In 2013, the Centers for Medicare and Medicaid Services (CMS) issued a guidance to reduce reimbursement issues for Mohs micrographic surgery (MMS).¹ One crucial question that remains is when and if these documentation guidelines will be formally implemented. The guidelines outlined by the CMS currently are regarded as suggestions until Medicare contractors adopt them into the local coverage determinations (LCDs).

Key Documentation Guidelines

To reduce MMS reimbursement issues, documentation in the patient’s medical record should support the medical necessity of the procedure and reflect the number and anatomic locations of specimens taken and the reason for the procedure should be clearly communicated. The specific tumor type also should be approved for treatment with MMS in the respective LCD.

Nonphysician providers are not authorized by Medicare to perform MMS. To ensure proper coding, both surgery and pathology must be performed by a single physician and should be supported by documentation in the patient’s medical record (eg, relevant chart notes should be made under the provider’s signature). These documentation guidelines are not new but are included in the CMS guidance to reiterate their importance in reducing MMS reimbursement issues.

Per customary clinical practice, the CMS guidance specifies that MMS documentation should include gross description of the tissue removed, including the location, number, and size of the lesions, as well as how many specimens were removed for each stage. However, the guidance diverges from routine MMS documentation requirements in its emphasis on providing a histologic description of the tissue removed. The guidance suggests that the depth of tumor invasion, pathologic pattern, cell morphology (which is not typically specified for skin cancers), and, if present, the existence of perineural invasion or scar tissue should be documented. If these features are constant across stages, they only need to be noted for the first stage.

Adapting Guidelines for Clinical Practice

The CMS guidance may create some conundrums for physicians regarding MMS documentation; for instance, if a tumor is cleared in one stage, as is often the case, no tumor will be seen on glass slides prepared to assess tissue margins during the procedure and therefore documentation of characteristics like depth and pattern will be impossible. Similarly, cell morphology is not a feature that usually is relevant for most squamous and basal cell carcinomas, although it may be useful in certain unusual instances, such as in cases of rare tumors with particular histologic features that may influence management and/or prognosis. When in doubt regarding the appropriate documentation method for MMS, the surgeon should use his or her best judgment based on clinical experience rather than simply following guidelines that may not be applicable.

Final Thoughts

The CMS guidance serves as a reminder of the documentation requirements for MMS and extends current practice by suggesting a detailed microscopic description of the removed tissue. The American Academy of Dermatology has developed a guide to help Mohs surgeons provide the necessary documentation without creating cumbersome chart notes.² Mohs surgeons should consult the most recent version of the LCD that applies to their geographic area to determine if the new documentation guidelines have been adopted.

In 2013, the Centers for Medicare and Medicaid Services (CMS) issued a guidance to reduce reimbursement issues for Mohs micrographic surgery (MMS).¹ One crucial question that remains is when and if these documentation guidelines will be formally implemented. The guidelines outlined by the CMS currently are regarded as suggestions until Medicare contractors adopt them into the local coverage determinations (LCDs).

Key Documentation Guidelines

To reduce MMS reimbursement issues, documentation in the patient’s medical record should support the medical necessity of the procedure and reflect the number and anatomic locations of specimens taken and the reason for the procedure should be clearly communicated. The specific tumor type also should be approved for treatment with MMS in the respective LCD.

Nonphysician providers are not authorized by Medicare to perform MMS. To ensure proper coding, both surgery and pathology must be performed by a single physician and should be supported by documentation in the patient’s medical record (eg, relevant chart notes should be made under the provider’s signature). These documentation guidelines are not new but are included in the CMS guidance to reiterate their importance in reducing MMS reimbursement issues.

Per customary clinical practice, the CMS guidance specifies that MMS documentation should include gross description of the tissue removed, including the location, number, and size of the lesions, as well as how many specimens were removed for each stage. However, the guidance diverges from routine MMS documentation requirements in its emphasis on providing a histologic description of the tissue removed. The guidance suggests that the depth of tumor invasion, pathologic pattern, cell morphology (which is not typically specified for skin cancers), and, if present, the existence of perineural invasion or scar tissue should be documented. If these features are constant across stages, they only need to be noted for the first stage.

Adapting Guidelines for Clinical Practice

The CMS guidance may create some conundrums for physicians regarding MMS documentation; for instance, if a tumor is cleared in one stage, as is often the case, no tumor will be seen on glass slides prepared to assess tissue margins during the procedure and therefore documentation of characteristics like depth and pattern will be impossible. Similarly, cell morphology is not a feature that usually is relevant for most squamous and basal cell carcinomas, although it may be useful in certain unusual instances, such as in cases of rare tumors with particular histologic features that may influence management and/or prognosis. When in doubt regarding the appropriate documentation method for MMS, the surgeon should use his or her best judgment based on clinical experience rather than simply following guidelines that may not be applicable.

Final Thoughts

The CMS guidance serves as a reminder of the documentation requirements for MMS and extends current practice by suggesting a detailed microscopic description of the removed tissue. The American Academy of Dermatology has developed a guide to help Mohs surgeons provide the necessary documentation without creating cumbersome chart notes.² Mohs surgeons should consult the most recent version of the LCD that applies to their geographic area to determine if the new documentation guidelines have been adopted.

In 2013, the Centers for Medicare and Medicaid Services (CMS) issued a guidance to reduce reimbursement issues for Mohs micrographic surgery (MMS).¹ One crucial question that remains is when and if these documentation guidelines will be formally implemented. The guidelines outlined by the CMS currently are regarded as suggestions until Medicare contractors adopt them into the local coverage determinations (LCDs).

Key Documentation Guidelines

To reduce MMS reimbursement issues, documentation in the patient’s medical record should support the medical necessity of the procedure and reflect the number and anatomic locations of specimens taken and the reason for the procedure should be clearly communicated. The specific tumor type also should be approved for treatment with MMS in the respective LCD.

Nonphysician providers are not authorized by Medicare to perform MMS. To ensure proper coding, both surgery and pathology must be performed by a single physician and should be supported by documentation in the patient’s medical record (eg, relevant chart notes should be made under the provider’s signature). These documentation guidelines are not new but are included in the CMS guidance to reiterate their importance in reducing MMS reimbursement issues.

Per customary clinical practice, the CMS guidance specifies that MMS documentation should include gross description of the tissue removed, including the location, number, and size of the lesions, as well as how many specimens were removed for each stage. However, the guidance diverges from routine MMS documentation requirements in its emphasis on providing a histologic description of the tissue removed. The guidance suggests that the depth of tumor invasion, pathologic pattern, cell morphology (which is not typically specified for skin cancers), and, if present, the existence of perineural invasion or scar tissue should be documented. If these features are constant across stages, they only need to be noted for the first stage.

Adapting Guidelines for Clinical Practice

The CMS guidance may create some conundrums for physicians regarding MMS documentation; for instance, if a tumor is cleared in one stage, as is often the case, no tumor will be seen on glass slides prepared to assess tissue margins during the procedure and therefore documentation of characteristics like depth and pattern will be impossible. Similarly, cell morphology is not a feature that usually is relevant for most squamous and basal cell carcinomas, although it may be useful in certain unusual instances, such as in cases of rare tumors with particular histologic features that may influence management and/or prognosis. When in doubt regarding the appropriate documentation method for MMS, the surgeon should use his or her best judgment based on clinical experience rather than simply following guidelines that may not be applicable.

Final Thoughts

The CMS guidance serves as a reminder of the documentation requirements for MMS and extends current practice by suggesting a detailed microscopic description of the removed tissue. The American Academy of Dermatology has developed a guide to help Mohs surgeons provide the necessary documentation without creating cumbersome chart notes.² Mohs surgeons should consult the most recent version of the LCD that applies to their geographic area to determine if the new documentation guidelines have been adopted.

SAN DIEGO – The use of hormone therapy was associated with a lower urine albumin-to-creatinine ratio and a decreased risk of albuminuria, results from a cross-sectional study suggest.

“This may be useful information for providers taking care of menopausal women who are considering the use of hormone therapy for vasomotor symptoms and are worried about the systemic effects of these medications,” lead study author Dr. Andrea G. Kattah said in an interview after the annual meeting of the American Society of Nephrology. “Though our data only show an association and not cause and effect, hormone therapy is associated with better kidney function in this study.”

Results from many animal studies suggest that estrogen can have beneficial effects on the kidneys, noted Dr. Kattah, who conducted the research with Dr. Vesna D. Garovic and colleagues in the division of hypertension and nephrology at the Mayo Clinic, Rochester, Minn.

“In addition, in human studies of chronic kidney disease, premenopausal women tend to have slower progression of kidney disease than men,” she said. “Studies on the effects of hormone therapy on kidney function in women have had variable results. We wanted to look at the association of hormone therapy and renal function in a large, multiethnic cohort with well-defined health conditions that may confound the relationship between hormone therapy and renal disease.”

Study participants included 2,217 women enrolled in the Family Blood Pressure Program, a multinetwork effort to study the genetics of hypertension. During a study visit between 2000 and 2004, the women completed questionnaires about medical history, menopausal status, and use of hormone therapy (HT) in the past month. Clinicians also took their blood pressure, measured their body mass index, and drew blood to determine levels of serum creatinine and urine albumin-to-creatinine ratio (UACR).

Of the 2,217 women, 673 were on HT and 1,544 were not, and their mean ages were 60 years and 63 years, respectively.

In unadjusted analysis, Dr. Kattah and her associates found that UACR was significantly lower in those on HT, compared with those who were not (3.5 mg/g creatinine vs. 5.2 mg/g creatinine, respectively, P less than .001), as was the number of women with an estimated glomerular filtration rate (eGFR) of less than 60 mL/min per 1.73 m² (7% vs. 10%, P = .003).

After adjusting for renal and cardiovascular risk factors including age, race, smoking, diabetes, hypertension, and family history of hypertension, the use of HT was still significantly associated with a lower UACR and decreased risk of microalbuminuria (odds ratio, 0.61). The association between HT and eGFR of less than 60 mL/min per 1.73 m² was no longer significant after adjustment, but there was a trend toward higher eGFR and fewer women with an eGFR of less than 60 mL/min per 1.73 m² among those on HT.

“Not surprisingly, the women taking hormone therapy were different than those who were not, and they generally had fewer health problems, such as diabetes and hyperlipidemia,” Dr. Kattah said. “However, after taking these differences into account in our models, we still found a significant decrease in the risk of having microalbuminuria in those on hormone therapy.”

Dr. Kattah acknowledged certain limitations of the study, including the fact that its design is “cross-sectional and cannot answer the question of whether or not hormone therapy can improve kidney function.

In addition, “we do not have data on how long women were taking hormone therapy, which other studies have suggested is an important factor.”

The researchers reported having no financial disclosures.

[email protected]

SAN DIEGO – The use of hormone therapy was associated with a lower urine albumin-to-creatinine ratio and a decreased risk of albuminuria, results from a cross-sectional study suggest.

“This may be useful information for providers taking care of menopausal women who are considering the use of hormone therapy for vasomotor symptoms and are worried about the systemic effects of these medications,” lead study author Dr. Andrea G. Kattah said in an interview after the annual meeting of the American Society of Nephrology. “Though our data only show an association and not cause and effect, hormone therapy is associated with better kidney function in this study.”

Results from many animal studies suggest that estrogen can have beneficial effects on the kidneys, noted Dr. Kattah, who conducted the research with Dr. Vesna D. Garovic and colleagues in the division of hypertension and nephrology at the Mayo Clinic, Rochester, Minn.

“In addition, in human studies of chronic kidney disease, premenopausal women tend to have slower progression of kidney disease than men,” she said. “Studies on the effects of hormone therapy on kidney function in women have had variable results. We wanted to look at the association of hormone therapy and renal function in a large, multiethnic cohort with well-defined health conditions that may confound the relationship between hormone therapy and renal disease.”

Study participants included 2,217 women enrolled in the Family Blood Pressure Program, a multinetwork effort to study the genetics of hypertension. During a study visit between 2000 and 2004, the women completed questionnaires about medical history, menopausal status, and use of hormone therapy (HT) in the past month. Clinicians also took their blood pressure, measured their body mass index, and drew blood to determine levels of serum creatinine and urine albumin-to-creatinine ratio (UACR).

Of the 2,217 women, 673 were on HT and 1,544 were not, and their mean ages were 60 years and 63 years, respectively.

In unadjusted analysis, Dr. Kattah and her associates found that UACR was significantly lower in those on HT, compared with those who were not (3.5 mg/g creatinine vs. 5.2 mg/g creatinine, respectively, P less than .001), as was the number of women with an estimated glomerular filtration rate (eGFR) of less than 60 mL/min per 1.73 m² (7% vs. 10%, P = .003).

After adjusting for renal and cardiovascular risk factors including age, race, smoking, diabetes, hypertension, and family history of hypertension, the use of HT was still significantly associated with a lower UACR and decreased risk of microalbuminuria (odds ratio, 0.61). The association between HT and eGFR of less than 60 mL/min per 1.73 m² was no longer significant after adjustment, but there was a trend toward higher eGFR and fewer women with an eGFR of less than 60 mL/min per 1.73 m² among those on HT.

“Not surprisingly, the women taking hormone therapy were different than those who were not, and they generally had fewer health problems, such as diabetes and hyperlipidemia,” Dr. Kattah said. “However, after taking these differences into account in our models, we still found a significant decrease in the risk of having microalbuminuria in those on hormone therapy.”

Dr. Kattah acknowledged certain limitations of the study, including the fact that its design is “cross-sectional and cannot answer the question of whether or not hormone therapy can improve kidney function.

In addition, “we do not have data on how long women were taking hormone therapy, which other studies have suggested is an important factor.”

The researchers reported having no financial disclosures.

[email protected]

SAN DIEGO – The use of hormone therapy was associated with a lower urine albumin-to-creatinine ratio and a decreased risk of albuminuria, results from a cross-sectional study suggest.

“This may be useful information for providers taking care of menopausal women who are considering the use of hormone therapy for vasomotor symptoms and are worried about the systemic effects of these medications,” lead study author Dr. Andrea G. Kattah said in an interview after the annual meeting of the American Society of Nephrology. “Though our data only show an association and not cause and effect, hormone therapy is associated with better kidney function in this study.”

Results from many animal studies suggest that estrogen can have beneficial effects on the kidneys, noted Dr. Kattah, who conducted the research with Dr. Vesna D. Garovic and colleagues in the division of hypertension and nephrology at the Mayo Clinic, Rochester, Minn.

“In addition, in human studies of chronic kidney disease, premenopausal women tend to have slower progression of kidney disease than men,” she said. “Studies on the effects of hormone therapy on kidney function in women have had variable results. We wanted to look at the association of hormone therapy and renal function in a large, multiethnic cohort with well-defined health conditions that may confound the relationship between hormone therapy and renal disease.”

Study participants included 2,217 women enrolled in the Family Blood Pressure Program, a multinetwork effort to study the genetics of hypertension. During a study visit between 2000 and 2004, the women completed questionnaires about medical history, menopausal status, and use of hormone therapy (HT) in the past month. Clinicians also took their blood pressure, measured their body mass index, and drew blood to determine levels of serum creatinine and urine albumin-to-creatinine ratio (UACR).

Of the 2,217 women, 673 were on HT and 1,544 were not, and their mean ages were 60 years and 63 years, respectively.

In unadjusted analysis, Dr. Kattah and her associates found that UACR was significantly lower in those on HT, compared with those who were not (3.5 mg/g creatinine vs. 5.2 mg/g creatinine, respectively, P less than .001), as was the number of women with an estimated glomerular filtration rate (eGFR) of less than 60 mL/min per 1.73 m² (7% vs. 10%, P = .003).

After adjusting for renal and cardiovascular risk factors including age, race, smoking, diabetes, hypertension, and family history of hypertension, the use of HT was still significantly associated with a lower UACR and decreased risk of microalbuminuria (odds ratio, 0.61). The association between HT and eGFR of less than 60 mL/min per 1.73 m² was no longer significant after adjustment, but there was a trend toward higher eGFR and fewer women with an eGFR of less than 60 mL/min per 1.73 m² among those on HT.

“Not surprisingly, the women taking hormone therapy were different than those who were not, and they generally had fewer health problems, such as diabetes and hyperlipidemia,” Dr. Kattah said. “However, after taking these differences into account in our models, we still found a significant decrease in the risk of having microalbuminuria in those on hormone therapy.”

Dr. Kattah acknowledged certain limitations of the study, including the fact that its design is “cross-sectional and cannot answer the question of whether or not hormone therapy can improve kidney function.

In addition, “we do not have data on how long women were taking hormone therapy, which other studies have suggested is an important factor.”

