Skin cancer is an important public health issue in the United States, as 1 in 5 Americans are projected to develop a cutaneous malignancy during their lifetime. Currently, 75% of all skin cancer–related deaths are due to malignant melanomas (MMs), though melanomas account for less than 5% of all skin cancers.¹ Early detection of MM is essential, as prognosis depends on tumor stage, particularly the depth of the melanoma.^2-4 In general, patients with thin, early-stage melanomas have a more than 96% survival rate, which drops to 14% in late-stage disease.^5,6 Five percent to 30% of all melanomas are identified incidentally on total-body skin examinations (TBSEs) performed by a trained provider and thus would not have been caught with only a focused skin examination or patient self-examination.^7,8 Nonetheless, the clinical utility of skin cancer screening with TBSEs remains controversial, largely due to the poor quality of data available to establish a notable mortality benefit from skin cancer screening. As a result, obtaining endorsement from the larger medical community, federal government, and health insurance industry to include routine TBSEs as part of a preventive care health care strategy has not occurred. The absence of definitive clinical care guidelines mandating routine TBSEs is one of the greatest barriers preventing access to appropriate dermatologic screening along with the paucity of trained providers; however, standardized total-body photography (TBP) promises to provide a way forward by lowering the costs of dermatologic screening while simultaneously leveraging technology to increase availability.

Impact on Biopsy Efficiency

Current US Preventive Services Task Force (USPSTF) guidelines state that evidence is insufficient to assess the balance of benefits and harms of visual skin examination by a clinician to screen for skin cancer in adults. The USPSTF noted that “[d]irect evidence on the effectiveness of screening in reducing melanoma morbidity and mortality is limited to a single fair-quality ecologic study with important methodological limitations” (ie, the Skin Cancer Research to Provide Evidence for Effectiveness of Screening in Northern Germany [SCREEN] study), and although information on harm is similarly sparse, “[t]he potential for harm clearly exists, including a high rate of unnecessary biopsies, possibly resulting in cosmetic or, more rarely, functional adverse effects, and the risk of overdiagnosis and overtreatment.”⁹ The majority of suspicious skin lesions excised during screenings are not cancerous. For example, the SCREEN study found that 20 to 55 excisions were performed to detect 1 case of melanoma.¹⁰ At that rate, the USPSTF also noted that approximately 4000 excisions would be required to prevent a single death from melanoma.⁹ Following the lead of the USPSTF, the Patient Protection and Affordable Care Act did not mandate that skin examinations be included as essential preventive coverage in its requirements for insurance coverage of primary care prevention. As such, dermatologists face financial pressure to avoid performing time-consuming TBSEs, regardless of their perceived utility.¹¹

As the USPSTF points out, the value of TBSEs relies on the examiner’s ability to correctly identify malignant lesions and minimize biopsies of benign lesions, a concept known as biopsy efficiency.⁹ Secondarily, a TBSE is time consuming, and the time required for a dermatologist to complete a TBSE given the high rate of benign findings may not be financially viable. We argue that the routine use of total-body skin imaging may offer a way forward in addressing these issues. Total-body photography involves a photographic system that can allow dermatologists to acquire standardized images that can be used for primary diagnosis and to track individual lesions over time. Nonmedical personnel and medical assistants can be easily trained to use standardized photography devices to quickly obtain high-quality clinical images, thereby greatly reducing the time and cost of obtaining these images. Studies have found that the use of photographic monitoring may improve biopsy efficiency.^12-15 A recent study by Truong et al¹⁶ found that TBP used to monitor all existing melanocytic lesions on patients substantially reduced the number of biopsies that patients required. These results reflect that most nevi, including clinically atypical nevi, are usually stable and unlikely to exhibit suspicious changes over time.^17,18 For this reason, the use of TBP could minimize unnecessary biopsies because clinically suspicious but stable nevi can be objectively documented and followed over time.

Standardized TBP also offers the ability for dermatologists to work synergistically with modern computer technology involving algorithms capable of analyzing high-quality images to autodiagnose or flag concerning lesions that may require biopsy. Esteva et al¹⁹ described their development of a deep learning algorithm that relies on a convolutional neural network (CNN). This CNN was trained to identify melanomas using a large data set of clinical dermatologic images and subsequently was able to distinguish MMs from benign nevi at a rate on par with a board-certified dermatologist.¹⁹ Widespread use of total-body imaging would create an enormous database of high-resolution images that would be ideally suited to the development of such computerized algorithms, which could then be applied to future images by way of artificial intelligence. Convolutional neural networks that use a single patient’s imaging over time could be developed to assess the change in number or size of benign nevi and identify lesions that are concerning for MM while simultaneously comparing them to a population-based data set.

On a large scale, such a capability would minimize the inefficiency and subjectivity of TBSEs as a tool for identifying malignancy. Currently, dermatologists are only able to track and document a few concerning lesions on a patient’s body, rendering the choice of which lesions require biopsy more subjective. Total-body photography, particularly if used with an algorithm capable of quickly analyzing all the nevi on a person’s body, largely eliminates such subjectivity by creating a standardized set of images that can be tracked over time and flagging concerning lesions prior to the dermatologist examining the patient. In this way, the specialty of dermatology could achieve the same model of objective evaluation of standardized clinical images as those employed in radiology, cardiology, and other clinical disciplines. The additional benefit of such a system would be lower costs, as the images could be acquired by nonmedical personnel and then undergo initial assessment by an algorithm, which would flag concerning lesions, similar to a modern electrocardiogram machine, allowing the dermatologist to use his/her time more efficiently by only focusing on concerning lesions with the confidence that the patient’s entire body has already been rigorously screened.

By using TBP to improve biopsy efficiency and the objectivity of the TBSE as a tool to detect skin cancer, we propose that the benefit-to-harm ratio of the TBSE would remarkably improve. Ultimately, this type of screening would meet the strict requirements to be included in preventive health care strategies and thereby improve access to dermatologic care.

The Use of TBP in the Military

Total-body photography has several specific applications in the military. Standardized imaging has the potential to improve dermatologic care for active-duty soldiers across space and time. First, a large percentage of deployment medical care is devoted to dermatologic issues. From 2008 to 2015, 5% of all medical encounters in the combat theaters of Iraq and Afghanistan involved dermatologic concerns.²⁰ Access to appropriate dermatologic care in a combat theater is important, as poorly controlled dermatologic conditions (eg, psoriasis, eczema) often require evacuation when left untreated. Although current TBP systems may not be portable or durable enough to survive in an austere deployment environment, we propose it would be feasible to have skin imaging booths at larger forward operating bases. The images could then be transported to a remote dermatologist to assess and recommend treatment. The expense of transporting and maintaining the imaging system in country would be offset by the expenses spared by not requiring a dermatologist in country and the reductions in costly medical evacuations from theater.

Although the US military population is younger and generally healthier than the general adult population due to extensive medical screening on admission, age limitations for active-duty service, a mandated active lifestyle, and access to good health care, there are still a substantial number of service members diagnosed with skin cancer each year.²¹ From 2005 through 2014, MM was the most common non–gender-specific cancer (n=1571); in men, only testicular cancer was more prevalent (1591 vs 1298 cases), and in women, only breast cancer was more prevalent (773 vs 273 cases). Furthermore, from 2004 to 2013, the incidence rates of melanoma have increased by 1.4%, while with other cancer rates have declined during the same time period.²¹ Thus, TBP as a screening modality across the military population is a promising method for improving detection of skin cancer and reducing morbidity and mortality.

Military medicine often is on the forefront of medical advances in technology, disease understanding, and clinical care due to the unique resources available in the military health care system, which allow investigators the ability to obtain vast amounts of epidemiologic data.²² The military health care system also is unique in its ability to mandate that its members obtain preventive health services. Thus, it would be possible for the military to mandate TBP at accession and retirement, for instance, or more frequently for annual screening. The implementation of such a program would improve the health of the military population and be a public health service by pioneering the use of a standardized TBP system across a large health care system to improve skin cancer detection.

Current Studies in the Military

The Dermatology Service at the Walter Reed National Military Medical Center (WRNMMC)(Bethesda, Maryland) is evaluating the use of a total-body digital skin imaging system under a grant from the Telemedicine and Advanced Technology Research Center of the US Army. The system in use was found to be particularly well suited for military dermatology because it offers standardized TBP processing, produces a report that can be uploaded to the US Department of Defense (DoD) electronic medical record system, and requires relatively brief training for ancillary personnel to operate. Regardless of the platform the DoD ultimately finds most suitable, it is critical that a standard exist for TBP to ensure that uniform data sets are generated to allow military and other DoD dermatologists as well as civilian health care providers to share clinical information. The goal of the current study at WRNMMC is to vet TBP platforms at WRNMMC so the military can then develop standards to procure additional platforms for placement throughout the Military Health System, Military Entrance Processing Stations, operational environments, and collaborating health care systems (eg, the Veterans Health Administration).

Once deployed broadly across the Military Health System, these TBP platforms would be part of a network of telehealth care. For acute dermatologic issues, diagnoses provided via teledermatology platforms can then be managed by health care providers utilizing appropriate clinical practice guidelines or by non–health care providers utilizing general medical knowledge databases. Such a system with TBP information collected at multiple access points across a service member’s career would build a repository of data that would be immensely useful to patients and to clinical research. Of particular interest to military researchers is that TBP data could be used to study which patients require in-person examinations or more careful monitoring; the proper intervals for skin cancer screening; and the assessment of the benefits of TBP in improving morbidity, mortality, and biopsy efficiency in the detection of MM as well as nonmelanoma skin cancers.

Limitations to Progress

Currently, there are multiple limitations to the implementation of TBP as a part of TBSE screening. First, the potential improvement in biopsy efficiency using TBP is predicated on its ability to prove nevi stability over time, but in younger populations, benign nevi are more likely to change or increase in number, which may reduce the biopsy efficiency of screening in a younger population, thereby negating some of the benefit of imaging and CNN assessment. For instance, Truong et al¹⁶ found that younger age (<30 years) did not show the same improvement in biopsy efficiency with the use of TBP, which the authors theorized may reflect “the dynamic nature of nevi in younger patients” that has been documented in other studies.^23,24 Approximately 65% of the active-duty military population is aged 18 to 30 years, and 98% of accessions to active duty occur in individuals aged 17 to 30 years.²⁵ As such, TBP may not improve biopsy efficiency in the active-duty military population as dramatically as it would across the general population.

A second limitation of the use of TBP in the active-duty military population is the ethics of implementing DoD-wide mandatory TBP. Although the TBP platform will be compliant with the Health Insurance Portability and Accountability Act, mandating that soldiers contribute their TBP to a repository of data that will then be used for research without explicitly requesting their consent is ethically problematic; however, since the 1950s, the DoD has collected serum samples from its service members for force protection and operations reasons as well as for the purpose of research.^22,26 Currently, the DoD Serum Repository collects serum samples as part of a mandatory human immunodeficiency virus screening program that evaluates service members every 2 years; this repository of human serum samples is accessible for research purposes without the consent of the individuals being studied.²⁷ These individuals are not informed of potential use of their serum specimens for research purposes and no consent forms or opt-out options are provided. Thus, although there is precedent in the DoD for such mass data collection, it is an ongoing ethical consideration.²⁸

RELATED ARTICLE: Gigapixel Photography for Skin Cancer Surveillance

Finally, although the potential use of TBP and computer algorithms to improve the efficiency and affordability of TBSEs is exciting, there are no existing computer algorithms that we are aware of that can be used with existing TBP platforms in the manner we proposed. However, we feel that computer algorithms, such as the one created by Esteva et al,¹⁹ are just the beginning and that the use of artificial intelligence is not far off. Even after the creation of a TBP-compatible algorithm adept at analyzing malignant lesions, however, this technology would need to be further evaluated in the clinical setting to determine its capability and practicality. Current TBP platforms also are limited by their large size, cost, and complexity. As TBP platforms improve, it is likely that more streamlined and less expensive versions of current models will greatly enhance the field of teledermatology, particularly in the military setting.

Skin cancer is an important public health issue in the United States, as 1 in 5 Americans are projected to develop a cutaneous malignancy during their lifetime. Currently, 75% of all skin cancer–related deaths are due to malignant melanomas (MMs), though melanomas account for less than 5% of all skin cancers.¹ Early detection of MM is essential, as prognosis depends on tumor stage, particularly the depth of the melanoma.^2-4 In general, patients with thin, early-stage melanomas have a more than 96% survival rate, which drops to 14% in late-stage disease.^5,6 Five percent to 30% of all melanomas are identified incidentally on total-body skin examinations (TBSEs) performed by a trained provider and thus would not have been caught with only a focused skin examination or patient self-examination.^7,8 Nonetheless, the clinical utility of skin cancer screening with TBSEs remains controversial, largely due to the poor quality of data available to establish a notable mortality benefit from skin cancer screening. As a result, obtaining endorsement from the larger medical community, federal government, and health insurance industry to include routine TBSEs as part of a preventive care health care strategy has not occurred. The absence of definitive clinical care guidelines mandating routine TBSEs is one of the greatest barriers preventing access to appropriate dermatologic screening along with the paucity of trained providers; however, standardized total-body photography (TBP) promises to provide a way forward by lowering the costs of dermatologic screening while simultaneously leveraging technology to increase availability.

Impact on Biopsy Efficiency

Current US Preventive Services Task Force (USPSTF) guidelines state that evidence is insufficient to assess the balance of benefits and harms of visual skin examination by a clinician to screen for skin cancer in adults. The USPSTF noted that “[d]irect evidence on the effectiveness of screening in reducing melanoma morbidity and mortality is limited to a single fair-quality ecologic study with important methodological limitations” (ie, the Skin Cancer Research to Provide Evidence for Effectiveness of Screening in Northern Germany [SCREEN] study), and although information on harm is similarly sparse, “[t]he potential for harm clearly exists, including a high rate of unnecessary biopsies, possibly resulting in cosmetic or, more rarely, functional adverse effects, and the risk of overdiagnosis and overtreatment.”⁹ The majority of suspicious skin lesions excised during screenings are not cancerous. For example, the SCREEN study found that 20 to 55 excisions were performed to detect 1 case of melanoma.¹⁰ At that rate, the USPSTF also noted that approximately 4000 excisions would be required to prevent a single death from melanoma.⁹ Following the lead of the USPSTF, the Patient Protection and Affordable Care Act did not mandate that skin examinations be included as essential preventive coverage in its requirements for insurance coverage of primary care prevention. As such, dermatologists face financial pressure to avoid performing time-consuming TBSEs, regardless of their perceived utility.¹¹

As the USPSTF points out, the value of TBSEs relies on the examiner’s ability to correctly identify malignant lesions and minimize biopsies of benign lesions, a concept known as biopsy efficiency.⁹ Secondarily, a TBSE is time consuming, and the time required for a dermatologist to complete a TBSE given the high rate of benign findings may not be financially viable. We argue that the routine use of total-body skin imaging may offer a way forward in addressing these issues. Total-body photography involves a photographic system that can allow dermatologists to acquire standardized images that can be used for primary diagnosis and to track individual lesions over time. Nonmedical personnel and medical assistants can be easily trained to use standardized photography devices to quickly obtain high-quality clinical images, thereby greatly reducing the time and cost of obtaining these images. Studies have found that the use of photographic monitoring may improve biopsy efficiency.^12-15 A recent study by Truong et al¹⁶ found that TBP used to monitor all existing melanocytic lesions on patients substantially reduced the number of biopsies that patients required. These results reflect that most nevi, including clinically atypical nevi, are usually stable and unlikely to exhibit suspicious changes over time.^17,18 For this reason, the use of TBP could minimize unnecessary biopsies because clinically suspicious but stable nevi can be objectively documented and followed over time.

