Study Overview

Objective. To determine the efficacy, both short and long term, of a behavioral intervention targeting overweight parents and their children simultaneously versus an intervention focused on weight management only for the child within the patient-centered medical home (PCMH).

Design. 4-center, 2-arm, randomized controlled trial.

Setting and participants. Study participants were recruited from 4 urban/suburban pediatric practices. Primary care providers (PCPs) recruited patients at the time of well or sick visits based on body mass index (BMI) flagged prior to the visit by Patient Enhancement Assistants (PEAs). 171 parent/child dyads were assessed for eligibility and 105 were randomized in blocks of 12 dyads using a random number generator and stratified by child’s gender. Pediatricians were blind to their patient’s group assignments. Inclusion criteria were as follows: children aged 2–5 with a BMI higher than the 85th percentile for both age and gender, and 1 parent with a BMI greater than 25. Exclusion criteria were limited to children who were small for gestational age and/or short stature, and child or parent inability to perform physical activity. Specific precautions were taken to prevent contamination between intervention and information control (IC) groups [1].

Intervention. Three PEAs who held a masters or bachelors degree in psychology, nutrition, exercise science, or equivalent, or were registered dietitians, were embedded within each PCMH practice. For both the intervention and IC groups, parents attended 13 one-hour group sessions led by a PEA over a 12-month period, followed by a 12-month follow-up period with 3 additional meetings. The PEA telephoned parents between scheduled meetings. Pediatricians reviewed child’s weight changes every 6 months during scheduled appointments and the PEA sent progress notes in between these visits [2]. Dietary, physical, and sedentary activity guidelines were given based on the recommendations of a national multi-organizational expert committee [3]. Parents were given specific goals for their child, including a 0.5- to 1-pound per week loss, 60 minutes per day of physical activity, and limiting TV and screen time to less than 2 hours per day.

In addition, the intervention group received parenting and behavior change strategies to promote both parent and child weight loss. Parents were instructed to weigh themselves and their child once per week and monitor physical activity and diet. They received individual meetings with the PEA before or after group meetings to review goal setting and food/physical activity diaries. Parents were also given a weight loss goal of 1 to 2 pounds per week and were advised to model physical activity by engaging in active play with their child for at least 10 minutes per day.

Main outcome measures. The main outcome measures were %0BMI and z-BMI. Percent 0BMI is defined as [(child’s BMI – 50th percentile BMI)/50th percentile BMI] x 100 [2]. The authors chose %0BMI as the primary outcome measure because z-BMI can diminish the effect of weight change in heavier children [4]. Both measures were expressed as mean ± standard error (SEM). Parent weight change was measured using BMI alone.

The child’s weight was measured at each session and height was measured at baseline, 3, 6, 12, 18, and 24 months. Parent weight was measured every session in the intervention group, but only at baseline, 6, 12, 18, and 24 months in the IC group. A standardized protocol was followed for all height and weight measurements. An intention to treat analysis (ITT) was conducted on all parent/child dyads, regardless of whether or not they completed the study (n = 96).

Results. Research assistants assessed 171 parent/child dyads for eligibility. 66 were excluded for either not meeting inclusion criteria (n = 24) or declining to participate (n = 42). 105 dyads were randomized, but 9 did not receive the allocated intervention because they did not start the study, resulting in a total of 96 dyads included in analysis: 46 in the intervention group and 50 in the IC. Twelve- and 24-month completion rates were 83% and 73% respectively; there was no difference in attrition between intervention and IC groups.

The mean child ages of the intervention and IC groups were 4.6 ± 0.2 and 4.4 ± 0.2 years, respectively. 33 of the 46 children in the intervention group and 37 of the 50 children in the IC group were identified as non-Hispanic white. The mean yearly income of all families was $65,729 ± $3068, with only 8.3% of families below $20,000.

The intervention group had greater decreases in child %0BMI from baseline to 6, 12, 18, and 24 months than the IC group. Similar trends were seen with child z-BMI. A slower increase in height was observed in the intervention group when compared with the IC at both 18 months (P < 0.001) and at 24 months (P < 0.02). Parents showed greater overall BMI reduction in the intervention group as opposed to the IC group at all time points (P < 0.001). BMI changes achieved at 6 months were maintained at 24 months. %0BMI and parent BMI changes were correlated from baseline to 12, 18, and 24 months. No significant baseline moderators were found among the children in either group.

Conclusion. This study demonstrated that within the PCMH model of pediatric primary care, an intervention focused on joint behavior change and weight modification treatment of parents and children led to better initial and sustained improvements in %0BMI and z-BMI (in children) and BMI (in parents) than a child-focused IC.

Commentary

Over one-third of children and adolescents are considered to be overweight or have obesity, a number that has doubled in the past 30 years [5]. Pediatrician and primary care physician visits are optimal places to identify overweight children who are at risk for obesity and begin prevention measures, although identifying overweight and obese younger children can be difficult [6]. This study used PEAs to aid physicians in identification, implementation, and delivery. With increasing evidence to support pediatrician involvement in intensive weight management in a primary versus specialty care setting, embedding PEAs within the PCMH model may be an important way to help deliver care for overweight/obese children [7].

Although many approaches have been considered to target childhood obesity, this study represents an important contribution to the literature because it demonstrates that a primary care–based intervention targeting parents as well as their young children is more efficacious for weight management than a more traditional, child-only focused intervention. In addition, the intervention included many different evidence-based components such as teaching behavior modification techniques to parents, consideration of parenting styles and techniques, and encouraging simultaneous parental weight modification. While the U.S. Preventive Services Task Force (USPSTF) recommends intensive interventions with 30 sessions over 2 years [8], this study was able to accomplish significant weight change in 13 sessions.

This intervention is unique in its integration of parenting techniques with other evidence-based strategies for child weight management. Although it has been shown in the literature that certain parenting styles can positively impact children’s health behaviors [9], namely the use of positive reinforcement and monitoring children’s health practices [10], only a few studies have looked at the impact of parenting interventions on childhood obesity. Mazzeo et al demonstrated a significant reduction in child BMI with a parenting-only intervention in the NOURISH trial [11], Slusser et al found a significant child BMI reduction using parent training for low-income, 2- to 4-year-old children [12], and Brotman et al conducted a longitudinal study demonstrating that a family intervention could decrease BMI and improve overall child health behaviors [13]. Despite these aforementioned studies, there is a lack of longitudinal data on the association between general parenting style and weight [14], and this study addresses this gap in literature by providing 2-year follow-up and demonstrating sustained impact on the intervention group.

This study had many additional strengths, including randomized design, primary care physician blinding, use of intention to treat analysis, standardization of measurement tools, clear justification of sample size, long-term follow-up, and the use of child-appropriate BMI measures (eg, %0BMI vs. z-BMI as primary outcome measure). In addition, the intervention setting in a PCMH follows the trend of increasing interest in exploring this model of health care delivery [15,16]. It is also important to note that the intervention and IC groups received the same number of group visits and phone calls, the only difference being the content and the extra 1:1 PEA sessions received by the intervention group.

The few weaknesses include that the PEAs could not be blinded to treatment allocation, and generalizability is limited by the mostly non-Hispanic white population and that only 8.3% of the study population had an annual household income of less than $20,000. All parents included in this study were on the high end of the obese range (BMI 30–39.9), with baseline BMI values of 37.2 and 36.2 in the intervention and IC groups respectively. In addition, the age of the children included in the study were on the high end of the designated 2- to 5-year-old range: 4.6 years (IC) and 4.4 years (intervention). Although findings were promising within this specific population, further research in younger and more diverse populations is necessary [11].

Finally, it is unclear whether this intervention is scalable, and a cost-effectiveness analysis of this intervention is needed. This study was designed to limit the PCP’s role and simplify the process of identifying and intervening on overweight children and their parents, yet this required 3 part-time PEAs and a project coordinator responsible for delivering all of the group sessions and providing follow-up counseling to both intervention and IC groups.

Applications for Clinical Practice

This study demonstrates that in a mostly white, urban/suburban population, a parenting and behavior modification intervention focused on both parent and child leads to greater improvements in %0BMI and z-BMI in the child and BMI reduction in parents compared with an intervention focused on the child alone within pediatric PCMH practices. This intervention should be tested in more diverse populations. This study also suggests further exploration of the use of PEAs to help clinicians address obesity within the PCMH model of primary care.

—Natalie Berner, BA, and Melanie Jay, MD, MS

Study Overview

Objective. To determine the efficacy, both short and long term, of a behavioral intervention targeting overweight parents and their children simultaneously versus an intervention focused on weight management only for the child within the patient-centered medical home (PCMH).

Design. 4-center, 2-arm, randomized controlled trial.

Setting and participants. Study participants were recruited from 4 urban/suburban pediatric practices. Primary care providers (PCPs) recruited patients at the time of well or sick visits based on body mass index (BMI) flagged prior to the visit by Patient Enhancement Assistants (PEAs). 171 parent/child dyads were assessed for eligibility and 105 were randomized in blocks of 12 dyads using a random number generator and stratified by child’s gender. Pediatricians were blind to their patient’s group assignments. Inclusion criteria were as follows: children aged 2–5 with a BMI higher than the 85th percentile for both age and gender, and 1 parent with a BMI greater than 25. Exclusion criteria were limited to children who were small for gestational age and/or short stature, and child or parent inability to perform physical activity. Specific precautions were taken to prevent contamination between intervention and information control (IC) groups [1].

Intervention. Three PEAs who held a masters or bachelors degree in psychology, nutrition, exercise science, or equivalent, or were registered dietitians, were embedded within each PCMH practice. For both the intervention and IC groups, parents attended 13 one-hour group sessions led by a PEA over a 12-month period, followed by a 12-month follow-up period with 3 additional meetings. The PEA telephoned parents between scheduled meetings. Pediatricians reviewed child’s weight changes every 6 months during scheduled appointments and the PEA sent progress notes in between these visits [2]. Dietary, physical, and sedentary activity guidelines were given based on the recommendations of a national multi-organizational expert committee [3]. Parents were given specific goals for their child, including a 0.5- to 1-pound per week loss, 60 minutes per day of physical activity, and limiting TV and screen time to less than 2 hours per day.

In addition, the intervention group received parenting and behavior change strategies to promote both parent and child weight loss. Parents were instructed to weigh themselves and their child once per week and monitor physical activity and diet. They received individual meetings with the PEA before or after group meetings to review goal setting and food/physical activity diaries. Parents were also given a weight loss goal of 1 to 2 pounds per week and were advised to model physical activity by engaging in active play with their child for at least 10 minutes per day.

Main outcome measures. The main outcome measures were %0BMI and z-BMI. Percent 0BMI is defined as [(child’s BMI – 50th percentile BMI)/50th percentile BMI] x 100 [2]. The authors chose %0BMI as the primary outcome measure because z-BMI can diminish the effect of weight change in heavier children [4]. Both measures were expressed as mean ± standard error (SEM). Parent weight change was measured using BMI alone.

The child’s weight was measured at each session and height was measured at baseline, 3, 6, 12, 18, and 24 months. Parent weight was measured every session in the intervention group, but only at baseline, 6, 12, 18, and 24 months in the IC group. A standardized protocol was followed for all height and weight measurements. An intention to treat analysis (ITT) was conducted on all parent/child dyads, regardless of whether or not they completed the study (n = 96).

Results. Research assistants assessed 171 parent/child dyads for eligibility. 66 were excluded for either not meeting inclusion criteria (n = 24) or declining to participate (n = 42). 105 dyads were randomized, but 9 did not receive the allocated intervention because they did not start the study, resulting in a total of 96 dyads included in analysis: 46 in the intervention group and 50 in the IC. Twelve- and 24-month completion rates were 83% and 73% respectively; there was no difference in attrition between intervention and IC groups.

The mean child ages of the intervention and IC groups were 4.6 ± 0.2 and 4.4 ± 0.2 years, respectively. 33 of the 46 children in the intervention group and 37 of the 50 children in the IC group were identified as non-Hispanic white. The mean yearly income of all families was $65,729 ± $3068, with only 8.3% of families below $20,000.

The intervention group had greater decreases in child %0BMI from baseline to 6, 12, 18, and 24 months than the IC group. Similar trends were seen with child z-BMI. A slower increase in height was observed in the intervention group when compared with the IC at both 18 months (P < 0.001) and at 24 months (P < 0.02). Parents showed greater overall BMI reduction in the intervention group as opposed to the IC group at all time points (P < 0.001). BMI changes achieved at 6 months were maintained at 24 months. %0BMI and parent BMI changes were correlated from baseline to 12, 18, and 24 months. No significant baseline moderators were found among the children in either group.

Conclusion. This study demonstrated that within the PCMH model of pediatric primary care, an intervention focused on joint behavior change and weight modification treatment of parents and children led to better initial and sustained improvements in %0BMI and z-BMI (in children) and BMI (in parents) than a child-focused IC.