The researchers reported having no financial disclosures.

[email protected]

The Leadership Academy, presented by SHM, was held in October in Austin, Texas. Three courses were offered: Leadership Foundations and two Advanced Leadership courses, Influential Management and Mastering Teamwork. These sessions are designed to offer training in leadership skills specifically for those working in the field of hospital medicine, as well as to provide career development and extensive networking among colleagues. I had the opportunity to attend the Mastering Teamwork course this year as one of a handful of pediatric hospitalists.

A large majority of attendees at the conference were hospitalists in internal medicine, but many other areas were represented as well, including pediatrics, family medicine, pulmonary/critical care, palliative care, and hospital administration. Although I was in the minority as a pediatric hospitalist, I found that all the information discussed was applicable to my own practice setting.

The Mastering Teamwork session began with a presentation given by Mark Williams, MD, FACP, MHM, and Amit Prachand, MEng, on secrets and misconceptions of teamwork. They discussed ways to improve organizational health by developing trust within the team, addressing and nurturing healthy conflict, obtaining commitment through clarity and buy-in, encouraging accountability, and focusing on team results. They also shared practical ideas for making meetings more valuable, with suggestions for preparation, the meeting itself, and follow-up.

Day two of Mastering Teamwork consisted of lectures and discussion on meta-leadership (defined as “overarching leadership that strategically links the work of different agencies”) within and throughout one’s sphere of influence. Leonard Marcus, PhD, a national leader in the fields of healthcare negotiation, conflict resolution, and emergency preparedness, led this session.

A new course offered to all levels of the Leadership Academy this year, on physician burnout, was led by Kay Cannon, MBA, MCC, a nationally recognized executive coach. This session, which certainly hit close to home for many attendees, was very well attended and well received. Causes include poor job fit and work demands exceeding resources. Signs of burnout were discussed, including fatigue, anxiety, depression, health problems, and breakdown. Burnout can have significant effects in the work place, from early retirements to poor morale to poor patient care. Cannon presented ways to improve burnout, with the idea of achieving a better balance between demands and resources.

Cannon also presented in the Mastering Teamwork course. Her topic, “Investing in Yourself,” consisted of a discussion about career paths and planning. Course members were encouraged to engage in self-assessment and a situational assessment of their positions and organizations. Attendees began to delineate personal and career goals and to develop action plans based on these goals.

To close the course, Jeffrey Wiese, MD, MHM, spoke on advanced communications. This broad session offered practical advice in multiple areas. Specific topics included building teams through mission and purpose, encouraging loyalty, and motivating performance and happiness, while touching on burnout and feedback as well. He also discussed leading a team through change, dealing with politics within an organization, and making decisions.

“Dr. Wiese was amazing; his first day hit the nail on the head in forming and keeping a team. He was blunt and to the point, and it was so helpful,” said Kayce Morton, DO, who attended the Mastering Teamwork session. “Dr. Marcus accentuated leadership at its best through his stories. Kay Cannon was great at discussing topics that affect our leadership every day—it was like a therapy session. This was a very stimulating conference.”

The Leadership Academy, and, specifically, the Mastering Teamwork course, was very valuable. The lessons learned were highly practical, regardless of one’s area of practice and level of leadership. Each of the speakers was engaging and well received. TH

Dr. Galloway is a pediatric hospitalist at Sanford Children’s Hospital in Sioux Falls, S.D., assistant professor of pediatrics at the University of South Dakota Sanford School of Medicine, and vice chief of the division of hospital pediatrics at USD SSOM and Sanford Children’s Hospital.

The Leadership Academy, presented by SHM, was held in October in Austin, Texas. Three courses were offered: Leadership Foundations and two Advanced Leadership courses, Influential Management and Mastering Teamwork. These sessions are designed to offer training in leadership skills specifically for those working in the field of hospital medicine, as well as to provide career development and extensive networking among colleagues. I had the opportunity to attend the Mastering Teamwork course this year as one of a handful of pediatric hospitalists.

A large majority of attendees at the conference were hospitalists in internal medicine, but many other areas were represented as well, including pediatrics, family medicine, pulmonary/critical care, palliative care, and hospital administration. Although I was in the minority as a pediatric hospitalist, I found that all the information discussed was applicable to my own practice setting.

The Mastering Teamwork session began with a presentation given by Mark Williams, MD, FACP, MHM, and Amit Prachand, MEng, on secrets and misconceptions of teamwork. They discussed ways to improve organizational health by developing trust within the team, addressing and nurturing healthy conflict, obtaining commitment through clarity and buy-in, encouraging accountability, and focusing on team results. They also shared practical ideas for making meetings more valuable, with suggestions for preparation, the meeting itself, and follow-up.

Day two of Mastering Teamwork consisted of lectures and discussion on meta-leadership (defined as “overarching leadership that strategically links the work of different agencies”) within and throughout one’s sphere of influence. Leonard Marcus, PhD, a national leader in the fields of healthcare negotiation, conflict resolution, and emergency preparedness, led this session.

A new course offered to all levels of the Leadership Academy this year, on physician burnout, was led by Kay Cannon, MBA, MCC, a nationally recognized executive coach. This session, which certainly hit close to home for many attendees, was very well attended and well received. Causes include poor job fit and work demands exceeding resources. Signs of burnout were discussed, including fatigue, anxiety, depression, health problems, and breakdown. Burnout can have significant effects in the work place, from early retirements to poor morale to poor patient care. Cannon presented ways to improve burnout, with the idea of achieving a better balance between demands and resources.

Cannon also presented in the Mastering Teamwork course. Her topic, “Investing in Yourself,” consisted of a discussion about career paths and planning. Course members were encouraged to engage in self-assessment and a situational assessment of their positions and organizations. Attendees began to delineate personal and career goals and to develop action plans based on these goals.

To close the course, Jeffrey Wiese, MD, MHM, spoke on advanced communications. This broad session offered practical advice in multiple areas. Specific topics included building teams through mission and purpose, encouraging loyalty, and motivating performance and happiness, while touching on burnout and feedback as well. He also discussed leading a team through change, dealing with politics within an organization, and making decisions.

“Dr. Wiese was amazing; his first day hit the nail on the head in forming and keeping a team. He was blunt and to the point, and it was so helpful,” said Kayce Morton, DO, who attended the Mastering Teamwork session. “Dr. Marcus accentuated leadership at its best through his stories. Kay Cannon was great at discussing topics that affect our leadership every day—it was like a therapy session. This was a very stimulating conference.”

The Leadership Academy, and, specifically, the Mastering Teamwork course, was very valuable. The lessons learned were highly practical, regardless of one’s area of practice and level of leadership. Each of the speakers was engaging and well received. TH

Dr. Galloway is a pediatric hospitalist at Sanford Children’s Hospital in Sioux Falls, S.D., assistant professor of pediatrics at the University of South Dakota Sanford School of Medicine, and vice chief of the division of hospital pediatrics at USD SSOM and Sanford Children’s Hospital.

The Leadership Academy, presented by SHM, was held in October in Austin, Texas. Three courses were offered: Leadership Foundations and two Advanced Leadership courses, Influential Management and Mastering Teamwork. These sessions are designed to offer training in leadership skills specifically for those working in the field of hospital medicine, as well as to provide career development and extensive networking among colleagues. I had the opportunity to attend the Mastering Teamwork course this year as one of a handful of pediatric hospitalists.

A large majority of attendees at the conference were hospitalists in internal medicine, but many other areas were represented as well, including pediatrics, family medicine, pulmonary/critical care, palliative care, and hospital administration. Although I was in the minority as a pediatric hospitalist, I found that all the information discussed was applicable to my own practice setting.

The Mastering Teamwork session began with a presentation given by Mark Williams, MD, FACP, MHM, and Amit Prachand, MEng, on secrets and misconceptions of teamwork. They discussed ways to improve organizational health by developing trust within the team, addressing and nurturing healthy conflict, obtaining commitment through clarity and buy-in, encouraging accountability, and focusing on team results. They also shared practical ideas for making meetings more valuable, with suggestions for preparation, the meeting itself, and follow-up.

Day two of Mastering Teamwork consisted of lectures and discussion on meta-leadership (defined as “overarching leadership that strategically links the work of different agencies”) within and throughout one’s sphere of influence. Leonard Marcus, PhD, a national leader in the fields of healthcare negotiation, conflict resolution, and emergency preparedness, led this session.

A new course offered to all levels of the Leadership Academy this year, on physician burnout, was led by Kay Cannon, MBA, MCC, a nationally recognized executive coach. This session, which certainly hit close to home for many attendees, was very well attended and well received. Causes include poor job fit and work demands exceeding resources. Signs of burnout were discussed, including fatigue, anxiety, depression, health problems, and breakdown. Burnout can have significant effects in the work place, from early retirements to poor morale to poor patient care. Cannon presented ways to improve burnout, with the idea of achieving a better balance between demands and resources.

Cannon also presented in the Mastering Teamwork course. Her topic, “Investing in Yourself,” consisted of a discussion about career paths and planning. Course members were encouraged to engage in self-assessment and a situational assessment of their positions and organizations. Attendees began to delineate personal and career goals and to develop action plans based on these goals.

To close the course, Jeffrey Wiese, MD, MHM, spoke on advanced communications. This broad session offered practical advice in multiple areas. Specific topics included building teams through mission and purpose, encouraging loyalty, and motivating performance and happiness, while touching on burnout and feedback as well. He also discussed leading a team through change, dealing with politics within an organization, and making decisions.

“Dr. Wiese was amazing; his first day hit the nail on the head in forming and keeping a team. He was blunt and to the point, and it was so helpful,” said Kayce Morton, DO, who attended the Mastering Teamwork session. “Dr. Marcus accentuated leadership at its best through his stories. Kay Cannon was great at discussing topics that affect our leadership every day—it was like a therapy session. This was a very stimulating conference.”

The Leadership Academy, and, specifically, the Mastering Teamwork course, was very valuable. The lessons learned were highly practical, regardless of one’s area of practice and level of leadership. Each of the speakers was engaging and well received. TH

Dr. Galloway is a pediatric hospitalist at Sanford Children’s Hospital in Sioux Falls, S.D., assistant professor of pediatrics at the University of South Dakota Sanford School of Medicine, and vice chief of the division of hospital pediatrics at USD SSOM and Sanford Children’s Hospital.

LAKE BUENA VISTA, FLA. – The nondiagnostic result rate was significantly lower with core needle biopsy than with fine needle aspiration as a first-line biopsy method for newly detected thyroid nodules in a comparative study.

In 631 pairs of initially detected thyroid nodules that were matched based on propensity score analysis, the nondiagnostic result rate was 1.4% when core needle biopsy (CNB) was used, compared with 8.1% with ultrasound-guided fine-needle aspiration. The indeterminate result rate was 5.1% vs. 8.1% with the two approaches, respectively, and the differences between the groups were statistically significant, Dr. Hyun Kyung Lim of Soonchunhyang University Seoul Hospital, Korea, reported at the International Thyroid Congress.

©Sebastian Kaulitzki/Fotolia.com

The nondiagnostic rate with CNB was also significantly lower than with fine-needle aspiration for nodules with calcifications, posterior location, or diameter less than 1 cm, Dr. Lim said at the meeting at the meeting held by the American Thyroid Association, Asia-Oceania Thyroid Association, European Thyroid Association, and Latin American Thyroid Society.

No difference was seen between the groups with respect to diagnostic performance based on degree of clinician experience.

The complication rate was higher with CNB than with fine -needle aspiration (3.6% vs. 1.6%), but complications were minor, Dr. Lim said.

Core needle biopsy has been suggested as a complementary tool for the diagnosis of thyroid nodules when the results of fine-needle aspiration are inconclusive, and the approach has been shown to be both safe and accurate for biopsy. However, its role as a first-line approach for thyroid nodule biopsy has been controversial and few studies have evaluated it as a first-line tool, she noted.

The current findings suggest that CNB is a safe and highly sensitive first-line biopsy method for such nodules, she concluded.

Dr. Lim reported having no disclosures.

[email protected]

LAKE BUENA VISTA, FLA. – The nondiagnostic result rate was significantly lower with core needle biopsy than with fine needle aspiration as a first-line biopsy method for newly detected thyroid nodules in a comparative study.

In 631 pairs of initially detected thyroid nodules that were matched based on propensity score analysis, the nondiagnostic result rate was 1.4% when core needle biopsy (CNB) was used, compared with 8.1% with ultrasound-guided fine-needle aspiration. The indeterminate result rate was 5.1% vs. 8.1% with the two approaches, respectively, and the differences between the groups were statistically significant, Dr. Hyun Kyung Lim of Soonchunhyang University Seoul Hospital, Korea, reported at the International Thyroid Congress.

©Sebastian Kaulitzki/Fotolia.com

The nondiagnostic rate with CNB was also significantly lower than with fine-needle aspiration for nodules with calcifications, posterior location, or diameter less than 1 cm, Dr. Lim said at the meeting at the meeting held by the American Thyroid Association, Asia-Oceania Thyroid Association, European Thyroid Association, and Latin American Thyroid Society.

No difference was seen between the groups with respect to diagnostic performance based on degree of clinician experience.

The complication rate was higher with CNB than with fine -needle aspiration (3.6% vs. 1.6%), but complications were minor, Dr. Lim said.

Core needle biopsy has been suggested as a complementary tool for the diagnosis of thyroid nodules when the results of fine-needle aspiration are inconclusive, and the approach has been shown to be both safe and accurate for biopsy. However, its role as a first-line approach for thyroid nodule biopsy has been controversial and few studies have evaluated it as a first-line tool, she noted.

The current findings suggest that CNB is a safe and highly sensitive first-line biopsy method for such nodules, she concluded.

Dr. Lim reported having no disclosures.

[email protected]

LAKE BUENA VISTA, FLA. – The nondiagnostic result rate was significantly lower with core needle biopsy than with fine needle aspiration as a first-line biopsy method for newly detected thyroid nodules in a comparative study.

In 631 pairs of initially detected thyroid nodules that were matched based on propensity score analysis, the nondiagnostic result rate was 1.4% when core needle biopsy (CNB) was used, compared with 8.1% with ultrasound-guided fine-needle aspiration. The indeterminate result rate was 5.1% vs. 8.1% with the two approaches, respectively, and the differences between the groups were statistically significant, Dr. Hyun Kyung Lim of Soonchunhyang University Seoul Hospital, Korea, reported at the International Thyroid Congress.

©Sebastian Kaulitzki/Fotolia.com

The nondiagnostic rate with CNB was also significantly lower than with fine-needle aspiration for nodules with calcifications, posterior location, or diameter less than 1 cm, Dr. Lim said at the meeting at the meeting held by the American Thyroid Association, Asia-Oceania Thyroid Association, European Thyroid Association, and Latin American Thyroid Society.

No difference was seen between the groups with respect to diagnostic performance based on degree of clinician experience.

The complication rate was higher with CNB than with fine -needle aspiration (3.6% vs. 1.6%), but complications were minor, Dr. Lim said.

Core needle biopsy has been suggested as a complementary tool for the diagnosis of thyroid nodules when the results of fine-needle aspiration are inconclusive, and the approach has been shown to be both safe and accurate for biopsy. However, its role as a first-line approach for thyroid nodule biopsy has been controversial and few studies have evaluated it as a first-line tool, she noted.

The current findings suggest that CNB is a safe and highly sensitive first-line biopsy method for such nodules, she concluded.

Dr. Lim reported having no disclosures.

[email protected]

A number of drugs are available for ophthalmic use. This review focuses on single drug products and, although combination drug products are not discussed, these formulations typically include the drugs reviewed here.

Since it appears that ophthalmic medications are commonly used for a wide range of conditions and ages, one would expect to see numerous reports of their use in the eyes of pregnant or breastfeeding patients. Unfortunately, the opposite is true. The majority of the drugs have no human pregnancy or lactation data. When there are human data, it invariably involves the systemic use of the drug for other indications, rather than its ophthalmic use. Moreover, the animal reproduction data are usually not relevant because they involve systemic drugs (e.g., IV or oral). Consequently, determining the level of risk an ophthalmic drug presents to an embryo and/or fetus is primarily based on time and dose, the two cardinal principles of teratology.

Avoiding exposure during organogenesis – the period when a drug can cause developmental toxicity (altered growth, structural anomalies, functional and/or behavioral deficits, or death) – is usually best, but may not be possible in some cases, including glaucoma, eye infections, and eye surgery. Fortunately, the systemic concentrations of drugs applied topically to the eye are typically thought to be low, even though the levels of most drugs have not been studied. Thus, the risk to the embryo and/or fetus in most cases can be considered low and the drug classified as compatible in pregnancy and breastfeeding.

