Take-Home Points

• Systematic use of PROMs allows physicians to review data on pain, physical function, and psychological status to aid in clinical decision-making and best practices.
• PROMs should include both general outcome measures (VAS, SF-36, or EQ-5D) and reliable, valid, and responsive disease specific measures.
• PROM questionnaires should collect pertinent information while limiting the length to maximize patient compliance and reliability.
• PROMIS has been developed to standardize questionnaires, but generality for specific orthopedic procedures may result in less effective measures.
• PROMs can also be used for predictive modeling, which has the potential to help develop more cost-effective care and predict expected outcomes and recovery trajectories for individual patients.

Owing to their unique ability to recognize patients as stakeholders in their own healthcare, patient-reported outcome measures (PROMs) are becoming increasingly popular in the assessment of medical and surgical outcomes.¹ PROMs are an outcome measures subset in which patients complete questionnaires about their perceptions of their overall health status and specific health limitations. By systematically using PROMs before and after a clearly defined episode of care, clinicians can collect data on perceived pain level, physical function, and psychological status and use the data to validate use of surgical procedures and shape clinical decisions about best practices.^2-4 Although mortality and morbidity rates and other traditional measures are valuable in assessing outcomes, they do not represent or communicate the larger impact of an episode of care. As many orthopedic procedures are elective, and some are low-risk, the evaluation of changes in quality of life and self-reported functional improvement is an important addition to morbidity and mortality rates in capturing the true impact of a surgical procedure and recovery. The patient’s preoperative and postoperative perspectives on his or her health status have become important as well; our healthcare system has been placing more emphasis on patient-centered quality care.^2,5

Although PROMs have many benefits, implementation in an orthopedic surgery practice has its challenges. With so many PROMs available, selecting those that fit the patient population for a specialized orthopedic surgery practice can be difficult. In addition, although PROM data are essential for research and for measuring individual or institutional recovery trajectories for surgical procedures, in a busy practice getting patients to provide these data can be difficult.

PROMs are heavily used for outcomes assessment in the orthopedics literature, but there are few resources for orthopedic surgeons who want to implement PROMs in their practices. In this article, we review the literature on the challenges of effectively implementing PROMs in an orthopedic surgery practice.

PROM Selection Considerations

PROMs can be categorized as either generic or disease-specific,⁴ but together they are used to adequately capture the impact, both broad and local, of an orthopedic condition.

Generic Outcome Measures

Generic outcome measures apply to a range of subspecialties or anatomical regions, allowing for evaluation of a patient’s overall health or quality of life. The most widely accepted measure of pain is the visual analog scale (VAS). The VAS for pain quantifies the level of pain a patient experiences at a given time on a graphic sliding scale from 0 (no pain) to 10 (worst possible pain). The VAS is used in clinical evaluation of pain and in reported outcomes literature.^6,7

Many generic PROMs assess mental health status in addition to physical limitations. Poor preoperative mental health status has been recognized as a predictor of worse outcomes across a variety of orthopedic procedures.^8,9 Therefore, to assess the overall influence of an orthopedic condition, it is important to include at least 1 generic PROM that assesses mental health status before and after an episode of care. Generic PROMs commonly used in orthopedic surgery include the 36-Item Short Form Health Survey (SF-36), the shorter SF-12, the Veterans RAND 12-Item Health Survey (VR-12), the World Health Organization Disability Assessment Schedule (WHODAS), the European Quality of Life-5 Dimensions (EQ-5D) index, and the 10-item Patient-Reported Outcomes Measurement Information System Global Health (PROMIS-10) scale.^10-14

Some generic outcome measures (eg, the EQ-5D index) offer the “utility” calculation, which represents a preference for a patient’s desired health status. Such utilities allow for a measurement of quality of life, represented by quality-adjusted life years (QALY), which is a standardized measure of disease burden. Calculated QALY from measures such as the EQ-5D can be used in cost-effectiveness analyses of surgical interventions and have been used to validate use of procedures, particularly in arthroplasty.^15-17

Disease-Specific Outcome Measures

Likewise, there is a range of disease-specific PROMs validated for use in orthopedic surgery, and providers select PROMs that fit their scope of practice. In anatomical regions such as the knee, hip, and shoulder, disease-specific outcome measures vary significantly by subspecialty and patient population. When selecting disease-specific PROMs, providers must consider tools such as reliability, validity, responsiveness, and available population norms. One study used Evaluating Measures of Patient-Reported Outcomes (EMPRO) to assess the quality of a PROM in shoulders and concluded that the American Shoulder and Elbow Surgeons (ASES) index, the Simple Shoulder Test (SST), and the Oxford Shoulder Score (OSS) were all supported for use in practice.¹⁸ It is important to note that reliability, validity, and responsiveness of a PROM may vary with the diagnosis or the patient population studied. For example, the SST was found to be responsive in assessing rotator cuff injury but not as useful in assessing shoulder instability or arthritis.¹⁹ Variable responsiveness highlights the need for a diagnosis-based level of PROM customization. For example, patients who undergo a surgical intervention for shoulder instability are given a customized survey, which includes PROMs specific to their condition, such as the Western Ontario Shoulder Instability (WOSI) index.²⁰ For patients with knee instability, similar considerations apply; specific measures such as the Lysholm score and the Tenger Activity Scale capture the impact of injury in physically demanding activities.²¹ When selecting disease-specific PROMs, providers should consult articles like those by Davidson and Keating²² and Bent and colleagues,²³ who present provider-friendly tools that can be used to examine the effectiveness of a PROM, and provide additional background information on selecting disease-specific PROMs. For hip and knee arthroplasty subspecialties, the International Society of Arthroplasty Registries (ISAR) created a working group that determines best practices for PROM collection and identifies PROMs most commonly reported in arthroplasty.²⁴

Questionnaire Length Considerations

When PROMs are used in a practice, a balance must be struck between gathering enough information to determine functionality and limiting the patient burden of questionnaire length. A decision to use several PROMs all at once, at a single data collection point, can lengthen the questionnaire significantly. One study found that, with use of longer questionnaires, patients may lose interest, resulting in decreased reliability and compliance.²⁵ For example, providers who use the long (42-item) Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire to assess knee function are often limited in what other PROMs they may administer at the same time. Efforts to shorten this questionnaire while still capturing necessary information led to the development of the 7-item KOOS Jr, which was validated for use in knee arthroplasty and had its 7 items drawn from the original 42.²⁶ Similarly, the 40-item Hip Disability and Osteoarthritis Outcome Score (HOOS) questionnaire was shortened to the 6-item HOOS Jr, which was validated for use in hip arthroplasty,²⁷ and the generic SF-36 was shortened to the SF-12.¹¹ Providers trying to build an outcomes database while minimizing patient burden should consider using the shorter versions of these questionnaires but should also consider their validity, as KOOS Jr and HOOS Jr have been validated for use only in knee and hip arthroplasty and not in other knee and hip conditions.

PROM Data Collection Considerations

Comprehensive collection of longitudinal PROM data poses many challenges for providers and patients. For providers, the greatest challenges are infrastructure, technology, and the personnel needed to administer and store paper or electronic surveys. For patients, the most common survey completion barriers are questionnaire length, confusing or irrelevant content, and, in the case of some older adults, inability to complete surveys electronically.²⁵

Identifying a nonresponsive or noncompliant patient population is an important issue in collecting PROM data for research or other purposes. A study of factors associated with higher nonresponse rates in elective surgery patients (N = 135,474) found that noncompliance was higher for males, patients under age 55 years, nonwhites, patients in the lowest socioeconomic quintile, patients living alone, patients needing assistance in completing questionnaires, and patients who previously underwent surgery for their condition.²⁸ In a systematic review of methods that increased the response rates of postal and electronic surveys, Edwards and colleagues²⁹ found significantly higher odds of response for patients who were prenotified of the survey, given shorter questionnaires, or given a deadline for survey completion. Of note, response rates were lower when the word survey was used in the subject line of an email. 

PROM distribution has evolved with the rise of technological advances that allow for electronic survey distribution and data capture. Several studies have found that electronically administered PROMs have high response rates.^3,30,31 In a study of patients who underwent total hip arthroplasty, Rolfson and colleagues³² found that response rates were significantly higher for those who were surveyed on paper than for those surveyed over the internet. A randomized controlled study found that, compared with paper surveys, digital tablet surveys effectively and reliably collected PROM data; in addition, digital tablets provided instant data storage, and improved survey completion by requiring that all questions be answered before the survey could be submitted.33 However, age, race/ethnicity, and income disparities in technology use must be considered when administering internet-based follow-up surveys and analyzing data collected with web-based methods.³⁴ A study of total joint arthroplasty candidates found that several groups were less likely to complete electronic PROM questionnaires: patients over age 75 years, Hispanic or black patients, patients with Medicare or Medicaid, patients who previously underwent orthopedic surgery, patients undergoing revision total joint arthroplasty, patients with other comorbidities, and patients whose primary language was not English.³⁵ Providers interested in implementing PROMs must consider their patient population when selecting a method for survey distribution and follow-up. A study found that a majority of PROMs were written at a level many patients may not have understood, because of their literacy level or age; this lack of understanding created a barrier to compliance in many patient populations.³⁶

PROM Limitations and PROMIS Use

Use of PROMs has its limitations. The large variety of PROMs available for use in orthopedic surgery has led to several standardization initiatives. The National Institutes of Health funded the development of PROMIS, a person-centered measures database that evaluates and monitors the physical, social, and emotional health of adults and children.³⁷ The goal of PROMIS is to develop a standardized method of selecting PROMs, so that all medical disciplines and subspecialties can choose an applicable set of questions from the PROMIS question bank and use it in practice. Orthopedic surgery can use questions pertaining to physical functioning of the lower and upper extremities as well as quality of life and mental health. PROMIS physical function questions have been validated for use in several areas of orthopedic surgery.^38-40 A disadvantage of PROMIS is the overgenerality of its questions, which may not be as effective in capturing the implications of specific diagnoses. For example, it is difficult to use generalized questions to determine the implications of a diagnosis such as shoulder instability, which may affect only higher functioning activities or sports. More research on best PROM selection practices is needed in order to either standardize PROMs or move toward use of a single database such as PROMIS.

Future Directions in PROM Applications

PROMs are being used for research and patient engagement, but there are many other applications on the horizon. As already mentioned, predictive modeling is of particular interest. The existence of vast collaborative PROM databases that capture a diverse patient population introduces the possibility of creating models capable of predicting a patient outcome and enhancing shared decision-making.³ Predicting good or excellent patient outcomes for specific patient populations may allow elimination of certain postoperative visits, thereby creating more cost-effective care and reducing the burden of unnecessary clinic visits for both patients and physicians.

As with other healthcare areas, PROM data collection technology is rapidly advancing. Not only has electronic technology almost entirely replaced paper-and-pencil collection methods, but a new method of outcome data collection has been developed: computerized adaptive testing (CAT). CAT uses item-response theory to minimize the number of questions patients must answer in order for validated and reliable outcome scores to be calculated. According to multiple studies, CAT used across several questionnaires has reliably assessed PROMs while minimizing floor and ceiling effects, eliminating irrelevant questions, and shortening survey completion time.^41-43

Besides becoming more patient-friendly and accessible across multiple interfaces (mobile devices and computers), PROMs are also beginning to be integrated into the electronic medical record, allowing easier access to information during chart reviews. Use of statistical and predictive modeling, as described by Chang,³ could give PROMs a role in clinical decision-making. Informing patients of their expected outcome and recovery trajectory—based on demographics, comorbidities, preoperative functional status, and other factors—could influence their decision to undergo surgical intervention. As Halawi and colleagues⁴⁴ pointed out, it is important to discuss patient expectations before surgery, as unrealistic ones can negatively affect outcomes and lead to dissatisfaction. With clinicians having ready access to statistics and models in patient charts, we may see a transformation in clinical practices and surgical decision-making.

Conclusion

PROMs offer many ways to improve research and clinical care in orthopedic surgery. However, implementing PROMs in practice is not without challenges. Interested orthopedic surgeons should select the PROMs that are most appropriate—reliable, validated, and responsive to their patient population. Electronic distribution of PROM questionnaires is effective and allows data to be stored on entry, but orthopedic surgeons must consider their patient population to ensure accurate data capture and compliance in longitudinal surveys. Proper implementation of PROMs in a practice can allow clinicians to formulate expectations for postoperative recovery and set reasonable postoperative goals while engaging patients in improving quality of care.

Take-Home Points

• Systematic use of PROMs allows physicians to review data on pain, physical function, and psychological status to aid in clinical decision-making and best practices.
• PROMs should include both general outcome measures (VAS, SF-36, or EQ-5D) and reliable, valid, and responsive disease specific measures.
• PROM questionnaires should collect pertinent information while limiting the length to maximize patient compliance and reliability.
• PROMIS has been developed to standardize questionnaires, but generality for specific orthopedic procedures may result in less effective measures.
• PROMs can also be used for predictive modeling, which has the potential to help develop more cost-effective care and predict expected outcomes and recovery trajectories for individual patients.

Owing to their unique ability to recognize patients as stakeholders in their own healthcare, patient-reported outcome measures (PROMs) are becoming increasingly popular in the assessment of medical and surgical outcomes.¹ PROMs are an outcome measures subset in which patients complete questionnaires about their perceptions of their overall health status and specific health limitations. By systematically using PROMs before and after a clearly defined episode of care, clinicians can collect data on perceived pain level, physical function, and psychological status and use the data to validate use of surgical procedures and shape clinical decisions about best practices.^2-4 Although mortality and morbidity rates and other traditional measures are valuable in assessing outcomes, they do not represent or communicate the larger impact of an episode of care. As many orthopedic procedures are elective, and some are low-risk, the evaluation of changes in quality of life and self-reported functional improvement is an important addition to morbidity and mortality rates in capturing the true impact of a surgical procedure and recovery. The patient’s preoperative and postoperative perspectives on his or her health status have become important as well; our healthcare system has been placing more emphasis on patient-centered quality care.^2,5

Although PROMs have many benefits, implementation in an orthopedic surgery practice has its challenges. With so many PROMs available, selecting those that fit the patient population for a specialized orthopedic surgery practice can be difficult. In addition, although PROM data are essential for research and for measuring individual or institutional recovery trajectories for surgical procedures, in a busy practice getting patients to provide these data can be difficult.

PROMs are heavily used for outcomes assessment in the orthopedics literature, but there are few resources for orthopedic surgeons who want to implement PROMs in their practices. In this article, we review the literature on the challenges of effectively implementing PROMs in an orthopedic surgery practice.

PROM Selection Considerations

PROMs can be categorized as either generic or disease-specific,⁴ but together they are used to adequately capture the impact, both broad and local, of an orthopedic condition.

Generic Outcome Measures

Generic outcome measures apply to a range of subspecialties or anatomical regions, allowing for evaluation of a patient’s overall health or quality of life. The most widely accepted measure of pain is the visual analog scale (VAS). The VAS for pain quantifies the level of pain a patient experiences at a given time on a graphic sliding scale from 0 (no pain) to 10 (worst possible pain). The VAS is used in clinical evaluation of pain and in reported outcomes literature.^6,7

Many generic PROMs assess mental health status in addition to physical limitations. Poor preoperative mental health status has been recognized as a predictor of worse outcomes across a variety of orthopedic procedures.^8,9 Therefore, to assess the overall influence of an orthopedic condition, it is important to include at least 1 generic PROM that assesses mental health status before and after an episode of care. Generic PROMs commonly used in orthopedic surgery include the 36-Item Short Form Health Survey (SF-36), the shorter SF-12, the Veterans RAND 12-Item Health Survey (VR-12), the World Health Organization Disability Assessment Schedule (WHODAS), the European Quality of Life-5 Dimensions (EQ-5D) index, and the 10-item Patient-Reported Outcomes Measurement Information System Global Health (PROMIS-10) scale.^10-14

Some generic outcome measures (eg, the EQ-5D index) offer the “utility” calculation, which represents a preference for a patient’s desired health status. Such utilities allow for a measurement of quality of life, represented by quality-adjusted life years (QALY), which is a standardized measure of disease burden. Calculated QALY from measures such as the EQ-5D can be used in cost-effectiveness analyses of surgical interventions and have been used to validate use of procedures, particularly in arthroplasty.^15-17

Disease-Specific Outcome Measures

Likewise, there is a range of disease-specific PROMs validated for use in orthopedic surgery, and providers select PROMs that fit their scope of practice. In anatomical regions such as the knee, hip, and shoulder, disease-specific outcome measures vary significantly by subspecialty and patient population. When selecting disease-specific PROMs, providers must consider tools such as reliability, validity, responsiveness, and available population norms. One study used Evaluating Measures of Patient-Reported Outcomes (EMPRO) to assess the quality of a PROM in shoulders and concluded that the American Shoulder and Elbow Surgeons (ASES) index, the Simple Shoulder Test (SST), and the Oxford Shoulder Score (OSS) were all supported for use in practice.¹⁸ It is important to note that reliability, validity, and responsiveness of a PROM may vary with the diagnosis or the patient population studied. For example, the SST was found to be responsive in assessing rotator cuff injury but not as useful in assessing shoulder instability or arthritis.¹⁹ Variable responsiveness highlights the need for a diagnosis-based level of PROM customization. For example, patients who undergo a surgical intervention for shoulder instability are given a customized survey, which includes PROMs specific to their condition, such as the Western Ontario Shoulder Instability (WOSI) index.²⁰ For patients with knee instability, similar considerations apply; specific measures such as the Lysholm score and the Tenger Activity Scale capture the impact of injury in physically demanding activities.²¹ When selecting disease-specific PROMs, providers should consult articles like those by Davidson and Keating²² and Bent and colleagues,²³ who present provider-friendly tools that can be used to examine the effectiveness of a PROM, and provide additional background information on selecting disease-specific PROMs. For hip and knee arthroplasty subspecialties, the International Society of Arthroplasty Registries (ISAR) created a working group that determines best practices for PROM collection and identifies PROMs most commonly reported in arthroplasty.²⁴

Questionnaire Length Considerations

When PROMs are used in a practice, a balance must be struck between gathering enough information to determine functionality and limiting the patient burden of questionnaire length. A decision to use several PROMs all at once, at a single data collection point, can lengthen the questionnaire significantly. One study found that, with use of longer questionnaires, patients may lose interest, resulting in decreased reliability and compliance.²⁵ For example, providers who use the long (42-item) Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire to assess knee function are often limited in what other PROMs they may administer at the same time. Efforts to shorten this questionnaire while still capturing necessary information led to the development of the 7-item KOOS Jr, which was validated for use in knee arthroplasty and had its 7 items drawn from the original 42.²⁶ Similarly, the 40-item Hip Disability and Osteoarthritis Outcome Score (HOOS) questionnaire was shortened to the 6-item HOOS Jr, which was validated for use in hip arthroplasty,²⁷ and the generic SF-36 was shortened to the SF-12.¹¹ Providers trying to build an outcomes database while minimizing patient burden should consider using the shorter versions of these questionnaires but should also consider their validity, as KOOS Jr and HOOS Jr have been validated for use only in knee and hip arthroplasty and not in other knee and hip conditions.

