From the Department of Family and Community Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, TX (Dr. Zare, Ms Klawans, Dr. Moreno), Department of Family Medicine and Community Medicine, Baylor College of Medicine, Houston, TX (Dr. Mejia de Grubb, Dr. Juneja, Dr. Zoorob)^, Department of Psychiatry, McGovern Medical School at the University of Texas Health Science Center, Houston, TX (Dr. Suchting), andHarris Health System, Houston TX (Ms. Mathis).

Abstract

• Objective: To describe a pilot project to improve care for patients with uncontrolled diabetes in a safety net clinic.
• Methods: One of 3 clinical teams was designated the intervention team. Changes implemented by the intervention team included patient referral to a dietician and/or clinical pharmacist, provision of patient education, and assignment of a case manager. We compared outcomes of patients in the intervention group (n = 71), vs those receiving care from the other 2 teams (usual care) (n = 188).
• Results: HbA1c significantly decreased over time for patients in the intervention group as well as the usual care group. Within the intervention group, visits to clinical pharmacist (P = 0.034) and education (P = 0.004) predicted significantly greater decreases in HbA1c over time.
• Conclusions: Diffusion of treatment may account for the overall HbA1c reduction regardless of treatment group. Results support the need for further pragmatic research to weigh the impact of unblinded designs, outcome measurement, and real-world behaviors on evidence-based interventions.

Key words: diabetes; safety net; multidisciplinary diabetes care; primary care; diffusion of treatment.

The prevalence of type 2 diabetes in the United States is significantly higher among Hispanics and African Americans than in the general population (13% vs. 9.3%) [1]. Similarly, diabetes is highly prevalent among the uninsured, and many patients delay or forgo treatment due to cost [2]. Subsequently, the rates of comorbidities, including stroke, hypertension, and CVD, are elevated in these groups [3].

Association between elevated HbA1c and morbidity and mortality is well-documented, and an HbA1c reduction of just 1% has been shown to reduce mortality and improve quality of life [4]. Uncontrolled diabetes also results in increased medical costs. Reducing HbA1c from 9.0 to 7.5 reduces annual expenditures by as much as 73% [5].

Metropolitan Houston and Harris County, Texas, has one of the largest uninsured metro populations in the United States (over 3.6 million) [6]. Harris Health System serves this uninsured population and is the fourth largest safety net health system in the nation. Approximately 40,000 patients with diabetes receive care within the health system, and 34% of them have an HbA1c value greater than 9.

Developing novel, cost-efficient treatment and management models is crucial when providing care for patients with uncontrolled diabetes. However, the study of implementation strategies to successfully integrate evidence-based interventions in primary care using pragmatic approaches that aim to determine the effectiveness of interventions in “the real world” remain a challenge [7,8]. To address this issue, a quality improvement project was instituted at one of the system’s health centers to improve the care of patients with uncontrolled diabetes (known HbA1c above 9).

Methods

Setting

The pilot project was conducted from 1 Oct 2015 to 31 Dec 2015 in a primary care community health center within Harris Health System in Houston, Texas. This pilot was the first step of an institutional effort to introduce a multidisciplinary model of care across all clinics [9]. Our health center has 6 family medicine providers and 1 advanced practice nurse practitioner, organized into 3 pods with 2 physicians each. We randomly selected 1 pod (team) and designated it the intervention group.

The Standards for Quality Improvement Reporting Excellence guidelines [10] were followed and institutional review board approval was obtained.

Intervention

Practice changes introduced in the intervention team were assignment of a case manager to all patients, referral to a dietician and clinical pharmacist as needed, and patient education sessions. The team’s nurse assumed the role of case manager. The case manager was responsible for reviewing a patient checklist based on the America Diabetes Association guideline for comprehensive diabetes medical evaluation at initial and follow-up visits. Referrals were based on ADA guideline recommendations. Onsite brief patient education was provided to all patients. In addition, patients were enrolled in a “Diabetes 101” class, which follows an evidence-based curriculum that includes participation in at least 2 monthly sessions. Patients were asked to return to the clinic for a follow-up visit after 3 months in order to monitor medication compliance, re-evaluate their care plan, and measure HbA1c The usual care group patients were managed based on the current Standards of Medical Care in Diabetes [11]. The usual care group included patients from the same clinic under the care of providers in the teams that were not included in the multidisciplinary intervention.