Commentary

Over one-third of children and adolescents are considered to be overweight or have obesity, a number that has doubled in the past 30 years [5]. Pediatrician and primary care physician visits are optimal places to identify overweight children who are at risk for obesity and begin prevention measures, although identifying overweight and obese younger children can be difficult [6]. This study used PEAs to aid physicians in identification, implementation, and delivery. With increasing evidence to support pediatrician involvement in intensive weight management in a primary versus specialty care setting, embedding PEAs within the PCMH model may be an important way to help deliver care for overweight/obese children [7].

Although many approaches have been considered to target childhood obesity, this study represents an important contribution to the literature because it demonstrates that a primary care–based intervention targeting parents as well as their young children is more efficacious for weight management than a more traditional, child-only focused intervention. In addition, the intervention included many different evidence-based components such as teaching behavior modification techniques to parents, consideration of parenting styles and techniques, and encouraging simultaneous parental weight modification. While the U.S. Preventive Services Task Force (USPSTF) recommends intensive interventions with 30 sessions over 2 years [8], this study was able to accomplish significant weight change in 13 sessions.

This intervention is unique in its integration of parenting techniques with other evidence-based strategies for child weight management. Although it has been shown in the literature that certain parenting styles can positively impact children’s health behaviors [9], namely the use of positive reinforcement and monitoring children’s health practices [10], only a few studies have looked at the impact of parenting interventions on childhood obesity. Mazzeo et al demonstrated a significant reduction in child BMI with a parenting-only intervention in the NOURISH trial [11], Slusser et al found a significant child BMI reduction using parent training for low-income, 2- to 4-year-old children [12], and Brotman et al conducted a longitudinal study demonstrating that a family intervention could decrease BMI and improve overall child health behaviors [13]. Despite these aforementioned studies, there is a lack of longitudinal data on the association between general parenting style and weight [14], and this study addresses this gap in literature by providing 2-year follow-up and demonstrating sustained impact on the intervention group.

This study had many additional strengths, including randomized design, primary care physician blinding, use of intention to treat analysis, standardization of measurement tools, clear justification of sample size, long-term follow-up, and the use of child-appropriate BMI measures (eg, %0BMI vs. z-BMI as primary outcome measure). In addition, the intervention setting in a PCMH follows the trend of increasing interest in exploring this model of health care delivery [15,16]. It is also important to note that the intervention and IC groups received the same number of group visits and phone calls, the only difference being the content and the extra 1:1 PEA sessions received by the intervention group.

The few weaknesses include that the PEAs could not be blinded to treatment allocation, and generalizability is limited by the mostly non-Hispanic white population and that only 8.3% of the study population had an annual household income of less than $20,000. All parents included in this study were on the high end of the obese range (BMI 30–39.9), with baseline BMI values of 37.2 and 36.2 in the intervention and IC groups respectively. In addition, the age of the children included in the study were on the high end of the designated 2- to 5-year-old range: 4.6 years (IC) and 4.4 years (intervention). Although findings were promising within this specific population, further research in younger and more diverse populations is necessary [11].

Finally, it is unclear whether this intervention is scalable, and a cost-effectiveness analysis of this intervention is needed. This study was designed to limit the PCP’s role and simplify the process of identifying and intervening on overweight children and their parents, yet this required 3 part-time PEAs and a project coordinator responsible for delivering all of the group sessions and providing follow-up counseling to both intervention and IC groups.

Applications for Clinical Practice

This study demonstrates that in a mostly white, urban/suburban population, a parenting and behavior modification intervention focused on both parent and child leads to greater improvements in %0BMI and z-BMI in the child and BMI reduction in parents compared with an intervention focused on the child alone within pediatric PCMH practices. This intervention should be tested in more diverse populations. This study also suggests further exploration of the use of PEAs to help clinicians address obesity within the PCMH model of primary care.

—Natalie Berner, BA, and Melanie Jay, MD, MS

Study Overview

Objective. To determine the efficacy, both short and long term, of a behavioral intervention targeting overweight parents and their children simultaneously versus an intervention focused on weight management only for the child within the patient-centered medical home (PCMH).

Design. 4-center, 2-arm, randomized controlled trial.

Setting and participants. Study participants were recruited from 4 urban/suburban pediatric practices. Primary care providers (PCPs) recruited patients at the time of well or sick visits based on body mass index (BMI) flagged prior to the visit by Patient Enhancement Assistants (PEAs). 171 parent/child dyads were assessed for eligibility and 105 were randomized in blocks of 12 dyads using a random number generator and stratified by child’s gender. Pediatricians were blind to their patient’s group assignments. Inclusion criteria were as follows: children aged 2–5 with a BMI higher than the 85th percentile for both age and gender, and 1 parent with a BMI greater than 25. Exclusion criteria were limited to children who were small for gestational age and/or short stature, and child or parent inability to perform physical activity. Specific precautions were taken to prevent contamination between intervention and information control (IC) groups [1].

Intervention. Three PEAs who held a masters or bachelors degree in psychology, nutrition, exercise science, or equivalent, or were registered dietitians, were embedded within each PCMH practice. For both the intervention and IC groups, parents attended 13 one-hour group sessions led by a PEA over a 12-month period, followed by a 12-month follow-up period with 3 additional meetings. The PEA telephoned parents between scheduled meetings. Pediatricians reviewed child’s weight changes every 6 months during scheduled appointments and the PEA sent progress notes in between these visits [2]. Dietary, physical, and sedentary activity guidelines were given based on the recommendations of a national multi-organizational expert committee [3]. Parents were given specific goals for their child, including a 0.5- to 1-pound per week loss, 60 minutes per day of physical activity, and limiting TV and screen time to less than 2 hours per day.

In addition, the intervention group received parenting and behavior change strategies to promote both parent and child weight loss. Parents were instructed to weigh themselves and their child once per week and monitor physical activity and diet. They received individual meetings with the PEA before or after group meetings to review goal setting and food/physical activity diaries. Parents were also given a weight loss goal of 1 to 2 pounds per week and were advised to model physical activity by engaging in active play with their child for at least 10 minutes per day.

Main outcome measures. The main outcome measures were %0BMI and z-BMI. Percent 0BMI is defined as [(child’s BMI – 50th percentile BMI)/50th percentile BMI] x 100 [2]. The authors chose %0BMI as the primary outcome measure because z-BMI can diminish the effect of weight change in heavier children [4]. Both measures were expressed as mean ± standard error (SEM). Parent weight change was measured using BMI alone.

The child’s weight was measured at each session and height was measured at baseline, 3, 6, 12, 18, and 24 months. Parent weight was measured every session in the intervention group, but only at baseline, 6, 12, 18, and 24 months in the IC group. A standardized protocol was followed for all height and weight measurements. An intention to treat analysis (ITT) was conducted on all parent/child dyads, regardless of whether or not they completed the study (n = 96).

Results. Research assistants assessed 171 parent/child dyads for eligibility. 66 were excluded for either not meeting inclusion criteria (n = 24) or declining to participate (n = 42). 105 dyads were randomized, but 9 did not receive the allocated intervention because they did not start the study, resulting in a total of 96 dyads included in analysis: 46 in the intervention group and 50 in the IC. Twelve- and 24-month completion rates were 83% and 73% respectively; there was no difference in attrition between intervention and IC groups.

The mean child ages of the intervention and IC groups were 4.6 ± 0.2 and 4.4 ± 0.2 years, respectively. 33 of the 46 children in the intervention group and 37 of the 50 children in the IC group were identified as non-Hispanic white. The mean yearly income of all families was $65,729 ± $3068, with only 8.3% of families below $20,000.

The intervention group had greater decreases in child %0BMI from baseline to 6, 12, 18, and 24 months than the IC group. Similar trends were seen with child z-BMI. A slower increase in height was observed in the intervention group when compared with the IC at both 18 months (P < 0.001) and at 24 months (P < 0.02). Parents showed greater overall BMI reduction in the intervention group as opposed to the IC group at all time points (P < 0.001). BMI changes achieved at 6 months were maintained at 24 months. %0BMI and parent BMI changes were correlated from baseline to 12, 18, and 24 months. No significant baseline moderators were found among the children in either group.

Conclusion. This study demonstrated that within the PCMH model of pediatric primary care, an intervention focused on joint behavior change and weight modification treatment of parents and children led to better initial and sustained improvements in %0BMI and z-BMI (in children) and BMI (in parents) than a child-focused IC.

Commentary

Over one-third of children and adolescents are considered to be overweight or have obesity, a number that has doubled in the past 30 years [5]. Pediatrician and primary care physician visits are optimal places to identify overweight children who are at risk for obesity and begin prevention measures, although identifying overweight and obese younger children can be difficult [6]. This study used PEAs to aid physicians in identification, implementation, and delivery. With increasing evidence to support pediatrician involvement in intensive weight management in a primary versus specialty care setting, embedding PEAs within the PCMH model may be an important way to help deliver care for overweight/obese children [7].

Although many approaches have been considered to target childhood obesity, this study represents an important contribution to the literature because it demonstrates that a primary care–based intervention targeting parents as well as their young children is more efficacious for weight management than a more traditional, child-only focused intervention. In addition, the intervention included many different evidence-based components such as teaching behavior modification techniques to parents, consideration of parenting styles and techniques, and encouraging simultaneous parental weight modification. While the U.S. Preventive Services Task Force (USPSTF) recommends intensive interventions with 30 sessions over 2 years [8], this study was able to accomplish significant weight change in 13 sessions.

This intervention is unique in its integration of parenting techniques with other evidence-based strategies for child weight management. Although it has been shown in the literature that certain parenting styles can positively impact children’s health behaviors [9], namely the use of positive reinforcement and monitoring children’s health practices [10], only a few studies have looked at the impact of parenting interventions on childhood obesity. Mazzeo et al demonstrated a significant reduction in child BMI with a parenting-only intervention in the NOURISH trial [11], Slusser et al found a significant child BMI reduction using parent training for low-income, 2- to 4-year-old children [12], and Brotman et al conducted a longitudinal study demonstrating that a family intervention could decrease BMI and improve overall child health behaviors [13]. Despite these aforementioned studies, there is a lack of longitudinal data on the association between general parenting style and weight [14], and this study addresses this gap in literature by providing 2-year follow-up and demonstrating sustained impact on the intervention group.

This study had many additional strengths, including randomized design, primary care physician blinding, use of intention to treat analysis, standardization of measurement tools, clear justification of sample size, long-term follow-up, and the use of child-appropriate BMI measures (eg, %0BMI vs. z-BMI as primary outcome measure). In addition, the intervention setting in a PCMH follows the trend of increasing interest in exploring this model of health care delivery [15,16]. It is also important to note that the intervention and IC groups received the same number of group visits and phone calls, the only difference being the content and the extra 1:1 PEA sessions received by the intervention group.

The few weaknesses include that the PEAs could not be blinded to treatment allocation, and generalizability is limited by the mostly non-Hispanic white population and that only 8.3% of the study population had an annual household income of less than $20,000. All parents included in this study were on the high end of the obese range (BMI 30–39.9), with baseline BMI values of 37.2 and 36.2 in the intervention and IC groups respectively. In addition, the age of the children included in the study were on the high end of the designated 2- to 5-year-old range: 4.6 years (IC) and 4.4 years (intervention). Although findings were promising within this specific population, further research in younger and more diverse populations is necessary [11].

Finally, it is unclear whether this intervention is scalable, and a cost-effectiveness analysis of this intervention is needed. This study was designed to limit the PCP’s role and simplify the process of identifying and intervening on overweight children and their parents, yet this required 3 part-time PEAs and a project coordinator responsible for delivering all of the group sessions and providing follow-up counseling to both intervention and IC groups.

Applications for Clinical Practice

This study demonstrates that in a mostly white, urban/suburban population, a parenting and behavior modification intervention focused on both parent and child leads to greater improvements in %0BMI and z-BMI in the child and BMI reduction in parents compared with an intervention focused on the child alone within pediatric PCMH practices. This intervention should be tested in more diverse populations. This study also suggests further exploration of the use of PEAs to help clinicians address obesity within the PCMH model of primary care.

—Natalie Berner, BA, and Melanie Jay, MD, MS

Pier Luigi Zinzani, MD, PhD

Photo by Larry Young

SAN FRANCISCO—Two phase 2 studies testing mogamulizumab in peripheral T-cell lymphomas (PTCLs) suggest that higher response rates don’t necessarily translate to an improvement in progression-free survival (PFS).

The anti-CCR4 antibody produced a higher overall response rate (ORR) in a Japanese study than in a European study—34% and 11%, respectively.

However, median PFS times were similar—about 2 months in both studies.

This similarity is all the more interesting because the studies enrolled different types of patients and followed different dosing schedules, according to Pier Luigi Zinzani, MD, PhD, of the University of Bologna in Italy.

Dr Zinzani discussed details of the European experience testing mogamulizumab in PTCL, comparing it to the Japanese experience, in a presentation at the 7th Annual T-cell Lymphoma Forum.

Kensei Tobinai, MD, PhD, of the National Cancer Center Hospital in Tokyo, Japan, also reviewed the Japanese experience (TCLF 2013, JCO 2014) during the meeting’s keynote address and presented data from an ancillary analysis of this study (which is unpublished).

