In a phase 3 trial, adding the quinolone derivative vosaroxin (Qinprezo) to treatment with cytarabine did not improve overall survival in patients with relapsed or refractory acute myeloid leukemia (AML).

However, the combination did confer a survival benefit when transplant patients were excluded from the analysis and in patients age 60 and older.

Results of this trial were recently announced by Sunesis Pharmaceuticals, the company developing vosaroxin.

The results are set to be presented in more detail at an upcoming scientific conference.

The trial, known as VALOR, enrolled 711 AML patients who had relapsed or become refractory to treatment for the first time. The patients were randomized to receive cytarabine plus vosaroxin or cytarabine plus placebo. They were stratified for age, geography, and disease status.

The trial did not meet its primary endpoint of demonstrating a significant improvement in overall survival. The median overall survival was 7.5 months in the vosaroxin-cytarabine arm and 6.1 months in the placebo-cytarabine arm (hazard ratio [HR]=0.865, P=0.06).

However, there was a significant benefit in complete response rate with vosaroxin over placebo—30.1% and 16.3%, respectively (P=0.0000148).

Because transplant could confound the primary analysis, the researchers planned a predefined analysis of overall survival censoring for stem cell transplant.

In this analysis, patients receiving the vosaroxin combination had a median overall survival of 6.7 months, compared to 5.3 months for placebo and cytarabine (HR=0.809, P=0.02).

Results according to age

For age, the researchers stratified patients into those age 60 years and older and those younger than 60 years at enrollment.

For the younger patients (n=260), the median overall survival was 9.1 months in the vosaroxin-cytarabine arm and 7.9 months in the placebo-cytarabine arm (HR=1.079, not significant).

The complete response rates were 26.9% and 20.8%, respectively (P=0.24). The rate of stem cell transplant was 45.8% in this age group.

For patients aged 60 years and older (n=451), the median overall survival was 7.1 months in the vosaroxin-cytarabine arm and 5.0 months in the placebo-cytarabine arm (HR=0.755, P=0.006).

The complete response rates were 31.9% and 13.8%, respectively (P=0.0000048). The rate of stem cell transplant was 20.2% for this age group.

Adverse events and mortality

In the intent-to-treat population, grade 3 or higher non-hematologic adverse events that were more common in the vosaroxin arm were gastrointestinal and infection-related toxicities. This is consistent with events observed in previous company trials.

The rate of serious adverse events was 55.5% in the vosaroxin-cytarabine arm and 35.7% in the placebo-cytarabine arm.

All-cause mortality rates were similar between the arms. Thirty-day mortality rates were 7.9% in the vosaroxin-cytarabine arm and 6.6% in the placebo-cytarabine arm. And 60-day mortality rates were 19.7% and 19.4%, respectively.

Regulatory plans

Based on the results of the trial, Sunesis plans to submit a marketing authorization application for vosaroxin to the European Medicines Agency. The company also plans to meet with the US Food and Drug Administration (FDA) to determine the appropriate regulatory path forward.

The FDA and the European Commission have already granted orphan designation to vosaroxin for the treatment of AML. The drug has been granted fast track designation by the FDA as well, for the potential treatment of relapsed or refractory AML in combination with cytarabine.

In a phase 3 trial, adding the quinolone derivative vosaroxin (Qinprezo) to treatment with cytarabine did not improve overall survival in patients with relapsed or refractory acute myeloid leukemia (AML).

However, the combination did confer a survival benefit when transplant patients were excluded from the analysis and in patients age 60 and older.

Results of this trial were recently announced by Sunesis Pharmaceuticals, the company developing vosaroxin.

The results are set to be presented in more detail at an upcoming scientific conference.

The trial, known as VALOR, enrolled 711 AML patients who had relapsed or become refractory to treatment for the first time. The patients were randomized to receive cytarabine plus vosaroxin or cytarabine plus placebo. They were stratified for age, geography, and disease status.

The trial did not meet its primary endpoint of demonstrating a significant improvement in overall survival. The median overall survival was 7.5 months in the vosaroxin-cytarabine arm and 6.1 months in the placebo-cytarabine arm (hazard ratio [HR]=0.865, P=0.06).

However, there was a significant benefit in complete response rate with vosaroxin over placebo—30.1% and 16.3%, respectively (P=0.0000148).

Because transplant could confound the primary analysis, the researchers planned a predefined analysis of overall survival censoring for stem cell transplant.

In this analysis, patients receiving the vosaroxin combination had a median overall survival of 6.7 months, compared to 5.3 months for placebo and cytarabine (HR=0.809, P=0.02).

Results according to age

For age, the researchers stratified patients into those age 60 years and older and those younger than 60 years at enrollment.

For the younger patients (n=260), the median overall survival was 9.1 months in the vosaroxin-cytarabine arm and 7.9 months in the placebo-cytarabine arm (HR=1.079, not significant).

The complete response rates were 26.9% and 20.8%, respectively (P=0.24). The rate of stem cell transplant was 45.8% in this age group.

For patients aged 60 years and older (n=451), the median overall survival was 7.1 months in the vosaroxin-cytarabine arm and 5.0 months in the placebo-cytarabine arm (HR=0.755, P=0.006).

The complete response rates were 31.9% and 13.8%, respectively (P=0.0000048). The rate of stem cell transplant was 20.2% for this age group.

Adverse events and mortality

In the intent-to-treat population, grade 3 or higher non-hematologic adverse events that were more common in the vosaroxin arm were gastrointestinal and infection-related toxicities. This is consistent with events observed in previous company trials.

The rate of serious adverse events was 55.5% in the vosaroxin-cytarabine arm and 35.7% in the placebo-cytarabine arm.

All-cause mortality rates were similar between the arms. Thirty-day mortality rates were 7.9% in the vosaroxin-cytarabine arm and 6.6% in the placebo-cytarabine arm. And 60-day mortality rates were 19.7% and 19.4%, respectively.

Regulatory plans

Based on the results of the trial, Sunesis plans to submit a marketing authorization application for vosaroxin to the European Medicines Agency. The company also plans to meet with the US Food and Drug Administration (FDA) to determine the appropriate regulatory path forward.

The FDA and the European Commission have already granted orphan designation to vosaroxin for the treatment of AML. The drug has been granted fast track designation by the FDA as well, for the potential treatment of relapsed or refractory AML in combination with cytarabine.

In a phase 3 trial, adding the quinolone derivative vosaroxin (Qinprezo) to treatment with cytarabine did not improve overall survival in patients with relapsed or refractory acute myeloid leukemia (AML).

However, the combination did confer a survival benefit when transplant patients were excluded from the analysis and in patients age 60 and older.

Results of this trial were recently announced by Sunesis Pharmaceuticals, the company developing vosaroxin.

The results are set to be presented in more detail at an upcoming scientific conference.

The trial, known as VALOR, enrolled 711 AML patients who had relapsed or become refractory to treatment for the first time. The patients were randomized to receive cytarabine plus vosaroxin or cytarabine plus placebo. They were stratified for age, geography, and disease status.

The trial did not meet its primary endpoint of demonstrating a significant improvement in overall survival. The median overall survival was 7.5 months in the vosaroxin-cytarabine arm and 6.1 months in the placebo-cytarabine arm (hazard ratio [HR]=0.865, P=0.06).

However, there was a significant benefit in complete response rate with vosaroxin over placebo—30.1% and 16.3%, respectively (P=0.0000148).

Because transplant could confound the primary analysis, the researchers planned a predefined analysis of overall survival censoring for stem cell transplant.

In this analysis, patients receiving the vosaroxin combination had a median overall survival of 6.7 months, compared to 5.3 months for placebo and cytarabine (HR=0.809, P=0.02).

Results according to age

For age, the researchers stratified patients into those age 60 years and older and those younger than 60 years at enrollment.

For the younger patients (n=260), the median overall survival was 9.1 months in the vosaroxin-cytarabine arm and 7.9 months in the placebo-cytarabine arm (HR=1.079, not significant).

The complete response rates were 26.9% and 20.8%, respectively (P=0.24). The rate of stem cell transplant was 45.8% in this age group.

For patients aged 60 years and older (n=451), the median overall survival was 7.1 months in the vosaroxin-cytarabine arm and 5.0 months in the placebo-cytarabine arm (HR=0.755, P=0.006).

The complete response rates were 31.9% and 13.8%, respectively (P=0.0000048). The rate of stem cell transplant was 20.2% for this age group.

Adverse events and mortality

In the intent-to-treat population, grade 3 or higher non-hematologic adverse events that were more common in the vosaroxin arm were gastrointestinal and infection-related toxicities. This is consistent with events observed in previous company trials.

The rate of serious adverse events was 55.5% in the vosaroxin-cytarabine arm and 35.7% in the placebo-cytarabine arm.

All-cause mortality rates were similar between the arms. Thirty-day mortality rates were 7.9% in the vosaroxin-cytarabine arm and 6.6% in the placebo-cytarabine arm. And 60-day mortality rates were 19.7% and 19.4%, respectively.

Regulatory plans

Based on the results of the trial, Sunesis plans to submit a marketing authorization application for vosaroxin to the European Medicines Agency. The company also plans to meet with the US Food and Drug Administration (FDA) to determine the appropriate regulatory path forward.

The FDA and the European Commission have already granted orphan designation to vosaroxin for the treatment of AML. The drug has been granted fast track designation by the FDA as well, for the potential treatment of relapsed or refractory AML in combination with cytarabine.

 Do you remember the discussion of the ethical dilemma of Huntington’s disease you probably participated in during medical school? The question was whether you would want to know that you were at risk for a chronic debilitating condition that would develop at some later age if there was nothing that could be done about it. In that discussion, you also may have heard about individuals who, after hearing about their risk status, become depressed or suicidal, depending on the story line.

Some pediatricians seem to have taken this example too far in arguing that there is no point in screening for issues of development, autism, maternal depression, or child mental health because “there are no services” available to treat them.

Despair is understandable. Physicians’ lack of knowledge about resources in the community is often a sore point among local agencies, parents, and even pediatricians themselves. In spite of United Way, state 3-1-1 programs ,and the occasionally available social worker, the resources with which we are familiar sometimes come from hard-working parents telling us about a program they found on their own. It also seems that, just when we hit upon a valuable resource, it runs out of funding, changes eligibility requirements, or loses key staff. Worse yet, we may rely on resources we know about because of our own children’s problems, activities, or friends. While the Internet is an increasingly valuable method of finding resources, there is no filter of the evidence-basis of the care provided, and the process of searching, vetting, and informing your patients is extremely time consuming, and often the patient is not eligible or has a long waiting period after all that.