PROM Data Collection Considerations

Comprehensive collection of longitudinal PROM data poses many challenges for providers and patients. For providers, the greatest challenges are infrastructure, technology, and the personnel needed to administer and store paper or electronic surveys. For patients, the most common survey completion barriers are questionnaire length, confusing or irrelevant content, and, in the case of some older adults, inability to complete surveys electronically.²⁵

Identifying a nonresponsive or noncompliant patient population is an important issue in collecting PROM data for research or other purposes. A study of factors associated with higher nonresponse rates in elective surgery patients (N = 135,474) found that noncompliance was higher for males, patients under age 55 years, nonwhites, patients in the lowest socioeconomic quintile, patients living alone, patients needing assistance in completing questionnaires, and patients who previously underwent surgery for their condition.²⁸ In a systematic review of methods that increased the response rates of postal and electronic surveys, Edwards and colleagues²⁹ found significantly higher odds of response for patients who were prenotified of the survey, given shorter questionnaires, or given a deadline for survey completion. Of note, response rates were lower when the word survey was used in the subject line of an email. 

PROM distribution has evolved with the rise of technological advances that allow for electronic survey distribution and data capture. Several studies have found that electronically administered PROMs have high response rates.^3,30,31 In a study of patients who underwent total hip arthroplasty, Rolfson and colleagues³² found that response rates were significantly higher for those who were surveyed on paper than for those surveyed over the internet. A randomized controlled study found that, compared with paper surveys, digital tablet surveys effectively and reliably collected PROM data; in addition, digital tablets provided instant data storage, and improved survey completion by requiring that all questions be answered before the survey could be submitted.33 However, age, race/ethnicity, and income disparities in technology use must be considered when administering internet-based follow-up surveys and analyzing data collected with web-based methods.³⁴ A study of total joint arthroplasty candidates found that several groups were less likely to complete electronic PROM questionnaires: patients over age 75 years, Hispanic or black patients, patients with Medicare or Medicaid, patients who previously underwent orthopedic surgery, patients undergoing revision total joint arthroplasty, patients with other comorbidities, and patients whose primary language was not English.³⁵ Providers interested in implementing PROMs must consider their patient population when selecting a method for survey distribution and follow-up. A study found that a majority of PROMs were written at a level many patients may not have understood, because of their literacy level or age; this lack of understanding created a barrier to compliance in many patient populations.³⁶

PROM Limitations and PROMIS Use

Use of PROMs has its limitations. The large variety of PROMs available for use in orthopedic surgery has led to several standardization initiatives. The National Institutes of Health funded the development of PROMIS, a person-centered measures database that evaluates and monitors the physical, social, and emotional health of adults and children.³⁷ The goal of PROMIS is to develop a standardized method of selecting PROMs, so that all medical disciplines and subspecialties can choose an applicable set of questions from the PROMIS question bank and use it in practice. Orthopedic surgery can use questions pertaining to physical functioning of the lower and upper extremities as well as quality of life and mental health. PROMIS physical function questions have been validated for use in several areas of orthopedic surgery.^38-40 A disadvantage of PROMIS is the overgenerality of its questions, which may not be as effective in capturing the implications of specific diagnoses. For example, it is difficult to use generalized questions to determine the implications of a diagnosis such as shoulder instability, which may affect only higher functioning activities or sports. More research on best PROM selection practices is needed in order to either standardize PROMs or move toward use of a single database such as PROMIS.

Future Directions in PROM Applications

PROMs are being used for research and patient engagement, but there are many other applications on the horizon. As already mentioned, predictive modeling is of particular interest. The existence of vast collaborative PROM databases that capture a diverse patient population introduces the possibility of creating models capable of predicting a patient outcome and enhancing shared decision-making.³ Predicting good or excellent patient outcomes for specific patient populations may allow elimination of certain postoperative visits, thereby creating more cost-effective care and reducing the burden of unnecessary clinic visits for both patients and physicians.

As with other healthcare areas, PROM data collection technology is rapidly advancing. Not only has electronic technology almost entirely replaced paper-and-pencil collection methods, but a new method of outcome data collection has been developed: computerized adaptive testing (CAT). CAT uses item-response theory to minimize the number of questions patients must answer in order for validated and reliable outcome scores to be calculated. According to multiple studies, CAT used across several questionnaires has reliably assessed PROMs while minimizing floor and ceiling effects, eliminating irrelevant questions, and shortening survey completion time.^41-43

Besides becoming more patient-friendly and accessible across multiple interfaces (mobile devices and computers), PROMs are also beginning to be integrated into the electronic medical record, allowing easier access to information during chart reviews. Use of statistical and predictive modeling, as described by Chang,³ could give PROMs a role in clinical decision-making. Informing patients of their expected outcome and recovery trajectory—based on demographics, comorbidities, preoperative functional status, and other factors—could influence their decision to undergo surgical intervention. As Halawi and colleagues⁴⁴ pointed out, it is important to discuss patient expectations before surgery, as unrealistic ones can negatively affect outcomes and lead to dissatisfaction. With clinicians having ready access to statistics and models in patient charts, we may see a transformation in clinical practices and surgical decision-making.

Conclusion

PROMs offer many ways to improve research and clinical care in orthopedic surgery. However, implementing PROMs in practice is not without challenges. Interested orthopedic surgeons should select the PROMs that are most appropriate—reliable, validated, and responsive to their patient population. Electronic distribution of PROM questionnaires is effective and allows data to be stored on entry, but orthopedic surgeons must consider their patient population to ensure accurate data capture and compliance in longitudinal surveys. Proper implementation of PROMs in a practice can allow clinicians to formulate expectations for postoperative recovery and set reasonable postoperative goals while engaging patients in improving quality of care.

Take-Home Points

• Systematic use of PROMs allows physicians to review data on pain, physical function, and psychological status to aid in clinical decision-making and best practices.
• PROMs should include both general outcome measures (VAS, SF-36, or EQ-5D) and reliable, valid, and responsive disease specific measures.
• PROM questionnaires should collect pertinent information while limiting the length to maximize patient compliance and reliability.
• PROMIS has been developed to standardize questionnaires, but generality for specific orthopedic procedures may result in less effective measures.
• PROMs can also be used for predictive modeling, which has the potential to help develop more cost-effective care and predict expected outcomes and recovery trajectories for individual patients.

Owing to their unique ability to recognize patients as stakeholders in their own healthcare, patient-reported outcome measures (PROMs) are becoming increasingly popular in the assessment of medical and surgical outcomes.¹ PROMs are an outcome measures subset in which patients complete questionnaires about their perceptions of their overall health status and specific health limitations. By systematically using PROMs before and after a clearly defined episode of care, clinicians can collect data on perceived pain level, physical function, and psychological status and use the data to validate use of surgical procedures and shape clinical decisions about best practices.^2-4 Although mortality and morbidity rates and other traditional measures are valuable in assessing outcomes, they do not represent or communicate the larger impact of an episode of care. As many orthopedic procedures are elective, and some are low-risk, the evaluation of changes in quality of life and self-reported functional improvement is an important addition to morbidity and mortality rates in capturing the true impact of a surgical procedure and recovery. The patient’s preoperative and postoperative perspectives on his or her health status have become important as well; our healthcare system has been placing more emphasis on patient-centered quality care.^2,5

Although PROMs have many benefits, implementation in an orthopedic surgery practice has its challenges. With so many PROMs available, selecting those that fit the patient population for a specialized orthopedic surgery practice can be difficult. In addition, although PROM data are essential for research and for measuring individual or institutional recovery trajectories for surgical procedures, in a busy practice getting patients to provide these data can be difficult.

PROMs are heavily used for outcomes assessment in the orthopedics literature, but there are few resources for orthopedic surgeons who want to implement PROMs in their practices. In this article, we review the literature on the challenges of effectively implementing PROMs in an orthopedic surgery practice.

PROM Selection Considerations

PROMs can be categorized as either generic or disease-specific,⁴ but together they are used to adequately capture the impact, both broad and local, of an orthopedic condition.

Generic Outcome Measures

Generic outcome measures apply to a range of subspecialties or anatomical regions, allowing for evaluation of a patient’s overall health or quality of life. The most widely accepted measure of pain is the visual analog scale (VAS). The VAS for pain quantifies the level of pain a patient experiences at a given time on a graphic sliding scale from 0 (no pain) to 10 (worst possible pain). The VAS is used in clinical evaluation of pain and in reported outcomes literature.^6,7

Many generic PROMs assess mental health status in addition to physical limitations. Poor preoperative mental health status has been recognized as a predictor of worse outcomes across a variety of orthopedic procedures.^8,9 Therefore, to assess the overall influence of an orthopedic condition, it is important to include at least 1 generic PROM that assesses mental health status before and after an episode of care. Generic PROMs commonly used in orthopedic surgery include the 36-Item Short Form Health Survey (SF-36), the shorter SF-12, the Veterans RAND 12-Item Health Survey (VR-12), the World Health Organization Disability Assessment Schedule (WHODAS), the European Quality of Life-5 Dimensions (EQ-5D) index, and the 10-item Patient-Reported Outcomes Measurement Information System Global Health (PROMIS-10) scale.^10-14

Some generic outcome measures (eg, the EQ-5D index) offer the “utility” calculation, which represents a preference for a patient’s desired health status. Such utilities allow for a measurement of quality of life, represented by quality-adjusted life years (QALY), which is a standardized measure of disease burden. Calculated QALY from measures such as the EQ-5D can be used in cost-effectiveness analyses of surgical interventions and have been used to validate use of procedures, particularly in arthroplasty.^15-17

Disease-Specific Outcome Measures

Likewise, there is a range of disease-specific PROMs validated for use in orthopedic surgery, and providers select PROMs that fit their scope of practice. In anatomical regions such as the knee, hip, and shoulder, disease-specific outcome measures vary significantly by subspecialty and patient population. When selecting disease-specific PROMs, providers must consider tools such as reliability, validity, responsiveness, and available population norms. One study used Evaluating Measures of Patient-Reported Outcomes (EMPRO) to assess the quality of a PROM in shoulders and concluded that the American Shoulder and Elbow Surgeons (ASES) index, the Simple Shoulder Test (SST), and the Oxford Shoulder Score (OSS) were all supported for use in practice.¹⁸ It is important to note that reliability, validity, and responsiveness of a PROM may vary with the diagnosis or the patient population studied. For example, the SST was found to be responsive in assessing rotator cuff injury but not as useful in assessing shoulder instability or arthritis.¹⁹ Variable responsiveness highlights the need for a diagnosis-based level of PROM customization. For example, patients who undergo a surgical intervention for shoulder instability are given a customized survey, which includes PROMs specific to their condition, such as the Western Ontario Shoulder Instability (WOSI) index.²⁰ For patients with knee instability, similar considerations apply; specific measures such as the Lysholm score and the Tenger Activity Scale capture the impact of injury in physically demanding activities.²¹ When selecting disease-specific PROMs, providers should consult articles like those by Davidson and Keating²² and Bent and colleagues,²³ who present provider-friendly tools that can be used to examine the effectiveness of a PROM, and provide additional background information on selecting disease-specific PROMs. For hip and knee arthroplasty subspecialties, the International Society of Arthroplasty Registries (ISAR) created a working group that determines best practices for PROM collection and identifies PROMs most commonly reported in arthroplasty.²⁴

Questionnaire Length Considerations

When PROMs are used in a practice, a balance must be struck between gathering enough information to determine functionality and limiting the patient burden of questionnaire length. A decision to use several PROMs all at once, at a single data collection point, can lengthen the questionnaire significantly. One study found that, with use of longer questionnaires, patients may lose interest, resulting in decreased reliability and compliance.²⁵ For example, providers who use the long (42-item) Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire to assess knee function are often limited in what other PROMs they may administer at the same time. Efforts to shorten this questionnaire while still capturing necessary information led to the development of the 7-item KOOS Jr, which was validated for use in knee arthroplasty and had its 7 items drawn from the original 42.²⁶ Similarly, the 40-item Hip Disability and Osteoarthritis Outcome Score (HOOS) questionnaire was shortened to the 6-item HOOS Jr, which was validated for use in hip arthroplasty,²⁷ and the generic SF-36 was shortened to the SF-12.¹¹ Providers trying to build an outcomes database while minimizing patient burden should consider using the shorter versions of these questionnaires but should also consider their validity, as KOOS Jr and HOOS Jr have been validated for use only in knee and hip arthroplasty and not in other knee and hip conditions.

PROM Data Collection Considerations

Comprehensive collection of longitudinal PROM data poses many challenges for providers and patients. For providers, the greatest challenges are infrastructure, technology, and the personnel needed to administer and store paper or electronic surveys. For patients, the most common survey completion barriers are questionnaire length, confusing or irrelevant content, and, in the case of some older adults, inability to complete surveys electronically.²⁵

Identifying a nonresponsive or noncompliant patient population is an important issue in collecting PROM data for research or other purposes. A study of factors associated with higher nonresponse rates in elective surgery patients (N = 135,474) found that noncompliance was higher for males, patients under age 55 years, nonwhites, patients in the lowest socioeconomic quintile, patients living alone, patients needing assistance in completing questionnaires, and patients who previously underwent surgery for their condition.²⁸ In a systematic review of methods that increased the response rates of postal and electronic surveys, Edwards and colleagues²⁹ found significantly higher odds of response for patients who were prenotified of the survey, given shorter questionnaires, or given a deadline for survey completion. Of note, response rates were lower when the word survey was used in the subject line of an email. 

PROM distribution has evolved with the rise of technological advances that allow for electronic survey distribution and data capture. Several studies have found that electronically administered PROMs have high response rates.^3,30,31 In a study of patients who underwent total hip arthroplasty, Rolfson and colleagues³² found that response rates were significantly higher for those who were surveyed on paper than for those surveyed over the internet. A randomized controlled study found that, compared with paper surveys, digital tablet surveys effectively and reliably collected PROM data; in addition, digital tablets provided instant data storage, and improved survey completion by requiring that all questions be answered before the survey could be submitted.33 However, age, race/ethnicity, and income disparities in technology use must be considered when administering internet-based follow-up surveys and analyzing data collected with web-based methods.³⁴ A study of total joint arthroplasty candidates found that several groups were less likely to complete electronic PROM questionnaires: patients over age 75 years, Hispanic or black patients, patients with Medicare or Medicaid, patients who previously underwent orthopedic surgery, patients undergoing revision total joint arthroplasty, patients with other comorbidities, and patients whose primary language was not English.³⁵ Providers interested in implementing PROMs must consider their patient population when selecting a method for survey distribution and follow-up. A study found that a majority of PROMs were written at a level many patients may not have understood, because of their literacy level or age; this lack of understanding created a barrier to compliance in many patient populations.³⁶

PROM Limitations and PROMIS Use

Use of PROMs has its limitations. The large variety of PROMs available for use in orthopedic surgery has led to several standardization initiatives. The National Institutes of Health funded the development of PROMIS, a person-centered measures database that evaluates and monitors the physical, social, and emotional health of adults and children.³⁷ The goal of PROMIS is to develop a standardized method of selecting PROMs, so that all medical disciplines and subspecialties can choose an applicable set of questions from the PROMIS question bank and use it in practice. Orthopedic surgery can use questions pertaining to physical functioning of the lower and upper extremities as well as quality of life and mental health. PROMIS physical function questions have been validated for use in several areas of orthopedic surgery.^38-40 A disadvantage of PROMIS is the overgenerality of its questions, which may not be as effective in capturing the implications of specific diagnoses. For example, it is difficult to use generalized questions to determine the implications of a diagnosis such as shoulder instability, which may affect only higher functioning activities or sports. More research on best PROM selection practices is needed in order to either standardize PROMs or move toward use of a single database such as PROMIS.

Future Directions in PROM Applications

PROMs are being used for research and patient engagement, but there are many other applications on the horizon. As already mentioned, predictive modeling is of particular interest. The existence of vast collaborative PROM databases that capture a diverse patient population introduces the possibility of creating models capable of predicting a patient outcome and enhancing shared decision-making.³ Predicting good or excellent patient outcomes for specific patient populations may allow elimination of certain postoperative visits, thereby creating more cost-effective care and reducing the burden of unnecessary clinic visits for both patients and physicians.

As with other healthcare areas, PROM data collection technology is rapidly advancing. Not only has electronic technology almost entirely replaced paper-and-pencil collection methods, but a new method of outcome data collection has been developed: computerized adaptive testing (CAT). CAT uses item-response theory to minimize the number of questions patients must answer in order for validated and reliable outcome scores to be calculated. According to multiple studies, CAT used across several questionnaires has reliably assessed PROMs while minimizing floor and ceiling effects, eliminating irrelevant questions, and shortening survey completion time.^41-43

Besides becoming more patient-friendly and accessible across multiple interfaces (mobile devices and computers), PROMs are also beginning to be integrated into the electronic medical record, allowing easier access to information during chart reviews. Use of statistical and predictive modeling, as described by Chang,³ could give PROMs a role in clinical decision-making. Informing patients of their expected outcome and recovery trajectory—based on demographics, comorbidities, preoperative functional status, and other factors—could influence their decision to undergo surgical intervention. As Halawi and colleagues⁴⁴ pointed out, it is important to discuss patient expectations before surgery, as unrealistic ones can negatively affect outcomes and lead to dissatisfaction. With clinicians having ready access to statistics and models in patient charts, we may see a transformation in clinical practices and surgical decision-making.

Conclusion

PROMs offer many ways to improve research and clinical care in orthopedic surgery. However, implementing PROMs in practice is not without challenges. Interested orthopedic surgeons should select the PROMs that are most appropriate—reliable, validated, and responsive to their patient population. Electronic distribution of PROM questionnaires is effective and allows data to be stored on entry, but orthopedic surgeons must consider their patient population to ensure accurate data capture and compliance in longitudinal surveys. Proper implementation of PROMs in a practice can allow clinicians to formulate expectations for postoperative recovery and set reasonable postoperative goals while engaging patients in improving quality of care.

