What is it about families that makes our patients so upset? Why can our patients not just walk away from conflict? Why do they get so bent out of shape when family members do not say or do what they expect them to do? We all have families that are less than ideal and struggle with how to manage difference.

This column gives psychiatrists a framework for thinking with families about the universal dilemma of managing difference. This dilemma can be viewed from the perspectives of the individual, the family, and society: Identity is formed in the crucible of the family, where parental introjects become a model for the child’s development and can be rejected as an adolescent or adult as individuals shape their own identity. Processes within the family shape family members’ relationships and, therefore, their expectations of one another. Strong boundaries provide safety for those inside the family versus those outside the family.

Individual perspective

Family members’ perspective and expectations of others depend on their family position. Children or young adults want to please the parent, and to be accepted and recognized for who they are. They want their unique qualities to be valued, they want to be loved, and they want to feel that they belong.

Unconscious psychological processes

The two main unconscious psychological processes that tangle up families are projection and projective identification. Projective identification is an unconscious process in which aspects of the self are split off and projected onto another person. In 1946, Melanie Klein introduced the term “projective identification” as follows: “Much of the hatred against parts of the self is now directed toward the mother. This leads to a particular form of identification which establishes the prototype of an aggressive object-relation. I suggest for these processes the term ‘projective identification’ ” (Int J Psychoanal. 1946;27[pt 3-4]:99-110).

Mutual projective processes can occur in committed relationships. The following scenario helps illustrate this: Ms. A. projects onto her husband her own feared and unwanted aggressive, dominating aspects of herself. The result is that she fears and respects him. He, in turn, comes to feel aggressive and dominating toward her, not only because of his own resources but because of her projections, which she forces onto him. He may, in turn, despise and disown timid and fearful aspects of his own personality and by a similar mechanism of projective identification force these unwanted aspects of himself onto his wife. Ms. A. is then composed of timid unaggressive parts of herself as well as his projections, and she carries these feelings as her part in the relationship. Some couples, like Mr. and Ms. A., live in such locked systems, dominated by mutual projections, with each not truly married to the other person but to the unwanted, split-off, and projected parts of themselves.

In this scenario, the husband becomes dominant and cruel, and the wife becomes stupidly timid and respectful. These marriages are stable, because each partner needs the other for narcissistic pathologic purposes (see “Some Psychodynamics of Large Groups” in “The Large Group: Dynamics and Therapy” [London: Karnac Books, 1975] and “The Ailment and Other Psychoanalytic Essays” [London: Free Association Books, 2015]).

Marriage offers an opportunity for individuals to work out these types of issues, or, in the case of Mr. and Ms. A, not work through them. Instead, they exist in tight mutual projections.

Family process perspective

Families function as a system or unit, and each person in the family has a role or function. When change occurs, basic rules of systems theory apply. For example, if the mother functions as the emotional barometer, no one else needs to pay attention to emotions, as that is the mother’s job. If she leaves or becomes ill, someone else will take on that role or the family will fall apart. If the father becomes depressed and unable to function in his role as a parent, the oldest child may have to step up to become the parent. When he gets better and his depression resolves, there may be tension – as the older child may not want to give up that role. There may be a disagreement in the family vision.

When the children grow and develop their own identities and lifestyles, the family has to adjust to include the adult children or cut them off. Individuals also may cut themselves off from the family if there are significant disagreements. There are variations, such as “semi-cutoffs,” where there is little contact except at ritualized holidays and significant family events. Therefore, tensions arise most clearly at these times when family members come together.

Boundaries protect the family

A family functions like a pack. As with most species, families and parents protect the young until they are able to care for themselves. The marriage contract specifies that spouses care for each other but additionally that they join extended families together. Family cares for family before caring for strangers. It is the elder’s role and responsibility to keep the family together, or the family members may drift apart or be subsumed into other family groups.

A clan is made up of related families that form a larger extended family unit. Historically, strong alliances, as in clans or family dynasties, become dominant socially. In recent history, the idea of clans has become less attractive as the idea of individualism has become the American ideal.

Modern families tend to be individually oriented and do not need their families for protection as much as primitive tribes did. Modern families have fairly loose boundaries, and problems can arise when the family tries to define boundaries and values.

Families also change composition with the impact of sociocultural influences, such as migration. However, the primitive social drive still forces us to form families and clans. This drive can explain much of the need for identifying people as “in or out” of the family. The Amish intentionally address this dilemma. At adolescence, the ritual of Rumspringa allows the young person to experience 1 year out of Amish life in Western life. The adolescent can then decide to be in or out. If the adolescent decides to be in, conformity to Amish lifestyle is required (“Serving the Amish,” Baltimore: Johns Hopkins University Press, 2014).

Lastly, our families provide memories of where we have come from and where we are going, both as individuals and as a clan. Powerful stories serve the next generation with a sense of belonging and a specific orientation to the world. The studies of third-generation Holocaust survivors attest to the power of family narratives. Individuals can choose to embrace the family narrative or alter it to allow individual growth.

Explaining families to families

When helping patients work through issues with their families, it is helpful to provide them with context. Among the important points we can make are:

● Families came into existence as a way to protect our young; this is true across the animal kingdom. Humans congregated into clans or tribes that demanded conformity and obedience to the chief. There was a clear sense of who was in and who was out. Many of the difficulties that we experience are tied to the primitive tension of needing to decide who is in and who is out. This is a normal function of families.

● These days, families have much looser boundaries, and individuals have the freedom to strike out on their own. Families have to grapple with their collective identity only when they get together at holiday times or transitional events like marriages, births, and deaths. So, is it worth getting upset about this? If so, ask patients what they would like to change – and why.

● With this background, the family can dive deeper. Ask your patients, “Is the issue a problem with roles within the family? Has there been a role transition? Has there been a death, serious illness, or birth? Has someone left, retired, or joined the family? How would you as a family like to proceed?”

● Lastly, is there a complicated tangled web or relationship that might be explained by mutual projective identifications? If so, refer to a colleague with family therapy skills.

Key points to keep in mind

1. Families should be placed in the context of clans and tribes.

2. Transitions and family events cause families to question their family identity, boundaries, and values.

3. Patients should explore their individual expectations about what families should do. This conversation can be extensive, and include cultural and generational flash points.

4. If there is a tangled web that makes no sense to you, refer to a colleague with family therapy skills.

Dr. Heru is professor of psychiatry at the University of Colorado Denver, Aurora. She is editor of “Working With Families in Medical Settings: A Multidisciplinary Guide for Psychiatrists and Other Health Professionals” (New York: Routledge, 2013). She has no conflicts of interest to disclose.

What is it about families that makes our patients so upset? Why can our patients not just walk away from conflict? Why do they get so bent out of shape when family members do not say or do what they expect them to do? We all have families that are less than ideal and struggle with how to manage difference.

This column gives psychiatrists a framework for thinking with families about the universal dilemma of managing difference. This dilemma can be viewed from the perspectives of the individual, the family, and society: Identity is formed in the crucible of the family, where parental introjects become a model for the child’s development and can be rejected as an adolescent or adult as individuals shape their own identity. Processes within the family shape family members’ relationships and, therefore, their expectations of one another. Strong boundaries provide safety for those inside the family versus those outside the family.

Individual perspective

Family members’ perspective and expectations of others depend on their family position. Children or young adults want to please the parent, and to be accepted and recognized for who they are. They want their unique qualities to be valued, they want to be loved, and they want to feel that they belong.

Unconscious psychological processes

The two main unconscious psychological processes that tangle up families are projection and projective identification. Projective identification is an unconscious process in which aspects of the self are split off and projected onto another person. In 1946, Melanie Klein introduced the term “projective identification” as follows: “Much of the hatred against parts of the self is now directed toward the mother. This leads to a particular form of identification which establishes the prototype of an aggressive object-relation. I suggest for these processes the term ‘projective identification’ ” (Int J Psychoanal. 1946;27[pt 3-4]:99-110).

Mutual projective processes can occur in committed relationships. The following scenario helps illustrate this: Ms. A. projects onto her husband her own feared and unwanted aggressive, dominating aspects of herself. The result is that she fears and respects him. He, in turn, comes to feel aggressive and dominating toward her, not only because of his own resources but because of her projections, which she forces onto him. He may, in turn, despise and disown timid and fearful aspects of his own personality and by a similar mechanism of projective identification force these unwanted aspects of himself onto his wife. Ms. A. is then composed of timid unaggressive parts of herself as well as his projections, and she carries these feelings as her part in the relationship. Some couples, like Mr. and Ms. A., live in such locked systems, dominated by mutual projections, with each not truly married to the other person but to the unwanted, split-off, and projected parts of themselves.

In this scenario, the husband becomes dominant and cruel, and the wife becomes stupidly timid and respectful. These marriages are stable, because each partner needs the other for narcissistic pathologic purposes (see “Some Psychodynamics of Large Groups” in “The Large Group: Dynamics and Therapy” [London: Karnac Books, 1975] and “The Ailment and Other Psychoanalytic Essays” [London: Free Association Books, 2015]).

Marriage offers an opportunity for individuals to work out these types of issues, or, in the case of Mr. and Ms. A, not work through them. Instead, they exist in tight mutual projections.

Family process perspective

Families function as a system or unit, and each person in the family has a role or function. When change occurs, basic rules of systems theory apply. For example, if the mother functions as the emotional barometer, no one else needs to pay attention to emotions, as that is the mother’s job. If she leaves or becomes ill, someone else will take on that role or the family will fall apart. If the father becomes depressed and unable to function in his role as a parent, the oldest child may have to step up to become the parent. When he gets better and his depression resolves, there may be tension – as the older child may not want to give up that role. There may be a disagreement in the family vision.

When the children grow and develop their own identities and lifestyles, the family has to adjust to include the adult children or cut them off. Individuals also may cut themselves off from the family if there are significant disagreements. There are variations, such as “semi-cutoffs,” where there is little contact except at ritualized holidays and significant family events. Therefore, tensions arise most clearly at these times when family members come together.

Boundaries protect the family

A family functions like a pack. As with most species, families and parents protect the young until they are able to care for themselves. The marriage contract specifies that spouses care for each other but additionally that they join extended families together. Family cares for family before caring for strangers. It is the elder’s role and responsibility to keep the family together, or the family members may drift apart or be subsumed into other family groups.

A clan is made up of related families that form a larger extended family unit. Historically, strong alliances, as in clans or family dynasties, become dominant socially. In recent history, the idea of clans has become less attractive as the idea of individualism has become the American ideal.

Modern families tend to be individually oriented and do not need their families for protection as much as primitive tribes did. Modern families have fairly loose boundaries, and problems can arise when the family tries to define boundaries and values.

Families also change composition with the impact of sociocultural influences, such as migration. However, the primitive social drive still forces us to form families and clans. This drive can explain much of the need for identifying people as “in or out” of the family. The Amish intentionally address this dilemma. At adolescence, the ritual of Rumspringa allows the young person to experience 1 year out of Amish life in Western life. The adolescent can then decide to be in or out. If the adolescent decides to be in, conformity to Amish lifestyle is required (“Serving the Amish,” Baltimore: Johns Hopkins University Press, 2014).

Lastly, our families provide memories of where we have come from and where we are going, both as individuals and as a clan. Powerful stories serve the next generation with a sense of belonging and a specific orientation to the world. The studies of third-generation Holocaust survivors attest to the power of family narratives. Individuals can choose to embrace the family narrative or alter it to allow individual growth.

Explaining families to families

When helping patients work through issues with their families, it is helpful to provide them with context. Among the important points we can make are:

● Families came into existence as a way to protect our young; this is true across the animal kingdom. Humans congregated into clans or tribes that demanded conformity and obedience to the chief. There was a clear sense of who was in and who was out. Many of the difficulties that we experience are tied to the primitive tension of needing to decide who is in and who is out. This is a normal function of families.

● These days, families have much looser boundaries, and individuals have the freedom to strike out on their own. Families have to grapple with their collective identity only when they get together at holiday times or transitional events like marriages, births, and deaths. So, is it worth getting upset about this? If so, ask patients what they would like to change – and why.

● With this background, the family can dive deeper. Ask your patients, “Is the issue a problem with roles within the family? Has there been a role transition? Has there been a death, serious illness, or birth? Has someone left, retired, or joined the family? How would you as a family like to proceed?”

● Lastly, is there a complicated tangled web or relationship that might be explained by mutual projective identifications? If so, refer to a colleague with family therapy skills.

Key points to keep in mind

1. Families should be placed in the context of clans and tribes.

2. Transitions and family events cause families to question their family identity, boundaries, and values.

3. Patients should explore their individual expectations about what families should do. This conversation can be extensive, and include cultural and generational flash points.

4. If there is a tangled web that makes no sense to you, refer to a colleague with family therapy skills.

Dr. Heru is professor of psychiatry at the University of Colorado Denver, Aurora. She is editor of “Working With Families in Medical Settings: A Multidisciplinary Guide for Psychiatrists and Other Health Professionals” (New York: Routledge, 2013). She has no conflicts of interest to disclose.

What is it about families that makes our patients so upset? Why can our patients not just walk away from conflict? Why do they get so bent out of shape when family members do not say or do what they expect them to do? We all have families that are less than ideal and struggle with how to manage difference.

This column gives psychiatrists a framework for thinking with families about the universal dilemma of managing difference. This dilemma can be viewed from the perspectives of the individual, the family, and society: Identity is formed in the crucible of the family, where parental introjects become a model for the child’s development and can be rejected as an adolescent or adult as individuals shape their own identity. Processes within the family shape family members’ relationships and, therefore, their expectations of one another. Strong boundaries provide safety for those inside the family versus those outside the family.

Individual perspective

Family members’ perspective and expectations of others depend on their family position. Children or young adults want to please the parent, and to be accepted and recognized for who they are. They want their unique qualities to be valued, they want to be loved, and they want to feel that they belong.

Unconscious psychological processes

The two main unconscious psychological processes that tangle up families are projection and projective identification. Projective identification is an unconscious process in which aspects of the self are split off and projected onto another person. In 1946, Melanie Klein introduced the term “projective identification” as follows: “Much of the hatred against parts of the self is now directed toward the mother. This leads to a particular form of identification which establishes the prototype of an aggressive object-relation. I suggest for these processes the term ‘projective identification’ ” (Int J Psychoanal. 1946;27[pt 3-4]:99-110).

Mutual projective processes can occur in committed relationships. The following scenario helps illustrate this: Ms. A. projects onto her husband her own feared and unwanted aggressive, dominating aspects of herself. The result is that she fears and respects him. He, in turn, comes to feel aggressive and dominating toward her, not only because of his own resources but because of her projections, which she forces onto him. He may, in turn, despise and disown timid and fearful aspects of his own personality and by a similar mechanism of projective identification force these unwanted aspects of himself onto his wife. Ms. A. is then composed of timid unaggressive parts of herself as well as his projections, and she carries these feelings as her part in the relationship. Some couples, like Mr. and Ms. A., live in such locked systems, dominated by mutual projections, with each not truly married to the other person but to the unwanted, split-off, and projected parts of themselves.

In this scenario, the husband becomes dominant and cruel, and the wife becomes stupidly timid and respectful. These marriages are stable, because each partner needs the other for narcissistic pathologic purposes (see “Some Psychodynamics of Large Groups” in “The Large Group: Dynamics and Therapy” [London: Karnac Books, 1975] and “The Ailment and Other Psychoanalytic Essays” [London: Free Association Books, 2015]).

Marriage offers an opportunity for individuals to work out these types of issues, or, in the case of Mr. and Ms. A, not work through them. Instead, they exist in tight mutual projections.

Family process perspective

Families function as a system or unit, and each person in the family has a role or function. When change occurs, basic rules of systems theory apply. For example, if the mother functions as the emotional barometer, no one else needs to pay attention to emotions, as that is the mother’s job. If she leaves or becomes ill, someone else will take on that role or the family will fall apart. If the father becomes depressed and unable to function in his role as a parent, the oldest child may have to step up to become the parent. When he gets better and his depression resolves, there may be tension – as the older child may not want to give up that role. There may be a disagreement in the family vision.

When the children grow and develop their own identities and lifestyles, the family has to adjust to include the adult children or cut them off. Individuals also may cut themselves off from the family if there are significant disagreements. There are variations, such as “semi-cutoffs,” where there is little contact except at ritualized holidays and significant family events. Therefore, tensions arise most clearly at these times when family members come together.

Boundaries protect the family

A family functions like a pack. As with most species, families and parents protect the young until they are able to care for themselves. The marriage contract specifies that spouses care for each other but additionally that they join extended families together. Family cares for family before caring for strangers. It is the elder’s role and responsibility to keep the family together, or the family members may drift apart or be subsumed into other family groups.

A clan is made up of related families that form a larger extended family unit. Historically, strong alliances, as in clans or family dynasties, become dominant socially. In recent history, the idea of clans has become less attractive as the idea of individualism has become the American ideal.

Modern families tend to be individually oriented and do not need their families for protection as much as primitive tribes did. Modern families have fairly loose boundaries, and problems can arise when the family tries to define boundaries and values.

Families also change composition with the impact of sociocultural influences, such as migration. However, the primitive social drive still forces us to form families and clans. This drive can explain much of the need for identifying people as “in or out” of the family. The Amish intentionally address this dilemma. At adolescence, the ritual of Rumspringa allows the young person to experience 1 year out of Amish life in Western life. The adolescent can then decide to be in or out. If the adolescent decides to be in, conformity to Amish lifestyle is required (“Serving the Amish,” Baltimore: Johns Hopkins University Press, 2014).

Lastly, our families provide memories of where we have come from and where we are going, both as individuals and as a clan. Powerful stories serve the next generation with a sense of belonging and a specific orientation to the world. The studies of third-generation Holocaust survivors attest to the power of family narratives. Individuals can choose to embrace the family narrative or alter it to allow individual growth.

Explaining families to families

When helping patients work through issues with their families, it is helpful to provide them with context. Among the important points we can make are:

● Families came into existence as a way to protect our young; this is true across the animal kingdom. Humans congregated into clans or tribes that demanded conformity and obedience to the chief. There was a clear sense of who was in and who was out. Many of the difficulties that we experience are tied to the primitive tension of needing to decide who is in and who is out. This is a normal function of families.

● These days, families have much looser boundaries, and individuals have the freedom to strike out on their own. Families have to grapple with their collective identity only when they get together at holiday times or transitional events like marriages, births, and deaths. So, is it worth getting upset about this? If so, ask patients what they would like to change – and why.

● With this background, the family can dive deeper. Ask your patients, “Is the issue a problem with roles within the family? Has there been a role transition? Has there been a death, serious illness, or birth? Has someone left, retired, or joined the family? How would you as a family like to proceed?”

● Lastly, is there a complicated tangled web or relationship that might be explained by mutual projective identifications? If so, refer to a colleague with family therapy skills.

Key points to keep in mind

1. Families should be placed in the context of clans and tribes.

2. Transitions and family events cause families to question their family identity, boundaries, and values.

3. Patients should explore their individual expectations about what families should do. This conversation can be extensive, and include cultural and generational flash points.

4. If there is a tangled web that makes no sense to you, refer to a colleague with family therapy skills.

Dr. Heru is professor of psychiatry at the University of Colorado Denver, Aurora. She is editor of “Working With Families in Medical Settings: A Multidisciplinary Guide for Psychiatrists and Other Health Professionals” (New York: Routledge, 2013). She has no conflicts of interest to disclose.

NATIONAL HARBOR, MD. – Whole pelvic radiation delivered in addition to chemotherapy in women who present with stage IVB cervical cancer confers significant 12-month overall and progression-free survival benefits, according to findings from a multi-institutional retrospective review.

Of 127 patients diagnosed during 2005-2015 at four academic high-volume centers, 31 received no treatment or elected hospice care and, of the remaining patients, 34 received whole pelvic radiation (WPR) in addition to chemotherapy, and 62 received chemotherapy alone, which is the standard of care. The median overall survival was 14.1 vs. 6.9 months with vs. without WPR, and the median progression-free survival was 10 vs. 5 months, respectively, Victoria B. Perkins, MD, said at the annual meeting of the Society of Gynecologic Oncology.