There are important reasons not to succumb to throwing up one’s hands about service availability. And more important reasons to still screen even if you do not know where to refer.

Screening using validated tools is recommended by the American Academy of Pediatrics because parent concern and even clinical observation are not adequately sensitive to detect significant problems of development and mental health, even when done by experienced physicians who know families well. The process of screening sends an important message to the parents – that you care about the child’s progress and are using proven methods to ensure that it is going well and consider it part of complete medical care.

And families often already think that their child may have a problem, even when they don’t bring it up. Perhaps deep down they are afraid that somehow raising the question of autism will make it true. They may be in denial, are feeling guilty, or are under pressure from their spouse, relatives, or friends not to worry, that “he will grow out” of it, that better discipline will fix the problem, etc. They may even care so much about your positive regard that they do not want to seem overly anxious, obsessive, or be regarded as a failure for having a “defective” child. They, like you, also may be in despair about finding effective help.

But there can be serious consequences to not screening, even when you are not sure what you will do with the results. The family may push the child with delays or mental health problems beyond his abilities, and even become negative and punitive in trying to make him succeed, in the process promoting unnecessary behavior problems, discouragement, and even defiance in the child. Failure to detect also means failure to list the child on a registry for follow-up to determine progress or refer when resources become available. Some problems of development or mental health that are detected by screening may have medical causes that you can treat, even though counseling or therapy interventions are not available. Examples include hearing or vision deficits causing delays or anemia, sleep apnea, or hypothyroidism or maternal depression or attention-deficit/hyperactivity disorder (ADHD). For issues with a genetic basis, siblings may be born with same problem during the period of delay in making a diagnosis, a prime example being Fragile X. In untold cases, the family loses trust in you and in the medical system for not acknowledging a problem.

In many cases, your acknowledgment, explanation, sympathy, and advice can help enormously. Families can cope better, garner support from family or friends, deal with the child’s behavior better, and find steps to take to help their child in their own ways, even without formal services, once told that their child has a specific problem.

On a system level, it is important to realize that how services are established and maintained is far less rational than might be imagined. State programs, schools, hospitals, and insurers all have legal requirements to provide services within a certain time frame once referred. Even if the services are not there to help a your child or family right now, the referral itself adds to the data used to determine if services are adequate and to plan for additional service types or capacity. The Autism Waiver is one such example where waits are years long, but getting on the list is crucial to the future of the program.

Until you screen and give parents information – especially middle-class parents – we will never have the resources. As it was for lead paint, until we identified prevalence of elevated lead levels and the harm associated, we got no action on lead paint removal policies. Another example where complaints about access made a difference, is the relatively new Paul Wellstone and Pete Domenici Mental Health Parity and Addiction Equity Act of 2008 that requires health insurers and health plans to guarantee that financial requirements on benefits for mental health, such as copays, deductibles, and limitations on treatment benefits, are not more restrictive than those that are for medical benefits. This does not guarantee that services will be available or of high quality, but is a step toward accessibility.

You may be one of the many pediatricians who consider advocacy a basic component of your professional responsibilities. If you cannot advocate for services that you see your patients in need of, you can pass your concerns onto a group that does. Many American Academy of Pediatrics state chapters have so-called Pediatric Councils that receive ideas about system problems and put group pressure on leaders in the state to address them.

As in the historic painting of the physician leaning over the ill child whom he could not cure, after detection through screening our thoughtful evaluation, explanations, shared concern, and our patients’ advocacy have great value even when specific services are not yet available.

Dr. Howard is an assistant professor of pediatrics at the Johns Hopkins University, Baltimore, and creator of CHADIS (www.chadis.com). She has no other relevant disclosures. Dr. Howard’s contribution to this publication was as a paid expert to Frontline Medical News. E-mail her at [email protected].

 Do you remember the discussion of the ethical dilemma of Huntington’s disease you probably participated in during medical school? The question was whether you would want to know that you were at risk for a chronic debilitating condition that would develop at some later age if there was nothing that could be done about it. In that discussion, you also may have heard about individuals who, after hearing about their risk status, become depressed or suicidal, depending on the story line.

Some pediatricians seem to have taken this example too far in arguing that there is no point in screening for issues of development, autism, maternal depression, or child mental health because “there are no services” available to treat them.

Despair is understandable. Physicians’ lack of knowledge about resources in the community is often a sore point among local agencies, parents, and even pediatricians themselves. In spite of United Way, state 3-1-1 programs ,and the occasionally available social worker, the resources with which we are familiar sometimes come from hard-working parents telling us about a program they found on their own. It also seems that, just when we hit upon a valuable resource, it runs out of funding, changes eligibility requirements, or loses key staff. Worse yet, we may rely on resources we know about because of our own children’s problems, activities, or friends. While the Internet is an increasingly valuable method of finding resources, there is no filter of the evidence-basis of the care provided, and the process of searching, vetting, and informing your patients is extremely time consuming, and often the patient is not eligible or has a long waiting period after all that.

There are important reasons not to succumb to throwing up one’s hands about service availability. And more important reasons to still screen even if you do not know where to refer.

Screening using validated tools is recommended by the American Academy of Pediatrics because parent concern and even clinical observation are not adequately sensitive to detect significant problems of development and mental health, even when done by experienced physicians who know families well. The process of screening sends an important message to the parents – that you care about the child’s progress and are using proven methods to ensure that it is going well and consider it part of complete medical care.

And families often already think that their child may have a problem, even when they don’t bring it up. Perhaps deep down they are afraid that somehow raising the question of autism will make it true. They may be in denial, are feeling guilty, or are under pressure from their spouse, relatives, or friends not to worry, that “he will grow out” of it, that better discipline will fix the problem, etc. They may even care so much about your positive regard that they do not want to seem overly anxious, obsessive, or be regarded as a failure for having a “defective” child. They, like you, also may be in despair about finding effective help.

But there can be serious consequences to not screening, even when you are not sure what you will do with the results. The family may push the child with delays or mental health problems beyond his abilities, and even become negative and punitive in trying to make him succeed, in the process promoting unnecessary behavior problems, discouragement, and even defiance in the child. Failure to detect also means failure to list the child on a registry for follow-up to determine progress or refer when resources become available. Some problems of development or mental health that are detected by screening may have medical causes that you can treat, even though counseling or therapy interventions are not available. Examples include hearing or vision deficits causing delays or anemia, sleep apnea, or hypothyroidism or maternal depression or attention-deficit/hyperactivity disorder (ADHD). For issues with a genetic basis, siblings may be born with same problem during the period of delay in making a diagnosis, a prime example being Fragile X. In untold cases, the family loses trust in you and in the medical system for not acknowledging a problem.

In many cases, your acknowledgment, explanation, sympathy, and advice can help enormously. Families can cope better, garner support from family or friends, deal with the child’s behavior better, and find steps to take to help their child in their own ways, even without formal services, once told that their child has a specific problem.

On a system level, it is important to realize that how services are established and maintained is far less rational than might be imagined. State programs, schools, hospitals, and insurers all have legal requirements to provide services within a certain time frame once referred. Even if the services are not there to help a your child or family right now, the referral itself adds to the data used to determine if services are adequate and to plan for additional service types or capacity. The Autism Waiver is one such example where waits are years long, but getting on the list is crucial to the future of the program.

Until you screen and give parents information – especially middle-class parents – we will never have the resources. As it was for lead paint, until we identified prevalence of elevated lead levels and the harm associated, we got no action on lead paint removal policies. Another example where complaints about access made a difference, is the relatively new Paul Wellstone and Pete Domenici Mental Health Parity and Addiction Equity Act of 2008 that requires health insurers and health plans to guarantee that financial requirements on benefits for mental health, such as copays, deductibles, and limitations on treatment benefits, are not more restrictive than those that are for medical benefits. This does not guarantee that services will be available or of high quality, but is a step toward accessibility.

You may be one of the many pediatricians who consider advocacy a basic component of your professional responsibilities. If you cannot advocate for services that you see your patients in need of, you can pass your concerns onto a group that does. Many American Academy of Pediatrics state chapters have so-called Pediatric Councils that receive ideas about system problems and put group pressure on leaders in the state to address them.

As in the historic painting of the physician leaning over the ill child whom he could not cure, after detection through screening our thoughtful evaluation, explanations, shared concern, and our patients’ advocacy have great value even when specific services are not yet available.

Dr. Howard is an assistant professor of pediatrics at the Johns Hopkins University, Baltimore, and creator of CHADIS (www.chadis.com). She has no other relevant disclosures. Dr. Howard’s contribution to this publication was as a paid expert to Frontline Medical News. E-mail her at [email protected].

 Do you remember the discussion of the ethical dilemma of Huntington’s disease you probably participated in during medical school? The question was whether you would want to know that you were at risk for a chronic debilitating condition that would develop at some later age if there was nothing that could be done about it. In that discussion, you also may have heard about individuals who, after hearing about their risk status, become depressed or suicidal, depending on the story line.

Some pediatricians seem to have taken this example too far in arguing that there is no point in screening for issues of development, autism, maternal depression, or child mental health because “there are no services” available to treat them.

Despair is understandable. Physicians’ lack of knowledge about resources in the community is often a sore point among local agencies, parents, and even pediatricians themselves. In spite of United Way, state 3-1-1 programs ,and the occasionally available social worker, the resources with which we are familiar sometimes come from hard-working parents telling us about a program they found on their own. It also seems that, just when we hit upon a valuable resource, it runs out of funding, changes eligibility requirements, or loses key staff. Worse yet, we may rely on resources we know about because of our own children’s problems, activities, or friends. While the Internet is an increasingly valuable method of finding resources, there is no filter of the evidence-basis of the care provided, and the process of searching, vetting, and informing your patients is extremely time consuming, and often the patient is not eligible or has a long waiting period after all that.

There are important reasons not to succumb to throwing up one’s hands about service availability. And more important reasons to still screen even if you do not know where to refer.