Take-Home Points

• The SCR is a viable treatment option for massive, irreparable RCTs.
• Arm position and exact measurement between anchors will help ensure proper graft tensioning.
• Anterior and posterior tension and margin convergence are critical to stabilizing the graft.
• Acromial-humeral distance, ASES, and VAS scores are improved and maintained over long-term follow-up.
• The dermal allograft should be 3.0 mm or thicker.

Conventional treatments for irreparable massive rotator cuff tears (RCTs) have ranged from nonoperative care to débridement and biceps tenotomy,^1,2 partial cuff repair,^3,4 bridging patch grafts,⁵ tendon transfers,^6,7 and reverse total shoulder arthroplasty (RTSA).^8,9 Superior capsular reconstruction (SCR), originally described by Mihata and colleagues,¹⁰ has been developed as an alternative to these interventions. Dr. Hirahara modified the technique to use dermal allograft instead of fascia lata autograft.^10,11

Biomechanical analysis has confirmed the integral role of the superior capsule in shoulder function.^10,12-14 In the presence of a massive RCT, the humeral head migrates superiorly, causing significant pain and functional deficits, such as pseudoparalysis. It is theorized that reestablishing this important stabilizer—centering the humeral head in the glenoid and allowing the larger muscles to move the arm about a proper fulcrum—improves function and decreases pain.

Using ultrasonography (US), radiography, magnetic resonance imaging (MRI), clinical outcome scores, and a visual analog scale (VAS) for pain, we prospectively evaluated minimum 2-year clinical outcomes of performing SCR with dermal allograft for irreparable RCTs.

Methods

Except where noted otherwise, all products mentioned in this section were made by Arthrex.

Surgical Technique

The surgical technique used here was described by Hirahara and Adams.¹¹ ArthroFlex dermal allograft was attached to the greater tuberosity and the glenoid, creating a superior restraint that replaced the anatomical superior capsule (Figures 1A, 1B). Some cases included biceps tenotomy, subscapularis repair, or infraspinatus repair.

Medial fixation was obtained with a PASTA (partial articular supraspinatus tendon avulsion) bridge-type construct¹⁵ that consisted of two 3.0-mm BioComposite SutureTak anchors (placed medially on the glenoid rim, medial to the labrum) and a 3.5-mm BioComposite Vented SwiveLock. In some cases, a significant amount of tissue was present medially, and the third anchor was not used; instead, a double surgeon knot was used to fixate the double pulley medially.

Posterior margin convergence (PMC) was performed in all cases. Anterior margin convergence (AMC) was performed in only 3 cases.

Clinical Evaluation

All patients who underwent SCR were followed prospectively, and all signed an informed consent form. Between 2014 and the time of this study, 9 patients had surgery with a minimum 2-year follow-up. Before surgery, all patients received a diagnosis of full-thickness RCT with decreased acromial-humeral distance (AHD). One patient had RTSA 18 months after surgery, did not reach the 2-year follow-up, and was excluded from the data analysis. Patients were clinically evaluated on the 100-point American Shoulder and Elbow Surgeons (ASES) shoulder index and on a 10-point VAS for pain—before surgery, monthly for the first 6 months after surgery, then every 6 months until 2 years after surgery, and yearly thereafter. These patients were compared with Dr. Hirahara’s historical control patients, who had undergone repair of massive RCTs. Mean graft size was calculated and reported. Cases were separated and analyzed on the basis of whether AMC was performed. Student t tests were used to determine statistical differences between study patients’ preoperative and postoperative scores, between study and historical control patients, and between patients who had AMC performed and those who did not (P < .05).

Imaging

For all SCR patients, preoperative and postoperative radiographs were obtained in 2 planes: anterior-posterior with arm in neutral rotation, and scapular Y. On anteroposterior radiographs, AHD was measured from the most proximal aspect of the humeral head in a vertical line to the most inferior portion of the acromion (Figures 2A, 2B).

Results

The Table provides an overview of the study results. Eight patients (6 men, 2 women) met the final inclusion criteria for postoperative ASES and VAS data analysis.

AHD was measured on a standard anteroposterior radiograph in neutral rotation. The Hamada grading scale16 was used to classify the massive RCTs before and after surgery. Before surgery, 4 were grade 4A, 1 grade 3, 2 grade 2, and 1 grade 1; immediately after surgery, all were grade 1 (AHD, ≥6 mm). Two years after surgery, 1 patient had an AHD of 4.6 mm after a failure caused by a fall. Mean (SD) preoperative AHD was 4.50 (2.25) mm (range, 1.7-7.9 mm). Radiographs obtained immediately (mean, 1.22 months; range, 1 day-2.73 months) after surgery showed AHD was significantly (P < .0008) increased (mean, 8.48 mm; SD, 1.25 mm; range, 6.0-10.0 mm) (Figure 5).

Mean graft size was 2.9 mm medial × 3.6 mm lateral × 5.4 mm anterior × 5.4 mm posterior. Three patients had AMC performed. There was a significant (P < .05) difference in ASES scores between patients who had AMC performed (93) and those who did not (77).

Ultrasonography

Two weeks to 2 months after surgery, all patients had an intact capsular graft and no pulsatile vessels on US. Between 4 months and 10 months, US showed the construct intact laterally in all cases, a pulsatile vessel in the graft at the tuberosity (evidence of blood flow) in 4 of 5 cases, and a pulsatile vessel hypertrophied in 2 cases (Figures 6A, 6B).

Magnetic Resonance Imaging

Before surgery, 4 patients had Goutallier¹⁷ stage 4 rotator cuff muscle degeneration, 2 had stage 3 degeneration, and 2 had stage 2 degeneration. Throughout the follow-up period, US was as effective as MRI in determining graft integrity, graft thickness, and greater tuberosity fixation. Therefore, the SCRs were assessed primarily with US. MRI was ordered only if a failure was suspected or if the patient had some form of trauma. A total of 7 MRIs were ordered for 5 of the 8 patients in the study. The graft was intact in 4 of the 5 (Figures 7A-7C) and ruptured in the fifth.

Discussion

Mihata and colleagues¹⁰ published 2-year data for their reconstructive procedure with fascia lata autograft. In a modification of their procedure, Dr. Hirahara used dermal allograft to recreate the superior capsule.¹¹ The results of the present 2-year study mirror the clinical outcomes reported by Mihata and colleagues¹⁰ and confirm that SCR improves functional outcomes and increases AHD regardless of graft type used.

The outcomes of the SCR patients in our study were significantly better than the outcomes of the historical control patients, who underwent repair of massive RCTs. Although there was no significant difference in the 2 groups’ ASES scores, the control patients had significantly higher postoperative VAS pain scores. We think that, as more patients undergo SCR and the population sample increases, we will see a significant difference in ASES scores as well (our SCR patients already showed a trend toward improved ASES scores).

Compared with RTSA, SCR has fewer risks and fewer complications and does not limit further surgical options.^8,9,18 The 9 patients who had surgery with a minimum 2-year follow-up in our study had 4 complications. Six months after surgery, 1 patient fell and tore the infraspinatus and subscapularis muscles. Outcomes continued to improve, and no issues were reported, despite a decrease in AHD, from 8 mm immediately after surgery to 4.6 mm 2 years after surgery.

Two patients were in motor vehicle accidents. In 1 case, the accident occurred about 2 months after surgery. This patient also sustained a possible injury in a fall after receiving general anesthesia for a dental procedure. After having done very well the preceding months, the patient now reported increasing pain and dysfunction. MRI showed loss of glenoid fixation. Improved ASES and VAS pain scores were maintained throughout the follow-up period. AHD was increased at 13 months and mildly decreased at 2 years. Glenoid fixation was obtained with 2 anchors and a double surgeon knot. When possible, however, it is best to add an anchor and double-row fixation, as 3 anchors and a double-row construct are biomechanically stronger.^19-24

The other motor vehicle accident occurred about 23 months after surgery. Two months later, a graft rupture was found on US and MRI, but the patient was maintaining full range of motion, AHD, and improved strength. The 1.5-mm graft in this patient was thinner than the 3.5-mm grafts in the rest of the study group. This was the only patient who developed a graft rupture rather than loss of fixation.

If only patients with graft thickness >3.0 mm are included in the data analysis, mean ASES score rises to 89.76, and mean VAS pain score drops to 0. Therefore, we argue against using a graft thinner than 3.5 mm. Our excellent study results indicate that larger grafts are unnecessary. Mihata and colleagues¹⁰ used fascia lata grafts of 6 mm to 8 mm. Ultimate load to failure is significantly higher for dermal allograft than for fascia lata graft.²⁵ In SCR, the stronger dermal allograft withstands applied forces and repeated deformations and has excellent clinical outcomes.

Only 1 patient had a failure that required RTSA. VAS pain scores were lower and ASES scores were improved the first year after surgery, but then function deteriorated. The patient said there was no specific precipitating incident. Computed tomography arthrogram, ordered to assess the construct, showed anterior and superior subluxation of the humeral head, even with an intact subscapularis tendon—an indication of underlying instability, which most likely caused the failure. Eighteen months after surgery, the patient was able to undergo RTSA. On further evaluation of this patient’s procedure, it was determined that the graft needed better fixation anteriorly.

Mihata and colleagues^10,12,14 indicated that AMC was unnecessary, and our procedure did not require it. However, data in our prospective evaluation began showing improved outcomes with AMC. As dermal allograft is more elastic than fascia lata autograft,²⁵ we concluded that graft tensioning is key to the success of this procedure. Graft tension depends on many factors, including exact measurement of the distances between the anchors to punch holes in the graft, arm position to set the relationship between the anchor distances, and AMC and PMC. We recommend placing the arm in neutral rotation, neutral flexion, and abduction with the patient at rest, based on the size of the patient’s latissimus dorsi. Too much abduction causes overtensioning, and excess rotation or flexion-extension changes the distance between the glenoid and the greater tuberosity asymmetrically, from anterior to posterior. With the arm in neutral position, distances between anchors are accurately measured, and these measurements are used to determine graft size.

Graft tension is also needed to control the amount of elasticity allowed by the graft and thereby maintain stability, as shown by the Poisson ratio, the ratio of transverse contraction to longitudinal extension on a material in the presence of a stretching force. As applied to SCR, it is the ratio of mediolateral elasticity to anteroposterior deformation or constraint. If the graft is appropriately secured in the anteroposterior direction by way of ACM and PMC, elongation in the medial-lateral direction will be limited—reducing the elasticity of the graft, improving overall stability, and ultimately producing better clinical outcomes. This issue was discussed by Burkhart and colleagues²⁶ with respect to the “rotator cable complex,” which now might be best described as the “rotator-capsule cable complex.” In our study, this phenomenon was evident in the finding that patients who had AMC performed did significantly better than patients who did not have AMC performed. The ability of dermal allograft to deform in these dimensions without failure while allowing excellent range of motion makes dermal allograft an exceptional choice for grafting during SCR. Mihata25 also found dermal allograft had a clear advantage in providing better range of motion, whereas fascia lata autograft resulted in a stiffer construct. 

Dermal allograft can also incorporate into the body and transform into host tissue. The literature has described musculoskeletal US as an effective diagnostic and interventional tool.^27-31 We used it to evaluate graft size, patency, and viability. As can be seen on US, the native rotator cuff does not have any pulsatile vessels and is fed by capillary flow. Dermal allograft has native vasculature built into the tissue. After 4 months to 8 months, presence of pulsatile vessels within the graft at the greater tuberosity indicates clear revascularization and incorporation of the tissue (Figure 6B). Disappearance of pulsatile vessels on US after 1 year indicates transformation to a stabilizing structure analogous to capsule or ligament with capillary flow. US also showed graft hypertrophy after 2 years, supporting a finding of integration and growth.

Conclusion

In the past, patients with irreparable massive RCTs had few good surgical management options, RTSA being the most definitive. SCR is technically challenging and requires use of specific implantation methods but can provide patients with outstanding relief. Our clinical data showed that technically well executed SCR effectively restores the superior restraints in the glenohumeral joint and thereby increases function and decreases pain in patients with irreparable massive RCTs, even after 2 years.

Take-Home Points

• The SCR is a viable treatment option for massive, irreparable RCTs.
• Arm position and exact measurement between anchors will help ensure proper graft tensioning.
• Anterior and posterior tension and margin convergence are critical to stabilizing the graft.
• Acromial-humeral distance, ASES, and VAS scores are improved and maintained over long-term follow-up.
• The dermal allograft should be 3.0 mm or thicker.

Conventional treatments for irreparable massive rotator cuff tears (RCTs) have ranged from nonoperative care to débridement and biceps tenotomy,^1,2 partial cuff repair,^3,4 bridging patch grafts,⁵ tendon transfers,^6,7 and reverse total shoulder arthroplasty (RTSA).^8,9 Superior capsular reconstruction (SCR), originally described by Mihata and colleagues,¹⁰ has been developed as an alternative to these interventions. Dr. Hirahara modified the technique to use dermal allograft instead of fascia lata autograft.^10,11

Biomechanical analysis has confirmed the integral role of the superior capsule in shoulder function.^10,12-14 In the presence of a massive RCT, the humeral head migrates superiorly, causing significant pain and functional deficits, such as pseudoparalysis. It is theorized that reestablishing this important stabilizer—centering the humeral head in the glenoid and allowing the larger muscles to move the arm about a proper fulcrum—improves function and decreases pain.

Using ultrasonography (US), radiography, magnetic resonance imaging (MRI), clinical outcome scores, and a visual analog scale (VAS) for pain, we prospectively evaluated minimum 2-year clinical outcomes of performing SCR with dermal allograft for irreparable RCTs.

Methods

Except where noted otherwise, all products mentioned in this section were made by Arthrex.

Surgical Technique

The surgical technique used here was described by Hirahara and Adams.¹¹ ArthroFlex dermal allograft was attached to the greater tuberosity and the glenoid, creating a superior restraint that replaced the anatomical superior capsule (Figures 1A, 1B). Some cases included biceps tenotomy, subscapularis repair, or infraspinatus repair.

Medial fixation was obtained with a PASTA (partial articular supraspinatus tendon avulsion) bridge-type construct¹⁵ that consisted of two 3.0-mm BioComposite SutureTak anchors (placed medially on the glenoid rim, medial to the labrum) and a 3.5-mm BioComposite Vented SwiveLock. In some cases, a significant amount of tissue was present medially, and the third anchor was not used; instead, a double surgeon knot was used to fixate the double pulley medially.

Posterior margin convergence (PMC) was performed in all cases. Anterior margin convergence (AMC) was performed in only 3 cases.

Clinical Evaluation

All patients who underwent SCR were followed prospectively, and all signed an informed consent form. Between 2014 and the time of this study, 9 patients had surgery with a minimum 2-year follow-up. Before surgery, all patients received a diagnosis of full-thickness RCT with decreased acromial-humeral distance (AHD). One patient had RTSA 18 months after surgery, did not reach the 2-year follow-up, and was excluded from the data analysis. Patients were clinically evaluated on the 100-point American Shoulder and Elbow Surgeons (ASES) shoulder index and on a 10-point VAS for pain—before surgery, monthly for the first 6 months after surgery, then every 6 months until 2 years after surgery, and yearly thereafter. These patients were compared with Dr. Hirahara’s historical control patients, who had undergone repair of massive RCTs. Mean graft size was calculated and reported. Cases were separated and analyzed on the basis of whether AMC was performed. Student t tests were used to determine statistical differences between study patients’ preoperative and postoperative scores, between study and historical control patients, and between patients who had AMC performed and those who did not (P < .05).

Imaging

For all SCR patients, preoperative and postoperative radiographs were obtained in 2 planes: anterior-posterior with arm in neutral rotation, and scapular Y. On anteroposterior radiographs, AHD was measured from the most proximal aspect of the humeral head in a vertical line to the most inferior portion of the acromion (Figures 2A, 2B).

Results

The Table provides an overview of the study results. Eight patients (6 men, 2 women) met the final inclusion criteria for postoperative ASES and VAS data analysis.

AHD was measured on a standard anteroposterior radiograph in neutral rotation. The Hamada grading scale16 was used to classify the massive RCTs before and after surgery. Before surgery, 4 were grade 4A, 1 grade 3, 2 grade 2, and 1 grade 1; immediately after surgery, all were grade 1 (AHD, ≥6 mm). Two years after surgery, 1 patient had an AHD of 4.6 mm after a failure caused by a fall. Mean (SD) preoperative AHD was 4.50 (2.25) mm (range, 1.7-7.9 mm). Radiographs obtained immediately (mean, 1.22 months; range, 1 day-2.73 months) after surgery showed AHD was significantly (P < .0008) increased (mean, 8.48 mm; SD, 1.25 mm; range, 6.0-10.0 mm) (Figure 5).

Mean graft size was 2.9 mm medial × 3.6 mm lateral × 5.4 mm anterior × 5.4 mm posterior. Three patients had AMC performed. There was a significant (P < .05) difference in ASES scores between patients who had AMC performed (93) and those who did not (77).

Ultrasonography

Two weeks to 2 months after surgery, all patients had an intact capsular graft and no pulsatile vessels on US. Between 4 months and 10 months, US showed the construct intact laterally in all cases, a pulsatile vessel in the graft at the tuberosity (evidence of blood flow) in 4 of 5 cases, and a pulsatile vessel hypertrophied in 2 cases (Figures 6A, 6B).

Magnetic Resonance Imaging

Before surgery, 4 patients had Goutallier¹⁷ stage 4 rotator cuff muscle degeneration, 2 had stage 3 degeneration, and 2 had stage 2 degeneration. Throughout the follow-up period, US was as effective as MRI in determining graft integrity, graft thickness, and greater tuberosity fixation. Therefore, the SCRs were assessed primarily with US. MRI was ordered only if a failure was suspected or if the patient had some form of trauma. A total of 7 MRIs were ordered for 5 of the 8 patients in the study. The graft was intact in 4 of the 5 (Figures 7A-7C) and ruptured in the fifth.

Discussion

Mihata and colleagues¹⁰ published 2-year data for their reconstructive procedure with fascia lata autograft. In a modification of their procedure, Dr. Hirahara used dermal allograft to recreate the superior capsule.¹¹ The results of the present 2-year study mirror the clinical outcomes reported by Mihata and colleagues¹⁰ and confirm that SCR improves functional outcomes and increases AHD regardless of graft type used.