Of note, the rates of pelvic-related morbidity, including ureteral obstruction, vaginal or rectal bleeding, pelvic infection, pelvic pain, and fistula, did not differ significantly between the groups, said Dr. Perkins of the University of Oklahoma Health Sciences Center, Oklahoma City.

Study subjects were women with a median age of 54 years. A little more than a third (36%) were white, 35% were Hispanic, and 16% were black. Most (75%) had squamous cell carcinoma, and 95% were grade 2 or 3.

There were no significant differences in the demographics, location of [metastatic] disease, or distribution of chemotherapy type between the two groups, she said, noting that “interestingly, 26% of patients in the chemotherapy alone group received additional bevacizumab, compared to only 12% in the whole pelvic radiation with chemotherapy group.

“This could reflect the change in treatment strategy with the approval of bevacizumab during the treatment period,” Dr. Perkins noted.

About 5% of women have stage IVB cervical cancer at the time of diagnosis, but 5-year survival in these women is only about 15%.

“The mainstay of treatment is platinum and taxane with or without bevacizumab. In clinical practice, treatment of stage IVB disease varies,” Dr. Perkins said.

One strategy follows the guidance of phase III trials looking at chemotherapy with palliative radiation as needed.

“However, a significant number of patients experience morbidity and mortality directly related to their pelvic disease, such as vaginal bleeding, ureteral obstruction, fistulization, infections, and pain. Thus, an alternative approach is aimed at treating bulky pelvic disease with whole pelvic radiation followed by systemic chemotherapy with the goal to control symptoms and theoretically reduce recurrences in the pelvic field, which can be highly problematic in terms of symptomatic control,” she said, noting that this novel approach has not been formally studied.

The aim of the current review was to determine if WPR with chemotherapy would reduce pelvic morbidity and improve overall and progression-free survival.

“Survival in stage IVB disease remains extremely poor. Perhaps adding whole pelvic radiation to systemic chemotherapy has utility without increasing morbidity. However, the addition of whole pelvic radiation did not improve pelvic-related morbidity as previously hypothesized,” she said.

The study was limited by varied chemotherapy regimens in both groups and by changes in standard treatment practice during the span of study. It also was limited by the retrospective design, small sample size, and lack of quality of life data, but the findings support further study regarding subgroups of patients who could benefit the most from this treatment strategy, she concluded, noting, however, that such study is challenging because of the rarity of stage IVB disease.

Dr. Perkins reported having no disclosures.

[email protected]

NATIONAL HARBOR, MD. – Whole pelvic radiation delivered in addition to chemotherapy in women who present with stage IVB cervical cancer confers significant 12-month overall and progression-free survival benefits, according to findings from a multi-institutional retrospective review.

Of 127 patients diagnosed during 2005-2015 at four academic high-volume centers, 31 received no treatment or elected hospice care and, of the remaining patients, 34 received whole pelvic radiation (WPR) in addition to chemotherapy, and 62 received chemotherapy alone, which is the standard of care. The median overall survival was 14.1 vs. 6.9 months with vs. without WPR, and the median progression-free survival was 10 vs. 5 months, respectively, Victoria B. Perkins, MD, said at the annual meeting of the Society of Gynecologic Oncology.

Of note, the rates of pelvic-related morbidity, including ureteral obstruction, vaginal or rectal bleeding, pelvic infection, pelvic pain, and fistula, did not differ significantly between the groups, said Dr. Perkins of the University of Oklahoma Health Sciences Center, Oklahoma City.

Study subjects were women with a median age of 54 years. A little more than a third (36%) were white, 35% were Hispanic, and 16% were black. Most (75%) had squamous cell carcinoma, and 95% were grade 2 or 3.

There were no significant differences in the demographics, location of [metastatic] disease, or distribution of chemotherapy type between the two groups, she said, noting that “interestingly, 26% of patients in the chemotherapy alone group received additional bevacizumab, compared to only 12% in the whole pelvic radiation with chemotherapy group.

“This could reflect the change in treatment strategy with the approval of bevacizumab during the treatment period,” Dr. Perkins noted.

About 5% of women have stage IVB cervical cancer at the time of diagnosis, but 5-year survival in these women is only about 15%.

“The mainstay of treatment is platinum and taxane with or without bevacizumab. In clinical practice, treatment of stage IVB disease varies,” Dr. Perkins said.

One strategy follows the guidance of phase III trials looking at chemotherapy with palliative radiation as needed.

“However, a significant number of patients experience morbidity and mortality directly related to their pelvic disease, such as vaginal bleeding, ureteral obstruction, fistulization, infections, and pain. Thus, an alternative approach is aimed at treating bulky pelvic disease with whole pelvic radiation followed by systemic chemotherapy with the goal to control symptoms and theoretically reduce recurrences in the pelvic field, which can be highly problematic in terms of symptomatic control,” she said, noting that this novel approach has not been formally studied.

The aim of the current review was to determine if WPR with chemotherapy would reduce pelvic morbidity and improve overall and progression-free survival.

“Survival in stage IVB disease remains extremely poor. Perhaps adding whole pelvic radiation to systemic chemotherapy has utility without increasing morbidity. However, the addition of whole pelvic radiation did not improve pelvic-related morbidity as previously hypothesized,” she said.

The study was limited by varied chemotherapy regimens in both groups and by changes in standard treatment practice during the span of study. It also was limited by the retrospective design, small sample size, and lack of quality of life data, but the findings support further study regarding subgroups of patients who could benefit the most from this treatment strategy, she concluded, noting, however, that such study is challenging because of the rarity of stage IVB disease.

Dr. Perkins reported having no disclosures.

[email protected]

NATIONAL HARBOR, MD. – Whole pelvic radiation delivered in addition to chemotherapy in women who present with stage IVB cervical cancer confers significant 12-month overall and progression-free survival benefits, according to findings from a multi-institutional retrospective review.

Of 127 patients diagnosed during 2005-2015 at four academic high-volume centers, 31 received no treatment or elected hospice care and, of the remaining patients, 34 received whole pelvic radiation (WPR) in addition to chemotherapy, and 62 received chemotherapy alone, which is the standard of care. The median overall survival was 14.1 vs. 6.9 months with vs. without WPR, and the median progression-free survival was 10 vs. 5 months, respectively, Victoria B. Perkins, MD, said at the annual meeting of the Society of Gynecologic Oncology.

Of note, the rates of pelvic-related morbidity, including ureteral obstruction, vaginal or rectal bleeding, pelvic infection, pelvic pain, and fistula, did not differ significantly between the groups, said Dr. Perkins of the University of Oklahoma Health Sciences Center, Oklahoma City.

Study subjects were women with a median age of 54 years. A little more than a third (36%) were white, 35% were Hispanic, and 16% were black. Most (75%) had squamous cell carcinoma, and 95% were grade 2 or 3.

There were no significant differences in the demographics, location of [metastatic] disease, or distribution of chemotherapy type between the two groups, she said, noting that “interestingly, 26% of patients in the chemotherapy alone group received additional bevacizumab, compared to only 12% in the whole pelvic radiation with chemotherapy group.

“This could reflect the change in treatment strategy with the approval of bevacizumab during the treatment period,” Dr. Perkins noted.

About 5% of women have stage IVB cervical cancer at the time of diagnosis, but 5-year survival in these women is only about 15%.

“The mainstay of treatment is platinum and taxane with or without bevacizumab. In clinical practice, treatment of stage IVB disease varies,” Dr. Perkins said.

One strategy follows the guidance of phase III trials looking at chemotherapy with palliative radiation as needed.

“However, a significant number of patients experience morbidity and mortality directly related to their pelvic disease, such as vaginal bleeding, ureteral obstruction, fistulization, infections, and pain. Thus, an alternative approach is aimed at treating bulky pelvic disease with whole pelvic radiation followed by systemic chemotherapy with the goal to control symptoms and theoretically reduce recurrences in the pelvic field, which can be highly problematic in terms of symptomatic control,” she said, noting that this novel approach has not been formally studied.

The aim of the current review was to determine if WPR with chemotherapy would reduce pelvic morbidity and improve overall and progression-free survival.

“Survival in stage IVB disease remains extremely poor. Perhaps adding whole pelvic radiation to systemic chemotherapy has utility without increasing morbidity. However, the addition of whole pelvic radiation did not improve pelvic-related morbidity as previously hypothesized,” she said.

The study was limited by varied chemotherapy regimens in both groups and by changes in standard treatment practice during the span of study. It also was limited by the retrospective design, small sample size, and lack of quality of life data, but the findings support further study regarding subgroups of patients who could benefit the most from this treatment strategy, she concluded, noting, however, that such study is challenging because of the rarity of stage IVB disease.

Dr. Perkins reported having no disclosures.

[email protected]

National Harbor, MD. – Patients, even those with surgically-confirmed risk factors, fared well when they received adjuvant chemotherapy without radiotherapy for early-stage cervical cancer.

In a retrospective review of 101 patients, Kwang-Beom Lee, MD, and his associates found that patients with known surgical risk factors had a posttreatment disease-free survival rate of 94.6%, a 5-year overall survival rate of 90.6%. and a disease-specific 5-year survival rate of 96.2%. These figures compare with survival rates of 79.4%, 90.6%, and 90.6%, respectively, for early-stage cervical cancer patients with lymph node metastasis.

Dr. Lee, professor of obstetrics and gynecology at Gachon University School of Medicine, Incheon, South Korea, said that about 3,600 cases of cervical cancer are diagnosed each year in Korea, and a little more than half (58%) are early-stage cancers. Most Korean patients with International Federation of Gynecology and Obstetrics (FIGO) stage IA2-IIA cancer will receive a radical hysterectomy with lymphadenectomy, he said at the annual meeting of the Society of Gynecologic Oncology.

Dr. Lee and his colleagues sought to ascertain morbidity when patients with early cervical cancer received either adjuvant radiotherapy or concurrent chemoradiotherapy (CCRT), and to explore the potential role that chemotherapy alone might play in these patients.

Accordingly, one of the primary outcomes of the study was to determine outcomes of adjuvant chemotherapy alone for patients with FIGO stage IB-IIA cervical cancer who had surgically-confirmed risk factors, and who received radical surgery.

The surgically-confirmed factors included lymphovascular space invasion, depth of penetration, and tumor size.

Currently, Dr. Lee said, evidence indicates that CCRT for patients with high risk factors improves both progression-free survival and overall survival. For patients with intermediate risk factors, radiotherapy is associated with increased progression-free survival.

The researchers examined 101 patients in this category who were treated between March of 2006 and December of 2014 at two Korean academic medical centers, excluding patients who had positive tumor margins, who received neoadjuvant chemotherapy, or who had microscopic parametrium involvement.

The mean age of the patients was 47.1 years (range, 23-73 years). Their mean body mass index was 23.1, and two thirds of patients were premenopausal. Most patients (73.3%, n = 74) had stage IB1 cancer, while 23 (22.8%) had stage IB2 cancer, and 4 (3.9%) had stage IIA cancer. Most patients (74.3%, n = 75) had squamous cell cancer.

The radical procedure performed was a type C radical hysterectomy; patients underwent pelvic lymph node dissection, with or without para-aortic node dissection. Pelvic nodes included all of the common iliac nodes, the external and internal iliac chains, and the obturator nodes. Para-aortic node dissection included dissection up to the level of the inferior mesenteric artery.

A total of 50 patients received pelvic lymph node and para-aortic lymph node dissection, with a mean 54.5 tumors retrieved per patient. A mean of 4.58 pelvic nodes were assessed as metastatic. A mean of 11.2 para-aortic nodes were retrieved, and of these, a mean 5.3 were metastatic.

All together, 76 patients had a combination of three surgically-confirmed risk factors without positive lymph nodes; the remaining 25 patients had positive lymph nodes (4 with pelvic and para-aortic involvement, the remaining with pelvic involvement alone), and were included irrespective of whether they met other risk factor criteria.

Dr. Lee said that the protocol for chemotherapy paralelled Protocol 92 from the Gynecologic Oncology Group; patients received chemotherapy if the combination of tumor diameter, depth of stromal invasion, and lymphovascular space invasion met Protocol 92 criteria for treatment, or if more than one lymph node metastasis was found.

The chemotherapy regime for intermediate-risk patients called for six cycles of either platinum alone (n = 47), or platinum with paclitaxel (n = 54). High-risk patients received six cycles of paclitaxel and platinum.

Patients were followed for a median of 65 months, and a total of 14 patients had a recurrence.

Dr. Lee reported no conflicts of interest.
 

[email protected]

On Twitter @karioakes

National Harbor, MD. – Patients, even those with surgically-confirmed risk factors, fared well when they received adjuvant chemotherapy without radiotherapy for early-stage cervical cancer.

In a retrospective review of 101 patients, Kwang-Beom Lee, MD, and his associates found that patients with known surgical risk factors had a posttreatment disease-free survival rate of 94.6%, a 5-year overall survival rate of 90.6%. and a disease-specific 5-year survival rate of 96.2%. These figures compare with survival rates of 79.4%, 90.6%, and 90.6%, respectively, for early-stage cervical cancer patients with lymph node metastasis.

Dr. Lee, professor of obstetrics and gynecology at Gachon University School of Medicine, Incheon, South Korea, said that about 3,600 cases of cervical cancer are diagnosed each year in Korea, and a little more than half (58%) are early-stage cancers. Most Korean patients with International Federation of Gynecology and Obstetrics (FIGO) stage IA2-IIA cancer will receive a radical hysterectomy with lymphadenectomy, he said at the annual meeting of the Society of Gynecologic Oncology.

Dr. Lee and his colleagues sought to ascertain morbidity when patients with early cervical cancer received either adjuvant radiotherapy or concurrent chemoradiotherapy (CCRT), and to explore the potential role that chemotherapy alone might play in these patients.

Accordingly, one of the primary outcomes of the study was to determine outcomes of adjuvant chemotherapy alone for patients with FIGO stage IB-IIA cervical cancer who had surgically-confirmed risk factors, and who received radical surgery.

The surgically-confirmed factors included lymphovascular space invasion, depth of penetration, and tumor size.

Currently, Dr. Lee said, evidence indicates that CCRT for patients with high risk factors improves both progression-free survival and overall survival. For patients with intermediate risk factors, radiotherapy is associated with increased progression-free survival.

The researchers examined 101 patients in this category who were treated between March of 2006 and December of 2014 at two Korean academic medical centers, excluding patients who had positive tumor margins, who received neoadjuvant chemotherapy, or who had microscopic parametrium involvement.

The mean age of the patients was 47.1 years (range, 23-73 years). Their mean body mass index was 23.1, and two thirds of patients were premenopausal. Most patients (73.3%, n = 74) had stage IB1 cancer, while 23 (22.8%) had stage IB2 cancer, and 4 (3.9%) had stage IIA cancer. Most patients (74.3%, n = 75) had squamous cell cancer.

The radical procedure performed was a type C radical hysterectomy; patients underwent pelvic lymph node dissection, with or without para-aortic node dissection. Pelvic nodes included all of the common iliac nodes, the external and internal iliac chains, and the obturator nodes. Para-aortic node dissection included dissection up to the level of the inferior mesenteric artery.

A total of 50 patients received pelvic lymph node and para-aortic lymph node dissection, with a mean 54.5 tumors retrieved per patient. A mean of 4.58 pelvic nodes were assessed as metastatic. A mean of 11.2 para-aortic nodes were retrieved, and of these, a mean 5.3 were metastatic.

All together, 76 patients had a combination of three surgically-confirmed risk factors without positive lymph nodes; the remaining 25 patients had positive lymph nodes (4 with pelvic and para-aortic involvement, the remaining with pelvic involvement alone), and were included irrespective of whether they met other risk factor criteria.

Dr. Lee said that the protocol for chemotherapy paralelled Protocol 92 from the Gynecologic Oncology Group; patients received chemotherapy if the combination of tumor diameter, depth of stromal invasion, and lymphovascular space invasion met Protocol 92 criteria for treatment, or if more than one lymph node metastasis was found.

The chemotherapy regime for intermediate-risk patients called for six cycles of either platinum alone (n = 47), or platinum with paclitaxel (n = 54). High-risk patients received six cycles of paclitaxel and platinum.

Patients were followed for a median of 65 months, and a total of 14 patients had a recurrence.

Dr. Lee reported no conflicts of interest.
 

[email protected]

On Twitter @karioakes

National Harbor, MD. – Patients, even those with surgically-confirmed risk factors, fared well when they received adjuvant chemotherapy without radiotherapy for early-stage cervical cancer.

In a retrospective review of 101 patients, Kwang-Beom Lee, MD, and his associates found that patients with known surgical risk factors had a posttreatment disease-free survival rate of 94.6%, a 5-year overall survival rate of 90.6%. and a disease-specific 5-year survival rate of 96.2%. These figures compare with survival rates of 79.4%, 90.6%, and 90.6%, respectively, for early-stage cervical cancer patients with lymph node metastasis.

Dr. Lee, professor of obstetrics and gynecology at Gachon University School of Medicine, Incheon, South Korea, said that about 3,600 cases of cervical cancer are diagnosed each year in Korea, and a little more than half (58%) are early-stage cancers. Most Korean patients with International Federation of Gynecology and Obstetrics (FIGO) stage IA2-IIA cancer will receive a radical hysterectomy with lymphadenectomy, he said at the annual meeting of the Society of Gynecologic Oncology.

Dr. Lee and his colleagues sought to ascertain morbidity when patients with early cervical cancer received either adjuvant radiotherapy or concurrent chemoradiotherapy (CCRT), and to explore the potential role that chemotherapy alone might play in these patients.

Accordingly, one of the primary outcomes of the study was to determine outcomes of adjuvant chemotherapy alone for patients with FIGO stage IB-IIA cervical cancer who had surgically-confirmed risk factors, and who received radical surgery.

The surgically-confirmed factors included lymphovascular space invasion, depth of penetration, and tumor size.

Currently, Dr. Lee said, evidence indicates that CCRT for patients with high risk factors improves both progression-free survival and overall survival. For patients with intermediate risk factors, radiotherapy is associated with increased progression-free survival.

The researchers examined 101 patients in this category who were treated between March of 2006 and December of 2014 at two Korean academic medical centers, excluding patients who had positive tumor margins, who received neoadjuvant chemotherapy, or who had microscopic parametrium involvement.

The mean age of the patients was 47.1 years (range, 23-73 years). Their mean body mass index was 23.1, and two thirds of patients were premenopausal. Most patients (73.3%, n = 74) had stage IB1 cancer, while 23 (22.8%) had stage IB2 cancer, and 4 (3.9%) had stage IIA cancer. Most patients (74.3%, n = 75) had squamous cell cancer.

The radical procedure performed was a type C radical hysterectomy; patients underwent pelvic lymph node dissection, with or without para-aortic node dissection. Pelvic nodes included all of the common iliac nodes, the external and internal iliac chains, and the obturator nodes. Para-aortic node dissection included dissection up to the level of the inferior mesenteric artery.

A total of 50 patients received pelvic lymph node and para-aortic lymph node dissection, with a mean 54.5 tumors retrieved per patient. A mean of 4.58 pelvic nodes were assessed as metastatic. A mean of 11.2 para-aortic nodes were retrieved, and of these, a mean 5.3 were metastatic.

All together, 76 patients had a combination of three surgically-confirmed risk factors without positive lymph nodes; the remaining 25 patients had positive lymph nodes (4 with pelvic and para-aortic involvement, the remaining with pelvic involvement alone), and were included irrespective of whether they met other risk factor criteria.

Dr. Lee said that the protocol for chemotherapy paralelled Protocol 92 from the Gynecologic Oncology Group; patients received chemotherapy if the combination of tumor diameter, depth of stromal invasion, and lymphovascular space invasion met Protocol 92 criteria for treatment, or if more than one lymph node metastasis was found.

The chemotherapy regime for intermediate-risk patients called for six cycles of either platinum alone (n = 47), or platinum with paclitaxel (n = 54). High-risk patients received six cycles of paclitaxel and platinum.

Patients were followed for a median of 65 months, and a total of 14 patients had a recurrence.

Dr. Lee reported no conflicts of interest.
 

[email protected]

On Twitter @karioakes

Of the 94,474 ischemic strokes that occurred in a nationwide registry among patients with known atrial fibrillation, 84% were preceded by inadequate anticoagulation, according to a report published online March 14 in JAMA.