If a topical eye drug must be used during pregnancy or lactation, teach the patient how to decrease the amount of drug reaching the systemic circulation. This involves placing pressure over the tear duct in the corner of the eye for 1 minute or more, then removing any excess solution with absorbent tissue.

In the sections below, drugs are shown by indication or by pharmacologic class. The term “human eye data” refers to the use of the drug in pregnancy and/or lactation.

Glaucoma

If you are caring for a pregnant patient who is being treated for glaucoma, two recent reviews may be helpful: Surv Ophthalmol. 2011 Jul-Aug;56(4):324-35 and Curr Opin Ophthalmol. 2014 Mar;25(2):93-7.

Sympathomimetics (alpha-adrenergic agonists) include apraclonidine (Iopidine), which has no human eye data, and brimonidine (Alphagan P), which has one case report in pregnancy and breastfeeding showing no fetal or nursing infant harm.

Four of the five beta-adrenergic blockers have no human eye data: betaxolol (Betoptic), carteolol (Ocupress), levobunolol (Betagan), and metipranolol, but there are two case reports for timolol (Betimol, Istalol, Timoptic, Timoptic-XE) showing no fetal harm in one newborn and growth restriction in the other.

Among the miotics, there are limited human eye data for pilocarpine (Isopto Carpine) and no fetal harm was observed. For echothiophate iodide (Phospholine Iodide), there is one case report of a normal full-term infant whose mother was treated with the agent up to 32 weeks’ gestation and then with pilocarpine for 8 weeks (Arch Ophthalmol. 1968 Mar;79[3]:283-5).

Fuse/Thinkstock.com

Carbonic anhydrase inhibitors include brinzolamide (Azopt), which has no human eye data, and dorzolamide (Trusopt), which has growth restriction in one case treated with fixed combination of dorzolamide and timolol. There are no human eye data for unoprostone isopropyl (Rescula), a synthetic docosanoid.

Of the four prostaglandin analogs, three have no human eye data, bimatoprost (Lumigan), tafluprost (Zioptan), and travoprost (Travatan Z). There were 11 pregnancies exposed to latanoprost (Xalatan). The outcomes of these cases were one lost to follow-up, one miscarriage, and nine infants without congenital anomalies (Am J Ophthalmol. 2004 Aug;138[2]:305-6).

Mitomycin (Mitosol) is an antimetabolite that is given topically to the surgical site of glaucoma filtration surgery. No reports of its use in pregnant humans have been located. According to the manufacturer, clinically significant systemic concentrations are not expected.

Antiseptics

Povidone-iodine (Betadine) is indicated for prepping of the periocular region. There does not appear to be any risk to the embryo-fetus or nursing infant from this indication.

Antihistamines

The four ophthalmic agents in this class are alcaftadine (Lastacaft), azelastine (Optivar), emedastine (Emadine), and epinastine (Elestat). There are no human eye data for these agents but, like antihistamines given systemically, they are probably compatible in pregnancy and lactation.

Antihistamine-mast cell stabilizers

There are no human eye data for bepotastine (Bepreve), ketotifen (Alaway), and olopatadine (Pataday, Patanol). Peak plasma concentrations of bepotastine were 5.1-7.3 ng/mL for 1-2 hours after instillation and were less than 2 ng/mL at 24 hours. It appears that these drugs can also be classified as compatible in pregnancy and lactation.

Anti-infectives

Ten anti-infectives are available for topical treatment of eye infections (systemic concentrations if known): besifloxacin (Besivance) (0.43 ng/mL), ciprofloxacin (less than 2.5 ng/mL), gentamicin, gatifloxacin (Zymaxid) (less than 5 ng/mL), levofloxacin (Iquix) (10.9 ng/mL), moxifloxacin (Vigamox) (2.7 ng/mL), ofloxacin (1.9 ng/mL), sulfacetamide (Isopto Cetamide), and tobramycin. The tenth agent, natamycin (Natacyn), is an antifungal. According to the manufacturer, systemic absorption is not expected.

None of these agents have human eye data, but they are usually considered compatible in pregnancy and breastfeeding when systemic formulations are used, so they should be compatible when used in the eye.

Antivirals

Ganciclovir (Zirgan) has no human eye data but, according to the manufacturer, the daily ophthalmic dose is about 0.04% and 0.1% of the oral and IV doses, respectively. Thus, minimal systemic exposure is expected. Trifluridine (Viroptic) also has no eye human data. As reported in the product information, detectable blood concentrations of the drug were not found in healthy normal subjects indicating that systemic absorption was negligible.

Corticosteroids

Among the nine corticosteroid products, six are suspensions or ointments, one is an injection, and two are implants. In most nonpregnant patients receiving the dexamethasone (Ozurdex) intravitreal implant, plasma dexamethasone concentrations were undetectable (less than 50 pg/mL) but, in some, ranged from 52 pg/mL to 102 pg/mL. There is only one case report describing the use of topical dexamethasone suspension (Maxidex) in pregnancy. In that case, dexamethasone and clindamycin were given in the first and second trimesters and the woman eventually gave birth to a normal full term infant (Int Ophthalmol. 1998-1999;22[2]:85-8).

For the fluocinolone (Retisert) ocular implant, systemic absorption of detectable amounts of the drug have not been observed. In a second report, a patient who had type 1 diabetes and was 6 months pregnant received a 2-mg intravitreal injection of triamcinolone (Triesence) in both eyes. No adverse effects in the mother or fetus were noted (Clin Ophthalmol. 2011;5:439-41).

There are no human eye data for five topical corticosteroids: difluprednate (Durezol), fluorometholone (Flarex, Fluor-OP, FML), loteprednol (Alrex, Lotemax), prednisolone (Econopred), and rimexolone (Vexol). Only two of the five drugs had information about systemic absorption. For difluprednate, blood levels were below the quantification limit (50 ng/mL). Extremely low levels were detected after the use of rimexolone with a mean serum concentration of 130 pg/mL (range less than 80-470 pg/mL).

Cycloplegics-mydriatics

This class includes four anticholinergic agents: atropine, cyclopentolate (Cyclogyl), homatropine, and tropicamide (Mydriacyl). Systemic absorption has not been studied for these drugs and there are no reports of their use in pregnancy or lactation.

Cystine-depleting agents

There are no reports describing the use of cysteamine (Cystaran) in human pregnancy or lactation. Since the drug is given as one drop in each eye every waking hour, transfer to the systemic circulation should be expected, but the amount, if it occurs, has not been reported.

Immunologics

There are no reports on the use of cyclosporine (Restasis) eye drops in human pregnancy or during breastfeeding. However, data for the systemic use of the drug during these conditions has shown it to be low risk. After long term ophthalmic use, blood concentrations of the drug were below the quantitation limit of 0.1 ng/mL.

Local anesthetics

The three drugs in this class are lidocaine, proparacaine (Alcaine), and tetracaine (Altacaine, Tetravisc). There is no information regarding the use of these agents in pregnancy or lactation. Since they are used for brief periods, the risk to an embryo or nursing infant appears to be nil.

Mast cell stabilizers

There are three drugs in this class that can be used topically in the eye: cromolyn, lodoxamide (Alomide), and nedocromil (Alocril). There are no human eye data for these agents. Systemic concentrations of lodoxamide were below the detection limit of 2.5 ng/mL.

Miotics

The two miotics are acetylcholine (Miochol E) and carbachol (Carbastat, Miostat). Both are used immediately before eye surgery. The amount, if any, in the systemic circulation is unknown. No reports of human eye use in pregnancy or lactation have been found.

NSAIDs

The five drugs in this class are bromfenac (Xibrom), diclofenac (Voltaren), flurbiprofen (Ocufen), ketorolac, and nepafenac (Nevanac). Although it has not been studied, the estimated plasma level for bromfenac is less than 50 ng/mL. For diclofenac, the plasma concentration was below the limit of quantification (10 ng/mL). In a study conducted with ketorolac, only 5 of 26 subjects had detectable plasma concentrations (10.7 to 22.5 ng/mL). These levels were about 2% of the peak plasma levels after oral dosing. For nepafenac, the peak plasma concentrations of the parent drug and active metabolite were 0.3 and 0.4 ng/mL, respectively. These data suggest that the risk to the embryo-fetus or a nursing infant are nil.

Photodynamic therapy

Verteporfin (Visudyne) is given intravenously. Three reports have described its use in three pregnancies. In all cases, the infants were healthy at birth and had normal growth (Acta Ophthalmol Scand. 2004 Oct;82[5]:623-4, Eye [Lond]. 2009 Jun;23[6]:1479, and Aust N Z J Obstet Gynaecol. 2009 Apr;49[2]:236-7).

Proteolytic enzymes

No human eye data were found for ocriplasmin (Jetrea), an agent given as an intravitreal injection. Although it was not studied, detectable levels of the drug in the systemic circulation are not expected, according to the manufacturer.

Selective vascular endothelial growth factor antagonists

There are three agents in this class: aflibercept (Eylea), pegaptanib (Macugen), and ranibizumab (Lucentis). There are no human eye data for these drugs. All are given as intravitreal injection. The systemic concentrations of the three drugs were a mean 0.02 mcg/mL; 80 ng/mL (after a dose of 10 times the recommended dose); and an estimated minimum 0.22 ng/mL, respectively. These data suggest that the risk to the embryo-fetus or a nursing infant is nil.

Sympathomimetics (decongestants)

There are four ophthalmic agents in this class and none have human eye data. Naphazoline (Naphcon, Vasocon) is the only one of the four that requires a prescription. No reports describing the systemic absorption, if any, have been found. The other three agents are available over the counter. They are oxymetazoline (Visine L.R.), phenylephrine, and tetrahydrozoline (Opti-Clear). Although the amount reaching the systemic circulation was not provided by the manufacturers for these three agents, a caution was placed on phenylephrine stating that systemic absorption, although rare, might cause alpha-adrenergic effects, such as a rise in blood pressure and reflex atropine-sensitive bradycardia.

The risk to the embryo-fetus or nursing infant from ophthalmic drugs appears to be low, with the possible exception of phenylephrine. Nevertheless, if any of these agents are used in pregnancy or during breastfeeding, careful assessment of the embryo-fetus and nursing infant should be conducted. Moreover, research on the potential effects of ophthalmic drugs on the embryo-fetus and nursing infant are desperately needed.

Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco; and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He is coauthor of “Drugs in Pregnancy and Lactation,” and coeditor of “Diseases, Complications, and Drug Therapy in Obstetrics.” He has no relevant financial disclosures.

A number of drugs are available for ophthalmic use. This review focuses on single drug products and, although combination drug products are not discussed, these formulations typically include the drugs reviewed here.

Since it appears that ophthalmic medications are commonly used for a wide range of conditions and ages, one would expect to see numerous reports of their use in the eyes of pregnant or breastfeeding patients. Unfortunately, the opposite is true. The majority of the drugs have no human pregnancy or lactation data. When there are human data, it invariably involves the systemic use of the drug for other indications, rather than its ophthalmic use. Moreover, the animal reproduction data are usually not relevant because they involve systemic drugs (e.g., IV or oral). Consequently, determining the level of risk an ophthalmic drug presents to an embryo and/or fetus is primarily based on time and dose, the two cardinal principles of teratology.

Avoiding exposure during organogenesis – the period when a drug can cause developmental toxicity (altered growth, structural anomalies, functional and/or behavioral deficits, or death) – is usually best, but may not be possible in some cases, including glaucoma, eye infections, and eye surgery. Fortunately, the systemic concentrations of drugs applied topically to the eye are typically thought to be low, even though the levels of most drugs have not been studied. Thus, the risk to the embryo and/or fetus in most cases can be considered low and the drug classified as compatible in pregnancy and breastfeeding.

If a topical eye drug must be used during pregnancy or lactation, teach the patient how to decrease the amount of drug reaching the systemic circulation. This involves placing pressure over the tear duct in the corner of the eye for 1 minute or more, then removing any excess solution with absorbent tissue.

In the sections below, drugs are shown by indication or by pharmacologic class. The term “human eye data” refers to the use of the drug in pregnancy and/or lactation.

Glaucoma

If you are caring for a pregnant patient who is being treated for glaucoma, two recent reviews may be helpful: Surv Ophthalmol. 2011 Jul-Aug;56(4):324-35 and Curr Opin Ophthalmol. 2014 Mar;25(2):93-7.

Sympathomimetics (alpha-adrenergic agonists) include apraclonidine (Iopidine), which has no human eye data, and brimonidine (Alphagan P), which has one case report in pregnancy and breastfeeding showing no fetal or nursing infant harm.

Four of the five beta-adrenergic blockers have no human eye data: betaxolol (Betoptic), carteolol (Ocupress), levobunolol (Betagan), and metipranolol, but there are two case reports for timolol (Betimol, Istalol, Timoptic, Timoptic-XE) showing no fetal harm in one newborn and growth restriction in the other.

Among the miotics, there are limited human eye data for pilocarpine (Isopto Carpine) and no fetal harm was observed. For echothiophate iodide (Phospholine Iodide), there is one case report of a normal full-term infant whose mother was treated with the agent up to 32 weeks’ gestation and then with pilocarpine for 8 weeks (Arch Ophthalmol. 1968 Mar;79[3]:283-5).

Fuse/Thinkstock.com

Carbonic anhydrase inhibitors include brinzolamide (Azopt), which has no human eye data, and dorzolamide (Trusopt), which has growth restriction in one case treated with fixed combination of dorzolamide and timolol. There are no human eye data for unoprostone isopropyl (Rescula), a synthetic docosanoid.

Of the four prostaglandin analogs, three have no human eye data, bimatoprost (Lumigan), tafluprost (Zioptan), and travoprost (Travatan Z). There were 11 pregnancies exposed to latanoprost (Xalatan). The outcomes of these cases were one lost to follow-up, one miscarriage, and nine infants without congenital anomalies (Am J Ophthalmol. 2004 Aug;138[2]:305-6).

Mitomycin (Mitosol) is an antimetabolite that is given topically to the surgical site of glaucoma filtration surgery. No reports of its use in pregnant humans have been located. According to the manufacturer, clinically significant systemic concentrations are not expected.

Antiseptics

Povidone-iodine (Betadine) is indicated for prepping of the periocular region. There does not appear to be any risk to the embryo-fetus or nursing infant from this indication.

Antihistamines

The four ophthalmic agents in this class are alcaftadine (Lastacaft), azelastine (Optivar), emedastine (Emadine), and epinastine (Elestat). There are no human eye data for these agents but, like antihistamines given systemically, they are probably compatible in pregnancy and lactation.

Antihistamine-mast cell stabilizers

There are no human eye data for bepotastine (Bepreve), ketotifen (Alaway), and olopatadine (Pataday, Patanol). Peak plasma concentrations of bepotastine were 5.1-7.3 ng/mL for 1-2 hours after instillation and were less than 2 ng/mL at 24 hours. It appears that these drugs can also be classified as compatible in pregnancy and lactation.

Anti-infectives

Ten anti-infectives are available for topical treatment of eye infections (systemic concentrations if known): besifloxacin (Besivance) (0.43 ng/mL), ciprofloxacin (less than 2.5 ng/mL), gentamicin, gatifloxacin (Zymaxid) (less than 5 ng/mL), levofloxacin (Iquix) (10.9 ng/mL), moxifloxacin (Vigamox) (2.7 ng/mL), ofloxacin (1.9 ng/mL), sulfacetamide (Isopto Cetamide), and tobramycin. The tenth agent, natamycin (Natacyn), is an antifungal. According to the manufacturer, systemic absorption is not expected.

None of these agents have human eye data, but they are usually considered compatible in pregnancy and breastfeeding when systemic formulations are used, so they should be compatible when used in the eye.

Antivirals

Ganciclovir (Zirgan) has no human eye data but, according to the manufacturer, the daily ophthalmic dose is about 0.04% and 0.1% of the oral and IV doses, respectively. Thus, minimal systemic exposure is expected. Trifluridine (Viroptic) also has no eye human data. As reported in the product information, detectable blood concentrations of the drug were not found in healthy normal subjects indicating that systemic absorption was negligible.

Corticosteroids

Among the nine corticosteroid products, six are suspensions or ointments, one is an injection, and two are implants. In most nonpregnant patients receiving the dexamethasone (Ozurdex) intravitreal implant, plasma dexamethasone concentrations were undetectable (less than 50 pg/mL) but, in some, ranged from 52 pg/mL to 102 pg/mL. There is only one case report describing the use of topical dexamethasone suspension (Maxidex) in pregnancy. In that case, dexamethasone and clindamycin were given in the first and second trimesters and the woman eventually gave birth to a normal full term infant (Int Ophthalmol. 1998-1999;22[2]:85-8).