Standardized TBP also offers the ability for dermatologists to work synergistically with modern computer technology involving algorithms capable of analyzing high-quality images to autodiagnose or flag concerning lesions that may require biopsy. Esteva et al¹⁹ described their development of a deep learning algorithm that relies on a convolutional neural network (CNN). This CNN was trained to identify melanomas using a large data set of clinical dermatologic images and subsequently was able to distinguish MMs from benign nevi at a rate on par with a board-certified dermatologist.¹⁹ Widespread use of total-body imaging would create an enormous database of high-resolution images that would be ideally suited to the development of such computerized algorithms, which could then be applied to future images by way of artificial intelligence. Convolutional neural networks that use a single patient’s imaging over time could be developed to assess the change in number or size of benign nevi and identify lesions that are concerning for MM while simultaneously comparing them to a population-based data set.

On a large scale, such a capability would minimize the inefficiency and subjectivity of TBSEs as a tool for identifying malignancy. Currently, dermatologists are only able to track and document a few concerning lesions on a patient’s body, rendering the choice of which lesions require biopsy more subjective. Total-body photography, particularly if used with an algorithm capable of quickly analyzing all the nevi on a person’s body, largely eliminates such subjectivity by creating a standardized set of images that can be tracked over time and flagging concerning lesions prior to the dermatologist examining the patient. In this way, the specialty of dermatology could achieve the same model of objective evaluation of standardized clinical images as those employed in radiology, cardiology, and other clinical disciplines. The additional benefit of such a system would be lower costs, as the images could be acquired by nonmedical personnel and then undergo initial assessment by an algorithm, which would flag concerning lesions, similar to a modern electrocardiogram machine, allowing the dermatologist to use his/her time more efficiently by only focusing on concerning lesions with the confidence that the patient’s entire body has already been rigorously screened.

By using TBP to improve biopsy efficiency and the objectivity of the TBSE as a tool to detect skin cancer, we propose that the benefit-to-harm ratio of the TBSE would remarkably improve. Ultimately, this type of screening would meet the strict requirements to be included in preventive health care strategies and thereby improve access to dermatologic care.

The Use of TBP in the Military

Total-body photography has several specific applications in the military. Standardized imaging has the potential to improve dermatologic care for active-duty soldiers across space and time. First, a large percentage of deployment medical care is devoted to dermatologic issues. From 2008 to 2015, 5% of all medical encounters in the combat theaters of Iraq and Afghanistan involved dermatologic concerns.²⁰ Access to appropriate dermatologic care in a combat theater is important, as poorly controlled dermatologic conditions (eg, psoriasis, eczema) often require evacuation when left untreated. Although current TBP systems may not be portable or durable enough to survive in an austere deployment environment, we propose it would be feasible to have skin imaging booths at larger forward operating bases. The images could then be transported to a remote dermatologist to assess and recommend treatment. The expense of transporting and maintaining the imaging system in country would be offset by the expenses spared by not requiring a dermatologist in country and the reductions in costly medical evacuations from theater.

Although the US military population is younger and generally healthier than the general adult population due to extensive medical screening on admission, age limitations for active-duty service, a mandated active lifestyle, and access to good health care, there are still a substantial number of service members diagnosed with skin cancer each year.²¹ From 2005 through 2014, MM was the most common non–gender-specific cancer (n=1571); in men, only testicular cancer was more prevalent (1591 vs 1298 cases), and in women, only breast cancer was more prevalent (773 vs 273 cases). Furthermore, from 2004 to 2013, the incidence rates of melanoma have increased by 1.4%, while with other cancer rates have declined during the same time period.²¹ Thus, TBP as a screening modality across the military population is a promising method for improving detection of skin cancer and reducing morbidity and mortality.

Military medicine often is on the forefront of medical advances in technology, disease understanding, and clinical care due to the unique resources available in the military health care system, which allow investigators the ability to obtain vast amounts of epidemiologic data.²² The military health care system also is unique in its ability to mandate that its members obtain preventive health services. Thus, it would be possible for the military to mandate TBP at accession and retirement, for instance, or more frequently for annual screening. The implementation of such a program would improve the health of the military population and be a public health service by pioneering the use of a standardized TBP system across a large health care system to improve skin cancer detection.

Current Studies in the Military

The Dermatology Service at the Walter Reed National Military Medical Center (WRNMMC)(Bethesda, Maryland) is evaluating the use of a total-body digital skin imaging system under a grant from the Telemedicine and Advanced Technology Research Center of the US Army. The system in use was found to be particularly well suited for military dermatology because it offers standardized TBP processing, produces a report that can be uploaded to the US Department of Defense (DoD) electronic medical record system, and requires relatively brief training for ancillary personnel to operate. Regardless of the platform the DoD ultimately finds most suitable, it is critical that a standard exist for TBP to ensure that uniform data sets are generated to allow military and other DoD dermatologists as well as civilian health care providers to share clinical information. The goal of the current study at WRNMMC is to vet TBP platforms at WRNMMC so the military can then develop standards to procure additional platforms for placement throughout the Military Health System, Military Entrance Processing Stations, operational environments, and collaborating health care systems (eg, the Veterans Health Administration).

Once deployed broadly across the Military Health System, these TBP platforms would be part of a network of telehealth care. For acute dermatologic issues, diagnoses provided via teledermatology platforms can then be managed by health care providers utilizing appropriate clinical practice guidelines or by non–health care providers utilizing general medical knowledge databases. Such a system with TBP information collected at multiple access points across a service member’s career would build a repository of data that would be immensely useful to patients and to clinical research. Of particular interest to military researchers is that TBP data could be used to study which patients require in-person examinations or more careful monitoring; the proper intervals for skin cancer screening; and the assessment of the benefits of TBP in improving morbidity, mortality, and biopsy efficiency in the detection of MM as well as nonmelanoma skin cancers.

Limitations to Progress

Currently, there are multiple limitations to the implementation of TBP as a part of TBSE screening. First, the potential improvement in biopsy efficiency using TBP is predicated on its ability to prove nevi stability over time, but in younger populations, benign nevi are more likely to change or increase in number, which may reduce the biopsy efficiency of screening in a younger population, thereby negating some of the benefit of imaging and CNN assessment. For instance, Truong et al¹⁶ found that younger age (<30 years) did not show the same improvement in biopsy efficiency with the use of TBP, which the authors theorized may reflect “the dynamic nature of nevi in younger patients” that has been documented in other studies.^23,24 Approximately 65% of the active-duty military population is aged 18 to 30 years, and 98% of accessions to active duty occur in individuals aged 17 to 30 years.²⁵ As such, TBP may not improve biopsy efficiency in the active-duty military population as dramatically as it would across the general population.

A second limitation of the use of TBP in the active-duty military population is the ethics of implementing DoD-wide mandatory TBP. Although the TBP platform will be compliant with the Health Insurance Portability and Accountability Act, mandating that soldiers contribute their TBP to a repository of data that will then be used for research without explicitly requesting their consent is ethically problematic; however, since the 1950s, the DoD has collected serum samples from its service members for force protection and operations reasons as well as for the purpose of research.^22,26 Currently, the DoD Serum Repository collects serum samples as part of a mandatory human immunodeficiency virus screening program that evaluates service members every 2 years; this repository of human serum samples is accessible for research purposes without the consent of the individuals being studied.²⁷ These individuals are not informed of potential use of their serum specimens for research purposes and no consent forms or opt-out options are provided. Thus, although there is precedent in the DoD for such mass data collection, it is an ongoing ethical consideration.²⁸

RELATED ARTICLE: Gigapixel Photography for Skin Cancer Surveillance

Finally, although the potential use of TBP and computer algorithms to improve the efficiency and affordability of TBSEs is exciting, there are no existing computer algorithms that we are aware of that can be used with existing TBP platforms in the manner we proposed. However, we feel that computer algorithms, such as the one created by Esteva et al,¹⁹ are just the beginning and that the use of artificial intelligence is not far off. Even after the creation of a TBP-compatible algorithm adept at analyzing malignant lesions, however, this technology would need to be further evaluated in the clinical setting to determine its capability and practicality. Current TBP platforms also are limited by their large size, cost, and complexity. As TBP platforms improve, it is likely that more streamlined and less expensive versions of current models will greatly enhance the field of teledermatology, particularly in the military setting.

Skin cancer is an important public health issue in the United States, as 1 in 5 Americans are projected to develop a cutaneous malignancy during their lifetime. Currently, 75% of all skin cancer–related deaths are due to malignant melanomas (MMs), though melanomas account for less than 5% of all skin cancers.¹ Early detection of MM is essential, as prognosis depends on tumor stage, particularly the depth of the melanoma.^2-4 In general, patients with thin, early-stage melanomas have a more than 96% survival rate, which drops to 14% in late-stage disease.^5,6 Five percent to 30% of all melanomas are identified incidentally on total-body skin examinations (TBSEs) performed by a trained provider and thus would not have been caught with only a focused skin examination or patient self-examination.^7,8 Nonetheless, the clinical utility of skin cancer screening with TBSEs remains controversial, largely due to the poor quality of data available to establish a notable mortality benefit from skin cancer screening. As a result, obtaining endorsement from the larger medical community, federal government, and health insurance industry to include routine TBSEs as part of a preventive care health care strategy has not occurred. The absence of definitive clinical care guidelines mandating routine TBSEs is one of the greatest barriers preventing access to appropriate dermatologic screening along with the paucity of trained providers; however, standardized total-body photography (TBP) promises to provide a way forward by lowering the costs of dermatologic screening while simultaneously leveraging technology to increase availability.

Impact on Biopsy Efficiency

Current US Preventive Services Task Force (USPSTF) guidelines state that evidence is insufficient to assess the balance of benefits and harms of visual skin examination by a clinician to screen for skin cancer in adults. The USPSTF noted that “[d]irect evidence on the effectiveness of screening in reducing melanoma morbidity and mortality is limited to a single fair-quality ecologic study with important methodological limitations” (ie, the Skin Cancer Research to Provide Evidence for Effectiveness of Screening in Northern Germany [SCREEN] study), and although information on harm is similarly sparse, “[t]he potential for harm clearly exists, including a high rate of unnecessary biopsies, possibly resulting in cosmetic or, more rarely, functional adverse effects, and the risk of overdiagnosis and overtreatment.”⁹ The majority of suspicious skin lesions excised during screenings are not cancerous. For example, the SCREEN study found that 20 to 55 excisions were performed to detect 1 case of melanoma.¹⁰ At that rate, the USPSTF also noted that approximately 4000 excisions would be required to prevent a single death from melanoma.⁹ Following the lead of the USPSTF, the Patient Protection and Affordable Care Act did not mandate that skin examinations be included as essential preventive coverage in its requirements for insurance coverage of primary care prevention. As such, dermatologists face financial pressure to avoid performing time-consuming TBSEs, regardless of their perceived utility.¹¹

As the USPSTF points out, the value of TBSEs relies on the examiner’s ability to correctly identify malignant lesions and minimize biopsies of benign lesions, a concept known as biopsy efficiency.⁹ Secondarily, a TBSE is time consuming, and the time required for a dermatologist to complete a TBSE given the high rate of benign findings may not be financially viable. We argue that the routine use of total-body skin imaging may offer a way forward in addressing these issues. Total-body photography involves a photographic system that can allow dermatologists to acquire standardized images that can be used for primary diagnosis and to track individual lesions over time. Nonmedical personnel and medical assistants can be easily trained to use standardized photography devices to quickly obtain high-quality clinical images, thereby greatly reducing the time and cost of obtaining these images. Studies have found that the use of photographic monitoring may improve biopsy efficiency.^12-15 A recent study by Truong et al¹⁶ found that TBP used to monitor all existing melanocytic lesions on patients substantially reduced the number of biopsies that patients required. These results reflect that most nevi, including clinically atypical nevi, are usually stable and unlikely to exhibit suspicious changes over time.^17,18 For this reason, the use of TBP could minimize unnecessary biopsies because clinically suspicious but stable nevi can be objectively documented and followed over time.

Standardized TBP also offers the ability for dermatologists to work synergistically with modern computer technology involving algorithms capable of analyzing high-quality images to autodiagnose or flag concerning lesions that may require biopsy. Esteva et al¹⁹ described their development of a deep learning algorithm that relies on a convolutional neural network (CNN). This CNN was trained to identify melanomas using a large data set of clinical dermatologic images and subsequently was able to distinguish MMs from benign nevi at a rate on par with a board-certified dermatologist.¹⁹ Widespread use of total-body imaging would create an enormous database of high-resolution images that would be ideally suited to the development of such computerized algorithms, which could then be applied to future images by way of artificial intelligence. Convolutional neural networks that use a single patient’s imaging over time could be developed to assess the change in number or size of benign nevi and identify lesions that are concerning for MM while simultaneously comparing them to a population-based data set.

On a large scale, such a capability would minimize the inefficiency and subjectivity of TBSEs as a tool for identifying malignancy. Currently, dermatologists are only able to track and document a few concerning lesions on a patient’s body, rendering the choice of which lesions require biopsy more subjective. Total-body photography, particularly if used with an algorithm capable of quickly analyzing all the nevi on a person’s body, largely eliminates such subjectivity by creating a standardized set of images that can be tracked over time and flagging concerning lesions prior to the dermatologist examining the patient. In this way, the specialty of dermatology could achieve the same model of objective evaluation of standardized clinical images as those employed in radiology, cardiology, and other clinical disciplines. The additional benefit of such a system would be lower costs, as the images could be acquired by nonmedical personnel and then undergo initial assessment by an algorithm, which would flag concerning lesions, similar to a modern electrocardiogram machine, allowing the dermatologist to use his/her time more efficiently by only focusing on concerning lesions with the confidence that the patient’s entire body has already been rigorously screened.

By using TBP to improve biopsy efficiency and the objectivity of the TBSE as a tool to detect skin cancer, we propose that the benefit-to-harm ratio of the TBSE would remarkably improve. Ultimately, this type of screening would meet the strict requirements to be included in preventive health care strategies and thereby improve access to dermatologic care.

The Use of TBP in the Military

Total-body photography has several specific applications in the military. Standardized imaging has the potential to improve dermatologic care for active-duty soldiers across space and time. First, a large percentage of deployment medical care is devoted to dermatologic issues. From 2008 to 2015, 5% of all medical encounters in the combat theaters of Iraq and Afghanistan involved dermatologic concerns.²⁰ Access to appropriate dermatologic care in a combat theater is important, as poorly controlled dermatologic conditions (eg, psoriasis, eczema) often require evacuation when left untreated. Although current TBP systems may not be portable or durable enough to survive in an austere deployment environment, we propose it would be feasible to have skin imaging booths at larger forward operating bases. The images could then be transported to a remote dermatologist to assess and recommend treatment. The expense of transporting and maintaining the imaging system in country would be offset by the expenses spared by not requiring a dermatologist in country and the reductions in costly medical evacuations from theater.