Analysis

Data abstracted from de-identified patient records included HbA1c values, interventions received, and sociodemographic data. Generalized linear mixed modeling (GLMM) was used to examine changes in patient HbA1c levels over time [12]. All models included a random intercept to account for correlated observations within patient. All analyses were performed using Proc GLIMMIX in SAS v. 9.3 [13].

Results

A total 271 patients with HbA1c above 9 were included in the analysis: 71 in the intervention group and 188 in the usual care group. The intervention group was further differentiated by month of enrollment: October (n = 37), November (n = 27), and December (n = 9). Mean patient age in the overall sample was 51.6 years. 

In the intervention group, most patients received patient education 56% (n = 40), almost half had a clinical pharmacy visit, but only 17% (n = 12) received a dietitian consultation. Overall, there was a 1.4% decrease in HbA1c in the intervention group, compared to a 1.3% HbA1c decrease in the usual care group.

GLMM was used to examine differences in HbA1c levels according to month of intervention enrollment (October vs. November vs. December) in the intervention group over time. Figure 1 shows predicted HbA1c values over time with trend lines fit for each of the three subgroups. 

Preliminary analysis showed that potential contamination (diffusion of the treatment) would be likely to attenuate differences in the outcomes between the intervention and usual care conditions. Further analysis by subgroups were conducted to describe the intervention potential “spillover” to the usual care group participants not intended to receive the intervention. GLMM also examined differences in HbA1c levels between the intervention and usual care groups over time. The interaction between each treatment group and time was not statistically significant (F(2,268) = 1.34, P = 0.26), indicating that changes in HbA1c over time were not related to treatment group. A statistically reliable main effect for time (F(1,268) = 44.33, P < 0.001) indicated that in all groups, HbA1c values significantly decreased over time.

Follow-up analyses utilized GLMM to examine differences in HbA1c levels among patients in both groups who received at least one of the interventions (visiting a dietician, clinical pharmacist, education session, and clinical case manager). The interaction between intervention and time was not statistically significant for visiting the dietician, receiving education, or being assigned a case manager. The interaction between time and visiting a clinical pharmacist was statistically significant (F(1,204)= 7.78, P = 0.01) such that patients visiting the clinical pharmacist had lower HbA1c values over time relative to those that did not (Figure 2). 

Discussion

HbA1c decreased significantly among intervention patients with uncontrolled diabetes over a 3-month period, regardless of which month they entered the study. However, there was no significant difference in HbA1c reduction between patients who received all 4 multidisciplinary interventions, one intervention, or those who received usual care. Patients in the intervention who attended clinical pharmacist visits had significantly greater HbA1c reduction than patients who did not, as did patients who attended a diabetes education session by a patient educator.

Diffusion of treatment may account for the overall HbA1c reduction regardless of treatment group. Diffusion refers to the unintended spread of a treatment effect when participants receive some or all treatments from an intervention to which they were not assigned, making outcomes descriptions of all study groups more challenging [14]. During the implementation period, other physicians and nurses in the clinic were aware of the multidisciplinary care model being piloted, and may have taken the initiative to connect their patients with clinical pharmacists, dieticians, certified diabetes educators, and clinical case managers. Pragmatic interventions are intended to maintain the internal validity of randomized control trials, yet they are meant to be implemented as close as possible to real-world settings in order to help patients, clinicians, and payers making informed health care decisions [8]. In this regard, participants in the control group could be exposed to the intervention through staff contact between the assigned groups implementing some of the intervention under study. In that case, the diffusion of treatment would be likely to attenuate differences in the outcomes between treatment and control groups [15].

This study has several limitations. We studied a small sample of patients that reflected the primary care population in one clinic in a safety net system with minority, underserved, and high-risk patients. Although attempts were made to keep the intervention limited to the intervention pod, diffusion of treatment might have impacted the internal validity of this intervention.