For the fluocinolone (Retisert) ocular implant, systemic absorption of detectable amounts of the drug have not been observed. In a second report, a patient who had type 1 diabetes and was 6 months pregnant received a 2-mg intravitreal injection of triamcinolone (Triesence) in both eyes. No adverse effects in the mother or fetus were noted (Clin Ophthalmol. 2011;5:439-41).

There are no human eye data for five topical corticosteroids: difluprednate (Durezol), fluorometholone (Flarex, Fluor-OP, FML), loteprednol (Alrex, Lotemax), prednisolone (Econopred), and rimexolone (Vexol). Only two of the five drugs had information about systemic absorption. For difluprednate, blood levels were below the quantification limit (50 ng/mL). Extremely low levels were detected after the use of rimexolone with a mean serum concentration of 130 pg/mL (range less than 80-470 pg/mL).

Cycloplegics-mydriatics

This class includes four anticholinergic agents: atropine, cyclopentolate (Cyclogyl), homatropine, and tropicamide (Mydriacyl). Systemic absorption has not been studied for these drugs and there are no reports of their use in pregnancy or lactation.

Cystine-depleting agents

There are no reports describing the use of cysteamine (Cystaran) in human pregnancy or lactation. Since the drug is given as one drop in each eye every waking hour, transfer to the systemic circulation should be expected, but the amount, if it occurs, has not been reported.

Immunologics

There are no reports on the use of cyclosporine (Restasis) eye drops in human pregnancy or during breastfeeding. However, data for the systemic use of the drug during these conditions has shown it to be low risk. After long term ophthalmic use, blood concentrations of the drug were below the quantitation limit of 0.1 ng/mL.

Local anesthetics

The three drugs in this class are lidocaine, proparacaine (Alcaine), and tetracaine (Altacaine, Tetravisc). There is no information regarding the use of these agents in pregnancy or lactation. Since they are used for brief periods, the risk to an embryo or nursing infant appears to be nil.

Mast cell stabilizers

There are three drugs in this class that can be used topically in the eye: cromolyn, lodoxamide (Alomide), and nedocromil (Alocril). There are no human eye data for these agents. Systemic concentrations of lodoxamide were below the detection limit of 2.5 ng/mL.

Miotics

The two miotics are acetylcholine (Miochol E) and carbachol (Carbastat, Miostat). Both are used immediately before eye surgery. The amount, if any, in the systemic circulation is unknown. No reports of human eye use in pregnancy or lactation have been found.

NSAIDs

The five drugs in this class are bromfenac (Xibrom), diclofenac (Voltaren), flurbiprofen (Ocufen), ketorolac, and nepafenac (Nevanac). Although it has not been studied, the estimated plasma level for bromfenac is less than 50 ng/mL. For diclofenac, the plasma concentration was below the limit of quantification (10 ng/mL). In a study conducted with ketorolac, only 5 of 26 subjects had detectable plasma concentrations (10.7 to 22.5 ng/mL). These levels were about 2% of the peak plasma levels after oral dosing. For nepafenac, the peak plasma concentrations of the parent drug and active metabolite were 0.3 and 0.4 ng/mL, respectively. These data suggest that the risk to the embryo-fetus or a nursing infant are nil.

Photodynamic therapy

Verteporfin (Visudyne) is given intravenously. Three reports have described its use in three pregnancies. In all cases, the infants were healthy at birth and had normal growth (Acta Ophthalmol Scand. 2004 Oct;82[5]:623-4, Eye [Lond]. 2009 Jun;23[6]:1479, and Aust N Z J Obstet Gynaecol. 2009 Apr;49[2]:236-7).

Proteolytic enzymes

No human eye data were found for ocriplasmin (Jetrea), an agent given as an intravitreal injection. Although it was not studied, detectable levels of the drug in the systemic circulation are not expected, according to the manufacturer.

Selective vascular endothelial growth factor antagonists

There are three agents in this class: aflibercept (Eylea), pegaptanib (Macugen), and ranibizumab (Lucentis). There are no human eye data for these drugs. All are given as intravitreal injection. The systemic concentrations of the three drugs were a mean 0.02 mcg/mL; 80 ng/mL (after a dose of 10 times the recommended dose); and an estimated minimum 0.22 ng/mL, respectively. These data suggest that the risk to the embryo-fetus or a nursing infant is nil.

Sympathomimetics (decongestants)

There are four ophthalmic agents in this class and none have human eye data. Naphazoline (Naphcon, Vasocon) is the only one of the four that requires a prescription. No reports describing the systemic absorption, if any, have been found. The other three agents are available over the counter. They are oxymetazoline (Visine L.R.), phenylephrine, and tetrahydrozoline (Opti-Clear). Although the amount reaching the systemic circulation was not provided by the manufacturers for these three agents, a caution was placed on phenylephrine stating that systemic absorption, although rare, might cause alpha-adrenergic effects, such as a rise in blood pressure and reflex atropine-sensitive bradycardia.

The risk to the embryo-fetus or nursing infant from ophthalmic drugs appears to be low, with the possible exception of phenylephrine. Nevertheless, if any of these agents are used in pregnancy or during breastfeeding, careful assessment of the embryo-fetus and nursing infant should be conducted. Moreover, research on the potential effects of ophthalmic drugs on the embryo-fetus and nursing infant are desperately needed.

Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco; and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He is coauthor of “Drugs in Pregnancy and Lactation,” and coeditor of “Diseases, Complications, and Drug Therapy in Obstetrics.” He has no relevant financial disclosures.

A number of drugs are available for ophthalmic use. This review focuses on single drug products and, although combination drug products are not discussed, these formulations typically include the drugs reviewed here.

Since it appears that ophthalmic medications are commonly used for a wide range of conditions and ages, one would expect to see numerous reports of their use in the eyes of pregnant or breastfeeding patients. Unfortunately, the opposite is true. The majority of the drugs have no human pregnancy or lactation data. When there are human data, it invariably involves the systemic use of the drug for other indications, rather than its ophthalmic use. Moreover, the animal reproduction data are usually not relevant because they involve systemic drugs (e.g., IV or oral). Consequently, determining the level of risk an ophthalmic drug presents to an embryo and/or fetus is primarily based on time and dose, the two cardinal principles of teratology.

Avoiding exposure during organogenesis – the period when a drug can cause developmental toxicity (altered growth, structural anomalies, functional and/or behavioral deficits, or death) – is usually best, but may not be possible in some cases, including glaucoma, eye infections, and eye surgery. Fortunately, the systemic concentrations of drugs applied topically to the eye are typically thought to be low, even though the levels of most drugs have not been studied. Thus, the risk to the embryo and/or fetus in most cases can be considered low and the drug classified as compatible in pregnancy and breastfeeding.

If a topical eye drug must be used during pregnancy or lactation, teach the patient how to decrease the amount of drug reaching the systemic circulation. This involves placing pressure over the tear duct in the corner of the eye for 1 minute or more, then removing any excess solution with absorbent tissue.

In the sections below, drugs are shown by indication or by pharmacologic class. The term “human eye data” refers to the use of the drug in pregnancy and/or lactation.

Glaucoma

If you are caring for a pregnant patient who is being treated for glaucoma, two recent reviews may be helpful: Surv Ophthalmol. 2011 Jul-Aug;56(4):324-35 and Curr Opin Ophthalmol. 2014 Mar;25(2):93-7.

Sympathomimetics (alpha-adrenergic agonists) include apraclonidine (Iopidine), which has no human eye data, and brimonidine (Alphagan P), which has one case report in pregnancy and breastfeeding showing no fetal or nursing infant harm.

Four of the five beta-adrenergic blockers have no human eye data: betaxolol (Betoptic), carteolol (Ocupress), levobunolol (Betagan), and metipranolol, but there are two case reports for timolol (Betimol, Istalol, Timoptic, Timoptic-XE) showing no fetal harm in one newborn and growth restriction in the other.

Among the miotics, there are limited human eye data for pilocarpine (Isopto Carpine) and no fetal harm was observed. For echothiophate iodide (Phospholine Iodide), there is one case report of a normal full-term infant whose mother was treated with the agent up to 32 weeks’ gestation and then with pilocarpine for 8 weeks (Arch Ophthalmol. 1968 Mar;79[3]:283-5).

Fuse/Thinkstock.com

Carbonic anhydrase inhibitors include brinzolamide (Azopt), which has no human eye data, and dorzolamide (Trusopt), which has growth restriction in one case treated with fixed combination of dorzolamide and timolol. There are no human eye data for unoprostone isopropyl (Rescula), a synthetic docosanoid.

Of the four prostaglandin analogs, three have no human eye data, bimatoprost (Lumigan), tafluprost (Zioptan), and travoprost (Travatan Z). There were 11 pregnancies exposed to latanoprost (Xalatan). The outcomes of these cases were one lost to follow-up, one miscarriage, and nine infants without congenital anomalies (Am J Ophthalmol. 2004 Aug;138[2]:305-6).

Mitomycin (Mitosol) is an antimetabolite that is given topically to the surgical site of glaucoma filtration surgery. No reports of its use in pregnant humans have been located. According to the manufacturer, clinically significant systemic concentrations are not expected.

Antiseptics

Povidone-iodine (Betadine) is indicated for prepping of the periocular region. There does not appear to be any risk to the embryo-fetus or nursing infant from this indication.

Antihistamines

The four ophthalmic agents in this class are alcaftadine (Lastacaft), azelastine (Optivar), emedastine (Emadine), and epinastine (Elestat). There are no human eye data for these agents but, like antihistamines given systemically, they are probably compatible in pregnancy and lactation.

Antihistamine-mast cell stabilizers

There are no human eye data for bepotastine (Bepreve), ketotifen (Alaway), and olopatadine (Pataday, Patanol). Peak plasma concentrations of bepotastine were 5.1-7.3 ng/mL for 1-2 hours after instillation and were less than 2 ng/mL at 24 hours. It appears that these drugs can also be classified as compatible in pregnancy and lactation.

Anti-infectives

Ten anti-infectives are available for topical treatment of eye infections (systemic concentrations if known): besifloxacin (Besivance) (0.43 ng/mL), ciprofloxacin (less than 2.5 ng/mL), gentamicin, gatifloxacin (Zymaxid) (less than 5 ng/mL), levofloxacin (Iquix) (10.9 ng/mL), moxifloxacin (Vigamox) (2.7 ng/mL), ofloxacin (1.9 ng/mL), sulfacetamide (Isopto Cetamide), and tobramycin. The tenth agent, natamycin (Natacyn), is an antifungal. According to the manufacturer, systemic absorption is not expected.

None of these agents have human eye data, but they are usually considered compatible in pregnancy and breastfeeding when systemic formulations are used, so they should be compatible when used in the eye.

Antivirals

Ganciclovir (Zirgan) has no human eye data but, according to the manufacturer, the daily ophthalmic dose is about 0.04% and 0.1% of the oral and IV doses, respectively. Thus, minimal systemic exposure is expected. Trifluridine (Viroptic) also has no eye human data. As reported in the product information, detectable blood concentrations of the drug were not found in healthy normal subjects indicating that systemic absorption was negligible.

Corticosteroids

Among the nine corticosteroid products, six are suspensions or ointments, one is an injection, and two are implants. In most nonpregnant patients receiving the dexamethasone (Ozurdex) intravitreal implant, plasma dexamethasone concentrations were undetectable (less than 50 pg/mL) but, in some, ranged from 52 pg/mL to 102 pg/mL. There is only one case report describing the use of topical dexamethasone suspension (Maxidex) in pregnancy. In that case, dexamethasone and clindamycin were given in the first and second trimesters and the woman eventually gave birth to a normal full term infant (Int Ophthalmol. 1998-1999;22[2]:85-8).

For the fluocinolone (Retisert) ocular implant, systemic absorption of detectable amounts of the drug have not been observed. In a second report, a patient who had type 1 diabetes and was 6 months pregnant received a 2-mg intravitreal injection of triamcinolone (Triesence) in both eyes. No adverse effects in the mother or fetus were noted (Clin Ophthalmol. 2011;5:439-41).

There are no human eye data for five topical corticosteroids: difluprednate (Durezol), fluorometholone (Flarex, Fluor-OP, FML), loteprednol (Alrex, Lotemax), prednisolone (Econopred), and rimexolone (Vexol). Only two of the five drugs had information about systemic absorption. For difluprednate, blood levels were below the quantification limit (50 ng/mL). Extremely low levels were detected after the use of rimexolone with a mean serum concentration of 130 pg/mL (range less than 80-470 pg/mL).

Cycloplegics-mydriatics

This class includes four anticholinergic agents: atropine, cyclopentolate (Cyclogyl), homatropine, and tropicamide (Mydriacyl). Systemic absorption has not been studied for these drugs and there are no reports of their use in pregnancy or lactation.

Cystine-depleting agents

There are no reports describing the use of cysteamine (Cystaran) in human pregnancy or lactation. Since the drug is given as one drop in each eye every waking hour, transfer to the systemic circulation should be expected, but the amount, if it occurs, has not been reported.

Immunologics

There are no reports on the use of cyclosporine (Restasis) eye drops in human pregnancy or during breastfeeding. However, data for the systemic use of the drug during these conditions has shown it to be low risk. After long term ophthalmic use, blood concentrations of the drug were below the quantitation limit of 0.1 ng/mL.

Local anesthetics

The three drugs in this class are lidocaine, proparacaine (Alcaine), and tetracaine (Altacaine, Tetravisc). There is no information regarding the use of these agents in pregnancy or lactation. Since they are used for brief periods, the risk to an embryo or nursing infant appears to be nil.

Mast cell stabilizers

There are three drugs in this class that can be used topically in the eye: cromolyn, lodoxamide (Alomide), and nedocromil (Alocril). There are no human eye data for these agents. Systemic concentrations of lodoxamide were below the detection limit of 2.5 ng/mL.

Miotics

The two miotics are acetylcholine (Miochol E) and carbachol (Carbastat, Miostat). Both are used immediately before eye surgery. The amount, if any, in the systemic circulation is unknown. No reports of human eye use in pregnancy or lactation have been found.

NSAIDs

The five drugs in this class are bromfenac (Xibrom), diclofenac (Voltaren), flurbiprofen (Ocufen), ketorolac, and nepafenac (Nevanac). Although it has not been studied, the estimated plasma level for bromfenac is less than 50 ng/mL. For diclofenac, the plasma concentration was below the limit of quantification (10 ng/mL). In a study conducted with ketorolac, only 5 of 26 subjects had detectable plasma concentrations (10.7 to 22.5 ng/mL). These levels were about 2% of the peak plasma levels after oral dosing. For nepafenac, the peak plasma concentrations of the parent drug and active metabolite were 0.3 and 0.4 ng/mL, respectively. These data suggest that the risk to the embryo-fetus or a nursing infant are nil.

Photodynamic therapy

Verteporfin (Visudyne) is given intravenously. Three reports have described its use in three pregnancies. In all cases, the infants were healthy at birth and had normal growth (Acta Ophthalmol Scand. 2004 Oct;82[5]:623-4, Eye [Lond]. 2009 Jun;23[6]:1479, and Aust N Z J Obstet Gynaecol. 2009 Apr;49[2]:236-7).

Proteolytic enzymes

No human eye data were found for ocriplasmin (Jetrea), an agent given as an intravitreal injection. Although it was not studied, detectable levels of the drug in the systemic circulation are not expected, according to the manufacturer.

Selective vascular endothelial growth factor antagonists

There are three agents in this class: aflibercept (Eylea), pegaptanib (Macugen), and ranibizumab (Lucentis). There are no human eye data for these drugs. All are given as intravitreal injection. The systemic concentrations of the three drugs were a mean 0.02 mcg/mL; 80 ng/mL (after a dose of 10 times the recommended dose); and an estimated minimum 0.22 ng/mL, respectively. These data suggest that the risk to the embryo-fetus or a nursing infant is nil.

Sympathomimetics (decongestants)

There are four ophthalmic agents in this class and none have human eye data. Naphazoline (Naphcon, Vasocon) is the only one of the four that requires a prescription. No reports describing the systemic absorption, if any, have been found. The other three agents are available over the counter. They are oxymetazoline (Visine L.R.), phenylephrine, and tetrahydrozoline (Opti-Clear). Although the amount reaching the systemic circulation was not provided by the manufacturers for these three agents, a caution was placed on phenylephrine stating that systemic absorption, although rare, might cause alpha-adrenergic effects, such as a rise in blood pressure and reflex atropine-sensitive bradycardia.