All of the research was sponsored by Kyowa Hakko Kirin Co., Ltd., the company developing mogamulizumab.

The Japanese experience

The Japanese study included 29 patients with PTCL and 8 with cutaneous T-cell lymphoma (CTCL). All patients had relapsed after their last chemotherapy regimen, and none had received an allogeneic stem cell transplant (allo-SCT). The PTCL patients had a median age of 67, and 69% were male.

All patients received mogamulizumab at 1.0 mg/kg/day weekly for 8 weeks. The ORR was 35%—34% for PTCL patients and 38% for CTCL patients.

Among PTCL patients, there were 5 complete responses (CRs) and 5 partial responses (PRs). Nine patients had stable disease (SD), and 10 progressed.

Of the 16 patients with PTCL-not otherwise specified (PTCL-NOS), 1 had a CR, 2 had a PR, 6 had SD, and 7 progressed. Of the 12 patients with angioimmunoblastic T-cell lymphoma (AITL), 3 had a CR, 3 had a PR, 3 had SD, and 3 progressed. The only patient with ALK- anaplastic large-cell lymphoma (ALCL) had an unconfirmed CR.

The ancillary analysis showed that tumor shrinkage of the target lesions occurred in 72% (21/29) of patients with PTCL. The patients’ median duration of response was 6.4 months, and the median time to response was 1.9 months.

Overall, the median PFS was 3.0 months—2.0 months in patients with PTCL and 3.4 months in patients with CTCL.

Common adverse events (for both PTCL and CTCL patients) included lymphopenia (81%), skin disorders (51%), leukopenia (43%), neutropenia (38%), thrombocytopenia (38%), pyrexia (30%), acute infusion reactions (24%), and anemia (14%).

Dr Tobinai noted that these results are not as favorable as those observed when patients with adult T-cell leukemia-lymphoma receive mogamulizumab.

“But compared to the efficacy rate of other approved agents—pralatrexate and romidepsin—this antibody has promising efficacy,” he said.

In fact, the results of this study prompted the December approval of mogamulizumab to treat PTCL and CTCL patients in Japan.

The European experience

The European study differed from the Japanese study in a few ways, Dr Zinzani pointed out. The European study only enrolled patients with PTCL. And it included patients with relapsed (49%) or refractory (51%) disease, whereas the Japanese study only included relapsed patients.

Furthermore, the Japanese study did not include any patients with an ECOG performance status of 2, while the European study did (39%). And the dosing schedule differed between the 2 studies.

In the European study, patients received mogamulizumab at 1 mg/kg once weekly for 4 weeks and then once every 2 weeks until they progressed or developed unacceptable toxicity.

There were 38 patients in the safety analysis. They had a median age of 58.5 years, and 61% were male.

Thirty-five of these patients were included in the efficacy analysis. They had a median of 2 prior treatments (range, 1-8), and 17 patients (49%) had responded to their last therapy.

The patients had PTCL-NOS (43%, 15/35), AITL (34%, 12), transformed mycosis fungoides (9%, 3), ALK- ALCL (11%, 4), and ALK+ ALCL (3%, 1).

The ORR was 11% (n=4), and 46% of patients (n=16) had SD or better. Two patients with PTCL-NOS responded, as did 2 with AITL.

Six patients with PTCL-NOS had SD, as did 3 with AITL, 1 with transformed mycosis fungoides, and 2 with ALK- ALCL.

The median duration of response (including SD) was 2.9 months. And the median PFS was 2.1 months. Two patients (1 with ALK- ALCL and 1 with PTCL-NOS) went on to allo-SCT.

The most frequent adverse events (occurring in at least 10% of patients) were drug eruption (n=12), pyrexia (n=9), pruritus (n=7), diarrhea (n=7), cough (n=6), vomiting (n=6), thrombocytopenia (n=6), hypotension (n=4), headache (n=4), peripheral edema (n=4), asthenia (n=4), nausea (n=4), anemia (n=4), and neutropenia (n=4).

“For the European experience, there were some differences from the Japanese experience,” Dr Zinzani said in closing. “It was worse in terms of overall response rate—only 11%—but roughly 50% of patients attained at least stable disease. And there was an acceptable safety profile in these really heavily pretreated, relapsed/refractory PTCL patients.”

Pier Luigi Zinzani, MD, PhD

Photo by Larry Young

SAN FRANCISCO—Two phase 2 studies testing mogamulizumab in peripheral T-cell lymphomas (PTCLs) suggest that higher response rates don’t necessarily translate to an improvement in progression-free survival (PFS).

The anti-CCR4 antibody produced a higher overall response rate (ORR) in a Japanese study than in a European study—34% and 11%, respectively.

However, median PFS times were similar—about 2 months in both studies.

This similarity is all the more interesting because the studies enrolled different types of patients and followed different dosing schedules, according to Pier Luigi Zinzani, MD, PhD, of the University of Bologna in Italy.

Dr Zinzani discussed details of the European experience testing mogamulizumab in PTCL, comparing it to the Japanese experience, in a presentation at the 7th Annual T-cell Lymphoma Forum.

Kensei Tobinai, MD, PhD, of the National Cancer Center Hospital in Tokyo, Japan, also reviewed the Japanese experience (TCLF 2013, JCO 2014) during the meeting’s keynote address and presented data from an ancillary analysis of this study (which is unpublished).

All of the research was sponsored by Kyowa Hakko Kirin Co., Ltd., the company developing mogamulizumab.

The Japanese experience

The Japanese study included 29 patients with PTCL and 8 with cutaneous T-cell lymphoma (CTCL). All patients had relapsed after their last chemotherapy regimen, and none had received an allogeneic stem cell transplant (allo-SCT). The PTCL patients had a median age of 67, and 69% were male.

All patients received mogamulizumab at 1.0 mg/kg/day weekly for 8 weeks. The ORR was 35%—34% for PTCL patients and 38% for CTCL patients.

Among PTCL patients, there were 5 complete responses (CRs) and 5 partial responses (PRs). Nine patients had stable disease (SD), and 10 progressed.

Of the 16 patients with PTCL-not otherwise specified (PTCL-NOS), 1 had a CR, 2 had a PR, 6 had SD, and 7 progressed. Of the 12 patients with angioimmunoblastic T-cell lymphoma (AITL), 3 had a CR, 3 had a PR, 3 had SD, and 3 progressed. The only patient with ALK- anaplastic large-cell lymphoma (ALCL) had an unconfirmed CR.

The ancillary analysis showed that tumor shrinkage of the target lesions occurred in 72% (21/29) of patients with PTCL. The patients’ median duration of response was 6.4 months, and the median time to response was 1.9 months.

Overall, the median PFS was 3.0 months—2.0 months in patients with PTCL and 3.4 months in patients with CTCL.

Common adverse events (for both PTCL and CTCL patients) included lymphopenia (81%), skin disorders (51%), leukopenia (43%), neutropenia (38%), thrombocytopenia (38%), pyrexia (30%), acute infusion reactions (24%), and anemia (14%).

Dr Tobinai noted that these results are not as favorable as those observed when patients with adult T-cell leukemia-lymphoma receive mogamulizumab.

“But compared to the efficacy rate of other approved agents—pralatrexate and romidepsin—this antibody has promising efficacy,” he said.

In fact, the results of this study prompted the December approval of mogamulizumab to treat PTCL and CTCL patients in Japan.

The European experience

The European study differed from the Japanese study in a few ways, Dr Zinzani pointed out. The European study only enrolled patients with PTCL. And it included patients with relapsed (49%) or refractory (51%) disease, whereas the Japanese study only included relapsed patients.

Furthermore, the Japanese study did not include any patients with an ECOG performance status of 2, while the European study did (39%). And the dosing schedule differed between the 2 studies.

In the European study, patients received mogamulizumab at 1 mg/kg once weekly for 4 weeks and then once every 2 weeks until they progressed or developed unacceptable toxicity.

There were 38 patients in the safety analysis. They had a median age of 58.5 years, and 61% were male.

Thirty-five of these patients were included in the efficacy analysis. They had a median of 2 prior treatments (range, 1-8), and 17 patients (49%) had responded to their last therapy.

The patients had PTCL-NOS (43%, 15/35), AITL (34%, 12), transformed mycosis fungoides (9%, 3), ALK- ALCL (11%, 4), and ALK+ ALCL (3%, 1).

The ORR was 11% (n=4), and 46% of patients (n=16) had SD or better. Two patients with PTCL-NOS responded, as did 2 with AITL.

Six patients with PTCL-NOS had SD, as did 3 with AITL, 1 with transformed mycosis fungoides, and 2 with ALK- ALCL.

The median duration of response (including SD) was 2.9 months. And the median PFS was 2.1 months. Two patients (1 with ALK- ALCL and 1 with PTCL-NOS) went on to allo-SCT.

The most frequent adverse events (occurring in at least 10% of patients) were drug eruption (n=12), pyrexia (n=9), pruritus (n=7), diarrhea (n=7), cough (n=6), vomiting (n=6), thrombocytopenia (n=6), hypotension (n=4), headache (n=4), peripheral edema (n=4), asthenia (n=4), nausea (n=4), anemia (n=4), and neutropenia (n=4).

“For the European experience, there were some differences from the Japanese experience,” Dr Zinzani said in closing. “It was worse in terms of overall response rate—only 11%—but roughly 50% of patients attained at least stable disease. And there was an acceptable safety profile in these really heavily pretreated, relapsed/refractory PTCL patients.”

Pier Luigi Zinzani, MD, PhD

Photo by Larry Young

SAN FRANCISCO—Two phase 2 studies testing mogamulizumab in peripheral T-cell lymphomas (PTCLs) suggest that higher response rates don’t necessarily translate to an improvement in progression-free survival (PFS).

The anti-CCR4 antibody produced a higher overall response rate (ORR) in a Japanese study than in a European study—34% and 11%, respectively.

However, median PFS times were similar—about 2 months in both studies.

This similarity is all the more interesting because the studies enrolled different types of patients and followed different dosing schedules, according to Pier Luigi Zinzani, MD, PhD, of the University of Bologna in Italy.

Dr Zinzani discussed details of the European experience testing mogamulizumab in PTCL, comparing it to the Japanese experience, in a presentation at the 7th Annual T-cell Lymphoma Forum.

Kensei Tobinai, MD, PhD, of the National Cancer Center Hospital in Tokyo, Japan, also reviewed the Japanese experience (TCLF 2013, JCO 2014) during the meeting’s keynote address and presented data from an ancillary analysis of this study (which is unpublished).

All of the research was sponsored by Kyowa Hakko Kirin Co., Ltd., the company developing mogamulizumab.

The Japanese experience

The Japanese study included 29 patients with PTCL and 8 with cutaneous T-cell lymphoma (CTCL). All patients had relapsed after their last chemotherapy regimen, and none had received an allogeneic stem cell transplant (allo-SCT). The PTCL patients had a median age of 67, and 69% were male.

All patients received mogamulizumab at 1.0 mg/kg/day weekly for 8 weeks. The ORR was 35%—34% for PTCL patients and 38% for CTCL patients.

Among PTCL patients, there were 5 complete responses (CRs) and 5 partial responses (PRs). Nine patients had stable disease (SD), and 10 progressed.

Of the 16 patients with PTCL-not otherwise specified (PTCL-NOS), 1 had a CR, 2 had a PR, 6 had SD, and 7 progressed. Of the 12 patients with angioimmunoblastic T-cell lymphoma (AITL), 3 had a CR, 3 had a PR, 3 had SD, and 3 progressed. The only patient with ALK- anaplastic large-cell lymphoma (ALCL) had an unconfirmed CR.

The ancillary analysis showed that tumor shrinkage of the target lesions occurred in 72% (21/29) of patients with PTCL. The patients’ median duration of response was 6.4 months, and the median time to response was 1.9 months.

Overall, the median PFS was 3.0 months—2.0 months in patients with PTCL and 3.4 months in patients with CTCL.

Common adverse events (for both PTCL and CTCL patients) included lymphopenia (81%), skin disorders (51%), leukopenia (43%), neutropenia (38%), thrombocytopenia (38%), pyrexia (30%), acute infusion reactions (24%), and anemia (14%).

Dr Tobinai noted that these results are not as favorable as those observed when patients with adult T-cell leukemia-lymphoma receive mogamulizumab.

“But compared to the efficacy rate of other approved agents—pralatrexate and romidepsin—this antibody has promising efficacy,” he said.

In fact, the results of this study prompted the December approval of mogamulizumab to treat PTCL and CTCL patients in Japan.

The European experience

The European study differed from the Japanese study in a few ways, Dr Zinzani pointed out. The European study only enrolled patients with PTCL. And it included patients with relapsed (49%) or refractory (51%) disease, whereas the Japanese study only included relapsed patients.

Furthermore, the Japanese study did not include any patients with an ECOG performance status of 2, while the European study did (39%). And the dosing schedule differed between the 2 studies.