Although the US military population is younger and generally healthier than the general adult population due to extensive medical screening on admission, age limitations for active-duty service, a mandated active lifestyle, and access to good health care, there are still a substantial number of service members diagnosed with skin cancer each year.²¹ From 2005 through 2014, MM was the most common non–gender-specific cancer (n=1571); in men, only testicular cancer was more prevalent (1591 vs 1298 cases), and in women, only breast cancer was more prevalent (773 vs 273 cases). Furthermore, from 2004 to 2013, the incidence rates of melanoma have increased by 1.4%, while with other cancer rates have declined during the same time period.²¹ Thus, TBP as a screening modality across the military population is a promising method for improving detection of skin cancer and reducing morbidity and mortality.

Military medicine often is on the forefront of medical advances in technology, disease understanding, and clinical care due to the unique resources available in the military health care system, which allow investigators the ability to obtain vast amounts of epidemiologic data.²² The military health care system also is unique in its ability to mandate that its members obtain preventive health services. Thus, it would be possible for the military to mandate TBP at accession and retirement, for instance, or more frequently for annual screening. The implementation of such a program would improve the health of the military population and be a public health service by pioneering the use of a standardized TBP system across a large health care system to improve skin cancer detection.

Current Studies in the Military

The Dermatology Service at the Walter Reed National Military Medical Center (WRNMMC)(Bethesda, Maryland) is evaluating the use of a total-body digital skin imaging system under a grant from the Telemedicine and Advanced Technology Research Center of the US Army. The system in use was found to be particularly well suited for military dermatology because it offers standardized TBP processing, produces a report that can be uploaded to the US Department of Defense (DoD) electronic medical record system, and requires relatively brief training for ancillary personnel to operate. Regardless of the platform the DoD ultimately finds most suitable, it is critical that a standard exist for TBP to ensure that uniform data sets are generated to allow military and other DoD dermatologists as well as civilian health care providers to share clinical information. The goal of the current study at WRNMMC is to vet TBP platforms at WRNMMC so the military can then develop standards to procure additional platforms for placement throughout the Military Health System, Military Entrance Processing Stations, operational environments, and collaborating health care systems (eg, the Veterans Health Administration).

Once deployed broadly across the Military Health System, these TBP platforms would be part of a network of telehealth care. For acute dermatologic issues, diagnoses provided via teledermatology platforms can then be managed by health care providers utilizing appropriate clinical practice guidelines or by non–health care providers utilizing general medical knowledge databases. Such a system with TBP information collected at multiple access points across a service member’s career would build a repository of data that would be immensely useful to patients and to clinical research. Of particular interest to military researchers is that TBP data could be used to study which patients require in-person examinations or more careful monitoring; the proper intervals for skin cancer screening; and the assessment of the benefits of TBP in improving morbidity, mortality, and biopsy efficiency in the detection of MM as well as nonmelanoma skin cancers.

Limitations to Progress

Currently, there are multiple limitations to the implementation of TBP as a part of TBSE screening. First, the potential improvement in biopsy efficiency using TBP is predicated on its ability to prove nevi stability over time, but in younger populations, benign nevi are more likely to change or increase in number, which may reduce the biopsy efficiency of screening in a younger population, thereby negating some of the benefit of imaging and CNN assessment. For instance, Truong et al¹⁶ found that younger age (<30 years) did not show the same improvement in biopsy efficiency with the use of TBP, which the authors theorized may reflect “the dynamic nature of nevi in younger patients” that has been documented in other studies.^23,24 Approximately 65% of the active-duty military population is aged 18 to 30 years, and 98% of accessions to active duty occur in individuals aged 17 to 30 years.²⁵ As such, TBP may not improve biopsy efficiency in the active-duty military population as dramatically as it would across the general population.

A second limitation of the use of TBP in the active-duty military population is the ethics of implementing DoD-wide mandatory TBP. Although the TBP platform will be compliant with the Health Insurance Portability and Accountability Act, mandating that soldiers contribute their TBP to a repository of data that will then be used for research without explicitly requesting their consent is ethically problematic; however, since the 1950s, the DoD has collected serum samples from its service members for force protection and operations reasons as well as for the purpose of research.^22,26 Currently, the DoD Serum Repository collects serum samples as part of a mandatory human immunodeficiency virus screening program that evaluates service members every 2 years; this repository of human serum samples is accessible for research purposes without the consent of the individuals being studied.²⁷ These individuals are not informed of potential use of their serum specimens for research purposes and no consent forms or opt-out options are provided. Thus, although there is precedent in the DoD for such mass data collection, it is an ongoing ethical consideration.²⁸

RELATED ARTICLE: Gigapixel Photography for Skin Cancer Surveillance

Finally, although the potential use of TBP and computer algorithms to improve the efficiency and affordability of TBSEs is exciting, there are no existing computer algorithms that we are aware of that can be used with existing TBP platforms in the manner we proposed. However, we feel that computer algorithms, such as the one created by Esteva et al,¹⁹ are just the beginning and that the use of artificial intelligence is not far off. Even after the creation of a TBP-compatible algorithm adept at analyzing malignant lesions, however, this technology would need to be further evaluated in the clinical setting to determine its capability and practicality. Current TBP platforms also are limited by their large size, cost, and complexity. As TBP platforms improve, it is likely that more streamlined and less expensive versions of current models will greatly enhance the field of teledermatology, particularly in the military setting.

Antenatal corticosteroid treat-ment prior to preterm birth is the most important pharmacologic intervention available to obstetricians to improve newborn health. Antenatal corticosteroids reduce preterm newborn morbidity and mortality.¹ The American College of Obstetricians and Gynecologists (ACOG) recently has summarized updated recommendations for the use of antenatal steroid treatment.²

ACOG guidance includes:

• “A single course of corticosteroids is recommended for pregnant women between 24 0/7 weeks and 33 6/7 weeks of gestation, including for those with ruptured membranes and multiple gestations.” This guidance is supported by many high-quality trials and meta-analyses.¹
• A single course of corticosteroids “may be considered for pregnant women starting at 23 0/7 weeks of gestation who are at risk of preterm delivery within 7 days.”
• “A single repeat course of antenatal corticosteroids should be considered in women who are less than 34 0/7 weeks of gestation who have an imminent risk of preterm delivery within the next 7 days and whose prior course of antenatal corticosteroids was administered more than 14 days previously.” A repeat course of corticosteroids could be considered as early as 7 days from the prior dose.
• No more than 2 courses of antenatal steroids should be administered.

An important new ACOG recommendation is:

• “A single course of betamethasone is recommended for pregnant women between 34 0/7 and 36 6/7 weeks of gestation at risk of preterm birth within 7 days, and who have not received a previous course of antenatal corticosteroids.”

This recommendation is based, in part, on a high-quality, randomized trial including 2,831 women at high risk for preterm birth between 34 0/7 and 36 6/7 weeks of gestation who were randomly assigned to receive a course of betamethasone or placebo. The newborn and maternal outcomes observed in this study are summarized in the TABLE.³

A few points relevant to the Antenatal Late Preterm Steroids study bear emphasizing. The women enrolled in this trial were at high risk for preterm delivery based on preterm labor with a cervical dilation of ≥3 cm or 75% effacement, spontaneous rupture of the membranes, or a planned late preterm delivery by cesarean or induction. No tocolytics were administered to women in this study, and approximately 40% of the women delivered within 24 hours of entry into the trial and only received 1 dose of corticosteroid or placebo.

Women with multiple gestations, pregestational diabetes, or a prior course of corticosteroids were not included in the trial; therefore, this study cannot guide our clinical practice for these subgroups of women. Of note, betamethasone should not be administered to women in the late preterm who have chorioamnionitis.

Related article:
When could use of antenatal corticosteroids in the late preterm birth period be beneficial?

The investigators calculated that 35 women would need to be treated to prevent one case of the primary outcome: a composite score of the use of respiratory support. Consequently, 34 fetuses who do not benefit from treatment are exposed in utero to betamethasone. Long-term follow-up of infants born to mothers participating in this study is currently underway.

A recent meta-analysis of 3 trials including 3,200 women at high risk for preterm delivery at 34 0/7 to 36 6/7 weeks of gestation reported that the corticosteroid administration reduced newborn risk for transient tachypnea of the newborn (relative risk [RR], 0.72; 95% confidence interval [CI], 0.56−0.92), severe respiratory distress syndrome (RR, 0.60; 95% CI, 0.33−0.94), and use of surfactant (RR, 0.61; 95% CI, 0.38−0.99).⁴

The recommendation to offer a single course of betamethasone for pregnant women between 34 0/7 and 36 6/7 weeks of gestation at risk for preterm birth has not been embraced enthusiastically by all obstetricians. Many experts have emphasized that the known risks of late preterm betamethasone, including neonatal hypoglycemia and the unknown long-term risks of treatment, including suboptimal neurodevelopmental, cardiovascular, and metabolic outcomes should dampen enthusiasm for embracing the new ACOG recommendation.⁵ Experts also emphasize that late preterm newborns are less likely to benefit from antenatal corticosteroid treatment than babies born at less than 34 weeks. Hence, many late preterm newborns will be exposed to a potentially harmful intervention and have only a small chance of benefiting from the treatment.⁶

Many neonatologists believe that for the newborn, the benefits of maternal corticosteroid treatment outweigh the risks.^7–9 In a 30-year follow-up of 534 newborns participating in antenatal corticosteroid trials, treatment had no effect on body size, blood lipids, blood pressure, plasma cortisol, prevalence of diabetes, lung function, history of cardiovascular disease, educational attainment, or socioeconomic status. Corticosteroid treatment was associated with increased insulin secretion in response to a glucose load.¹⁰ In this study, the mothers received treatment at a median of 33 weeks of gestation and births occurred at a median of 35 weeks. Hence this study is relevant to the issue of late preterm corticosteroid treatment.

Balancing risks and benefits is complex. Balancing immediate benefits against long-term risks is most challenging. Regarding antenatal steroid use there are many unknowns, including optimal dose, drug formulation, and timing from treatment to delivery. In addition we need more high-quality data delineating the long-term effects of antenatal corticosteroids on childhood and adult health.

Read about 3 options to use in your practice

Consider these 3 options for your practice

As noted, the Antenatal Late Preterm Steroids trial investigators are pursuing long-term follow-up of the children born after maternal treatment with antenatal glucocorticoids. Both ACOG and the Society for Maternal-Fetal Medicine (SMFM)¹¹ recommend administration of antenatal glucocorticoids to women at high risk for late preterm delivery. However, since some experts are concerned that a great number of babies born late preterm will have been exposed to glucocorticoids, whose long-term risks are not well known, with only a few babies having a modest short-term benefit, 3 options could be considered for your clinical practice.

Related article:
Need for caution before extending the use of antenatal corticosteroids beyond 34 weeks’ gestation

Option 1

Follow the ACOG and SMFM suggestion that all women with a high risk of late preterm birth be offered antenatal corticosteroids. Counsel the mother and family about the potential risks and benefits and involve them in the decision.

Two alternative options are to limit antenatal corticosteroid treatment to subgroups of late preterm babies most likely to benefit from treatment, those born by cesarean delivery and those born at the earliest gestational ages.

Option 2

Limit the use of antenatal corticosteroids in the late preterm to women who are scheduled for a cesarean delivery for an obstetric indication between 34 0/7 weeks and 36 6/7 weeks of gestation. This approach greatly reduces the number of babies born in the late preterm that will be exposed to antenatal corticosteroids and focuses the treatment on a subset of babies who are certain to be born preterm and most likely to benefit.

Option 3

Limit the use of antenatal corticosteroids to women at high risk for preterm birth whose newborns are most likely to benefit from treatment—women at 34 0/7 to 35 6/7 weeks of gestation. Neonates born in the 34th or 35th week of gestation are at higher risk for morbidity than those born in the 36th week of gestation and are likely to derive the greatest benefit from antenatal corticosteroid treatment.^3,12

My advice

Yogi Berra advised, “It is tough to make predictions, especially about the future.” Although ACOG and SMFM have recommended administration of glucocorticoids to women at high risk for late preterm birth, many experts caution that until the long-term effects of antenatal corticosteroids are better characterized we should limit the use of corticosteroids in the late preterm.^5,6,13 My prediction is that long-term follow-up studies will not document significant adverse effects of one course of late preterm antenatal glucocorticoid treatment on children. My advice is to start offering antenatal corticosteroids to some women at high risk for late preterm delivery.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Antenatal corticosteroid treat-ment prior to preterm birth is the most important pharmacologic intervention available to obstetricians to improve newborn health. Antenatal corticosteroids reduce preterm newborn morbidity and mortality.¹ The American College of Obstetricians and Gynecologists (ACOG) recently has summarized updated recommendations for the use of antenatal steroid treatment.²

ACOG guidance includes:

• “A single course of corticosteroids is recommended for pregnant women between 24 0/7 weeks and 33 6/7 weeks of gestation, including for those with ruptured membranes and multiple gestations.” This guidance is supported by many high-quality trials and meta-analyses.¹
• A single course of corticosteroids “may be considered for pregnant women starting at 23 0/7 weeks of gestation who are at risk of preterm delivery within 7 days.”
• “A single repeat course of antenatal corticosteroids should be considered in women who are less than 34 0/7 weeks of gestation who have an imminent risk of preterm delivery within the next 7 days and whose prior course of antenatal corticosteroids was administered more than 14 days previously.” A repeat course of corticosteroids could be considered as early as 7 days from the prior dose.
• No more than 2 courses of antenatal steroids should be administered.

An important new ACOG recommendation is:

• “A single course of betamethasone is recommended for pregnant women between 34 0/7 and 36 6/7 weeks of gestation at risk of preterm birth within 7 days, and who have not received a previous course of antenatal corticosteroids.”

This recommendation is based, in part, on a high-quality, randomized trial including 2,831 women at high risk for preterm birth between 34 0/7 and 36 6/7 weeks of gestation who were randomly assigned to receive a course of betamethasone or placebo. The newborn and maternal outcomes observed in this study are summarized in the TABLE.³

A few points relevant to the Antenatal Late Preterm Steroids study bear emphasizing. The women enrolled in this trial were at high risk for preterm delivery based on preterm labor with a cervical dilation of ≥3 cm or 75% effacement, spontaneous rupture of the membranes, or a planned late preterm delivery by cesarean or induction. No tocolytics were administered to women in this study, and approximately 40% of the women delivered within 24 hours of entry into the trial and only received 1 dose of corticosteroid or placebo.

Women with multiple gestations, pregestational diabetes, or a prior course of corticosteroids were not included in the trial; therefore, this study cannot guide our clinical practice for these subgroups of women. Of note, betamethasone should not be administered to women in the late preterm who have chorioamnionitis.

Related article:
When could use of antenatal corticosteroids in the late preterm birth period be beneficial?