The risk to the embryo-fetus or nursing infant from ophthalmic drugs appears to be low, with the possible exception of phenylephrine. Nevertheless, if any of these agents are used in pregnancy or during breastfeeding, careful assessment of the embryo-fetus and nursing infant should be conducted. Moreover, research on the potential effects of ophthalmic drugs on the embryo-fetus and nursing infant are desperately needed.

Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco; and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He is coauthor of “Drugs in Pregnancy and Lactation,” and coeditor of “Diseases, Complications, and Drug Therapy in Obstetrics.” He has no relevant financial disclosures.

SAN DIEGO – Among patients with pulmonary hypertension presenting for elective surgery, self-reported poor functional status is associated with multiple comorbidities and is independently predictive of longer hospital length of stay, results from an ongoing single-center study suggest.

“Patients with pulmonary hypertension (PHTN) presenting for elective surgery are at significantly higher risk for adverse perioperative outcomes, including increased hospital length of stay, right ventricular failure, cardiac arrhythmia, persistent postoperative hypoxemia, coronary ischemia and death,” researchers led by Dr. Aalap C. Shah wrote in an abstract presented at the at the annual meeting of the American Society of Anesthesiologists. “The diagnosis of PHTN is based on costly echocardiographic examination and right heart catheterization and should be reserved for high-risk patients. No studies have assessed the role of self-reported functional classification on PHTN severity stratification, and few studies have achieved a sufficiently large patient sample size.”

In an effort to evaluate the predictive value of self-reported exercise tolerance on echocardiogram findings, outcomes, and length of stay (LOS) after noncardiac, nonobstetric surgery, the researchers queried the University of Washington database for all PHTN seen in preoperative anesthesia clinic for noncardiac, nonobstetric procedures from April 2007 through September 2013. Inclusion criteria required an echocardiogram less than 1 year prior to the procedure and available patient-reported functional status, which was defined as less than four metabolic equivalents (METS) in exercise testing or four METS or greater. Dr. Shah, formerly a resident in the University of Washington’s department of anesthesiology and pain medicine, and his associates used univariate analyses to compare functional status with echocardiographic findings, complication rates, and length of stay (LOS). At the meeting he presented results from 294 patients evaluated to date: 143 with normal functional status and 151 with poor functional status. Their mean age was 62 years, and 51% of patients were female.

Compared with their counterparts with normal functional status, patients with poor functional status trended toward a higher complication rate at hospital discharge (14.6% vs. 7%, respectively; P = .041) and had a higher cumulative rate of complications (33 vs. 15; P = .035). However, no association between functional status and complications was observed 30 days postoperatively.

Patients with poor functional status had a significantly longer average LOS, compared with patients with normal functional status (7.21 vs. 4.73 days; P = .047). Open surgical approach was also an independent predictor of increased LOS (odds ratio 2.39; P = .005). No significant independent predictors of complications were observed at discharge or 30 days postoperatively.

“Going forward, the goal is to use these data to create a risk stratification algorithm to figure out: Does a patient with good functional status and pulmonary hypertension undergoing toe surgery, for example, really need an echocardiogram before getting surgery?” said Dr. Shah said, who is now an anesthesiology fellow at Boston Children’s Hospital. “Hopefully we can show that using these risk stratification algorithms can decrease the costs and decrease the time to actually getting surgery.”

The researchers reported having no financial disclosures.

[email protected]

SAN DIEGO – Among patients with pulmonary hypertension presenting for elective surgery, self-reported poor functional status is associated with multiple comorbidities and is independently predictive of longer hospital length of stay, results from an ongoing single-center study suggest.

“Patients with pulmonary hypertension (PHTN) presenting for elective surgery are at significantly higher risk for adverse perioperative outcomes, including increased hospital length of stay, right ventricular failure, cardiac arrhythmia, persistent postoperative hypoxemia, coronary ischemia and death,” researchers led by Dr. Aalap C. Shah wrote in an abstract presented at the at the annual meeting of the American Society of Anesthesiologists. “The diagnosis of PHTN is based on costly echocardiographic examination and right heart catheterization and should be reserved for high-risk patients. No studies have assessed the role of self-reported functional classification on PHTN severity stratification, and few studies have achieved a sufficiently large patient sample size.”

In an effort to evaluate the predictive value of self-reported exercise tolerance on echocardiogram findings, outcomes, and length of stay (LOS) after noncardiac, nonobstetric surgery, the researchers queried the University of Washington database for all PHTN seen in preoperative anesthesia clinic for noncardiac, nonobstetric procedures from April 2007 through September 2013. Inclusion criteria required an echocardiogram less than 1 year prior to the procedure and available patient-reported functional status, which was defined as less than four metabolic equivalents (METS) in exercise testing or four METS or greater. Dr. Shah, formerly a resident in the University of Washington’s department of anesthesiology and pain medicine, and his associates used univariate analyses to compare functional status with echocardiographic findings, complication rates, and length of stay (LOS). At the meeting he presented results from 294 patients evaluated to date: 143 with normal functional status and 151 with poor functional status. Their mean age was 62 years, and 51% of patients were female.

Compared with their counterparts with normal functional status, patients with poor functional status trended toward a higher complication rate at hospital discharge (14.6% vs. 7%, respectively; P = .041) and had a higher cumulative rate of complications (33 vs. 15; P = .035). However, no association between functional status and complications was observed 30 days postoperatively.

Patients with poor functional status had a significantly longer average LOS, compared with patients with normal functional status (7.21 vs. 4.73 days; P = .047). Open surgical approach was also an independent predictor of increased LOS (odds ratio 2.39; P = .005). No significant independent predictors of complications were observed at discharge or 30 days postoperatively.

“Going forward, the goal is to use these data to create a risk stratification algorithm to figure out: Does a patient with good functional status and pulmonary hypertension undergoing toe surgery, for example, really need an echocardiogram before getting surgery?” said Dr. Shah said, who is now an anesthesiology fellow at Boston Children’s Hospital. “Hopefully we can show that using these risk stratification algorithms can decrease the costs and decrease the time to actually getting surgery.”

The researchers reported having no financial disclosures.

[email protected]

SAN DIEGO – Among patients with pulmonary hypertension presenting for elective surgery, self-reported poor functional status is associated with multiple comorbidities and is independently predictive of longer hospital length of stay, results from an ongoing single-center study suggest.

“Patients with pulmonary hypertension (PHTN) presenting for elective surgery are at significantly higher risk for adverse perioperative outcomes, including increased hospital length of stay, right ventricular failure, cardiac arrhythmia, persistent postoperative hypoxemia, coronary ischemia and death,” researchers led by Dr. Aalap C. Shah wrote in an abstract presented at the at the annual meeting of the American Society of Anesthesiologists. “The diagnosis of PHTN is based on costly echocardiographic examination and right heart catheterization and should be reserved for high-risk patients. No studies have assessed the role of self-reported functional classification on PHTN severity stratification, and few studies have achieved a sufficiently large patient sample size.”

In an effort to evaluate the predictive value of self-reported exercise tolerance on echocardiogram findings, outcomes, and length of stay (LOS) after noncardiac, nonobstetric surgery, the researchers queried the University of Washington database for all PHTN seen in preoperative anesthesia clinic for noncardiac, nonobstetric procedures from April 2007 through September 2013. Inclusion criteria required an echocardiogram less than 1 year prior to the procedure and available patient-reported functional status, which was defined as less than four metabolic equivalents (METS) in exercise testing or four METS or greater. Dr. Shah, formerly a resident in the University of Washington’s department of anesthesiology and pain medicine, and his associates used univariate analyses to compare functional status with echocardiographic findings, complication rates, and length of stay (LOS). At the meeting he presented results from 294 patients evaluated to date: 143 with normal functional status and 151 with poor functional status. Their mean age was 62 years, and 51% of patients were female.

Compared with their counterparts with normal functional status, patients with poor functional status trended toward a higher complication rate at hospital discharge (14.6% vs. 7%, respectively; P = .041) and had a higher cumulative rate of complications (33 vs. 15; P = .035). However, no association between functional status and complications was observed 30 days postoperatively.

Patients with poor functional status had a significantly longer average LOS, compared with patients with normal functional status (7.21 vs. 4.73 days; P = .047). Open surgical approach was also an independent predictor of increased LOS (odds ratio 2.39; P = .005). No significant independent predictors of complications were observed at discharge or 30 days postoperatively.

“Going forward, the goal is to use these data to create a risk stratification algorithm to figure out: Does a patient with good functional status and pulmonary hypertension undergoing toe surgery, for example, really need an echocardiogram before getting surgery?” said Dr. Shah said, who is now an anesthesiology fellow at Boston Children’s Hospital. “Hopefully we can show that using these risk stratification algorithms can decrease the costs and decrease the time to actually getting surgery.”

The researchers reported having no financial disclosures.

[email protected]

The Senate passed a bill that would require childproof packaging for liquid nicotine products.

The Child Nicotine Poisoning Prevention Act of 2015 (S. 142), also would codify Food and Drug Administration authority to regulate the packaging of liquid nicotine that is used to refill various electronic nicotine delivery systems.

S. 142 passed by unanimous consent in the Senate on Dec. 10. The House of Representatives has not taken action on the bill.

“Just a small amount of this stuff can injure or even kill a small child,” Sen. Bill Nelson (D-Fla.), the bill’s sponsor, said in a statement. “Making these bottles childproof is just common sense.”

In 2014, poison control centers received more than 3,000 calls related to e-cigarette nicotine exposure, including one toddler death, according to a statement from the American Academy of Pediatrics.

“With e-cigarettes becoming more and more common in households across the country, we cannot afford to wait another day to protect children from poisonous liquid nicotine,” AAP President Dr. Sandra Hassink said.

[email protected]

The Senate passed a bill that would require childproof packaging for liquid nicotine products.

The Child Nicotine Poisoning Prevention Act of 2015 (S. 142), also would codify Food and Drug Administration authority to regulate the packaging of liquid nicotine that is used to refill various electronic nicotine delivery systems.

S. 142 passed by unanimous consent in the Senate on Dec. 10. The House of Representatives has not taken action on the bill.

“Just a small amount of this stuff can injure or even kill a small child,” Sen. Bill Nelson (D-Fla.), the bill’s sponsor, said in a statement. “Making these bottles childproof is just common sense.”

In 2014, poison control centers received more than 3,000 calls related to e-cigarette nicotine exposure, including one toddler death, according to a statement from the American Academy of Pediatrics.

“With e-cigarettes becoming more and more common in households across the country, we cannot afford to wait another day to protect children from poisonous liquid nicotine,” AAP President Dr. Sandra Hassink said.

[email protected]

The Senate passed a bill that would require childproof packaging for liquid nicotine products.

The Child Nicotine Poisoning Prevention Act of 2015 (S. 142), also would codify Food and Drug Administration authority to regulate the packaging of liquid nicotine that is used to refill various electronic nicotine delivery systems.

S. 142 passed by unanimous consent in the Senate on Dec. 10. The House of Representatives has not taken action on the bill.

“Just a small amount of this stuff can injure or even kill a small child,” Sen. Bill Nelson (D-Fla.), the bill’s sponsor, said in a statement. “Making these bottles childproof is just common sense.”

In 2014, poison control centers received more than 3,000 calls related to e-cigarette nicotine exposure, including one toddler death, according to a statement from the American Academy of Pediatrics.

“With e-cigarettes becoming more and more common in households across the country, we cannot afford to wait another day to protect children from poisonous liquid nicotine,” AAP President Dr. Sandra Hassink said.

[email protected]

Atopic dermatitis (AD) is a multifactorial inflammatory disorder with an estimated prevalence of 279,889,120 cases worldwide.1 Most cases of AD begin in early childhood (with almost 85% developing by 5 years of age),² but recent studies have found that 40% to over 80% of cases persist into adulthood.^1,3,4 Although a previous study focused largely on T helper type 1/T helper type 2 (Th2) immune dysregulation as the pathogenesis of the disease,⁵ disruption of the skin barrier and systemic inflammation are at the center of current AD research. In AD, breakdown of the skin barrier results in increased transepidermal water loss, reduced skin hydration, and increased antigen presentation by Langerhans cells initiating inflammation.6-8 The cascade largely activated is the Th2 and T helper type 22 cascade with resultant cytokine release (ie, IL-4, IL-13, IL-2, IL-8, IL-10, IL-17, IL-22, tumor necrosis factor α, interferon γ).^9,10 In active AD, Th2 inflammation and barrier breakdown result in reduced filaggrin and claudin 1 expression, resulting in further exacerbation of the barrier defect and enhancing the risk of development of asthma and hay fever as well as transcutaneous sensitization to a variety of food allergens (eg, peanuts).^9,11,12 Although all of these immunologic features are well established in AD, controversy remains as to whether AD is caused by systemic inflammation triggering barrier dysfunction (the “inside-out” hypothesis) or from the epidermal skin barrier disruption triggering immunologic imbalance (the “outside-in” hypothesis).

Inside-Out Hypothesis

While barrier impairment appears to occur in all patients with AD, it still is unclear how AD begins. The inside-out hypothesis suggests that cutaneous inflammation precedes barrier impairment and in fact may result in an impaired skin barrier. It has previously been reported that inflammatory states weaken the barrier by downregulating filaggrin production in the skin.¹³ Barrier disruption may be accompanied by transcutaneous penetration of allergens and increased Staphylococcus aureus counts. Recently, mutations and polymorphisms of inflammatory genes have been linked to AD (eg, single nucleotide polymorphisms of the IL4RA [interleukin 4 receptor, alpha] and CD14 [cluster of differentiation 14] genes, the serine protease inhibitor SPINK5 [serine peptidase inhibitor, Kazal type 5], RANTES [chemokine (C-C motif) ligand 5], IL-4, IL-13).¹⁴ These alterations highlight the role of systemic inflammation in triggering AD.

Outside-In Hypothesis

The outside-in hypothesis suggests that the impaired skin barrier precedes AD and is required for immune dysregulation to occur. This hypothesis was largely advanced by a study demonstrating that deactivating mutations of the filaggrin gene were linked to nearly 20% of AD cases in Northern European populations.15 Filaggrin (chromosome 1q21.3) performs an essential function in the skin barrier through its differential cleavage and the breakdown and release of natural moisturizing factor.¹⁶ Filaggrin gene mutations are associated with persistent AD, and it has been posited that environmental factors such as temperature and humidity also can affect filaggrin production as it relates to barrier function.17-19 Skin barrier disruption results in increased cutaneous and systemic Th2 responses (ie, IL-4/13), with thymic stromal lymphopoietin as the potential mechanism of Th2 cell recruitment.^10,20 Inflammatory Th2 cells triggered by an impaired skin barrier also may predispose patients to the development of allergic diseases such as asthma, in line with Atopic March, or the progression of AD to other forms of atopy (eg, food allergy, asthma).^5,7,21-23

The outside-in hypothesis may only explain the root pathogenesis of AD in a subset of patients, however, as only 1 in 5 cases of AD in Northern European and Asian populations are associated with underlying filaggrin mutations (which are only present in about 10% of those who are unaffected by AD).¹⁵ Filaggrin does not appear to account for the basis of AD in all cases. In a study of 762 newborns in Cincinnati, Ohio, 39% of children with at least one parent with atopy developed AD by 3 years of age, about quadruple of what would be projected based on filaggrin defects in general population studies, which are noted in only about 10% of white individuals.²⁴ Furthermore, less than 5% of patients of African descent have mutations of the filaggrin 1 gene.²⁵

Implications for the Prevention and Treatment of Atopic Dermatitis

Preventative strategies for AD currently are in development. Atopic dermatitis may be unpreventable because the in utero environment triggers some of the barrier alterations, which can be noted as early as 2 days following birth and will predict early-onset AD. The putative mechanism is via Th2 cytokines (IL-4, IL-13).²⁶

Certainly, application of over-the-counter and prescription emollients are mainstays of treatment for AD and may suffice as monotherapy in cases of mild disease. In a recent randomized trial in the United States and the United Kingdom, emollients were used in newborns considered at high risk for AD (family history of atopy) until 6 months of age.²⁷ The risk of AD development was reduced by half, irrespective of the emollient used. Unfortunately, 21.8% of children without a family history of atopy will develop AD; therefore, not all cases can be prevented if use of emollients is limited to newborns with a family history of atopy.²⁸ Long-term follow-up is needed to track whether emollient use in newborns will prevent AD indefinitely.