In summary, our results support the need for further systematic research work to weigh the impact of unblinded designs, simplified recruitment and outcome measurement, and real-world behaviors (such as noncompliance, cross over, and dropout) on evidence-based and multidisciplinary clinical interventions.

Acknowledgements: The authors would like to thank Krystal Gamarra, MSW, LCSW, and Hope Galvan, MS, RN, CVRN-BC, CDE for assistance with project implementation and data collection throughout this process.

Corresponding author: Maria C. Mejia de Grubb, MD, MPH, 3751 Kirby Dr, Suite 600, Houston, TX 77098, [email protected].

Financial disclosures: None.

From the Department of Family and Community Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, TX (Dr. Zare, Ms Klawans, Dr. Moreno), Department of Family Medicine and Community Medicine, Baylor College of Medicine, Houston, TX (Dr. Mejia de Grubb, Dr. Juneja, Dr. Zoorob)^, Department of Psychiatry, McGovern Medical School at the University of Texas Health Science Center, Houston, TX (Dr. Suchting), andHarris Health System, Houston TX (Ms. Mathis).

Abstract

• Objective: To describe a pilot project to improve care for patients with uncontrolled diabetes in a safety net clinic.
• Methods: One of 3 clinical teams was designated the intervention team. Changes implemented by the intervention team included patient referral to a dietician and/or clinical pharmacist, provision of patient education, and assignment of a case manager. We compared outcomes of patients in the intervention group (n = 71), vs those receiving care from the other 2 teams (usual care) (n = 188).
• Results: HbA1c significantly decreased over time for patients in the intervention group as well as the usual care group. Within the intervention group, visits to clinical pharmacist (P = 0.034) and education (P = 0.004) predicted significantly greater decreases in HbA1c over time.
• Conclusions: Diffusion of treatment may account for the overall HbA1c reduction regardless of treatment group. Results support the need for further pragmatic research to weigh the impact of unblinded designs, outcome measurement, and real-world behaviors on evidence-based interventions.

Key words: diabetes; safety net; multidisciplinary diabetes care; primary care; diffusion of treatment.

The prevalence of type 2 diabetes in the United States is significantly higher among Hispanics and African Americans than in the general population (13% vs. 9.3%) [1]. Similarly, diabetes is highly prevalent among the uninsured, and many patients delay or forgo treatment due to cost [2]. Subsequently, the rates of comorbidities, including stroke, hypertension, and CVD, are elevated in these groups [3].

Association between elevated HbA1c and morbidity and mortality is well-documented, and an HbA1c reduction of just 1% has been shown to reduce mortality and improve quality of life [4]. Uncontrolled diabetes also results in increased medical costs. Reducing HbA1c from 9.0 to 7.5 reduces annual expenditures by as much as 73% [5].

Metropolitan Houston and Harris County, Texas, has one of the largest uninsured metro populations in the United States (over 3.6 million) [6]. Harris Health System serves this uninsured population and is the fourth largest safety net health system in the nation. Approximately 40,000 patients with diabetes receive care within the health system, and 34% of them have an HbA1c value greater than 9.

Developing novel, cost-efficient treatment and management models is crucial when providing care for patients with uncontrolled diabetes. However, the study of implementation strategies to successfully integrate evidence-based interventions in primary care using pragmatic approaches that aim to determine the effectiveness of interventions in “the real world” remain a challenge [7,8]. To address this issue, a quality improvement project was instituted at one of the system’s health centers to improve the care of patients with uncontrolled diabetes (known HbA1c above 9).

Methods

Setting

The pilot project was conducted from 1 Oct 2015 to 31 Dec 2015 in a primary care community health center within Harris Health System in Houston, Texas. This pilot was the first step of an institutional effort to introduce a multidisciplinary model of care across all clinics [9]. Our health center has 6 family medicine providers and 1 advanced practice nurse practitioner, organized into 3 pods with 2 physicians each. We randomly selected 1 pod (team) and designated it the intervention group.