In the European study, patients received mogamulizumab at 1 mg/kg once weekly for 4 weeks and then once every 2 weeks until they progressed or developed unacceptable toxicity.

There were 38 patients in the safety analysis. They had a median age of 58.5 years, and 61% were male.

Thirty-five of these patients were included in the efficacy analysis. They had a median of 2 prior treatments (range, 1-8), and 17 patients (49%) had responded to their last therapy.

The patients had PTCL-NOS (43%, 15/35), AITL (34%, 12), transformed mycosis fungoides (9%, 3), ALK- ALCL (11%, 4), and ALK+ ALCL (3%, 1).

The ORR was 11% (n=4), and 46% of patients (n=16) had SD or better. Two patients with PTCL-NOS responded, as did 2 with AITL.

Six patients with PTCL-NOS had SD, as did 3 with AITL, 1 with transformed mycosis fungoides, and 2 with ALK- ALCL.

The median duration of response (including SD) was 2.9 months. And the median PFS was 2.1 months. Two patients (1 with ALK- ALCL and 1 with PTCL-NOS) went on to allo-SCT.

The most frequent adverse events (occurring in at least 10% of patients) were drug eruption (n=12), pyrexia (n=9), pruritus (n=7), diarrhea (n=7), cough (n=6), vomiting (n=6), thrombocytopenia (n=6), hypotension (n=4), headache (n=4), peripheral edema (n=4), asthenia (n=4), nausea (n=4), anemia (n=4), and neutropenia (n=4).

“For the European experience, there were some differences from the Japanese experience,” Dr Zinzani said in closing. “It was worse in terms of overall response rate—only 11%—but roughly 50% of patients attained at least stable disease. And there was an acceptable safety profile in these really heavily pretreated, relapsed/refractory PTCL patients.”

Drugs in vials

Photo by Bill Branson

A new analysis indicates that certain high-cost therapies for hematologic malignancies provide reasonable value for money spent.

Most cost-effectiveness ratios were lower than thresholds commonly used to establish cost-effectiveness in the US—$50,000 or $100,000 per quality-adjusted life year (QALY) gained.

The median cost-effectiveness ratio was highest for chronic myeloid leukemia (CML), at $55,000/QALY, and lowest for non-Hodgkin lymphoma (NHL), at $21,500/QALY.

Researchers presented these data in Blood.

“Given the increased discussion about the high cost of these treatments, we were somewhat surprised to discover that their cost-effectiveness ratios were lower than expected,” said study author Peter J. Neumann, ScD, of Tufts Medical Center in Boston.

“Our analysis had a small sample size and included both industry- and non-industry-funded studies. In addition, cost-effectiveness ratios may have changed over time as associated costs or benefits have changed. However, the study underscores that debates in healthcare should consider the value of breakthrough drugs and not just costs.”

With that issue in mind, Dr Neumann and his colleagues had conducted a systematic review of studies published between 1996 and 2012 that examined the cost utility of agents for hematologic malignancies. The cost utility of a drug was depicted as a ratio of a drug’s total cost per patient QALY gained.

The researchers identified 29 studies, 22 of which were industry-funded. Nine studies were conducted from a US perspective, 6 from the UK, 3 from Norway, 3 from Sweden, 2 from France, 1 from Canada, 1 from Finland, and 4 from “other” countries.

The team grouped studies according to malignancy—CML, chronic lymphocytic leukemia (CLL), NHL, and multiple myeloma (MM)—as well as by treatment—α interferon, alemtuzumab, bendamustine, bortezomib, dasatinib, imatinib, lenalidomide, rituximab alone or in combination, and thalidomide.

The studies reported 44 cost-effectiveness ratios, most concerning interventions for NHL (41%) or CML (30%). Most ratios pertained to rituximab (43%), α interferon (18%), or imatinib (16%), and the most common intervention-disease combination was rituximab (alone or in combination) for NHL (36%).

The median cost-effectiveness ratios fluctuated over time, rising from $35,000/QALY (1996-2002) to $52,000/QALY (2003-2006), then falling to $22,000/QALY (2007-2012).

The median cost-effectiveness ratio reported by industry-funded studies was lower ($26,000/QALY) than for non-industry-funded studies ($33,000/QALY).

Four cost-effectiveness ratios, 1 from an industry-funded study, exceeded $100,000/QALY. This included 2 studies of bortezomib in MM, 1 of α interferon in CML, and 1 of imatinib in CML.

The researchers said these results suggest that many new treatments for hematologic malignancies may confer reasonable value for money spent. The distribution of cost-effectiveness ratios is comparable to those for cancers overall and for other healthcare fields, they said.

This study was funded by internal resources at the Center for the Evaluation of Value and Risk in Health. The center receives funding from federal, private foundation, and pharmaceutical industry sources.

Drugs in vials

Photo by Bill Branson

A new analysis indicates that certain high-cost therapies for hematologic malignancies provide reasonable value for money spent.

Most cost-effectiveness ratios were lower than thresholds commonly used to establish cost-effectiveness in the US—$50,000 or $100,000 per quality-adjusted life year (QALY) gained.

The median cost-effectiveness ratio was highest for chronic myeloid leukemia (CML), at $55,000/QALY, and lowest for non-Hodgkin lymphoma (NHL), at $21,500/QALY.

Researchers presented these data in Blood.

“Given the increased discussion about the high cost of these treatments, we were somewhat surprised to discover that their cost-effectiveness ratios were lower than expected,” said study author Peter J. Neumann, ScD, of Tufts Medical Center in Boston.

“Our analysis had a small sample size and included both industry- and non-industry-funded studies. In addition, cost-effectiveness ratios may have changed over time as associated costs or benefits have changed. However, the study underscores that debates in healthcare should consider the value of breakthrough drugs and not just costs.”

With that issue in mind, Dr Neumann and his colleagues had conducted a systematic review of studies published between 1996 and 2012 that examined the cost utility of agents for hematologic malignancies. The cost utility of a drug was depicted as a ratio of a drug’s total cost per patient QALY gained.

The researchers identified 29 studies, 22 of which were industry-funded. Nine studies were conducted from a US perspective, 6 from the UK, 3 from Norway, 3 from Sweden, 2 from France, 1 from Canada, 1 from Finland, and 4 from “other” countries.

The team grouped studies according to malignancy—CML, chronic lymphocytic leukemia (CLL), NHL, and multiple myeloma (MM)—as well as by treatment—α interferon, alemtuzumab, bendamustine, bortezomib, dasatinib, imatinib, lenalidomide, rituximab alone or in combination, and thalidomide.

The studies reported 44 cost-effectiveness ratios, most concerning interventions for NHL (41%) or CML (30%). Most ratios pertained to rituximab (43%), α interferon (18%), or imatinib (16%), and the most common intervention-disease combination was rituximab (alone or in combination) for NHL (36%).

The median cost-effectiveness ratios fluctuated over time, rising from $35,000/QALY (1996-2002) to $52,000/QALY (2003-2006), then falling to $22,000/QALY (2007-2012).

The median cost-effectiveness ratio reported by industry-funded studies was lower ($26,000/QALY) than for non-industry-funded studies ($33,000/QALY).

Four cost-effectiveness ratios, 1 from an industry-funded study, exceeded $100,000/QALY. This included 2 studies of bortezomib in MM, 1 of α interferon in CML, and 1 of imatinib in CML.

The researchers said these results suggest that many new treatments for hematologic malignancies may confer reasonable value for money spent. The distribution of cost-effectiveness ratios is comparable to those for cancers overall and for other healthcare fields, they said.

This study was funded by internal resources at the Center for the Evaluation of Value and Risk in Health. The center receives funding from federal, private foundation, and pharmaceutical industry sources.

Drugs in vials

Photo by Bill Branson

A new analysis indicates that certain high-cost therapies for hematologic malignancies provide reasonable value for money spent.

Most cost-effectiveness ratios were lower than thresholds commonly used to establish cost-effectiveness in the US—$50,000 or $100,000 per quality-adjusted life year (QALY) gained.

The median cost-effectiveness ratio was highest for chronic myeloid leukemia (CML), at $55,000/QALY, and lowest for non-Hodgkin lymphoma (NHL), at $21,500/QALY.

Researchers presented these data in Blood.

“Given the increased discussion about the high cost of these treatments, we were somewhat surprised to discover that their cost-effectiveness ratios were lower than expected,” said study author Peter J. Neumann, ScD, of Tufts Medical Center in Boston.

“Our analysis had a small sample size and included both industry- and non-industry-funded studies. In addition, cost-effectiveness ratios may have changed over time as associated costs or benefits have changed. However, the study underscores that debates in healthcare should consider the value of breakthrough drugs and not just costs.”

With that issue in mind, Dr Neumann and his colleagues had conducted a systematic review of studies published between 1996 and 2012 that examined the cost utility of agents for hematologic malignancies. The cost utility of a drug was depicted as a ratio of a drug’s total cost per patient QALY gained.

The researchers identified 29 studies, 22 of which were industry-funded. Nine studies were conducted from a US perspective, 6 from the UK, 3 from Norway, 3 from Sweden, 2 from France, 1 from Canada, 1 from Finland, and 4 from “other” countries.

The team grouped studies according to malignancy—CML, chronic lymphocytic leukemia (CLL), NHL, and multiple myeloma (MM)—as well as by treatment—α interferon, alemtuzumab, bendamustine, bortezomib, dasatinib, imatinib, lenalidomide, rituximab alone or in combination, and thalidomide.

The studies reported 44 cost-effectiveness ratios, most concerning interventions for NHL (41%) or CML (30%). Most ratios pertained to rituximab (43%), α interferon (18%), or imatinib (16%), and the most common intervention-disease combination was rituximab (alone or in combination) for NHL (36%).

The median cost-effectiveness ratios fluctuated over time, rising from $35,000/QALY (1996-2002) to $52,000/QALY (2003-2006), then falling to $22,000/QALY (2007-2012).

The median cost-effectiveness ratio reported by industry-funded studies was lower ($26,000/QALY) than for non-industry-funded studies ($33,000/QALY).

Four cost-effectiveness ratios, 1 from an industry-funded study, exceeded $100,000/QALY. This included 2 studies of bortezomib in MM, 1 of α interferon in CML, and 1 of imatinib in CML.

The researchers said these results suggest that many new treatments for hematologic malignancies may confer reasonable value for money spent. The distribution of cost-effectiveness ratios is comparable to those for cancers overall and for other healthcare fields, they said.

This study was funded by internal resources at the Center for the Evaluation of Value and Risk in Health. The center receives funding from federal, private foundation, and pharmaceutical industry sources.

The three most exposed areas of the body that give away a person’s age are the face, neck, and hands. Rejuvenation of the hands is an often simple and nice addition to facial and neck aesthetic rejuvenation.

When examining aging hands, the three most prominent features are decreased volume in the interosseous spaces (leading to increased crepiness of the skin and increased show of extensor tendons), lentigines, and prominent veins. Therefore, the treatment for hands is quite simple: Restore volume, treat the pigmented lesions, and if needed, treat the prominent veins.

The anatomy of the dorsal hand can be divided into three major compartments. First, the skin, which on the dorsal hand is quite pliable. Second, the subcutaneous tissue, which consists of a loose areolar tissue where the lymphatics and veins lie. Third, beneath the subcutaneous tissue is the dorsal fascia of the hand, which is contiguous with extensor tendons and underlying compartments. It is in the subcutaneous layer (or loose areolar tissue) where fillers or fat are placed to treat volume loss.

While several fillers are currently used off label for hand rejuvenation, the Food and Drug Administration is meeting in February to consider officially approving Radiesse for this indication. Currently, hyaluronic acid (HA) fillers, calcium- hydroxylapatite (Radiesse), poly-L-lactic acid, and autologous fat are all utilized. I tend to use HAs in this location because of the reversibility, if needed, and decreased risk of nodule formation. Several techniques exist, including injecting between each tendon space vs. a bolus technique. I tend to use a bolus technique, where one or two boluses are injected while tenting the skin up to ensure injection into the correct plane and to avoid the vessels. Subsequently, the boluses are massaged into place while the patient makes a fist.

Once the interosseous spaces have been treated, the veins often appear less prominent and often don’t require direct treatment. I typically do not treat the dorsal hand veins, but sclerotherapy can be performed. Lentigines may be treated with a variety of devices including intense pulse light, Q-switched lasers, and fractionated nonablative lasers. Chemical peels and topical antipigment agents also may help to a lesser degree or also may be used for maintenance to keep the lentigines away.

Dr. Talakoub and Dr. Wesley are co-contributors to a monthly Aesthetic Dermatology column in Dermatology News. Dr. Talakoub is in private practice in McLean, Va. Dr. Wesley practices dermatology in Beverly Hills, Calif. This month’s column is by Dr. Wesley.

The three most exposed areas of the body that give away a person’s age are the face, neck, and hands. Rejuvenation of the hands is an often simple and nice addition to facial and neck aesthetic rejuvenation.