Prevention of AD onset using systemic interventions has also been investigated. Probiotics have been suggested as a means to modify the gut microbiota and reduce systemic and mucosal inflammation. Lactobacillus reuteri taken prenatally by pregnant women and by newborns has shown mild benefit in preventing some forms of AD.29 Although they are not approved by the US Food and Drug Administration for this indication, systemic interventions for moderate-to-severe AD such as methotrexate and cyclosporine certainly have shown benefit in managing ongoing illness and breaking the cycle of disease.³⁰ The efficacy of these agents points to the role of systemic inflammation in ongoing AD activity. Moreover, the inside-out hypothesis recently has led to the proliferation of promising new therapeutic agents in the pipeline to treat the systemic Th2 inflammation that occurs in severe AD (eg, anti–IL-4/13 receptor antibody, anti–IL-13 antibodies, and biologics targeting IL-12/23, IL-22, and IL-31 receptors).³¹

Final Thoughts

Atopic dermatitis is a multifactorial disease associated with barrier disruption and intense systemic inflammation. It is likely that both the inside-out and outside-in hypotheses hold true in different subsets of AD patients. It is clear that some individuals are born with filaggrin defects that sufficiently trigger systemic inflammation, resulting in AD. On the other hand, there are clearly some individuals with inflammatory dysregulation that results in systemic inflammation and secondary barrier disruption. Until we can determine the genomic triggering or promoting event in each individual patient, large-scale introduction of active prevention and severity reduction strategies may not be realistic. In the meantime, we can approach AD in childhood from the inside out, through appropriate treatment of systemic inflammation of AD, and from the outside in, with treatment and prevention via emollient use in newborns.

Atopic dermatitis (AD) is a multifactorial inflammatory disorder with an estimated prevalence of 279,889,120 cases worldwide.1 Most cases of AD begin in early childhood (with almost 85% developing by 5 years of age),² but recent studies have found that 40% to over 80% of cases persist into adulthood.^1,3,4 Although a previous study focused largely on T helper type 1/T helper type 2 (Th2) immune dysregulation as the pathogenesis of the disease,⁵ disruption of the skin barrier and systemic inflammation are at the center of current AD research. In AD, breakdown of the skin barrier results in increased transepidermal water loss, reduced skin hydration, and increased antigen presentation by Langerhans cells initiating inflammation.6-8 The cascade largely activated is the Th2 and T helper type 22 cascade with resultant cytokine release (ie, IL-4, IL-13, IL-2, IL-8, IL-10, IL-17, IL-22, tumor necrosis factor α, interferon γ).^9,10 In active AD, Th2 inflammation and barrier breakdown result in reduced filaggrin and claudin 1 expression, resulting in further exacerbation of the barrier defect and enhancing the risk of development of asthma and hay fever as well as transcutaneous sensitization to a variety of food allergens (eg, peanuts).^9,11,12 Although all of these immunologic features are well established in AD, controversy remains as to whether AD is caused by systemic inflammation triggering barrier dysfunction (the “inside-out” hypothesis) or from the epidermal skin barrier disruption triggering immunologic imbalance (the “outside-in” hypothesis).

Inside-Out Hypothesis

While barrier impairment appears to occur in all patients with AD, it still is unclear how AD begins. The inside-out hypothesis suggests that cutaneous inflammation precedes barrier impairment and in fact may result in an impaired skin barrier. It has previously been reported that inflammatory states weaken the barrier by downregulating filaggrin production in the skin.¹³ Barrier disruption may be accompanied by transcutaneous penetration of allergens and increased Staphylococcus aureus counts. Recently, mutations and polymorphisms of inflammatory genes have been linked to AD (eg, single nucleotide polymorphisms of the IL4RA [interleukin 4 receptor, alpha] and CD14 [cluster of differentiation 14] genes, the serine protease inhibitor SPINK5 [serine peptidase inhibitor, Kazal type 5], RANTES [chemokine (C-C motif) ligand 5], IL-4, IL-13).¹⁴ These alterations highlight the role of systemic inflammation in triggering AD.

Outside-In Hypothesis

The outside-in hypothesis suggests that the impaired skin barrier precedes AD and is required for immune dysregulation to occur. This hypothesis was largely advanced by a study demonstrating that deactivating mutations of the filaggrin gene were linked to nearly 20% of AD cases in Northern European populations.15 Filaggrin (chromosome 1q21.3) performs an essential function in the skin barrier through its differential cleavage and the breakdown and release of natural moisturizing factor.¹⁶ Filaggrin gene mutations are associated with persistent AD, and it has been posited that environmental factors such as temperature and humidity also can affect filaggrin production as it relates to barrier function.17-19 Skin barrier disruption results in increased cutaneous and systemic Th2 responses (ie, IL-4/13), with thymic stromal lymphopoietin as the potential mechanism of Th2 cell recruitment.^10,20 Inflammatory Th2 cells triggered by an impaired skin barrier also may predispose patients to the development of allergic diseases such as asthma, in line with Atopic March, or the progression of AD to other forms of atopy (eg, food allergy, asthma).^5,7,21-23

The outside-in hypothesis may only explain the root pathogenesis of AD in a subset of patients, however, as only 1 in 5 cases of AD in Northern European and Asian populations are associated with underlying filaggrin mutations (which are only present in about 10% of those who are unaffected by AD).¹⁵ Filaggrin does not appear to account for the basis of AD in all cases. In a study of 762 newborns in Cincinnati, Ohio, 39% of children with at least one parent with atopy developed AD by 3 years of age, about quadruple of what would be projected based on filaggrin defects in general population studies, which are noted in only about 10% of white individuals.²⁴ Furthermore, less than 5% of patients of African descent have mutations of the filaggrin 1 gene.²⁵

Implications for the Prevention and Treatment of Atopic Dermatitis

Preventative strategies for AD currently are in development. Atopic dermatitis may be unpreventable because the in utero environment triggers some of the barrier alterations, which can be noted as early as 2 days following birth and will predict early-onset AD. The putative mechanism is via Th2 cytokines (IL-4, IL-13).²⁶

Certainly, application of over-the-counter and prescription emollients are mainstays of treatment for AD and may suffice as monotherapy in cases of mild disease. In a recent randomized trial in the United States and the United Kingdom, emollients were used in newborns considered at high risk for AD (family history of atopy) until 6 months of age.²⁷ The risk of AD development was reduced by half, irrespective of the emollient used. Unfortunately, 21.8% of children without a family history of atopy will develop AD; therefore, not all cases can be prevented if use of emollients is limited to newborns with a family history of atopy.²⁸ Long-term follow-up is needed to track whether emollient use in newborns will prevent AD indefinitely.

Prevention of AD onset using systemic interventions has also been investigated. Probiotics have been suggested as a means to modify the gut microbiota and reduce systemic and mucosal inflammation. Lactobacillus reuteri taken prenatally by pregnant women and by newborns has shown mild benefit in preventing some forms of AD.29 Although they are not approved by the US Food and Drug Administration for this indication, systemic interventions for moderate-to-severe AD such as methotrexate and cyclosporine certainly have shown benefit in managing ongoing illness and breaking the cycle of disease.³⁰ The efficacy of these agents points to the role of systemic inflammation in ongoing AD activity. Moreover, the inside-out hypothesis recently has led to the proliferation of promising new therapeutic agents in the pipeline to treat the systemic Th2 inflammation that occurs in severe AD (eg, anti–IL-4/13 receptor antibody, anti–IL-13 antibodies, and biologics targeting IL-12/23, IL-22, and IL-31 receptors).³¹

Final Thoughts

Atopic dermatitis is a multifactorial disease associated with barrier disruption and intense systemic inflammation. It is likely that both the inside-out and outside-in hypotheses hold true in different subsets of AD patients. It is clear that some individuals are born with filaggrin defects that sufficiently trigger systemic inflammation, resulting in AD. On the other hand, there are clearly some individuals with inflammatory dysregulation that results in systemic inflammation and secondary barrier disruption. Until we can determine the genomic triggering or promoting event in each individual patient, large-scale introduction of active prevention and severity reduction strategies may not be realistic. In the meantime, we can approach AD in childhood from the inside out, through appropriate treatment of systemic inflammation of AD, and from the outside in, with treatment and prevention via emollient use in newborns.

Atopic dermatitis (AD) is a multifactorial inflammatory disorder with an estimated prevalence of 279,889,120 cases worldwide.1 Most cases of AD begin in early childhood (with almost 85% developing by 5 years of age),² but recent studies have found that 40% to over 80% of cases persist into adulthood.^1,3,4 Although a previous study focused largely on T helper type 1/T helper type 2 (Th2) immune dysregulation as the pathogenesis of the disease,⁵ disruption of the skin barrier and systemic inflammation are at the center of current AD research. In AD, breakdown of the skin barrier results in increased transepidermal water loss, reduced skin hydration, and increased antigen presentation by Langerhans cells initiating inflammation.6-8 The cascade largely activated is the Th2 and T helper type 22 cascade with resultant cytokine release (ie, IL-4, IL-13, IL-2, IL-8, IL-10, IL-17, IL-22, tumor necrosis factor α, interferon γ).^9,10 In active AD, Th2 inflammation and barrier breakdown result in reduced filaggrin and claudin 1 expression, resulting in further exacerbation of the barrier defect and enhancing the risk of development of asthma and hay fever as well as transcutaneous sensitization to a variety of food allergens (eg, peanuts).^9,11,12 Although all of these immunologic features are well established in AD, controversy remains as to whether AD is caused by systemic inflammation triggering barrier dysfunction (the “inside-out” hypothesis) or from the epidermal skin barrier disruption triggering immunologic imbalance (the “outside-in” hypothesis).

Inside-Out Hypothesis

While barrier impairment appears to occur in all patients with AD, it still is unclear how AD begins. The inside-out hypothesis suggests that cutaneous inflammation precedes barrier impairment and in fact may result in an impaired skin barrier. It has previously been reported that inflammatory states weaken the barrier by downregulating filaggrin production in the skin.¹³ Barrier disruption may be accompanied by transcutaneous penetration of allergens and increased Staphylococcus aureus counts. Recently, mutations and polymorphisms of inflammatory genes have been linked to AD (eg, single nucleotide polymorphisms of the IL4RA [interleukin 4 receptor, alpha] and CD14 [cluster of differentiation 14] genes, the serine protease inhibitor SPINK5 [serine peptidase inhibitor, Kazal type 5], RANTES [chemokine (C-C motif) ligand 5], IL-4, IL-13).¹⁴ These alterations highlight the role of systemic inflammation in triggering AD.

Outside-In Hypothesis

The outside-in hypothesis suggests that the impaired skin barrier precedes AD and is required for immune dysregulation to occur. This hypothesis was largely advanced by a study demonstrating that deactivating mutations of the filaggrin gene were linked to nearly 20% of AD cases in Northern European populations.15 Filaggrin (chromosome 1q21.3) performs an essential function in the skin barrier through its differential cleavage and the breakdown and release of natural moisturizing factor.¹⁶ Filaggrin gene mutations are associated with persistent AD, and it has been posited that environmental factors such as temperature and humidity also can affect filaggrin production as it relates to barrier function.17-19 Skin barrier disruption results in increased cutaneous and systemic Th2 responses (ie, IL-4/13), with thymic stromal lymphopoietin as the potential mechanism of Th2 cell recruitment.^10,20 Inflammatory Th2 cells triggered by an impaired skin barrier also may predispose patients to the development of allergic diseases such as asthma, in line with Atopic March, or the progression of AD to other forms of atopy (eg, food allergy, asthma).^5,7,21-23

The outside-in hypothesis may only explain the root pathogenesis of AD in a subset of patients, however, as only 1 in 5 cases of AD in Northern European and Asian populations are associated with underlying filaggrin mutations (which are only present in about 10% of those who are unaffected by AD).¹⁵ Filaggrin does not appear to account for the basis of AD in all cases. In a study of 762 newborns in Cincinnati, Ohio, 39% of children with at least one parent with atopy developed AD by 3 years of age, about quadruple of what would be projected based on filaggrin defects in general population studies, which are noted in only about 10% of white individuals.²⁴ Furthermore, less than 5% of patients of African descent have mutations of the filaggrin 1 gene.²⁵

Implications for the Prevention and Treatment of Atopic Dermatitis

Preventative strategies for AD currently are in development. Atopic dermatitis may be unpreventable because the in utero environment triggers some of the barrier alterations, which can be noted as early as 2 days following birth and will predict early-onset AD. The putative mechanism is via Th2 cytokines (IL-4, IL-13).²⁶

Certainly, application of over-the-counter and prescription emollients are mainstays of treatment for AD and may suffice as monotherapy in cases of mild disease. In a recent randomized trial in the United States and the United Kingdom, emollients were used in newborns considered at high risk for AD (family history of atopy) until 6 months of age.²⁷ The risk of AD development was reduced by half, irrespective of the emollient used. Unfortunately, 21.8% of children without a family history of atopy will develop AD; therefore, not all cases can be prevented if use of emollients is limited to newborns with a family history of atopy.²⁸ Long-term follow-up is needed to track whether emollient use in newborns will prevent AD indefinitely.

Prevention of AD onset using systemic interventions has also been investigated. Probiotics have been suggested as a means to modify the gut microbiota and reduce systemic and mucosal inflammation. Lactobacillus reuteri taken prenatally by pregnant women and by newborns has shown mild benefit in preventing some forms of AD.29 Although they are not approved by the US Food and Drug Administration for this indication, systemic interventions for moderate-to-severe AD such as methotrexate and cyclosporine certainly have shown benefit in managing ongoing illness and breaking the cycle of disease.³⁰ The efficacy of these agents points to the role of systemic inflammation in ongoing AD activity. Moreover, the inside-out hypothesis recently has led to the proliferation of promising new therapeutic agents in the pipeline to treat the systemic Th2 inflammation that occurs in severe AD (eg, anti–IL-4/13 receptor antibody, anti–IL-13 antibodies, and biologics targeting IL-12/23, IL-22, and IL-31 receptors).³¹

Final Thoughts

Atopic dermatitis is a multifactorial disease associated with barrier disruption and intense systemic inflammation. It is likely that both the inside-out and outside-in hypotheses hold true in different subsets of AD patients. It is clear that some individuals are born with filaggrin defects that sufficiently trigger systemic inflammation, resulting in AD. On the other hand, there are clearly some individuals with inflammatory dysregulation that results in systemic inflammation and secondary barrier disruption. Until we can determine the genomic triggering or promoting event in each individual patient, large-scale introduction of active prevention and severity reduction strategies may not be realistic. In the meantime, we can approach AD in childhood from the inside out, through appropriate treatment of systemic inflammation of AD, and from the outside in, with treatment and prevention via emollient use in newborns.

What does your patient need to know at the first visit?

The most essential information to share with patients at the first visit (as well as at all subsequent visits) is your eczema action plan, which should include discussion and potential modification of bathing regimens, use of topical emollients and medications, and exposure to detergents. It also is important to discuss the patient’s disease pattern (eg, triggers, seasonal flares, other forms of atopy), medication history, and past treatment responses. The eczema action plan is extremely vital for a variety of reasons. As a physician, I can’t be present every time a patient has a severe flare, and it would be difficult—both physically and financially—for patients to come in to my office every time a flare occurs. Patients and their caregivers need to develop a sense of empowerment at the first visit so they can address symptoms as they arise and actively prevent severe flares by following a gentle skin care plan that includes topical emollients and gentle cleansing.

I also like to emphasize to my eczema patients that they are not alone. In the United States, almost one-quarter of the population may have eczema. It’s also essential to explain to patients/caregivers that eczema is not caused by food allergies and cannot be cured by food elimination or other dietary modifications. Finally, I like to explain to patients that there is no true cure for eczema and that they will need to follow the action plan throughout their lifetime to help treat and prevent flares. Follow-up visits to review therapeutic response and review the patient’s eczema action plan can reinforce adherence and knowledge about the disease.

What are your go-to treatments? Are there any side effects?

Typically I prescribe 3 to 4 medications, which include an agent for the head and neck areas and/or areas of sensitive or thin skin, an agent for the body, an antihistamine to address sleep disturbances, and a rescue medication, which is a somewhat stronger topical agent for severe areas if present. Elimination of triggers such as fragrance and wool can be discussed. Review of Staphylococcus aureus as a trigger and addressing this trigger with bleach baths or other modifications (eg, topical antibacterials for crusted areas of skin) is needed.

Eczema treatment is a multistep process that varies by individual as well as by cost. For most eczema patients, treatment typically costs hundreds of dollars per year; therefore, I try to be mindful of the financial hardship that can be brought on by the need for many products. The mainstay of eczema therapy includes topical emollients along with gentle cleansers, laundry detergents, and other topical products. Topical corticosteroids are the first-line treatment and have been used for over 60 years with good outcomes in most patients when used judiciously; however, side effects including striae, glaucoma and hypothalamic-pituitary-adrenal axis suppression can occur. Topical corticosteroids should be selected by class and formulation—ointments and some newer base formulations are known to cause the least amount of stinging. In infants, the least potent agent that clears the skin effectively may maximize outcomes and minimize risk for side effects. Topical calcineurin inhibitors may be a good option in patients who do not respond to corticosteroids and are supported by excellent clinical evidence; however, be sure to consider the black box warnings.^1-3 Sedating antihistamines can be prescribed for bedtime usage in pruritic patients who experience sleep disturbances.