Screening using validated tools is recommended by the American Academy of Pediatrics because parent concern and even clinical observation are not adequately sensitive to detect significant problems of development and mental health, even when done by experienced physicians who know families well. The process of screening sends an important message to the parents – that you care about the child’s progress and are using proven methods to ensure that it is going well and consider it part of complete medical care.

And families often already think that their child may have a problem, even when they don’t bring it up. Perhaps deep down they are afraid that somehow raising the question of autism will make it true. They may be in denial, are feeling guilty, or are under pressure from their spouse, relatives, or friends not to worry, that “he will grow out” of it, that better discipline will fix the problem, etc. They may even care so much about your positive regard that they do not want to seem overly anxious, obsessive, or be regarded as a failure for having a “defective” child. They, like you, also may be in despair about finding effective help.

But there can be serious consequences to not screening, even when you are not sure what you will do with the results. The family may push the child with delays or mental health problems beyond his abilities, and even become negative and punitive in trying to make him succeed, in the process promoting unnecessary behavior problems, discouragement, and even defiance in the child. Failure to detect also means failure to list the child on a registry for follow-up to determine progress or refer when resources become available. Some problems of development or mental health that are detected by screening may have medical causes that you can treat, even though counseling or therapy interventions are not available. Examples include hearing or vision deficits causing delays or anemia, sleep apnea, or hypothyroidism or maternal depression or attention-deficit/hyperactivity disorder (ADHD). For issues with a genetic basis, siblings may be born with same problem during the period of delay in making a diagnosis, a prime example being Fragile X. In untold cases, the family loses trust in you and in the medical system for not acknowledging a problem.

In many cases, your acknowledgment, explanation, sympathy, and advice can help enormously. Families can cope better, garner support from family or friends, deal with the child’s behavior better, and find steps to take to help their child in their own ways, even without formal services, once told that their child has a specific problem.

On a system level, it is important to realize that how services are established and maintained is far less rational than might be imagined. State programs, schools, hospitals, and insurers all have legal requirements to provide services within a certain time frame once referred. Even if the services are not there to help a your child or family right now, the referral itself adds to the data used to determine if services are adequate and to plan for additional service types or capacity. The Autism Waiver is one such example where waits are years long, but getting on the list is crucial to the future of the program.

Until you screen and give parents information – especially middle-class parents – we will never have the resources. As it was for lead paint, until we identified prevalence of elevated lead levels and the harm associated, we got no action on lead paint removal policies. Another example where complaints about access made a difference, is the relatively new Paul Wellstone and Pete Domenici Mental Health Parity and Addiction Equity Act of 2008 that requires health insurers and health plans to guarantee that financial requirements on benefits for mental health, such as copays, deductibles, and limitations on treatment benefits, are not more restrictive than those that are for medical benefits. This does not guarantee that services will be available or of high quality, but is a step toward accessibility.

You may be one of the many pediatricians who consider advocacy a basic component of your professional responsibilities. If you cannot advocate for services that you see your patients in need of, you can pass your concerns onto a group that does. Many American Academy of Pediatrics state chapters have so-called Pediatric Councils that receive ideas about system problems and put group pressure on leaders in the state to address them.

As in the historic painting of the physician leaning over the ill child whom he could not cure, after detection through screening our thoughtful evaluation, explanations, shared concern, and our patients’ advocacy have great value even when specific services are not yet available.

Dr. Howard is an assistant professor of pediatrics at the Johns Hopkins University, Baltimore, and creator of CHADIS (www.chadis.com). She has no other relevant disclosures. Dr. Howard’s contribution to this publication was as a paid expert to Frontline Medical News. E-mail her at [email protected].

Case Report

A 14-year-old adolescent boy presented to the dermatology clinic at our institution for evaluation of a hyperpigmented hairy patch on the right side of the face that had been present since birth. The patient reported the lesion originally had involved the right cheek, neck, and back but had gradually expanded to include the right side of the upper lip and oral mucosa. His medical history was remarkable for acne, which was currently being managed with topical treatments. There was no family history of similar conditions. There were no mental or developmental deformities since birth.

Physical examination revealed a hyperpigmented patch with hypertrichosis on the right side of the body involving the back, neck, and cheek (Figure 1), as well as hyperpigmentation involving the right side of the upper lip and oral mucosa (Figure 2A). Slight facial asymmetry also was noted. Dental examination revealed irregular spacing and decreased growth of the teeth on the right side of the mouth (Figure 2B).

Figure 1. Hyperpigmented hairy patch on the right cheek (Becker nevus) in a patient with hemimaxillary enlargement, asymmetry of the face, tooth abnormalities, and skin findings (HATS syndrome).

Figure 2. Some hyperpigmentation involving the oral mucosa on the right side (A) and dental abnormalities (B).

A biopsy of the hyperpigmented patch on the back revealed mild regular acanthosis, basal hypermelanosis, slight papillomatosis, and hair structures within the dermis with features that were consistent with a Becker nevus. A dental radiograph demonstrated hyperplasia of the right maxillary alveolus and basal bone area with 2 missing permanent teeth (fourth and fifth premolars)(Figure 3). Computed axial tomography revealed enlargement of the maxillary bone on the right side.

Figure 3. Dental radiograph demonstrated hyperplasia of the right maxillary alveolus and basal bone area with 2 missing permanent teeth (fourth and fifth premolars).

The constellation of clinical, histopathologic, and radiologic findings was consistent with a diagnosis of hemimaxillary enlargement, asymmetry of the face, tooth abnormalities, and skin findings (HATS syndrome). The treatment plan involved surgical modification of the maxillary bone to correct the hyperplasia on the affected side and implanting 2 artificial premolars. Additionally, laser therapy using a Q-switched ruby laser, frequency-doubled Nd:YAG, 1550-nm erbium-doped fiber laser, or 755-nm alexandrite laser was considered to treat the hyperpigmentation associ-ated with the Becker nevus.

Comment

HATS syndrome is a rare, local developmental defect involving the first and second branchial arches. It generally is detected at birth or in early childhood and is associated with unilateral abnormalities of the bones, teeth, gums, and skin. It is more common in boys than girls (1.8:1.0 ratio), with an age range of 2 to 28 years; there is a peak in the first decade of life.¹ It was first described by Miles et al² in 1987 in a case of congenital mild facial asymmetry, unilateral enlargement of the maxillary gingiva and alveolar bone, hypoplastic teeth, and hypertrichosis in the affected area. The investigators at that time suggested the term hemimaxillofacial dysplasia (HD). In 1990, Danforth et al³ reported 8 additional cases with similar features but without known skin changes; they proposed the term segmental odontomaxillary dysplasia (SOD). In 1996, Desalvo et al⁴ reported a case of SOD involving a 7-year-old girl with an area of hypopigmentation of the lip on the affected side, and Packota et al⁵ described the radiographic features of 12 cases of SOD. In subsequent years, other cases of HD or SOD were reported in the literature.^1,6-16 In 2004, Welsch and Stein¹⁷ reported 1 patient with a Becker nevus of the skin and recommended the acronym HATS. Armstrong et al¹⁸ reported 2 cases of SOD with new histopathologic findings of the teeth (eg, fibrous enlargement of the pulps, an irregular pulp-dentin interface displaying many pseudoinclusions, pulp stones). In 2008, Porwal et al¹⁹ reported a case of HD in which maxillary hypoplasia rather than hyperplasia was noted, which emphasized the variability of the maxillary dysplasia. Koenig et al²⁰ reported a case of SOD with facial hypertrichosis, commissural lip clefting, and hyperlinear palms. Bhatia et al²¹ reported another case of SOD with a new finding of unilateral ectopic eyelashes.

The etiology remains unknown, but theories include an alteration that occurs in utero or in in-fancy; the possibility of a systemic or endocrine aberration; a postzygotic mutation resulting in genotypic and phenotypic mosaicism of bone and skin, similar to McCune-Albright syndrome; and viral or bacterial infection along the branches of the maxillary division of the trigeminal nerve.^1,15 Bone defects include unilateral enlargement of the maxillary alveolar process and thickening of the vertically oriented trabeculae, which is detected radiographically. A reduction in size of the maxillary sinus and nasal airway was reported in about one-half of cases¹ and can be detected easily by computed tomography scanning. Missing permanent premolar teeth, tooth shape abnormalities, delayed eruption of teeth, abnormal spacing of teeth, hypoplastic teeth, enlarged teeth, and gingival thickening also are common oral findings.¹ The skin manifestations of HATS syndrome are not static but progress well into adolescence¹⁵ and can include facial asymmetry, hypertrichosis, Becker nevus, hairy nevus, lip hypopigmentation, discontinuity of the vermilion border, depression of the cheek, and facial erythema.¹⁷

The differential diagnosis includes hemifacial hyperplasia, monostotic fibrous dysplasia, and regional odontodysplasia.¹ Little information is available concerning the treatment of patients with this condition.¹⁵ The reported treatment modalities include combined surgical and orthodontic treatment of unerupted teeth (premolar/canine), prosthodontic treatment, gingivoplasty, recontouring osteotomy for severe facial asymmetry, and reconstructive jaw surgery.^1,6,11,15 Successful treatment of Becker nevi with the Q-switched ruby laser, erbium:YAG laser, and 755-nm alexandrite laser have been reported.^22-24

Conclusion

There is a need for continued reporting of cases of HATS syndrome in addition to long-term follow-up to document the natural history of the condition and to establish the appropriate treatment.

Case Report

A 14-year-old adolescent boy presented to the dermatology clinic at our institution for evaluation of a hyperpigmented hairy patch on the right side of the face that had been present since birth. The patient reported the lesion originally had involved the right cheek, neck, and back but had gradually expanded to include the right side of the upper lip and oral mucosa. His medical history was remarkable for acne, which was currently being managed with topical treatments. There was no family history of similar conditions. There were no mental or developmental deformities since birth.

Physical examination revealed a hyperpigmented patch with hypertrichosis on the right side of the body involving the back, neck, and cheek (Figure 1), as well as hyperpigmentation involving the right side of the upper lip and oral mucosa (Figure 2A). Slight facial asymmetry also was noted. Dental examination revealed irregular spacing and decreased growth of the teeth on the right side of the mouth (Figure 2B).