The outcomes of the SCR patients in our study were significantly better than the outcomes of the historical control patients, who underwent repair of massive RCTs. Although there was no significant difference in the 2 groups’ ASES scores, the control patients had significantly higher postoperative VAS pain scores. We think that, as more patients undergo SCR and the population sample increases, we will see a significant difference in ASES scores as well (our SCR patients already showed a trend toward improved ASES scores).

Compared with RTSA, SCR has fewer risks and fewer complications and does not limit further surgical options.^8,9,18 The 9 patients who had surgery with a minimum 2-year follow-up in our study had 4 complications. Six months after surgery, 1 patient fell and tore the infraspinatus and subscapularis muscles. Outcomes continued to improve, and no issues were reported, despite a decrease in AHD, from 8 mm immediately after surgery to 4.6 mm 2 years after surgery.

Two patients were in motor vehicle accidents. In 1 case, the accident occurred about 2 months after surgery. This patient also sustained a possible injury in a fall after receiving general anesthesia for a dental procedure. After having done very well the preceding months, the patient now reported increasing pain and dysfunction. MRI showed loss of glenoid fixation. Improved ASES and VAS pain scores were maintained throughout the follow-up period. AHD was increased at 13 months and mildly decreased at 2 years. Glenoid fixation was obtained with 2 anchors and a double surgeon knot. When possible, however, it is best to add an anchor and double-row fixation, as 3 anchors and a double-row construct are biomechanically stronger.^19-24

The other motor vehicle accident occurred about 23 months after surgery. Two months later, a graft rupture was found on US and MRI, but the patient was maintaining full range of motion, AHD, and improved strength. The 1.5-mm graft in this patient was thinner than the 3.5-mm grafts in the rest of the study group. This was the only patient who developed a graft rupture rather than loss of fixation.

If only patients with graft thickness >3.0 mm are included in the data analysis, mean ASES score rises to 89.76, and mean VAS pain score drops to 0. Therefore, we argue against using a graft thinner than 3.5 mm. Our excellent study results indicate that larger grafts are unnecessary. Mihata and colleagues¹⁰ used fascia lata grafts of 6 mm to 8 mm. Ultimate load to failure is significantly higher for dermal allograft than for fascia lata graft.²⁵ In SCR, the stronger dermal allograft withstands applied forces and repeated deformations and has excellent clinical outcomes.

Only 1 patient had a failure that required RTSA. VAS pain scores were lower and ASES scores were improved the first year after surgery, but then function deteriorated. The patient said there was no specific precipitating incident. Computed tomography arthrogram, ordered to assess the construct, showed anterior and superior subluxation of the humeral head, even with an intact subscapularis tendon—an indication of underlying instability, which most likely caused the failure. Eighteen months after surgery, the patient was able to undergo RTSA. On further evaluation of this patient’s procedure, it was determined that the graft needed better fixation anteriorly.

Mihata and colleagues^10,12,14 indicated that AMC was unnecessary, and our procedure did not require it. However, data in our prospective evaluation began showing improved outcomes with AMC. As dermal allograft is more elastic than fascia lata autograft,²⁵ we concluded that graft tensioning is key to the success of this procedure. Graft tension depends on many factors, including exact measurement of the distances between the anchors to punch holes in the graft, arm position to set the relationship between the anchor distances, and AMC and PMC. We recommend placing the arm in neutral rotation, neutral flexion, and abduction with the patient at rest, based on the size of the patient’s latissimus dorsi. Too much abduction causes overtensioning, and excess rotation or flexion-extension changes the distance between the glenoid and the greater tuberosity asymmetrically, from anterior to posterior. With the arm in neutral position, distances between anchors are accurately measured, and these measurements are used to determine graft size.

Graft tension is also needed to control the amount of elasticity allowed by the graft and thereby maintain stability, as shown by the Poisson ratio, the ratio of transverse contraction to longitudinal extension on a material in the presence of a stretching force. As applied to SCR, it is the ratio of mediolateral elasticity to anteroposterior deformation or constraint. If the graft is appropriately secured in the anteroposterior direction by way of ACM and PMC, elongation in the medial-lateral direction will be limited—reducing the elasticity of the graft, improving overall stability, and ultimately producing better clinical outcomes. This issue was discussed by Burkhart and colleagues²⁶ with respect to the “rotator cable complex,” which now might be best described as the “rotator-capsule cable complex.” In our study, this phenomenon was evident in the finding that patients who had AMC performed did significantly better than patients who did not have AMC performed. The ability of dermal allograft to deform in these dimensions without failure while allowing excellent range of motion makes dermal allograft an exceptional choice for grafting during SCR. Mihata25 also found dermal allograft had a clear advantage in providing better range of motion, whereas fascia lata autograft resulted in a stiffer construct. 

Dermal allograft can also incorporate into the body and transform into host tissue. The literature has described musculoskeletal US as an effective diagnostic and interventional tool.^27-31 We used it to evaluate graft size, patency, and viability. As can be seen on US, the native rotator cuff does not have any pulsatile vessels and is fed by capillary flow. Dermal allograft has native vasculature built into the tissue. After 4 months to 8 months, presence of pulsatile vessels within the graft at the greater tuberosity indicates clear revascularization and incorporation of the tissue (Figure 6B). Disappearance of pulsatile vessels on US after 1 year indicates transformation to a stabilizing structure analogous to capsule or ligament with capillary flow. US also showed graft hypertrophy after 2 years, supporting a finding of integration and growth.

Conclusion

In the past, patients with irreparable massive RCTs had few good surgical management options, RTSA being the most definitive. SCR is technically challenging and requires use of specific implantation methods but can provide patients with outstanding relief. Our clinical data showed that technically well executed SCR effectively restores the superior restraints in the glenohumeral joint and thereby increases function and decreases pain in patients with irreparable massive RCTs, even after 2 years.

Take-Home Points

• The SCR is a viable treatment option for massive, irreparable RCTs.
• Arm position and exact measurement between anchors will help ensure proper graft tensioning.
• Anterior and posterior tension and margin convergence are critical to stabilizing the graft.
• Acromial-humeral distance, ASES, and VAS scores are improved and maintained over long-term follow-up.
• The dermal allograft should be 3.0 mm or thicker.

Conventional treatments for irreparable massive rotator cuff tears (RCTs) have ranged from nonoperative care to débridement and biceps tenotomy,^1,2 partial cuff repair,^3,4 bridging patch grafts,⁵ tendon transfers,^6,7 and reverse total shoulder arthroplasty (RTSA).^8,9 Superior capsular reconstruction (SCR), originally described by Mihata and colleagues,¹⁰ has been developed as an alternative to these interventions. Dr. Hirahara modified the technique to use dermal allograft instead of fascia lata autograft.^10,11

Biomechanical analysis has confirmed the integral role of the superior capsule in shoulder function.^10,12-14 In the presence of a massive RCT, the humeral head migrates superiorly, causing significant pain and functional deficits, such as pseudoparalysis. It is theorized that reestablishing this important stabilizer—centering the humeral head in the glenoid and allowing the larger muscles to move the arm about a proper fulcrum—improves function and decreases pain.

Using ultrasonography (US), radiography, magnetic resonance imaging (MRI), clinical outcome scores, and a visual analog scale (VAS) for pain, we prospectively evaluated minimum 2-year clinical outcomes of performing SCR with dermal allograft for irreparable RCTs.

Methods

Except where noted otherwise, all products mentioned in this section were made by Arthrex.

Surgical Technique

The surgical technique used here was described by Hirahara and Adams.¹¹ ArthroFlex dermal allograft was attached to the greater tuberosity and the glenoid, creating a superior restraint that replaced the anatomical superior capsule (Figures 1A, 1B). Some cases included biceps tenotomy, subscapularis repair, or infraspinatus repair.

Medial fixation was obtained with a PASTA (partial articular supraspinatus tendon avulsion) bridge-type construct¹⁵ that consisted of two 3.0-mm BioComposite SutureTak anchors (placed medially on the glenoid rim, medial to the labrum) and a 3.5-mm BioComposite Vented SwiveLock. In some cases, a significant amount of tissue was present medially, and the third anchor was not used; instead, a double surgeon knot was used to fixate the double pulley medially.

Posterior margin convergence (PMC) was performed in all cases. Anterior margin convergence (AMC) was performed in only 3 cases.

Clinical Evaluation

All patients who underwent SCR were followed prospectively, and all signed an informed consent form. Between 2014 and the time of this study, 9 patients had surgery with a minimum 2-year follow-up. Before surgery, all patients received a diagnosis of full-thickness RCT with decreased acromial-humeral distance (AHD). One patient had RTSA 18 months after surgery, did not reach the 2-year follow-up, and was excluded from the data analysis. Patients were clinically evaluated on the 100-point American Shoulder and Elbow Surgeons (ASES) shoulder index and on a 10-point VAS for pain—before surgery, monthly for the first 6 months after surgery, then every 6 months until 2 years after surgery, and yearly thereafter. These patients were compared with Dr. Hirahara’s historical control patients, who had undergone repair of massive RCTs. Mean graft size was calculated and reported. Cases were separated and analyzed on the basis of whether AMC was performed. Student t tests were used to determine statistical differences between study patients’ preoperative and postoperative scores, between study and historical control patients, and between patients who had AMC performed and those who did not (P < .05).

Imaging

For all SCR patients, preoperative and postoperative radiographs were obtained in 2 planes: anterior-posterior with arm in neutral rotation, and scapular Y. On anteroposterior radiographs, AHD was measured from the most proximal aspect of the humeral head in a vertical line to the most inferior portion of the acromion (Figures 2A, 2B).

Results

The Table provides an overview of the study results. Eight patients (6 men, 2 women) met the final inclusion criteria for postoperative ASES and VAS data analysis.

AHD was measured on a standard anteroposterior radiograph in neutral rotation. The Hamada grading scale16 was used to classify the massive RCTs before and after surgery. Before surgery, 4 were grade 4A, 1 grade 3, 2 grade 2, and 1 grade 1; immediately after surgery, all were grade 1 (AHD, ≥6 mm). Two years after surgery, 1 patient had an AHD of 4.6 mm after a failure caused by a fall. Mean (SD) preoperative AHD was 4.50 (2.25) mm (range, 1.7-7.9 mm). Radiographs obtained immediately (mean, 1.22 months; range, 1 day-2.73 months) after surgery showed AHD was significantly (P < .0008) increased (mean, 8.48 mm; SD, 1.25 mm; range, 6.0-10.0 mm) (Figure 5).

Mean graft size was 2.9 mm medial × 3.6 mm lateral × 5.4 mm anterior × 5.4 mm posterior. Three patients had AMC performed. There was a significant (P < .05) difference in ASES scores between patients who had AMC performed (93) and those who did not (77).

Ultrasonography

Two weeks to 2 months after surgery, all patients had an intact capsular graft and no pulsatile vessels on US. Between 4 months and 10 months, US showed the construct intact laterally in all cases, a pulsatile vessel in the graft at the tuberosity (evidence of blood flow) in 4 of 5 cases, and a pulsatile vessel hypertrophied in 2 cases (Figures 6A, 6B).

Magnetic Resonance Imaging

Before surgery, 4 patients had Goutallier¹⁷ stage 4 rotator cuff muscle degeneration, 2 had stage 3 degeneration, and 2 had stage 2 degeneration. Throughout the follow-up period, US was as effective as MRI in determining graft integrity, graft thickness, and greater tuberosity fixation. Therefore, the SCRs were assessed primarily with US. MRI was ordered only if a failure was suspected or if the patient had some form of trauma. A total of 7 MRIs were ordered for 5 of the 8 patients in the study. The graft was intact in 4 of the 5 (Figures 7A-7C) and ruptured in the fifth.

Discussion

Mihata and colleagues¹⁰ published 2-year data for their reconstructive procedure with fascia lata autograft. In a modification of their procedure, Dr. Hirahara used dermal allograft to recreate the superior capsule.¹¹ The results of the present 2-year study mirror the clinical outcomes reported by Mihata and colleagues¹⁰ and confirm that SCR improves functional outcomes and increases AHD regardless of graft type used.

The outcomes of the SCR patients in our study were significantly better than the outcomes of the historical control patients, who underwent repair of massive RCTs. Although there was no significant difference in the 2 groups’ ASES scores, the control patients had significantly higher postoperative VAS pain scores. We think that, as more patients undergo SCR and the population sample increases, we will see a significant difference in ASES scores as well (our SCR patients already showed a trend toward improved ASES scores).

Compared with RTSA, SCR has fewer risks and fewer complications and does not limit further surgical options.^8,9,18 The 9 patients who had surgery with a minimum 2-year follow-up in our study had 4 complications. Six months after surgery, 1 patient fell and tore the infraspinatus and subscapularis muscles. Outcomes continued to improve, and no issues were reported, despite a decrease in AHD, from 8 mm immediately after surgery to 4.6 mm 2 years after surgery.

Two patients were in motor vehicle accidents. In 1 case, the accident occurred about 2 months after surgery. This patient also sustained a possible injury in a fall after receiving general anesthesia for a dental procedure. After having done very well the preceding months, the patient now reported increasing pain and dysfunction. MRI showed loss of glenoid fixation. Improved ASES and VAS pain scores were maintained throughout the follow-up period. AHD was increased at 13 months and mildly decreased at 2 years. Glenoid fixation was obtained with 2 anchors and a double surgeon knot. When possible, however, it is best to add an anchor and double-row fixation, as 3 anchors and a double-row construct are biomechanically stronger.^19-24

The other motor vehicle accident occurred about 23 months after surgery. Two months later, a graft rupture was found on US and MRI, but the patient was maintaining full range of motion, AHD, and improved strength. The 1.5-mm graft in this patient was thinner than the 3.5-mm grafts in the rest of the study group. This was the only patient who developed a graft rupture rather than loss of fixation.

If only patients with graft thickness >3.0 mm are included in the data analysis, mean ASES score rises to 89.76, and mean VAS pain score drops to 0. Therefore, we argue against using a graft thinner than 3.5 mm. Our excellent study results indicate that larger grafts are unnecessary. Mihata and colleagues¹⁰ used fascia lata grafts of 6 mm to 8 mm. Ultimate load to failure is significantly higher for dermal allograft than for fascia lata graft.²⁵ In SCR, the stronger dermal allograft withstands applied forces and repeated deformations and has excellent clinical outcomes.

Only 1 patient had a failure that required RTSA. VAS pain scores were lower and ASES scores were improved the first year after surgery, but then function deteriorated. The patient said there was no specific precipitating incident. Computed tomography arthrogram, ordered to assess the construct, showed anterior and superior subluxation of the humeral head, even with an intact subscapularis tendon—an indication of underlying instability, which most likely caused the failure. Eighteen months after surgery, the patient was able to undergo RTSA. On further evaluation of this patient’s procedure, it was determined that the graft needed better fixation anteriorly.

Mihata and colleagues^10,12,14 indicated that AMC was unnecessary, and our procedure did not require it. However, data in our prospective evaluation began showing improved outcomes with AMC. As dermal allograft is more elastic than fascia lata autograft,²⁵ we concluded that graft tensioning is key to the success of this procedure. Graft tension depends on many factors, including exact measurement of the distances between the anchors to punch holes in the graft, arm position to set the relationship between the anchor distances, and AMC and PMC. We recommend placing the arm in neutral rotation, neutral flexion, and abduction with the patient at rest, based on the size of the patient’s latissimus dorsi. Too much abduction causes overtensioning, and excess rotation or flexion-extension changes the distance between the glenoid and the greater tuberosity asymmetrically, from anterior to posterior. With the arm in neutral position, distances between anchors are accurately measured, and these measurements are used to determine graft size.

Graft tension is also needed to control the amount of elasticity allowed by the graft and thereby maintain stability, as shown by the Poisson ratio, the ratio of transverse contraction to longitudinal extension on a material in the presence of a stretching force. As applied to SCR, it is the ratio of mediolateral elasticity to anteroposterior deformation or constraint. If the graft is appropriately secured in the anteroposterior direction by way of ACM and PMC, elongation in the medial-lateral direction will be limited—reducing the elasticity of the graft, improving overall stability, and ultimately producing better clinical outcomes. This issue was discussed by Burkhart and colleagues²⁶ with respect to the “rotator cable complex,” which now might be best described as the “rotator-capsule cable complex.” In our study, this phenomenon was evident in the finding that patients who had AMC performed did significantly better than patients who did not have AMC performed. The ability of dermal allograft to deform in these dimensions without failure while allowing excellent range of motion makes dermal allograft an exceptional choice for grafting during SCR. Mihata25 also found dermal allograft had a clear advantage in providing better range of motion, whereas fascia lata autograft resulted in a stiffer construct. 

Dermal allograft can also incorporate into the body and transform into host tissue. The literature has described musculoskeletal US as an effective diagnostic and interventional tool.^27-31 We used it to evaluate graft size, patency, and viability. As can be seen on US, the native rotator cuff does not have any pulsatile vessels and is fed by capillary flow. Dermal allograft has native vasculature built into the tissue. After 4 months to 8 months, presence of pulsatile vessels within the graft at the greater tuberosity indicates clear revascularization and incorporation of the tissue (Figure 6B). Disappearance of pulsatile vessels on US after 1 year indicates transformation to a stabilizing structure analogous to capsule or ligament with capillary flow. US also showed graft hypertrophy after 2 years, supporting a finding of integration and growth.

Conclusion

In the past, patients with irreparable massive RCTs had few good surgical management options, RTSA being the most definitive. SCR is technically challenging and requires use of specific implantation methods but can provide patients with outstanding relief. Our clinical data showed that technically well executed SCR effectively restores the superior restraints in the glenohumeral joint and thereby increases function and decreases pain in patients with irreparable massive RCTs, even after 2 years.

On a recent visit to my daughter’s school, I caught sight of a set of encyclopedias on the shelf. It brought me back to the days where I would open my own set to find out the information I needed to write reports for school. But my sense of nostalgia was short lived as I thought about all of the limitations of the format. If it wasn’t in the encyclopedias, I couldn’t write the report and would need to head to the library. The Internet changed all of that. Now, when I want to know something I don’t look it up in a book anymore. I ask Siri or Alexa or head to the Google home page. When one of my kids asks me a question I can’t answer, like how a tornado forms, I take out my phone and search for the answer on the Internet.