Fully 30% of the patients in this retrospective cohort study weren’t taking any form of antithrombotic therapy before their stroke, even though all of them had atrial fibrillation (AF) and most of them had additional risk factors as well. And although nearly 20,000 of the study participants were taking warfarin before their stroke, 64% of them were taking subtherapeutic doses, said Ying Xian, MD, PhD, of the department of neurology at the Duke Clinical Research Institute, Durham, N.C., and his associates.

Of the 94,474 ischemic strokes that occurred in a nationwide registry among patients with known atrial fibrillation, 84% were preceded by inadequate anticoagulation, according to a report published online March 14 in JAMA.

Fully 30% of the patients in this retrospective cohort study weren’t taking any form of antithrombotic therapy before their stroke, even though all of them had atrial fibrillation (AF) and most of them had additional risk factors as well. And although nearly 20,000 of the study participants were taking warfarin before their stroke, 64% of them were taking subtherapeutic doses, said Ying Xian, MD, PhD, of the department of neurology at the Duke Clinical Research Institute, Durham, N.C., and his associates.

Of the 94,474 ischemic strokes that occurred in a nationwide registry among patients with known atrial fibrillation, 84% were preceded by inadequate anticoagulation, according to a report published online March 14 in JAMA.

Fully 30% of the patients in this retrospective cohort study weren’t taking any form of antithrombotic therapy before their stroke, even though all of them had atrial fibrillation (AF) and most of them had additional risk factors as well. And although nearly 20,000 of the study participants were taking warfarin before their stroke, 64% of them were taking subtherapeutic doses, said Ying Xian, MD, PhD, of the department of neurology at the Duke Clinical Research Institute, Durham, N.C., and his associates.

HOUSTON – Mobile stroke units – specially equipped ambulances that bring a diagnostic CT scanner and therapeutic thrombolysis directly to patients in the field – have begun to proliferate across the United States, although they remain investigational, with no clear proof of their incremental clinical value or cost effectiveness.

The first U.S. mobile stroke unit (MSU) launched in Houston in early 2014 (following the world’s first in Berlin, which began running in early 2011), and by early 2017, at least eight other U.S. MSUs were in operation, most of them put into service during the prior 15 months. U.S. MSU locations now include Cleveland; Denver; Memphis; New York; Toledo, Ohio; Trenton, N.J., and Northwestern Medicine and Rush University Medical Center in the western Chicago region. A tenth MSU is slated to start operation at the University of California, Los Angeles later this year.

Early data collected at some of these sites show that initiating care of an acute ischemic stroke patient in an MSU shaves precious minutes off the time it takes to start thrombolytic therapy with tissue plasminogen activator (tPA) compared with that at a hospital, and findings from preliminary analyses suggest better functional outcomes for patients treated this way. However, leaders in the nascent field readily admit that the data needed to clearly prove the benefit patients receive from operating MSUs are still a few years off. This uncertainty about the added benefit to patients from MSUs couples with one clear fact: MSUs are expensive to start up, with a price tag of roughly $1 million to get a MSU on the road for the first time, and also expensive to operate, with one estimate for the annual cost of keeping an MSU on the street at about $500,000 per year for staffing, supplies, and other expenses.

“Every U.S. MSU I know of started with philanthropic gifts, but you need a business model” to keep the program running long-term, James C. Grotta, MD, said during a session focused on MSUs at the International Stroke Conference sponsored by the American Heart Association. “You can’t sustain an MSU with philanthropy,” said Dr. Grotta, professor of neurology at the University of Texas Health Science Center in Houston, director and founder of the Houston MSU, and acknowledged godfather of all U.S. MSUs.

Mitchel L. Zoler/Frontline Medical News

Mitchel L. Zoler/Frontline Medical News

Mitchel L. Zoler/Frontline Medical News

Early data on effectiveness

Dr. Nour reported some of the best evidence for the incremental clinical benefit of MSUs based on the reduced time for starting a tPA infusion. She used data collected by the Berlin group and published in September 2016 that compared the treatment courses and outcomes of patients managed with an MSU with similar patients managed by conventional ambulance transport for whom CT scan assessment and the start of TPA treatment did not begin until the patient reached a hospital.

The German analysis showed that, in the observational Pre-Hospital Acute Neurological Therapy and Optimization of Medical Care in Stroke Patients–Study (PHANTOM-S), among 353 patients treated by conventional transport, the median time from stroke onset to thrombolysis was 112 minutes, compared with a median of 73 minutes among 305 patients managed with an MSU, a statistically significant difference. However, the study found no significant difference for its primary endpoint: the percentage of patients with a modified Rankin Scale score of 0-1 when measured 90 days after their respective strokes. This outcome occurred in 47% of the control patients managed conventionally and in 53% of those managed by an MSU, a difference that fell short of statistical significance (Lancet Neurol. 2016 Sept;15[10]:1035-43).

Dr. Nour attributed the lack of statistical significance for this primary endpoint to the relatively small number of patients enrolled in PHANTOM-S. “The study was underpowered,” she said.

Dr. Nour presented an analysis at the meeting that extrapolated the results out to 1,000 hypothetical patients and tallied the benefits that a larger number of patients could expect to receive if their outcomes paralleled those seen in the published results. It showed that, among 1,000 stroke patients treated with an MSU, 58 were expected to be free from disability 90 days later, and an additional 124 patients would have some improvement in their 90 day clinical outcome based on their modified Rankin Scale scores when compared with patients undergoing conventional hospitalization.

“If this finding was confirmed in a larger, controlled study, it would suggest that MSU-based thrombolysis has substantial clinical benefit,” she concluded.

Another recent report looked at the first 100 stroke patients treated by the Cleveland MSU during 2014. Researchers at the Cleveland Clinic and Case Western Reserve University said that 16 of those 100 patients received tPA, and the median time from their emergency call to thrombolytic treatment was 38.5 minutes faster than for 53 stroke patients treated during the same period at emergency departments operated by the Cleveland Clinic, a statistically significant difference. However, this report included no data on clinical outcomes (Neurology. 2017 March 8. doi: 10.1212/WNL.0000000000003786).
 

Running the financial numbers

Nailing down the incremental clinical benefit from MSUs is clearly a very important part of determining the value of this strategy, but another very practical concern is how much the service costs and whether it is financially sustainable.

“We did a cost-effectiveness analysis based on the PHANTOM-S data, and we were conservative by only looking at the benefit from early tPA treatment,” Heinrich J. Audebert, MD, professor of neurology at Charité Hospital in Berlin and head of the team running Berlin’s MSU, said during the MSU session at the meeting. “We did not take into account saving money by avoiding long-term stroke disability and just considered the cost of [immediate] care and the quality adjusted life years. We calculated a cost of $35,000 per quality adjusted life year, which is absolutely acceptable.”

He cautioned that this analysis was not based on actual outcomes but on the numbers needed to treat calculated from the PHANTOM-S results. “We need to now show this in controlled trials,” he admitted.

Mitchel L. Zoler/Frontline Medical News

Mitchel L. Zoler/Frontline Medical News

Waiting for more data

Despite these advances and the steady recent growth of MSUs, significant skepticism remains. “While mobile stroke units seem like a good idea and there is genuine hope that they will improve outcomes for selected stroke patients, there is not yet any evidence that this is the case,” wrote Bryan Bledsoe, DO, in a January 2017 editorial in the Journal of Emergency Medical Services. “They are expensive and financially non-sustainable. Without widespread deployment, they stand to benefit few, if any, patients. The money spent on these devices would be better spent on improving the current EMS system including paramedic education, the availability of stroke centers, and on the early recognition of ELVO [emergent large vessel occlusion] strokes,” wrote Dr. Bledsoe, professor of emergency medicine at the University of Nevada in Las Vegas.

Two other experts voiced concerns about MSUs in an editorial that accompanied a Cleveland Clinic report in March. “Even if MSUs meet an acceptable societal threshold for cost effectiveness, cost efficiency may prove a taller order to achieve return on investment for individual health systems and communities,” wrote Andrew M. Southerland, MD, and Ethan S. Brandler, MD (Neurology. 2017 March 8. doi: 10.1212/WNL.0000000000003833). They cited the Cleveland report, which noted that the group’s first 100 MSU-treated patients came from a total of 317 MSU deployments and included 217 trips that were canceled prior to the MSU’s arrival at the patient’s location. In Berlin’s initial experience, more than 2,000 MSU deployments led to 200 TPA treatments and 349 cancellations before arrival, noted Dr. Southerland, a neurologist at the University of Virginia in Charlottesville, and Dr. Brandler, an emergency medicine physician at Stony Brook (N.Y.) University.

“Hope remains that future trials may demonstrate the ultimate potential of mobile stroke units to improve long-term outcomes for more patients by treating them more quickly and effectively. In the meantime, ongoing efforts are needed to streamline MSU cost and efficiency,” they wrote.

Proponents of MSUs agree that what’s needed now are more data to prove efficacy and cost effectiveness, as well as better integration into EMS programs. The first opportunity for documenting the clinical impact of MSUs on larger numbers of U.S. patients may be from the BEnefits of Stroke Treatment Delivered using a Mobile Stroke Unit Compared to Standard Management by Emergency Medical Services (BEST-MSU) Study, funded by the Patient-Centered Outcomes Research Institute. This study is collecting data from the MSU programs in Denver Houston, and Memphis. Although currently designed to enroll 697 patients, Dr. Grotta said he hopes to kick that up to 1,000 patients.

“We are following the healthcare use and its cost for every enrolled MSU and conventional patient for 1 year,” Dr. Grotta explained in an interview. He hopes these results will provide the data needed to move MSUs from investigational status to routine and reimbursable care.

Dr. Southerland and Dr. Brandler suggested that “making MSUs multipurpose vehicles might also enhance cost-effectiveness,” an option that Dr. Grotta and his colleagues embrace. The MSUs on U.S. roads already also treat patients with intracranial hemorrhages using blood pressure reduction medications. Other neurologic diagnoses considered potential targets for MSU interventions include encephalopathy, seizures, central nervous system–tumors, and infections.

Stroke is a prime example of “a disease that is extremely time sensitive, and for the first time the field of stroke is ahead of the rest of the medical world in trying to speed treatment,” Dr. Grotta said. “We could add other diagnostic equipment monitored by telemedicine specialists. The MSU concept could be expanded to make it much more cost effective” and spur wider adoption by EMS, he suggested.

Dr. Grotta is a consultant to Frazer, a company that produces mobile stroke units, and to Stryker Corporation, and he has received research support from Genentech. Dr. Saver has been a consultant to and received research support from St. Jude. Dr. Audebert has received honoraria from Pfizer, Boehringer Ingelheim, Bristol-Myers Squibb, and Ever Pharma. He has been a consultant to ReNeuron, and he has served as an expert witness for Pfizer and for Lundbeck. Dr. Hussain has been a consultant to Pulsar. Dr. Alexandrov has been a speaker for Genentech. Dr. Nour, Dr. Wu, Dr. Bledsoe, Dr. Southerland, and Dr. Brandler had no disclosures.

[email protected]

On Twitter @mitchelzoler
 

HOUSTON – Mobile stroke units – specially equipped ambulances that bring a diagnostic CT scanner and therapeutic thrombolysis directly to patients in the field – have begun to proliferate across the United States, although they remain investigational, with no clear proof of their incremental clinical value or cost effectiveness.

The first U.S. mobile stroke unit (MSU) launched in Houston in early 2014 (following the world’s first in Berlin, which began running in early 2011), and by early 2017, at least eight other U.S. MSUs were in operation, most of them put into service during the prior 15 months. U.S. MSU locations now include Cleveland; Denver; Memphis; New York; Toledo, Ohio; Trenton, N.J., and Northwestern Medicine and Rush University Medical Center in the western Chicago region. A tenth MSU is slated to start operation at the University of California, Los Angeles later this year.

Early data collected at some of these sites show that initiating care of an acute ischemic stroke patient in an MSU shaves precious minutes off the time it takes to start thrombolytic therapy with tissue plasminogen activator (tPA) compared with that at a hospital, and findings from preliminary analyses suggest better functional outcomes for patients treated this way. However, leaders in the nascent field readily admit that the data needed to clearly prove the benefit patients receive from operating MSUs are still a few years off. This uncertainty about the added benefit to patients from MSUs couples with one clear fact: MSUs are expensive to start up, with a price tag of roughly $1 million to get a MSU on the road for the first time, and also expensive to operate, with one estimate for the annual cost of keeping an MSU on the street at about $500,000 per year for staffing, supplies, and other expenses.

“Every U.S. MSU I know of started with philanthropic gifts, but you need a business model” to keep the program running long-term, James C. Grotta, MD, said during a session focused on MSUs at the International Stroke Conference sponsored by the American Heart Association. “You can’t sustain an MSU with philanthropy,” said Dr. Grotta, professor of neurology at the University of Texas Health Science Center in Houston, director and founder of the Houston MSU, and acknowledged godfather of all U.S. MSUs.

Mitchel L. Zoler/Frontline Medical News

Mitchel L. Zoler/Frontline Medical News

Mitchel L. Zoler/Frontline Medical News

Early data on effectiveness

Dr. Nour reported some of the best evidence for the incremental clinical benefit of MSUs based on the reduced time for starting a tPA infusion. She used data collected by the Berlin group and published in September 2016 that compared the treatment courses and outcomes of patients managed with an MSU with similar patients managed by conventional ambulance transport for whom CT scan assessment and the start of TPA treatment did not begin until the patient reached a hospital.

The German analysis showed that, in the observational Pre-Hospital Acute Neurological Therapy and Optimization of Medical Care in Stroke Patients–Study (PHANTOM-S), among 353 patients treated by conventional transport, the median time from stroke onset to thrombolysis was 112 minutes, compared with a median of 73 minutes among 305 patients managed with an MSU, a statistically significant difference. However, the study found no significant difference for its primary endpoint: the percentage of patients with a modified Rankin Scale score of 0-1 when measured 90 days after their respective strokes. This outcome occurred in 47% of the control patients managed conventionally and in 53% of those managed by an MSU, a difference that fell short of statistical significance (Lancet Neurol. 2016 Sept;15[10]:1035-43).

Dr. Nour attributed the lack of statistical significance for this primary endpoint to the relatively small number of patients enrolled in PHANTOM-S. “The study was underpowered,” she said.

Dr. Nour presented an analysis at the meeting that extrapolated the results out to 1,000 hypothetical patients and tallied the benefits that a larger number of patients could expect to receive if their outcomes paralleled those seen in the published results. It showed that, among 1,000 stroke patients treated with an MSU, 58 were expected to be free from disability 90 days later, and an additional 124 patients would have some improvement in their 90 day clinical outcome based on their modified Rankin Scale scores when compared with patients undergoing conventional hospitalization.

“If this finding was confirmed in a larger, controlled study, it would suggest that MSU-based thrombolysis has substantial clinical benefit,” she concluded.

Another recent report looked at the first 100 stroke patients treated by the Cleveland MSU during 2014. Researchers at the Cleveland Clinic and Case Western Reserve University said that 16 of those 100 patients received tPA, and the median time from their emergency call to thrombolytic treatment was 38.5 minutes faster than for 53 stroke patients treated during the same period at emergency departments operated by the Cleveland Clinic, a statistically significant difference. However, this report included no data on clinical outcomes (Neurology. 2017 March 8. doi: 10.1212/WNL.0000000000003786).
 

Running the financial numbers

Nailing down the incremental clinical benefit from MSUs is clearly a very important part of determining the value of this strategy, but another very practical concern is how much the service costs and whether it is financially sustainable.

“We did a cost-effectiveness analysis based on the PHANTOM-S data, and we were conservative by only looking at the benefit from early tPA treatment,” Heinrich J. Audebert, MD, professor of neurology at Charité Hospital in Berlin and head of the team running Berlin’s MSU, said during the MSU session at the meeting. “We did not take into account saving money by avoiding long-term stroke disability and just considered the cost of [immediate] care and the quality adjusted life years. We calculated a cost of $35,000 per quality adjusted life year, which is absolutely acceptable.”

He cautioned that this analysis was not based on actual outcomes but on the numbers needed to treat calculated from the PHANTOM-S results. “We need to now show this in controlled trials,” he admitted.

Mitchel L. Zoler/Frontline Medical News

Mitchel L. Zoler/Frontline Medical News

Waiting for more data

Despite these advances and the steady recent growth of MSUs, significant skepticism remains. “While mobile stroke units seem like a good idea and there is genuine hope that they will improve outcomes for selected stroke patients, there is not yet any evidence that this is the case,” wrote Bryan Bledsoe, DO, in a January 2017 editorial in the Journal of Emergency Medical Services. “They are expensive and financially non-sustainable. Without widespread deployment, they stand to benefit few, if any, patients. The money spent on these devices would be better spent on improving the current EMS system including paramedic education, the availability of stroke centers, and on the early recognition of ELVO [emergent large vessel occlusion] strokes,” wrote Dr. Bledsoe, professor of emergency medicine at the University of Nevada in Las Vegas.

Two other experts voiced concerns about MSUs in an editorial that accompanied a Cleveland Clinic report in March. “Even if MSUs meet an acceptable societal threshold for cost effectiveness, cost efficiency may prove a taller order to achieve return on investment for individual health systems and communities,” wrote Andrew M. Southerland, MD, and Ethan S. Brandler, MD (Neurology. 2017 March 8. doi: 10.1212/WNL.0000000000003833). They cited the Cleveland report, which noted that the group’s first 100 MSU-treated patients came from a total of 317 MSU deployments and included 217 trips that were canceled prior to the MSU’s arrival at the patient’s location. In Berlin’s initial experience, more than 2,000 MSU deployments led to 200 TPA treatments and 349 cancellations before arrival, noted Dr. Southerland, a neurologist at the University of Virginia in Charlottesville, and Dr. Brandler, an emergency medicine physician at Stony Brook (N.Y.) University.

“Hope remains that future trials may demonstrate the ultimate potential of mobile stroke units to improve long-term outcomes for more patients by treating them more quickly and effectively. In the meantime, ongoing efforts are needed to streamline MSU cost and efficiency,” they wrote.

Proponents of MSUs agree that what’s needed now are more data to prove efficacy and cost effectiveness, as well as better integration into EMS programs. The first opportunity for documenting the clinical impact of MSUs on larger numbers of U.S. patients may be from the BEnefits of Stroke Treatment Delivered using a Mobile Stroke Unit Compared to Standard Management by Emergency Medical Services (BEST-MSU) Study, funded by the Patient-Centered Outcomes Research Institute. This study is collecting data from the MSU programs in Denver Houston, and Memphis. Although currently designed to enroll 697 patients, Dr. Grotta said he hopes to kick that up to 1,000 patients.

“We are following the healthcare use and its cost for every enrolled MSU and conventional patient for 1 year,” Dr. Grotta explained in an interview. He hopes these results will provide the data needed to move MSUs from investigational status to routine and reimbursable care.

Dr. Southerland and Dr. Brandler suggested that “making MSUs multipurpose vehicles might also enhance cost-effectiveness,” an option that Dr. Grotta and his colleagues embrace. The MSUs on U.S. roads already also treat patients with intracranial hemorrhages using blood pressure reduction medications. Other neurologic diagnoses considered potential targets for MSU interventions include encephalopathy, seizures, central nervous system–tumors, and infections.

Stroke is a prime example of “a disease that is extremely time sensitive, and for the first time the field of stroke is ahead of the rest of the medical world in trying to speed treatment,” Dr. Grotta said. “We could add other diagnostic equipment monitored by telemedicine specialists. The MSU concept could be expanded to make it much more cost effective” and spur wider adoption by EMS, he suggested.

Dr. Grotta is a consultant to Frazer, a company that produces mobile stroke units, and to Stryker Corporation, and he has received research support from Genentech. Dr. Saver has been a consultant to and received research support from St. Jude. Dr. Audebert has received honoraria from Pfizer, Boehringer Ingelheim, Bristol-Myers Squibb, and Ever Pharma. He has been a consultant to ReNeuron, and he has served as an expert witness for Pfizer and for Lundbeck. Dr. Hussain has been a consultant to Pulsar. Dr. Alexandrov has been a speaker for Genentech. Dr. Nour, Dr. Wu, Dr. Bledsoe, Dr. Southerland, and Dr. Brandler had no disclosures.