When examining aging hands, the three most prominent features are decreased volume in the interosseous spaces (leading to increased crepiness of the skin and increased show of extensor tendons), lentigines, and prominent veins. Therefore, the treatment for hands is quite simple: Restore volume, treat the pigmented lesions, and if needed, treat the prominent veins.

The anatomy of the dorsal hand can be divided into three major compartments. First, the skin, which on the dorsal hand is quite pliable. Second, the subcutaneous tissue, which consists of a loose areolar tissue where the lymphatics and veins lie. Third, beneath the subcutaneous tissue is the dorsal fascia of the hand, which is contiguous with extensor tendons and underlying compartments. It is in the subcutaneous layer (or loose areolar tissue) where fillers or fat are placed to treat volume loss.

While several fillers are currently used off label for hand rejuvenation, the Food and Drug Administration is meeting in February to consider officially approving Radiesse for this indication. Currently, hyaluronic acid (HA) fillers, calcium- hydroxylapatite (Radiesse), poly-L-lactic acid, and autologous fat are all utilized. I tend to use HAs in this location because of the reversibility, if needed, and decreased risk of nodule formation. Several techniques exist, including injecting between each tendon space vs. a bolus technique. I tend to use a bolus technique, where one or two boluses are injected while tenting the skin up to ensure injection into the correct plane and to avoid the vessels. Subsequently, the boluses are massaged into place while the patient makes a fist.

Once the interosseous spaces have been treated, the veins often appear less prominent and often don’t require direct treatment. I typically do not treat the dorsal hand veins, but sclerotherapy can be performed. Lentigines may be treated with a variety of devices including intense pulse light, Q-switched lasers, and fractionated nonablative lasers. Chemical peels and topical antipigment agents also may help to a lesser degree or also may be used for maintenance to keep the lentigines away.

Dr. Talakoub and Dr. Wesley are co-contributors to a monthly Aesthetic Dermatology column in Dermatology News. Dr. Talakoub is in private practice in McLean, Va. Dr. Wesley practices dermatology in Beverly Hills, Calif. This month’s column is by Dr. Wesley.

The three most exposed areas of the body that give away a person’s age are the face, neck, and hands. Rejuvenation of the hands is an often simple and nice addition to facial and neck aesthetic rejuvenation.

When examining aging hands, the three most prominent features are decreased volume in the interosseous spaces (leading to increased crepiness of the skin and increased show of extensor tendons), lentigines, and prominent veins. Therefore, the treatment for hands is quite simple: Restore volume, treat the pigmented lesions, and if needed, treat the prominent veins.

The anatomy of the dorsal hand can be divided into three major compartments. First, the skin, which on the dorsal hand is quite pliable. Second, the subcutaneous tissue, which consists of a loose areolar tissue where the lymphatics and veins lie. Third, beneath the subcutaneous tissue is the dorsal fascia of the hand, which is contiguous with extensor tendons and underlying compartments. It is in the subcutaneous layer (or loose areolar tissue) where fillers or fat are placed to treat volume loss.

While several fillers are currently used off label for hand rejuvenation, the Food and Drug Administration is meeting in February to consider officially approving Radiesse for this indication. Currently, hyaluronic acid (HA) fillers, calcium- hydroxylapatite (Radiesse), poly-L-lactic acid, and autologous fat are all utilized. I tend to use HAs in this location because of the reversibility, if needed, and decreased risk of nodule formation. Several techniques exist, including injecting between each tendon space vs. a bolus technique. I tend to use a bolus technique, where one or two boluses are injected while tenting the skin up to ensure injection into the correct plane and to avoid the vessels. Subsequently, the boluses are massaged into place while the patient makes a fist.

Once the interosseous spaces have been treated, the veins often appear less prominent and often don’t require direct treatment. I typically do not treat the dorsal hand veins, but sclerotherapy can be performed. Lentigines may be treated with a variety of devices including intense pulse light, Q-switched lasers, and fractionated nonablative lasers. Chemical peels and topical antipigment agents also may help to a lesser degree or also may be used for maintenance to keep the lentigines away.

Dr. Talakoub and Dr. Wesley are co-contributors to a monthly Aesthetic Dermatology column in Dermatology News. Dr. Talakoub is in private practice in McLean, Va. Dr. Wesley practices dermatology in Beverly Hills, Calif. This month’s column is by Dr. Wesley.

Velcade (bortezomib)

Photo courtesy of Millennium

The European Commission (EC) has approved bortezomib (Velcade) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) to treat adults with previously untreated mantle cell lymphoma (MCL) in whom hematopoietic stem cell transplant (HSCT) is considered unsuitable.

Now, bortezomib can be marketed for this indication in all 28 countries of the European Union (EU).

Bortezomib is already approved in the EU to treat multiple myeloma (MM), either as monotherapy or in combination with other agents.

The EC’s approval of bortezomib in MCL is based on data from a phase 3 study known as LYM-3002.

This randomized trial included 487 patients with newly diagnosed MCL who were ineligible, or not considered, for HSCT. Patients were randomized to receive VR-CAP or R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).

The VR-CAP regimen significantly improved progression-free survival (PFS), the primary endpoint, when compared to R-CHOP.

According to an independent review committee, there was a 59% improvement in PFS for the VR-CAP arm compared to the R-CHOP arm, with median times of 24.7 months and 14.4 months, respectively (hazard ratio=0.63; P<0.001).

Study investigators reported a 96% increase in PFS with VR-CAP compared to R-CHOP, with median times of 30.7 months and 16.1 months, respectively (hazard ratio=0.51, P<0.001).

VR-CAP was associated with additional, but manageable, toxicity when compared to R-CHOP. Serious adverse events (AEs) were reported in 38% and 30% of patients, respectively. And grade 3 or higher AEs were reported in 93% and 85% of patients, respectively.

Treatment discontinuation due to AEs occurred in 9% of patients in the VR-CAP arm and 7% in the R-CHOP arm. On-treatment, drug-related deaths occurred in 2% and 3% of patients, respectively.

About bortezomib

Bortezomib works by reversibly interrupting the normal working of cell proteasomes, inducing cancerous cells to stop growing and die.

In addition to the new MCL indication, the drug is approved in the EU to treat various stages of MM. It’s approved in combination with melphalan and prednisone to treat previously untreated adults with MM who are unsuitable for high-dose chemotherapy with HSCT.

Bortezomib is also approved in combination with dexamethasone, or with dexamethasone plus thalidomide, to treat previously untreated MM patients set to receive high-dose chemotherapy followed by HSCT.

And the drug is approved as monotherapy or in combination with pegylated liposomal doxorubicin or dexamethasone to treat adults with MM whose disease has progressed after at least one other treatment and who have already had, or cannot undergo, HSCT.

Bortezomib is approved in more than 90 countries and has been used to treat more than 550,000 patients worldwide.

The product is co-developed by Millennium, the Takeda Oncology Company, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, and Janssen Pharmaceutical Companies.

Millennium is responsible for commercialization in the US. Janssen Pharmaceutical Companies are responsible for commercialization in Europe and the rest of the world. Takeda Pharmaceutical Company Limited and Janssen Pharmaceutical K.K. co-promote the drug in Japan.

Velcade (bortezomib)

Photo courtesy of Millennium

The European Commission (EC) has approved bortezomib (Velcade) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) to treat adults with previously untreated mantle cell lymphoma (MCL) in whom hematopoietic stem cell transplant (HSCT) is considered unsuitable.

Now, bortezomib can be marketed for this indication in all 28 countries of the European Union (EU).

Bortezomib is already approved in the EU to treat multiple myeloma (MM), either as monotherapy or in combination with other agents.

The EC’s approval of bortezomib in MCL is based on data from a phase 3 study known as LYM-3002.

This randomized trial included 487 patients with newly diagnosed MCL who were ineligible, or not considered, for HSCT. Patients were randomized to receive VR-CAP or R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).

The VR-CAP regimen significantly improved progression-free survival (PFS), the primary endpoint, when compared to R-CHOP.

According to an independent review committee, there was a 59% improvement in PFS for the VR-CAP arm compared to the R-CHOP arm, with median times of 24.7 months and 14.4 months, respectively (hazard ratio=0.63; P<0.001).

Study investigators reported a 96% increase in PFS with VR-CAP compared to R-CHOP, with median times of 30.7 months and 16.1 months, respectively (hazard ratio=0.51, P<0.001).

VR-CAP was associated with additional, but manageable, toxicity when compared to R-CHOP. Serious adverse events (AEs) were reported in 38% and 30% of patients, respectively. And grade 3 or higher AEs were reported in 93% and 85% of patients, respectively.

Treatment discontinuation due to AEs occurred in 9% of patients in the VR-CAP arm and 7% in the R-CHOP arm. On-treatment, drug-related deaths occurred in 2% and 3% of patients, respectively.

About bortezomib

Bortezomib works by reversibly interrupting the normal working of cell proteasomes, inducing cancerous cells to stop growing and die.

In addition to the new MCL indication, the drug is approved in the EU to treat various stages of MM. It’s approved in combination with melphalan and prednisone to treat previously untreated adults with MM who are unsuitable for high-dose chemotherapy with HSCT.

Bortezomib is also approved in combination with dexamethasone, or with dexamethasone plus thalidomide, to treat previously untreated MM patients set to receive high-dose chemotherapy followed by HSCT.

And the drug is approved as monotherapy or in combination with pegylated liposomal doxorubicin or dexamethasone to treat adults with MM whose disease has progressed after at least one other treatment and who have already had, or cannot undergo, HSCT.

Bortezomib is approved in more than 90 countries and has been used to treat more than 550,000 patients worldwide.

The product is co-developed by Millennium, the Takeda Oncology Company, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, and Janssen Pharmaceutical Companies.

Millennium is responsible for commercialization in the US. Janssen Pharmaceutical Companies are responsible for commercialization in Europe and the rest of the world. Takeda Pharmaceutical Company Limited and Janssen Pharmaceutical K.K. co-promote the drug in Japan.

Velcade (bortezomib)

Photo courtesy of Millennium

The European Commission (EC) has approved bortezomib (Velcade) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) to treat adults with previously untreated mantle cell lymphoma (MCL) in whom hematopoietic stem cell transplant (HSCT) is considered unsuitable.

Now, bortezomib can be marketed for this indication in all 28 countries of the European Union (EU).

Bortezomib is already approved in the EU to treat multiple myeloma (MM), either as monotherapy or in combination with other agents.

The EC’s approval of bortezomib in MCL is based on data from a phase 3 study known as LYM-3002.

This randomized trial included 487 patients with newly diagnosed MCL who were ineligible, or not considered, for HSCT. Patients were randomized to receive VR-CAP or R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).

The VR-CAP regimen significantly improved progression-free survival (PFS), the primary endpoint, when compared to R-CHOP.

According to an independent review committee, there was a 59% improvement in PFS for the VR-CAP arm compared to the R-CHOP arm, with median times of 24.7 months and 14.4 months, respectively (hazard ratio=0.63; P<0.001).

Study investigators reported a 96% increase in PFS with VR-CAP compared to R-CHOP, with median times of 30.7 months and 16.1 months, respectively (hazard ratio=0.51, P<0.001).

VR-CAP was associated with additional, but manageable, toxicity when compared to R-CHOP. Serious adverse events (AEs) were reported in 38% and 30% of patients, respectively. And grade 3 or higher AEs were reported in 93% and 85% of patients, respectively.

Treatment discontinuation due to AEs occurred in 9% of patients in the VR-CAP arm and 7% in the R-CHOP arm. On-treatment, drug-related deaths occurred in 2% and 3% of patients, respectively.

About bortezomib

Bortezomib works by reversibly interrupting the normal working of cell proteasomes, inducing cancerous cells to stop growing and die.

In addition to the new MCL indication, the drug is approved in the EU to treat various stages of MM. It’s approved in combination with melphalan and prednisone to treat previously untreated adults with MM who are unsuitable for high-dose chemotherapy with HSCT.

Bortezomib is also approved in combination with dexamethasone, or with dexamethasone plus thalidomide, to treat previously untreated MM patients set to receive high-dose chemotherapy followed by HSCT.

And the drug is approved as monotherapy or in combination with pegylated liposomal doxorubicin or dexamethasone to treat adults with MM whose disease has progressed after at least one other treatment and who have already had, or cannot undergo, HSCT.

Bortezomib is approved in more than 90 countries and has been used to treat more than 550,000 patients worldwide.

The product is co-developed by Millennium, the Takeda Oncology Company, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, and Janssen Pharmaceutical Companies.

Millennium is responsible for commercialization in the US. Janssen Pharmaceutical Companies are responsible for commercialization in Europe and the rest of the world. Takeda Pharmaceutical Company Limited and Janssen Pharmaceutical K.K. co-promote the drug in Japan.

NEW YORK– The REACH Institute trains primary care clinicians to include more mental health assessment and management in their practices, Dr. Lawrence V. Amsel said during an interview at the psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.