The investigators calculated that 35 women would need to be treated to prevent one case of the primary outcome: a composite score of the use of respiratory support. Consequently, 34 fetuses who do not benefit from treatment are exposed in utero to betamethasone. Long-term follow-up of infants born to mothers participating in this study is currently underway.

A recent meta-analysis of 3 trials including 3,200 women at high risk for preterm delivery at 34 0/7 to 36 6/7 weeks of gestation reported that the corticosteroid administration reduced newborn risk for transient tachypnea of the newborn (relative risk [RR], 0.72; 95% confidence interval [CI], 0.56−0.92), severe respiratory distress syndrome (RR, 0.60; 95% CI, 0.33−0.94), and use of surfactant (RR, 0.61; 95% CI, 0.38−0.99).⁴

The recommendation to offer a single course of betamethasone for pregnant women between 34 0/7 and 36 6/7 weeks of gestation at risk for preterm birth has not been embraced enthusiastically by all obstetricians. Many experts have emphasized that the known risks of late preterm betamethasone, including neonatal hypoglycemia and the unknown long-term risks of treatment, including suboptimal neurodevelopmental, cardiovascular, and metabolic outcomes should dampen enthusiasm for embracing the new ACOG recommendation.⁵ Experts also emphasize that late preterm newborns are less likely to benefit from antenatal corticosteroid treatment than babies born at less than 34 weeks. Hence, many late preterm newborns will be exposed to a potentially harmful intervention and have only a small chance of benefiting from the treatment.⁶

Many neonatologists believe that for the newborn, the benefits of maternal corticosteroid treatment outweigh the risks.^7–9 In a 30-year follow-up of 534 newborns participating in antenatal corticosteroid trials, treatment had no effect on body size, blood lipids, blood pressure, plasma cortisol, prevalence of diabetes, lung function, history of cardiovascular disease, educational attainment, or socioeconomic status. Corticosteroid treatment was associated with increased insulin secretion in response to a glucose load.¹⁰ In this study, the mothers received treatment at a median of 33 weeks of gestation and births occurred at a median of 35 weeks. Hence this study is relevant to the issue of late preterm corticosteroid treatment.

Balancing risks and benefits is complex. Balancing immediate benefits against long-term risks is most challenging. Regarding antenatal steroid use there are many unknowns, including optimal dose, drug formulation, and timing from treatment to delivery. In addition we need more high-quality data delineating the long-term effects of antenatal corticosteroids on childhood and adult health.

Read about 3 options to use in your practice

Consider these 3 options for your practice

As noted, the Antenatal Late Preterm Steroids trial investigators are pursuing long-term follow-up of the children born after maternal treatment with antenatal glucocorticoids. Both ACOG and the Society for Maternal-Fetal Medicine (SMFM)¹¹ recommend administration of antenatal glucocorticoids to women at high risk for late preterm delivery. However, since some experts are concerned that a great number of babies born late preterm will have been exposed to glucocorticoids, whose long-term risks are not well known, with only a few babies having a modest short-term benefit, 3 options could be considered for your clinical practice.

Related article:
Need for caution before extending the use of antenatal corticosteroids beyond 34 weeks’ gestation

Option 1

Follow the ACOG and SMFM suggestion that all women with a high risk of late preterm birth be offered antenatal corticosteroids. Counsel the mother and family about the potential risks and benefits and involve them in the decision.

Two alternative options are to limit antenatal corticosteroid treatment to subgroups of late preterm babies most likely to benefit from treatment, those born by cesarean delivery and those born at the earliest gestational ages.

Option 2

Limit the use of antenatal corticosteroids in the late preterm to women who are scheduled for a cesarean delivery for an obstetric indication between 34 0/7 weeks and 36 6/7 weeks of gestation. This approach greatly reduces the number of babies born in the late preterm that will be exposed to antenatal corticosteroids and focuses the treatment on a subset of babies who are certain to be born preterm and most likely to benefit.

Option 3

Limit the use of antenatal corticosteroids to women at high risk for preterm birth whose newborns are most likely to benefit from treatment—women at 34 0/7 to 35 6/7 weeks of gestation. Neonates born in the 34th or 35th week of gestation are at higher risk for morbidity than those born in the 36th week of gestation and are likely to derive the greatest benefit from antenatal corticosteroid treatment.^3,12

My advice

Yogi Berra advised, “It is tough to make predictions, especially about the future.” Although ACOG and SMFM have recommended administration of glucocorticoids to women at high risk for late preterm birth, many experts caution that until the long-term effects of antenatal corticosteroids are better characterized we should limit the use of corticosteroids in the late preterm.^5,6,13 My prediction is that long-term follow-up studies will not document significant adverse effects of one course of late preterm antenatal glucocorticoid treatment on children. My advice is to start offering antenatal corticosteroids to some women at high risk for late preterm delivery.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Antenatal corticosteroid treat-ment prior to preterm birth is the most important pharmacologic intervention available to obstetricians to improve newborn health. Antenatal corticosteroids reduce preterm newborn morbidity and mortality.¹ The American College of Obstetricians and Gynecologists (ACOG) recently has summarized updated recommendations for the use of antenatal steroid treatment.²

ACOG guidance includes:

• “A single course of corticosteroids is recommended for pregnant women between 24 0/7 weeks and 33 6/7 weeks of gestation, including for those with ruptured membranes and multiple gestations.” This guidance is supported by many high-quality trials and meta-analyses.¹
• A single course of corticosteroids “may be considered for pregnant women starting at 23 0/7 weeks of gestation who are at risk of preterm delivery within 7 days.”
• “A single repeat course of antenatal corticosteroids should be considered in women who are less than 34 0/7 weeks of gestation who have an imminent risk of preterm delivery within the next 7 days and whose prior course of antenatal corticosteroids was administered more than 14 days previously.” A repeat course of corticosteroids could be considered as early as 7 days from the prior dose.
• No more than 2 courses of antenatal steroids should be administered.

An important new ACOG recommendation is:

• “A single course of betamethasone is recommended for pregnant women between 34 0/7 and 36 6/7 weeks of gestation at risk of preterm birth within 7 days, and who have not received a previous course of antenatal corticosteroids.”

This recommendation is based, in part, on a high-quality, randomized trial including 2,831 women at high risk for preterm birth between 34 0/7 and 36 6/7 weeks of gestation who were randomly assigned to receive a course of betamethasone or placebo. The newborn and maternal outcomes observed in this study are summarized in the TABLE.³

A few points relevant to the Antenatal Late Preterm Steroids study bear emphasizing. The women enrolled in this trial were at high risk for preterm delivery based on preterm labor with a cervical dilation of ≥3 cm or 75% effacement, spontaneous rupture of the membranes, or a planned late preterm delivery by cesarean or induction. No tocolytics were administered to women in this study, and approximately 40% of the women delivered within 24 hours of entry into the trial and only received 1 dose of corticosteroid or placebo.

Women with multiple gestations, pregestational diabetes, or a prior course of corticosteroids were not included in the trial; therefore, this study cannot guide our clinical practice for these subgroups of women. Of note, betamethasone should not be administered to women in the late preterm who have chorioamnionitis.

Related article:
When could use of antenatal corticosteroids in the late preterm birth period be beneficial?

The investigators calculated that 35 women would need to be treated to prevent one case of the primary outcome: a composite score of the use of respiratory support. Consequently, 34 fetuses who do not benefit from treatment are exposed in utero to betamethasone. Long-term follow-up of infants born to mothers participating in this study is currently underway.

A recent meta-analysis of 3 trials including 3,200 women at high risk for preterm delivery at 34 0/7 to 36 6/7 weeks of gestation reported that the corticosteroid administration reduced newborn risk for transient tachypnea of the newborn (relative risk [RR], 0.72; 95% confidence interval [CI], 0.56−0.92), severe respiratory distress syndrome (RR, 0.60; 95% CI, 0.33−0.94), and use of surfactant (RR, 0.61; 95% CI, 0.38−0.99).⁴

The recommendation to offer a single course of betamethasone for pregnant women between 34 0/7 and 36 6/7 weeks of gestation at risk for preterm birth has not been embraced enthusiastically by all obstetricians. Many experts have emphasized that the known risks of late preterm betamethasone, including neonatal hypoglycemia and the unknown long-term risks of treatment, including suboptimal neurodevelopmental, cardiovascular, and metabolic outcomes should dampen enthusiasm for embracing the new ACOG recommendation.⁵ Experts also emphasize that late preterm newborns are less likely to benefit from antenatal corticosteroid treatment than babies born at less than 34 weeks. Hence, many late preterm newborns will be exposed to a potentially harmful intervention and have only a small chance of benefiting from the treatment.⁶

Many neonatologists believe that for the newborn, the benefits of maternal corticosteroid treatment outweigh the risks.^7–9 In a 30-year follow-up of 534 newborns participating in antenatal corticosteroid trials, treatment had no effect on body size, blood lipids, blood pressure, plasma cortisol, prevalence of diabetes, lung function, history of cardiovascular disease, educational attainment, or socioeconomic status. Corticosteroid treatment was associated with increased insulin secretion in response to a glucose load.¹⁰ In this study, the mothers received treatment at a median of 33 weeks of gestation and births occurred at a median of 35 weeks. Hence this study is relevant to the issue of late preterm corticosteroid treatment.

Balancing risks and benefits is complex. Balancing immediate benefits against long-term risks is most challenging. Regarding antenatal steroid use there are many unknowns, including optimal dose, drug formulation, and timing from treatment to delivery. In addition we need more high-quality data delineating the long-term effects of antenatal corticosteroids on childhood and adult health.

Read about 3 options to use in your practice

Consider these 3 options for your practice

As noted, the Antenatal Late Preterm Steroids trial investigators are pursuing long-term follow-up of the children born after maternal treatment with antenatal glucocorticoids. Both ACOG and the Society for Maternal-Fetal Medicine (SMFM)¹¹ recommend administration of antenatal glucocorticoids to women at high risk for late preterm delivery. However, since some experts are concerned that a great number of babies born late preterm will have been exposed to glucocorticoids, whose long-term risks are not well known, with only a few babies having a modest short-term benefit, 3 options could be considered for your clinical practice.

Related article:
Need for caution before extending the use of antenatal corticosteroids beyond 34 weeks’ gestation

Option 1

Follow the ACOG and SMFM suggestion that all women with a high risk of late preterm birth be offered antenatal corticosteroids. Counsel the mother and family about the potential risks and benefits and involve them in the decision.

Two alternative options are to limit antenatal corticosteroid treatment to subgroups of late preterm babies most likely to benefit from treatment, those born by cesarean delivery and those born at the earliest gestational ages.

Option 2

Limit the use of antenatal corticosteroids in the late preterm to women who are scheduled for a cesarean delivery for an obstetric indication between 34 0/7 weeks and 36 6/7 weeks of gestation. This approach greatly reduces the number of babies born in the late preterm that will be exposed to antenatal corticosteroids and focuses the treatment on a subset of babies who are certain to be born preterm and most likely to benefit.

Option 3

Limit the use of antenatal corticosteroids to women at high risk for preterm birth whose newborns are most likely to benefit from treatment—women at 34 0/7 to 35 6/7 weeks of gestation. Neonates born in the 34th or 35th week of gestation are at higher risk for morbidity than those born in the 36th week of gestation and are likely to derive the greatest benefit from antenatal corticosteroid treatment.^3,12

My advice

Yogi Berra advised, “It is tough to make predictions, especially about the future.” Although ACOG and SMFM have recommended administration of glucocorticoids to women at high risk for late preterm birth, many experts caution that until the long-term effects of antenatal corticosteroids are better characterized we should limit the use of corticosteroids in the late preterm.^5,6,13 My prediction is that long-term follow-up studies will not document significant adverse effects of one course of late preterm antenatal glucocorticoid treatment on children. My advice is to start offering antenatal corticosteroids to some women at high risk for late preterm delivery.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

ORLANDO – Cushing’s disease may begin to exert its harmful cardiovascular effects quite early, a small pediatric study has found.

Children as young as 6 years old with the disorder already may show signs of cardiovascular remodeling, with stiffer aortas and higher aortic pulse-wave velocity than do age-matched controls, Hailey Blain and Maya Lodish, MD, said at the annual meeting of the Endocrine Society.

Michele G Sullivan

[email protected]

ORLANDO – Cushing’s disease may begin to exert its harmful cardiovascular effects quite early, a small pediatric study has found.

Children as young as 6 years old with the disorder already may show signs of cardiovascular remodeling, with stiffer aortas and higher aortic pulse-wave velocity than do age-matched controls, Hailey Blain and Maya Lodish, MD, said at the annual meeting of the Endocrine Society.

Michele G Sullivan

[email protected]

ORLANDO – Cushing’s disease may begin to exert its harmful cardiovascular effects quite early, a small pediatric study has found.

Children as young as 6 years old with the disorder already may show signs of cardiovascular remodeling, with stiffer aortas and higher aortic pulse-wave velocity than do age-matched controls, Hailey Blain and Maya Lodish, MD, said at the annual meeting of the Endocrine Society.

Michele G Sullivan

[email protected]

Hearing loss and tinnitus (ringing or other noises in the ears or head) have been problematic for military service members and veterans for many years. Military personnel are exposed to high levels of noise in operational and training settings. In spite of hearing conservation efforts, hearing loss and auditory injuries (including tinnitus) continue to occur. Although current military leadership teaches the importance of hearing protection, that was not usually the case until the past few decades. Military leadership provides the means for hearing protection and monitors risk through conservation and hearing readiness programs. Unfortunately, the need for hearing during battle often overrides the expediency of using hearing protective devices.

Military members often equate hearing protection with increased vulnerability, widening the gap between preventive efforts and hearing preservation. It is therefore not surprising that tinnitus and hearing loss have been the 2 most common service-connected disabilities for veterans for a decade.¹ These conditions are irreversible; affected service members and veterans need strategies to cope with distress associated with these chronic conditions. Clinical care often is essential to manage the associated distress and mental health (MH) symptoms, such as sleep disturbance, irritability, isolation, tension, and low mood.

There is no cure for tinnitus, meaning there is no proven method to permanently eliminate or even reduce the perception of tinnitus. Intervention for tinnitus therefore is limited to methods intended to mitigate reactions to tinnitus, with the ultimate goal to facilitate good quality of life in spite of the perception of this unwanted auditory anomaly. These methods include numerous means of utilizing therapeutic sound.² Sound therapy, however, has been shown in controlled trials to be effective only when accompanied by counseling, which often focuses on teaching different coping skills.³ In such instances, MH providers can become an integral part of the hearing health team to assist patients in the management of their tinnitus.

Evidence-Based Practice

Evidence-based research should guide clinical services that are offered for tinnitus. Randomized controlled trials (RCTs) comprise the most important source for such evidence.⁴ Cochrane Reviews uses meta-analyses to examine rigorous RCTs to determine which methods have credible evidence. One of these reviews conducted in 2007 and updated in 2010 concluded that cognitive behavioral therapy (CBT) can improve depression scores and reduce distress for many people with bothersome tinnitus.^5,6 Another Cochrane Review concluded that sound therapy combined with counseling can be beneficial, but on its own, sound therapy has not been shown to result in significant benefit.³ Yet another Cochrane Review focused on using hearing aids with patients who have both hearing loss and bothersome tinnitus; the researchers concluded that “there is currently no evidence to support or refute their use as a more routine intervention for tinnitus.”⁷ However, many patients and clinicians report hearing aids are helpful for coping with tinnitus.