[email protected]

On Twitter @mitchelzoler
 

HOUSTON – Mobile stroke units – specially equipped ambulances that bring a diagnostic CT scanner and therapeutic thrombolysis directly to patients in the field – have begun to proliferate across the United States, although they remain investigational, with no clear proof of their incremental clinical value or cost effectiveness.

The first U.S. mobile stroke unit (MSU) launched in Houston in early 2014 (following the world’s first in Berlin, which began running in early 2011), and by early 2017, at least eight other U.S. MSUs were in operation, most of them put into service during the prior 15 months. U.S. MSU locations now include Cleveland; Denver; Memphis; New York; Toledo, Ohio; Trenton, N.J., and Northwestern Medicine and Rush University Medical Center in the western Chicago region. A tenth MSU is slated to start operation at the University of California, Los Angeles later this year.

Early data collected at some of these sites show that initiating care of an acute ischemic stroke patient in an MSU shaves precious minutes off the time it takes to start thrombolytic therapy with tissue plasminogen activator (tPA) compared with that at a hospital, and findings from preliminary analyses suggest better functional outcomes for patients treated this way. However, leaders in the nascent field readily admit that the data needed to clearly prove the benefit patients receive from operating MSUs are still a few years off. This uncertainty about the added benefit to patients from MSUs couples with one clear fact: MSUs are expensive to start up, with a price tag of roughly $1 million to get a MSU on the road for the first time, and also expensive to operate, with one estimate for the annual cost of keeping an MSU on the street at about $500,000 per year for staffing, supplies, and other expenses.

“Every U.S. MSU I know of started with philanthropic gifts, but you need a business model” to keep the program running long-term, James C. Grotta, MD, said during a session focused on MSUs at the International Stroke Conference sponsored by the American Heart Association. “You can’t sustain an MSU with philanthropy,” said Dr. Grotta, professor of neurology at the University of Texas Health Science Center in Houston, director and founder of the Houston MSU, and acknowledged godfather of all U.S. MSUs.

Mitchel L. Zoler/Frontline Medical News

Mitchel L. Zoler/Frontline Medical News

Mitchel L. Zoler/Frontline Medical News

Early data on effectiveness

Dr. Nour reported some of the best evidence for the incremental clinical benefit of MSUs based on the reduced time for starting a tPA infusion. She used data collected by the Berlin group and published in September 2016 that compared the treatment courses and outcomes of patients managed with an MSU with similar patients managed by conventional ambulance transport for whom CT scan assessment and the start of TPA treatment did not begin until the patient reached a hospital.

The German analysis showed that, in the observational Pre-Hospital Acute Neurological Therapy and Optimization of Medical Care in Stroke Patients–Study (PHANTOM-S), among 353 patients treated by conventional transport, the median time from stroke onset to thrombolysis was 112 minutes, compared with a median of 73 minutes among 305 patients managed with an MSU, a statistically significant difference. However, the study found no significant difference for its primary endpoint: the percentage of patients with a modified Rankin Scale score of 0-1 when measured 90 days after their respective strokes. This outcome occurred in 47% of the control patients managed conventionally and in 53% of those managed by an MSU, a difference that fell short of statistical significance (Lancet Neurol. 2016 Sept;15[10]:1035-43).

Dr. Nour attributed the lack of statistical significance for this primary endpoint to the relatively small number of patients enrolled in PHANTOM-S. “The study was underpowered,” she said.

Dr. Nour presented an analysis at the meeting that extrapolated the results out to 1,000 hypothetical patients and tallied the benefits that a larger number of patients could expect to receive if their outcomes paralleled those seen in the published results. It showed that, among 1,000 stroke patients treated with an MSU, 58 were expected to be free from disability 90 days later, and an additional 124 patients would have some improvement in their 90 day clinical outcome based on their modified Rankin Scale scores when compared with patients undergoing conventional hospitalization.

“If this finding was confirmed in a larger, controlled study, it would suggest that MSU-based thrombolysis has substantial clinical benefit,” she concluded.

Another recent report looked at the first 100 stroke patients treated by the Cleveland MSU during 2014. Researchers at the Cleveland Clinic and Case Western Reserve University said that 16 of those 100 patients received tPA, and the median time from their emergency call to thrombolytic treatment was 38.5 minutes faster than for 53 stroke patients treated during the same period at emergency departments operated by the Cleveland Clinic, a statistically significant difference. However, this report included no data on clinical outcomes (Neurology. 2017 March 8. doi: 10.1212/WNL.0000000000003786).
 

Running the financial numbers

Nailing down the incremental clinical benefit from MSUs is clearly a very important part of determining the value of this strategy, but another very practical concern is how much the service costs and whether it is financially sustainable.

“We did a cost-effectiveness analysis based on the PHANTOM-S data, and we were conservative by only looking at the benefit from early tPA treatment,” Heinrich J. Audebert, MD, professor of neurology at Charité Hospital in Berlin and head of the team running Berlin’s MSU, said during the MSU session at the meeting. “We did not take into account saving money by avoiding long-term stroke disability and just considered the cost of [immediate] care and the quality adjusted life years. We calculated a cost of $35,000 per quality adjusted life year, which is absolutely acceptable.”

He cautioned that this analysis was not based on actual outcomes but on the numbers needed to treat calculated from the PHANTOM-S results. “We need to now show this in controlled trials,” he admitted.

Mitchel L. Zoler/Frontline Medical News

Mitchel L. Zoler/Frontline Medical News

Waiting for more data

Despite these advances and the steady recent growth of MSUs, significant skepticism remains. “While mobile stroke units seem like a good idea and there is genuine hope that they will improve outcomes for selected stroke patients, there is not yet any evidence that this is the case,” wrote Bryan Bledsoe, DO, in a January 2017 editorial in the Journal of Emergency Medical Services. “They are expensive and financially non-sustainable. Without widespread deployment, they stand to benefit few, if any, patients. The money spent on these devices would be better spent on improving the current EMS system including paramedic education, the availability of stroke centers, and on the early recognition of ELVO [emergent large vessel occlusion] strokes,” wrote Dr. Bledsoe, professor of emergency medicine at the University of Nevada in Las Vegas.

Two other experts voiced concerns about MSUs in an editorial that accompanied a Cleveland Clinic report in March. “Even if MSUs meet an acceptable societal threshold for cost effectiveness, cost efficiency may prove a taller order to achieve return on investment for individual health systems and communities,” wrote Andrew M. Southerland, MD, and Ethan S. Brandler, MD (Neurology. 2017 March 8. doi: 10.1212/WNL.0000000000003833). They cited the Cleveland report, which noted that the group’s first 100 MSU-treated patients came from a total of 317 MSU deployments and included 217 trips that were canceled prior to the MSU’s arrival at the patient’s location. In Berlin’s initial experience, more than 2,000 MSU deployments led to 200 TPA treatments and 349 cancellations before arrival, noted Dr. Southerland, a neurologist at the University of Virginia in Charlottesville, and Dr. Brandler, an emergency medicine physician at Stony Brook (N.Y.) University.

“Hope remains that future trials may demonstrate the ultimate potential of mobile stroke units to improve long-term outcomes for more patients by treating them more quickly and effectively. In the meantime, ongoing efforts are needed to streamline MSU cost and efficiency,” they wrote.

Proponents of MSUs agree that what’s needed now are more data to prove efficacy and cost effectiveness, as well as better integration into EMS programs. The first opportunity for documenting the clinical impact of MSUs on larger numbers of U.S. patients may be from the BEnefits of Stroke Treatment Delivered using a Mobile Stroke Unit Compared to Standard Management by Emergency Medical Services (BEST-MSU) Study, funded by the Patient-Centered Outcomes Research Institute. This study is collecting data from the MSU programs in Denver Houston, and Memphis. Although currently designed to enroll 697 patients, Dr. Grotta said he hopes to kick that up to 1,000 patients.

“We are following the healthcare use and its cost for every enrolled MSU and conventional patient for 1 year,” Dr. Grotta explained in an interview. He hopes these results will provide the data needed to move MSUs from investigational status to routine and reimbursable care.

Dr. Southerland and Dr. Brandler suggested that “making MSUs multipurpose vehicles might also enhance cost-effectiveness,” an option that Dr. Grotta and his colleagues embrace. The MSUs on U.S. roads already also treat patients with intracranial hemorrhages using blood pressure reduction medications. Other neurologic diagnoses considered potential targets for MSU interventions include encephalopathy, seizures, central nervous system–tumors, and infections.

Stroke is a prime example of “a disease that is extremely time sensitive, and for the first time the field of stroke is ahead of the rest of the medical world in trying to speed treatment,” Dr. Grotta said. “We could add other diagnostic equipment monitored by telemedicine specialists. The MSU concept could be expanded to make it much more cost effective” and spur wider adoption by EMS, he suggested.

Dr. Grotta is a consultant to Frazer, a company that produces mobile stroke units, and to Stryker Corporation, and he has received research support from Genentech. Dr. Saver has been a consultant to and received research support from St. Jude. Dr. Audebert has received honoraria from Pfizer, Boehringer Ingelheim, Bristol-Myers Squibb, and Ever Pharma. He has been a consultant to ReNeuron, and he has served as an expert witness for Pfizer and for Lundbeck. Dr. Hussain has been a consultant to Pulsar. Dr. Alexandrov has been a speaker for Genentech. Dr. Nour, Dr. Wu, Dr. Bledsoe, Dr. Southerland, and Dr. Brandler had no disclosures.

[email protected]

On Twitter @mitchelzoler
 

An estimated 1 in 10 high school students uses synthetic cannabinoids, which are linked to multiple other risk behaviors, and use is more likely among students with depressive symptoms, marijuana use, and alcohol use, investigators in two studies reported.

Synthetic cannabinoids are structurally similar to delta-9-tetrahydrocannabinol, but they may be more potent, with adverse health effects not seen with natural tetrahydrocannabinol in marijuana. These synthetic products are accessible to teens online, in convenience stores, and in smoke shops. Past research has suggested that adolescents aren’t aware of the possible negative effects of these products, such as tachycardia, hypertension, lethargy, nausea, vomiting, irritability, chest pain, hallucinations, confusion, and vertigo.

Courtesy DEA

An estimated 1 in 10 high school students uses synthetic cannabinoids, which are linked to multiple other risk behaviors, and use is more likely among students with depressive symptoms, marijuana use, and alcohol use, investigators in two studies reported.

Synthetic cannabinoids are structurally similar to delta-9-tetrahydrocannabinol, but they may be more potent, with adverse health effects not seen with natural tetrahydrocannabinol in marijuana. These synthetic products are accessible to teens online, in convenience stores, and in smoke shops. Past research has suggested that adolescents aren’t aware of the possible negative effects of these products, such as tachycardia, hypertension, lethargy, nausea, vomiting, irritability, chest pain, hallucinations, confusion, and vertigo.

Courtesy DEA

An estimated 1 in 10 high school students uses synthetic cannabinoids, which are linked to multiple other risk behaviors, and use is more likely among students with depressive symptoms, marijuana use, and alcohol use, investigators in two studies reported.

Synthetic cannabinoids are structurally similar to delta-9-tetrahydrocannabinol, but they may be more potent, with adverse health effects not seen with natural tetrahydrocannabinol in marijuana. These synthetic products are accessible to teens online, in convenience stores, and in smoke shops. Past research has suggested that adolescents aren’t aware of the possible negative effects of these products, such as tachycardia, hypertension, lethargy, nausea, vomiting, irritability, chest pain, hallucinations, confusion, and vertigo.

Courtesy DEA

Ursolic acid (3beta-hydroxy-urs-12-en-28-oic acid) is a pentacyclic triterpenoid found naturally in apples, waxy berries, rosemary, oregano, and several other plants and herbs used in medicine and the diet.^1,2 It is known to have significant antioxidant, anti-inflammatory, and antiproliferative properties, and has also been associated with a wider range of biologic activities, including anticancer, antimicrobial, antitumor, antiwrinkle, anti-HIV, cytotoxic, and hepatoprotective.^3,4 In addition, ursolic acid is the focus of human clinical trials for potential uses in cancer and skin wrinkles.⁴ While this triterpenoid is known to suppress tumor formation and viability in various kinds of cancer, including skin cancer, several forms of cancer are resistant to ursolic acid.

RobinCraigPhoto/Thinkstock

Anti-inflammatory activity

In a 2013 study of the antibacterial and anti-inflammatory effects of Syzygium jambos on acne, Sharma et al. found that ursolic acid was one of the constituents of the leaf extracts that contributed to a significant suppression of the release of inflammatory cytokines interleukin (IL)-8 and tumor necrosis factor-alpha.⁵

In 2010, Yang et al. identified ursolic acid as a key constituent of Acanthopanax koreanum fruit, a popular fruit in Jeju Island, South Korea, extracts of which they found to exhibit significant anti-inflammatory activity and suitability as a topical agent.⁶

Yasukawa et al. conducted an in vivo two-stage carcinogenesis test in mice in 2009 in which extracts of the branches of Hippophae rhamnoides displayed significant antitumor activity after initiation with 7,12-dimethylbenz[a]anthracene (DMBA) and promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA). Ursolic acid and (-)-epigallocatechin were the constituents found to have the greatest inhibitory effects on TPA-induced inflammation.⁷

Anticancer activity

In 2015, Cho et al. reported on the inhibitory effects on skin tumor promotion from the topical application of ursolic acid, resveratrol, or the combination of the two prior to TPA treatment on mouse skin. The combination of the two botanical agents yielded the strongest suppression of TPA-induced epidermal hyperproliferation, skin inflammation, inflammatory gene expression, and skin tumor promotion.¹¹

In another study that year buttressing the combination of the two botanical agents, Junco et al. demonstrated that chloroquine could be used to sensitize B16F10 metastatic mouse melanoma to the anticancer activities of ursolic acid and resveratrol. The investigators concluded that the combination of ursolic acid or resveratrol with chloroquine has potential for inclusion in melanoma treatment in humans.¹² Previously, Junco et al. observed that the anti–skin cancer effects of ursolic acid are augmented by P-glycoprotein inhibitors, and that ursolic acid and the stilbene resveratrol, a potent antioxidant, work synergistically, although not by blocking P-glycoprotein. The investigators suggested that ursolic acid along with resveratrol and/or P-glycoprotein inhibitors have potential as effective anti–skin cancer regimens.

In 2014, Lee et al. showed that ursolic acid can differentially modulate apoptosis in cutaneous melanoma and retinal pigment epithelial cells exposed to ultraviolet to visible broadband radiation, exhibiting the potential to protect normal cells while sensitizing melanoma cells to the effects of UV radiation.¹³ These findings supported earlier work by the team showing that pretreatment of human cells derived from a malignant skin melanoma markedly enhanced the sensitivity of melanoma cells to UV radiation, while providing some photoprotection to retinal pigment epithelium.

Also that year, Soica et al. demonstrated, using in vitro tests and in vivo skin cancer models, that the mixture of oleanolic and ursolic acids and in complex with cyclodextrin rendered a synergistic antitumor activity.¹⁴

A year earlier, Kowalczyk et al. showed that the combined action of phytochemicals – dietary calcium D-glucarate and topical ursolic acid and resveratrol – was effective in suppressing the initiation (with 7,12-dimethylbenz[a]anthracene [DMBA]) and promotion (with TPA) of skin tumorigenesis in SENCAR mice. Ursolic acid alone or in combination with calcium D-glucarate significantly diminished epidermal hyperplasia when applied during promotion. All of the antipromotion protocols led to significant decreases in cyclooxygenase-2 and interleukin (IL)-6 expression. The researchers concluded that ursolic acid strongly inhibits skin tumor promotion and inflammatory signaling, and warrants attention as a potential preventive agent against skin and other epithelial cancers.¹⁵ Kowalczyk et al. had previously found that ursolic acid and other phytochemicals displayed significant in vitro and in vivo antioxidant and antitumorigenic activity, inhibiting murine skin carcinogenesis by blunting tumor initiation and tumor promotion/progression.¹⁶

In 2006, beta-ursolic acid isolated from Salvia officinalis was found by Jedinák et al. to be effective in suppressing lung colonization of beta16 mouse melanoma cells in vivo.¹⁷

Huang et al. showed in 1994 that extracts of the leaves of Rosmarinus officinalis (rosemary) were effective in suppressing tumor initiation and promotion in a two-stage skin tumorigenesis mouse model. Topically applied ursolic acid isolated from the leaves was found to hinder TPA-induced ear inflammation, ornithine decarboxylase activity, and tumor promotion. The number of tumors per mouse also declined significantly due to the topical application of ursolic acid concurrent with twice weekly application of the tumor-promoter TPA in DMBA-initiated mice.¹⁸

Antiaging and other activities

In 2015, Herndon et al. conducted an open-label clinical trial in 37 females (aged 35-60 years) to ascertain the effectiveness of an anti-aging moisturizer containing Astragalus membranaceus root extract, a peptide blend including palmitoyl tripeptide-38, standardized rosemary leaf extract (ursolic acid), tetrahexyldecyl ascorbate (THD ascorbate), and ubiquinone (coenzyme Q10). Subjects were instructed to apply the moisturizer once in the morning and once in the evening, and were assessed at baseline, and after 4, 8, and 12 weeks of twice daily application. Clinical evaluations after 8 weeks revealed a statistically significant improvement in all grading parameters (fine lines and wrinkles, clarity/brightness, visual roughness, tactile roughness, redness, hyperpigmentation, and overall appearance), with even more pronounced improvement at 12 weeks. The product was found to be mild and well tolerated, and digital photography reinforced clinical assessments and self-evaluations.¹⁹

Lee et al. reported in 2012 on in vitro results suggesting that ursolic acid was effective as an inhibitor of matrix metalloproteinase (MMP)-1 after UVB exposure and was more effective than retinoic acid.²⁰

Based on studies with hairless mice, Lim et al. found in 2007 that ursolic and oleanolic acids can enhance the recovery of skin barrier function and, via peroxisome proliferator-activated receptor-alpha, spur epidermal keratinocyte differentiation. They concluded that both acids have potential for use as agents to promote epidermal permeability barrier function.²¹

In 2003, Soo et al. observed that pretreatment with ursolic acid inhibited UVA-induced oxidative stress and activation and expression of MMP-2 in HaCaT human keratinocytes. They concluded that ursolic acid may merit attention for the prevention of UVA-induced photoaging.²²

Three years earlier, Yarosh et al. showed that liposomes containing ursolic acid augmented ceramide content in cultured normal human epidermal keratinocytes and collagen content in cultured normal human dermal fibroblasts. Over an 11-day period, clinical tests with the ursolic acid–containing liposome (Merotaine) revealed increases in the ceramide content in human skin.²³ Two years later, many of the same researchers duplicated their results. This new study also demonstrated that ursolic acid liposomes raise ceramide levels in normal human epidermal keratinocytes, in contrast to the effects of retinoic acid, earlier shown to reduce such levels. They concluded that ursolic acid liposomes show promise for use alone or in combination to replenish or maintain cutaneous ceramide and collagen levels.²⁴ Notably, ursolic acid is incorporated into topical oils and creams intended to confer rejuvenating effects to the skin.
 

Conclusion

Ursolic acid is a compelling ingredient. I especially will be interested in the results of ongoing human clinical trials of this triterpenoid for treating cancer and skin wrinkles. As it is, ursolic acid is known to exert significant inhibitory activity against tumor formation and tumor cell viability in the laboratory. Given its wide range of biologic activity, and some promising cutaneous results, there is reason to believe that ursolic acid has the potential to play an increasingly useful role in topical skin care agents and dermatologic practice.