How do you keep patients compliant with treatment?

Patients can only comply with treatment if they have an adequate supply of the treatment product. It is important to prescribe the right amount of product needed to treat the affected area. Provision of refills for recurrent disease also can ensure long-term treatment compliance.

It also is important to have a conversation with patients about the nature of their disease flares. In my practice, patients typically report having seasonal flares, especially in midsummer temperatures or when the indoor heating kicks on in late fall. Encourage patients to schedule appointments in advance of these seasons; refilling medications beforehand and liberal application of emollients also can mitigate seasonal flares.

Finally, I try to recommend or prescribe treatments that appeal to patients both physically and emotionally. Some patients have a fear of using topical corticosteroids (known as corticophobia or steroid phobia). For these patients, I maximize the use of topical emollients and/or enhanced emollients (eg, agents with lipid additives and ceramides) to reduce the need for topical corticosteroids. I also have found that many preteen boys dislike “sticky” emollients, so light or midweight creams may be more tolerable for nightly use in this population. Another common scenario is the patient who prefers natural products. There are a variety of natural agents available that can aid in the treatment of eczema, including coconut oil, ceramide-based products, and oleodistillates. I try to refer to the literature to encourage the use of natural products that are backed by good science rather than big hype.

What do you do if patients refuse treatment?

As a physician, I can’t force patients or their caregivers to adhere to the therapies I prescribe; however, most patients are genuinely seeking a better quality of life and therefore there usually is at least some aspect of a skin care regimen they will follow to achieve relief when needed. First I make sure that serious issues (eg, bacterial infections) are addressed. I do mention to patients/caregivers that lack of treatment with topical prescription agents may have biological consequences; for example, there is evidence to support the Atopic March (ie, progression of atopic diseases to food allergies, asthma, etc). Consequences also can include discomfort, reduced quality of life, and negative effects on personal relationships; pediatric patients also may be stigmatized by their peers. Exploration of the root cause of treatment refusal usually yields a helpful discussion with the patient/caregiver about their fears as well as alternative treatment agents. Sometimes I engage the pediatrician/primary care physician, an allergist, or a family member in the discussion to enhance compliance and provide patient/caregiver support. At the very least, most patients/caregivers will adhere to trigger avoidance and barrier repair through application of emollients.

What resources do you recommend to patients for more information?

There are many resources available to patients that may enhance the overall management of eczema. I give my patients an educational handout about eczema as well as a hardcopy of their personal eczema action plan. For pediatric patients, I write the child’s first name and the date to help his or her caregivers remember when they received the plan. Examples of eczema action plans can be found in published resources ranging from simple to complex regimens and should be tailored to the physician’s own patient education and treatment patterns.^4,5 The National Eczema Association Web site (https://nationaleczema.org/) provides many resources for patients, including educational tools and an online community.

What does your patient need to know at the first visit?

The most essential information to share with patients at the first visit (as well as at all subsequent visits) is your eczema action plan, which should include discussion and potential modification of bathing regimens, use of topical emollients and medications, and exposure to detergents. It also is important to discuss the patient’s disease pattern (eg, triggers, seasonal flares, other forms of atopy), medication history, and past treatment responses. The eczema action plan is extremely vital for a variety of reasons. As a physician, I can’t be present every time a patient has a severe flare, and it would be difficult—both physically and financially—for patients to come in to my office every time a flare occurs. Patients and their caregivers need to develop a sense of empowerment at the first visit so they can address symptoms as they arise and actively prevent severe flares by following a gentle skin care plan that includes topical emollients and gentle cleansing.

I also like to emphasize to my eczema patients that they are not alone. In the United States, almost one-quarter of the population may have eczema. It’s also essential to explain to patients/caregivers that eczema is not caused by food allergies and cannot be cured by food elimination or other dietary modifications. Finally, I like to explain to patients that there is no true cure for eczema and that they will need to follow the action plan throughout their lifetime to help treat and prevent flares. Follow-up visits to review therapeutic response and review the patient’s eczema action plan can reinforce adherence and knowledge about the disease.

What are your go-to treatments? Are there any side effects?

Typically I prescribe 3 to 4 medications, which include an agent for the head and neck areas and/or areas of sensitive or thin skin, an agent for the body, an antihistamine to address sleep disturbances, and a rescue medication, which is a somewhat stronger topical agent for severe areas if present. Elimination of triggers such as fragrance and wool can be discussed. Review of Staphylococcus aureus as a trigger and addressing this trigger with bleach baths or other modifications (eg, topical antibacterials for crusted areas of skin) is needed.

Eczema treatment is a multistep process that varies by individual as well as by cost. For most eczema patients, treatment typically costs hundreds of dollars per year; therefore, I try to be mindful of the financial hardship that can be brought on by the need for many products. The mainstay of eczema therapy includes topical emollients along with gentle cleansers, laundry detergents, and other topical products. Topical corticosteroids are the first-line treatment and have been used for over 60 years with good outcomes in most patients when used judiciously; however, side effects including striae, glaucoma and hypothalamic-pituitary-adrenal axis suppression can occur. Topical corticosteroids should be selected by class and formulation—ointments and some newer base formulations are known to cause the least amount of stinging. In infants, the least potent agent that clears the skin effectively may maximize outcomes and minimize risk for side effects. Topical calcineurin inhibitors may be a good option in patients who do not respond to corticosteroids and are supported by excellent clinical evidence; however, be sure to consider the black box warnings.^1-3 Sedating antihistamines can be prescribed for bedtime usage in pruritic patients who experience sleep disturbances.

How do you keep patients compliant with treatment?

Patients can only comply with treatment if they have an adequate supply of the treatment product. It is important to prescribe the right amount of product needed to treat the affected area. Provision of refills for recurrent disease also can ensure long-term treatment compliance.

It also is important to have a conversation with patients about the nature of their disease flares. In my practice, patients typically report having seasonal flares, especially in midsummer temperatures or when the indoor heating kicks on in late fall. Encourage patients to schedule appointments in advance of these seasons; refilling medications beforehand and liberal application of emollients also can mitigate seasonal flares.

Finally, I try to recommend or prescribe treatments that appeal to patients both physically and emotionally. Some patients have a fear of using topical corticosteroids (known as corticophobia or steroid phobia). For these patients, I maximize the use of topical emollients and/or enhanced emollients (eg, agents with lipid additives and ceramides) to reduce the need for topical corticosteroids. I also have found that many preteen boys dislike “sticky” emollients, so light or midweight creams may be more tolerable for nightly use in this population. Another common scenario is the patient who prefers natural products. There are a variety of natural agents available that can aid in the treatment of eczema, including coconut oil, ceramide-based products, and oleodistillates. I try to refer to the literature to encourage the use of natural products that are backed by good science rather than big hype.

What do you do if patients refuse treatment?

As a physician, I can’t force patients or their caregivers to adhere to the therapies I prescribe; however, most patients are genuinely seeking a better quality of life and therefore there usually is at least some aspect of a skin care regimen they will follow to achieve relief when needed. First I make sure that serious issues (eg, bacterial infections) are addressed. I do mention to patients/caregivers that lack of treatment with topical prescription agents may have biological consequences; for example, there is evidence to support the Atopic March (ie, progression of atopic diseases to food allergies, asthma, etc). Consequences also can include discomfort, reduced quality of life, and negative effects on personal relationships; pediatric patients also may be stigmatized by their peers. Exploration of the root cause of treatment refusal usually yields a helpful discussion with the patient/caregiver about their fears as well as alternative treatment agents. Sometimes I engage the pediatrician/primary care physician, an allergist, or a family member in the discussion to enhance compliance and provide patient/caregiver support. At the very least, most patients/caregivers will adhere to trigger avoidance and barrier repair through application of emollients.

What resources do you recommend to patients for more information?

There are many resources available to patients that may enhance the overall management of eczema. I give my patients an educational handout about eczema as well as a hardcopy of their personal eczema action plan. For pediatric patients, I write the child’s first name and the date to help his or her caregivers remember when they received the plan. Examples of eczema action plans can be found in published resources ranging from simple to complex regimens and should be tailored to the physician’s own patient education and treatment patterns.^4,5 The National Eczema Association Web site (https://nationaleczema.org/) provides many resources for patients, including educational tools and an online community.

What does your patient need to know at the first visit?

The most essential information to share with patients at the first visit (as well as at all subsequent visits) is your eczema action plan, which should include discussion and potential modification of bathing regimens, use of topical emollients and medications, and exposure to detergents. It also is important to discuss the patient’s disease pattern (eg, triggers, seasonal flares, other forms of atopy), medication history, and past treatment responses. The eczema action plan is extremely vital for a variety of reasons. As a physician, I can’t be present every time a patient has a severe flare, and it would be difficult—both physically and financially—for patients to come in to my office every time a flare occurs. Patients and their caregivers need to develop a sense of empowerment at the first visit so they can address symptoms as they arise and actively prevent severe flares by following a gentle skin care plan that includes topical emollients and gentle cleansing.

I also like to emphasize to my eczema patients that they are not alone. In the United States, almost one-quarter of the population may have eczema. It’s also essential to explain to patients/caregivers that eczema is not caused by food allergies and cannot be cured by food elimination or other dietary modifications. Finally, I like to explain to patients that there is no true cure for eczema and that they will need to follow the action plan throughout their lifetime to help treat and prevent flares. Follow-up visits to review therapeutic response and review the patient’s eczema action plan can reinforce adherence and knowledge about the disease.

What are your go-to treatments? Are there any side effects?

Typically I prescribe 3 to 4 medications, which include an agent for the head and neck areas and/or areas of sensitive or thin skin, an agent for the body, an antihistamine to address sleep disturbances, and a rescue medication, which is a somewhat stronger topical agent for severe areas if present. Elimination of triggers such as fragrance and wool can be discussed. Review of Staphylococcus aureus as a trigger and addressing this trigger with bleach baths or other modifications (eg, topical antibacterials for crusted areas of skin) is needed.

Eczema treatment is a multistep process that varies by individual as well as by cost. For most eczema patients, treatment typically costs hundreds of dollars per year; therefore, I try to be mindful of the financial hardship that can be brought on by the need for many products. The mainstay of eczema therapy includes topical emollients along with gentle cleansers, laundry detergents, and other topical products. Topical corticosteroids are the first-line treatment and have been used for over 60 years with good outcomes in most patients when used judiciously; however, side effects including striae, glaucoma and hypothalamic-pituitary-adrenal axis suppression can occur. Topical corticosteroids should be selected by class and formulation—ointments and some newer base formulations are known to cause the least amount of stinging. In infants, the least potent agent that clears the skin effectively may maximize outcomes and minimize risk for side effects. Topical calcineurin inhibitors may be a good option in patients who do not respond to corticosteroids and are supported by excellent clinical evidence; however, be sure to consider the black box warnings.^1-3 Sedating antihistamines can be prescribed for bedtime usage in pruritic patients who experience sleep disturbances.

How do you keep patients compliant with treatment?

Patients can only comply with treatment if they have an adequate supply of the treatment product. It is important to prescribe the right amount of product needed to treat the affected area. Provision of refills for recurrent disease also can ensure long-term treatment compliance.

It also is important to have a conversation with patients about the nature of their disease flares. In my practice, patients typically report having seasonal flares, especially in midsummer temperatures or when the indoor heating kicks on in late fall. Encourage patients to schedule appointments in advance of these seasons; refilling medications beforehand and liberal application of emollients also can mitigate seasonal flares.

Finally, I try to recommend or prescribe treatments that appeal to patients both physically and emotionally. Some patients have a fear of using topical corticosteroids (known as corticophobia or steroid phobia). For these patients, I maximize the use of topical emollients and/or enhanced emollients (eg, agents with lipid additives and ceramides) to reduce the need for topical corticosteroids. I also have found that many preteen boys dislike “sticky” emollients, so light or midweight creams may be more tolerable for nightly use in this population. Another common scenario is the patient who prefers natural products. There are a variety of natural agents available that can aid in the treatment of eczema, including coconut oil, ceramide-based products, and oleodistillates. I try to refer to the literature to encourage the use of natural products that are backed by good science rather than big hype.

What do you do if patients refuse treatment?

As a physician, I can’t force patients or their caregivers to adhere to the therapies I prescribe; however, most patients are genuinely seeking a better quality of life and therefore there usually is at least some aspect of a skin care regimen they will follow to achieve relief when needed. First I make sure that serious issues (eg, bacterial infections) are addressed. I do mention to patients/caregivers that lack of treatment with topical prescription agents may have biological consequences; for example, there is evidence to support the Atopic March (ie, progression of atopic diseases to food allergies, asthma, etc). Consequences also can include discomfort, reduced quality of life, and negative effects on personal relationships; pediatric patients also may be stigmatized by their peers. Exploration of the root cause of treatment refusal usually yields a helpful discussion with the patient/caregiver about their fears as well as alternative treatment agents. Sometimes I engage the pediatrician/primary care physician, an allergist, or a family member in the discussion to enhance compliance and provide patient/caregiver support. At the very least, most patients/caregivers will adhere to trigger avoidance and barrier repair through application of emollients.

What resources do you recommend to patients for more information?

There are many resources available to patients that may enhance the overall management of eczema. I give my patients an educational handout about eczema as well as a hardcopy of their personal eczema action plan. For pediatric patients, I write the child’s first name and the date to help his or her caregivers remember when they received the plan. Examples of eczema action plans can be found in published resources ranging from simple to complex regimens and should be tailored to the physician’s own patient education and treatment patterns.^4,5 The National Eczema Association Web site (https://nationaleczema.org/) provides many resources for patients, including educational tools and an online community.

Richard Stone, MD

Photo courtesy of ASH

ORLANDO, FL—After almost 10 years, during which time no new drug for acute myeloid leukemia (AML) has been approved, results of the RATIFY trial are available.

In this trial, investigators evaluated midostaurin in combination with chemotherapy for younger patients with FLT3-mutated AML.

Patients who received midostaurin in their regimen instead of placebo experienced significantly longer overall survival (OS) and event-free survival (EFS).

“The primary endpoint of the trial was overall survival—which was very important—uncensored for transplant,” said Richard Stone, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts.

“This is very much a ‘real-world’ trial. We just took patients from the start and saw how they did until the end.”

Dr Stone presented results from the trial during the plenary session of the 2015 ASH Annual Meeting (abstract 6*).

Midostaurin (PKC412), developed as a VEGF and protein kinase C inhibitor, is a known FLT3 inhibitor that specifically inhibits the growth of leukemic cell lines.

As a multi-kinase inhibitor, its potency against FLT3 may be limited, but it is active against both ITD and TKD mutations. Because AML is polyclonal at diagnosis, a multi-targeted inhibitor may have an advantage in newly diagnosed AML.

As a single agent, Dr Stone explained, midostaurin produced few remissions in advanced, mutant AML. But when combined with chemotherapy in a phase 1B study in newly diagnosed patients, it produced encouraging results.

So members of the Alliance for Clinical Trials in Oncology, formerly CALGB, and many other cooperative groups around the world—the AMLSG, CETLAM, ECOG, EORTC, GIMEMA, NCIC, OSHO, PETHEMA, SAL, and SWOG—conducted a phase 3, randomized, double-blind trial of induction and consolidation with or without midostaurin in patients younger than 60 with newly diagnosed FLT3-mutated AML.

The primary endpoint was OS, and secondary endpoints were OS censored and uncensored at the time of transplant, complete remission (CR) rates, EFS, disease-free survival (DFS), and adverse events.

Mark Levis, MD, of Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland, who introduced the plenary presentation, suggested that OS may not be the best primary endpoint for an AML trial, given the long time it takes to complete a trial like this.

He pointed out that, “while we waited for RATIFY to accrue and mature, our approach to the disease changed.” Allogeneic transplant is now often the favored consolidation.

Eligibility criteria

Patients aged 18 to 60 with normal end-organ function and documented AML were eligible to enroll. Patients could not have had acute promyelocytic leukemia.

Their FLT3 mutation had to be centrally determined prior to enrollment by 1 of 9 academic labs around the world, and results had to be obtainable within 48 hours of sample collection.

Patients could receive up to 5 days of hydroxyurea prior to the start of treatment while awaiting the results of the mutation analysis.

Trial design

Investigators randomized patients to induction of daunorubicin and cytarabine with either midostaurin or placebo.