The American Academy of Otolaryngology–Head and Neck Surgery Foundation (AAO-HNSF) published a clinical practice guideline (CPG) for the management of tinnitus.⁸ Developing the CPG involved a comprehensive evaluation of the peer-reviewed literature, including the available Cochrane Reviews, to identify appropriate RCTs to inform evidence-based recommendations. Cognitive behavioral therapy was the only intervention for tinnitus recommended in the CPG. Cognitive behavioral therapy targets emotional response by identifying behaviors, thoughts, and beliefs that may be altered.⁹ For tinnitus, CBT typically includes stress management including relaxation exercises, purposeful distraction, and changing how individuals view and appraise their tinnitus.

Both the CPG and Cochrane Reviews concluded that CBT has the strongest evidence base for reducing effects of tinnitus. It should be noted that the CPG recommended teaching patients basic information about tinnitus management and stated that it was optional (due to limited research evidence) to use sound therapy to augment coping skills training.

Progressive Tinnitus Management

Tinnitus research at the VA National Center for Rehabilitative Auditory Research (NCRAR) has led to the development and refinement of an interdisciplinary program called Progressive Tinnitus Management (PTM). Audiologists and MH providers work together to deliver portions of the protocol. In addition, otolaryngologists are important for patients requiring a medical examination. Audiologists, MH providers, and otolaryngologists comprise the hearing health team for tinnitus management. The PTM program involves 5 stepped-care levels of management, and patients receive only the levels they need.

Level 1 is the referral level, which specifies guidelines for any clinician who encounters patients experiencing tinnitus. The “standard” referral is to audiology for a hearing evaluation (PTM level 2)—every patient reporting tinnitus should have a hearing evaluation and brief tinnitus assessment. Less typical would be an urgent referral to a different provider for certain symptoms such as referral to ENT for sudden hearing loss.

Patients who desire intervention for bothersome tinnitus are offered PTM skills education (level 3). At this level, patients are taught facts and skills that they need to self-manage their tinnitus-related problems. Ideally, the audiologist and MH provider collaborate to deliver the level 3 intervention, which utilizes a 5-session (2 with an audiologist and 3 with a MH provider) problem-solving method. Audiologists explain different forms of sound therapy, and MH providers deliver brief CBT. The research studies and clinics that use PTM have shown that the majority of patients who receive the level 3 skills education interventions have their tinnitus needs met to the degree that they do not desire further services.

Those relatively few patients who desire further services are invited for a PTM interdisciplinary evaluation (level 4), which involves a more in-depth needs evaluation by both an audiologist and a MH provider. Based on the outcome of the level 4 evaluation, clear treatment goals are discussed with the patient. If the patient and providers mutually agree that further intervention is needed, then the patient is offered PTM individualized support (level 5), which involves one-on-one services by an audiologist and/or a MH provider. The providers then build on the lessons taught during level 3 and address barriers to enacting the already discussed skills. The MH provider also may expand on CBT skills that were provided in level 3, offering care such as CBT for insomnia during level 5, depending on the specific needs and desires of the patient.

At the NCRAR, a pilot study and 2 RCTs of PTM have been completed.¹⁰ The first of these 2 RCTs was a clinical effectiveness study of PTM that was conducted in 2 VA audiology clinics: Memphis, Tennessee, and West Haven, Connecticut.¹¹ Patients who came to the clinics signed up for the study if they felt that the PTM level 3 intervention might be helpful. Half of the 300 veterans in the study were enrolled to receive PTM right away, and half were put on a 6-month wait list. The PTM group showed significantly greater benefit than that of the wait-list group.

The second RCT of PTM was motivated by the high number of service members and veterans with a history of traumatic brain injury (TBI), which is strongly associated with tinnitus.¹² The PTM level 3 skills education was administered to participants individually over the telephone by both an audiologist and a psychologist. Participants, located all over the U.S., had bothersome tinnitus, and some had experienced ≥ 1 TBI. They were randomized to receive either Tele-PTM immediately for 6 months or to be put on a 6-month wait list. The Tele-PTM group showed much greater improvement than that of the wait-list group.

Both of these recent RCTs have validated the effectiveness of PTM and demonstrated that PTM should be considered for the practice of evidence-based tinnitus management. PTM is mostly consistent with the AAO-HNSF CPG and provides a structured and defined framework for implementing both assessment and intervention services for patients who report tinnitus. As such, VA Central Office has endorsed PTM as an effective intervention for tinnitus management and has recommended its use at VAMCs. The NCRAR researchers have provided PTM training to hundreds of VA audiologists and MH providers, yet the level of implementation across the VA system of care varies widely.

VA Survey

In 2015, in partnership with the VA Offices of Audiology and Speech Pathology and Mental Health Services, and the Health Services Research & Development/Quality Enhancement Research Initiative (HSR&D/QUERI), the NCRAR conducted a study to examine PTM variation across sites via surveys and/or interviews of VA Audiology and MH programs nationwide.^13,14 The objectives of this study were to: (1) describe current tinnitus-management practices in VAMCs; (2) identify barriers and facilitators to PTM program implementation based on clinics that have fully, partially, or not implemented PTM; and (3) determine readiness to implement PTM within VISN 20 (Northwest states and Alaska).

Clinicians at VAMCs nationwide were surveyed regarding current provision of tinnitus clinical services. Requests were sent to audiology programs and MH programs at 142 major VAMCs along with instructions to complete the online survey. Responses were received from 87 audiologists and 66 MH providers. Clinicians at VAMCs with full PTM, partial PTM, and no-PTM (based on survey results) were then interviewed regarding site-specific barriers and facilitators to implementing and providing PTM, readiness to adopt PTM, and strategies for full PTM implementation.

Key findings from the study demonstrated the following: (1) There is considerable between-site variability in how PTM is implemented, particularly with the delivery of the MH portion of the protocol; (2) audiologists show higher levels of readiness to provide tinnitus services than do MH providers (7% of MH survey respondents vs 62% of audiologists reported their site implementing PTM); (3) 66% of MH survey respondents were interested in receiving training in tinnitus management (note that online PTM training for MH does not yet exist); (4) PTM implementation barriers include audio-visual technology issues, room scheduling, as well as lack of collaboration and colocation between MH and audiology departments, administrative time/support, group facilitator skills, and availability of PTM materials.

Overall, results of this HSR&D/QUERI-funded study suggested the need to develop MH-specific training to support the necessary interdisciplinary engagement. Although a patient workbook is available to order and visual presentation aids may be accessed online, it became clear that lack of MH participation in the inherently interdisciplinary PTM skills education was the most common deviation from PTM.

DoD an VA Questionnaire

In 2014 the DoD Hearing Center of Excellence (HCE) conducted the DoD and VA Tinnitus Evaluation, Management, and Treatment Assessment.¹³ The HCE conducted this questionnaire under the Tinnitus Care Quality Improvement, Process Development, and Implementation Plan, to develop, establish, and implement an interdisciplinary and ongoing process to continually assess and improve the quality and continuum of tinnitus care delivered to service members and veterans at a consistent, enterprise-wide level. The HCE developed the questionnaire to: (1) identify DoD and VA audiologists and otolaryngologists and their institutions providing comprehensive tinnitus care; (2) assess current tinnitus evaluation and management/treatment protocols used; (3) disseminate common practice improvements to all providers for enhancing overall tinnitus evaluation and management/treatment; and (4) evaluate implementation of improvements to include efficiency of implementation and efficacy of improvements.

The questionnaire was administered using SurveyMonkey (San Mateo, CA) and was disseminated by the otolaryngology and audiology consultants to the Army, Navy, and Air Force surgeons general and specialty leaders as well as through VA specialty leaders. Also, the HCE posted the link for the questionnaire on its website for 11 months. A total of 200 providers responded to the questionnaire, of which 13 did not indicate their specialty (eg, otolaryngology) or classification (eg, DoD active duty) and were excluded from data analysis. The 187 qualified respondents included 66 DoD audiologists, 120 VA audiologists, and 1 DoD otolaryngologist.

The questionnaire results indicated that DoD and VA respondents provided tinnitus services for their patients at similar rates (72% of DoD providers and 79% of VA providers). The use of PTM by those same providers, however, was far more widespread in VA (66%) than it was in DoD (37%). Of the providers indicating they did not offer tinnitus clinical services, the main reasons given were lack of necessary training/expertise, lack of time, and insufficient clinical support. The majority of respondents indicated they had training on tinnitus evaluation and/or management and that they were comfortable providing these services; despite this, most providers indicated a need or desire for tinnitus-specific training and education. These results suggested that more support and education for hearing health care providers were needed to implement PTM in VA and, especially, in DoD.

About half of the respondents indicated that psychological/behavioral treatment services, which would correspond to PTM levels 3 and 5, are available for patients at their facility who have tinnitus. It is encouraging to know that some patients with problematic tinnitus are receiving MH services. However, it is essential that patients with any degree of bothersome tinnitus have access to evidence-based clinical services, which would require CBT delivered by a qualified MH provider.

Conclusion

Numerous VA and DoD clinics have begun providing PTM. Individual sites, however, typically adapt the program during the process of implementation.^13,14 The most common adaptation that sites make to PTM is to proceed with level 3 skills education without the assistance of MH, and thus CBT, due to the lack of provider availability. It is unknown what impact this has on the effectiveness of PTM. Skills education forms the heart of PTM and addresses the needs of the majority of patients who seek intervention.

Collaboration with MH is integral to the delivery of PTM. Mental health providers partner in PTM levels 3 and 5 by providing CBT, which has the strongest evidence for reducing tinnitus distress among all interventions and always will be critical to the provision of PTM. Clearly VA MH programs need to increase involvement in veterans’ tinnitus management. Increased involvement may be accomplished by (1) developing training or other materials that increase understanding of MH’s role in addressing tinnitus; (2) developing pathways for coordination of care between audiology and MH providers, including different models of coordination based on individual site needs; and (3) documenting the prevalence of tinnitus-MH comorbidities to empirically justify the need for such coordination between audiology and MH providers.

To address gaps identified in the VA survey and in a similar questionnaire conducted by HCE regarding tinnitus care in VA and DoD, the NCRAR, HCE, and Walter Reed National Military Medical Center are collaborating on several initiatives to improve tinnitus services for service members and veterans.^13-15 These efforts include enhancing service member and veteran access to VA and DoD MH services in PTM.

Hearing loss and tinnitus (ringing or other noises in the ears or head) have been problematic for military service members and veterans for many years. Military personnel are exposed to high levels of noise in operational and training settings. In spite of hearing conservation efforts, hearing loss and auditory injuries (including tinnitus) continue to occur. Although current military leadership teaches the importance of hearing protection, that was not usually the case until the past few decades. Military leadership provides the means for hearing protection and monitors risk through conservation and hearing readiness programs. Unfortunately, the need for hearing during battle often overrides the expediency of using hearing protective devices.

Military members often equate hearing protection with increased vulnerability, widening the gap between preventive efforts and hearing preservation. It is therefore not surprising that tinnitus and hearing loss have been the 2 most common service-connected disabilities for veterans for a decade.¹ These conditions are irreversible; affected service members and veterans need strategies to cope with distress associated with these chronic conditions. Clinical care often is essential to manage the associated distress and mental health (MH) symptoms, such as sleep disturbance, irritability, isolation, tension, and low mood.

There is no cure for tinnitus, meaning there is no proven method to permanently eliminate or even reduce the perception of tinnitus. Intervention for tinnitus therefore is limited to methods intended to mitigate reactions to tinnitus, with the ultimate goal to facilitate good quality of life in spite of the perception of this unwanted auditory anomaly. These methods include numerous means of utilizing therapeutic sound.² Sound therapy, however, has been shown in controlled trials to be effective only when accompanied by counseling, which often focuses on teaching different coping skills.³ In such instances, MH providers can become an integral part of the hearing health team to assist patients in the management of their tinnitus.

Evidence-Based Practice

Evidence-based research should guide clinical services that are offered for tinnitus. Randomized controlled trials (RCTs) comprise the most important source for such evidence.⁴ Cochrane Reviews uses meta-analyses to examine rigorous RCTs to determine which methods have credible evidence. One of these reviews conducted in 2007 and updated in 2010 concluded that cognitive behavioral therapy (CBT) can improve depression scores and reduce distress for many people with bothersome tinnitus.^5,6 Another Cochrane Review concluded that sound therapy combined with counseling can be beneficial, but on its own, sound therapy has not been shown to result in significant benefit.³ Yet another Cochrane Review focused on using hearing aids with patients who have both hearing loss and bothersome tinnitus; the researchers concluded that “there is currently no evidence to support or refute their use as a more routine intervention for tinnitus.”⁷ However, many patients and clinicians report hearing aids are helpful for coping with tinnitus.

The American Academy of Otolaryngology–Head and Neck Surgery Foundation (AAO-HNSF) published a clinical practice guideline (CPG) for the management of tinnitus.⁸ Developing the CPG involved a comprehensive evaluation of the peer-reviewed literature, including the available Cochrane Reviews, to identify appropriate RCTs to inform evidence-based recommendations. Cognitive behavioral therapy was the only intervention for tinnitus recommended in the CPG. Cognitive behavioral therapy targets emotional response by identifying behaviors, thoughts, and beliefs that may be altered.⁹ For tinnitus, CBT typically includes stress management including relaxation exercises, purposeful distraction, and changing how individuals view and appraise their tinnitus.

Both the CPG and Cochrane Reviews concluded that CBT has the strongest evidence base for reducing effects of tinnitus. It should be noted that the CPG recommended teaching patients basic information about tinnitus management and stated that it was optional (due to limited research evidence) to use sound therapy to augment coping skills training.

Progressive Tinnitus Management

Tinnitus research at the VA National Center for Rehabilitative Auditory Research (NCRAR) has led to the development and refinement of an interdisciplinary program called Progressive Tinnitus Management (PTM). Audiologists and MH providers work together to deliver portions of the protocol. In addition, otolaryngologists are important for patients requiring a medical examination. Audiologists, MH providers, and otolaryngologists comprise the hearing health team for tinnitus management. The PTM program involves 5 stepped-care levels of management, and patients receive only the levels they need.

Level 1 is the referral level, which specifies guidelines for any clinician who encounters patients experiencing tinnitus. The “standard” referral is to audiology for a hearing evaluation (PTM level 2)—every patient reporting tinnitus should have a hearing evaluation and brief tinnitus assessment. Less typical would be an urgent referral to a different provider for certain symptoms such as referral to ENT for sudden hearing loss.

Patients who desire intervention for bothersome tinnitus are offered PTM skills education (level 3). At this level, patients are taught facts and skills that they need to self-manage their tinnitus-related problems. Ideally, the audiologist and MH provider collaborate to deliver the level 3 intervention, which utilizes a 5-session (2 with an audiologist and 3 with a MH provider) problem-solving method. Audiologists explain different forms of sound therapy, and MH providers deliver brief CBT. The research studies and clinics that use PTM have shown that the majority of patients who receive the level 3 skills education interventions have their tinnitus needs met to the degree that they do not desire further services.