Figure 1. Hyperpigmented hairy patch on the right cheek (Becker nevus) in a patient with hemimaxillary enlargement, asymmetry of the face, tooth abnormalities, and skin findings (HATS syndrome).

Figure 2. Some hyperpigmentation involving the oral mucosa on the right side (A) and dental abnormalities (B).

A biopsy of the hyperpigmented patch on the back revealed mild regular acanthosis, basal hypermelanosis, slight papillomatosis, and hair structures within the dermis with features that were consistent with a Becker nevus. A dental radiograph demonstrated hyperplasia of the right maxillary alveolus and basal bone area with 2 missing permanent teeth (fourth and fifth premolars)(Figure 3). Computed axial tomography revealed enlargement of the maxillary bone on the right side.

Figure 3. Dental radiograph demonstrated hyperplasia of the right maxillary alveolus and basal bone area with 2 missing permanent teeth (fourth and fifth premolars).

The constellation of clinical, histopathologic, and radiologic findings was consistent with a diagnosis of hemimaxillary enlargement, asymmetry of the face, tooth abnormalities, and skin findings (HATS syndrome). The treatment plan involved surgical modification of the maxillary bone to correct the hyperplasia on the affected side and implanting 2 artificial premolars. Additionally, laser therapy using a Q-switched ruby laser, frequency-doubled Nd:YAG, 1550-nm erbium-doped fiber laser, or 755-nm alexandrite laser was considered to treat the hyperpigmentation associ-ated with the Becker nevus.

Comment

HATS syndrome is a rare, local developmental defect involving the first and second branchial arches. It generally is detected at birth or in early childhood and is associated with unilateral abnormalities of the bones, teeth, gums, and skin. It is more common in boys than girls (1.8:1.0 ratio), with an age range of 2 to 28 years; there is a peak in the first decade of life.¹ It was first described by Miles et al² in 1987 in a case of congenital mild facial asymmetry, unilateral enlargement of the maxillary gingiva and alveolar bone, hypoplastic teeth, and hypertrichosis in the affected area. The investigators at that time suggested the term hemimaxillofacial dysplasia (HD). In 1990, Danforth et al³ reported 8 additional cases with similar features but without known skin changes; they proposed the term segmental odontomaxillary dysplasia (SOD). In 1996, Desalvo et al⁴ reported a case of SOD involving a 7-year-old girl with an area of hypopigmentation of the lip on the affected side, and Packota et al⁵ described the radiographic features of 12 cases of SOD. In subsequent years, other cases of HD or SOD were reported in the literature.^1,6-16 In 2004, Welsch and Stein¹⁷ reported 1 patient with a Becker nevus of the skin and recommended the acronym HATS. Armstrong et al¹⁸ reported 2 cases of SOD with new histopathologic findings of the teeth (eg, fibrous enlargement of the pulps, an irregular pulp-dentin interface displaying many pseudoinclusions, pulp stones). In 2008, Porwal et al¹⁹ reported a case of HD in which maxillary hypoplasia rather than hyperplasia was noted, which emphasized the variability of the maxillary dysplasia. Koenig et al²⁰ reported a case of SOD with facial hypertrichosis, commissural lip clefting, and hyperlinear palms. Bhatia et al²¹ reported another case of SOD with a new finding of unilateral ectopic eyelashes.

The etiology remains unknown, but theories include an alteration that occurs in utero or in in-fancy; the possibility of a systemic or endocrine aberration; a postzygotic mutation resulting in genotypic and phenotypic mosaicism of bone and skin, similar to McCune-Albright syndrome; and viral or bacterial infection along the branches of the maxillary division of the trigeminal nerve.^1,15 Bone defects include unilateral enlargement of the maxillary alveolar process and thickening of the vertically oriented trabeculae, which is detected radiographically. A reduction in size of the maxillary sinus and nasal airway was reported in about one-half of cases¹ and can be detected easily by computed tomography scanning. Missing permanent premolar teeth, tooth shape abnormalities, delayed eruption of teeth, abnormal spacing of teeth, hypoplastic teeth, enlarged teeth, and gingival thickening also are common oral findings.¹ The skin manifestations of HATS syndrome are not static but progress well into adolescence¹⁵ and can include facial asymmetry, hypertrichosis, Becker nevus, hairy nevus, lip hypopigmentation, discontinuity of the vermilion border, depression of the cheek, and facial erythema.¹⁷

The differential diagnosis includes hemifacial hyperplasia, monostotic fibrous dysplasia, and regional odontodysplasia.¹ Little information is available concerning the treatment of patients with this condition.¹⁵ The reported treatment modalities include combined surgical and orthodontic treatment of unerupted teeth (premolar/canine), prosthodontic treatment, gingivoplasty, recontouring osteotomy for severe facial asymmetry, and reconstructive jaw surgery.^1,6,11,15 Successful treatment of Becker nevi with the Q-switched ruby laser, erbium:YAG laser, and 755-nm alexandrite laser have been reported.^22-24

Conclusion

There is a need for continued reporting of cases of HATS syndrome in addition to long-term follow-up to document the natural history of the condition and to establish the appropriate treatment.

Case Report

A 14-year-old adolescent boy presented to the dermatology clinic at our institution for evaluation of a hyperpigmented hairy patch on the right side of the face that had been present since birth. The patient reported the lesion originally had involved the right cheek, neck, and back but had gradually expanded to include the right side of the upper lip and oral mucosa. His medical history was remarkable for acne, which was currently being managed with topical treatments. There was no family history of similar conditions. There were no mental or developmental deformities since birth.

Physical examination revealed a hyperpigmented patch with hypertrichosis on the right side of the body involving the back, neck, and cheek (Figure 1), as well as hyperpigmentation involving the right side of the upper lip and oral mucosa (Figure 2A). Slight facial asymmetry also was noted. Dental examination revealed irregular spacing and decreased growth of the teeth on the right side of the mouth (Figure 2B).

Figure 1. Hyperpigmented hairy patch on the right cheek (Becker nevus) in a patient with hemimaxillary enlargement, asymmetry of the face, tooth abnormalities, and skin findings (HATS syndrome).

Figure 2. Some hyperpigmentation involving the oral mucosa on the right side (A) and dental abnormalities (B).

A biopsy of the hyperpigmented patch on the back revealed mild regular acanthosis, basal hypermelanosis, slight papillomatosis, and hair structures within the dermis with features that were consistent with a Becker nevus. A dental radiograph demonstrated hyperplasia of the right maxillary alveolus and basal bone area with 2 missing permanent teeth (fourth and fifth premolars)(Figure 3). Computed axial tomography revealed enlargement of the maxillary bone on the right side.

Figure 3. Dental radiograph demonstrated hyperplasia of the right maxillary alveolus and basal bone area with 2 missing permanent teeth (fourth and fifth premolars).

The constellation of clinical, histopathologic, and radiologic findings was consistent with a diagnosis of hemimaxillary enlargement, asymmetry of the face, tooth abnormalities, and skin findings (HATS syndrome). The treatment plan involved surgical modification of the maxillary bone to correct the hyperplasia on the affected side and implanting 2 artificial premolars. Additionally, laser therapy using a Q-switched ruby laser, frequency-doubled Nd:YAG, 1550-nm erbium-doped fiber laser, or 755-nm alexandrite laser was considered to treat the hyperpigmentation associ-ated with the Becker nevus.

Comment

HATS syndrome is a rare, local developmental defect involving the first and second branchial arches. It generally is detected at birth or in early childhood and is associated with unilateral abnormalities of the bones, teeth, gums, and skin. It is more common in boys than girls (1.8:1.0 ratio), with an age range of 2 to 28 years; there is a peak in the first decade of life.¹ It was first described by Miles et al² in 1987 in a case of congenital mild facial asymmetry, unilateral enlargement of the maxillary gingiva and alveolar bone, hypoplastic teeth, and hypertrichosis in the affected area. The investigators at that time suggested the term hemimaxillofacial dysplasia (HD). In 1990, Danforth et al³ reported 8 additional cases with similar features but without known skin changes; they proposed the term segmental odontomaxillary dysplasia (SOD). In 1996, Desalvo et al⁴ reported a case of SOD involving a 7-year-old girl with an area of hypopigmentation of the lip on the affected side, and Packota et al⁵ described the radiographic features of 12 cases of SOD. In subsequent years, other cases of HD or SOD were reported in the literature.^1,6-16 In 2004, Welsch and Stein¹⁷ reported 1 patient with a Becker nevus of the skin and recommended the acronym HATS. Armstrong et al¹⁸ reported 2 cases of SOD with new histopathologic findings of the teeth (eg, fibrous enlargement of the pulps, an irregular pulp-dentin interface displaying many pseudoinclusions, pulp stones). In 2008, Porwal et al¹⁹ reported a case of HD in which maxillary hypoplasia rather than hyperplasia was noted, which emphasized the variability of the maxillary dysplasia. Koenig et al²⁰ reported a case of SOD with facial hypertrichosis, commissural lip clefting, and hyperlinear palms. Bhatia et al²¹ reported another case of SOD with a new finding of unilateral ectopic eyelashes.

The etiology remains unknown, but theories include an alteration that occurs in utero or in in-fancy; the possibility of a systemic or endocrine aberration; a postzygotic mutation resulting in genotypic and phenotypic mosaicism of bone and skin, similar to McCune-Albright syndrome; and viral or bacterial infection along the branches of the maxillary division of the trigeminal nerve.^1,15 Bone defects include unilateral enlargement of the maxillary alveolar process and thickening of the vertically oriented trabeculae, which is detected radiographically. A reduction in size of the maxillary sinus and nasal airway was reported in about one-half of cases¹ and can be detected easily by computed tomography scanning. Missing permanent premolar teeth, tooth shape abnormalities, delayed eruption of teeth, abnormal spacing of teeth, hypoplastic teeth, enlarged teeth, and gingival thickening also are common oral findings.¹ The skin manifestations of HATS syndrome are not static but progress well into adolescence¹⁵ and can include facial asymmetry, hypertrichosis, Becker nevus, hairy nevus, lip hypopigmentation, discontinuity of the vermilion border, depression of the cheek, and facial erythema.¹⁷

The differential diagnosis includes hemifacial hyperplasia, monostotic fibrous dysplasia, and regional odontodysplasia.¹ Little information is available concerning the treatment of patients with this condition.¹⁵ The reported treatment modalities include combined surgical and orthodontic treatment of unerupted teeth (premolar/canine), prosthodontic treatment, gingivoplasty, recontouring osteotomy for severe facial asymmetry, and reconstructive jaw surgery.^1,6,11,15 Successful treatment of Becker nevi with the Q-switched ruby laser, erbium:YAG laser, and 755-nm alexandrite laser have been reported.^22-24

Conclusion

There is a need for continued reporting of cases of HATS syndrome in addition to long-term follow-up to document the natural history of the condition and to establish the appropriate treatment.