Daunorubicin was administered at 60 mg/m² by intravenous push on days 1-3, cytarabine at 200 mg/m² per day on days 1-7, and midostaurin at 50 mg orally twice a day on days 8-21.

A second cycle of induction was given based on day 21 bone marrow biopsy.

When patients achieved CR, they went on to consolidation with high-dose cytarabine (3 g/m² over 3 hours every 12 hours on days 1, 3, and 5) and either midostaurin at the same induction dose or placebo.

After up to 4 doses of consolidation, patients went on to maintenance therapy for 12 months. This consisted of placebo or midostaurin at the same dose twice daily on days 1-28.

Patient population

The investigators screened 3279 patients younger than 60 years with newly diagnosed AML and found 27% (n=887) to be FLT3-positive.

They randomized 717 patients—81% of the FLT3-positive patients—to either the midostaurin arm (n=360) or the placebo arm (n=357). These 717 patients were evaluable for the intent-to-treat analysis.

The median age was 47.1 (range, 19.0–59.8) in the midostaurin arm and 48.6 (range, 18.0–60.9) in the placebo arm. There were significantly more males in the midostaurin arm (48.1%) than in the placebo arm (40.6%, P=0.045).

And the arms were almost identical for FLT3 stratification. In the midostaurin group, 22.5% had FLT3 TKD (no ITD), 47.5% had an ITD allelic ratio (+/- FLT3 TKD) less than 0.7, and 30.0% had a ratio of 0.7 or more.

In the placebo arm, 22.7% had FLT3 TKD, and 47.6% and 29.7% had ITD allelic ratios less than and greater than 0.7, respectively.

Safety

Rash/desquamation was the only significant difference in grade 3-4 non-hematologic events between the arms, with 13% in the midostaurin arm and 8% in the placebo arm (P=0.02).

Other grade 3-4 non-hematologic events occurring in 10% of patients or more included, in the midostaurin and placebo arms, respectively: febrile neutropenia (81%, 82%), infection (40%, 38%), diarrhea (15%, 16%), hypokalemia (13%, 17%), pain (13%, 13%), other infection (12%, 12%), ALT/SGPT (12%, 9%), and fatigue (9%, 11%).

There were 18 deaths (5%) in the midostaurin arm and 19 (5.3%) in the placebo arm during induction and consolidation treatment.

Efficacy

OS was superior for patients randomized to midostaurin. The median survival was 74.7 months (range, 31.7-not estimable) in the midostaurin arm and 25.6 months (range,18.6-42.9) in the placebo arm (P=0.0076).

Overall, there were 357 deaths, 171 and 186 in the midostaurin and placebo arms, respectively.

The 5-year survival rate was 50.9% for midostaurin and 43.9% for placebo.

EFS was also superior for patients randomized to midostaurin (P=0.0032), at a median of 8.0 months for midostaurin and 3.6 months for placebo. The 5-year EFS was 27.5% for midostaurin and 19.3% for placebo.

The CR rates by day 60 were not significantly different between the arms, at 59% and 53% for midostaurin and placebo, respectively. And the median time to CR was the same in each group, at 35 days.

The survival benefit, both overall and event-free, was consistent regardless of whether the patients were FLT3-ITD high, low, or FLT3-TKD.

The OS and EFS benefits were also consistent in censored and uncensored analyses, despite the high stem cell transplant rate. Four hundred eight patients (57%) received a transplant, 212 in the midostaurin arm and 196 in the placebo arm.

“The trial was positive whether you censored the patients at transplant or you kept following them for the whole time,” Dr Stone said.

He concluded that this type of international collaborative AML study based on genotype at diagnosis is feasible to do. But it took “a lot of collaboration, a lot of cooperation, a lot of persistence, because the trial took a long time to conceive of, conduct, and analyze.”

*Data in the presentation differ from the abstract.

Richard Stone, MD

Photo courtesy of ASH

ORLANDO, FL—After almost 10 years, during which time no new drug for acute myeloid leukemia (AML) has been approved, results of the RATIFY trial are available.

In this trial, investigators evaluated midostaurin in combination with chemotherapy for younger patients with FLT3-mutated AML.

Patients who received midostaurin in their regimen instead of placebo experienced significantly longer overall survival (OS) and event-free survival (EFS).

“The primary endpoint of the trial was overall survival—which was very important—uncensored for transplant,” said Richard Stone, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts.

“This is very much a ‘real-world’ trial. We just took patients from the start and saw how they did until the end.”

Dr Stone presented results from the trial during the plenary session of the 2015 ASH Annual Meeting (abstract 6*).

Midostaurin (PKC412), developed as a VEGF and protein kinase C inhibitor, is a known FLT3 inhibitor that specifically inhibits the growth of leukemic cell lines.

As a multi-kinase inhibitor, its potency against FLT3 may be limited, but it is active against both ITD and TKD mutations. Because AML is polyclonal at diagnosis, a multi-targeted inhibitor may have an advantage in newly diagnosed AML.

As a single agent, Dr Stone explained, midostaurin produced few remissions in advanced, mutant AML. But when combined with chemotherapy in a phase 1B study in newly diagnosed patients, it produced encouraging results.

So members of the Alliance for Clinical Trials in Oncology, formerly CALGB, and many other cooperative groups around the world—the AMLSG, CETLAM, ECOG, EORTC, GIMEMA, NCIC, OSHO, PETHEMA, SAL, and SWOG—conducted a phase 3, randomized, double-blind trial of induction and consolidation with or without midostaurin in patients younger than 60 with newly diagnosed FLT3-mutated AML.

The primary endpoint was OS, and secondary endpoints were OS censored and uncensored at the time of transplant, complete remission (CR) rates, EFS, disease-free survival (DFS), and adverse events.

Mark Levis, MD, of Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland, who introduced the plenary presentation, suggested that OS may not be the best primary endpoint for an AML trial, given the long time it takes to complete a trial like this.

He pointed out that, “while we waited for RATIFY to accrue and mature, our approach to the disease changed.” Allogeneic transplant is now often the favored consolidation.

Eligibility criteria

Patients aged 18 to 60 with normal end-organ function and documented AML were eligible to enroll. Patients could not have had acute promyelocytic leukemia.

Their FLT3 mutation had to be centrally determined prior to enrollment by 1 of 9 academic labs around the world, and results had to be obtainable within 48 hours of sample collection.

Patients could receive up to 5 days of hydroxyurea prior to the start of treatment while awaiting the results of the mutation analysis.

Trial design

Investigators randomized patients to induction of daunorubicin and cytarabine with either midostaurin or placebo.

Daunorubicin was administered at 60 mg/m² by intravenous push on days 1-3, cytarabine at 200 mg/m² per day on days 1-7, and midostaurin at 50 mg orally twice a day on days 8-21.

A second cycle of induction was given based on day 21 bone marrow biopsy.

When patients achieved CR, they went on to consolidation with high-dose cytarabine (3 g/m² over 3 hours every 12 hours on days 1, 3, and 5) and either midostaurin at the same induction dose or placebo.

After up to 4 doses of consolidation, patients went on to maintenance therapy for 12 months. This consisted of placebo or midostaurin at the same dose twice daily on days 1-28.

Patient population

The investigators screened 3279 patients younger than 60 years with newly diagnosed AML and found 27% (n=887) to be FLT3-positive.

They randomized 717 patients—81% of the FLT3-positive patients—to either the midostaurin arm (n=360) or the placebo arm (n=357). These 717 patients were evaluable for the intent-to-treat analysis.

The median age was 47.1 (range, 19.0–59.8) in the midostaurin arm and 48.6 (range, 18.0–60.9) in the placebo arm. There were significantly more males in the midostaurin arm (48.1%) than in the placebo arm (40.6%, P=0.045).

And the arms were almost identical for FLT3 stratification. In the midostaurin group, 22.5% had FLT3 TKD (no ITD), 47.5% had an ITD allelic ratio (+/- FLT3 TKD) less than 0.7, and 30.0% had a ratio of 0.7 or more.

In the placebo arm, 22.7% had FLT3 TKD, and 47.6% and 29.7% had ITD allelic ratios less than and greater than 0.7, respectively.

Safety

Rash/desquamation was the only significant difference in grade 3-4 non-hematologic events between the arms, with 13% in the midostaurin arm and 8% in the placebo arm (P=0.02).

Other grade 3-4 non-hematologic events occurring in 10% of patients or more included, in the midostaurin and placebo arms, respectively: febrile neutropenia (81%, 82%), infection (40%, 38%), diarrhea (15%, 16%), hypokalemia (13%, 17%), pain (13%, 13%), other infection (12%, 12%), ALT/SGPT (12%, 9%), and fatigue (9%, 11%).

There were 18 deaths (5%) in the midostaurin arm and 19 (5.3%) in the placebo arm during induction and consolidation treatment.

Efficacy

OS was superior for patients randomized to midostaurin. The median survival was 74.7 months (range, 31.7-not estimable) in the midostaurin arm and 25.6 months (range,18.6-42.9) in the placebo arm (P=0.0076).

Overall, there were 357 deaths, 171 and 186 in the midostaurin and placebo arms, respectively.

The 5-year survival rate was 50.9% for midostaurin and 43.9% for placebo.

EFS was also superior for patients randomized to midostaurin (P=0.0032), at a median of 8.0 months for midostaurin and 3.6 months for placebo. The 5-year EFS was 27.5% for midostaurin and 19.3% for placebo.

The CR rates by day 60 were not significantly different between the arms, at 59% and 53% for midostaurin and placebo, respectively. And the median time to CR was the same in each group, at 35 days.

The survival benefit, both overall and event-free, was consistent regardless of whether the patients were FLT3-ITD high, low, or FLT3-TKD.

The OS and EFS benefits were also consistent in censored and uncensored analyses, despite the high stem cell transplant rate. Four hundred eight patients (57%) received a transplant, 212 in the midostaurin arm and 196 in the placebo arm.

“The trial was positive whether you censored the patients at transplant or you kept following them for the whole time,” Dr Stone said.

He concluded that this type of international collaborative AML study based on genotype at diagnosis is feasible to do. But it took “a lot of collaboration, a lot of cooperation, a lot of persistence, because the trial took a long time to conceive of, conduct, and analyze.”

*Data in the presentation differ from the abstract.

Richard Stone, MD

Photo courtesy of ASH

ORLANDO, FL—After almost 10 years, during which time no new drug for acute myeloid leukemia (AML) has been approved, results of the RATIFY trial are available.

In this trial, investigators evaluated midostaurin in combination with chemotherapy for younger patients with FLT3-mutated AML.

Patients who received midostaurin in their regimen instead of placebo experienced significantly longer overall survival (OS) and event-free survival (EFS).

“The primary endpoint of the trial was overall survival—which was very important—uncensored for transplant,” said Richard Stone, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts.

“This is very much a ‘real-world’ trial. We just took patients from the start and saw how they did until the end.”

Dr Stone presented results from the trial during the plenary session of the 2015 ASH Annual Meeting (abstract 6*).

Midostaurin (PKC412), developed as a VEGF and protein kinase C inhibitor, is a known FLT3 inhibitor that specifically inhibits the growth of leukemic cell lines.

As a multi-kinase inhibitor, its potency against FLT3 may be limited, but it is active against both ITD and TKD mutations. Because AML is polyclonal at diagnosis, a multi-targeted inhibitor may have an advantage in newly diagnosed AML.

As a single agent, Dr Stone explained, midostaurin produced few remissions in advanced, mutant AML. But when combined with chemotherapy in a phase 1B study in newly diagnosed patients, it produced encouraging results.

So members of the Alliance for Clinical Trials in Oncology, formerly CALGB, and many other cooperative groups around the world—the AMLSG, CETLAM, ECOG, EORTC, GIMEMA, NCIC, OSHO, PETHEMA, SAL, and SWOG—conducted a phase 3, randomized, double-blind trial of induction and consolidation with or without midostaurin in patients younger than 60 with newly diagnosed FLT3-mutated AML.

The primary endpoint was OS, and secondary endpoints were OS censored and uncensored at the time of transplant, complete remission (CR) rates, EFS, disease-free survival (DFS), and adverse events.

Mark Levis, MD, of Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland, who introduced the plenary presentation, suggested that OS may not be the best primary endpoint for an AML trial, given the long time it takes to complete a trial like this.

He pointed out that, “while we waited for RATIFY to accrue and mature, our approach to the disease changed.” Allogeneic transplant is now often the favored consolidation.

Eligibility criteria

Patients aged 18 to 60 with normal end-organ function and documented AML were eligible to enroll. Patients could not have had acute promyelocytic leukemia.

Their FLT3 mutation had to be centrally determined prior to enrollment by 1 of 9 academic labs around the world, and results had to be obtainable within 48 hours of sample collection.

Patients could receive up to 5 days of hydroxyurea prior to the start of treatment while awaiting the results of the mutation analysis.

Trial design

Investigators randomized patients to induction of daunorubicin and cytarabine with either midostaurin or placebo.

Daunorubicin was administered at 60 mg/m² by intravenous push on days 1-3, cytarabine at 200 mg/m² per day on days 1-7, and midostaurin at 50 mg orally twice a day on days 8-21.

A second cycle of induction was given based on day 21 bone marrow biopsy.

When patients achieved CR, they went on to consolidation with high-dose cytarabine (3 g/m² over 3 hours every 12 hours on days 1, 3, and 5) and either midostaurin at the same induction dose or placebo.

After up to 4 doses of consolidation, patients went on to maintenance therapy for 12 months. This consisted of placebo or midostaurin at the same dose twice daily on days 1-28.

Patient population

The investigators screened 3279 patients younger than 60 years with newly diagnosed AML and found 27% (n=887) to be FLT3-positive.

They randomized 717 patients—81% of the FLT3-positive patients—to either the midostaurin arm (n=360) or the placebo arm (n=357). These 717 patients were evaluable for the intent-to-treat analysis.

The median age was 47.1 (range, 19.0–59.8) in the midostaurin arm and 48.6 (range, 18.0–60.9) in the placebo arm. There were significantly more males in the midostaurin arm (48.1%) than in the placebo arm (40.6%, P=0.045).

And the arms were almost identical for FLT3 stratification. In the midostaurin group, 22.5% had FLT3 TKD (no ITD), 47.5% had an ITD allelic ratio (+/- FLT3 TKD) less than 0.7, and 30.0% had a ratio of 0.7 or more.

In the placebo arm, 22.7% had FLT3 TKD, and 47.6% and 29.7% had ITD allelic ratios less than and greater than 0.7, respectively.

Safety

Rash/desquamation was the only significant difference in grade 3-4 non-hematologic events between the arms, with 13% in the midostaurin arm and 8% in the placebo arm (P=0.02).

Other grade 3-4 non-hematologic events occurring in 10% of patients or more included, in the midostaurin and placebo arms, respectively: febrile neutropenia (81%, 82%), infection (40%, 38%), diarrhea (15%, 16%), hypokalemia (13%, 17%), pain (13%, 13%), other infection (12%, 12%), ALT/SGPT (12%, 9%), and fatigue (9%, 11%).

There were 18 deaths (5%) in the midostaurin arm and 19 (5.3%) in the placebo arm during induction and consolidation treatment.

Efficacy

OS was superior for patients randomized to midostaurin. The median survival was 74.7 months (range, 31.7-not estimable) in the midostaurin arm and 25.6 months (range,18.6-42.9) in the placebo arm (P=0.0076).

Overall, there were 357 deaths, 171 and 186 in the midostaurin and placebo arms, respectively.

The 5-year survival rate was 50.9% for midostaurin and 43.9% for placebo.

EFS was also superior for patients randomized to midostaurin (P=0.0032), at a median of 8.0 months for midostaurin and 3.6 months for placebo. The 5-year EFS was 27.5% for midostaurin and 19.3% for placebo.

The CR rates by day 60 were not significantly different between the arms, at 59% and 53% for midostaurin and placebo, respectively. And the median time to CR was the same in each group, at 35 days.

The survival benefit, both overall and event-free, was consistent regardless of whether the patients were FLT3-ITD high, low, or FLT3-TKD.

The OS and EFS benefits were also consistent in censored and uncensored analyses, despite the high stem cell transplant rate. Four hundred eight patients (57%) received a transplant, 212 in the midostaurin arm and 196 in the placebo arm.

“The trial was positive whether you censored the patients at transplant or you kept following them for the whole time,” Dr Stone said.

He concluded that this type of international collaborative AML study based on genotype at diagnosis is feasible to do. But it took “a lot of collaboration, a lot of cooperation, a lot of persistence, because the trial took a long time to conceive of, conduct, and analyze.”

*Data in the presentation differ from the abstract.