Those relatively few patients who desire further services are invited for a PTM interdisciplinary evaluation (level 4), which involves a more in-depth needs evaluation by both an audiologist and a MH provider. Based on the outcome of the level 4 evaluation, clear treatment goals are discussed with the patient. If the patient and providers mutually agree that further intervention is needed, then the patient is offered PTM individualized support (level 5), which involves one-on-one services by an audiologist and/or a MH provider. The providers then build on the lessons taught during level 3 and address barriers to enacting the already discussed skills. The MH provider also may expand on CBT skills that were provided in level 3, offering care such as CBT for insomnia during level 5, depending on the specific needs and desires of the patient.

At the NCRAR, a pilot study and 2 RCTs of PTM have been completed.¹⁰ The first of these 2 RCTs was a clinical effectiveness study of PTM that was conducted in 2 VA audiology clinics: Memphis, Tennessee, and West Haven, Connecticut.¹¹ Patients who came to the clinics signed up for the study if they felt that the PTM level 3 intervention might be helpful. Half of the 300 veterans in the study were enrolled to receive PTM right away, and half were put on a 6-month wait list. The PTM group showed significantly greater benefit than that of the wait-list group.

The second RCT of PTM was motivated by the high number of service members and veterans with a history of traumatic brain injury (TBI), which is strongly associated with tinnitus.¹² The PTM level 3 skills education was administered to participants individually over the telephone by both an audiologist and a psychologist. Participants, located all over the U.S., had bothersome tinnitus, and some had experienced ≥ 1 TBI. They were randomized to receive either Tele-PTM immediately for 6 months or to be put on a 6-month wait list. The Tele-PTM group showed much greater improvement than that of the wait-list group.

Both of these recent RCTs have validated the effectiveness of PTM and demonstrated that PTM should be considered for the practice of evidence-based tinnitus management. PTM is mostly consistent with the AAO-HNSF CPG and provides a structured and defined framework for implementing both assessment and intervention services for patients who report tinnitus. As such, VA Central Office has endorsed PTM as an effective intervention for tinnitus management and has recommended its use at VAMCs. The NCRAR researchers have provided PTM training to hundreds of VA audiologists and MH providers, yet the level of implementation across the VA system of care varies widely.

VA Survey

In 2015, in partnership with the VA Offices of Audiology and Speech Pathology and Mental Health Services, and the Health Services Research & Development/Quality Enhancement Research Initiative (HSR&D/QUERI), the NCRAR conducted a study to examine PTM variation across sites via surveys and/or interviews of VA Audiology and MH programs nationwide.^13,14 The objectives of this study were to: (1) describe current tinnitus-management practices in VAMCs; (2) identify barriers and facilitators to PTM program implementation based on clinics that have fully, partially, or not implemented PTM; and (3) determine readiness to implement PTM within VISN 20 (Northwest states and Alaska).

Clinicians at VAMCs nationwide were surveyed regarding current provision of tinnitus clinical services. Requests were sent to audiology programs and MH programs at 142 major VAMCs along with instructions to complete the online survey. Responses were received from 87 audiologists and 66 MH providers. Clinicians at VAMCs with full PTM, partial PTM, and no-PTM (based on survey results) were then interviewed regarding site-specific barriers and facilitators to implementing and providing PTM, readiness to adopt PTM, and strategies for full PTM implementation.

Key findings from the study demonstrated the following: (1) There is considerable between-site variability in how PTM is implemented, particularly with the delivery of the MH portion of the protocol; (2) audiologists show higher levels of readiness to provide tinnitus services than do MH providers (7% of MH survey respondents vs 62% of audiologists reported their site implementing PTM); (3) 66% of MH survey respondents were interested in receiving training in tinnitus management (note that online PTM training for MH does not yet exist); (4) PTM implementation barriers include audio-visual technology issues, room scheduling, as well as lack of collaboration and colocation between MH and audiology departments, administrative time/support, group facilitator skills, and availability of PTM materials.

Overall, results of this HSR&D/QUERI-funded study suggested the need to develop MH-specific training to support the necessary interdisciplinary engagement. Although a patient workbook is available to order and visual presentation aids may be accessed online, it became clear that lack of MH participation in the inherently interdisciplinary PTM skills education was the most common deviation from PTM.

DoD an VA Questionnaire

In 2014 the DoD Hearing Center of Excellence (HCE) conducted the DoD and VA Tinnitus Evaluation, Management, and Treatment Assessment.¹³ The HCE conducted this questionnaire under the Tinnitus Care Quality Improvement, Process Development, and Implementation Plan, to develop, establish, and implement an interdisciplinary and ongoing process to continually assess and improve the quality and continuum of tinnitus care delivered to service members and veterans at a consistent, enterprise-wide level. The HCE developed the questionnaire to: (1) identify DoD and VA audiologists and otolaryngologists and their institutions providing comprehensive tinnitus care; (2) assess current tinnitus evaluation and management/treatment protocols used; (3) disseminate common practice improvements to all providers for enhancing overall tinnitus evaluation and management/treatment; and (4) evaluate implementation of improvements to include efficiency of implementation and efficacy of improvements.

The questionnaire was administered using SurveyMonkey (San Mateo, CA) and was disseminated by the otolaryngology and audiology consultants to the Army, Navy, and Air Force surgeons general and specialty leaders as well as through VA specialty leaders. Also, the HCE posted the link for the questionnaire on its website for 11 months. A total of 200 providers responded to the questionnaire, of which 13 did not indicate their specialty (eg, otolaryngology) or classification (eg, DoD active duty) and were excluded from data analysis. The 187 qualified respondents included 66 DoD audiologists, 120 VA audiologists, and 1 DoD otolaryngologist.

The questionnaire results indicated that DoD and VA respondents provided tinnitus services for their patients at similar rates (72% of DoD providers and 79% of VA providers). The use of PTM by those same providers, however, was far more widespread in VA (66%) than it was in DoD (37%). Of the providers indicating they did not offer tinnitus clinical services, the main reasons given were lack of necessary training/expertise, lack of time, and insufficient clinical support. The majority of respondents indicated they had training on tinnitus evaluation and/or management and that they were comfortable providing these services; despite this, most providers indicated a need or desire for tinnitus-specific training and education. These results suggested that more support and education for hearing health care providers were needed to implement PTM in VA and, especially, in DoD.

About half of the respondents indicated that psychological/behavioral treatment services, which would correspond to PTM levels 3 and 5, are available for patients at their facility who have tinnitus. It is encouraging to know that some patients with problematic tinnitus are receiving MH services. However, it is essential that patients with any degree of bothersome tinnitus have access to evidence-based clinical services, which would require CBT delivered by a qualified MH provider.

Conclusion

Numerous VA and DoD clinics have begun providing PTM. Individual sites, however, typically adapt the program during the process of implementation.^13,14 The most common adaptation that sites make to PTM is to proceed with level 3 skills education without the assistance of MH, and thus CBT, due to the lack of provider availability. It is unknown what impact this has on the effectiveness of PTM. Skills education forms the heart of PTM and addresses the needs of the majority of patients who seek intervention.

Collaboration with MH is integral to the delivery of PTM. Mental health providers partner in PTM levels 3 and 5 by providing CBT, which has the strongest evidence for reducing tinnitus distress among all interventions and always will be critical to the provision of PTM. Clearly VA MH programs need to increase involvement in veterans’ tinnitus management. Increased involvement may be accomplished by (1) developing training or other materials that increase understanding of MH’s role in addressing tinnitus; (2) developing pathways for coordination of care between audiology and MH providers, including different models of coordination based on individual site needs; and (3) documenting the prevalence of tinnitus-MH comorbidities to empirically justify the need for such coordination between audiology and MH providers.

To address gaps identified in the VA survey and in a similar questionnaire conducted by HCE regarding tinnitus care in VA and DoD, the NCRAR, HCE, and Walter Reed National Military Medical Center are collaborating on several initiatives to improve tinnitus services for service members and veterans.^13-15 These efforts include enhancing service member and veteran access to VA and DoD MH services in PTM.

Hearing loss and tinnitus (ringing or other noises in the ears or head) have been problematic for military service members and veterans for many years. Military personnel are exposed to high levels of noise in operational and training settings. In spite of hearing conservation efforts, hearing loss and auditory injuries (including tinnitus) continue to occur. Although current military leadership teaches the importance of hearing protection, that was not usually the case until the past few decades. Military leadership provides the means for hearing protection and monitors risk through conservation and hearing readiness programs. Unfortunately, the need for hearing during battle often overrides the expediency of using hearing protective devices.

Military members often equate hearing protection with increased vulnerability, widening the gap between preventive efforts and hearing preservation. It is therefore not surprising that tinnitus and hearing loss have been the 2 most common service-connected disabilities for veterans for a decade.¹ These conditions are irreversible; affected service members and veterans need strategies to cope with distress associated with these chronic conditions. Clinical care often is essential to manage the associated distress and mental health (MH) symptoms, such as sleep disturbance, irritability, isolation, tension, and low mood.

There is no cure for tinnitus, meaning there is no proven method to permanently eliminate or even reduce the perception of tinnitus. Intervention for tinnitus therefore is limited to methods intended to mitigate reactions to tinnitus, with the ultimate goal to facilitate good quality of life in spite of the perception of this unwanted auditory anomaly. These methods include numerous means of utilizing therapeutic sound.² Sound therapy, however, has been shown in controlled trials to be effective only when accompanied by counseling, which often focuses on teaching different coping skills.³ In such instances, MH providers can become an integral part of the hearing health team to assist patients in the management of their tinnitus.

Evidence-Based Practice

Evidence-based research should guide clinical services that are offered for tinnitus. Randomized controlled trials (RCTs) comprise the most important source for such evidence.⁴ Cochrane Reviews uses meta-analyses to examine rigorous RCTs to determine which methods have credible evidence. One of these reviews conducted in 2007 and updated in 2010 concluded that cognitive behavioral therapy (CBT) can improve depression scores and reduce distress for many people with bothersome tinnitus.^5,6 Another Cochrane Review concluded that sound therapy combined with counseling can be beneficial, but on its own, sound therapy has not been shown to result in significant benefit.³ Yet another Cochrane Review focused on using hearing aids with patients who have both hearing loss and bothersome tinnitus; the researchers concluded that “there is currently no evidence to support or refute their use as a more routine intervention for tinnitus.”⁷ However, many patients and clinicians report hearing aids are helpful for coping with tinnitus.

The American Academy of Otolaryngology–Head and Neck Surgery Foundation (AAO-HNSF) published a clinical practice guideline (CPG) for the management of tinnitus.⁸ Developing the CPG involved a comprehensive evaluation of the peer-reviewed literature, including the available Cochrane Reviews, to identify appropriate RCTs to inform evidence-based recommendations. Cognitive behavioral therapy was the only intervention for tinnitus recommended in the CPG. Cognitive behavioral therapy targets emotional response by identifying behaviors, thoughts, and beliefs that may be altered.⁹ For tinnitus, CBT typically includes stress management including relaxation exercises, purposeful distraction, and changing how individuals view and appraise their tinnitus.

Both the CPG and Cochrane Reviews concluded that CBT has the strongest evidence base for reducing effects of tinnitus. It should be noted that the CPG recommended teaching patients basic information about tinnitus management and stated that it was optional (due to limited research evidence) to use sound therapy to augment coping skills training.

Progressive Tinnitus Management

Tinnitus research at the VA National Center for Rehabilitative Auditory Research (NCRAR) has led to the development and refinement of an interdisciplinary program called Progressive Tinnitus Management (PTM). Audiologists and MH providers work together to deliver portions of the protocol. In addition, otolaryngologists are important for patients requiring a medical examination. Audiologists, MH providers, and otolaryngologists comprise the hearing health team for tinnitus management. The PTM program involves 5 stepped-care levels of management, and patients receive only the levels they need.

Level 1 is the referral level, which specifies guidelines for any clinician who encounters patients experiencing tinnitus. The “standard” referral is to audiology for a hearing evaluation (PTM level 2)—every patient reporting tinnitus should have a hearing evaluation and brief tinnitus assessment. Less typical would be an urgent referral to a different provider for certain symptoms such as referral to ENT for sudden hearing loss.

Patients who desire intervention for bothersome tinnitus are offered PTM skills education (level 3). At this level, patients are taught facts and skills that they need to self-manage their tinnitus-related problems. Ideally, the audiologist and MH provider collaborate to deliver the level 3 intervention, which utilizes a 5-session (2 with an audiologist and 3 with a MH provider) problem-solving method. Audiologists explain different forms of sound therapy, and MH providers deliver brief CBT. The research studies and clinics that use PTM have shown that the majority of patients who receive the level 3 skills education interventions have their tinnitus needs met to the degree that they do not desire further services.

Those relatively few patients who desire further services are invited for a PTM interdisciplinary evaluation (level 4), which involves a more in-depth needs evaluation by both an audiologist and a MH provider. Based on the outcome of the level 4 evaluation, clear treatment goals are discussed with the patient. If the patient and providers mutually agree that further intervention is needed, then the patient is offered PTM individualized support (level 5), which involves one-on-one services by an audiologist and/or a MH provider. The providers then build on the lessons taught during level 3 and address barriers to enacting the already discussed skills. The MH provider also may expand on CBT skills that were provided in level 3, offering care such as CBT for insomnia during level 5, depending on the specific needs and desires of the patient.

At the NCRAR, a pilot study and 2 RCTs of PTM have been completed.¹⁰ The first of these 2 RCTs was a clinical effectiveness study of PTM that was conducted in 2 VA audiology clinics: Memphis, Tennessee, and West Haven, Connecticut.¹¹ Patients who came to the clinics signed up for the study if they felt that the PTM level 3 intervention might be helpful. Half of the 300 veterans in the study were enrolled to receive PTM right away, and half were put on a 6-month wait list. The PTM group showed significantly greater benefit than that of the wait-list group.

The second RCT of PTM was motivated by the high number of service members and veterans with a history of traumatic brain injury (TBI), which is strongly associated with tinnitus.¹² The PTM level 3 skills education was administered to participants individually over the telephone by both an audiologist and a psychologist. Participants, located all over the U.S., had bothersome tinnitus, and some had experienced ≥ 1 TBI. They were randomized to receive either Tele-PTM immediately for 6 months or to be put on a 6-month wait list. The Tele-PTM group showed much greater improvement than that of the wait-list group.

Both of these recent RCTs have validated the effectiveness of PTM and demonstrated that PTM should be considered for the practice of evidence-based tinnitus management. PTM is mostly consistent with the AAO-HNSF CPG and provides a structured and defined framework for implementing both assessment and intervention services for patients who report tinnitus. As such, VA Central Office has endorsed PTM as an effective intervention for tinnitus management and has recommended its use at VAMCs. The NCRAR researchers have provided PTM training to hundreds of VA audiologists and MH providers, yet the level of implementation across the VA system of care varies widely.