To the Editor:
Flurbiprofen, a member of the phenylalkanoic acid derivative group of nonsteroidal anti-inflammatory drugs (NSAIDs), are commonly used to treat fever, inflammation, and pain of arthritis.¹ The exact prevalence of allergic reactions to NSAIDs in the general population is not known. Rhinoconjunctivitis, bronchospasm, urticaria, angioedema, and anaphylaxis can occur as an allergic reaction to NSAIDs. Isolated angioedema following NSAID ingestion typically involves the face, particularly the periorbital skin, lips, and mouth.² These patients may develop urticaria and/or angioedema only after NSAID ingestion, but they do not have underlying chronic urticaria. We report a rare case of isolated unilateral eyelid angioedema with flurbiprofen.

A 39-year-old man presented with the onset of unilateral angioedema of the left upper eyelid that had developed approximately 30 minutes after taking flurbiprofen (100 mg). He reported frequent use of flurbiprofen for headaches. The patient also had a history of taking aspirin, ibuprofen, diclofenac, etodolac, and naproxen sodium as needed for migraines with no prior angioedema. He had no history of chronic urticaria or allergic disease. The patient was treated with oral pheniramine hydrogen maleate and angioedema resolved after 12 hours. Three days later, the patient used flurbiprofen again for a headache. He was readmitted to our clinic with unilateral angioedema of the left upper eyelid (Figure). The symptoms started approximately 30 minutes after taking flurbiprofen. Angioedema resolved within 1 day with oral pheniramine.

Unilateral angioedema of the left upper eyelid following use of flurbiprofen for headaches.

Nonsteroidal anti-inflammatory drugs are the most commonly prescribed class of drugs in the world and are the most common cause of all adverse drug reactions.³ Urticaria, angioedema, and anaphylaxis are common adverse reactions to NSAIDs. The prevalence of urticaria and angioedema to NSAIDs has been reported to be 0.1% to 3% worldwide.⁴

Angioedema is an abrupt localized swelling of the skin and mucous membranes of the face, lips, mouth, throat, larynx, extremities, and genitalia. Angioedema generally develops over minutes to hours and resolves in 24 to 48 hours.⁵ Angioedema without urticaria is the clinical syndrome that can be caused by an adverse drug reaction. In an Italian review of 2137 reactions, NSAIDs were causative agents in 33.6% of patients with drug-induced angioedema.⁶ In another study, Leeyaphan et al⁵ reported that 50% of patients with drug-induced angioedema resulted from NSAIDs, commonly with ibuprofen and diclofenac. Although angioedema is due to inhibition of cyclooxygenase 1, overproduction of leukotrienes, and possibly IgE-mediated reactions to single drugs,⁷ localized unilateral eyelid angioedema with NSAIDs is rare. The exact mechanism of localized eyelid edema is not known.⁸ We believe that the unilateral eyelid angioedema in our patient was caused by flurbiprofen use because the reaction recurred when the drug was used again.

To the Editor:
Flurbiprofen, a member of the phenylalkanoic acid derivative group of nonsteroidal anti-inflammatory drugs (NSAIDs), are commonly used to treat fever, inflammation, and pain of arthritis.¹ The exact prevalence of allergic reactions to NSAIDs in the general population is not known. Rhinoconjunctivitis, bronchospasm, urticaria, angioedema, and anaphylaxis can occur as an allergic reaction to NSAIDs. Isolated angioedema following NSAID ingestion typically involves the face, particularly the periorbital skin, lips, and mouth.² These patients may develop urticaria and/or angioedema only after NSAID ingestion, but they do not have underlying chronic urticaria. We report a rare case of isolated unilateral eyelid angioedema with flurbiprofen.

A 39-year-old man presented with the onset of unilateral angioedema of the left upper eyelid that had developed approximately 30 minutes after taking flurbiprofen (100 mg). He reported frequent use of flurbiprofen for headaches. The patient also had a history of taking aspirin, ibuprofen, diclofenac, etodolac, and naproxen sodium as needed for migraines with no prior angioedema. He had no history of chronic urticaria or allergic disease. The patient was treated with oral pheniramine hydrogen maleate and angioedema resolved after 12 hours. Three days later, the patient used flurbiprofen again for a headache. He was readmitted to our clinic with unilateral angioedema of the left upper eyelid (Figure). The symptoms started approximately 30 minutes after taking flurbiprofen. Angioedema resolved within 1 day with oral pheniramine.

Unilateral angioedema of the left upper eyelid following use of flurbiprofen for headaches.

Nonsteroidal anti-inflammatory drugs are the most commonly prescribed class of drugs in the world and are the most common cause of all adverse drug reactions.³ Urticaria, angioedema, and anaphylaxis are common adverse reactions to NSAIDs. The prevalence of urticaria and angioedema to NSAIDs has been reported to be 0.1% to 3% worldwide.⁴

Angioedema is an abrupt localized swelling of the skin and mucous membranes of the face, lips, mouth, throat, larynx, extremities, and genitalia. Angioedema generally develops over minutes to hours and resolves in 24 to 48 hours.⁵ Angioedema without urticaria is the clinical syndrome that can be caused by an adverse drug reaction. In an Italian review of 2137 reactions, NSAIDs were causative agents in 33.6% of patients with drug-induced angioedema.⁶ In another study, Leeyaphan et al⁵ reported that 50% of patients with drug-induced angioedema resulted from NSAIDs, commonly with ibuprofen and diclofenac. Although angioedema is due to inhibition of cyclooxygenase 1, overproduction of leukotrienes, and possibly IgE-mediated reactions to single drugs,⁷ localized unilateral eyelid angioedema with NSAIDs is rare. The exact mechanism of localized eyelid edema is not known.⁸ We believe that the unilateral eyelid angioedema in our patient was caused by flurbiprofen use because the reaction recurred when the drug was used again.

To the Editor:
Flurbiprofen, a member of the phenylalkanoic acid derivative group of nonsteroidal anti-inflammatory drugs (NSAIDs), are commonly used to treat fever, inflammation, and pain of arthritis.¹ The exact prevalence of allergic reactions to NSAIDs in the general population is not known. Rhinoconjunctivitis, bronchospasm, urticaria, angioedema, and anaphylaxis can occur as an allergic reaction to NSAIDs. Isolated angioedema following NSAID ingestion typically involves the face, particularly the periorbital skin, lips, and mouth.² These patients may develop urticaria and/or angioedema only after NSAID ingestion, but they do not have underlying chronic urticaria. We report a rare case of isolated unilateral eyelid angioedema with flurbiprofen.

A 39-year-old man presented with the onset of unilateral angioedema of the left upper eyelid that had developed approximately 30 minutes after taking flurbiprofen (100 mg). He reported frequent use of flurbiprofen for headaches. The patient also had a history of taking aspirin, ibuprofen, diclofenac, etodolac, and naproxen sodium as needed for migraines with no prior angioedema. He had no history of chronic urticaria or allergic disease. The patient was treated with oral pheniramine hydrogen maleate and angioedema resolved after 12 hours. Three days later, the patient used flurbiprofen again for a headache. He was readmitted to our clinic with unilateral angioedema of the left upper eyelid (Figure). The symptoms started approximately 30 minutes after taking flurbiprofen. Angioedema resolved within 1 day with oral pheniramine.

Unilateral angioedema of the left upper eyelid following use of flurbiprofen for headaches.

Nonsteroidal anti-inflammatory drugs are the most commonly prescribed class of drugs in the world and are the most common cause of all adverse drug reactions.³ Urticaria, angioedema, and anaphylaxis are common adverse reactions to NSAIDs. The prevalence of urticaria and angioedema to NSAIDs has been reported to be 0.1% to 3% worldwide.⁴

Angioedema is an abrupt localized swelling of the skin and mucous membranes of the face, lips, mouth, throat, larynx, extremities, and genitalia. Angioedema generally develops over minutes to hours and resolves in 24 to 48 hours.⁵ Angioedema without urticaria is the clinical syndrome that can be caused by an adverse drug reaction. In an Italian review of 2137 reactions, NSAIDs were causative agents in 33.6% of patients with drug-induced angioedema.⁶ In another study, Leeyaphan et al⁵ reported that 50% of patients with drug-induced angioedema resulted from NSAIDs, commonly with ibuprofen and diclofenac. Although angioedema is due to inhibition of cyclooxygenase 1, overproduction of leukotrienes, and possibly IgE-mediated reactions to single drugs,⁷ localized unilateral eyelid angioedema with NSAIDs is rare. The exact mechanism of localized eyelid edema is not known.⁸ We believe that the unilateral eyelid angioedema in our patient was caused by flurbiprofen use because the reaction recurred when the drug was used again.

Genetic barcoding technology

allows scientists to identify

differences in blood cell origin

Credit: Camargo Lab

By developing a tracking system for stem cells, researchers may have discovered previously unrecognized features of hematopoiesis.

Their work suggests the main drivers of steady-state hematopoiesis are not hematopoietic stem cells (HSCs) but their less pluripotent descendants, progenitor cells.

The team speculates that stable populations of long-lived progenitor cells are responsible for giving rise to specific blood cell types, while HSCs likely act as essential reserves.

The research, published in Nature, indicates that progenitor cells could be just as valuable as HSCs for blood regeneration therapies.

The work challenges what textbooks have long read: that HSCs maintain the day-to-day renewal of blood, a conclusion drawn from their importance in re-establishing blood cell populations after bone marrow transplants.

Due to a lack of tools to study how blood forms in a normal context, no one was able to track the origin of blood cells without doing a transplant.

Fernando Camargo, PhD, of Boston Children’s Hospital in Massachusetts, and his colleagues addressed this problem with a tool that generates a unique barcode in the DNA of all HSCs and their progenitor cells in a mouse.