Many primary care clinicians don’t feel adequately trained to interview patients, guage their mental status, and then act on the findings by treatment or referral. But over the past decade, psychiatrists have developed and validated several tools that are appropriate for a primary care practice, said Dr. Amsel, a clinical psychiatrist at Columbia University in New York, and a faculty member of the REACH Institute, a New York–based nonprofit focused on disseminating mental health skills to primary care clinicians, teachers, parents, and others. The program also tries to make clinicians comfortable prescribing psychiatric medications and links them with psychiatrists who can provide consultations when needed.

“It’s kind of like a psychiatrist extender,” when a psychiatrist consults with several primary care clinicians, which allows for improved psychiatric care of many more patients, he said.

Dr. Amsel is on the faculty of the REACH Institute.

[email protected]

On Twitter@mitchelzoler

NEW YORK– The REACH Institute trains primary care clinicians to include more mental health assessment and management in their practices, Dr. Lawrence V. Amsel said during an interview at the psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.

Many primary care clinicians don’t feel adequately trained to interview patients, guage their mental status, and then act on the findings by treatment or referral. But over the past decade, psychiatrists have developed and validated several tools that are appropriate for a primary care practice, said Dr. Amsel, a clinical psychiatrist at Columbia University in New York, and a faculty member of the REACH Institute, a New York–based nonprofit focused on disseminating mental health skills to primary care clinicians, teachers, parents, and others. The program also tries to make clinicians comfortable prescribing psychiatric medications and links them with psychiatrists who can provide consultations when needed.

“It’s kind of like a psychiatrist extender,” when a psychiatrist consults with several primary care clinicians, which allows for improved psychiatric care of many more patients, he said.

Dr. Amsel is on the faculty of the REACH Institute.

[email protected]

On Twitter@mitchelzoler

NEW YORK– The REACH Institute trains primary care clinicians to include more mental health assessment and management in their practices, Dr. Lawrence V. Amsel said during an interview at the psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.

Many primary care clinicians don’t feel adequately trained to interview patients, guage their mental status, and then act on the findings by treatment or referral. But over the past decade, psychiatrists have developed and validated several tools that are appropriate for a primary care practice, said Dr. Amsel, a clinical psychiatrist at Columbia University in New York, and a faculty member of the REACH Institute, a New York–based nonprofit focused on disseminating mental health skills to primary care clinicians, teachers, parents, and others. The program also tries to make clinicians comfortable prescribing psychiatric medications and links them with psychiatrists who can provide consultations when needed.

“It’s kind of like a psychiatrist extender,” when a psychiatrist consults with several primary care clinicians, which allows for improved psychiatric care of many more patients, he said.

Dr. Amsel is on the faculty of the REACH Institute.

[email protected]

On Twitter@mitchelzoler

Rudolph Virchow clearly demonstrated the association between malignancy and venous thromboembolic events. VTE – deep vein thrombosis and pulmonary embolism – affect between 15% and 38% of patients with gynecologic malignancies after surgery.

The rate of pulmonary embolism (PE) in this patient population can be as high as 6.8%, with the case fatality rate being 11%-12% (Obstet. Gynecol. 2012;119:155-67). Other factors associated with the development of VTE include prior VTE, older age, African American race, prolonged operative time, obesity, and prior radiation therapy (Obstet. Gynecol. 1987;69:146-50). The risk of VTE in women undergoing gynecologic surgery is quadrupled in the presence of malignancy(Obstet. Gynecol. 2006;107:666-71) and these patients are twice as likely to die from a VTE compared to matched controls (Gynecol. Oncol. 2007;106:439-45).

Additionally, cancer patients are typically older, have longer and more complex surgeries, and the presence of a pelvic mass further contributes to venous stasis (Obstet. Gynecol. 2012;119:155-67).

Although the treatment of VTE is fairly similar between patients with malignancy and those without cancer, treatment of a VTE in patients with cancer can be further complicated by higher VTE recurrence rates and increased risk of bleeding. Furthermore, issues related to the malignant disease process such as prognosis, presence and location of metastasis, and life expectancy should be taken into consideration when managing VTE in this patient population.

Generally, in the setting of an acute or recurrent VTE, initial therapy with a parenteral anticoagulant (heparin or low-molecular-weight heparins [LMWH]) should be immediately instituted in patients with a gynecologic malignancy, unless there is evidence of active bleeding or any other contraindication for the use of an anticoagulant.

Other factors associated with cancer such as immobilization, the presence of metastases, and impaired renal function with a creatinine clearance less than 30 mL/min, may increase the risk of bleeding complications but are not absolute contraindications to anticoagulation (Thromb. Haemost. 2008;100:435-9). The initial treatment phase, which last for 5-10 days, is then followed by a longer treatment phase lasting 3-6 months.

In the majority of cases, LMWH is the preferred agent for both the initial and prolonged treatment phase assuming adequate renal function. Based on evidence from a meta-analysis of 16 randomized controlled trials in cancer patients receiving initial anticoagulation for VTE, LMWH is associated with a 30% reduction in mortality without an increased risk of bleeding in comparison to unfractionated heparin (Cochrane Database. Syst. Rev. 2014;6:CD006649).

When compared with the vitamin K antagonist warfarin, LMWH appears to be associated with a significantly reduced rate of recurrent VTE (hazard ratio, 0.47; 95% confidence interval 0.32-0.71). However, this was not associated with a survival advantage (N. Engl. J. Med. 2003;349:146-53).

There are no trials comparing the different formulations of LMWH. In our practice, we routinely use the LMWH enoxaparin dosed at 1 mg/kg subcutaneously twice daily. Other well-studied LMWHs include dalteparin and tinzaparin.

LMWHs are primarily renally excreted, thus, in patients with compromised renal function, the biological half-life of the medication may be prolonged, leading to potential bleeding complications. The majority of LMWH trials excluded patients with creatinine clearance less than 30 mL/min, therefore, in patients with compromised renal function, one option would be to decrease the daily dose by as much as 50% and closely monitor antifactor XA levels. Alternatively, the use of unfractionated heparin in the acute setting followed by warfarin with close monitoring of the patient’s international normalized ratio could prove less cumbersome and ultimately safer for these patients. However, given the limitations of the currently available data we would not recommend the routine use of newer oral anticoagulation agents.

Patients with a malignancy are at increased risk for the development of a recurrent VTE even in the setting of anticoagulation. Some of the risks factors for this phenomenon include presence of central venous catheters, interruption of therapy for procedures, and immobilization. In cases of recurrent VTE, consideration should be given to extending the duration of treatment beyond the initial planned 3-6 months. Other patients that may benefit from extended therapy include those with continued immobility or active cancer burden.

LMWH is also the preferred agent for extended therapy based on very limited evidence from experimental studies suggesting that LMWH may have antineoplastic effects and thus a survival advantage. However, in the setting of a recurrent VTE, there is very limited data on which to base the choice of extended treatment. Options include switching the therapeutic agent, increasing the dose or frequency of administration, or placement of an inferior vena cava filter. Consultation with a hematologist may also be warranted in this and more complicated scenarios.

Ultimately, LMWH appears to be the best available therapy for patients with a gynecologic malignancy. However, the decision to anticoagulate should be carefully planned out, taking into consideration the individual patient’s disease burden and associated comorbidities in order to select the most appropriate treatment option.

Dr. Roque is a fellow in the gynecologic oncology program at the University of North Carolina at Chapel Hill. Dr. Clarke-Pearson is the chair and the Robert A. Ross Distinguished Professor of Obstetrics and Gynecology and a professor in the division of gynecologic oncology at the university. Dr. Roque and Dr. Clarke-Pearson said they had no relevant financial disclosures.

Rudolph Virchow clearly demonstrated the association between malignancy and venous thromboembolic events. VTE – deep vein thrombosis and pulmonary embolism – affect between 15% and 38% of patients with gynecologic malignancies after surgery.

The rate of pulmonary embolism (PE) in this patient population can be as high as 6.8%, with the case fatality rate being 11%-12% (Obstet. Gynecol. 2012;119:155-67). Other factors associated with the development of VTE include prior VTE, older age, African American race, prolonged operative time, obesity, and prior radiation therapy (Obstet. Gynecol. 1987;69:146-50). The risk of VTE in women undergoing gynecologic surgery is quadrupled in the presence of malignancy(Obstet. Gynecol. 2006;107:666-71) and these patients are twice as likely to die from a VTE compared to matched controls (Gynecol. Oncol. 2007;106:439-45).

Additionally, cancer patients are typically older, have longer and more complex surgeries, and the presence of a pelvic mass further contributes to venous stasis (Obstet. Gynecol. 2012;119:155-67).

Although the treatment of VTE is fairly similar between patients with malignancy and those without cancer, treatment of a VTE in patients with cancer can be further complicated by higher VTE recurrence rates and increased risk of bleeding. Furthermore, issues related to the malignant disease process such as prognosis, presence and location of metastasis, and life expectancy should be taken into consideration when managing VTE in this patient population.

Generally, in the setting of an acute or recurrent VTE, initial therapy with a parenteral anticoagulant (heparin or low-molecular-weight heparins [LMWH]) should be immediately instituted in patients with a gynecologic malignancy, unless there is evidence of active bleeding or any other contraindication for the use of an anticoagulant.

Other factors associated with cancer such as immobilization, the presence of metastases, and impaired renal function with a creatinine clearance less than 30 mL/min, may increase the risk of bleeding complications but are not absolute contraindications to anticoagulation (Thromb. Haemost. 2008;100:435-9). The initial treatment phase, which last for 5-10 days, is then followed by a longer treatment phase lasting 3-6 months.

In the majority of cases, LMWH is the preferred agent for both the initial and prolonged treatment phase assuming adequate renal function. Based on evidence from a meta-analysis of 16 randomized controlled trials in cancer patients receiving initial anticoagulation for VTE, LMWH is associated with a 30% reduction in mortality without an increased risk of bleeding in comparison to unfractionated heparin (Cochrane Database. Syst. Rev. 2014;6:CD006649).

When compared with the vitamin K antagonist warfarin, LMWH appears to be associated with a significantly reduced rate of recurrent VTE (hazard ratio, 0.47; 95% confidence interval 0.32-0.71). However, this was not associated with a survival advantage (N. Engl. J. Med. 2003;349:146-53).

There are no trials comparing the different formulations of LMWH. In our practice, we routinely use the LMWH enoxaparin dosed at 1 mg/kg subcutaneously twice daily. Other well-studied LMWHs include dalteparin and tinzaparin.

LMWHs are primarily renally excreted, thus, in patients with compromised renal function, the biological half-life of the medication may be prolonged, leading to potential bleeding complications. The majority of LMWH trials excluded patients with creatinine clearance less than 30 mL/min, therefore, in patients with compromised renal function, one option would be to decrease the daily dose by as much as 50% and closely monitor antifactor XA levels. Alternatively, the use of unfractionated heparin in the acute setting followed by warfarin with close monitoring of the patient’s international normalized ratio could prove less cumbersome and ultimately safer for these patients. However, given the limitations of the currently available data we would not recommend the routine use of newer oral anticoagulation agents.

Patients with a malignancy are at increased risk for the development of a recurrent VTE even in the setting of anticoagulation. Some of the risks factors for this phenomenon include presence of central venous catheters, interruption of therapy for procedures, and immobilization. In cases of recurrent VTE, consideration should be given to extending the duration of treatment beyond the initial planned 3-6 months. Other patients that may benefit from extended therapy include those with continued immobility or active cancer burden.

LMWH is also the preferred agent for extended therapy based on very limited evidence from experimental studies suggesting that LMWH may have antineoplastic effects and thus a survival advantage. However, in the setting of a recurrent VTE, there is very limited data on which to base the choice of extended treatment. Options include switching the therapeutic agent, increasing the dose or frequency of administration, or placement of an inferior vena cava filter. Consultation with a hematologist may also be warranted in this and more complicated scenarios.

Ultimately, LMWH appears to be the best available therapy for patients with a gynecologic malignancy. However, the decision to anticoagulate should be carefully planned out, taking into consideration the individual patient’s disease burden and associated comorbidities in order to select the most appropriate treatment option.

Dr. Roque is a fellow in the gynecologic oncology program at the University of North Carolina at Chapel Hill. Dr. Clarke-Pearson is the chair and the Robert A. Ross Distinguished Professor of Obstetrics and Gynecology and a professor in the division of gynecologic oncology at the university. Dr. Roque and Dr. Clarke-Pearson said they had no relevant financial disclosures.

Rudolph Virchow clearly demonstrated the association between malignancy and venous thromboembolic events. VTE – deep vein thrombosis and pulmonary embolism – affect between 15% and 38% of patients with gynecologic malignancies after surgery.

The rate of pulmonary embolism (PE) in this patient population can be as high as 6.8%, with the case fatality rate being 11%-12% (Obstet. Gynecol. 2012;119:155-67). Other factors associated with the development of VTE include prior VTE, older age, African American race, prolonged operative time, obesity, and prior radiation therapy (Obstet. Gynecol. 1987;69:146-50). The risk of VTE in women undergoing gynecologic surgery is quadrupled in the presence of malignancy(Obstet. Gynecol. 2006;107:666-71) and these patients are twice as likely to die from a VTE compared to matched controls (Gynecol. Oncol. 2007;106:439-45).

