 plays a major role in the recruitment of leukemia cells in the B-cell follicles.

The FDCs also provide growth factors that promote the proliferation of leukemia cells in the stromal niche.

When the researchers inhibited the binding of the lymphotoxin to the lymphotoxin-beta receptor on the FDCs with an immunologically active substance, they were able to end this ping-pong match between leukemia cells and the FDCs and dramatically reduce tumor growth.

The team thus identified two different targets that may complement the chemotherapy currently used to treat CLL. The first is blocking the chemokine/homing receptor CXCR5 on the leukemia cells, which prevents the cancer cells from lodging in the B-cell follicle.

The second is blocking the lymphotoxin-beta receptor on the FDCs so the reciprocal crosstalk between the leukemia cells and the FDCs is interrupted and tumor development is reduced.

From the results of their study, the researchers infer that chemotherapies already in clinical use combined with immune therapies that interrupt the crosstalk between leukemia cells and the FDCs may be beneficial.

This combination could prevent the residual leukemia cells that have escaped chemotherapy or radiation therapy from recovering in the stromal cell niche and from triggering a relapse.