The Standards for Quality Improvement Reporting Excellence guidelines [10] were followed and institutional review board approval was obtained.

Intervention

Practice changes introduced in the intervention team were assignment of a case manager to all patients, referral to a dietician and clinical pharmacist as needed, and patient education sessions. The team’s nurse assumed the role of case manager. The case manager was responsible for reviewing a patient checklist based on the America Diabetes Association guideline for comprehensive diabetes medical evaluation at initial and follow-up visits. Referrals were based on ADA guideline recommendations. Onsite brief patient education was provided to all patients. In addition, patients were enrolled in a “Diabetes 101” class, which follows an evidence-based curriculum that includes participation in at least 2 monthly sessions. Patients were asked to return to the clinic for a follow-up visit after 3 months in order to monitor medication compliance, re-evaluate their care plan, and measure HbA1c The usual care group patients were managed based on the current Standards of Medical Care in Diabetes [11]. The usual care group included patients from the same clinic under the care of providers in the teams that were not included in the multidisciplinary intervention.

Analysis

Data abstracted from de-identified patient records included HbA1c values, interventions received, and sociodemographic data. Generalized linear mixed modeling (GLMM) was used to examine changes in patient HbA1c levels over time [12]. All models included a random intercept to account for correlated observations within patient. All analyses were performed using Proc GLIMMIX in SAS v. 9.3 [13].

Results

A total 271 patients with HbA1c above 9 were included in the analysis: 71 in the intervention group and 188 in the usual care group. The intervention group was further differentiated by month of enrollment: October (n = 37), November (n = 27), and December (n = 9). Mean patient age in the overall sample was 51.6 years. 

In the intervention group, most patients received patient education 56% (n = 40), almost half had a clinical pharmacy visit, but only 17% (n = 12) received a dietitian consultation. Overall, there was a 1.4% decrease in HbA1c in the intervention group, compared to a 1.3% HbA1c decrease in the usual care group.

GLMM was used to examine differences in HbA1c levels according to month of intervention enrollment (October vs. November vs. December) in the intervention group over time. Figure 1 shows predicted HbA1c values over time with trend lines fit for each of the three subgroups. 

Preliminary analysis showed that potential contamination (diffusion of the treatment) would be likely to attenuate differences in the outcomes between the intervention and usual care conditions. Further analysis by subgroups were conducted to describe the intervention potential “spillover” to the usual care group participants not intended to receive the intervention. GLMM also examined differences in HbA1c levels between the intervention and usual care groups over time. The interaction between each treatment group and time was not statistically significant (F(2,268) = 1.34, P = 0.26), indicating that changes in HbA1c over time were not related to treatment group. A statistically reliable main effect for time (F(1,268) = 44.33, P < 0.001) indicated that in all groups, HbA1c values significantly decreased over time.

Follow-up analyses utilized GLMM to examine differences in HbA1c levels among patients in both groups who received at least one of the interventions (visiting a dietician, clinical pharmacist, education session, and clinical case manager). The interaction between intervention and time was not statistically significant for visiting the dietician, receiving education, or being assigned a case manager. The interaction between time and visiting a clinical pharmacist was statistically significant (F(1,204)= 7.78, P = 0.01) such that patients visiting the clinical pharmacist had lower HbA1c values over time relative to those that did not (Figure 2). 

Discussion

HbA1c decreased significantly among intervention patients with uncontrolled diabetes over a 3-month period, regardless of which month they entered the study. However, there was no significant difference in HbA1c reduction between patients who received all 4 multidisciplinary interventions, one intervention, or those who received usual care. Patients in the intervention who attended clinical pharmacist visits had significantly greater HbA1c reduction than patients who did not, as did patients who attended a diabetes education session by a patient educator.