References

1. J Dermatol. 2007 Sep;34(9):625-34.

2. Folia Histochem Cytobiol. 2011;49(4):664-9.

3. J Cosmet Dermatol. 2004 Jan;3(1):26-34.

4. J Enzyme Inhib Med Chem. 2011 Oct;26(5):616-42.

5. BMC Complement Altern Med. 2013 Oct 29;13:292.

6. J Biomed Biotechnol. 2010;2010:715739.

7. Fitoterapia. 2009 Apr;80(3):164-7.

8. Biosci Biotechnol Biochem. 2004 Jan;68(1):85-90.

9. J Ethnopharmacol. 2002 Oct;82(2-3):229-37.

10. Eur J Pharmacol. 1997 Sep 3;334(1):103-5.

11. Cancer Prev Res (Phila). 2015 Sep;8(9):817-25.

12. Melanoma Res. 2015 Apr;25(2):103-12.

13. Apoptosis. 2014 May;19(5):816-28.

14. Molecules. 2014 Apr 17;19(4):4924-40.

15. Int J Oncol. 2013 Sep;43(3):911-8.

16. Carcinogenesis. 2009 Jun;30(6):1008-15.

17. Z Naturforsch C. 2006 Nov-Dec;61(11-12):777-82.

18. Cancer Res. 1994 Feb 1;54(3):701-8.

19. J Drugs Dermatol. 2015 Jul;14(7):699-704.

20. Bioorg Khim. 2012 May-Jun;38(3):374-81.

21. J Dermatol. 2007;34(9):625-34.

22. Eur J Pharmacol. 2003 Aug 29;476(3):173-8.

23. Horm Res. 2000;54(5-6):318-21.

24. Arch Dermatol Res. 2002 Jan;293(11):569-75.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in the Design District in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote the textbook “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and a book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Her latest book, “Cosmeceuticals and Cosmetic Ingredients,” was published in November 2014. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Evolus, Galderma, GlaxoSmithKline, Kythera Biopharmaceuticals, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Topix Pharmaceuticals, and Unilever. Dr. Baumann also developed and owns the Baumann Skin Type Solution skin typing systems and related products.

Ursolic acid (3beta-hydroxy-urs-12-en-28-oic acid) is a pentacyclic triterpenoid found naturally in apples, waxy berries, rosemary, oregano, and several other plants and herbs used in medicine and the diet.^1,2 It is known to have significant antioxidant, anti-inflammatory, and antiproliferative properties, and has also been associated with a wider range of biologic activities, including anticancer, antimicrobial, antitumor, antiwrinkle, anti-HIV, cytotoxic, and hepatoprotective.^3,4 In addition, ursolic acid is the focus of human clinical trials for potential uses in cancer and skin wrinkles.⁴ While this triterpenoid is known to suppress tumor formation and viability in various kinds of cancer, including skin cancer, several forms of cancer are resistant to ursolic acid.

RobinCraigPhoto/Thinkstock

Anti-inflammatory activity

In a 2013 study of the antibacterial and anti-inflammatory effects of Syzygium jambos on acne, Sharma et al. found that ursolic acid was one of the constituents of the leaf extracts that contributed to a significant suppression of the release of inflammatory cytokines interleukin (IL)-8 and tumor necrosis factor-alpha.⁵

In 2010, Yang et al. identified ursolic acid as a key constituent of Acanthopanax koreanum fruit, a popular fruit in Jeju Island, South Korea, extracts of which they found to exhibit significant anti-inflammatory activity and suitability as a topical agent.⁶

Yasukawa et al. conducted an in vivo two-stage carcinogenesis test in mice in 2009 in which extracts of the branches of Hippophae rhamnoides displayed significant antitumor activity after initiation with 7,12-dimethylbenz[a]anthracene (DMBA) and promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA). Ursolic acid and (-)-epigallocatechin were the constituents found to have the greatest inhibitory effects on TPA-induced inflammation.⁷

Anticancer activity

In 2015, Cho et al. reported on the inhibitory effects on skin tumor promotion from the topical application of ursolic acid, resveratrol, or the combination of the two prior to TPA treatment on mouse skin. The combination of the two botanical agents yielded the strongest suppression of TPA-induced epidermal hyperproliferation, skin inflammation, inflammatory gene expression, and skin tumor promotion.¹¹

In another study that year buttressing the combination of the two botanical agents, Junco et al. demonstrated that chloroquine could be used to sensitize B16F10 metastatic mouse melanoma to the anticancer activities of ursolic acid and resveratrol. The investigators concluded that the combination of ursolic acid or resveratrol with chloroquine has potential for inclusion in melanoma treatment in humans.¹² Previously, Junco et al. observed that the anti–skin cancer effects of ursolic acid are augmented by P-glycoprotein inhibitors, and that ursolic acid and the stilbene resveratrol, a potent antioxidant, work synergistically, although not by blocking P-glycoprotein. The investigators suggested that ursolic acid along with resveratrol and/or P-glycoprotein inhibitors have potential as effective anti–skin cancer regimens.

In 2014, Lee et al. showed that ursolic acid can differentially modulate apoptosis in cutaneous melanoma and retinal pigment epithelial cells exposed to ultraviolet to visible broadband radiation, exhibiting the potential to protect normal cells while sensitizing melanoma cells to the effects of UV radiation.¹³ These findings supported earlier work by the team showing that pretreatment of human cells derived from a malignant skin melanoma markedly enhanced the sensitivity of melanoma cells to UV radiation, while providing some photoprotection to retinal pigment epithelium.

Also that year, Soica et al. demonstrated, using in vitro tests and in vivo skin cancer models, that the mixture of oleanolic and ursolic acids and in complex with cyclodextrin rendered a synergistic antitumor activity.¹⁴

A year earlier, Kowalczyk et al. showed that the combined action of phytochemicals – dietary calcium D-glucarate and topical ursolic acid and resveratrol – was effective in suppressing the initiation (with 7,12-dimethylbenz[a]anthracene [DMBA]) and promotion (with TPA) of skin tumorigenesis in SENCAR mice. Ursolic acid alone or in combination with calcium D-glucarate significantly diminished epidermal hyperplasia when applied during promotion. All of the antipromotion protocols led to significant decreases in cyclooxygenase-2 and interleukin (IL)-6 expression. The researchers concluded that ursolic acid strongly inhibits skin tumor promotion and inflammatory signaling, and warrants attention as a potential preventive agent against skin and other epithelial cancers.¹⁵ Kowalczyk et al. had previously found that ursolic acid and other phytochemicals displayed significant in vitro and in vivo antioxidant and antitumorigenic activity, inhibiting murine skin carcinogenesis by blunting tumor initiation and tumor promotion/progression.¹⁶

In 2006, beta-ursolic acid isolated from Salvia officinalis was found by Jedinák et al. to be effective in suppressing lung colonization of beta16 mouse melanoma cells in vivo.¹⁷

Huang et al. showed in 1994 that extracts of the leaves of Rosmarinus officinalis (rosemary) were effective in suppressing tumor initiation and promotion in a two-stage skin tumorigenesis mouse model. Topically applied ursolic acid isolated from the leaves was found to hinder TPA-induced ear inflammation, ornithine decarboxylase activity, and tumor promotion. The number of tumors per mouse also declined significantly due to the topical application of ursolic acid concurrent with twice weekly application of the tumor-promoter TPA in DMBA-initiated mice.¹⁸

Antiaging and other activities

In 2015, Herndon et al. conducted an open-label clinical trial in 37 females (aged 35-60 years) to ascertain the effectiveness of an anti-aging moisturizer containing Astragalus membranaceus root extract, a peptide blend including palmitoyl tripeptide-38, standardized rosemary leaf extract (ursolic acid), tetrahexyldecyl ascorbate (THD ascorbate), and ubiquinone (coenzyme Q10). Subjects were instructed to apply the moisturizer once in the morning and once in the evening, and were assessed at baseline, and after 4, 8, and 12 weeks of twice daily application. Clinical evaluations after 8 weeks revealed a statistically significant improvement in all grading parameters (fine lines and wrinkles, clarity/brightness, visual roughness, tactile roughness, redness, hyperpigmentation, and overall appearance), with even more pronounced improvement at 12 weeks. The product was found to be mild and well tolerated, and digital photography reinforced clinical assessments and self-evaluations.¹⁹

Lee et al. reported in 2012 on in vitro results suggesting that ursolic acid was effective as an inhibitor of matrix metalloproteinase (MMP)-1 after UVB exposure and was more effective than retinoic acid.²⁰

Based on studies with hairless mice, Lim et al. found in 2007 that ursolic and oleanolic acids can enhance the recovery of skin barrier function and, via peroxisome proliferator-activated receptor-alpha, spur epidermal keratinocyte differentiation. They concluded that both acids have potential for use as agents to promote epidermal permeability barrier function.²¹

In 2003, Soo et al. observed that pretreatment with ursolic acid inhibited UVA-induced oxidative stress and activation and expression of MMP-2 in HaCaT human keratinocytes. They concluded that ursolic acid may merit attention for the prevention of UVA-induced photoaging.²²

Three years earlier, Yarosh et al. showed that liposomes containing ursolic acid augmented ceramide content in cultured normal human epidermal keratinocytes and collagen content in cultured normal human dermal fibroblasts. Over an 11-day period, clinical tests with the ursolic acid–containing liposome (Merotaine) revealed increases in the ceramide content in human skin.²³ Two years later, many of the same researchers duplicated their results. This new study also demonstrated that ursolic acid liposomes raise ceramide levels in normal human epidermal keratinocytes, in contrast to the effects of retinoic acid, earlier shown to reduce such levels. They concluded that ursolic acid liposomes show promise for use alone or in combination to replenish or maintain cutaneous ceramide and collagen levels.²⁴ Notably, ursolic acid is incorporated into topical oils and creams intended to confer rejuvenating effects to the skin.
 

Conclusion

Ursolic acid is a compelling ingredient. I especially will be interested in the results of ongoing human clinical trials of this triterpenoid for treating cancer and skin wrinkles. As it is, ursolic acid is known to exert significant inhibitory activity against tumor formation and tumor cell viability in the laboratory. Given its wide range of biologic activity, and some promising cutaneous results, there is reason to believe that ursolic acid has the potential to play an increasingly useful role in topical skin care agents and dermatologic practice.

References

1. J Dermatol. 2007 Sep;34(9):625-34.

2. Folia Histochem Cytobiol. 2011;49(4):664-9.

3. J Cosmet Dermatol. 2004 Jan;3(1):26-34.

4. J Enzyme Inhib Med Chem. 2011 Oct;26(5):616-42.

5. BMC Complement Altern Med. 2013 Oct 29;13:292.

6. J Biomed Biotechnol. 2010;2010:715739.

7. Fitoterapia. 2009 Apr;80(3):164-7.

8. Biosci Biotechnol Biochem. 2004 Jan;68(1):85-90.

9. J Ethnopharmacol. 2002 Oct;82(2-3):229-37.

10. Eur J Pharmacol. 1997 Sep 3;334(1):103-5.

11. Cancer Prev Res (Phila). 2015 Sep;8(9):817-25.

12. Melanoma Res. 2015 Apr;25(2):103-12.

13. Apoptosis. 2014 May;19(5):816-28.

14. Molecules. 2014 Apr 17;19(4):4924-40.

15. Int J Oncol. 2013 Sep;43(3):911-8.

16. Carcinogenesis. 2009 Jun;30(6):1008-15.

17. Z Naturforsch C. 2006 Nov-Dec;61(11-12):777-82.

18. Cancer Res. 1994 Feb 1;54(3):701-8.

19. J Drugs Dermatol. 2015 Jul;14(7):699-704.

20. Bioorg Khim. 2012 May-Jun;38(3):374-81.

21. J Dermatol. 2007;34(9):625-34.

22. Eur J Pharmacol. 2003 Aug 29;476(3):173-8.

23. Horm Res. 2000;54(5-6):318-21.

24. Arch Dermatol Res. 2002 Jan;293(11):569-75.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in the Design District in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote the textbook “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and a book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Her latest book, “Cosmeceuticals and Cosmetic Ingredients,” was published in November 2014. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Evolus, Galderma, GlaxoSmithKline, Kythera Biopharmaceuticals, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Topix Pharmaceuticals, and Unilever. Dr. Baumann also developed and owns the Baumann Skin Type Solution skin typing systems and related products.

Ursolic acid (3beta-hydroxy-urs-12-en-28-oic acid) is a pentacyclic triterpenoid found naturally in apples, waxy berries, rosemary, oregano, and several other plants and herbs used in medicine and the diet.^1,2 It is known to have significant antioxidant, anti-inflammatory, and antiproliferative properties, and has also been associated with a wider range of biologic activities, including anticancer, antimicrobial, antitumor, antiwrinkle, anti-HIV, cytotoxic, and hepatoprotective.^3,4 In addition, ursolic acid is the focus of human clinical trials for potential uses in cancer and skin wrinkles.⁴ While this triterpenoid is known to suppress tumor formation and viability in various kinds of cancer, including skin cancer, several forms of cancer are resistant to ursolic acid.

RobinCraigPhoto/Thinkstock

Anti-inflammatory activity

In a 2013 study of the antibacterial and anti-inflammatory effects of Syzygium jambos on acne, Sharma et al. found that ursolic acid was one of the constituents of the leaf extracts that contributed to a significant suppression of the release of inflammatory cytokines interleukin (IL)-8 and tumor necrosis factor-alpha.⁵

In 2010, Yang et al. identified ursolic acid as a key constituent of Acanthopanax koreanum fruit, a popular fruit in Jeju Island, South Korea, extracts of which they found to exhibit significant anti-inflammatory activity and suitability as a topical agent.⁶

Yasukawa et al. conducted an in vivo two-stage carcinogenesis test in mice in 2009 in which extracts of the branches of Hippophae rhamnoides displayed significant antitumor activity after initiation with 7,12-dimethylbenz[a]anthracene (DMBA) and promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA). Ursolic acid and (-)-epigallocatechin were the constituents found to have the greatest inhibitory effects on TPA-induced inflammation.⁷

Anticancer activity

In 2015, Cho et al. reported on the inhibitory effects on skin tumor promotion from the topical application of ursolic acid, resveratrol, or the combination of the two prior to TPA treatment on mouse skin. The combination of the two botanical agents yielded the strongest suppression of TPA-induced epidermal hyperproliferation, skin inflammation, inflammatory gene expression, and skin tumor promotion.¹¹

In another study that year buttressing the combination of the two botanical agents, Junco et al. demonstrated that chloroquine could be used to sensitize B16F10 metastatic mouse melanoma to the anticancer activities of ursolic acid and resveratrol. The investigators concluded that the combination of ursolic acid or resveratrol with chloroquine has potential for inclusion in melanoma treatment in humans.¹² Previously, Junco et al. observed that the anti–skin cancer effects of ursolic acid are augmented by P-glycoprotein inhibitors, and that ursolic acid and the stilbene resveratrol, a potent antioxidant, work synergistically, although not by blocking P-glycoprotein. The investigators suggested that ursolic acid along with resveratrol and/or P-glycoprotein inhibitors have potential as effective anti–skin cancer regimens.

In 2014, Lee et al. showed that ursolic acid can differentially modulate apoptosis in cutaneous melanoma and retinal pigment epithelial cells exposed to ultraviolet to visible broadband radiation, exhibiting the potential to protect normal cells while sensitizing melanoma cells to the effects of UV radiation.¹³ These findings supported earlier work by the team showing that pretreatment of human cells derived from a malignant skin melanoma markedly enhanced the sensitivity of melanoma cells to UV radiation, while providing some photoprotection to retinal pigment epithelium.

Also that year, Soica et al. demonstrated, using in vitro tests and in vivo skin cancer models, that the mixture of oleanolic and ursolic acids and in complex with cyclodextrin rendered a synergistic antitumor activity.¹⁴

A year earlier, Kowalczyk et al. showed that the combined action of phytochemicals – dietary calcium D-glucarate and topical ursolic acid and resveratrol – was effective in suppressing the initiation (with 7,12-dimethylbenz[a]anthracene [DMBA]) and promotion (with TPA) of skin tumorigenesis in SENCAR mice. Ursolic acid alone or in combination with calcium D-glucarate significantly diminished epidermal hyperplasia when applied during promotion. All of the antipromotion protocols led to significant decreases in cyclooxygenase-2 and interleukin (IL)-6 expression. The researchers concluded that ursolic acid strongly inhibits skin tumor promotion and inflammatory signaling, and warrants attention as a potential preventive agent against skin and other epithelial cancers.¹⁵ Kowalczyk et al. had previously found that ursolic acid and other phytochemicals displayed significant in vitro and in vivo antioxidant and antitumorigenic activity, inhibiting murine skin carcinogenesis by blunting tumor initiation and tumor promotion/progression.¹⁶

In 2006, beta-ursolic acid isolated from Salvia officinalis was found by Jedinák et al. to be effective in suppressing lung colonization of beta16 mouse melanoma cells in vivo.¹⁷

Huang et al. showed in 1994 that extracts of the leaves of Rosmarinus officinalis (rosemary) were effective in suppressing tumor initiation and promotion in a two-stage skin tumorigenesis mouse model. Topically applied ursolic acid isolated from the leaves was found to hinder TPA-induced ear inflammation, ornithine decarboxylase activity, and tumor promotion. The number of tumors per mouse also declined significantly due to the topical application of ursolic acid concurrent with twice weekly application of the tumor-promoter TPA in DMBA-initiated mice.¹⁸

Antiaging and other activities

In 2015, Herndon et al. conducted an open-label clinical trial in 37 females (aged 35-60 years) to ascertain the effectiveness of an anti-aging moisturizer containing Astragalus membranaceus root extract, a peptide blend including palmitoyl tripeptide-38, standardized rosemary leaf extract (ursolic acid), tetrahexyldecyl ascorbate (THD ascorbate), and ubiquinone (coenzyme Q10). Subjects were instructed to apply the moisturizer once in the morning and once in the evening, and were assessed at baseline, and after 4, 8, and 12 weeks of twice daily application. Clinical evaluations after 8 weeks revealed a statistically significant improvement in all grading parameters (fine lines and wrinkles, clarity/brightness, visual roughness, tactile roughness, redness, hyperpigmentation, and overall appearance), with even more pronounced improvement at 12 weeks. The product was found to be mild and well tolerated, and digital photography reinforced clinical assessments and self-evaluations.¹⁹

Lee et al. reported in 2012 on in vitro results suggesting that ursolic acid was effective as an inhibitor of matrix metalloproteinase (MMP)-1 after UVB exposure and was more effective than retinoic acid.²⁰

Based on studies with hairless mice, Lim et al. found in 2007 that ursolic and oleanolic acids can enhance the recovery of skin barrier function and, via peroxisome proliferator-activated receptor-alpha, spur epidermal keratinocyte differentiation. They concluded that both acids have potential for use as agents to promote epidermal permeability barrier function.²¹

In 2003, Soo et al. observed that pretreatment with ursolic acid inhibited UVA-induced oxidative stress and activation and expression of MMP-2 in HaCaT human keratinocytes. They concluded that ursolic acid may merit attention for the prevention of UVA-induced photoaging.²²

Three years earlier, Yarosh et al. showed that liposomes containing ursolic acid augmented ceramide content in cultured normal human epidermal keratinocytes and collagen content in cultured normal human dermal fibroblasts. Over an 11-day period, clinical tests with the ursolic acid–containing liposome (Merotaine) revealed increases in the ceramide content in human skin.²³ Two years later, many of the same researchers duplicated their results. This new study also demonstrated that ursolic acid liposomes raise ceramide levels in normal human epidermal keratinocytes, in contrast to the effects of retinoic acid, earlier shown to reduce such levels. They concluded that ursolic acid liposomes show promise for use alone or in combination to replenish or maintain cutaneous ceramide and collagen levels.²⁴ Notably, ursolic acid is incorporated into topical oils and creams intended to confer rejuvenating effects to the skin.
 

Conclusion

Ursolic acid is a compelling ingredient. I especially will be interested in the results of ongoing human clinical trials of this triterpenoid for treating cancer and skin wrinkles. As it is, ursolic acid is known to exert significant inhibitory activity against tumor formation and tumor cell viability in the laboratory. Given its wide range of biologic activity, and some promising cutaneous results, there is reason to believe that ursolic acid has the potential to play an increasingly useful role in topical skin care agents and dermatologic practice.