When a tagged cell divides, all of its descendant cells possess the same barcode. This biological inventory system makes it possible to determine the number of HSCs/progenitors being used to make blood and how long they live, as well as answer fundamental questions about where individual blood cells come from.

“There’s never been such a robust experimental method that could allow people to look at lineage relationships between mature cell types in the body without doing transplantation,” said study author Jianlong Sun, PhD, also of Boston Children’s Hospital.

“One of the major directions we can now go is to revisit the entire blood cell hierarchy and see how the current knowledge holds true when we use this internal labeling system.”

“People have tried using viruses to tag blood cells in the past, but the cells needed to be taken out of the body, infected, and re-transplanted, which raised a number of issues,” Dr Camargo noted. “I wanted to figure out a way to label blood cells inside of the body, and the best idea I had was to use mobile genetic elements called transposons.”

A transposon is a piece of genetic code that can jump to a random point in DNA when exposed to the enzyme transposase. Dr Camargo’s approach works using transgenic mice that possess a single fish-derived transposon in all of their blood cells.

When one of these mice is exposed to transposase, each of its blood cells’ transposons changes location. The location in the DNA where a transposon moves acts as an individual cell’s barcode, so that if the mouse’s blood is taken a few months later, any cell with the same transposon location can be linked back to its parent cell.

Now, the researchers are planning to explore more applications for their barcode tool.

“We are also tremendously excited to use this tool to barcode and track descendants of different stem cells or progenitor cells for a range of conditions, from aging to the normal immune response,” Dr Sun said.

“We first used this technology for blood analysis. However, this system can also help address basic questions about cell populations in solid tissue. You can imagine being able to look at tumor progression or identify the precise origins of cancer cells that have broken off from a tumor and are now circulating in the blood.”

Genetic barcoding technology

allows scientists to identify

differences in blood cell origin

Credit: Camargo Lab

By developing a tracking system for stem cells, researchers may have discovered previously unrecognized features of hematopoiesis.

Their work suggests the main drivers of steady-state hematopoiesis are not hematopoietic stem cells (HSCs) but their less pluripotent descendants, progenitor cells.

The team speculates that stable populations of long-lived progenitor cells are responsible for giving rise to specific blood cell types, while HSCs likely act as essential reserves.

The research, published in Nature, indicates that progenitor cells could be just as valuable as HSCs for blood regeneration therapies.

The work challenges what textbooks have long read: that HSCs maintain the day-to-day renewal of blood, a conclusion drawn from their importance in re-establishing blood cell populations after bone marrow transplants.

Due to a lack of tools to study how blood forms in a normal context, no one was able to track the origin of blood cells without doing a transplant.

Fernando Camargo, PhD, of Boston Children’s Hospital in Massachusetts, and his colleagues addressed this problem with a tool that generates a unique barcode in the DNA of all HSCs and their progenitor cells in a mouse.

When a tagged cell divides, all of its descendant cells possess the same barcode. This biological inventory system makes it possible to determine the number of HSCs/progenitors being used to make blood and how long they live, as well as answer fundamental questions about where individual blood cells come from.

“There’s never been such a robust experimental method that could allow people to look at lineage relationships between mature cell types in the body without doing transplantation,” said study author Jianlong Sun, PhD, also of Boston Children’s Hospital.

“One of the major directions we can now go is to revisit the entire blood cell hierarchy and see how the current knowledge holds true when we use this internal labeling system.”

“People have tried using viruses to tag blood cells in the past, but the cells needed to be taken out of the body, infected, and re-transplanted, which raised a number of issues,” Dr Camargo noted. “I wanted to figure out a way to label blood cells inside of the body, and the best idea I had was to use mobile genetic elements called transposons.”

A transposon is a piece of genetic code that can jump to a random point in DNA when exposed to the enzyme transposase. Dr Camargo’s approach works using transgenic mice that possess a single fish-derived transposon in all of their blood cells.

When one of these mice is exposed to transposase, each of its blood cells’ transposons changes location. The location in the DNA where a transposon moves acts as an individual cell’s barcode, so that if the mouse’s blood is taken a few months later, any cell with the same transposon location can be linked back to its parent cell.

Now, the researchers are planning to explore more applications for their barcode tool.

“We are also tremendously excited to use this tool to barcode and track descendants of different stem cells or progenitor cells for a range of conditions, from aging to the normal immune response,” Dr Sun said.

“We first used this technology for blood analysis. However, this system can also help address basic questions about cell populations in solid tissue. You can imagine being able to look at tumor progression or identify the precise origins of cancer cells that have broken off from a tumor and are now circulating in the blood.”

Genetic barcoding technology

allows scientists to identify

differences in blood cell origin

Credit: Camargo Lab

By developing a tracking system for stem cells, researchers may have discovered previously unrecognized features of hematopoiesis.

Their work suggests the main drivers of steady-state hematopoiesis are not hematopoietic stem cells (HSCs) but their less pluripotent descendants, progenitor cells.

The team speculates that stable populations of long-lived progenitor cells are responsible for giving rise to specific blood cell types, while HSCs likely act as essential reserves.

The research, published in Nature, indicates that progenitor cells could be just as valuable as HSCs for blood regeneration therapies.

The work challenges what textbooks have long read: that HSCs maintain the day-to-day renewal of blood, a conclusion drawn from their importance in re-establishing blood cell populations after bone marrow transplants.

Due to a lack of tools to study how blood forms in a normal context, no one was able to track the origin of blood cells without doing a transplant.

Fernando Camargo, PhD, of Boston Children’s Hospital in Massachusetts, and his colleagues addressed this problem with a tool that generates a unique barcode in the DNA of all HSCs and their progenitor cells in a mouse.

When a tagged cell divides, all of its descendant cells possess the same barcode. This biological inventory system makes it possible to determine the number of HSCs/progenitors being used to make blood and how long they live, as well as answer fundamental questions about where individual blood cells come from.

“There’s never been such a robust experimental method that could allow people to look at lineage relationships between mature cell types in the body without doing transplantation,” said study author Jianlong Sun, PhD, also of Boston Children’s Hospital.

“One of the major directions we can now go is to revisit the entire blood cell hierarchy and see how the current knowledge holds true when we use this internal labeling system.”

“People have tried using viruses to tag blood cells in the past, but the cells needed to be taken out of the body, infected, and re-transplanted, which raised a number of issues,” Dr Camargo noted. “I wanted to figure out a way to label blood cells inside of the body, and the best idea I had was to use mobile genetic elements called transposons.”

A transposon is a piece of genetic code that can jump to a random point in DNA when exposed to the enzyme transposase. Dr Camargo’s approach works using transgenic mice that possess a single fish-derived transposon in all of their blood cells.

When one of these mice is exposed to transposase, each of its blood cells’ transposons changes location. The location in the DNA where a transposon moves acts as an individual cell’s barcode, so that if the mouse’s blood is taken a few months later, any cell with the same transposon location can be linked back to its parent cell.

Now, the researchers are planning to explore more applications for their barcode tool.

“We are also tremendously excited to use this tool to barcode and track descendants of different stem cells or progenitor cells for a range of conditions, from aging to the normal immune response,” Dr Sun said.

“We first used this technology for blood analysis. However, this system can also help address basic questions about cell populations in solid tissue. You can imagine being able to look at tumor progression or identify the precise origins of cancer cells that have broken off from a tumor and are now circulating in the blood.”

Monoclonal antibodies

Credit: Linda Bartlett

In a new draft guidance, the UK’s National Institute for Health and Care Excellence (NICE) has said it cannot recommend obinutuzumab (Gazyvaro) to treat chronic lymphocytic leukemia (CLL).

NICE CEO Sir Andrew Dillon said that although data suggest obinutuzumab is effective, there were too many “uncertainties” in the information submitted by Roche, the company developing the drug.

So NICE cannot be sure obinutuzumab would be an effective use of the National Health Service’s resources.

This is despite the fact that Roche offered to discount the drug’s list price of £26,496 per treatment course.

NICE is accepting comments on the draft guidance until 5 pm on October 23.

Obinutuzumab is a glycoengineered, humanized, monoclonal antibody that selectively binds to the extracellular domain of the CD20 antigen on B cells. The drug induces antibody-dependent cellular cytotoxicity and caspase-independent apoptosis.

The European Commission approved obinutuzumab in July for use in combination with chlorambucil to treat patients with previously untreated CLL who have comorbidities that make them ineligible to receive fludarabine-based therapy.

Obinutuzumab was approved for this indication in the US in November 2013.

Obinutuzumab is marketed as Gazyvaro in the European Union and Switzerland but as Gazyva in the US and the rest of the world.

Monoclonal antibodies

Credit: Linda Bartlett

In a new draft guidance, the UK’s National Institute for Health and Care Excellence (NICE) has said it cannot recommend obinutuzumab (Gazyvaro) to treat chronic lymphocytic leukemia (CLL).

NICE CEO Sir Andrew Dillon said that although data suggest obinutuzumab is effective, there were too many “uncertainties” in the information submitted by Roche, the company developing the drug.

So NICE cannot be sure obinutuzumab would be an effective use of the National Health Service’s resources.

This is despite the fact that Roche offered to discount the drug’s list price of £26,496 per treatment course.

NICE is accepting comments on the draft guidance until 5 pm on October 23.

Obinutuzumab is a glycoengineered, humanized, monoclonal antibody that selectively binds to the extracellular domain of the CD20 antigen on B cells. The drug induces antibody-dependent cellular cytotoxicity and caspase-independent apoptosis.

The European Commission approved obinutuzumab in July for use in combination with chlorambucil to treat patients with previously untreated CLL who have comorbidities that make them ineligible to receive fludarabine-based therapy.

Obinutuzumab was approved for this indication in the US in November 2013.

Obinutuzumab is marketed as Gazyvaro in the European Union and Switzerland but as Gazyva in the US and the rest of the world.

Monoclonal antibodies

Credit: Linda Bartlett

In a new draft guidance, the UK’s National Institute for Health and Care Excellence (NICE) has said it cannot recommend obinutuzumab (Gazyvaro) to treat chronic lymphocytic leukemia (CLL).

NICE CEO Sir Andrew Dillon said that although data suggest obinutuzumab is effective, there were too many “uncertainties” in the information submitted by Roche, the company developing the drug.