Diffusion of treatment may account for the overall HbA1c reduction regardless of treatment group. Diffusion refers to the unintended spread of a treatment effect when participants receive some or all treatments from an intervention to which they were not assigned, making outcomes descriptions of all study groups more challenging [14]. During the implementation period, other physicians and nurses in the clinic were aware of the multidisciplinary care model being piloted, and may have taken the initiative to connect their patients with clinical pharmacists, dieticians, certified diabetes educators, and clinical case managers. Pragmatic interventions are intended to maintain the internal validity of randomized control trials, yet they are meant to be implemented as close as possible to real-world settings in order to help patients, clinicians, and payers making informed health care decisions [8]. In this regard, participants in the control group could be exposed to the intervention through staff contact between the assigned groups implementing some of the intervention under study. In that case, the diffusion of treatment would be likely to attenuate differences in the outcomes between treatment and control groups [15].

This study has several limitations. We studied a small sample of patients that reflected the primary care population in one clinic in a safety net system with minority, underserved, and high-risk patients. Although attempts were made to keep the intervention limited to the intervention pod, diffusion of treatment might have impacted the internal validity of this intervention.

In summary, our results support the need for further systematic research work to weigh the impact of unblinded designs, simplified recruitment and outcome measurement, and real-world behaviors (such as noncompliance, cross over, and dropout) on evidence-based and multidisciplinary clinical interventions.

Acknowledgements: The authors would like to thank Krystal Gamarra, MSW, LCSW, and Hope Galvan, MS, RN, CVRN-BC, CDE for assistance with project implementation and data collection throughout this process.

Corresponding author: Maria C. Mejia de Grubb, MD, MPH, 3751 Kirby Dr, Suite 600, Houston, TX 77098, [email protected].

Financial disclosures: None.

From the Department of Family and Community Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, TX (Dr. Zare, Ms Klawans, Dr. Moreno), Department of Family Medicine and Community Medicine, Baylor College of Medicine, Houston, TX (Dr. Mejia de Grubb, Dr. Juneja, Dr. Zoorob)^, Department of Psychiatry, McGovern Medical School at the University of Texas Health Science Center, Houston, TX (Dr. Suchting), andHarris Health System, Houston TX (Ms. Mathis).

Abstract

• Objective: To describe a pilot project to improve care for patients with uncontrolled diabetes in a safety net clinic.
• Methods: One of 3 clinical teams was designated the intervention team. Changes implemented by the intervention team included patient referral to a dietician and/or clinical pharmacist, provision of patient education, and assignment of a case manager. We compared outcomes of patients in the intervention group (n = 71), vs those receiving care from the other 2 teams (usual care) (n = 188).
• Results: HbA1c significantly decreased over time for patients in the intervention group as well as the usual care group. Within the intervention group, visits to clinical pharmacist (P = 0.034) and education (P = 0.004) predicted significantly greater decreases in HbA1c over time.
• Conclusions: Diffusion of treatment may account for the overall HbA1c reduction regardless of treatment group. Results support the need for further pragmatic research to weigh the impact of unblinded designs, outcome measurement, and real-world behaviors on evidence-based interventions.

Key words: diabetes; safety net; multidisciplinary diabetes care; primary care; diffusion of treatment.

The prevalence of type 2 diabetes in the United States is significantly higher among Hispanics and African Americans than in the general population (13% vs. 9.3%) [1]. Similarly, diabetes is highly prevalent among the uninsured, and many patients delay or forgo treatment due to cost [2]. Subsequently, the rates of comorbidities, including stroke, hypertension, and CVD, are elevated in these groups [3].

Association between elevated HbA1c and morbidity and mortality is well-documented, and an HbA1c reduction of just 1% has been shown to reduce mortality and improve quality of life [4]. Uncontrolled diabetes also results in increased medical costs. Reducing HbA1c from 9.0 to 7.5 reduces annual expenditures by as much as 73% [5].

Metropolitan Houston and Harris County, Texas, has one of the largest uninsured metro populations in the United States (over 3.6 million) [6]. Harris Health System serves this uninsured population and is the fourth largest safety net health system in the nation. Approximately 40,000 patients with diabetes receive care within the health system, and 34% of them have an HbA1c value greater than 9.