When it comes to medical information, I can’t remember the last time I opened up a journal sitting on my shelf and leafed through the contents to identify the article I needed. I simply go online and search PubMed or download the article from the AJO website. My office is no longer filled with volumes of journals, and I need only my phone to research whatever topic I’m interested in.

The way I prefer to prepare for cases has changed as well. In the past I would simply open a book or technique article and read about the best way to perform the case. Now, I prefer to watch a video or download the technique guide. I find it easier and faster than reading a book chapter or article.

When we began to change the format of the journal, we stated that AJO would be filled with practical information that would be directly impactful to your practice. That’s the number one criteria we utilize when evaluating content. We wanted to make AJO the journal you wanted to read, because it would improve your knowledge, your outcomes, and your bottom line. We have made many changes to AJO in the last 2 years of print issues. But to truly provide the experience our readers demand and deserve, we have to take a huge next step. Right now we are limited by page and word counts, printed media, and advertising pages. We receive hundreds of submissions a month, yet can only print a fraction of the great material we receive.

If you’ve been following the journal for the last 24 months, you’ve noticed that we have been testing the limits of printed media. We’ve included QR codes for videos, companion PDFs, patient information sheets, and downloadable reports to incorporate into your practice.

The way we access the journal is also changing. We’ve looked closely at our web statistics since the redesign. Our website visits have gone up by a factor of 6 with nearly half of our website traffic coming from mobile usage. It became clear that the days of the printed journal are slowly coming to an end. Surgeons don’t have time to read the journal cover to cover, and now most of our traffic comes from our eBlasts. Surgeons find an article that catches their eye and click a link to find out more. We’ve dramatically increased our eBlasts, and our website volume has been increasing exponentially.

While these small steps have been met with great success, it’s now time to make a giant leap. But unlike most journals, where the online version is just an electronic copy of the printed book, we wanted to make the new AJO something vastly different. We wanted to change the way surgeons utilized a journal and interacted with it on a daily basis. We wanted to be the electronic companion to your practice; a trusted, media rich, peer-reviewed source where you and your patients can turn to for the practical day-to-day information you can use to improve your practice.

We’ve built it, and now I’m proud to unveil it. Beginning January 1, AJO will be published exclusively online. All articles will still be PubMed cited, but will contain more photos, videos, handouts and all the information you need to replicate the findings or procedures in your practice. For example, new surgical techniques will be published with the presenting surgeon’s preference cards, rehab protocols, surgical video, and a PowerPoint presentation that can be presented to referral sources or prospective patients.

New features on our web portal will include:

An orthopedic product guide: A database organized by pathology which contains all of the relevant orthopedic products that could be used for treatment. Relevant products will be cross-referenced to articles so you can quickly identify and order equipment for new cases.

Smart article selection: You can filter the articles that match your interests and have them delivered directly to your inbox. For example, foot and ankle surgeons will no longer need to sift through hundreds of pages to find articles relevant to their practice.

A coding and billing section: Discuss and share tips and tricks with your peers and ask questions of the experts. Regular articles will present relevant codes and how to use them appropriately to get the reimbursement you deserve for your services.

Practice management and business strategies: Get advice from, and interact with, the experts in all areas of your practice.

Ask the experts: Present your cases to our editorial board and enjoy a written, peer-reviewed response. Discuss cases and mutual challenges in communities organized by subspecialty and sport. Cover a high school football team? Imagine a place where you can present your football-related injury to the world’s best football doctors and have them review and comment on the case.

These are just some of the changes you will see in the coming months. We will continuously work to improve and welcome your future suggestions as to how we can provide a truly valuable, customized journal.

Looking to the future, it is my opinion that patient-reported outcome scores will be a large part of what we do. By presenting our successful outcomes, we will ultimately justify the procedures which we perform and justify the reimbursement to third party payers. In this issue, we examine the concept of patient-reported outcome measures (PROMs), and how and why to apply them to your practice.

On a recent visit to my daughter’s school, I caught sight of a set of encyclopedias on the shelf. It brought me back to the days where I would open my own set to find out the information I needed to write reports for school. But my sense of nostalgia was short lived as I thought about all of the limitations of the format. If it wasn’t in the encyclopedias, I couldn’t write the report and would need to head to the library. The Internet changed all of that. Now, when I want to know something I don’t look it up in a book anymore. I ask Siri or Alexa or head to the Google home page. When one of my kids asks me a question I can’t answer, like how a tornado forms, I take out my phone and search for the answer on the Internet.

When it comes to medical information, I can’t remember the last time I opened up a journal sitting on my shelf and leafed through the contents to identify the article I needed. I simply go online and search PubMed or download the article from the AJO website. My office is no longer filled with volumes of journals, and I need only my phone to research whatever topic I’m interested in.

The way I prefer to prepare for cases has changed as well. In the past I would simply open a book or technique article and read about the best way to perform the case. Now, I prefer to watch a video or download the technique guide. I find it easier and faster than reading a book chapter or article.

When we began to change the format of the journal, we stated that AJO would be filled with practical information that would be directly impactful to your practice. That’s the number one criteria we utilize when evaluating content. We wanted to make AJO the journal you wanted to read, because it would improve your knowledge, your outcomes, and your bottom line. We have made many changes to AJO in the last 2 years of print issues. But to truly provide the experience our readers demand and deserve, we have to take a huge next step. Right now we are limited by page and word counts, printed media, and advertising pages. We receive hundreds of submissions a month, yet can only print a fraction of the great material we receive.

If you’ve been following the journal for the last 24 months, you’ve noticed that we have been testing the limits of printed media. We’ve included QR codes for videos, companion PDFs, patient information sheets, and downloadable reports to incorporate into your practice.

The way we access the journal is also changing. We’ve looked closely at our web statistics since the redesign. Our website visits have gone up by a factor of 6 with nearly half of our website traffic coming from mobile usage. It became clear that the days of the printed journal are slowly coming to an end. Surgeons don’t have time to read the journal cover to cover, and now most of our traffic comes from our eBlasts. Surgeons find an article that catches their eye and click a link to find out more. We’ve dramatically increased our eBlasts, and our website volume has been increasing exponentially.

While these small steps have been met with great success, it’s now time to make a giant leap. But unlike most journals, where the online version is just an electronic copy of the printed book, we wanted to make the new AJO something vastly different. We wanted to change the way surgeons utilized a journal and interacted with it on a daily basis. We wanted to be the electronic companion to your practice; a trusted, media rich, peer-reviewed source where you and your patients can turn to for the practical day-to-day information you can use to improve your practice.

We’ve built it, and now I’m proud to unveil it. Beginning January 1, AJO will be published exclusively online. All articles will still be PubMed cited, but will contain more photos, videos, handouts and all the information you need to replicate the findings or procedures in your practice. For example, new surgical techniques will be published with the presenting surgeon’s preference cards, rehab protocols, surgical video, and a PowerPoint presentation that can be presented to referral sources or prospective patients.

New features on our web portal will include:

An orthopedic product guide: A database organized by pathology which contains all of the relevant orthopedic products that could be used for treatment. Relevant products will be cross-referenced to articles so you can quickly identify and order equipment for new cases.

Smart article selection: You can filter the articles that match your interests and have them delivered directly to your inbox. For example, foot and ankle surgeons will no longer need to sift through hundreds of pages to find articles relevant to their practice.

A coding and billing section: Discuss and share tips and tricks with your peers and ask questions of the experts. Regular articles will present relevant codes and how to use them appropriately to get the reimbursement you deserve for your services.

Practice management and business strategies: Get advice from, and interact with, the experts in all areas of your practice.

Ask the experts: Present your cases to our editorial board and enjoy a written, peer-reviewed response. Discuss cases and mutual challenges in communities organized by subspecialty and sport. Cover a high school football team? Imagine a place where you can present your football-related injury to the world’s best football doctors and have them review and comment on the case.

These are just some of the changes you will see in the coming months. We will continuously work to improve and welcome your future suggestions as to how we can provide a truly valuable, customized journal.

Looking to the future, it is my opinion that patient-reported outcome scores will be a large part of what we do. By presenting our successful outcomes, we will ultimately justify the procedures which we perform and justify the reimbursement to third party payers. In this issue, we examine the concept of patient-reported outcome measures (PROMs), and how and why to apply them to your practice.

On a recent visit to my daughter’s school, I caught sight of a set of encyclopedias on the shelf. It brought me back to the days where I would open my own set to find out the information I needed to write reports for school. But my sense of nostalgia was short lived as I thought about all of the limitations of the format. If it wasn’t in the encyclopedias, I couldn’t write the report and would need to head to the library. The Internet changed all of that. Now, when I want to know something I don’t look it up in a book anymore. I ask Siri or Alexa or head to the Google home page. When one of my kids asks me a question I can’t answer, like how a tornado forms, I take out my phone and search for the answer on the Internet.

When it comes to medical information, I can’t remember the last time I opened up a journal sitting on my shelf and leafed through the contents to identify the article I needed. I simply go online and search PubMed or download the article from the AJO website. My office is no longer filled with volumes of journals, and I need only my phone to research whatever topic I’m interested in.

The way I prefer to prepare for cases has changed as well. In the past I would simply open a book or technique article and read about the best way to perform the case. Now, I prefer to watch a video or download the technique guide. I find it easier and faster than reading a book chapter or article.

When we began to change the format of the journal, we stated that AJO would be filled with practical information that would be directly impactful to your practice. That’s the number one criteria we utilize when evaluating content. We wanted to make AJO the journal you wanted to read, because it would improve your knowledge, your outcomes, and your bottom line. We have made many changes to AJO in the last 2 years of print issues. But to truly provide the experience our readers demand and deserve, we have to take a huge next step. Right now we are limited by page and word counts, printed media, and advertising pages. We receive hundreds of submissions a month, yet can only print a fraction of the great material we receive.

If you’ve been following the journal for the last 24 months, you’ve noticed that we have been testing the limits of printed media. We’ve included QR codes for videos, companion PDFs, patient information sheets, and downloadable reports to incorporate into your practice.

The way we access the journal is also changing. We’ve looked closely at our web statistics since the redesign. Our website visits have gone up by a factor of 6 with nearly half of our website traffic coming from mobile usage. It became clear that the days of the printed journal are slowly coming to an end. Surgeons don’t have time to read the journal cover to cover, and now most of our traffic comes from our eBlasts. Surgeons find an article that catches their eye and click a link to find out more. We’ve dramatically increased our eBlasts, and our website volume has been increasing exponentially.

While these small steps have been met with great success, it’s now time to make a giant leap. But unlike most journals, where the online version is just an electronic copy of the printed book, we wanted to make the new AJO something vastly different. We wanted to change the way surgeons utilized a journal and interacted with it on a daily basis. We wanted to be the electronic companion to your practice; a trusted, media rich, peer-reviewed source where you and your patients can turn to for the practical day-to-day information you can use to improve your practice.

We’ve built it, and now I’m proud to unveil it. Beginning January 1, AJO will be published exclusively online. All articles will still be PubMed cited, but will contain more photos, videos, handouts and all the information you need to replicate the findings or procedures in your practice. For example, new surgical techniques will be published with the presenting surgeon’s preference cards, rehab protocols, surgical video, and a PowerPoint presentation that can be presented to referral sources or prospective patients.

New features on our web portal will include:

An orthopedic product guide: A database organized by pathology which contains all of the relevant orthopedic products that could be used for treatment. Relevant products will be cross-referenced to articles so you can quickly identify and order equipment for new cases.

Smart article selection: You can filter the articles that match your interests and have them delivered directly to your inbox. For example, foot and ankle surgeons will no longer need to sift through hundreds of pages to find articles relevant to their practice.

A coding and billing section: Discuss and share tips and tricks with your peers and ask questions of the experts. Regular articles will present relevant codes and how to use them appropriately to get the reimbursement you deserve for your services.

Practice management and business strategies: Get advice from, and interact with, the experts in all areas of your practice.

Ask the experts: Present your cases to our editorial board and enjoy a written, peer-reviewed response. Discuss cases and mutual challenges in communities organized by subspecialty and sport. Cover a high school football team? Imagine a place where you can present your football-related injury to the world’s best football doctors and have them review and comment on the case.

These are just some of the changes you will see in the coming months. We will continuously work to improve and welcome your future suggestions as to how we can provide a truly valuable, customized journal.

Looking to the future, it is my opinion that patient-reported outcome scores will be a large part of what we do. By presenting our successful outcomes, we will ultimately justify the procedures which we perform and justify the reimbursement to third party payers. In this issue, we examine the concept of patient-reported outcome measures (PROMs), and how and why to apply them to your practice.

No one in the family is certain when this 6-year-old boy first developed the red spot on his nose, but it is increasingly noticeable. And with school picture day approaching, they would like the redness to resolve.

Their primary care provider reassured them, at length, that it was benign and would eventually resolve without treatment. The lesion causes no symptoms and is purely a cosmetic concern.

The child is otherwise healthy and has been since birth.

EXAMINATION
A pinpoint red dot can be seen on the upper nasal bridge, just to the right of the midline. Tiny linear red “legs” extend from the central dot, like spokes on a wheel. In aggregate, the lesion measures about 3 mm in diameter. There is no palpable component.

However, the entire lesion is blanchable: Pinpoint pressure on the central dot causes it to blanch, and as the pressure is released, the legs of the lesion refill immediately from the center outward. When a glass slide is pressed against the lesion (a process called diascopy) and then released, the same process occurs.

What is the diagnosis?

SAs affect 10% to 15% of children and occur only in areas along the path of the superior vena cava. Besides the face, they can be found on the trunk, arms, and dorsal hands.

When solitary, these lesions are benign and can be either left to clear on their own or removed by laser or electrodessication. The presence of three or more lesions warrants further investigation, since multiple SAs can signify underlying disease (eg, cirrhosis of the liver, thyrotoxicosis, or systemic sclerosis).

This patient was not inclined to let us treat the lesion; within a few years, a teasing comment from a classmate or two may change his mind! But with a little luck, it will disappear on its own eventually.

TAKE-HOME LEARNING POINTS

• Spider angiomas (SAs) are actually dilated telangiectatic arterioles manifesting as blanchable, bright red, pinpoint papules with venous “legs” that extend from the center.
• SAs affect 10% to 15% of all children and are confined to areas drained by the superior vena cava.
• Pressure on the lesion with a glass slide (a process called diascopy) causes total blanching; this, along with the clinical findings, confirms the diagnosis.
• Most SAs resolve on their own eventually, but they can be destroyed by laser or electrodessication.
• The presence of more than three SAs should prompt a search for potential causes, such as liver disease, thyrotoxicosis, or systemic sclerosis.

No one in the family is certain when this 6-year-old boy first developed the red spot on his nose, but it is increasingly noticeable. And with school picture day approaching, they would like the redness to resolve.

Their primary care provider reassured them, at length, that it was benign and would eventually resolve without treatment. The lesion causes no symptoms and is purely a cosmetic concern.

The child is otherwise healthy and has been since birth.

EXAMINATION
A pinpoint red dot can be seen on the upper nasal bridge, just to the right of the midline. Tiny linear red “legs” extend from the central dot, like spokes on a wheel. In aggregate, the lesion measures about 3 mm in diameter. There is no palpable component.

However, the entire lesion is blanchable: Pinpoint pressure on the central dot causes it to blanch, and as the pressure is released, the legs of the lesion refill immediately from the center outward. When a glass slide is pressed against the lesion (a process called diascopy) and then released, the same process occurs.

What is the diagnosis?

SAs affect 10% to 15% of children and occur only in areas along the path of the superior vena cava. Besides the face, they can be found on the trunk, arms, and dorsal hands.

When solitary, these lesions are benign and can be either left to clear on their own or removed by laser or electrodessication. The presence of three or more lesions warrants further investigation, since multiple SAs can signify underlying disease (eg, cirrhosis of the liver, thyrotoxicosis, or systemic sclerosis).

This patient was not inclined to let us treat the lesion; within a few years, a teasing comment from a classmate or two may change his mind! But with a little luck, it will disappear on its own eventually.

TAKE-HOME LEARNING POINTS

• Spider angiomas (SAs) are actually dilated telangiectatic arterioles manifesting as blanchable, bright red, pinpoint papules with venous “legs” that extend from the center.
• SAs affect 10% to 15% of all children and are confined to areas drained by the superior vena cava.
• Pressure on the lesion with a glass slide (a process called diascopy) causes total blanching; this, along with the clinical findings, confirms the diagnosis.
• Most SAs resolve on their own eventually, but they can be destroyed by laser or electrodessication.
• The presence of more than three SAs should prompt a search for potential causes, such as liver disease, thyrotoxicosis, or systemic sclerosis.

No one in the family is certain when this 6-year-old boy first developed the red spot on his nose, but it is increasingly noticeable. And with school picture day approaching, they would like the redness to resolve.

Their primary care provider reassured them, at length, that it was benign and would eventually resolve without treatment. The lesion causes no symptoms and is purely a cosmetic concern.

The child is otherwise healthy and has been since birth.

EXAMINATION
A pinpoint red dot can be seen on the upper nasal bridge, just to the right of the midline. Tiny linear red “legs” extend from the central dot, like spokes on a wheel. In aggregate, the lesion measures about 3 mm in diameter. There is no palpable component.

However, the entire lesion is blanchable: Pinpoint pressure on the central dot causes it to blanch, and as the pressure is released, the legs of the lesion refill immediately from the center outward. When a glass slide is pressed against the lesion (a process called diascopy) and then released, the same process occurs.

What is the diagnosis?

SAs affect 10% to 15% of children and occur only in areas along the path of the superior vena cava. Besides the face, they can be found on the trunk, arms, and dorsal hands.

When solitary, these lesions are benign and can be either left to clear on their own or removed by laser or electrodessication. The presence of three or more lesions warrants further investigation, since multiple SAs can signify underlying disease (eg, cirrhosis of the liver, thyrotoxicosis, or systemic sclerosis).

This patient was not inclined to let us treat the lesion; within a few years, a teasing comment from a classmate or two may change his mind! But with a little luck, it will disappear on its own eventually.

TAKE-HOME LEARNING POINTS

• Spider angiomas (SAs) are actually dilated telangiectatic arterioles manifesting as blanchable, bright red, pinpoint papules with venous “legs” that extend from the center.
• SAs affect 10% to 15% of all children and are confined to areas drained by the superior vena cava.
• Pressure on the lesion with a glass slide (a process called diascopy) causes total blanching; this, along with the clinical findings, confirms the diagnosis.
• Most SAs resolve on their own eventually, but they can be destroyed by laser or electrodessication.
• The presence of more than three SAs should prompt a search for potential causes, such as liver disease, thyrotoxicosis, or systemic sclerosis.