So NICE cannot be sure obinutuzumab would be an effective use of the National Health Service’s resources.

This is despite the fact that Roche offered to discount the drug’s list price of £26,496 per treatment course.

NICE is accepting comments on the draft guidance until 5 pm on October 23.

Obinutuzumab is a glycoengineered, humanized, monoclonal antibody that selectively binds to the extracellular domain of the CD20 antigen on B cells. The drug induces antibody-dependent cellular cytotoxicity and caspase-independent apoptosis.

The European Commission approved obinutuzumab in July for use in combination with chlorambucil to treat patients with previously untreated CLL who have comorbidities that make them ineligible to receive fludarabine-based therapy.

Obinutuzumab was approved for this indication in the US in November 2013.

Obinutuzumab is marketed as Gazyvaro in the European Union and Switzerland but as Gazyva in the US and the rest of the world.

Piglet

Credit: USDA

Scientists have created a novel drug capsule coated with tiny needles that can inject drugs directly into the lining of the stomach after the capsule is swallowed.

In experiments with pigs, the capsule delivered insulin more efficiently than an injection under the skin, and there were no harmful side effects as the capsule passed through the digestive system.

The researchers anticipate the capsule would be most useful for delivering biopharmaceuticals such as antibodies to treat cancers and other disorders.

“This could be a way that the patient can circumvent the need to have an infusion or subcutaneous administration of a drug,” said Giovanni Traverso, MB BChir, PhD, of Massachusetts General Hospital in Boston.

He and his colleagues described their capsule in the Journal of Pharmaceutical Sciences.

The team had set out to design a capsule that would serve as a platform for the delivery of a wide range of therapeutics, prevent degradation of the drugs, and inject the payload directly into the lining of the gastrointestinal tract.

Their prototype acrylic capsule, 2 cm long and 1 cm in diameter, includes a reservoir for the drug and is coated with hollow, stainless steel needles about 5 mm long.

Previous studies of accidental ingestion of sharp objects in human patients have suggested that it could be safe to swallow a capsule coated with short needles. Because there are no pain receptors in the gastrointestinal tract, patients would not feel any pain from the drug injection.

To test whether this type of capsule could allow safe and effective drug delivery, the researchers tested it in pigs, with insulin as the drug payload.

It took more than a week for the capsules to move through the entire digestive tract, and the researchers found no traces of tissue damage, supporting the potential safety of this novel approach.

They also found the microneedles successfully injected insulin into the lining of the stomach, small intestine, and colon, causing the animals’ blood glucose levels to drop. This reduction in blood glucose was faster and larger than the drop seen when the same amount of glucose was given by subcutaneous injection.

“The kinetics are much better, and much faster-onset, than those seen with traditional under-the-skin administration,” Dr Traverso said. “For molecules that are particularly difficult to absorb, this would be a way of actually administering them at much higher efficiency.”

This approach could also be used to administer vaccines that normally have to be injected, the researchers said.

The team now plans to modify the capsule so that peristalsis would slowly squeeze the drug out of the capsule as it travels through the digestive tract.

They are also working on capsules with needles made of degradable polymers and sugar that would break off and become embedded in the gut lining, where they would slowly disintegrate and release the drug. This would further minimize any safety concern.

Piglet

Credit: USDA

Scientists have created a novel drug capsule coated with tiny needles that can inject drugs directly into the lining of the stomach after the capsule is swallowed.

In experiments with pigs, the capsule delivered insulin more efficiently than an injection under the skin, and there were no harmful side effects as the capsule passed through the digestive system.

The researchers anticipate the capsule would be most useful for delivering biopharmaceuticals such as antibodies to treat cancers and other disorders.

“This could be a way that the patient can circumvent the need to have an infusion or subcutaneous administration of a drug,” said Giovanni Traverso, MB BChir, PhD, of Massachusetts General Hospital in Boston.

He and his colleagues described their capsule in the Journal of Pharmaceutical Sciences.

The team had set out to design a capsule that would serve as a platform for the delivery of a wide range of therapeutics, prevent degradation of the drugs, and inject the payload directly into the lining of the gastrointestinal tract.

Their prototype acrylic capsule, 2 cm long and 1 cm in diameter, includes a reservoir for the drug and is coated with hollow, stainless steel needles about 5 mm long.

Previous studies of accidental ingestion of sharp objects in human patients have suggested that it could be safe to swallow a capsule coated with short needles. Because there are no pain receptors in the gastrointestinal tract, patients would not feel any pain from the drug injection.

To test whether this type of capsule could allow safe and effective drug delivery, the researchers tested it in pigs, with insulin as the drug payload.

It took more than a week for the capsules to move through the entire digestive tract, and the researchers found no traces of tissue damage, supporting the potential safety of this novel approach.

They also found the microneedles successfully injected insulin into the lining of the stomach, small intestine, and colon, causing the animals’ blood glucose levels to drop. This reduction in blood glucose was faster and larger than the drop seen when the same amount of glucose was given by subcutaneous injection.

“The kinetics are much better, and much faster-onset, than those seen with traditional under-the-skin administration,” Dr Traverso said. “For molecules that are particularly difficult to absorb, this would be a way of actually administering them at much higher efficiency.”

This approach could also be used to administer vaccines that normally have to be injected, the researchers said.

The team now plans to modify the capsule so that peristalsis would slowly squeeze the drug out of the capsule as it travels through the digestive tract.

They are also working on capsules with needles made of degradable polymers and sugar that would break off and become embedded in the gut lining, where they would slowly disintegrate and release the drug. This would further minimize any safety concern.

Piglet

Credit: USDA

Scientists have created a novel drug capsule coated with tiny needles that can inject drugs directly into the lining of the stomach after the capsule is swallowed.

In experiments with pigs, the capsule delivered insulin more efficiently than an injection under the skin, and there were no harmful side effects as the capsule passed through the digestive system.

The researchers anticipate the capsule would be most useful for delivering biopharmaceuticals such as antibodies to treat cancers and other disorders.

“This could be a way that the patient can circumvent the need to have an infusion or subcutaneous administration of a drug,” said Giovanni Traverso, MB BChir, PhD, of Massachusetts General Hospital in Boston.

He and his colleagues described their capsule in the Journal of Pharmaceutical Sciences.

The team had set out to design a capsule that would serve as a platform for the delivery of a wide range of therapeutics, prevent degradation of the drugs, and inject the payload directly into the lining of the gastrointestinal tract.

Their prototype acrylic capsule, 2 cm long and 1 cm in diameter, includes a reservoir for the drug and is coated with hollow, stainless steel needles about 5 mm long.

Previous studies of accidental ingestion of sharp objects in human patients have suggested that it could be safe to swallow a capsule coated with short needles. Because there are no pain receptors in the gastrointestinal tract, patients would not feel any pain from the drug injection.

To test whether this type of capsule could allow safe and effective drug delivery, the researchers tested it in pigs, with insulin as the drug payload.

It took more than a week for the capsules to move through the entire digestive tract, and the researchers found no traces of tissue damage, supporting the potential safety of this novel approach.

They also found the microneedles successfully injected insulin into the lining of the stomach, small intestine, and colon, causing the animals’ blood glucose levels to drop. This reduction in blood glucose was faster and larger than the drop seen when the same amount of glucose was given by subcutaneous injection.

“The kinetics are much better, and much faster-onset, than those seen with traditional under-the-skin administration,” Dr Traverso said. “For molecules that are particularly difficult to absorb, this would be a way of actually administering them at much higher efficiency.”

This approach could also be used to administer vaccines that normally have to be injected, the researchers said.

The team now plans to modify the capsule so that peristalsis would slowly squeeze the drug out of the capsule as it travels through the digestive tract.

They are also working on capsules with needles made of degradable polymers and sugar that would break off and become embedded in the gut lining, where they would slowly disintegrate and release the drug. This would further minimize any safety concern.

CHICAGO – A premenopausal breast cancer patient’s follicle-stimulating hormone level upon completion of chemotherapy predicts her risk of bone loss during the ensuing 12 months, Dr. Laila S. Tabatabai reported at the joint meeting of the International Congress of Endocrinology and the Endocrine Society.

“This may have significant implications for preserving bone health in premenopausal women with breast cancer. Appropriate use of FSH as a marker for premature ovarian failure and as a predictor of bone loss after breast cancer treatment may allow for the timely implementation of preventive measures to reduce fracture risk,” said Dr. Tabatabai of Johns Hopkins University, Baltimore.

© iStock / ThinkStockPhotos.com

She presented a secondary analysis from the Exercise for Bone Health: Young Breast Cancer Survivors Study, in which 206 women who were under age 55 and had completed adjuvant chemotherapy for breast cancer were randomized to a 12-month structured exercise program conducted through the YMCA or to a control group that received a monthly health newsletter.

Investigators measured baseline levels of FSH, bone turnover markers, calciotropic hormones, and high-sensitivity C-reactive protein. At 1 year follow-up, only baseline FSH level was significantly related to bone loss.

After adjustment for age, ethnicity, baseline bone mineral density, and assignment to the exercise or control arm, multivariate analysis showed that only women in the lowest tertile for baseline FSH – that is, a level of 21.1 IU/L or less – maintained their baseline bone mineral density at the lumbar spine. They averaged a 0.007% increase over 12 months. In contrast, women in the middle tertile, with a baseline FSH of 21.2-61.6 IU/L, had a mean 0.96% decrease in bone density, and those in the highest tertile, with an FSH of 61.7-124.6 IU/L, averaged a 2.2% bone loss.

“Of note, bone loss was seen with an FSH greater than 21 IU/L, a lower level than is typical of diagnostic criteria for premature ovarian failure,” Dr. Tabatabai observed.

Tamoxifen therapy, time since chemotherapy, and baseline estradiol levels were not related to bone loss or preservation. Baseline CTX (urinary C-terminal crosslinking telopeptide) was the only bone turnover marker associated with subsequent bone loss, but this relationship was marginal.

Also noteworthy was the finding that absence of menstruation did not predict bone loss, said Dr. Tabatabai. Less than 60% of women in the lowest FSH tertile reported menstruating both at baseline and at 12 months, yet they maintained bone mass.