VA Survey

In 2015, in partnership with the VA Offices of Audiology and Speech Pathology and Mental Health Services, and the Health Services Research & Development/Quality Enhancement Research Initiative (HSR&D/QUERI), the NCRAR conducted a study to examine PTM variation across sites via surveys and/or interviews of VA Audiology and MH programs nationwide.^13,14 The objectives of this study were to: (1) describe current tinnitus-management practices in VAMCs; (2) identify barriers and facilitators to PTM program implementation based on clinics that have fully, partially, or not implemented PTM; and (3) determine readiness to implement PTM within VISN 20 (Northwest states and Alaska).

Clinicians at VAMCs nationwide were surveyed regarding current provision of tinnitus clinical services. Requests were sent to audiology programs and MH programs at 142 major VAMCs along with instructions to complete the online survey. Responses were received from 87 audiologists and 66 MH providers. Clinicians at VAMCs with full PTM, partial PTM, and no-PTM (based on survey results) were then interviewed regarding site-specific barriers and facilitators to implementing and providing PTM, readiness to adopt PTM, and strategies for full PTM implementation.

Key findings from the study demonstrated the following: (1) There is considerable between-site variability in how PTM is implemented, particularly with the delivery of the MH portion of the protocol; (2) audiologists show higher levels of readiness to provide tinnitus services than do MH providers (7% of MH survey respondents vs 62% of audiologists reported their site implementing PTM); (3) 66% of MH survey respondents were interested in receiving training in tinnitus management (note that online PTM training for MH does not yet exist); (4) PTM implementation barriers include audio-visual technology issues, room scheduling, as well as lack of collaboration and colocation between MH and audiology departments, administrative time/support, group facilitator skills, and availability of PTM materials.

Overall, results of this HSR&D/QUERI-funded study suggested the need to develop MH-specific training to support the necessary interdisciplinary engagement. Although a patient workbook is available to order and visual presentation aids may be accessed online, it became clear that lack of MH participation in the inherently interdisciplinary PTM skills education was the most common deviation from PTM.

DoD an VA Questionnaire

In 2014 the DoD Hearing Center of Excellence (HCE) conducted the DoD and VA Tinnitus Evaluation, Management, and Treatment Assessment.¹³ The HCE conducted this questionnaire under the Tinnitus Care Quality Improvement, Process Development, and Implementation Plan, to develop, establish, and implement an interdisciplinary and ongoing process to continually assess and improve the quality and continuum of tinnitus care delivered to service members and veterans at a consistent, enterprise-wide level. The HCE developed the questionnaire to: (1) identify DoD and VA audiologists and otolaryngologists and their institutions providing comprehensive tinnitus care; (2) assess current tinnitus evaluation and management/treatment protocols used; (3) disseminate common practice improvements to all providers for enhancing overall tinnitus evaluation and management/treatment; and (4) evaluate implementation of improvements to include efficiency of implementation and efficacy of improvements.

The questionnaire was administered using SurveyMonkey (San Mateo, CA) and was disseminated by the otolaryngology and audiology consultants to the Army, Navy, and Air Force surgeons general and specialty leaders as well as through VA specialty leaders. Also, the HCE posted the link for the questionnaire on its website for 11 months. A total of 200 providers responded to the questionnaire, of which 13 did not indicate their specialty (eg, otolaryngology) or classification (eg, DoD active duty) and were excluded from data analysis. The 187 qualified respondents included 66 DoD audiologists, 120 VA audiologists, and 1 DoD otolaryngologist.

The questionnaire results indicated that DoD and VA respondents provided tinnitus services for their patients at similar rates (72% of DoD providers and 79% of VA providers). The use of PTM by those same providers, however, was far more widespread in VA (66%) than it was in DoD (37%). Of the providers indicating they did not offer tinnitus clinical services, the main reasons given were lack of necessary training/expertise, lack of time, and insufficient clinical support. The majority of respondents indicated they had training on tinnitus evaluation and/or management and that they were comfortable providing these services; despite this, most providers indicated a need or desire for tinnitus-specific training and education. These results suggested that more support and education for hearing health care providers were needed to implement PTM in VA and, especially, in DoD.

About half of the respondents indicated that psychological/behavioral treatment services, which would correspond to PTM levels 3 and 5, are available for patients at their facility who have tinnitus. It is encouraging to know that some patients with problematic tinnitus are receiving MH services. However, it is essential that patients with any degree of bothersome tinnitus have access to evidence-based clinical services, which would require CBT delivered by a qualified MH provider.

Conclusion

Numerous VA and DoD clinics have begun providing PTM. Individual sites, however, typically adapt the program during the process of implementation.^13,14 The most common adaptation that sites make to PTM is to proceed with level 3 skills education without the assistance of MH, and thus CBT, due to the lack of provider availability. It is unknown what impact this has on the effectiveness of PTM. Skills education forms the heart of PTM and addresses the needs of the majority of patients who seek intervention.

Collaboration with MH is integral to the delivery of PTM. Mental health providers partner in PTM levels 3 and 5 by providing CBT, which has the strongest evidence for reducing tinnitus distress among all interventions and always will be critical to the provision of PTM. Clearly VA MH programs need to increase involvement in veterans’ tinnitus management. Increased involvement may be accomplished by (1) developing training or other materials that increase understanding of MH’s role in addressing tinnitus; (2) developing pathways for coordination of care between audiology and MH providers, including different models of coordination based on individual site needs; and (3) documenting the prevalence of tinnitus-MH comorbidities to empirically justify the need for such coordination between audiology and MH providers.

To address gaps identified in the VA survey and in a similar questionnaire conducted by HCE regarding tinnitus care in VA and DoD, the NCRAR, HCE, and Walter Reed National Military Medical Center are collaborating on several initiatives to improve tinnitus services for service members and veterans.^13-15 These efforts include enhancing service member and veteran access to VA and DoD MH services in PTM.

Photo by Chad McNeeley

Results of a phase 3 trial revealed similar outcomes in patients who underwent allogeneic hematopoietic stem cell transplant (HSCT) to treat myelodysplastic syndromes (MDS), regardless of the conditioning regimen they received.

Rates of engraftment, graft-vs-host disease (GVHD), relapse, and survival were similar between patients who received reduced-intensity conditioning (RIC) and those who received standard myeloablative conditioning (MAC) before HSCT.

Researchers reported these results in the Journal of Clinical Oncology.

“Our study shed new light on expected benefits of a reduced-intensity conditioning regimen that can be offered as a curative treatment approach, especially in older patients with MDS,” said study author Nicolaus Kröger, MD, of University Hospital Eppendorf in Hamburg, Germany.

Patient characteristics

The study, known as RICMAC, involved 129 patients who underwent HSCT between May 2004 and December 2012 at 18 transplant units in 7 countries.

Patients were randomized in a 1:1 ratio to RIC (n=65) or MAC (n=64) and were stratified according to donor type, age, and blast count.

The median age was 50 (range, 19-64) in the MAC arm and 51 (range, 22-63) in the RIC arm. The median blast percentage was 4% (range, 0-18) and 5% (range, 0-18), respectively.

According to IPSS, most patients in both arms had intermediate-I-risk disease (28 MAC, 25 RIC) or intermediate-II-risk disease (18 MAC, 24 RIC).

Similar numbers of patients in each arm had low cytogenetic risk (24 MAC, 28 RIC), intermediate cytogenetic risk (17 MAC, 13 RIC), and high cytogenetic risk (17 MAC, 18 RIC).

Thirty-three patients in the MAC arm and 32 in the RIC arm received ATG as GVHD prophylaxis.

Patients received grafts from matched related donors (17 MAC, 16 RIC), matched unrelated donors (36 MAC, 38 RIC), or mismatched related/unrelated donors (11 in both arms).

Most patients received peripheral blood stem cell grafts—61 in the MAC arm and 59 in the RIC arm.

Results

The researchers said engraftment was comparable between the arms. There were 4 graft failures in the MAC arm and 3 in the RIC arm (P=0.72). The median time to leukocyte engraftment was 15 days in both arms. The median time to platelet engraftment was 15 days in the RIC arm and 16 in the MAC arm (P=0.33).

There was no significant difference in the cumulative incidence of GVHD between the RIC and MAC arms:

• Grade 2-4 acute GVHD—32.3% and 37.5%, respectively
• Grade 3-4 acute GVHD—15% and 14%, respectively (P=0.35 for between-arm difference for all acute GVHD)
• Chronic GVHD—61.6% and 64.7%, respectively (P=0.76).

Though the occurrence of infection was similar between the MAC and RIC arms (48 and 44, respectively), the rate of infection was higher in the MAC arm than the RIC arm.

The rate of infection in the first 100 days was 6.9 per 100 person-years in the MAC arm and 4.3 in the RIC arm (P=0.002). The rate of infection during the total follow-up was 2.0 per 100 person-years in the MAC arm and 1.4 in the RIC arm (P=0.002).

There was no significant difference between the RIC and MAC arms with regard to the cumulative incidence of nonrelapse mortality after 1 year—16.9% and 25.3%, respectively (P=0.29).

And there was no significant difference in the cumulative incidence of relapse at 2 years—17% and 14.8%, respectively (P=0.6).

The 2-year relapse-free survival rate was similar in the MAC and RIC arms—58.3% and 62.4% (P=0.58)—as was the 2-year overall survival rate—63.2% and 76.3%, respectively (P=0.08). 

Photo by Chad McNeeley

Results of a phase 3 trial revealed similar outcomes in patients who underwent allogeneic hematopoietic stem cell transplant (HSCT) to treat myelodysplastic syndromes (MDS), regardless of the conditioning regimen they received.

Rates of engraftment, graft-vs-host disease (GVHD), relapse, and survival were similar between patients who received reduced-intensity conditioning (RIC) and those who received standard myeloablative conditioning (MAC) before HSCT.

Researchers reported these results in the Journal of Clinical Oncology.

“Our study shed new light on expected benefits of a reduced-intensity conditioning regimen that can be offered as a curative treatment approach, especially in older patients with MDS,” said study author Nicolaus Kröger, MD, of University Hospital Eppendorf in Hamburg, Germany.

Patient characteristics

The study, known as RICMAC, involved 129 patients who underwent HSCT between May 2004 and December 2012 at 18 transplant units in 7 countries.

Patients were randomized in a 1:1 ratio to RIC (n=65) or MAC (n=64) and were stratified according to donor type, age, and blast count.

The median age was 50 (range, 19-64) in the MAC arm and 51 (range, 22-63) in the RIC arm. The median blast percentage was 4% (range, 0-18) and 5% (range, 0-18), respectively.

According to IPSS, most patients in both arms had intermediate-I-risk disease (28 MAC, 25 RIC) or intermediate-II-risk disease (18 MAC, 24 RIC).

Similar numbers of patients in each arm had low cytogenetic risk (24 MAC, 28 RIC), intermediate cytogenetic risk (17 MAC, 13 RIC), and high cytogenetic risk (17 MAC, 18 RIC).

Thirty-three patients in the MAC arm and 32 in the RIC arm received ATG as GVHD prophylaxis.

Patients received grafts from matched related donors (17 MAC, 16 RIC), matched unrelated donors (36 MAC, 38 RIC), or mismatched related/unrelated donors (11 in both arms).

Most patients received peripheral blood stem cell grafts—61 in the MAC arm and 59 in the RIC arm.

Results

The researchers said engraftment was comparable between the arms. There were 4 graft failures in the MAC arm and 3 in the RIC arm (P=0.72). The median time to leukocyte engraftment was 15 days in both arms. The median time to platelet engraftment was 15 days in the RIC arm and 16 in the MAC arm (P=0.33).

There was no significant difference in the cumulative incidence of GVHD between the RIC and MAC arms:

• Grade 2-4 acute GVHD—32.3% and 37.5%, respectively
• Grade 3-4 acute GVHD—15% and 14%, respectively (P=0.35 for between-arm difference for all acute GVHD)
• Chronic GVHD—61.6% and 64.7%, respectively (P=0.76).

Though the occurrence of infection was similar between the MAC and RIC arms (48 and 44, respectively), the rate of infection was higher in the MAC arm than the RIC arm.

The rate of infection in the first 100 days was 6.9 per 100 person-years in the MAC arm and 4.3 in the RIC arm (P=0.002). The rate of infection during the total follow-up was 2.0 per 100 person-years in the MAC arm and 1.4 in the RIC arm (P=0.002).

There was no significant difference between the RIC and MAC arms with regard to the cumulative incidence of nonrelapse mortality after 1 year—16.9% and 25.3%, respectively (P=0.29).

And there was no significant difference in the cumulative incidence of relapse at 2 years—17% and 14.8%, respectively (P=0.6).

The 2-year relapse-free survival rate was similar in the MAC and RIC arms—58.3% and 62.4% (P=0.58)—as was the 2-year overall survival rate—63.2% and 76.3%, respectively (P=0.08). 

Photo by Chad McNeeley

Results of a phase 3 trial revealed similar outcomes in patients who underwent allogeneic hematopoietic stem cell transplant (HSCT) to treat myelodysplastic syndromes (MDS), regardless of the conditioning regimen they received.

Rates of engraftment, graft-vs-host disease (GVHD), relapse, and survival were similar between patients who received reduced-intensity conditioning (RIC) and those who received standard myeloablative conditioning (MAC) before HSCT.

Researchers reported these results in the Journal of Clinical Oncology.

“Our study shed new light on expected benefits of a reduced-intensity conditioning regimen that can be offered as a curative treatment approach, especially in older patients with MDS,” said study author Nicolaus Kröger, MD, of University Hospital Eppendorf in Hamburg, Germany.

Patient characteristics

The study, known as RICMAC, involved 129 patients who underwent HSCT between May 2004 and December 2012 at 18 transplant units in 7 countries.

Patients were randomized in a 1:1 ratio to RIC (n=65) or MAC (n=64) and were stratified according to donor type, age, and blast count.

The median age was 50 (range, 19-64) in the MAC arm and 51 (range, 22-63) in the RIC arm. The median blast percentage was 4% (range, 0-18) and 5% (range, 0-18), respectively.

According to IPSS, most patients in both arms had intermediate-I-risk disease (28 MAC, 25 RIC) or intermediate-II-risk disease (18 MAC, 24 RIC).

Similar numbers of patients in each arm had low cytogenetic risk (24 MAC, 28 RIC), intermediate cytogenetic risk (17 MAC, 13 RIC), and high cytogenetic risk (17 MAC, 18 RIC).

Thirty-three patients in the MAC arm and 32 in the RIC arm received ATG as GVHD prophylaxis.

Patients received grafts from matched related donors (17 MAC, 16 RIC), matched unrelated donors (36 MAC, 38 RIC), or mismatched related/unrelated donors (11 in both arms).

Most patients received peripheral blood stem cell grafts—61 in the MAC arm and 59 in the RIC arm.

Results

The researchers said engraftment was comparable between the arms. There were 4 graft failures in the MAC arm and 3 in the RIC arm (P=0.72). The median time to leukocyte engraftment was 15 days in both arms. The median time to platelet engraftment was 15 days in the RIC arm and 16 in the MAC arm (P=0.33).