Developing novel, cost-efficient treatment and management models is crucial when providing care for patients with uncontrolled diabetes. However, the study of implementation strategies to successfully integrate evidence-based interventions in primary care using pragmatic approaches that aim to determine the effectiveness of interventions in “the real world” remain a challenge [7,8]. To address this issue, a quality improvement project was instituted at one of the system’s health centers to improve the care of patients with uncontrolled diabetes (known HbA1c above 9).

Methods

Setting

The pilot project was conducted from 1 Oct 2015 to 31 Dec 2015 in a primary care community health center within Harris Health System in Houston, Texas. This pilot was the first step of an institutional effort to introduce a multidisciplinary model of care across all clinics [9]. Our health center has 6 family medicine providers and 1 advanced practice nurse practitioner, organized into 3 pods with 2 physicians each. We randomly selected 1 pod (team) and designated it the intervention group.

The Standards for Quality Improvement Reporting Excellence guidelines [10] were followed and institutional review board approval was obtained.

Intervention

Practice changes introduced in the intervention team were assignment of a case manager to all patients, referral to a dietician and clinical pharmacist as needed, and patient education sessions. The team’s nurse assumed the role of case manager. The case manager was responsible for reviewing a patient checklist based on the America Diabetes Association guideline for comprehensive diabetes medical evaluation at initial and follow-up visits. Referrals were based on ADA guideline recommendations. Onsite brief patient education was provided to all patients. In addition, patients were enrolled in a “Diabetes 101” class, which follows an evidence-based curriculum that includes participation in at least 2 monthly sessions. Patients were asked to return to the clinic for a follow-up visit after 3 months in order to monitor medication compliance, re-evaluate their care plan, and measure HbA1c The usual care group patients were managed based on the current Standards of Medical Care in Diabetes [11]. The usual care group included patients from the same clinic under the care of providers in the teams that were not included in the multidisciplinary intervention.

Analysis

Data abstracted from de-identified patient records included HbA1c values, interventions received, and sociodemographic data. Generalized linear mixed modeling (GLMM) was used to examine changes in patient HbA1c levels over time [12]. All models included a random intercept to account for correlated observations within patient. All analyses were performed using Proc GLIMMIX in SAS v. 9.3 [13].

Results

A total 271 patients with HbA1c above 9 were included in the analysis: 71 in the intervention group and 188 in the usual care group. The intervention group was further differentiated by month of enrollment: October (n = 37), November (n = 27), and December (n = 9). Mean patient age in the overall sample was 51.6 years. 

In the intervention group, most patients received patient education 56% (n = 40), almost half had a clinical pharmacy visit, but only 17% (n = 12) received a dietitian consultation. Overall, there was a 1.4% decrease in HbA1c in the intervention group, compared to a 1.3% HbA1c decrease in the usual care group.

GLMM was used to examine differences in HbA1c levels according to month of intervention enrollment (October vs. November vs. December) in the intervention group over time. Figure 1 shows predicted HbA1c values over time with trend lines fit for each of the three subgroups. 

Preliminary analysis showed that potential contamination (diffusion of the treatment) would be likely to attenuate differences in the outcomes between the intervention and usual care conditions. Further analysis by subgroups were conducted to describe the intervention potential “spillover” to the usual care group participants not intended to receive the intervention. GLMM also examined differences in HbA1c levels between the intervention and usual care groups over time. The interaction between each treatment group and time was not statistically significant (F(2,268) = 1.34, P = 0.26), indicating that changes in HbA1c over time were not related to treatment group. A statistically reliable main effect for time (F(1,268) = 44.33, P < 0.001) indicated that in all groups, HbA1c values significantly decreased over time.

Follow-up analyses utilized GLMM to examine differences in HbA1c levels among patients in both groups who received at least one of the interventions (visiting a dietician, clinical pharmacist, education session, and clinical case manager). The interaction between intervention and time was not statistically significant for visiting the dietician, receiving education, or being assigned a case manager. The interaction between time and visiting a clinical pharmacist was statistically significant (F(1,204)= 7.78, P = 0.01) such that patients visiting the clinical pharmacist had lower HbA1c values over time relative to those that did not (Figure 2). 