Additionally, cancer patients are typically older, have longer and more complex surgeries, and the presence of a pelvic mass further contributes to venous stasis (Obstet. Gynecol. 2012;119:155-67).

Although the treatment of VTE is fairly similar between patients with malignancy and those without cancer, treatment of a VTE in patients with cancer can be further complicated by higher VTE recurrence rates and increased risk of bleeding. Furthermore, issues related to the malignant disease process such as prognosis, presence and location of metastasis, and life expectancy should be taken into consideration when managing VTE in this patient population.

Generally, in the setting of an acute or recurrent VTE, initial therapy with a parenteral anticoagulant (heparin or low-molecular-weight heparins [LMWH]) should be immediately instituted in patients with a gynecologic malignancy, unless there is evidence of active bleeding or any other contraindication for the use of an anticoagulant.

Other factors associated with cancer such as immobilization, the presence of metastases, and impaired renal function with a creatinine clearance less than 30 mL/min, may increase the risk of bleeding complications but are not absolute contraindications to anticoagulation (Thromb. Haemost. 2008;100:435-9). The initial treatment phase, which last for 5-10 days, is then followed by a longer treatment phase lasting 3-6 months.

In the majority of cases, LMWH is the preferred agent for both the initial and prolonged treatment phase assuming adequate renal function. Based on evidence from a meta-analysis of 16 randomized controlled trials in cancer patients receiving initial anticoagulation for VTE, LMWH is associated with a 30% reduction in mortality without an increased risk of bleeding in comparison to unfractionated heparin (Cochrane Database. Syst. Rev. 2014;6:CD006649).

When compared with the vitamin K antagonist warfarin, LMWH appears to be associated with a significantly reduced rate of recurrent VTE (hazard ratio, 0.47; 95% confidence interval 0.32-0.71). However, this was not associated with a survival advantage (N. Engl. J. Med. 2003;349:146-53).

There are no trials comparing the different formulations of LMWH. In our practice, we routinely use the LMWH enoxaparin dosed at 1 mg/kg subcutaneously twice daily. Other well-studied LMWHs include dalteparin and tinzaparin.

LMWHs are primarily renally excreted, thus, in patients with compromised renal function, the biological half-life of the medication may be prolonged, leading to potential bleeding complications. The majority of LMWH trials excluded patients with creatinine clearance less than 30 mL/min, therefore, in patients with compromised renal function, one option would be to decrease the daily dose by as much as 50% and closely monitor antifactor XA levels. Alternatively, the use of unfractionated heparin in the acute setting followed by warfarin with close monitoring of the patient’s international normalized ratio could prove less cumbersome and ultimately safer for these patients. However, given the limitations of the currently available data we would not recommend the routine use of newer oral anticoagulation agents.

Patients with a malignancy are at increased risk for the development of a recurrent VTE even in the setting of anticoagulation. Some of the risks factors for this phenomenon include presence of central venous catheters, interruption of therapy for procedures, and immobilization. In cases of recurrent VTE, consideration should be given to extending the duration of treatment beyond the initial planned 3-6 months. Other patients that may benefit from extended therapy include those with continued immobility or active cancer burden.

LMWH is also the preferred agent for extended therapy based on very limited evidence from experimental studies suggesting that LMWH may have antineoplastic effects and thus a survival advantage. However, in the setting of a recurrent VTE, there is very limited data on which to base the choice of extended treatment. Options include switching the therapeutic agent, increasing the dose or frequency of administration, or placement of an inferior vena cava filter. Consultation with a hematologist may also be warranted in this and more complicated scenarios.

Ultimately, LMWH appears to be the best available therapy for patients with a gynecologic malignancy. However, the decision to anticoagulate should be carefully planned out, taking into consideration the individual patient’s disease burden and associated comorbidities in order to select the most appropriate treatment option.

Dr. Roque is a fellow in the gynecologic oncology program at the University of North Carolina at Chapel Hill. Dr. Clarke-Pearson is the chair and the Robert A. Ross Distinguished Professor of Obstetrics and Gynecology and a professor in the division of gynecologic oncology at the university. Dr. Roque and Dr. Clarke-Pearson said they had no relevant financial disclosures.

NEW YORK – Making primary care clinicians comfortable performing basic mental health diagnoses and management is vital for adequately treating U.S. patients with psychiatric disorders, Dr. Lawrence V. Amsel said at a psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.

In many parts of the United States there are “far fewer mental health practitioners than are needed.” Training primary care clinicians so that they are willing to do more mental health work can help address this issue, said Dr. Amsel, a clinical psychiatrist at Columbia University in New York and a faculty member of the REACH Institute, a New York–based nonprofit focused on disseminating mental health skills to primary care clinicians, teachers, parents, and others. “It’s like producing psychiatric extenders.” By consulting with a broad range of primary care clinicians, a psychiatrist can take care of a lot more kids than usual in a single psychiatric practice,” Dr. Amsel said.

But encouraging primary care providers to become more active in mental health diagnosis and management is not easy. “Most prescriptions for mental health indications are now written by primary care clinicians, but they often describe themselves as uncomfortable prescribing these medications and not adequately trained,” Dr. Amsel said in an interview.

“Their main anxiety comes from making the wrong diagnosis and then doing harm” as a consequence of their error, he explained during his talk at the meeting. Training by the REACH curriculum highlights the role of well-validated tools now available for refining assessment of a patient and boosting confidence in the diagnosis. This includes instruments like the Pediatric Symptom Checklist and the Mental Status Exam. “Reliable and validated tools are available to improve identification and assessment of mental health problems that can be used efficiently in clinical practice,” Dr. Amsel said.

Another aspect to mental health management that often troubles primary care clinicians is doubt about their knowledge and ability to safely and effectively prescribe psychiatric medications. The REACH Institute curriculum tells clinicians to focus on each patient’s primary diagnosis and treat that first, and whenever possible to use medications that are evidence based, with good supporting documentation from double-blind, randomized, controlled trials.

“We recommend that clinicians get a summary slide of the evidence that they can show to patients or family members if necessary to make clear that there is a scientific basis for the treatment and that it is based on facts and data rather than on opinion,” he said.

Training for primary care clinicians also emphasizes that management goes beyond drug treatment and also must include a psychosocial plan for each patient.

Members of the health care system have begun to “recognize that mental health is responsible for much if not most disability. Until now, this importance had not been recognized. Now that it is being recognized, I think people will develop systems that increase the capacity for identifying children with mental health issues and provide them with improved care,” Dr. Amsel said.

Dr. Amsel had no disclosures aside from his work for the REACH Institute.

[email protected]

On Twitter @mitchelzoler

NEW YORK – Making primary care clinicians comfortable performing basic mental health diagnoses and management is vital for adequately treating U.S. patients with psychiatric disorders, Dr. Lawrence V. Amsel said at a psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.

In many parts of the United States there are “far fewer mental health practitioners than are needed.” Training primary care clinicians so that they are willing to do more mental health work can help address this issue, said Dr. Amsel, a clinical psychiatrist at Columbia University in New York and a faculty member of the REACH Institute, a New York–based nonprofit focused on disseminating mental health skills to primary care clinicians, teachers, parents, and others. “It’s like producing psychiatric extenders.” By consulting with a broad range of primary care clinicians, a psychiatrist can take care of a lot more kids than usual in a single psychiatric practice,” Dr. Amsel said.

But encouraging primary care providers to become more active in mental health diagnosis and management is not easy. “Most prescriptions for mental health indications are now written by primary care clinicians, but they often describe themselves as uncomfortable prescribing these medications and not adequately trained,” Dr. Amsel said in an interview.

“Their main anxiety comes from making the wrong diagnosis and then doing harm” as a consequence of their error, he explained during his talk at the meeting. Training by the REACH curriculum highlights the role of well-validated tools now available for refining assessment of a patient and boosting confidence in the diagnosis. This includes instruments like the Pediatric Symptom Checklist and the Mental Status Exam. “Reliable and validated tools are available to improve identification and assessment of mental health problems that can be used efficiently in clinical practice,” Dr. Amsel said.

Another aspect to mental health management that often troubles primary care clinicians is doubt about their knowledge and ability to safely and effectively prescribe psychiatric medications. The REACH Institute curriculum tells clinicians to focus on each patient’s primary diagnosis and treat that first, and whenever possible to use medications that are evidence based, with good supporting documentation from double-blind, randomized, controlled trials.

“We recommend that clinicians get a summary slide of the evidence that they can show to patients or family members if necessary to make clear that there is a scientific basis for the treatment and that it is based on facts and data rather than on opinion,” he said.

Training for primary care clinicians also emphasizes that management goes beyond drug treatment and also must include a psychosocial plan for each patient.

Members of the health care system have begun to “recognize that mental health is responsible for much if not most disability. Until now, this importance had not been recognized. Now that it is being recognized, I think people will develop systems that increase the capacity for identifying children with mental health issues and provide them with improved care,” Dr. Amsel said.

Dr. Amsel had no disclosures aside from his work for the REACH Institute.

[email protected]

On Twitter @mitchelzoler

NEW YORK – Making primary care clinicians comfortable performing basic mental health diagnoses and management is vital for adequately treating U.S. patients with psychiatric disorders, Dr. Lawrence V. Amsel said at a psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.

In many parts of the United States there are “far fewer mental health practitioners than are needed.” Training primary care clinicians so that they are willing to do more mental health work can help address this issue, said Dr. Amsel, a clinical psychiatrist at Columbia University in New York and a faculty member of the REACH Institute, a New York–based nonprofit focused on disseminating mental health skills to primary care clinicians, teachers, parents, and others. “It’s like producing psychiatric extenders.” By consulting with a broad range of primary care clinicians, a psychiatrist can take care of a lot more kids than usual in a single psychiatric practice,” Dr. Amsel said.

But encouraging primary care providers to become more active in mental health diagnosis and management is not easy. “Most prescriptions for mental health indications are now written by primary care clinicians, but they often describe themselves as uncomfortable prescribing these medications and not adequately trained,” Dr. Amsel said in an interview.

“Their main anxiety comes from making the wrong diagnosis and then doing harm” as a consequence of their error, he explained during his talk at the meeting. Training by the REACH curriculum highlights the role of well-validated tools now available for refining assessment of a patient and boosting confidence in the diagnosis. This includes instruments like the Pediatric Symptom Checklist and the Mental Status Exam. “Reliable and validated tools are available to improve identification and assessment of mental health problems that can be used efficiently in clinical practice,” Dr. Amsel said.

Another aspect to mental health management that often troubles primary care clinicians is doubt about their knowledge and ability to safely and effectively prescribe psychiatric medications. The REACH Institute curriculum tells clinicians to focus on each patient’s primary diagnosis and treat that first, and whenever possible to use medications that are evidence based, with good supporting documentation from double-blind, randomized, controlled trials.

“We recommend that clinicians get a summary slide of the evidence that they can show to patients or family members if necessary to make clear that there is a scientific basis for the treatment and that it is based on facts and data rather than on opinion,” he said.

Training for primary care clinicians also emphasizes that management goes beyond drug treatment and also must include a psychosocial plan for each patient.

Members of the health care system have begun to “recognize that mental health is responsible for much if not most disability. Until now, this importance had not been recognized. Now that it is being recognized, I think people will develop systems that increase the capacity for identifying children with mental health issues and provide them with improved care,” Dr. Amsel said.

Dr. Amsel had no disclosures aside from his work for the REACH Institute.

[email protected]

On Twitter @mitchelzoler

CLL in the bone marrow

The genetic variability of chronic lymphocytic leukemia (CLL) appears to predict its aggressiveness, according to a study published in Genome Medicine.

Investigators found evidence suggesting that greater variability in gene expression is associated with more aggressive disease.

The team analyzed gene expression in two cohorts of CLL patients—those with IgVH mutations and a good prognosis and those with unmutated CLL who have more aggressive disease.

The researchers examined 70 mutated and 52 unmutated CLL samples, as well as 20 control samples taken from healthy individuals.

Unmutated, aggressive CLL showed increased gene expression variability across individuals, whereas gene expression variability was lower in less aggressive, mutated CLL.

The investigators validated these observations by comparing them against a second sample group consisting of 24 mutated and 36 unmutated CLL samples.

The results suggested that CLL aggressiveness is specifically determined by a set of 500 genes showing increased expression variability across individuals. The genes are involved in processes such as adaptation to the environment, cell death, tumor growth, and drug resistance.

“Our conclusion is that the coefficient of variation for gene expression in CLL efficiently predicts its aggressiveness,” said study author Alfonso Valencia, PhD, of Centro Nacional de Investigaciones Oncologicas (CNIO) in Madrid, Spain.

“More importantly, if further research confirms these findings, a classifier based on the measurement of gene expression variability could be created to predict the disease subtype of CLL patients.”

The researchers said their next step is to discover the mechanisms responsible for the high levels of expression variability for a given gene across individuals.