There was no significant difference in the cumulative incidence of GVHD between the RIC and MAC arms:

• Grade 2-4 acute GVHD—32.3% and 37.5%, respectively
• Grade 3-4 acute GVHD—15% and 14%, respectively (P=0.35 for between-arm difference for all acute GVHD)
• Chronic GVHD—61.6% and 64.7%, respectively (P=0.76).

Though the occurrence of infection was similar between the MAC and RIC arms (48 and 44, respectively), the rate of infection was higher in the MAC arm than the RIC arm.

The rate of infection in the first 100 days was 6.9 per 100 person-years in the MAC arm and 4.3 in the RIC arm (P=0.002). The rate of infection during the total follow-up was 2.0 per 100 person-years in the MAC arm and 1.4 in the RIC arm (P=0.002).

There was no significant difference between the RIC and MAC arms with regard to the cumulative incidence of nonrelapse mortality after 1 year—16.9% and 25.3%, respectively (P=0.29).

And there was no significant difference in the cumulative incidence of relapse at 2 years—17% and 14.8%, respectively (P=0.6).

The 2-year relapse-free survival rate was similar in the MAC and RIC arms—58.3% and 62.4% (P=0.58)—as was the 2-year overall survival rate—63.2% and 76.3%, respectively (P=0.08). 

General Medical Sciences

The US Food and Drug Administration (FDA) has granted orphan drug designation for SB-525 as a treatment for hemophilia A.

SB-525 is a recombinant adeno-associated virus 2/6 (AAV2/6) vector that expresses a human F8 complementary DNA (cDNA) cassette.

The vector encodes a liver-specific promoter module, and AAV2/6 exhibits liver tropism.

This provides the potential for long-term hepatic production of factor VIII in patients with hemophilia A, according to Sangamo Therapeutics, Inc., the company developing SB-525.

In research presented at the 2016 ASH Annual Meeting (abstract 1173), SB-525 induced the expression of significant levels of human factor VIII in mice and non-human primates (NHPs). SB-525 also corrected the bleeding defect in a mouse model of hemophilia A.

Dosing studies in NHPs demonstrated a robust and reproducible dose response curve, according to researchers. In these animals, mean human factor VIII levels ranged from 5% of normal at the lowest dose to 230% at the highest (AAV doses in the 6 x 10¹¹ – 6 x 10¹² vgs/kg range).

The researchers said the peak circulating human factor VIII levels in these experiments exceeded levels previously reported in NHPs. And this could significantly reduce the dose required to achieve therapeutically relevant levels in human subjects.

Sangamo is planning to open a phase 1/2 trial of SB-525 in adults with hemophilia A later this quarter.

About orphan designation

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

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

General Medical Sciences

The US Food and Drug Administration (FDA) has granted orphan drug designation for SB-525 as a treatment for hemophilia A.

SB-525 is a recombinant adeno-associated virus 2/6 (AAV2/6) vector that expresses a human F8 complementary DNA (cDNA) cassette.

The vector encodes a liver-specific promoter module, and AAV2/6 exhibits liver tropism.

This provides the potential for long-term hepatic production of factor VIII in patients with hemophilia A, according to Sangamo Therapeutics, Inc., the company developing SB-525.

In research presented at the 2016 ASH Annual Meeting (abstract 1173), SB-525 induced the expression of significant levels of human factor VIII in mice and non-human primates (NHPs). SB-525 also corrected the bleeding defect in a mouse model of hemophilia A.

Dosing studies in NHPs demonstrated a robust and reproducible dose response curve, according to researchers. In these animals, mean human factor VIII levels ranged from 5% of normal at the lowest dose to 230% at the highest (AAV doses in the 6 x 10¹¹ – 6 x 10¹² vgs/kg range).

The researchers said the peak circulating human factor VIII levels in these experiments exceeded levels previously reported in NHPs. And this could significantly reduce the dose required to achieve therapeutically relevant levels in human subjects.

Sangamo is planning to open a phase 1/2 trial of SB-525 in adults with hemophilia A later this quarter.

About orphan designation

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

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

General Medical Sciences

The US Food and Drug Administration (FDA) has granted orphan drug designation for SB-525 as a treatment for hemophilia A.

SB-525 is a recombinant adeno-associated virus 2/6 (AAV2/6) vector that expresses a human F8 complementary DNA (cDNA) cassette.

The vector encodes a liver-specific promoter module, and AAV2/6 exhibits liver tropism.

This provides the potential for long-term hepatic production of factor VIII in patients with hemophilia A, according to Sangamo Therapeutics, Inc., the company developing SB-525.

In research presented at the 2016 ASH Annual Meeting (abstract 1173), SB-525 induced the expression of significant levels of human factor VIII in mice and non-human primates (NHPs). SB-525 also corrected the bleeding defect in a mouse model of hemophilia A.

Dosing studies in NHPs demonstrated a robust and reproducible dose response curve, according to researchers. In these animals, mean human factor VIII levels ranged from 5% of normal at the lowest dose to 230% at the highest (AAV doses in the 6 x 10¹¹ – 6 x 10¹² vgs/kg range).

The researchers said the peak circulating human factor VIII levels in these experiments exceeded levels previously reported in NHPs. And this could significantly reduce the dose required to achieve therapeutically relevant levels in human subjects.

Sangamo is planning to open a phase 1/2 trial of SB-525 in adults with hemophilia A later this quarter.

About orphan designation

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

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

Image by Spencer Phillips

The US Food and Drug Administration (FDA) has granted fast track designation to SB-FIX for the treatment of hemophilia B.

SB-FIX is a zinc finger nuclease (ZFN)-mediated genome-editing product candidate.

It is designed to be used as a one-time treatment that will provide stable, continuous production of factor IX (FIX) for the lifetime of the patient.

The ZFN-mediated in vivo genome-editing approach makes use of the albumin gene locus, a highly expressing and liver-specific genomic “safe-harbor site,” that can be edited with ZFNs to accept and express therapeutic genes.

The approach is designed to enable the patient’s liver to permanently produce circulating therapeutic levels of a corrective protein product.

This differs from conventional adeno-associated virus complementary DNA gene therapy approaches, which are non-integrating and may “wash out” of the liver as cells divide and turn over.

Sangamo Therapeutics, Inc., the company developing SB-FIX, has initiated a phase 1/2 trial of SB-FIX in adults with hemophilia B. The trial is open, and subjects are being screened for enrollment.

In addition to fast track designation, SB-FIX has orphan designation from the FDA (granted in 2016).

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 biologic 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.

About orphan designation

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

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

Image by Spencer Phillips

The US Food and Drug Administration (FDA) has granted fast track designation to SB-FIX for the treatment of hemophilia B.

SB-FIX is a zinc finger nuclease (ZFN)-mediated genome-editing product candidate.

It is designed to be used as a one-time treatment that will provide stable, continuous production of factor IX (FIX) for the lifetime of the patient.

The ZFN-mediated in vivo genome-editing approach makes use of the albumin gene locus, a highly expressing and liver-specific genomic “safe-harbor site,” that can be edited with ZFNs to accept and express therapeutic genes.

The approach is designed to enable the patient’s liver to permanently produce circulating therapeutic levels of a corrective protein product.

This differs from conventional adeno-associated virus complementary DNA gene therapy approaches, which are non-integrating and may “wash out” of the liver as cells divide and turn over.

Sangamo Therapeutics, Inc., the company developing SB-FIX, has initiated a phase 1/2 trial of SB-FIX in adults with hemophilia B. The trial is open, and subjects are being screened for enrollment.

In addition to fast track designation, SB-FIX has orphan designation from the FDA (granted in 2016).

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 biologic 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.

About orphan designation

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

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

Image by Spencer Phillips

The US Food and Drug Administration (FDA) has granted fast track designation to SB-FIX for the treatment of hemophilia B.

SB-FIX is a zinc finger nuclease (ZFN)-mediated genome-editing product candidate.

It is designed to be used as a one-time treatment that will provide stable, continuous production of factor IX (FIX) for the lifetime of the patient.

The ZFN-mediated in vivo genome-editing approach makes use of the albumin gene locus, a highly expressing and liver-specific genomic “safe-harbor site,” that can be edited with ZFNs to accept and express therapeutic genes.

The approach is designed to enable the patient’s liver to permanently produce circulating therapeutic levels of a corrective protein product.

This differs from conventional adeno-associated virus complementary DNA gene therapy approaches, which are non-integrating and may “wash out” of the liver as cells divide and turn over.

Sangamo Therapeutics, Inc., the company developing SB-FIX, has initiated a phase 1/2 trial of SB-FIX in adults with hemophilia B. The trial is open, and subjects are being screened for enrollment.

In addition to fast track designation, SB-FIX has orphan designation from the FDA (granted in 2016).

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 biologic 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.

About orphan designation

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

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

Photo by George Hodan

Tablet-based, multimedia-enhanced medical training improves examination results among medical students and residents, according to research published in PLOS ONE.

“Ideally, medical training should be taking place at the patient’s bedside rather than in lecture halls,” said study author Daniel C. Baumgart, MD, PhD, of Charité Medical School at Humboldt-University of Berlin in Germany.

“Communication devices, such as tablet computers, digital assistants, and smartphones, make medical data and learning materials available anywhere and anytime. Therefore, our aim was to study the impact of a systematic integration of such devices into medical teaching and training.”

The researchers studied 55 final-year medical students and medical residents doing an inpatient service rotation. The subjects were assigned to receive a tablet personal computer (PC) with a custom multimedia education software package (n=24) or to a control group (n=31).

The multimedia package tested included the Mobile Medical Educator software package (developed in-house) as well as other multimedia learning materials, such as eBooks, eJournals, slide kits, podcasts, videos, animations, image data, and the American College of Physicians’ validated self-assessment software.

The participants had to complete MKSAP® (medical knowledge self-assessment program) exams at the beginning and the end of their training rotations. The final MKSAP score was the study’s primary endpoint.

The mean MKSAP score improved in the tablet PC group but not the control group. The final mean score was significantly higher in the tablet PC group than the control group—59 and 48, respectively (P<0.001).

When the researchers adjusted their analysis for subjects’ baseline score and potential confounders, the tablet PC group had, on average, 11% better MKSAP test results than the control group (P<0.001).

“We were able to show improvements in internal medicine exam results, which were independent of socio-demographic factors,” Dr Baumgart said. “Participant feedback was particularly positive in relation to an integrated, fully digitized workflow for clinical practice and training.” 

Photo by George Hodan

Tablet-based, multimedia-enhanced medical training improves examination results among medical students and residents, according to research published in PLOS ONE.

“Ideally, medical training should be taking place at the patient’s bedside rather than in lecture halls,” said study author Daniel C. Baumgart, MD, PhD, of Charité Medical School at Humboldt-University of Berlin in Germany.

“Communication devices, such as tablet computers, digital assistants, and smartphones, make medical data and learning materials available anywhere and anytime. Therefore, our aim was to study the impact of a systematic integration of such devices into medical teaching and training.”

The researchers studied 55 final-year medical students and medical residents doing an inpatient service rotation. The subjects were assigned to receive a tablet personal computer (PC) with a custom multimedia education software package (n=24) or to a control group (n=31).

The multimedia package tested included the Mobile Medical Educator software package (developed in-house) as well as other multimedia learning materials, such as eBooks, eJournals, slide kits, podcasts, videos, animations, image data, and the American College of Physicians’ validated self-assessment software.

The participants had to complete MKSAP® (medical knowledge self-assessment program) exams at the beginning and the end of their training rotations. The final MKSAP score was the study’s primary endpoint.

The mean MKSAP score improved in the tablet PC group but not the control group. The final mean score was significantly higher in the tablet PC group than the control group—59 and 48, respectively (P<0.001).

When the researchers adjusted their analysis for subjects’ baseline score and potential confounders, the tablet PC group had, on average, 11% better MKSAP test results than the control group (P<0.001).

“We were able to show improvements in internal medicine exam results, which were independent of socio-demographic factors,” Dr Baumgart said. “Participant feedback was particularly positive in relation to an integrated, fully digitized workflow for clinical practice and training.” 

Photo by George Hodan

Tablet-based, multimedia-enhanced medical training improves examination results among medical students and residents, according to research published in PLOS ONE.

“Ideally, medical training should be taking place at the patient’s bedside rather than in lecture halls,” said study author Daniel C. Baumgart, MD, PhD, of Charité Medical School at Humboldt-University of Berlin in Germany.

“Communication devices, such as tablet computers, digital assistants, and smartphones, make medical data and learning materials available anywhere and anytime. Therefore, our aim was to study the impact of a systematic integration of such devices into medical teaching and training.”

The researchers studied 55 final-year medical students and medical residents doing an inpatient service rotation. The subjects were assigned to receive a tablet personal computer (PC) with a custom multimedia education software package (n=24) or to a control group (n=31).

The multimedia package tested included the Mobile Medical Educator software package (developed in-house) as well as other multimedia learning materials, such as eBooks, eJournals, slide kits, podcasts, videos, animations, image data, and the American College of Physicians’ validated self-assessment software.

The participants had to complete MKSAP® (medical knowledge self-assessment program) exams at the beginning and the end of their training rotations. The final MKSAP score was the study’s primary endpoint.

The mean MKSAP score improved in the tablet PC group but not the control group. The final mean score was significantly higher in the tablet PC group than the control group—59 and 48, respectively (P<0.001).

When the researchers adjusted their analysis for subjects’ baseline score and potential confounders, the tablet PC group had, on average, 11% better MKSAP test results than the control group (P<0.001).

“We were able to show improvements in internal medicine exam results, which were independent of socio-demographic factors,” Dr Baumgart said. “Participant feedback was particularly positive in relation to an integrated, fully digitized workflow for clinical practice and training.” 

Every additional day of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia in hospitalized children was associated with a 50% increased risk of developing a complication, reported Rana F. Hamdy, MD, of Children’s National Health System, Washington, and her associates.

That was one of the findings of a study performed to determine the epidemiology, clinical outcomes, and risk factors for treatment failure in pediatric MRSA bacteremia. It took place in three hospitals, one each in Philadelphia, Baltimore, and Salt Lake City.

Courtesy U.S. National Institute of Allergy and Infectious Diseases

[email protected]

Every additional day of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia in hospitalized children was associated with a 50% increased risk of developing a complication, reported Rana F. Hamdy, MD, of Children’s National Health System, Washington, and her associates.

That was one of the findings of a study performed to determine the epidemiology, clinical outcomes, and risk factors for treatment failure in pediatric MRSA bacteremia. It took place in three hospitals, one each in Philadelphia, Baltimore, and Salt Lake City.

Courtesy U.S. National Institute of Allergy and Infectious Diseases

[email protected]

Every additional day of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia in hospitalized children was associated with a 50% increased risk of developing a complication, reported Rana F. Hamdy, MD, of Children’s National Health System, Washington, and her associates.

That was one of the findings of a study performed to determine the epidemiology, clinical outcomes, and risk factors for treatment failure in pediatric MRSA bacteremia. It took place in three hospitals, one each in Philadelphia, Baltimore, and Salt Lake City.

Courtesy U.S. National Institute of Allergy and Infectious Diseases

[email protected]