Chemotherapy in premenopausal women often results in premature ovarian failure, bone loss, and amenorrhea. This comes about because the medications damage ovarian follicles and steroid-producing cells, with resultant reduced production of estradiol and inhibin B. This results in loss of feedback inhibition of pituitary gonadotropins along with increased FSH levels, Dr. Tabatabai explained.

She said that since hers is the first study to look at biomarkers to predict bone loss in premenopausal breast cancer patients after chemotherapy, the findings need confirmation. Further studies also should aim to pin down the optimal timing of FSH measurement in relation to breast cancer treatment.

[email protected]

CHICAGO – A premenopausal breast cancer patient’s follicle-stimulating hormone level upon completion of chemotherapy predicts her risk of bone loss during the ensuing 12 months, Dr. Laila S. Tabatabai reported at the joint meeting of the International Congress of Endocrinology and the Endocrine Society.

“This may have significant implications for preserving bone health in premenopausal women with breast cancer. Appropriate use of FSH as a marker for premature ovarian failure and as a predictor of bone loss after breast cancer treatment may allow for the timely implementation of preventive measures to reduce fracture risk,” said Dr. Tabatabai of Johns Hopkins University, Baltimore.

© iStock / ThinkStockPhotos.com

She presented a secondary analysis from the Exercise for Bone Health: Young Breast Cancer Survivors Study, in which 206 women who were under age 55 and had completed adjuvant chemotherapy for breast cancer were randomized to a 12-month structured exercise program conducted through the YMCA or to a control group that received a monthly health newsletter.

Investigators measured baseline levels of FSH, bone turnover markers, calciotropic hormones, and high-sensitivity C-reactive protein. At 1 year follow-up, only baseline FSH level was significantly related to bone loss.

After adjustment for age, ethnicity, baseline bone mineral density, and assignment to the exercise or control arm, multivariate analysis showed that only women in the lowest tertile for baseline FSH – that is, a level of 21.1 IU/L or less – maintained their baseline bone mineral density at the lumbar spine. They averaged a 0.007% increase over 12 months. In contrast, women in the middle tertile, with a baseline FSH of 21.2-61.6 IU/L, had a mean 0.96% decrease in bone density, and those in the highest tertile, with an FSH of 61.7-124.6 IU/L, averaged a 2.2% bone loss.

“Of note, bone loss was seen with an FSH greater than 21 IU/L, a lower level than is typical of diagnostic criteria for premature ovarian failure,” Dr. Tabatabai observed.

Tamoxifen therapy, time since chemotherapy, and baseline estradiol levels were not related to bone loss or preservation. Baseline CTX (urinary C-terminal crosslinking telopeptide) was the only bone turnover marker associated with subsequent bone loss, but this relationship was marginal.

Also noteworthy was the finding that absence of menstruation did not predict bone loss, said Dr. Tabatabai. Less than 60% of women in the lowest FSH tertile reported menstruating both at baseline and at 12 months, yet they maintained bone mass.

Chemotherapy in premenopausal women often results in premature ovarian failure, bone loss, and amenorrhea. This comes about because the medications damage ovarian follicles and steroid-producing cells, with resultant reduced production of estradiol and inhibin B. This results in loss of feedback inhibition of pituitary gonadotropins along with increased FSH levels, Dr. Tabatabai explained.

She said that since hers is the first study to look at biomarkers to predict bone loss in premenopausal breast cancer patients after chemotherapy, the findings need confirmation. Further studies also should aim to pin down the optimal timing of FSH measurement in relation to breast cancer treatment.

[email protected]

CHICAGO – A premenopausal breast cancer patient’s follicle-stimulating hormone level upon completion of chemotherapy predicts her risk of bone loss during the ensuing 12 months, Dr. Laila S. Tabatabai reported at the joint meeting of the International Congress of Endocrinology and the Endocrine Society.

“This may have significant implications for preserving bone health in premenopausal women with breast cancer. Appropriate use of FSH as a marker for premature ovarian failure and as a predictor of bone loss after breast cancer treatment may allow for the timely implementation of preventive measures to reduce fracture risk,” said Dr. Tabatabai of Johns Hopkins University, Baltimore.

© iStock / ThinkStockPhotos.com

She presented a secondary analysis from the Exercise for Bone Health: Young Breast Cancer Survivors Study, in which 206 women who were under age 55 and had completed adjuvant chemotherapy for breast cancer were randomized to a 12-month structured exercise program conducted through the YMCA or to a control group that received a monthly health newsletter.

Investigators measured baseline levels of FSH, bone turnover markers, calciotropic hormones, and high-sensitivity C-reactive protein. At 1 year follow-up, only baseline FSH level was significantly related to bone loss.

After adjustment for age, ethnicity, baseline bone mineral density, and assignment to the exercise or control arm, multivariate analysis showed that only women in the lowest tertile for baseline FSH – that is, a level of 21.1 IU/L or less – maintained their baseline bone mineral density at the lumbar spine. They averaged a 0.007% increase over 12 months. In contrast, women in the middle tertile, with a baseline FSH of 21.2-61.6 IU/L, had a mean 0.96% decrease in bone density, and those in the highest tertile, with an FSH of 61.7-124.6 IU/L, averaged a 2.2% bone loss.

“Of note, bone loss was seen with an FSH greater than 21 IU/L, a lower level than is typical of diagnostic criteria for premature ovarian failure,” Dr. Tabatabai observed.

Tamoxifen therapy, time since chemotherapy, and baseline estradiol levels were not related to bone loss or preservation. Baseline CTX (urinary C-terminal crosslinking telopeptide) was the only bone turnover marker associated with subsequent bone loss, but this relationship was marginal.

Also noteworthy was the finding that absence of menstruation did not predict bone loss, said Dr. Tabatabai. Less than 60% of women in the lowest FSH tertile reported menstruating both at baseline and at 12 months, yet they maintained bone mass.

Chemotherapy in premenopausal women often results in premature ovarian failure, bone loss, and amenorrhea. This comes about because the medications damage ovarian follicles and steroid-producing cells, with resultant reduced production of estradiol and inhibin B. This results in loss of feedback inhibition of pituitary gonadotropins along with increased FSH levels, Dr. Tabatabai explained.

She said that since hers is the first study to look at biomarkers to predict bone loss in premenopausal breast cancer patients after chemotherapy, the findings need confirmation. Further studies also should aim to pin down the optimal timing of FSH measurement in relation to breast cancer treatment.

[email protected]

SANTA CLARA, CALIF. – When Dr. Omar Dawood demonstrated the AliveCor Heart Monitor with a new app and algorithm for detecting atrial fibrillation on stage at the Health 2.0 fall conference 2014, it showed that his heart was in normal sinus rhythm – but he had a heart rate of 135 beats per minute.

Chalk it up to the excitement of speaking before an audience of physicians and technologists about this new mobile ECG tool, Dr. Dawood said. “I’m not always that anxious.”

The AliveCor device attaches to the back of iPhones or Android-based smartphones and sells for $60-$199, depending on the model of smartphone. The Food and Drug Administration approved it in 2013, and patients have used it since March 2014. The device sends an ECG reading to a cardiologist or cardiac technician, who sends a reply within 24 hours.

With the new, free app, however, patients get an immediate result from the device showing whether or not they are likely to have atrial fibrillation. The FDA cleared the algorithm for the app in August 2014, and the company launched it on the marketplace at the Health 2.0 conference.

Validation studies have shown that the AliveCor system performs comparably to a traditional 12-lead ECG, Dr. Dawood said in a video interview.

For other recent news on studies of AliveCor in clinical settings, see our Evidence-Based Apps column.

Dr. Dawood, a surgeon by training, is a clinical adviser at AliveCor and also works for a separate technology company.

[email protected]


On Twitter @sherryboschert

SANTA CLARA, CALIF. – When Dr. Omar Dawood demonstrated the AliveCor Heart Monitor with a new app and algorithm for detecting atrial fibrillation on stage at the Health 2.0 fall conference 2014, it showed that his heart was in normal sinus rhythm – but he had a heart rate of 135 beats per minute.

Chalk it up to the excitement of speaking before an audience of physicians and technologists about this new mobile ECG tool, Dr. Dawood said. “I’m not always that anxious.”

The AliveCor device attaches to the back of iPhones or Android-based smartphones and sells for $60-$199, depending on the model of smartphone. The Food and Drug Administration approved it in 2013, and patients have used it since March 2014. The device sends an ECG reading to a cardiologist or cardiac technician, who sends a reply within 24 hours.

With the new, free app, however, patients get an immediate result from the device showing whether or not they are likely to have atrial fibrillation. The FDA cleared the algorithm for the app in August 2014, and the company launched it on the marketplace at the Health 2.0 conference.

Validation studies have shown that the AliveCor system performs comparably to a traditional 12-lead ECG, Dr. Dawood said in a video interview.

For other recent news on studies of AliveCor in clinical settings, see our Evidence-Based Apps column.

Dr. Dawood, a surgeon by training, is a clinical adviser at AliveCor and also works for a separate technology company.

[email protected]


On Twitter @sherryboschert

SANTA CLARA, CALIF. – When Dr. Omar Dawood demonstrated the AliveCor Heart Monitor with a new app and algorithm for detecting atrial fibrillation on stage at the Health 2.0 fall conference 2014, it showed that his heart was in normal sinus rhythm – but he had a heart rate of 135 beats per minute.

Chalk it up to the excitement of speaking before an audience of physicians and technologists about this new mobile ECG tool, Dr. Dawood said. “I’m not always that anxious.”

The AliveCor device attaches to the back of iPhones or Android-based smartphones and sells for $60-$199, depending on the model of smartphone. The Food and Drug Administration approved it in 2013, and patients have used it since March 2014. The device sends an ECG reading to a cardiologist or cardiac technician, who sends a reply within 24 hours.

With the new, free app, however, patients get an immediate result from the device showing whether or not they are likely to have atrial fibrillation. The FDA cleared the algorithm for the app in August 2014, and the company launched it on the marketplace at the Health 2.0 conference.

Validation studies have shown that the AliveCor system performs comparably to a traditional 12-lead ECG, Dr. Dawood said in a video interview.

For other recent news on studies of AliveCor in clinical settings, see our Evidence-Based Apps column.

Dr. Dawood, a surgeon by training, is a clinical adviser at AliveCor and also works for a separate technology company.

[email protected]


On Twitter @sherryboschert