Bone marrow aspirate showing plasma cells of multiple myeloma

NEW YORK, NY—The B-cell maturation antigen (BCMA) is emerging as a promising target in multiple myeloma (MM), according to Adam D. Cohen, MD, of the University of Pennsylvania in Philadelphia.

BCMA is highly expressed on MM cells and, with its 2 ligands, is responsible for maintaining normal plasma cell homeostasis.

“And it’s really not expressed on any other normal tissues of the body,” Dr Cohen said.

“Importantly, BCMA is not just sitting on the cell surface as a target but actually promotes myeloma pathogenesis.”

Dr Cohen reviewed the progress being made using BCMA as a target in MM, paying particular attention to chimeric antigen receptor (CAR) T cells. He presented the update at Lymphoma & Myeloma 2017.

NCI BCMA-specific CARs

The first CAR to specifically target BCMA in MM was developed at the National Cancer Institute (NCI). It consisted of a murine single-chain variable fragment (scFv), CD3/CD28 signaling domains, and a gamma-retroviral vector.

Investigators conducted the first-in-human trial of this CAR T-cell therapy in 12 relapsed/refractory MM patients.

All patients received a lymphodepleting conditioning regimen of cyclophosphamide and fludarabine and a single infusion of 1 of 4 doses of the CAR T-cell therapy.

At higher dose levels, the BCMA-CAR produced objective responses “even in these highly refractory patients,” Dr Cohen said. “Some responses lasted 4 to 6 months.”

Patients who had the greatest degree of expansion of CAR T cells were the ones who had the best responses.

The BCMA-CAR is associated with the same toxicities as the CD19-directed CAR T-cell therapies now approved in acute lymphoblastic leukemia and non-Hodgkin lymphoma—cytokine release syndrome (CRS) and neurotoxicity.

The NCI study (NCT02215967) is ongoing.

Penn BCMA-specific CAR

A different BCMA CAR is being investigated at the University of Pennsylvania. It is a fully human CAR that consists of a human scFv, CD3/4-1BB costimulatory domains, and a lentiviral vector.

Investigators designed the first-in-human trial* (NCT02546167) with 3 different cohorts.

Patients in cohort 1 received 5 x 10⁸ CAR T cells without any lymphodepleting chemotherapy.

The remaining patients received cyclophosphamide, followed by 5 x 10⁷ CAR T cells in cohort 2 and 5 x 10⁸ CAR T cells in cohort 3.

Dr Cohen reviewed current data from cohort 1, which included 9 patients. They were a median age of 57 (range, 44-70), and 67% were male. They were heavily pretreated with a median of 9 prior lines of therapy (range, 4-11).

All had high-risk cytogenetics, 67% had deletion 17p or TP53 mutation, and they had a median of 80% bone marrow plasma cells (range, 15%-95%).

“Despite this,” Dr Cohen said, “we were able to generate, successfully, CAR T cells from all patients, although 1 patient did require a second apheresis and manufacturing attempt.”

Four of the 9 patients achieved very good partial responses, and an additional 2 patients had minimal responses.

One patient had a stringent CR (sCR) for close to 2 years without having any intervening therapy.

“[The sCR] shows the potential for this [therapy] to create a durable remission in a patient without any other therapy,” Dr Cohen said. “And this patient still has circulating CAR cells detectable.”

Most of the other patients did not have as durable a response. Responses lasted a median of 3 to 5 months before the patients relapsed.

Dr Cohen noted that the Penn data confirm the NCI experience showing proof of principle.

“You can target BCMA with these cells and get objective responses that can lead to a durable one in a subset of patients,” he added.

Dr Cohen is scheduled to report the preliminary data on the cyclophosphamide cohorts (cohorts 2 and 3) at ASH 2017. Those cohorts, he said, are showing a bit more persistence and increased frequency of responses.

Other BCMA-specific CAR trials

Another BCMA CAR, bb2121, consists of a human anti-BCMA scFv, a lentiviral vector, and a CD3/4-1BB costimulatory domain.

In the first-in-human trial of bb2121* (NCT02658929), all 21 patients received cyclophosphamide and fludarabine conditioning first.

There were “very impressive response rates in this study,” Dr Cohen said.

Once patients were dosed at the higher levels of 150 million cells or greater, every patient responded.

“Many responses are still durable,” he pointed out, “some approaching a year.”

LCAR-B38M is structurally different from the other BCMA-specific CARs. It has 2 binding sites for BCMA.

Thirty-five patients enrolled on the trial of LCAR-B38M (NCT03090659), and 19 were evaluable for response.

Patients had a median of 3 or 4 lines of prior therapy. All received cyclophosphamide alone as conditioning.

All 19 evaluable patients responded, and 14 (74%) achieved an sCR.

Dr Cohen noted the differences among the 4 trials: costimulatory domains varied, the Penn study did not require a pre-existing level of BCMA on the MM cells, other studies excluded patients who didn’t meet a certain threshold level of BCMA expression, median lines of prior therapy differed, and conditioning regimens differed as well.

All trials, however, presented data on fewer than 20 patients.

“And so I think it’s a little too early to compare head-to-head between all of these, but they all are really demonstrating promising results so far,” he observed.

Toxicities

“Unfortunately, there’s no free lunch with CAR T cells,” Dr Cohen stated, “and these extraordinary responses do come at the cost of several somewhat unique toxicities that can be serious.”

Toxicities have included:

• Tumor lysis syndrome, which is expected and manageable
• B-cell aplasia, which is not as much of an issue with BCMA as with CD19-directed CAR Ts, since most B cells don’t express BCMA
• Hypogammaglobulinemia, which can be mitigated with IVIG
• CRS, which can be alleviated with tocilizumab
• Neurotoxicity and encephalopathy, which do not occur as frequently as CRS.

“These, I think, are things we still obviously need to learn more about and try to mitigate before this [BCMA-directed CAR therapy] is expanded and brought earlier to patients,” Dr Cohen said.

“The other issues with CAR T cells are logistical. Limited access (the procedure is available at only a few centers); manufacturing can take 2 to 4 weeks, during which time it is difficult to maintain disease control; and the cost is significant.”

“We are really in the early days of CAR cells for myeloma, but, certainly, this appears very bright in terms of its future.” 

* Data from the presentation differ from the abstract.

Bone marrow aspirate showing plasma cells of multiple myeloma

NEW YORK, NY—The B-cell maturation antigen (BCMA) is emerging as a promising target in multiple myeloma (MM), according to Adam D. Cohen, MD, of the University of Pennsylvania in Philadelphia.

BCMA is highly expressed on MM cells and, with its 2 ligands, is responsible for maintaining normal plasma cell homeostasis.

“And it’s really not expressed on any other normal tissues of the body,” Dr Cohen said.

“Importantly, BCMA is not just sitting on the cell surface as a target but actually promotes myeloma pathogenesis.”

Dr Cohen reviewed the progress being made using BCMA as a target in MM, paying particular attention to chimeric antigen receptor (CAR) T cells. He presented the update at Lymphoma & Myeloma 2017.

NCI BCMA-specific CARs

The first CAR to specifically target BCMA in MM was developed at the National Cancer Institute (NCI). It consisted of a murine single-chain variable fragment (scFv), CD3/CD28 signaling domains, and a gamma-retroviral vector.

Investigators conducted the first-in-human trial of this CAR T-cell therapy in 12 relapsed/refractory MM patients.

All patients received a lymphodepleting conditioning regimen of cyclophosphamide and fludarabine and a single infusion of 1 of 4 doses of the CAR T-cell therapy.

At higher dose levels, the BCMA-CAR produced objective responses “even in these highly refractory patients,” Dr Cohen said. “Some responses lasted 4 to 6 months.”

Patients who had the greatest degree of expansion of CAR T cells were the ones who had the best responses.

The BCMA-CAR is associated with the same toxicities as the CD19-directed CAR T-cell therapies now approved in acute lymphoblastic leukemia and non-Hodgkin lymphoma—cytokine release syndrome (CRS) and neurotoxicity.

The NCI study (NCT02215967) is ongoing.

Penn BCMA-specific CAR

A different BCMA CAR is being investigated at the University of Pennsylvania. It is a fully human CAR that consists of a human scFv, CD3/4-1BB costimulatory domains, and a lentiviral vector.

Investigators designed the first-in-human trial* (NCT02546167) with 3 different cohorts.

Patients in cohort 1 received 5 x 10⁸ CAR T cells without any lymphodepleting chemotherapy.

The remaining patients received cyclophosphamide, followed by 5 x 10⁷ CAR T cells in cohort 2 and 5 x 10⁸ CAR T cells in cohort 3.

Dr Cohen reviewed current data from cohort 1, which included 9 patients. They were a median age of 57 (range, 44-70), and 67% were male. They were heavily pretreated with a median of 9 prior lines of therapy (range, 4-11).

All had high-risk cytogenetics, 67% had deletion 17p or TP53 mutation, and they had a median of 80% bone marrow plasma cells (range, 15%-95%).

“Despite this,” Dr Cohen said, “we were able to generate, successfully, CAR T cells from all patients, although 1 patient did require a second apheresis and manufacturing attempt.”

Four of the 9 patients achieved very good partial responses, and an additional 2 patients had minimal responses.

One patient had a stringent CR (sCR) for close to 2 years without having any intervening therapy.

“[The sCR] shows the potential for this [therapy] to create a durable remission in a patient without any other therapy,” Dr Cohen said. “And this patient still has circulating CAR cells detectable.”

Most of the other patients did not have as durable a response. Responses lasted a median of 3 to 5 months before the patients relapsed.

Dr Cohen noted that the Penn data confirm the NCI experience showing proof of principle.

“You can target BCMA with these cells and get objective responses that can lead to a durable one in a subset of patients,” he added.

Dr Cohen is scheduled to report the preliminary data on the cyclophosphamide cohorts (cohorts 2 and 3) at ASH 2017. Those cohorts, he said, are showing a bit more persistence and increased frequency of responses.

Other BCMA-specific CAR trials

Another BCMA CAR, bb2121, consists of a human anti-BCMA scFv, a lentiviral vector, and a CD3/4-1BB costimulatory domain.

In the first-in-human trial of bb2121* (NCT02658929), all 21 patients received cyclophosphamide and fludarabine conditioning first.

There were “very impressive response rates in this study,” Dr Cohen said.

Once patients were dosed at the higher levels of 150 million cells or greater, every patient responded.

“Many responses are still durable,” he pointed out, “some approaching a year.”

LCAR-B38M is structurally different from the other BCMA-specific CARs. It has 2 binding sites for BCMA.

Thirty-five patients enrolled on the trial of LCAR-B38M (NCT03090659), and 19 were evaluable for response.

Patients had a median of 3 or 4 lines of prior therapy. All received cyclophosphamide alone as conditioning.

All 19 evaluable patients responded, and 14 (74%) achieved an sCR.

Dr Cohen noted the differences among the 4 trials: costimulatory domains varied, the Penn study did not require a pre-existing level of BCMA on the MM cells, other studies excluded patients who didn’t meet a certain threshold level of BCMA expression, median lines of prior therapy differed, and conditioning regimens differed as well.

All trials, however, presented data on fewer than 20 patients.

“And so I think it’s a little too early to compare head-to-head between all of these, but they all are really demonstrating promising results so far,” he observed.

Toxicities

“Unfortunately, there’s no free lunch with CAR T cells,” Dr Cohen stated, “and these extraordinary responses do come at the cost of several somewhat unique toxicities that can be serious.”

Toxicities have included:

• Tumor lysis syndrome, which is expected and manageable
• B-cell aplasia, which is not as much of an issue with BCMA as with CD19-directed CAR Ts, since most B cells don’t express BCMA
• Hypogammaglobulinemia, which can be mitigated with IVIG
• CRS, which can be alleviated with tocilizumab
• Neurotoxicity and encephalopathy, which do not occur as frequently as CRS.

“These, I think, are things we still obviously need to learn more about and try to mitigate before this [BCMA-directed CAR therapy] is expanded and brought earlier to patients,” Dr Cohen said.

“The other issues with CAR T cells are logistical. Limited access (the procedure is available at only a few centers); manufacturing can take 2 to 4 weeks, during which time it is difficult to maintain disease control; and the cost is significant.”

“We are really in the early days of CAR cells for myeloma, but, certainly, this appears very bright in terms of its future.” 

* Data from the presentation differ from the abstract.

Bone marrow aspirate showing plasma cells of multiple myeloma

NEW YORK, NY—The B-cell maturation antigen (BCMA) is emerging as a promising target in multiple myeloma (MM), according to Adam D. Cohen, MD, of the University of Pennsylvania in Philadelphia.

BCMA is highly expressed on MM cells and, with its 2 ligands, is responsible for maintaining normal plasma cell homeostasis.

“And it’s really not expressed on any other normal tissues of the body,” Dr Cohen said.

“Importantly, BCMA is not just sitting on the cell surface as a target but actually promotes myeloma pathogenesis.”

Dr Cohen reviewed the progress being made using BCMA as a target in MM, paying particular attention to chimeric antigen receptor (CAR) T cells. He presented the update at Lymphoma & Myeloma 2017.

NCI BCMA-specific CARs

The first CAR to specifically target BCMA in MM was developed at the National Cancer Institute (NCI). It consisted of a murine single-chain variable fragment (scFv), CD3/CD28 signaling domains, and a gamma-retroviral vector.

Investigators conducted the first-in-human trial of this CAR T-cell therapy in 12 relapsed/refractory MM patients.

All patients received a lymphodepleting conditioning regimen of cyclophosphamide and fludarabine and a single infusion of 1 of 4 doses of the CAR T-cell therapy.

At higher dose levels, the BCMA-CAR produced objective responses “even in these highly refractory patients,” Dr Cohen said. “Some responses lasted 4 to 6 months.”

Patients who had the greatest degree of expansion of CAR T cells were the ones who had the best responses.

The BCMA-CAR is associated with the same toxicities as the CD19-directed CAR T-cell therapies now approved in acute lymphoblastic leukemia and non-Hodgkin lymphoma—cytokine release syndrome (CRS) and neurotoxicity.

The NCI study (NCT02215967) is ongoing.

Penn BCMA-specific CAR

A different BCMA CAR is being investigated at the University of Pennsylvania. It is a fully human CAR that consists of a human scFv, CD3/4-1BB costimulatory domains, and a lentiviral vector.

Investigators designed the first-in-human trial* (NCT02546167) with 3 different cohorts.

Patients in cohort 1 received 5 x 10⁸ CAR T cells without any lymphodepleting chemotherapy.

The remaining patients received cyclophosphamide, followed by 5 x 10⁷ CAR T cells in cohort 2 and 5 x 10⁸ CAR T cells in cohort 3.

Dr Cohen reviewed current data from cohort 1, which included 9 patients. They were a median age of 57 (range, 44-70), and 67% were male. They were heavily pretreated with a median of 9 prior lines of therapy (range, 4-11).

All had high-risk cytogenetics, 67% had deletion 17p or TP53 mutation, and they had a median of 80% bone marrow plasma cells (range, 15%-95%).

“Despite this,” Dr Cohen said, “we were able to generate, successfully, CAR T cells from all patients, although 1 patient did require a second apheresis and manufacturing attempt.”

Four of the 9 patients achieved very good partial responses, and an additional 2 patients had minimal responses.

One patient had a stringent CR (sCR) for close to 2 years without having any intervening therapy.

“[The sCR] shows the potential for this [therapy] to create a durable remission in a patient without any other therapy,” Dr Cohen said. “And this patient still has circulating CAR cells detectable.”

Most of the other patients did not have as durable a response. Responses lasted a median of 3 to 5 months before the patients relapsed.

Dr Cohen noted that the Penn data confirm the NCI experience showing proof of principle.

“You can target BCMA with these cells and get objective responses that can lead to a durable one in a subset of patients,” he added.

Dr Cohen is scheduled to report the preliminary data on the cyclophosphamide cohorts (cohorts 2 and 3) at ASH 2017. Those cohorts, he said, are showing a bit more persistence and increased frequency of responses.

Other BCMA-specific CAR trials

Another BCMA CAR, bb2121, consists of a human anti-BCMA scFv, a lentiviral vector, and a CD3/4-1BB costimulatory domain.

In the first-in-human trial of bb2121* (NCT02658929), all 21 patients received cyclophosphamide and fludarabine conditioning first.

There were “very impressive response rates in this study,” Dr Cohen said.

Once patients were dosed at the higher levels of 150 million cells or greater, every patient responded.

“Many responses are still durable,” he pointed out, “some approaching a year.”

LCAR-B38M is structurally different from the other BCMA-specific CARs. It has 2 binding sites for BCMA.

Thirty-five patients enrolled on the trial of LCAR-B38M (NCT03090659), and 19 were evaluable for response.

Patients had a median of 3 or 4 lines of prior therapy. All received cyclophosphamide alone as conditioning.

All 19 evaluable patients responded, and 14 (74%) achieved an sCR.

Dr Cohen noted the differences among the 4 trials: costimulatory domains varied, the Penn study did not require a pre-existing level of BCMA on the MM cells, other studies excluded patients who didn’t meet a certain threshold level of BCMA expression, median lines of prior therapy differed, and conditioning regimens differed as well.

All trials, however, presented data on fewer than 20 patients.

“And so I think it’s a little too early to compare head-to-head between all of these, but they all are really demonstrating promising results so far,” he observed.

Toxicities

“Unfortunately, there’s no free lunch with CAR T cells,” Dr Cohen stated, “and these extraordinary responses do come at the cost of several somewhat unique toxicities that can be serious.”

Toxicities have included:

• Tumor lysis syndrome, which is expected and manageable
• B-cell aplasia, which is not as much of an issue with BCMA as with CD19-directed CAR Ts, since most B cells don’t express BCMA
• Hypogammaglobulinemia, which can be mitigated with IVIG
• CRS, which can be alleviated with tocilizumab
• Neurotoxicity and encephalopathy, which do not occur as frequently as CRS.

“These, I think, are things we still obviously need to learn more about and try to mitigate before this [BCMA-directed CAR therapy] is expanded and brought earlier to patients,” Dr Cohen said.