References

1. J Dermatol. 2007 Sep;34(9):625-34.

2. Folia Histochem Cytobiol. 2011;49(4):664-9.

3. J Cosmet Dermatol. 2004 Jan;3(1):26-34.

4. J Enzyme Inhib Med Chem. 2011 Oct;26(5):616-42.

5. BMC Complement Altern Med. 2013 Oct 29;13:292.

6. J Biomed Biotechnol. 2010;2010:715739.

7. Fitoterapia. 2009 Apr;80(3):164-7.

8. Biosci Biotechnol Biochem. 2004 Jan;68(1):85-90.

9. J Ethnopharmacol. 2002 Oct;82(2-3):229-37.

10. Eur J Pharmacol. 1997 Sep 3;334(1):103-5.

11. Cancer Prev Res (Phila). 2015 Sep;8(9):817-25.

12. Melanoma Res. 2015 Apr;25(2):103-12.

13. Apoptosis. 2014 May;19(5):816-28.

14. Molecules. 2014 Apr 17;19(4):4924-40.

15. Int J Oncol. 2013 Sep;43(3):911-8.

16. Carcinogenesis. 2009 Jun;30(6):1008-15.

17. Z Naturforsch C. 2006 Nov-Dec;61(11-12):777-82.

18. Cancer Res. 1994 Feb 1;54(3):701-8.

19. J Drugs Dermatol. 2015 Jul;14(7):699-704.

20. Bioorg Khim. 2012 May-Jun;38(3):374-81.

21. J Dermatol. 2007;34(9):625-34.

22. Eur J Pharmacol. 2003 Aug 29;476(3):173-8.

23. Horm Res. 2000;54(5-6):318-21.

24. Arch Dermatol Res. 2002 Jan;293(11):569-75.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in the Design District in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote the textbook “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and a book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Her latest book, “Cosmeceuticals and Cosmetic Ingredients,” was published in November 2014. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Evolus, Galderma, GlaxoSmithKline, Kythera Biopharmaceuticals, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Topix Pharmaceuticals, and Unilever. Dr. Baumann also developed and owns the Baumann Skin Type Solution skin typing systems and related products.

People with cystic fibrosis (CF) survive an average of 10 years longer if they live in Canada than if they live in the United States, according to a report published online March 14 in Annals of Internal Medicine.

Differences between the two nations’ health care systems, including access to insurance, “may, in part, explain the Canadian survival advantage,” said Anne L. Stephenson, MD, PhD, of St. Michael’s Hospital, Toronto, and her associates.

People with cystic fibrosis (CF) survive an average of 10 years longer if they live in Canada than if they live in the United States, according to a report published online March 14 in Annals of Internal Medicine.

Differences between the two nations’ health care systems, including access to insurance, “may, in part, explain the Canadian survival advantage,” said Anne L. Stephenson, MD, PhD, of St. Michael’s Hospital, Toronto, and her associates.

People with cystic fibrosis (CF) survive an average of 10 years longer if they live in Canada than if they live in the United States, according to a report published online March 14 in Annals of Internal Medicine.

Differences between the two nations’ health care systems, including access to insurance, “may, in part, explain the Canadian survival advantage,” said Anne L. Stephenson, MD, PhD, of St. Michael’s Hospital, Toronto, and her associates.

Vocal cord dysfunction (VCD), also known as paradoxical vocal cord movement, is described as paroxysms of glottis obstruction due to true vocal cord adduction.¹ Since VCD presents as a constellation of symptoms associated with dyspnea, it often is misdiagnosed as asthma.² Vocal cord dysfunction often manifests as episodic dyspnea and wheezing, may occur with exercise, and may be minimally responsive to initial therapies. Flattened inspiratory curves may be noted on pulmonary function tests (PFTs), but direct laryngoscopy is the gold standard for diagnosis.³ A cohort of proven patients with VCD with a plateau in the inspiratory curve of PFTs also had a plateau on expiratory phase in 81% of cases.⁴

The differential diagnosis of patients presenting with upper airway symptoms is broad. It must include VCD, asthma, angioedema, laryngomalacia, vocal cord polyps, vocal cord tumors, and neurologic conditions such as brain stem compression or movement disorders. Essentially, all movement disorders of vocal cords must be considered, and organic causes of this movement disorder can be evaluated by visualization of the vocal cords. Triggers for VCD include exercise, airborne irritants, gastroesophageal reflux disease (GERD), allergic rhinitis, medications, and psychological conditions.⁵ Additionally, VCD can coexist with asthma, further complicating accurate diagnoses.⁶

Therapies are reported in case studies, but no large randomized controlled trials exist to evaluate current therapy options. Primary treatments of asthma therapy were largely ineffective, and ideal therapy includes a multidisciplinary approach, including speech therapy to optimize laryngeal control and treatment of all identified laryngeal irritants.⁶

The prevalence of VCD is unknown, with no prospective cohort studies completed to date and conflicting diagnostic criteria used in many case studies.⁷ A prevalence of 2.8% was noted in one particular cohort of 1,028 patients admitted to a rehabilitation center in a calendar year with the primary pulmonary diagnosis on admission.⁶ Females seemed to be affected at a higher ratio than were males, 2 to 3 females per 1 male diagnosis.⁷

In the military population, certain risk factors were noted in returning deployed members, including anxiety/high stress, exercise, and acute respiratory illnesses.⁸ In that particular cohort, 72% positive predictive value was noted for VCD if flattened inspiratory flow loops with negative methacholine challenge were present.

Diagnostic criteria are challenging, as symptoms such as dyspnea may be present acutely, last < 2 minutes, be self-limiting, and completely resolve outside of acute events. Stridor may be noted, primarily above the vocal cords, and less audible on chest auscultation.⁶ A goal of therapy, in addition to dedicated speech pathologist input, is optimizing comedical conditions, including GERD, allergic rhinitis, concomitant asthma, and any psychological diagnoses.⁹

Athletes are a particular subset of patients with VCD who are crucial to appropriately diagnose, including a detailed history and physical, PFTs, and proceeding to direct laryngoscopy to confirm diagnoses.¹⁰ Behavioral management includes rescue breathing techniques, and speech therapy programs focus on relaxation of the larynx and diaphragmatic breathing techniques, with the goal of establishing sense of control during acute events.¹⁰ Military service members are expected to operate at a high-intensity level similar to that of athletes, and treatments considered for athletes are applicable to military service members as well. Military strength and cardiovascular standards are measured by a combination of push-ups, sit-ups, and a run test, in addition to waist measurements. Some of the cohort were identified during physical fitness standard failures, usually in the run test, and ultimately received a pulmonology referral for wheezing or dyspnea with exertion. The objective of this retrospective cohort study was to evaluate 100 consecutively diagnosed cases of VCD in a military treatment facility.

Methods

The authors conducted a retrospective chart review of DoD military medical records of outpatient diagnoses in 100 consecutive diagnoses of VCD from January 2011 to February 2014. Institutional review board approval was obtained under Project RSM20130001E by the Exempt Determination Official at Eglin Air Force Base (AFB), Florida.

All cases were identified at time of VCD visualization and were diagnosed with video stroboscopy by speech therapy or by visual laryngoscopy by the otolaryngology or pulmonology departments via direct visualization.

Cases were collected chronologically, and all diagnosed cases at Eglin AFB hospital were included. Follow-up was scheduled with all patients diagnosed in Speech Therapy, and most patients were concurrently treated by Pulmonology or Allergy/Immunology. Pulmonary function tests were obtained in 98 of the 100 diagnosed cases. Patients eligible for care at Eglin AFB included active-duty and Reserve military members plus dependents and retirees.

The majority of patients diagnosed in this cohort were seen and diagnosed by Speech Therapy. Video stroboscopy is based on the principle that a movement of an object higher than a certain flicker rate appears to stand still to direct visualization, but with a rate of light exposure and imaging above the flicker rate by video, the true movement of the object can be identified.¹¹ Video stroboscopy is considered highly sensitive for organic disorders of vocal cords, but it is not specific for either organic or dysfunctional disorders.¹¹ It is still the gold standard above direct visualization, as it can detect abnormal movement of vocal cords above the critical rate that the human eye would perceive as not moving due to the frequency of movement (Figures 1 & 2).¹¹

In an older study, laryngoscopy was able to diagnose 100% of patients with symptomatic paradoxical vocal cord movement and additional 60% asymptomatic patients with a constellation of symptoms consistent with paradoxical vocal cord movement.¹²

Speech Therapy; Ear, Nose, and Throat (ENT); and Pulmonology may not perform direct visualization in these patients at initial presentation due to other suspected diagnoses. A more common test is the PFT, especially if asthma or other airway tract diseases are suspected (Figure 3).

Patient Descriptions

Study patients were referred for a variety of reasons, often from primary care clinics for concerns for asthma, episodic dyspnea, wheezing, or decreased exercise tolerance thought to be related to pulmonary or allergy causes. Pulmonology worked closely with Speech Therapy and referred VCD cases for speech evaluation, including video stroboscopy. Notably, of the patients in this cohort, although some were suspected to have asthma, those patients were ruled out during part of the pulmonology evaluation, both with PFT testing and methacholine challenges. An asthma diagnosis is important in a military treatment facility, as asthma is often grounds for discharge.

Patients ranged in age from 13 to 68 years, with a median age at 31 years diagnosis. Thirty-nine females and 61 males comprised the total case series. Speech Therapy diagnosed 97 patients, 96 were diagnosed at Eglin AFB hospital via stroboscopy. One patient was diagnosed off-base by Speech Therapy via direct visualization, 1 patient was diagnosed by Pulmonology on-base via direct visualization, and 2 patients were diagnosed by ENT on-base via direct visualization. These patients had direct laryngoscopy completed, often to rule out other organic causes for upper airway disease processes, and were found to have visual paradoxical vocal cord movement. Ninety-eight patients completed PFTs. Several patients were lost to follow-up, as can be common in a military population with frequent moves or members leaving service.

On record review, patient symptoms were present in the range of 2 months to 20 years, with a median duration of symptomatic reports lasting 2 years prior to diagnosis. Common diagnoses prior to visual VCD diagnosis included asthma, exercise-induced asthma, anxiety, and episodic wheezing. Risk factors that were evaluated in this case series included age, sex, body mass index (BMI), GERD, allergic rhinitis, postnasal drip, active smoker, previous smoker, and mental health diagnoses (Figure 4).

Pulmonary function test results were analyzed on 98 patients, including forced expiratory volume in 1 second (FEV₁); forced vital capacity (FVC), FEV₁/FVC ratio; peak inspiratory flow (PIF) and peak expiratory flow (PEF)—available in 97 studies; forced expiratory flow (FEF) at 25% to 75% of FVC (FEF 25%-75%)—available in 96 studies; and maximum voluntary ventilation (MVV) and MVV/FEV₁ ratio—available in 60 of 98 PFTs.

Interventions

All patients diagnosed by Speech Therapy on-base were provided with laryngeal relaxation techniques, diaphragmatic breathing techniques, and controlled inhale/exhale techniques at time of diagnosis, with frequent follow-up scheduled with Speech Therapy and Pulmonology. All diagnoses potentially contributing to laryngeal irritation were treated, including GERD, allergic rhinitis, smoking cessation, weight loss, and exercise recommendations as needed.

Patients reported improvement on follow-up appointments with Speech Therapy in overall control of symptoms, subjectively categorized as poor improvement, partial improvement, and complete improvement. This was a subjective measurement of improvement and fully dependent on follow-up care and patient reporting for improvement. No predefined number of follow-ups was determined; patients were followed monthly until they declined further care, fully improved, moved out of the military treatment system, or were lost to follow-up.

Treatment included structured Speech Therapy sessions. Response to treatment was subjectively qualified by patient report. Fifteen patients reported complete resolution of symptoms, 57 reported partial improvement, 24 reported poor improvement, and 4 patients were lost to follow-up.

Results

Risk factors for the diagnosis of VCD included possible associations with GERD, allergic rhinitis, smoking, prior smoking, BMI, and mental health diagnoses. Body mass index ranged from 17 to 36 in the case series, with median BMI of 27. Mental health diagnoses were present in 35 patients and included diagnoses of anxiety, depression, and adjustment disorders. Gastroesophageal reflux disease diagnosis was present in 59 of the case series patients, 80 had the diagnosis of allergic rhinitis, 63 were diagnosed with postnasal drip. Sixteen case series patients were current smokers. An additional 26 were previous smokers (at least 100 cigarettes in lifetime) for a total of 42 patients that were current or prior smokers.

The chart review was completed to evaluate for the presence of these diagnoses, which included previous treatments; for example, proton pump inhibitors for GERD, antidepressants for depression, or intranasal steroids for allergic rhinitis. The diagnosis was counted as present if the patient was currently being treated for the particular diagnosis in question.

PFT Data

Data from PFTs were available for 98 of 100 cases diagnosed. Review of data across all 98 patients is noted for median FEV₁ of 3.6, a median FVC of 4.5, with ratio of 0.80.

Since PFT values vary according to age, sex, and ethnicity, PFTs were analyzed for percent predicted values based on age, gender, and race. Notably, median values for FEV₁, FVC, and PEF were all close to 100% of the predicted value. The MVV percent predicted was available in 60 cases and was 93% of predicted values. The most significant difference from expected values was FEF 25% to 75%, at 84% of expected results.

Flow-volume loop evaluations on the 97 PFTs available were completed, and 58 of the 97 were noted for variable extrathoracic airway obstruction consistent with inspiratory inhibition in the patient population. This is 60% of the available PFTs in this cohort study.

Discussion

This retrospective chart review of 100 consecutive VCD diagnoses in a military treatment facility reinforces many of the findings currently available in the literature. As illustrated in a Chest review article, the diagnosis of VCD on history, physical examination, or PFTs remains ellusive.¹ The PFT evaluation contains some subjectivity regarding the flattening of inspiratory flow-volume loops and is not routinely reported in PFT results. In patients diagnosed with VCD, a clear consensus of treatment modalities remains lacking. Modification of risk factors (allergic rhinitis, GERD, smoking cessation, weight loss) assisted in self-reported patient improvement, as did focused speech therapy.

The median age of 31 years, likely reflected the younger military population served at Eglin AFB. Seventy-five of these patients were currently on active duty, 6 were retired from active duty (veterans), and 19 were dependents. The median time of symptoms to diagnosis was 2 years. Prior misdiagnosis with other diseases such as asthma was common. Also, referral to Pulmonology and Speech Therapy was usually completed after failed outpatient primary care management for the alternative diagnoses.

Improvement with therapy was mixed, and during the time of documented follow-up, 72 patients reported complete or partial improvement. Most active-duty patients in the partial improvement category based this subjective reporting on their ability to meet military physical fitness standards.

Previous data suggested a female predominance, but this study population was 61% male. Military populations are about 80% to 85% male, so an increase in male diagnosis is expected.

Many patients in the patient cohort arrived as a result of Pulmonology referrals with a presumptive diagnoses of asthma but were determined not to have asthma through PFT results inconsistent with asthma, no improvement with β-agonist therapies, and negative methacholine challenges (if performed). These results prompted evaluations for other conditions and eventually a VCD diagnosis. As noted, exclusion of asthma is of particular importance in a military population, as medical discharges often are pursued in service members with asthma whether controlled or uncontrolled. Lag time to referral also is possible in failures of military physical, which prompted medical evaluation once several failures had occurred over a 1- to 2-year time frame.

The PFT data evaluation was inconclusive for statistically significant changes when compared with age-matched normal PFT values. This also was noted in previous studies of VCD cases. Most notable was percent predicted values of FEF 25% to 75%, with 84% of expected values. The FEV₁, FVC, and PEF all fell within predicted values of normal, despite wide ranges in age, sex, and ethnicity among the subjects. Inspiratory flattening consistent with extrathoracic obstruction was present in 58 of the 97 PFTs available for review at Eglin AFB.

Limitations

Limitations to this retrospective case series are illustrated here. Cases were found only when VCD was diagnosed and coded; and it is the authors’ suspicion that many have been misdiagnosed or improperly treated for asthma or other pulmonary/oropharynx conditions. If providers are not familiar with VCD or if PFT readings do not comment on inspiratory findings, diagnosis is less likely. Some of the authors’ colleagues already have determined that postdeployment prevalence of VCD seems to be elevated.⁸

This cohort was completed on all patients in a military treatment facility, with 75 active-duty personnel, 6 veterans, and 19 dependents of varying ages. This case series is retrospective and tabulates suspected risk factors; stronger and more informative studies could certainly be completed in prospective studies (although likely difficult with low prevalence) or in treatment comparison studies at the time of diagnosis.

Since the cohort had varied and lengthy time to diagnosis from onset of related symptoms, the treatment patients received prior to diagnosis differed extensively. Diagnosis was completed by numerous primary care managers or other subspecialties prior to arrival to Pulmonology and Speech Therapy at Eglin AFB. Once diagnosed in Speech Therapy, consistent treatment options were provided to patients in accordance with standard of care.

It is the authors’ suspicion that VCD may have a higher prevalence than previously reported in the literature. Military service members are tested annually or biannually on physical fitness standards and are evaluated for medical reasons for recurrent fitness standard failures. This selection of patients is more likely to have a VCD evaluation as part of a comprehensive evaluation than is a healthy adult in a civilian population. A prospective study in military service members would be more fruitful and possibly yield a higher prevalence postdeployment.

Conclusion

Vocal cord dysfunction remains a difficult diagnosis to treat, because multiple comorbidities likely contribute to the diagnosis. This retrospective case series attempted to compile common themes and noted that most of the patients had 2 or more risk factors of smoking, allergic rhinitis, GERD, or mental health diagnoses. A prospective trial would be ideal to evaluate VCD further. A focused trial in the particular communities of athletes or of military service members may be of increased benefit to better define VCD. It is notable that 100 cases were found in a relatively short period for a community hospital, and prevalence may be higher than previously reported.

Vocal cord dysfunction (VCD), also known as paradoxical vocal cord movement, is described as paroxysms of glottis obstruction due to true vocal cord adduction.¹ Since VCD presents as a constellation of symptoms associated with dyspnea, it often is misdiagnosed as asthma.² Vocal cord dysfunction often manifests as episodic dyspnea and wheezing, may occur with exercise, and may be minimally responsive to initial therapies. Flattened inspiratory curves may be noted on pulmonary function tests (PFTs), but direct laryngoscopy is the gold standard for diagnosis.³ A cohort of proven patients with VCD with a plateau in the inspiratory curve of PFTs also had a plateau on expiratory phase in 81% of cases.⁴

The differential diagnosis of patients presenting with upper airway symptoms is broad. It must include VCD, asthma, angioedema, laryngomalacia, vocal cord polyps, vocal cord tumors, and neurologic conditions such as brain stem compression or movement disorders. Essentially, all movement disorders of vocal cords must be considered, and organic causes of this movement disorder can be evaluated by visualization of the vocal cords. Triggers for VCD include exercise, airborne irritants, gastroesophageal reflux disease (GERD), allergic rhinitis, medications, and psychological conditions.⁵ Additionally, VCD can coexist with asthma, further complicating accurate diagnoses.⁶

Therapies are reported in case studies, but no large randomized controlled trials exist to evaluate current therapy options. Primary treatments of asthma therapy were largely ineffective, and ideal therapy includes a multidisciplinary approach, including speech therapy to optimize laryngeal control and treatment of all identified laryngeal irritants.⁶

The prevalence of VCD is unknown, with no prospective cohort studies completed to date and conflicting diagnostic criteria used in many case studies.⁷ A prevalence of 2.8% was noted in one particular cohort of 1,028 patients admitted to a rehabilitation center in a calendar year with the primary pulmonary diagnosis on admission.⁶ Females seemed to be affected at a higher ratio than were males, 2 to 3 females per 1 male diagnosis.⁷

In the military population, certain risk factors were noted in returning deployed members, including anxiety/high stress, exercise, and acute respiratory illnesses.⁸ In that particular cohort, 72% positive predictive value was noted for VCD if flattened inspiratory flow loops with negative methacholine challenge were present.