Understanding the mechanisms underlying this phenomenon is of crucial relevance for oncology research, the investigators said, as it is linked to tumor heterogeneity, a key feature of cancer progression and drug resistance.

The greater the genetic variability in a tumor, the better it will adapt to its environment, and the more probabilities for this tumor to spread, develop resistance to cancer therapies, and metastasize to distant organs.

CLL in the bone marrow

The genetic variability of chronic lymphocytic leukemia (CLL) appears to predict its aggressiveness, according to a study published in Genome Medicine.

Investigators found evidence suggesting that greater variability in gene expression is associated with more aggressive disease.

The team analyzed gene expression in two cohorts of CLL patients—those with IgVH mutations and a good prognosis and those with unmutated CLL who have more aggressive disease.

The researchers examined 70 mutated and 52 unmutated CLL samples, as well as 20 control samples taken from healthy individuals.

Unmutated, aggressive CLL showed increased gene expression variability across individuals, whereas gene expression variability was lower in less aggressive, mutated CLL.

The investigators validated these observations by comparing them against a second sample group consisting of 24 mutated and 36 unmutated CLL samples.

The results suggested that CLL aggressiveness is specifically determined by a set of 500 genes showing increased expression variability across individuals. The genes are involved in processes such as adaptation to the environment, cell death, tumor growth, and drug resistance.

“Our conclusion is that the coefficient of variation for gene expression in CLL efficiently predicts its aggressiveness,” said study author Alfonso Valencia, PhD, of Centro Nacional de Investigaciones Oncologicas (CNIO) in Madrid, Spain.

“More importantly, if further research confirms these findings, a classifier based on the measurement of gene expression variability could be created to predict the disease subtype of CLL patients.”

The researchers said their next step is to discover the mechanisms responsible for the high levels of expression variability for a given gene across individuals.

Understanding the mechanisms underlying this phenomenon is of crucial relevance for oncology research, the investigators said, as it is linked to tumor heterogeneity, a key feature of cancer progression and drug resistance.

The greater the genetic variability in a tumor, the better it will adapt to its environment, and the more probabilities for this tumor to spread, develop resistance to cancer therapies, and metastasize to distant organs.

CLL in the bone marrow

The genetic variability of chronic lymphocytic leukemia (CLL) appears to predict its aggressiveness, according to a study published in Genome Medicine.

Investigators found evidence suggesting that greater variability in gene expression is associated with more aggressive disease.

The team analyzed gene expression in two cohorts of CLL patients—those with IgVH mutations and a good prognosis and those with unmutated CLL who have more aggressive disease.

The researchers examined 70 mutated and 52 unmutated CLL samples, as well as 20 control samples taken from healthy individuals.

Unmutated, aggressive CLL showed increased gene expression variability across individuals, whereas gene expression variability was lower in less aggressive, mutated CLL.

The investigators validated these observations by comparing them against a second sample group consisting of 24 mutated and 36 unmutated CLL samples.

The results suggested that CLL aggressiveness is specifically determined by a set of 500 genes showing increased expression variability across individuals. The genes are involved in processes such as adaptation to the environment, cell death, tumor growth, and drug resistance.

“Our conclusion is that the coefficient of variation for gene expression in CLL efficiently predicts its aggressiveness,” said study author Alfonso Valencia, PhD, of Centro Nacional de Investigaciones Oncologicas (CNIO) in Madrid, Spain.

“More importantly, if further research confirms these findings, a classifier based on the measurement of gene expression variability could be created to predict the disease subtype of CLL patients.”

The researchers said their next step is to discover the mechanisms responsible for the high levels of expression variability for a given gene across individuals.

Understanding the mechanisms underlying this phenomenon is of crucial relevance for oncology research, the investigators said, as it is linked to tumor heterogeneity, a key feature of cancer progression and drug resistance.

The greater the genetic variability in a tumor, the better it will adapt to its environment, and the more probabilities for this tumor to spread, develop resistance to cancer therapies, and metastasize to distant organs.

Doctor evaluating a patient

Credit: CDC

Reactivation of the hepatitis B virus (HBV) may be more of a risk than we anticipated, investigators have reported in Hepatology.

Their research indicates that HBV reactivation is associated with the use of chemotherapy, high-dose corticosteroids, biologics targeting tumor necrosis factor-alpha (TNF-α), and agents that aren’t really considered immunosuppressive.

HBV reactivation is also fairly common after organ transplant and hematopoietic stem cell transplant (HSCT).

As reactivation of HBV can be fatal, the study authors suggest routine screening of HBV in all patients prior to the start of these treatments.

The researchers noted that, in September 2013, the US Food and Drug Administration (FDA) issued a Drug Safety Communication in an attempt to decrease the risk of HBV reactivation. The communication advised healthcare professionals to screen patients for HBV prior to the administration of ofatumumab or rituximab.

“[T]his may be just the tip of the iceberg,” said Adrian Di Bisceglie, MD, of Saint Louis University School of Medicine in Missouri.

“Our research suggests that the issue of HBV reactivation may be an underappreciated clinical challenge that extends well beyond the use of just two anti-CD20 medications.”

After a systematic literature review, Dr Di Bisceglie and his colleagues identified 504 studies pertaining to reactivation of HBV.

The investigators reviewed 14 studies in which the antiviral agent lamivudine was used to prevent HBV reactivation in HBsAg-positive patients receiving chemotherapy. Among patients who did not receive lamivudine, HBV reactivation occurred in 32%. Thirteen percent of patients experienced liver failure, and 7% died.

The researchers also looked at patients undergoing HSCT. In one study, 61 patients had resolved HBV infection before HSCT. But 12 of these patients (20%) developed reverse seroconversion (reappearance of HBsAg in a person who was HBsAg-negative, anti-HBc-positive prior to HSCT).

The cumulative probability of reverse seroconversion was 9% a year after HSCT, 21.7% at 2 years, and 42.9% at 4 years.

The investigators also noted that high-dose corticosteroids carry a significant risk of HBV reactivation, both as part of combination treatment for malignancies and when used alone to treat benign conditions.

In addition, the researchers found data showing that HBV reactivation has occurred with antitumor agents that are not thought to be particularly immunosuppressive, such as imatinib and thalidomide. The team said this raises questions about the mechanisms by which drugs are causing HBV reactivation.

The investigators also looked at data from 257 patients with active or recovered HBV infection who received treatment with biological therapies targeting TNF-α.

Forty-two percent of the patients had elevations in serum aminotransferase levels, 39% had reappearance of HBV DNA, 16% had signs and symptoms of liver disease, and 5% died of liver failure.

HBV reactivation was more frequent among patients receiving infliximab than etanercept. It was 7-fold higher among patients who were HBsAg-positive (38%) than those who were HBsAg-negative but anti-HBc-positive (5%).

While it remains unclear how HBV reactivation occurs, experts believe a loss of immune control over viral replication may trigger the process.

“Further study and cooperation between various medical disciplines will help broaden understanding of HBV reactivation,” Dr Di Bisceglie concluded.

Doctor evaluating a patient

Credit: CDC

Reactivation of the hepatitis B virus (HBV) may be more of a risk than we anticipated, investigators have reported in Hepatology.

Their research indicates that HBV reactivation is associated with the use of chemotherapy, high-dose corticosteroids, biologics targeting tumor necrosis factor-alpha (TNF-α), and agents that aren’t really considered immunosuppressive.

HBV reactivation is also fairly common after organ transplant and hematopoietic stem cell transplant (HSCT).

As reactivation of HBV can be fatal, the study authors suggest routine screening of HBV in all patients prior to the start of these treatments.

The researchers noted that, in September 2013, the US Food and Drug Administration (FDA) issued a Drug Safety Communication in an attempt to decrease the risk of HBV reactivation. The communication advised healthcare professionals to screen patients for HBV prior to the administration of ofatumumab or rituximab.

“[T]his may be just the tip of the iceberg,” said Adrian Di Bisceglie, MD, of Saint Louis University School of Medicine in Missouri.

“Our research suggests that the issue of HBV reactivation may be an underappreciated clinical challenge that extends well beyond the use of just two anti-CD20 medications.”

After a systematic literature review, Dr Di Bisceglie and his colleagues identified 504 studies pertaining to reactivation of HBV.

The investigators reviewed 14 studies in which the antiviral agent lamivudine was used to prevent HBV reactivation in HBsAg-positive patients receiving chemotherapy. Among patients who did not receive lamivudine, HBV reactivation occurred in 32%. Thirteen percent of patients experienced liver failure, and 7% died.

The researchers also looked at patients undergoing HSCT. In one study, 61 patients had resolved HBV infection before HSCT. But 12 of these patients (20%) developed reverse seroconversion (reappearance of HBsAg in a person who was HBsAg-negative, anti-HBc-positive prior to HSCT).

The cumulative probability of reverse seroconversion was 9% a year after HSCT, 21.7% at 2 years, and 42.9% at 4 years.

The investigators also noted that high-dose corticosteroids carry a significant risk of HBV reactivation, both as part of combination treatment for malignancies and when used alone to treat benign conditions.

In addition, the researchers found data showing that HBV reactivation has occurred with antitumor agents that are not thought to be particularly immunosuppressive, such as imatinib and thalidomide. The team said this raises questions about the mechanisms by which drugs are causing HBV reactivation.

The investigators also looked at data from 257 patients with active or recovered HBV infection who received treatment with biological therapies targeting TNF-α.

Forty-two percent of the patients had elevations in serum aminotransferase levels, 39% had reappearance of HBV DNA, 16% had signs and symptoms of liver disease, and 5% died of liver failure.

HBV reactivation was more frequent among patients receiving infliximab than etanercept. It was 7-fold higher among patients who were HBsAg-positive (38%) than those who were HBsAg-negative but anti-HBc-positive (5%).

While it remains unclear how HBV reactivation occurs, experts believe a loss of immune control over viral replication may trigger the process.

“Further study and cooperation between various medical disciplines will help broaden understanding of HBV reactivation,” Dr Di Bisceglie concluded.

Doctor evaluating a patient

Credit: CDC

Reactivation of the hepatitis B virus (HBV) may be more of a risk than we anticipated, investigators have reported in Hepatology.

Their research indicates that HBV reactivation is associated with the use of chemotherapy, high-dose corticosteroids, biologics targeting tumor necrosis factor-alpha (TNF-α), and agents that aren’t really considered immunosuppressive.

HBV reactivation is also fairly common after organ transplant and hematopoietic stem cell transplant (HSCT).

As reactivation of HBV can be fatal, the study authors suggest routine screening of HBV in all patients prior to the start of these treatments.

The researchers noted that, in September 2013, the US Food and Drug Administration (FDA) issued a Drug Safety Communication in an attempt to decrease the risk of HBV reactivation. The communication advised healthcare professionals to screen patients for HBV prior to the administration of ofatumumab or rituximab.

“[T]his may be just the tip of the iceberg,” said Adrian Di Bisceglie, MD, of Saint Louis University School of Medicine in Missouri.

“Our research suggests that the issue of HBV reactivation may be an underappreciated clinical challenge that extends well beyond the use of just two anti-CD20 medications.”

After a systematic literature review, Dr Di Bisceglie and his colleagues identified 504 studies pertaining to reactivation of HBV.

The investigators reviewed 14 studies in which the antiviral agent lamivudine was used to prevent HBV reactivation in HBsAg-positive patients receiving chemotherapy. Among patients who did not receive lamivudine, HBV reactivation occurred in 32%. Thirteen percent of patients experienced liver failure, and 7% died.

The researchers also looked at patients undergoing HSCT. In one study, 61 patients had resolved HBV infection before HSCT. But 12 of these patients (20%) developed reverse seroconversion (reappearance of HBsAg in a person who was HBsAg-negative, anti-HBc-positive prior to HSCT).

The cumulative probability of reverse seroconversion was 9% a year after HSCT, 21.7% at 2 years, and 42.9% at 4 years.

The investigators also noted that high-dose corticosteroids carry a significant risk of HBV reactivation, both as part of combination treatment for malignancies and when used alone to treat benign conditions.

In addition, the researchers found data showing that HBV reactivation has occurred with antitumor agents that are not thought to be particularly immunosuppressive, such as imatinib and thalidomide. The team said this raises questions about the mechanisms by which drugs are causing HBV reactivation.

The investigators also looked at data from 257 patients with active or recovered HBV infection who received treatment with biological therapies targeting TNF-α.

Forty-two percent of the patients had elevations in serum aminotransferase levels, 39% had reappearance of HBV DNA, 16% had signs and symptoms of liver disease, and 5% died of liver failure.

HBV reactivation was more frequent among patients receiving infliximab than etanercept. It was 7-fold higher among patients who were HBsAg-positive (38%) than those who were HBsAg-negative but anti-HBc-positive (5%).

While it remains unclear how HBV reactivation occurs, experts believe a loss of immune control over viral replication may trigger the process.

“Further study and cooperation between various medical disciplines will help broaden understanding of HBV reactivation,” Dr Di Bisceglie concluded.