“The other issues with CAR T cells are logistical. Limited access (the procedure is available at only a few centers); manufacturing can take 2 to 4 weeks, during which time it is difficult to maintain disease control; and the cost is significant.”

“We are really in the early days of CAR cells for myeloma, but, certainly, this appears very bright in terms of its future.” 

* Data from the presentation differ from the abstract.

Photo by Rhoda Baer

SAN DIEGO—A study of acute myeloid leukemia (AML) patients has revealed misperceptions about treatment risks and the likelihood of cure.

Investigators surveyed 100 AML patients receiving intensive and non-intensive chemotherapy, as well as the patients’ oncologists.

The results showed that patients tended to overestimate both the risk of dying due to treatment and the likelihood of cure.

These findings were presented at the 2017 Palliative and Supportive Care in Oncology Symposium (abstract 43).

“Patients with AML face very challenging treatment decisions that are often placed upon them within days after being diagnosed,” said study investigator Areej El-Jawahri, MD, of Massachusetts General Hospital in Boston.

“Because they face a grave decision, they need to understand what the risks of treatment are versus the possibility of a cure.”

For this study, Dr El-Jawahri and her colleagues enrolled 50 patients who were receiving intensive care for AML (which usually meant hospitalization for 4 to 6 weeks) and 50 patients who were receiving non-intensive care (often given as outpatient treatment).

The patients’ median age was 71 (range, 60-100), and 92% were white. Six percent of patients had low-risk disease, 48% had intermediate-risk, and 46% had high-risk disease.

Within 3 days of starting treatment, both the patients and their physicians were given a questionnaire to assess how they perceived the likelihood of the patient dying from treatment.

One month later, patients and physicians completed a follow-up questionnaire to assess perceptions of patient prognosis. Within that time frame, most patients received laboratory results that more definitively established the type and stage of cancer.

At 24 weeks, the investigators asked patients if they had discussed their end-of-life wishes with their oncologists.

Results

Initially, most of the patient population (91.3%) thought it was “somewhat” or “extremely” likely they would die from their treatment. However, only 22% of treating oncologists said the same.

One month later, a majority of patients in both treatment groups thought it was “somewhat” or “extremely” likely they would be cured of their AML.

Specifically, 82.1% of patients receiving non-intensive chemotherapy said it was “somewhat” or “extremely” likely they would be cured, while 10% of their oncologists said the same.

Meanwhile, 97.6% of patients receiving intensive chemotherapy said it was “somewhat” or “extremely” likely they would be cured, and 42% of their oncologists said the same.

Overall, 77.8% of patients said they had not discussed their end-of-life wishes with their oncologists at 24 weeks.

“There were several very important factors we were not able to capture in our study, including what was actually discussed between patients and their oncologists and whether patients simply misunderstood or misheard the information conveyed to them,” Dr El-Jawahri said.

“Perhaps most importantly, we did not audio-record the discussions between the patients and their physicians, which could provide additional details regarding barriers to accurate prognostic understanding in these conversations.”

Related research and next steps

Prior to this study, Dr El-Jawahri and her colleagues had looked at similar perceptions in patients with solid tumor malignancies as well as in patients with hematologic malignancies who were receiving hematopoietic stem cell transplants.

The gaps in perception of treatment risk and cure for patients compared to their physicians were not as large in those cases as in the AML patients in this study. The investigators attribute this to higher levels of distress seen in AML patients due to the urgency of their treatment decisions.

Dr El-Jawahri and her colleagues have found that early consideration of palliative care in a treatment plan for patients with solid tumors improves patients’ understanding of the prognosis. The team hopes to implement a similar study in patients with AML.

“Clearly, there are important communication gaps between oncologists and their patients,” Dr El-Jawahri said. “We need to find ways to help physicians do a better job of communicating with their patients, especially in diseases like AML where stress levels are remarkably high.”

Photo by Rhoda Baer

SAN DIEGO—A study of acute myeloid leukemia (AML) patients has revealed misperceptions about treatment risks and the likelihood of cure.

Investigators surveyed 100 AML patients receiving intensive and non-intensive chemotherapy, as well as the patients’ oncologists.

The results showed that patients tended to overestimate both the risk of dying due to treatment and the likelihood of cure.

These findings were presented at the 2017 Palliative and Supportive Care in Oncology Symposium (abstract 43).

“Patients with AML face very challenging treatment decisions that are often placed upon them within days after being diagnosed,” said study investigator Areej El-Jawahri, MD, of Massachusetts General Hospital in Boston.

“Because they face a grave decision, they need to understand what the risks of treatment are versus the possibility of a cure.”

For this study, Dr El-Jawahri and her colleagues enrolled 50 patients who were receiving intensive care for AML (which usually meant hospitalization for 4 to 6 weeks) and 50 patients who were receiving non-intensive care (often given as outpatient treatment).

The patients’ median age was 71 (range, 60-100), and 92% were white. Six percent of patients had low-risk disease, 48% had intermediate-risk, and 46% had high-risk disease.

Within 3 days of starting treatment, both the patients and their physicians were given a questionnaire to assess how they perceived the likelihood of the patient dying from treatment.

One month later, patients and physicians completed a follow-up questionnaire to assess perceptions of patient prognosis. Within that time frame, most patients received laboratory results that more definitively established the type and stage of cancer.

At 24 weeks, the investigators asked patients if they had discussed their end-of-life wishes with their oncologists.

Results

Initially, most of the patient population (91.3%) thought it was “somewhat” or “extremely” likely they would die from their treatment. However, only 22% of treating oncologists said the same.

One month later, a majority of patients in both treatment groups thought it was “somewhat” or “extremely” likely they would be cured of their AML.

Specifically, 82.1% of patients receiving non-intensive chemotherapy said it was “somewhat” or “extremely” likely they would be cured, while 10% of their oncologists said the same.

Meanwhile, 97.6% of patients receiving intensive chemotherapy said it was “somewhat” or “extremely” likely they would be cured, and 42% of their oncologists said the same.

Overall, 77.8% of patients said they had not discussed their end-of-life wishes with their oncologists at 24 weeks.

“There were several very important factors we were not able to capture in our study, including what was actually discussed between patients and their oncologists and whether patients simply misunderstood or misheard the information conveyed to them,” Dr El-Jawahri said.

“Perhaps most importantly, we did not audio-record the discussions between the patients and their physicians, which could provide additional details regarding barriers to accurate prognostic understanding in these conversations.”

Related research and next steps

Prior to this study, Dr El-Jawahri and her colleagues had looked at similar perceptions in patients with solid tumor malignancies as well as in patients with hematologic malignancies who were receiving hematopoietic stem cell transplants.

The gaps in perception of treatment risk and cure for patients compared to their physicians were not as large in those cases as in the AML patients in this study. The investigators attribute this to higher levels of distress seen in AML patients due to the urgency of their treatment decisions.

Dr El-Jawahri and her colleagues have found that early consideration of palliative care in a treatment plan for patients with solid tumors improves patients’ understanding of the prognosis. The team hopes to implement a similar study in patients with AML.

“Clearly, there are important communication gaps between oncologists and their patients,” Dr El-Jawahri said. “We need to find ways to help physicians do a better job of communicating with their patients, especially in diseases like AML where stress levels are remarkably high.”

Photo by Rhoda Baer

SAN DIEGO—A study of acute myeloid leukemia (AML) patients has revealed misperceptions about treatment risks and the likelihood of cure.

Investigators surveyed 100 AML patients receiving intensive and non-intensive chemotherapy, as well as the patients’ oncologists.

The results showed that patients tended to overestimate both the risk of dying due to treatment and the likelihood of cure.

These findings were presented at the 2017 Palliative and Supportive Care in Oncology Symposium (abstract 43).

“Patients with AML face very challenging treatment decisions that are often placed upon them within days after being diagnosed,” said study investigator Areej El-Jawahri, MD, of Massachusetts General Hospital in Boston.

“Because they face a grave decision, they need to understand what the risks of treatment are versus the possibility of a cure.”

For this study, Dr El-Jawahri and her colleagues enrolled 50 patients who were receiving intensive care for AML (which usually meant hospitalization for 4 to 6 weeks) and 50 patients who were receiving non-intensive care (often given as outpatient treatment).

The patients’ median age was 71 (range, 60-100), and 92% were white. Six percent of patients had low-risk disease, 48% had intermediate-risk, and 46% had high-risk disease.

Within 3 days of starting treatment, both the patients and their physicians were given a questionnaire to assess how they perceived the likelihood of the patient dying from treatment.

One month later, patients and physicians completed a follow-up questionnaire to assess perceptions of patient prognosis. Within that time frame, most patients received laboratory results that more definitively established the type and stage of cancer.

At 24 weeks, the investigators asked patients if they had discussed their end-of-life wishes with their oncologists.

Results

Initially, most of the patient population (91.3%) thought it was “somewhat” or “extremely” likely they would die from their treatment. However, only 22% of treating oncologists said the same.

One month later, a majority of patients in both treatment groups thought it was “somewhat” or “extremely” likely they would be cured of their AML.

Specifically, 82.1% of patients receiving non-intensive chemotherapy said it was “somewhat” or “extremely” likely they would be cured, while 10% of their oncologists said the same.

Meanwhile, 97.6% of patients receiving intensive chemotherapy said it was “somewhat” or “extremely” likely they would be cured, and 42% of their oncologists said the same.

Overall, 77.8% of patients said they had not discussed their end-of-life wishes with their oncologists at 24 weeks.

“There were several very important factors we were not able to capture in our study, including what was actually discussed between patients and their oncologists and whether patients simply misunderstood or misheard the information conveyed to them,” Dr El-Jawahri said.

“Perhaps most importantly, we did not audio-record the discussions between the patients and their physicians, which could provide additional details regarding barriers to accurate prognostic understanding in these conversations.”

Related research and next steps

Prior to this study, Dr El-Jawahri and her colleagues had looked at similar perceptions in patients with solid tumor malignancies as well as in patients with hematologic malignancies who were receiving hematopoietic stem cell transplants.

The gaps in perception of treatment risk and cure for patients compared to their physicians were not as large in those cases as in the AML patients in this study. The investigators attribute this to higher levels of distress seen in AML patients due to the urgency of their treatment decisions.

Dr El-Jawahri and her colleagues have found that early consideration of palliative care in a treatment plan for patients with solid tumors improves patients’ understanding of the prognosis. The team hopes to implement a similar study in patients with AML.

“Clearly, there are important communication gaps between oncologists and their patients,” Dr El-Jawahri said. “We need to find ways to help physicians do a better job of communicating with their patients, especially in diseases like AML where stress levels are remarkably high.”

Micrograph showing MDS

The US Food and Drug Administration (FDA) has granted fast track designation to the telomerase inhibitor imetelstat.

The designation is for imetelstat as a potential treatment for adults who have transfusion-dependent anemia due to low or intermediate-1 risk myelodysplastic syndromes (MDS), do not have 5q deletion, and are refractory or resistant to treatment with an erythropoiesis-stimulating agent (ESA).

Imetelstat was initially developed by Geron Corporation and exclusively licensed to Janssen Biotech, Inc.

Janssen sponsored the application for fast track designation using preliminary data from IMerge, a trial in which researchers are studying transfusion-dependent patients with low- or intermediate-1 risk MDS who have relapsed after or are refractory to treatment with an ESA.

Part 1 of IMerge is a phase 2, single-arm trial. Part 2 is a phase 3, randomized, placebo-controlled trial.

Thirty-two patients have been enrolled in part 1 of IMerge. However, this part of the trial is expanding to enroll approximately 20 additional patients who do not have 5q deletion and are naïve to treatment with a hypomethylating agent and lenalidomide.

The expansion is based on results observed in a subset of the original 32 patients who had not received prior treatment with a hypomethylating agent or lenalidomide and did not have 5q deletion.

As of May 2017, this 13-patient subset showed an increased durability and rate of red blood cell transfusion-independence compared to the overall trial population.

Results in these patients and the rest of the original 32 patients are expected to be presented at an upcoming medical conference.

About fast track designation

The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.

Through the fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the new drug application or biologics license application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.

Micrograph showing MDS

The US Food and Drug Administration (FDA) has granted fast track designation to the telomerase inhibitor imetelstat.

The designation is for imetelstat as a potential treatment for adults who have transfusion-dependent anemia due to low or intermediate-1 risk myelodysplastic syndromes (MDS), do not have 5q deletion, and are refractory or resistant to treatment with an erythropoiesis-stimulating agent (ESA).

Imetelstat was initially developed by Geron Corporation and exclusively licensed to Janssen Biotech, Inc.

Janssen sponsored the application for fast track designation using preliminary data from IMerge, a trial in which researchers are studying transfusion-dependent patients with low- or intermediate-1 risk MDS who have relapsed after or are refractory to treatment with an ESA.

Part 1 of IMerge is a phase 2, single-arm trial. Part 2 is a phase 3, randomized, placebo-controlled trial.

Thirty-two patients have been enrolled in part 1 of IMerge. However, this part of the trial is expanding to enroll approximately 20 additional patients who do not have 5q deletion and are naïve to treatment with a hypomethylating agent and lenalidomide.

The expansion is based on results observed in a subset of the original 32 patients who had not received prior treatment with a hypomethylating agent or lenalidomide and did not have 5q deletion.

As of May 2017, this 13-patient subset showed an increased durability and rate of red blood cell transfusion-independence compared to the overall trial population.

Results in these patients and the rest of the original 32 patients are expected to be presented at an upcoming medical conference.

About fast track designation

The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.

Through the fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the new drug application or biologics license application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.

Micrograph showing MDS

The US Food and Drug Administration (FDA) has granted fast track designation to the telomerase inhibitor imetelstat.

The designation is for imetelstat as a potential treatment for adults who have transfusion-dependent anemia due to low or intermediate-1 risk myelodysplastic syndromes (MDS), do not have 5q deletion, and are refractory or resistant to treatment with an erythropoiesis-stimulating agent (ESA).

Imetelstat was initially developed by Geron Corporation and exclusively licensed to Janssen Biotech, Inc.

Janssen sponsored the application for fast track designation using preliminary data from IMerge, a trial in which researchers are studying transfusion-dependent patients with low- or intermediate-1 risk MDS who have relapsed after or are refractory to treatment with an ESA.

Part 1 of IMerge is a phase 2, single-arm trial. Part 2 is a phase 3, randomized, placebo-controlled trial.

Thirty-two patients have been enrolled in part 1 of IMerge. However, this part of the trial is expanding to enroll approximately 20 additional patients who do not have 5q deletion and are naïve to treatment with a hypomethylating agent and lenalidomide.

The expansion is based on results observed in a subset of the original 32 patients who had not received prior treatment with a hypomethylating agent or lenalidomide and did not have 5q deletion.

As of May 2017, this 13-patient subset showed an increased durability and rate of red blood cell transfusion-independence compared to the overall trial population.

Results in these patients and the rest of the original 32 patients are expected to be presented at an upcoming medical conference.

About fast track designation

The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.

Through the fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the new drug application or biologics license application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.

SILVER SPRING, MD. – Two Food and Drug Administration advisory panels have recommended approval of two new drug applications (NDA) for buprenorphine subcutaneous injections for the treatment of opioid dependence.

On Nov. 1, panelists recommended approval of some of the doses proposed in the NDA submitted by Braeburn Pharmaceuticals at the joint meeting of the Psychopharmacologic Drugs Advisory and the Drug Safety and Risk Management committees. The formulation, currently known as CAM2038, is intended to be used as part of a treatment plan that can include counseling and psychosocial support. The subcutaneous depot is available weekly, in 8-, 16-, 24-, and 32-mg injections, and monthly, in 64-, 96-, 128-, and 160-mg injections.

Courtesy Wikimedia Commons/FitzColinGerald/Creative Commons License

On the previous day, Oct. 31, the panelists voted 18-1 with no abstentions to recommend an NDA submitted by Indivior. This formulation is known as RBP-6000.

Both formulations must be administered by a health care provider using a prefilled syringe with a predetermined dosage. The injection forms a biodegradable subcutaneous depot that, as it degrades, releases buprenorphine at a steady and controlled pace over the course of treatment – increasing the success of treatment for opioid use disorder.

Braeburn’s NDA was based on results of a double-blind, randomized, within-subject, inpatient laboratory study of 47 patients over 14 days. Patients were randomized into two groups: 22 patients in the 24-mg group and 25 patients in the 32-mg group. Patients were administered an initial dose on day 0 and a follow-up dose on day 7. The results of the study found a complete blockade of opioids after the first injection that was sustained over the 1-week interdosing interval.

The committees said that of most of the doses should be approved, but a majority of committee members were uncomfortable with the higher doses.

Voting on Indivior’s NDA was based, in part, on the results of a randomized, double-blind, placebo-controlled, multicenter phase 3 study. The study lasted 24 weeks and randomly assigned 504 patients into one of three groups based on monthly dosing regimen of buprenorphine: 300 mg/300 mg, 300 mg/100 mg, and placebo. After randomization, the 300 mg/300 mg group had 201 patients, the 300 mg/100 mg group had 203 patients, and the placebo group had 100 patients. The study found that the primary and secondary endpoints were met, and significantly higher percentage of abstinence with subcutaneous buprenorphine were observed. Patients in both the 300 mg/300 mg and 300 mg/100 mg groups had very similar distributions of percentage of weeks patients abstained from opioid use with more than 20% of patients achieving 80%-100% abstinence from opioids during the course of the study, a significant improvement over the placebo group.

The panels’ recommendations come against the backdrop of the opioid epidemic in the United States, which President Trump has deemed a public health emergency. Many of the panel members and speakers at both meetings expressed support for the NDAs in that context and emphasized that, unlike sublingual administration of buprenorphine, these treatments do not require daily intervention. In addition, sublingual tablets are easier to abuse or more likely to lead to overdose because the patient must self-administer the medication. Expanding the toolkit of physicians who treat opioid use disorder might help stem the tide of the epidemic, some speakers said.

Usually, the FDA follows its advisory panels’ recommendations, which are not binding.

ilacy@frontlinemedcom.com

SILVER SPRING, MD. – Two Food and Drug Administration advisory panels have recommended approval of two new drug applications (NDA) for buprenorphine subcutaneous injections for the treatment of opioid dependence.

On Nov. 1, panelists recommended approval of some of the doses proposed in the NDA submitted by Braeburn Pharmaceuticals at the joint meeting of the Psychopharmacologic Drugs Advisory and the Drug Safety and Risk Management committees. The formulation, currently known as CAM2038, is intended to be used as part of a treatment plan that can include counseling and psychosocial support. The subcutaneous depot is available weekly, in 8-, 16-, 24-, and 32-mg injections, and monthly, in 64-, 96-, 128-, and 160-mg injections.