Diagnostic criteria are challenging, as symptoms such as dyspnea may be present acutely, last < 2 minutes, be self-limiting, and completely resolve outside of acute events. Stridor may be noted, primarily above the vocal cords, and less audible on chest auscultation.⁶ A goal of therapy, in addition to dedicated speech pathologist input, is optimizing comedical conditions, including GERD, allergic rhinitis, concomitant asthma, and any psychological diagnoses.⁹

Athletes are a particular subset of patients with VCD who are crucial to appropriately diagnose, including a detailed history and physical, PFTs, and proceeding to direct laryngoscopy to confirm diagnoses.¹⁰ Behavioral management includes rescue breathing techniques, and speech therapy programs focus on relaxation of the larynx and diaphragmatic breathing techniques, with the goal of establishing sense of control during acute events.¹⁰ Military service members are expected to operate at a high-intensity level similar to that of athletes, and treatments considered for athletes are applicable to military service members as well. Military strength and cardiovascular standards are measured by a combination of push-ups, sit-ups, and a run test, in addition to waist measurements. Some of the cohort were identified during physical fitness standard failures, usually in the run test, and ultimately received a pulmonology referral for wheezing or dyspnea with exertion. The objective of this retrospective cohort study was to evaluate 100 consecutively diagnosed cases of VCD in a military treatment facility.

Methods

The authors conducted a retrospective chart review of DoD military medical records of outpatient diagnoses in 100 consecutive diagnoses of VCD from January 2011 to February 2014. Institutional review board approval was obtained under Project RSM20130001E by the Exempt Determination Official at Eglin Air Force Base (AFB), Florida.

All cases were identified at time of VCD visualization and were diagnosed with video stroboscopy by speech therapy or by visual laryngoscopy by the otolaryngology or pulmonology departments via direct visualization.

Cases were collected chronologically, and all diagnosed cases at Eglin AFB hospital were included. Follow-up was scheduled with all patients diagnosed in Speech Therapy, and most patients were concurrently treated by Pulmonology or Allergy/Immunology. Pulmonary function tests were obtained in 98 of the 100 diagnosed cases. Patients eligible for care at Eglin AFB included active-duty and Reserve military members plus dependents and retirees.

The majority of patients diagnosed in this cohort were seen and diagnosed by Speech Therapy. Video stroboscopy is based on the principle that a movement of an object higher than a certain flicker rate appears to stand still to direct visualization, but with a rate of light exposure and imaging above the flicker rate by video, the true movement of the object can be identified.¹¹ Video stroboscopy is considered highly sensitive for organic disorders of vocal cords, but it is not specific for either organic or dysfunctional disorders.¹¹ It is still the gold standard above direct visualization, as it can detect abnormal movement of vocal cords above the critical rate that the human eye would perceive as not moving due to the frequency of movement (Figures 1 & 2).¹¹

In an older study, laryngoscopy was able to diagnose 100% of patients with symptomatic paradoxical vocal cord movement and additional 60% asymptomatic patients with a constellation of symptoms consistent with paradoxical vocal cord movement.¹²

Speech Therapy; Ear, Nose, and Throat (ENT); and Pulmonology may not perform direct visualization in these patients at initial presentation due to other suspected diagnoses. A more common test is the PFT, especially if asthma or other airway tract diseases are suspected (Figure 3).

Patient Descriptions

Study patients were referred for a variety of reasons, often from primary care clinics for concerns for asthma, episodic dyspnea, wheezing, or decreased exercise tolerance thought to be related to pulmonary or allergy causes. Pulmonology worked closely with Speech Therapy and referred VCD cases for speech evaluation, including video stroboscopy. Notably, of the patients in this cohort, although some were suspected to have asthma, those patients were ruled out during part of the pulmonology evaluation, both with PFT testing and methacholine challenges. An asthma diagnosis is important in a military treatment facility, as asthma is often grounds for discharge.

Patients ranged in age from 13 to 68 years, with a median age at 31 years diagnosis. Thirty-nine females and 61 males comprised the total case series. Speech Therapy diagnosed 97 patients, 96 were diagnosed at Eglin AFB hospital via stroboscopy. One patient was diagnosed off-base by Speech Therapy via direct visualization, 1 patient was diagnosed by Pulmonology on-base via direct visualization, and 2 patients were diagnosed by ENT on-base via direct visualization. These patients had direct laryngoscopy completed, often to rule out other organic causes for upper airway disease processes, and were found to have visual paradoxical vocal cord movement. Ninety-eight patients completed PFTs. Several patients were lost to follow-up, as can be common in a military population with frequent moves or members leaving service.

On record review, patient symptoms were present in the range of 2 months to 20 years, with a median duration of symptomatic reports lasting 2 years prior to diagnosis. Common diagnoses prior to visual VCD diagnosis included asthma, exercise-induced asthma, anxiety, and episodic wheezing. Risk factors that were evaluated in this case series included age, sex, body mass index (BMI), GERD, allergic rhinitis, postnasal drip, active smoker, previous smoker, and mental health diagnoses (Figure 4).

Pulmonary function test results were analyzed on 98 patients, including forced expiratory volume in 1 second (FEV₁); forced vital capacity (FVC), FEV₁/FVC ratio; peak inspiratory flow (PIF) and peak expiratory flow (PEF)—available in 97 studies; forced expiratory flow (FEF) at 25% to 75% of FVC (FEF 25%-75%)—available in 96 studies; and maximum voluntary ventilation (MVV) and MVV/FEV₁ ratio—available in 60 of 98 PFTs.

Interventions

All patients diagnosed by Speech Therapy on-base were provided with laryngeal relaxation techniques, diaphragmatic breathing techniques, and controlled inhale/exhale techniques at time of diagnosis, with frequent follow-up scheduled with Speech Therapy and Pulmonology. All diagnoses potentially contributing to laryngeal irritation were treated, including GERD, allergic rhinitis, smoking cessation, weight loss, and exercise recommendations as needed.

Patients reported improvement on follow-up appointments with Speech Therapy in overall control of symptoms, subjectively categorized as poor improvement, partial improvement, and complete improvement. This was a subjective measurement of improvement and fully dependent on follow-up care and patient reporting for improvement. No predefined number of follow-ups was determined; patients were followed monthly until they declined further care, fully improved, moved out of the military treatment system, or were lost to follow-up.

Treatment included structured Speech Therapy sessions. Response to treatment was subjectively qualified by patient report. Fifteen patients reported complete resolution of symptoms, 57 reported partial improvement, 24 reported poor improvement, and 4 patients were lost to follow-up.

Results

Risk factors for the diagnosis of VCD included possible associations with GERD, allergic rhinitis, smoking, prior smoking, BMI, and mental health diagnoses. Body mass index ranged from 17 to 36 in the case series, with median BMI of 27. Mental health diagnoses were present in 35 patients and included diagnoses of anxiety, depression, and adjustment disorders. Gastroesophageal reflux disease diagnosis was present in 59 of the case series patients, 80 had the diagnosis of allergic rhinitis, 63 were diagnosed with postnasal drip. Sixteen case series patients were current smokers. An additional 26 were previous smokers (at least 100 cigarettes in lifetime) for a total of 42 patients that were current or prior smokers.

The chart review was completed to evaluate for the presence of these diagnoses, which included previous treatments; for example, proton pump inhibitors for GERD, antidepressants for depression, or intranasal steroids for allergic rhinitis. The diagnosis was counted as present if the patient was currently being treated for the particular diagnosis in question.

PFT Data

Data from PFTs were available for 98 of 100 cases diagnosed. Review of data across all 98 patients is noted for median FEV₁ of 3.6, a median FVC of 4.5, with ratio of 0.80.

Since PFT values vary according to age, sex, and ethnicity, PFTs were analyzed for percent predicted values based on age, gender, and race. Notably, median values for FEV₁, FVC, and PEF were all close to 100% of the predicted value. The MVV percent predicted was available in 60 cases and was 93% of predicted values. The most significant difference from expected values was FEF 25% to 75%, at 84% of expected results.

Flow-volume loop evaluations on the 97 PFTs available were completed, and 58 of the 97 were noted for variable extrathoracic airway obstruction consistent with inspiratory inhibition in the patient population. This is 60% of the available PFTs in this cohort study.

Discussion

This retrospective chart review of 100 consecutive VCD diagnoses in a military treatment facility reinforces many of the findings currently available in the literature. As illustrated in a Chest review article, the diagnosis of VCD on history, physical examination, or PFTs remains ellusive.¹ The PFT evaluation contains some subjectivity regarding the flattening of inspiratory flow-volume loops and is not routinely reported in PFT results. In patients diagnosed with VCD, a clear consensus of treatment modalities remains lacking. Modification of risk factors (allergic rhinitis, GERD, smoking cessation, weight loss) assisted in self-reported patient improvement, as did focused speech therapy.

The median age of 31 years, likely reflected the younger military population served at Eglin AFB. Seventy-five of these patients were currently on active duty, 6 were retired from active duty (veterans), and 19 were dependents. The median time of symptoms to diagnosis was 2 years. Prior misdiagnosis with other diseases such as asthma was common. Also, referral to Pulmonology and Speech Therapy was usually completed after failed outpatient primary care management for the alternative diagnoses.

Improvement with therapy was mixed, and during the time of documented follow-up, 72 patients reported complete or partial improvement. Most active-duty patients in the partial improvement category based this subjective reporting on their ability to meet military physical fitness standards.

Previous data suggested a female predominance, but this study population was 61% male. Military populations are about 80% to 85% male, so an increase in male diagnosis is expected.

Many patients in the patient cohort arrived as a result of Pulmonology referrals with a presumptive diagnoses of asthma but were determined not to have asthma through PFT results inconsistent with asthma, no improvement with β-agonist therapies, and negative methacholine challenges (if performed). These results prompted evaluations for other conditions and eventually a VCD diagnosis. As noted, exclusion of asthma is of particular importance in a military population, as medical discharges often are pursued in service members with asthma whether controlled or uncontrolled. Lag time to referral also is possible in failures of military physical, which prompted medical evaluation once several failures had occurred over a 1- to 2-year time frame.

The PFT data evaluation was inconclusive for statistically significant changes when compared with age-matched normal PFT values. This also was noted in previous studies of VCD cases. Most notable was percent predicted values of FEF 25% to 75%, with 84% of expected values. The FEV₁, FVC, and PEF all fell within predicted values of normal, despite wide ranges in age, sex, and ethnicity among the subjects. Inspiratory flattening consistent with extrathoracic obstruction was present in 58 of the 97 PFTs available for review at Eglin AFB.

Limitations

Limitations to this retrospective case series are illustrated here. Cases were found only when VCD was diagnosed and coded; and it is the authors’ suspicion that many have been misdiagnosed or improperly treated for asthma or other pulmonary/oropharynx conditions. If providers are not familiar with VCD or if PFT readings do not comment on inspiratory findings, diagnosis is less likely. Some of the authors’ colleagues already have determined that postdeployment prevalence of VCD seems to be elevated.⁸

This cohort was completed on all patients in a military treatment facility, with 75 active-duty personnel, 6 veterans, and 19 dependents of varying ages. This case series is retrospective and tabulates suspected risk factors; stronger and more informative studies could certainly be completed in prospective studies (although likely difficult with low prevalence) or in treatment comparison studies at the time of diagnosis.

Since the cohort had varied and lengthy time to diagnosis from onset of related symptoms, the treatment patients received prior to diagnosis differed extensively. Diagnosis was completed by numerous primary care managers or other subspecialties prior to arrival to Pulmonology and Speech Therapy at Eglin AFB. Once diagnosed in Speech Therapy, consistent treatment options were provided to patients in accordance with standard of care.

It is the authors’ suspicion that VCD may have a higher prevalence than previously reported in the literature. Military service members are tested annually or biannually on physical fitness standards and are evaluated for medical reasons for recurrent fitness standard failures. This selection of patients is more likely to have a VCD evaluation as part of a comprehensive evaluation than is a healthy adult in a civilian population. A prospective study in military service members would be more fruitful and possibly yield a higher prevalence postdeployment.

Conclusion

Vocal cord dysfunction remains a difficult diagnosis to treat, because multiple comorbidities likely contribute to the diagnosis. This retrospective case series attempted to compile common themes and noted that most of the patients had 2 or more risk factors of smoking, allergic rhinitis, GERD, or mental health diagnoses. A prospective trial would be ideal to evaluate VCD further. A focused trial in the particular communities of athletes or of military service members may be of increased benefit to better define VCD. It is notable that 100 cases were found in a relatively short period for a community hospital, and prevalence may be higher than previously reported.

Vocal cord dysfunction (VCD), also known as paradoxical vocal cord movement, is described as paroxysms of glottis obstruction due to true vocal cord adduction.¹ Since VCD presents as a constellation of symptoms associated with dyspnea, it often is misdiagnosed as asthma.² Vocal cord dysfunction often manifests as episodic dyspnea and wheezing, may occur with exercise, and may be minimally responsive to initial therapies. Flattened inspiratory curves may be noted on pulmonary function tests (PFTs), but direct laryngoscopy is the gold standard for diagnosis.³ A cohort of proven patients with VCD with a plateau in the inspiratory curve of PFTs also had a plateau on expiratory phase in 81% of cases.⁴

The differential diagnosis of patients presenting with upper airway symptoms is broad. It must include VCD, asthma, angioedema, laryngomalacia, vocal cord polyps, vocal cord tumors, and neurologic conditions such as brain stem compression or movement disorders. Essentially, all movement disorders of vocal cords must be considered, and organic causes of this movement disorder can be evaluated by visualization of the vocal cords. Triggers for VCD include exercise, airborne irritants, gastroesophageal reflux disease (GERD), allergic rhinitis, medications, and psychological conditions.⁵ Additionally, VCD can coexist with asthma, further complicating accurate diagnoses.⁶

Therapies are reported in case studies, but no large randomized controlled trials exist to evaluate current therapy options. Primary treatments of asthma therapy were largely ineffective, and ideal therapy includes a multidisciplinary approach, including speech therapy to optimize laryngeal control and treatment of all identified laryngeal irritants.⁶

The prevalence of VCD is unknown, with no prospective cohort studies completed to date and conflicting diagnostic criteria used in many case studies.⁷ A prevalence of 2.8% was noted in one particular cohort of 1,028 patients admitted to a rehabilitation center in a calendar year with the primary pulmonary diagnosis on admission.⁶ Females seemed to be affected at a higher ratio than were males, 2 to 3 females per 1 male diagnosis.⁷

In the military population, certain risk factors were noted in returning deployed members, including anxiety/high stress, exercise, and acute respiratory illnesses.⁸ In that particular cohort, 72% positive predictive value was noted for VCD if flattened inspiratory flow loops with negative methacholine challenge were present.

Diagnostic criteria are challenging, as symptoms such as dyspnea may be present acutely, last < 2 minutes, be self-limiting, and completely resolve outside of acute events. Stridor may be noted, primarily above the vocal cords, and less audible on chest auscultation.⁶ A goal of therapy, in addition to dedicated speech pathologist input, is optimizing comedical conditions, including GERD, allergic rhinitis, concomitant asthma, and any psychological diagnoses.⁹

Athletes are a particular subset of patients with VCD who are crucial to appropriately diagnose, including a detailed history and physical, PFTs, and proceeding to direct laryngoscopy to confirm diagnoses.¹⁰ Behavioral management includes rescue breathing techniques, and speech therapy programs focus on relaxation of the larynx and diaphragmatic breathing techniques, with the goal of establishing sense of control during acute events.¹⁰ Military service members are expected to operate at a high-intensity level similar to that of athletes, and treatments considered for athletes are applicable to military service members as well. Military strength and cardiovascular standards are measured by a combination of push-ups, sit-ups, and a run test, in addition to waist measurements. Some of the cohort were identified during physical fitness standard failures, usually in the run test, and ultimately received a pulmonology referral for wheezing or dyspnea with exertion. The objective of this retrospective cohort study was to evaluate 100 consecutively diagnosed cases of VCD in a military treatment facility.

Methods

The authors conducted a retrospective chart review of DoD military medical records of outpatient diagnoses in 100 consecutive diagnoses of VCD from January 2011 to February 2014. Institutional review board approval was obtained under Project RSM20130001E by the Exempt Determination Official at Eglin Air Force Base (AFB), Florida.

All cases were identified at time of VCD visualization and were diagnosed with video stroboscopy by speech therapy or by visual laryngoscopy by the otolaryngology or pulmonology departments via direct visualization.

Cases were collected chronologically, and all diagnosed cases at Eglin AFB hospital were included. Follow-up was scheduled with all patients diagnosed in Speech Therapy, and most patients were concurrently treated by Pulmonology or Allergy/Immunology. Pulmonary function tests were obtained in 98 of the 100 diagnosed cases. Patients eligible for care at Eglin AFB included active-duty and Reserve military members plus dependents and retirees.

The majority of patients diagnosed in this cohort were seen and diagnosed by Speech Therapy. Video stroboscopy is based on the principle that a movement of an object higher than a certain flicker rate appears to stand still to direct visualization, but with a rate of light exposure and imaging above the flicker rate by video, the true movement of the object can be identified.¹¹ Video stroboscopy is considered highly sensitive for organic disorders of vocal cords, but it is not specific for either organic or dysfunctional disorders.¹¹ It is still the gold standard above direct visualization, as it can detect abnormal movement of vocal cords above the critical rate that the human eye would perceive as not moving due to the frequency of movement (Figures 1 & 2).¹¹

In an older study, laryngoscopy was able to diagnose 100% of patients with symptomatic paradoxical vocal cord movement and additional 60% asymptomatic patients with a constellation of symptoms consistent with paradoxical vocal cord movement.¹²

Speech Therapy; Ear, Nose, and Throat (ENT); and Pulmonology may not perform direct visualization in these patients at initial presentation due to other suspected diagnoses. A more common test is the PFT, especially if asthma or other airway tract diseases are suspected (Figure 3).

Patient Descriptions

Study patients were referred for a variety of reasons, often from primary care clinics for concerns for asthma, episodic dyspnea, wheezing, or decreased exercise tolerance thought to be related to pulmonary or allergy causes. Pulmonology worked closely with Speech Therapy and referred VCD cases for speech evaluation, including video stroboscopy. Notably, of the patients in this cohort, although some were suspected to have asthma, those patients were ruled out during part of the pulmonology evaluation, both with PFT testing and methacholine challenges. An asthma diagnosis is important in a military treatment facility, as asthma is often grounds for discharge.

Patients ranged in age from 13 to 68 years, with a median age at 31 years diagnosis. Thirty-nine females and 61 males comprised the total case series. Speech Therapy diagnosed 97 patients, 96 were diagnosed at Eglin AFB hospital via stroboscopy. One patient was diagnosed off-base by Speech Therapy via direct visualization, 1 patient was diagnosed by Pulmonology on-base via direct visualization, and 2 patients were diagnosed by ENT on-base via direct visualization. These patients had direct laryngoscopy completed, often to rule out other organic causes for upper airway disease processes, and were found to have visual paradoxical vocal cord movement. Ninety-eight patients completed PFTs. Several patients were lost to follow-up, as can be common in a military population with frequent moves or members leaving service.

On record review, patient symptoms were present in the range of 2 months to 20 years, with a median duration of symptomatic reports lasting 2 years prior to diagnosis. Common diagnoses prior to visual VCD diagnosis included asthma, exercise-induced asthma, anxiety, and episodic wheezing. Risk factors that were evaluated in this case series included age, sex, body mass index (BMI), GERD, allergic rhinitis, postnasal drip, active smoker, previous smoker, and mental health diagnoses (Figure 4).

Pulmonary function test results were analyzed on 98 patients, including forced expiratory volume in 1 second (FEV₁); forced vital capacity (FVC), FEV₁/FVC ratio; peak inspiratory flow (PIF) and peak expiratory flow (PEF)—available in 97 studies; forced expiratory flow (FEF) at 25% to 75% of FVC (FEF 25%-75%)—available in 96 studies; and maximum voluntary ventilation (MVV) and MVV/FEV₁ ratio—available in 60 of 98 PFTs.

Interventions

All patients diagnosed by Speech Therapy on-base were provided with laryngeal relaxation techniques, diaphragmatic breathing techniques, and controlled inhale/exhale techniques at time of diagnosis, with frequent follow-up scheduled with Speech Therapy and Pulmonology. All diagnoses potentially contributing to laryngeal irritation were treated, including GERD, allergic rhinitis, smoking cessation, weight loss, and exercise recommendations as needed.

Patients reported improvement on follow-up appointments with Speech Therapy in overall control of symptoms, subjectively categorized as poor improvement, partial improvement, and complete improvement. This was a subjective measurement of improvement and fully dependent on follow-up care and patient reporting for improvement. No predefined number of follow-ups was determined; patients were followed monthly until they declined further care, fully improved, moved out of the military treatment system, or were lost to follow-up.

Treatment included structured Speech Therapy sessions. Response to treatment was subjectively qualified by patient report. Fifteen patients reported complete resolution of symptoms, 57 reported partial improvement, 24 reported poor improvement, and 4 patients were lost to follow-up.

Results

Risk factors for the diagnosis of VCD included possible associations with GERD, allergic rhinitis, smoking, prior smoking, BMI, and mental health diagnoses. Body mass index ranged from 17 to 36 in the case series, with median BMI of 27. Mental health diagnoses were present in 35 patients and included diagnoses of anxiety, depression, and adjustment disorders. Gastroesophageal reflux disease diagnosis was present in 59 of the case series patients, 80 had the diagnosis of allergic rhinitis, 63 were diagnosed with postnasal drip. Sixteen case series patients were current smokers. An additional 26 were previous smokers (at least 100 cigarettes in lifetime) for a total of 42 patients that were current or prior smokers.

The chart review was completed to evaluate for the presence of these diagnoses, which included previous treatments; for example, proton pump inhibitors for GERD, antidepressants for depression, or intranasal steroids for allergic rhinitis. The diagnosis was counted as present if the patient was currently being treated for the particular diagnosis in question.

PFT Data

Data from PFTs were available for 98 of 100 cases diagnosed. Review of data across all 98 patients is noted for median FEV₁ of 3.6, a median FVC of 4.5, with ratio of 0.80.

Since PFT values vary according to age, sex, and ethnicity, PFTs were analyzed for percent predicted values based on age, gender, and race. Notably, median values for FEV₁, FVC, and PEF were all close to 100% of the predicted value. The MVV percent predicted was available in 60 cases and was 93% of predicted values. The most significant difference from expected values was FEF 25% to 75%, at 84% of expected results.

Flow-volume loop evaluations on the 97 PFTs available were completed, and 58 of the 97 were noted for variable extrathoracic airway obstruction consistent with inspiratory inhibition in the patient population. This is 60% of the available PFTs in this cohort study.

Discussion

This retrospective chart review of 100 consecutive VCD diagnoses in a military treatment facility reinforces many of the findings currently available in the literature. As illustrated in a Chest review article, the diagnosis of VCD on history, physical examination, or PFTs remains ellusive.¹ The PFT evaluation contains some subjectivity regarding the flattening of inspiratory flow-volume loops and is not routinely reported in PFT results. In patients diagnosed with VCD, a clear consensus of treatment modalities remains lacking. Modification of risk factors (allergic rhinitis, GERD, smoking cessation, weight loss) assisted in self-reported patient improvement, as did focused speech therapy.

The median age of 31 years, likely reflected the younger military population served at Eglin AFB. Seventy-five of these patients were currently on active duty, 6 were retired from active duty (veterans), and 19 were dependents. The median time of symptoms to diagnosis was 2 years. Prior misdiagnosis with other diseases such as asthma was common. Also, referral to Pulmonology and Speech Therapy was usually completed after failed outpatient primary care management for the alternative diagnoses.

Improvement with therapy was mixed, and during the time of documented follow-up, 72 patients reported complete or partial improvement. Most active-duty patients in the partial improvement category based this subjective reporting on their ability to meet military physical fitness standards.

Previous data suggested a female predominance, but this study population was 61% male. Military populations are about 80% to 85% male, so an increase in male diagnosis is expected.

Many patients in the patient cohort arrived as a result of Pulmonology referrals with a presumptive diagnoses of asthma but were determined not to have asthma through PFT results inconsistent with asthma, no improvement with β-agonist therapies, and negative methacholine challenges (if performed). These results prompted evaluations for other conditions and eventually a VCD diagnosis. As noted, exclusion of asthma is of particular importance in a military population, as medical discharges often are pursued in service members with asthma whether controlled or uncontrolled. Lag time to referral also is possible in failures of military physical, which prompted medical evaluation once several failures had occurred over a 1- to 2-year time frame.

The PFT data evaluation was inconclusive for statistically significant changes when compared with age-matched normal PFT values. This also was noted in previous studies of VCD cases. Most notable was percent predicted values of FEF 25% to 75%, with 84% of expected values. The FEV₁, FVC, and PEF all fell within predicted values of normal, despite wide ranges in age, sex, and ethnicity among the subjects. Inspiratory flattening consistent with extrathoracic obstruction was present in 58 of the 97 PFTs available for review at Eglin AFB.

Limitations

Limitations to this retrospective case series are illustrated here. Cases were found only when VCD was diagnosed and coded; and it is the authors’ suspicion that many have been misdiagnosed or improperly treated for asthma or other pulmonary/oropharynx conditions. If providers are not familiar with VCD or if PFT readings do not comment on inspiratory findings, diagnosis is less likely. Some of the authors’ colleagues already have determined that postdeployment prevalence of VCD seems to be elevated.⁸

This cohort was completed on all patients in a military treatment facility, with 75 active-duty personnel, 6 veterans, and 19 dependents of varying ages. This case series is retrospective and tabulates suspected risk factors; stronger and more informative studies could certainly be completed in prospective studies (although likely difficult with low prevalence) or in treatment comparison studies at the time of diagnosis.

Since the cohort had varied and lengthy time to diagnosis from onset of related symptoms, the treatment patients received prior to diagnosis differed extensively. Diagnosis was completed by numerous primary care managers or other subspecialties prior to arrival to Pulmonology and Speech Therapy at Eglin AFB. Once diagnosed in Speech Therapy, consistent treatment options were provided to patients in accordance with standard of care.

It is the authors’ suspicion that VCD may have a higher prevalence than previously reported in the literature. Military service members are tested annually or biannually on physical fitness standards and are evaluated for medical reasons for recurrent fitness standard failures. This selection of patients is more likely to have a VCD evaluation as part of a comprehensive evaluation than is a healthy adult in a civilian population. A prospective study in military service members would be more fruitful and possibly yield a higher prevalence postdeployment.

Conclusion

Vocal cord dysfunction remains a difficult diagnosis to treat, because multiple comorbidities likely contribute to the diagnosis. This retrospective case series attempted to compile common themes and noted that most of the patients had 2 or more risk factors of smoking, allergic rhinitis, GERD, or mental health diagnoses. A prospective trial would be ideal to evaluate VCD further. A focused trial in the particular communities of athletes or of military service members may be of increased benefit to better define VCD. It is notable that 100 cases were found in a relatively short period for a community hospital, and prevalence may be higher than previously reported.

Photo by Rhoda Baer

A new study suggests Hodgkin lymphoma (HL) survivors have a high risk of developing a second malignancy, particularly if they have a family history of that malignancy.

The research showed that HL survivors in Sweden were roughly 2.4 times more likely than individuals in the country’s general population to develop a second cancer.

The risk for HL survivors remained high 30 years after treatment, and the risk was even greater in HL survivors who had a family history of specific cancers.

“The vast majority of patients with Hodgkin lymphoma are cured with a combination of chemotherapy and radiotherapy,” said study author Amit Sud, MBChB, of The Institute of Cancer Research, London in the UK.

“Our research has shown that these patients are at substantially increased risk of a second cancer later in life and particularly if they have a family history of cancer.”

Dr Sud and his colleagues described this research in the Journal of Clinical Oncology.

The team analyzed data from the Swedish Family-Cancer Project Database. They identified 9522 HL patients diagnosed between 1965 and 2013. During a median follow-up of 12.6 years, there were 1215 second cancers in 1121 HL patients (12%).

Compared to the general population, the HL patients had a significantly higher risk of all second malignancies, with a standardized incident ratio (SIR) of 2.39 and an absolute excess risk of 71.2 cases per 10,000 person-years.

Cancer types

HL patients had a significantly increased risk of several malignancies. The overall SIRs were as follows:

• NHL—7.99
• Leukemia—6.46
• Connective tissue cancer—5.73
• Thyroid cancer—5.13
• Squamous cell carcinoma—4.44
• Lung cancer—3.61
• Pharyngeal cancer—3.52
• Esophageal cancer—2.62
• Brain cancer—2.58
• Breast cancer—2.52
• Colon cancer—2.21
• Pancreatic cancer—2.09
• Melanoma—2.08
• Colorectal cancer—1.85
• Stomach cancer—1.78
• Bladder cancer—1.57
• Prostate cancer—1.21.

The researchers calculated SIRs over time and found the risk for many of the cancers remained high over 30 years following HL treatment.

Family history

The researchers identified 28,277 first-degree relatives of the HL survivors. Thirty percent of HL survivors (n=2785) had 1 or more first-degree relatives with a family history of cancer.

The SIR for cancers was 1.02 in the relatives. The SIR for second cancers was 2.83 for HL survivors who had first-degree relatives with cancer and 2.16 for HL survivors who did not have any first-degree relatives with cancer.

The researchers said the increased risk of second malignancy was correlated with the number of first-degree relatives with cancer.

The SIR was 2.67 for HL patients who had a single first-degree relative with cancer and 3.40 for HL patients who had 2 or more first-degree relatives with cancer.

The SIRs for different cancer types (for HL patients with at least 1 first-degree relative with cancer and no first-degree relatives with cancer, respectively) were as follows:

• NHL—14.43 vs 7.83
• Leukemia—14.31 vs 6.37
• Squamous cell carcinoma—10.85 vs 4.30
• Lung cancer—11.24 vs 3.39
• Breast cancer—4.36 vs 2.36
• Colorectal cancer—3.71 vs 1.76.

Sex and age

The researchers found significant differences in the SIRs for second cancers between HL patients diagnosed before the age of 35 and those diagnosed after age 35.

For men, the SIRs were:

• All cancers—4.26 for <35, 2.08 for ≥ 35
• Colorectal cancer—4.07 for < 35, 1.73 for ≥35
• Lung cancer—6.16 for < 35, 3.20 for ≥35
• Breast cancer—12.60 for < 35, 4.58 for ≥35
• Squamous cell carcinoma—5.89 for < 35, 3.96 for ≥35
• NHL—15.9 for < 35, 6.93 for ≥35
• Leukemia—12.15 for < 35, 5.57 for ≥35.

For women, the SIRs were:

• All cancers—4.61 for <35, 1.73 for ≥ 35
• Colorectal cancer—1.31 for < 35, 1.65 for ≥35
• Lung cancer—8.84 for < 35, 2.50 for ≥35
• Breast cancer—6.00 for < 35, 1.14 for ≥35
• Squamous cell carcinoma—6.37 for < 35, 4.87 for ≥35
• NHL—6.23 for < 35, 6.55 for ≥35
• Leukemia—10.36 for < 35, 4.51 for ≥35.

“Younger women who have been treated with radiotherapy to the chest for Hodgkin lymphoma are already screened for breast cancer, but our study suggests that we should be looking at ways of monitoring survivors for other forms of cancer too, and potentially offering preventative interventions,” Dr Sud said.

“After patients are cured, they no longer encounter oncologists, so it’s important that other healthcare providers are aware of the increased risk to Hodgkin lymphoma survivors to improve early diagnosis of second cancers.”

Photo by Rhoda Baer

A new study suggests Hodgkin lymphoma (HL) survivors have a high risk of developing a second malignancy, particularly if they have a family history of that malignancy.

The research showed that HL survivors in Sweden were roughly 2.4 times more likely than individuals in the country’s general population to develop a second cancer.

The risk for HL survivors remained high 30 years after treatment, and the risk was even greater in HL survivors who had a family history of specific cancers.

“The vast majority of patients with Hodgkin lymphoma are cured with a combination of chemotherapy and radiotherapy,” said study author Amit Sud, MBChB, of The Institute of Cancer Research, London in the UK.

“Our research has shown that these patients are at substantially increased risk of a second cancer later in life and particularly if they have a family history of cancer.”

Dr Sud and his colleagues described this research in the Journal of Clinical Oncology.

The team analyzed data from the Swedish Family-Cancer Project Database. They identified 9522 HL patients diagnosed between 1965 and 2013. During a median follow-up of 12.6 years, there were 1215 second cancers in 1121 HL patients (12%).

Compared to the general population, the HL patients had a significantly higher risk of all second malignancies, with a standardized incident ratio (SIR) of 2.39 and an absolute excess risk of 71.2 cases per 10,000 person-years.

Cancer types

HL patients had a significantly increased risk of several malignancies. The overall SIRs were as follows:

• NHL—7.99
• Leukemia—6.46
• Connective tissue cancer—5.73
• Thyroid cancer—5.13
• Squamous cell carcinoma—4.44
• Lung cancer—3.61
• Pharyngeal cancer—3.52
• Esophageal cancer—2.62
• Brain cancer—2.58
• Breast cancer—2.52
• Colon cancer—2.21
• Pancreatic cancer—2.09
• Melanoma—2.08
• Colorectal cancer—1.85
• Stomach cancer—1.78
• Bladder cancer—1.57
• Prostate cancer—1.21.

The researchers calculated SIRs over time and found the risk for many of the cancers remained high over 30 years following HL treatment.

Family history

The researchers identified 28,277 first-degree relatives of the HL survivors. Thirty percent of HL survivors (n=2785) had 1 or more first-degree relatives with a family history of cancer.

The SIR for cancers was 1.02 in the relatives. The SIR for second cancers was 2.83 for HL survivors who had first-degree relatives with cancer and 2.16 for HL survivors who did not have any first-degree relatives with cancer.

The researchers said the increased risk of second malignancy was correlated with the number of first-degree relatives with cancer.

The SIR was 2.67 for HL patients who had a single first-degree relative with cancer and 3.40 for HL patients who had 2 or more first-degree relatives with cancer.

The SIRs for different cancer types (for HL patients with at least 1 first-degree relative with cancer and no first-degree relatives with cancer, respectively) were as follows:

• NHL—14.43 vs 7.83
• Leukemia—14.31 vs 6.37
• Squamous cell carcinoma—10.85 vs 4.30
• Lung cancer—11.24 vs 3.39
• Breast cancer—4.36 vs 2.36
• Colorectal cancer—3.71 vs 1.76.

Sex and age

The researchers found significant differences in the SIRs for second cancers between HL patients diagnosed before the age of 35 and those diagnosed after age 35.

For men, the SIRs were:

• All cancers—4.26 for <35, 2.08 for ≥ 35
• Colorectal cancer—4.07 for < 35, 1.73 for ≥35
• Lung cancer—6.16 for < 35, 3.20 for ≥35
• Breast cancer—12.60 for < 35, 4.58 for ≥35
• Squamous cell carcinoma—5.89 for < 35, 3.96 for ≥35
• NHL—15.9 for < 35, 6.93 for ≥35
• Leukemia—12.15 for < 35, 5.57 for ≥35.

For women, the SIRs were:

• All cancers—4.61 for <35, 1.73 for ≥ 35
• Colorectal cancer—1.31 for < 35, 1.65 for ≥35
• Lung cancer—8.84 for < 35, 2.50 for ≥35
• Breast cancer—6.00 for < 35, 1.14 for ≥35
• Squamous cell carcinoma—6.37 for < 35, 4.87 for ≥35
• NHL—6.23 for < 35, 6.55 for ≥35
• Leukemia—10.36 for < 35, 4.51 for ≥35.

“Younger women who have been treated with radiotherapy to the chest for Hodgkin lymphoma are already screened for breast cancer, but our study suggests that we should be looking at ways of monitoring survivors for other forms of cancer too, and potentially offering preventative interventions,” Dr Sud said.

“After patients are cured, they no longer encounter oncologists, so it’s important that other healthcare providers are aware of the increased risk to Hodgkin lymphoma survivors to improve early diagnosis of second cancers.”

Photo by Rhoda Baer

A new study suggests Hodgkin lymphoma (HL) survivors have a high risk of developing a second malignancy, particularly if they have a family history of that malignancy.

The research showed that HL survivors in Sweden were roughly 2.4 times more likely than individuals in the country’s general population to develop a second cancer.

The risk for HL survivors remained high 30 years after treatment, and the risk was even greater in HL survivors who had a family history of specific cancers.

“The vast majority of patients with Hodgkin lymphoma are cured with a combination of chemotherapy and radiotherapy,” said study author Amit Sud, MBChB, of The Institute of Cancer Research, London in the UK.

“Our research has shown that these patients are at substantially increased risk of a second cancer later in life and particularly if they have a family history of cancer.”

Dr Sud and his colleagues described this research in the Journal of Clinical Oncology.

The team analyzed data from the Swedish Family-Cancer Project Database. They identified 9522 HL patients diagnosed between 1965 and 2013. During a median follow-up of 12.6 years, there were 1215 second cancers in 1121 HL patients (12%).

Compared to the general population, the HL patients had a significantly higher risk of all second malignancies, with a standardized incident ratio (SIR) of 2.39 and an absolute excess risk of 71.2 cases per 10,000 person-years.

Cancer types

HL patients had a significantly increased risk of several malignancies. The overall SIRs were as follows:

• NHL—7.99
• Leukemia—6.46
• Connective tissue cancer—5.73
• Thyroid cancer—5.13
• Squamous cell carcinoma—4.44
• Lung cancer—3.61
• Pharyngeal cancer—3.52
• Esophageal cancer—2.62
• Brain cancer—2.58
• Breast cancer—2.52
• Colon cancer—2.21
• Pancreatic cancer—2.09
• Melanoma—2.08
• Colorectal cancer—1.85
• Stomach cancer—1.78
• Bladder cancer—1.57
• Prostate cancer—1.21.

The researchers calculated SIRs over time and found the risk for many of the cancers remained high over 30 years following HL treatment.

Family history

The researchers identified 28,277 first-degree relatives of the HL survivors. Thirty percent of HL survivors (n=2785) had 1 or more first-degree relatives with a family history of cancer.

The SIR for cancers was 1.02 in the relatives. The SIR for second cancers was 2.83 for HL survivors who had first-degree relatives with cancer and 2.16 for HL survivors who did not have any first-degree relatives with cancer.

The researchers said the increased risk of second malignancy was correlated with the number of first-degree relatives with cancer.

The SIR was 2.67 for HL patients who had a single first-degree relative with cancer and 3.40 for HL patients who had 2 or more first-degree relatives with cancer.

The SIRs for different cancer types (for HL patients with at least 1 first-degree relative with cancer and no first-degree relatives with cancer, respectively) were as follows:

• NHL—14.43 vs 7.83
• Leukemia—14.31 vs 6.37
• Squamous cell carcinoma—10.85 vs 4.30
• Lung cancer—11.24 vs 3.39
• Breast cancer—4.36 vs 2.36
• Colorectal cancer—3.71 vs 1.76.

Sex and age

The researchers found significant differences in the SIRs for second cancers between HL patients diagnosed before the age of 35 and those diagnosed after age 35.

For men, the SIRs were:

• All cancers—4.26 for <35, 2.08 for ≥ 35
• Colorectal cancer—4.07 for < 35, 1.73 for ≥35
• Lung cancer—6.16 for < 35, 3.20 for ≥35
• Breast cancer—12.60 for < 35, 4.58 for ≥35
• Squamous cell carcinoma—5.89 for < 35, 3.96 for ≥35
• NHL—15.9 for < 35, 6.93 for ≥35
• Leukemia—12.15 for < 35, 5.57 for ≥35.

For women, the SIRs were:

• All cancers—4.61 for <35, 1.73 for ≥ 35
• Colorectal cancer—1.31 for < 35, 1.65 for ≥35
• Lung cancer—8.84 for < 35, 2.50 for ≥35
• Breast cancer—6.00 for < 35, 1.14 for ≥35
• Squamous cell carcinoma—6.37 for < 35, 4.87 for ≥35
• NHL—6.23 for < 35, 6.55 for ≥35
• Leukemia—10.36 for < 35, 4.51 for ≥35.

“Younger women who have been treated with radiotherapy to the chest for Hodgkin lymphoma are already screened for breast cancer, but our study suggests that we should be looking at ways of monitoring survivors for other forms of cancer too, and potentially offering preventative interventions,” Dr Sud said.

“After patients are cured, they no longer encounter oncologists, so it’s important that other healthcare providers are aware of the increased risk to Hodgkin lymphoma survivors to improve early diagnosis of second cancers.”