Courtesy Wikimedia Commons/FitzColinGerald/Creative Commons License

On the previous day, Oct. 31, the panelists voted 18-1 with no abstentions to recommend an NDA submitted by Indivior. This formulation is known as RBP-6000.

Both formulations must be administered by a health care provider using a prefilled syringe with a predetermined dosage. The injection forms a biodegradable subcutaneous depot that, as it degrades, releases buprenorphine at a steady and controlled pace over the course of treatment – increasing the success of treatment for opioid use disorder.

Braeburn’s NDA was based on results of a double-blind, randomized, within-subject, inpatient laboratory study of 47 patients over 14 days. Patients were randomized into two groups: 22 patients in the 24-mg group and 25 patients in the 32-mg group. Patients were administered an initial dose on day 0 and a follow-up dose on day 7. The results of the study found a complete blockade of opioids after the first injection that was sustained over the 1-week interdosing interval.

The committees said that of most of the doses should be approved, but a majority of committee members were uncomfortable with the higher doses.

Voting on Indivior’s NDA was based, in part, on the results of a randomized, double-blind, placebo-controlled, multicenter phase 3 study. The study lasted 24 weeks and randomly assigned 504 patients into one of three groups based on monthly dosing regimen of buprenorphine: 300 mg/300 mg, 300 mg/100 mg, and placebo. After randomization, the 300 mg/300 mg group had 201 patients, the 300 mg/100 mg group had 203 patients, and the placebo group had 100 patients. The study found that the primary and secondary endpoints were met, and significantly higher percentage of abstinence with subcutaneous buprenorphine were observed. Patients in both the 300 mg/300 mg and 300 mg/100 mg groups had very similar distributions of percentage of weeks patients abstained from opioid use with more than 20% of patients achieving 80%-100% abstinence from opioids during the course of the study, a significant improvement over the placebo group.

The panels’ recommendations come against the backdrop of the opioid epidemic in the United States, which President Trump has deemed a public health emergency. Many of the panel members and speakers at both meetings expressed support for the NDAs in that context and emphasized that, unlike sublingual administration of buprenorphine, these treatments do not require daily intervention. In addition, sublingual tablets are easier to abuse or more likely to lead to overdose because the patient must self-administer the medication. Expanding the toolkit of physicians who treat opioid use disorder might help stem the tide of the epidemic, some speakers said.

Usually, the FDA follows its advisory panels’ recommendations, which are not binding.

ilacy@frontlinemedcom.com

SILVER SPRING, MD. – Two Food and Drug Administration advisory panels have recommended approval of two new drug applications (NDA) for buprenorphine subcutaneous injections for the treatment of opioid dependence.

On Nov. 1, panelists recommended approval of some of the doses proposed in the NDA submitted by Braeburn Pharmaceuticals at the joint meeting of the Psychopharmacologic Drugs Advisory and the Drug Safety and Risk Management committees. The formulation, currently known as CAM2038, is intended to be used as part of a treatment plan that can include counseling and psychosocial support. The subcutaneous depot is available weekly, in 8-, 16-, 24-, and 32-mg injections, and monthly, in 64-, 96-, 128-, and 160-mg injections.

Courtesy Wikimedia Commons/FitzColinGerald/Creative Commons License

On the previous day, Oct. 31, the panelists voted 18-1 with no abstentions to recommend an NDA submitted by Indivior. This formulation is known as RBP-6000.

Both formulations must be administered by a health care provider using a prefilled syringe with a predetermined dosage. The injection forms a biodegradable subcutaneous depot that, as it degrades, releases buprenorphine at a steady and controlled pace over the course of treatment – increasing the success of treatment for opioid use disorder.

Braeburn’s NDA was based on results of a double-blind, randomized, within-subject, inpatient laboratory study of 47 patients over 14 days. Patients were randomized into two groups: 22 patients in the 24-mg group and 25 patients in the 32-mg group. Patients were administered an initial dose on day 0 and a follow-up dose on day 7. The results of the study found a complete blockade of opioids after the first injection that was sustained over the 1-week interdosing interval.

The committees said that of most of the doses should be approved, but a majority of committee members were uncomfortable with the higher doses.

Voting on Indivior’s NDA was based, in part, on the results of a randomized, double-blind, placebo-controlled, multicenter phase 3 study. The study lasted 24 weeks and randomly assigned 504 patients into one of three groups based on monthly dosing regimen of buprenorphine: 300 mg/300 mg, 300 mg/100 mg, and placebo. After randomization, the 300 mg/300 mg group had 201 patients, the 300 mg/100 mg group had 203 patients, and the placebo group had 100 patients. The study found that the primary and secondary endpoints were met, and significantly higher percentage of abstinence with subcutaneous buprenorphine were observed. Patients in both the 300 mg/300 mg and 300 mg/100 mg groups had very similar distributions of percentage of weeks patients abstained from opioid use with more than 20% of patients achieving 80%-100% abstinence from opioids during the course of the study, a significant improvement over the placebo group.

The panels’ recommendations come against the backdrop of the opioid epidemic in the United States, which President Trump has deemed a public health emergency. Many of the panel members and speakers at both meetings expressed support for the NDAs in that context and emphasized that, unlike sublingual administration of buprenorphine, these treatments do not require daily intervention. In addition, sublingual tablets are easier to abuse or more likely to lead to overdose because the patient must self-administer the medication. Expanding the toolkit of physicians who treat opioid use disorder might help stem the tide of the epidemic, some speakers said.

Usually, the FDA follows its advisory panels’ recommendations, which are not binding.

ilacy@frontlinemedcom.com

A U.S. District Judge has ordered Philips North America, as well as two Philips officers, to cease manufacturing and distribution of automatic external defibrillators (AEDs) until they can comply with federal regulations in a consent decree, according to a statement from the Food and Drug Administration.

In a complaint filed with the decree, Philips North America in Andover, Mass., which operates as Philips Medical Systems and Philips Healthcare, sold compromised automatic external defibrillators and Q-CPR Meters in violation of current Federal Food, Drug and Cosmetic (FD&C) Act good manufacturing practice requirements. The injunction also applies to Carla Kriwet and Ojas Buch of the Patient Care and Monitoring Solutions business group, according to the statement.

lfranki@frontlinemedcom.com

A U.S. District Judge has ordered Philips North America, as well as two Philips officers, to cease manufacturing and distribution of automatic external defibrillators (AEDs) until they can comply with federal regulations in a consent decree, according to a statement from the Food and Drug Administration.

In a complaint filed with the decree, Philips North America in Andover, Mass., which operates as Philips Medical Systems and Philips Healthcare, sold compromised automatic external defibrillators and Q-CPR Meters in violation of current Federal Food, Drug and Cosmetic (FD&C) Act good manufacturing practice requirements. The injunction also applies to Carla Kriwet and Ojas Buch of the Patient Care and Monitoring Solutions business group, according to the statement.

lfranki@frontlinemedcom.com

A U.S. District Judge has ordered Philips North America, as well as two Philips officers, to cease manufacturing and distribution of automatic external defibrillators (AEDs) until they can comply with federal regulations in a consent decree, according to a statement from the Food and Drug Administration.

In a complaint filed with the decree, Philips North America in Andover, Mass., which operates as Philips Medical Systems and Philips Healthcare, sold compromised automatic external defibrillators and Q-CPR Meters in violation of current Federal Food, Drug and Cosmetic (FD&C) Act good manufacturing practice requirements. The injunction also applies to Carla Kriwet and Ojas Buch of the Patient Care and Monitoring Solutions business group, according to the statement.

lfranki@frontlinemedcom.com

WASHINGTON – A DNA vaccine developed at the National Institute of Allergy and Infectious Diseases Vaccine Research Center – one of five National Institutes of Health Zika vaccine candidates – has entered phase 2 testing in a trial underway in Brazil, Peru, Ecuador, Mexico, and Texas.

“The DNA vaccine is a simple 21st century way of developing vaccines that I think will become one of the major [methods of the future] for emerging infections, as opposed to growing a virus and inactivating or attenuating it,” Anthony S. Fauci, MD, said at the biennial meeting of the Diabetes in Pregnancy Study Group of North America. With Zika “this is the vaccine that is ahead of all the others.”

Sexual transmission

The Zika virus is part of a “long line of arboviruses that have threatened us in the Americas,” but infection with the organism is “the first – and may be the only – arthropod-borne or mosquito-borne infection that is also sexually transmitted,” Dr. Fauci said.

Sexual contact as an important mode of viral transmission “has been documented very clearly through a number of studies in which individuals clearly had no exposure to mosquitoes but were in fact a sexual partner of someone who got infected,” he said. And recent research suggests that the “female reproductive tract is a preferentially permissive site for Zika replication, which adds to the concern about sexual transmission.”

He cited a study published in July 2017 in PLOS Pathogens in which the Zika virus was found to preferentially replicate in the reproductive tract of female rhesus macaques who received vaginal inoculations of the virus.

Zika virus was “detected in the reproductive tract before it was detected in plasma, and replication levels in the reproductive tract did not reflect viral levels in other parts of the body,” according to the author summary. The kinetics of virus replication and dissemination after intravaginal inoculation were markedly different from what was previously seen in macaques infected with the Zika virus by subcutaneous infection, the report noted (PLOS Pathogens 13[7]:e1006537).

Dr. Fauci briefly described this and several other studies and findings that he said exemplify growing knowledge of the infection. He pointed to a prospective observational study that documents episodes of oligospermia in 15 men who presented with infection in 2016 in the French Caribbean (Lancet Infect Dis. 2017;17:1200-08).

Sperm counts fell in some of the study participants by about 50% between days 7 and 60 post infection, and the counts “recovered somewhat” by day 120. “We’re still following patients in prospective studies to determine if there’s a long-term effect in men,” he said.

In the meantime, he said, research in mice has shown that “without a doubt, Zika infection damages the testes,” Dr. Fauci said, noting that the mouse model is proving to be a good model for studying Zika’s effects. “They become oligospermic and have testicular atrophy.”
 

Maternal-fetal transmission

Regarding maternal-fetal transmission, there’s evidence that placental trophoblasts “are exquisitely permissive for Zika virus replication,” he said.

In another recent study, primary human placental trophoblasts from nonexposed donors were found to be infected by the Zika virus ex-vivo and permissive for viral RNA replication, compared with dengue virus, a fellow flavivirus (Sci Rep. 2017;7:41389. doi: 10.1038/srep41389).

However, Yoel Sadovsky, MD, who also presented at the meeting, explained that his lab’s ex-vivo studies show that primary human trophoblasts have inherent resistance to a number of viruses – and that trophoblasts are refractory to direct infection with the Zika virus. “We don’t think the trophoblasts are very permissive at all,” he said.

Moreover, trophoblasts appear to confer their antiviral effects to other nontrophoblast cells by releasing a particular type of interferon – type III interferon IFN1 – and by delivering certain micro-RNAs (C19MC miRNAs) that are packaged within trophoblast-derived nanovesicles called exosomes, said Dr. Sadovsky, scientific director of the Magee-Womens Research Institute and professor of ob.gyn., reproductive sciences, microbiology, and molecular genetics at the University of Pittsburgh.
 

WASHINGTON – A DNA vaccine developed at the National Institute of Allergy and Infectious Diseases Vaccine Research Center – one of five National Institutes of Health Zika vaccine candidates – has entered phase 2 testing in a trial underway in Brazil, Peru, Ecuador, Mexico, and Texas.

“The DNA vaccine is a simple 21st century way of developing vaccines that I think will become one of the major [methods of the future] for emerging infections, as opposed to growing a virus and inactivating or attenuating it,” Anthony S. Fauci, MD, said at the biennial meeting of the Diabetes in Pregnancy Study Group of North America. With Zika “this is the vaccine that is ahead of all the others.”

Sexual transmission

The Zika virus is part of a “long line of arboviruses that have threatened us in the Americas,” but infection with the organism is “the first – and may be the only – arthropod-borne or mosquito-borne infection that is also sexually transmitted,” Dr. Fauci said.

Sexual contact as an important mode of viral transmission “has been documented very clearly through a number of studies in which individuals clearly had no exposure to mosquitoes but were in fact a sexual partner of someone who got infected,” he said. And recent research suggests that the “female reproductive tract is a preferentially permissive site for Zika replication, which adds to the concern about sexual transmission.”

He cited a study published in July 2017 in PLOS Pathogens in which the Zika virus was found to preferentially replicate in the reproductive tract of female rhesus macaques who received vaginal inoculations of the virus.

Zika virus was “detected in the reproductive tract before it was detected in plasma, and replication levels in the reproductive tract did not reflect viral levels in other parts of the body,” according to the author summary. The kinetics of virus replication and dissemination after intravaginal inoculation were markedly different from what was previously seen in macaques infected with the Zika virus by subcutaneous infection, the report noted (PLOS Pathogens 13[7]:e1006537).

Dr. Fauci briefly described this and several other studies and findings that he said exemplify growing knowledge of the infection. He pointed to a prospective observational study that documents episodes of oligospermia in 15 men who presented with infection in 2016 in the French Caribbean (Lancet Infect Dis. 2017;17:1200-08).

Sperm counts fell in some of the study participants by about 50% between days 7 and 60 post infection, and the counts “recovered somewhat” by day 120. “We’re still following patients in prospective studies to determine if there’s a long-term effect in men,” he said.

In the meantime, he said, research in mice has shown that “without a doubt, Zika infection damages the testes,” Dr. Fauci said, noting that the mouse model is proving to be a good model for studying Zika’s effects. “They become oligospermic and have testicular atrophy.”
 

Maternal-fetal transmission

Regarding maternal-fetal transmission, there’s evidence that placental trophoblasts “are exquisitely permissive for Zika virus replication,” he said.

In another recent study, primary human placental trophoblasts from nonexposed donors were found to be infected by the Zika virus ex-vivo and permissive for viral RNA replication, compared with dengue virus, a fellow flavivirus (Sci Rep. 2017;7:41389. doi: 10.1038/srep41389).

However, Yoel Sadovsky, MD, who also presented at the meeting, explained that his lab’s ex-vivo studies show that primary human trophoblasts have inherent resistance to a number of viruses – and that trophoblasts are refractory to direct infection with the Zika virus. “We don’t think the trophoblasts are very permissive at all,” he said.

Moreover, trophoblasts appear to confer their antiviral effects to other nontrophoblast cells by releasing a particular type of interferon – type III interferon IFN1 – and by delivering certain micro-RNAs (C19MC miRNAs) that are packaged within trophoblast-derived nanovesicles called exosomes, said Dr. Sadovsky, scientific director of the Magee-Womens Research Institute and professor of ob.gyn., reproductive sciences, microbiology, and molecular genetics at the University of Pittsburgh.
 

WASHINGTON – A DNA vaccine developed at the National Institute of Allergy and Infectious Diseases Vaccine Research Center – one of five National Institutes of Health Zika vaccine candidates – has entered phase 2 testing in a trial underway in Brazil, Peru, Ecuador, Mexico, and Texas.

“The DNA vaccine is a simple 21st century way of developing vaccines that I think will become one of the major [methods of the future] for emerging infections, as opposed to growing a virus and inactivating or attenuating it,” Anthony S. Fauci, MD, said at the biennial meeting of the Diabetes in Pregnancy Study Group of North America. With Zika “this is the vaccine that is ahead of all the others.”

Sexual transmission

The Zika virus is part of a “long line of arboviruses that have threatened us in the Americas,” but infection with the organism is “the first – and may be the only – arthropod-borne or mosquito-borne infection that is also sexually transmitted,” Dr. Fauci said.

Sexual contact as an important mode of viral transmission “has been documented very clearly through a number of studies in which individuals clearly had no exposure to mosquitoes but were in fact a sexual partner of someone who got infected,” he said. And recent research suggests that the “female reproductive tract is a preferentially permissive site for Zika replication, which adds to the concern about sexual transmission.”

He cited a study published in July 2017 in PLOS Pathogens in which the Zika virus was found to preferentially replicate in the reproductive tract of female rhesus macaques who received vaginal inoculations of the virus.

Zika virus was “detected in the reproductive tract before it was detected in plasma, and replication levels in the reproductive tract did not reflect viral levels in other parts of the body,” according to the author summary. The kinetics of virus replication and dissemination after intravaginal inoculation were markedly different from what was previously seen in macaques infected with the Zika virus by subcutaneous infection, the report noted (PLOS Pathogens 13[7]:e1006537).

Dr. Fauci briefly described this and several other studies and findings that he said exemplify growing knowledge of the infection. He pointed to a prospective observational study that documents episodes of oligospermia in 15 men who presented with infection in 2016 in the French Caribbean (Lancet Infect Dis. 2017;17:1200-08).

Sperm counts fell in some of the study participants by about 50% between days 7 and 60 post infection, and the counts “recovered somewhat” by day 120. “We’re still following patients in prospective studies to determine if there’s a long-term effect in men,” he said.

In the meantime, he said, research in mice has shown that “without a doubt, Zika infection damages the testes,” Dr. Fauci said, noting that the mouse model is proving to be a good model for studying Zika’s effects. “They become oligospermic and have testicular atrophy.”
 

Maternal-fetal transmission

Regarding maternal-fetal transmission, there’s evidence that placental trophoblasts “are exquisitely permissive for Zika virus replication,” he said.

In another recent study, primary human placental trophoblasts from nonexposed donors were found to be infected by the Zika virus ex-vivo and permissive for viral RNA replication, compared with dengue virus, a fellow flavivirus (Sci Rep. 2017;7:41389. doi: 10.1038/srep41389).

However, Yoel Sadovsky, MD, who also presented at the meeting, explained that his lab’s ex-vivo studies show that primary human trophoblasts have inherent resistance to a number of viruses – and that trophoblasts are refractory to direct infection with the Zika virus. “We don’t think the trophoblasts are very permissive at all,” he said.

Moreover, trophoblasts appear to confer their antiviral effects to other nontrophoblast cells by releasing a particular type of interferon – type III interferon IFN1 – and by delivering certain micro-RNAs (C19MC miRNAs) that are packaged within trophoblast-derived nanovesicles called exosomes, said Dr. Sadovsky, scientific director of the Magee-Womens Research Institute and professor of ob.gyn., reproductive sciences, microbiology, and molecular genetics at the University of Pittsburgh.