Discussion

HbA1c decreased significantly among intervention patients with uncontrolled diabetes over a 3-month period, regardless of which month they entered the study. However, there was no significant difference in HbA1c reduction between patients who received all 4 multidisciplinary interventions, one intervention, or those who received usual care. Patients in the intervention who attended clinical pharmacist visits had significantly greater HbA1c reduction than patients who did not, as did patients who attended a diabetes education session by a patient educator.

Diffusion of treatment may account for the overall HbA1c reduction regardless of treatment group. Diffusion refers to the unintended spread of a treatment effect when participants receive some or all treatments from an intervention to which they were not assigned, making outcomes descriptions of all study groups more challenging [14]. During the implementation period, other physicians and nurses in the clinic were aware of the multidisciplinary care model being piloted, and may have taken the initiative to connect their patients with clinical pharmacists, dieticians, certified diabetes educators, and clinical case managers. Pragmatic interventions are intended to maintain the internal validity of randomized control trials, yet they are meant to be implemented as close as possible to real-world settings in order to help patients, clinicians, and payers making informed health care decisions [8]. In this regard, participants in the control group could be exposed to the intervention through staff contact between the assigned groups implementing some of the intervention under study. In that case, the diffusion of treatment would be likely to attenuate differences in the outcomes between treatment and control groups [15].

This study has several limitations. We studied a small sample of patients that reflected the primary care population in one clinic in a safety net system with minority, underserved, and high-risk patients. Although attempts were made to keep the intervention limited to the intervention pod, diffusion of treatment might have impacted the internal validity of this intervention.

In summary, our results support the need for further systematic research work to weigh the impact of unblinded designs, simplified recruitment and outcome measurement, and real-world behaviors (such as noncompliance, cross over, and dropout) on evidence-based and multidisciplinary clinical interventions.

Acknowledgements: The authors would like to thank Krystal Gamarra, MSW, LCSW, and Hope Galvan, MS, RN, CVRN-BC, CDE for assistance with project implementation and data collection throughout this process.

Corresponding author: Maria C. Mejia de Grubb, MD, MPH, 3751 Kirby Dr, Suite 600, Houston, TX 77098, [email protected].

Financial disclosures: None.

Study Overview

Objective. To determine the effect of a single prostate-specific antigen (PSA) screening and standardized diagnostic pathway on prostate cancer–specific mortality when compared with no screening.

Design. Cluster randomized controlled trial.

Setting and participants. The study was conducted at 573 primary care clinics in the United Kingdom. 419,582 men, 50 to 69 years of age, were recruited between 2001 and 2009 and follow-up ended in 2016. Primary care clinics were randomized to intervention or control. Men in intervention group primary care clinics received an invitation to a single PSA test followed by standardized prostate biopsy in men with PSA levels of 3 ng/mL or greater. A trial that compared radical prostatectomy, radiotherapy, and androgen deprivation therapy and active monitoring was embedded within the screening trial [1]. The control group practices provided standard treatment and PSA testing was provided only to men who requested it. The majority of primary practices were in urban areas (88%–90%) and with multiple partners within the practice (88%–89%). Cases of prostate cancer that were detected in the intervention or control groups during the course of the study were managed by the same clinicians.

Main outcome measures. Main study outcome measures were definite, probable, or intervention-related prostate cancer mortality at a median follow-up of 10 years. An independent cause of death evaluation committee that was blinded to group assignment determined the cause of death in each case. The secondary outcomes included all-cause mortality and prostate cancer stage and Gleason grade at cancer diagnosis. The analysis was an intention-to-screen analysis. Survival analysis using Kaplan-Meier plots were done to demonstrate cumulative incidence of outcomes discussed above. Mixed effects Poisson regression models were used to compare prostate cancer incidence and mortality in intervention vs. control practices accounting for clustering.

Main results. A total of 189,386 men were in the intervention group, 40% attended the PSA testing clinic, and 67,313 (36%) had a blood sample taken for PSA testing, resulting in 64,436 valid PSA test result. 6857 (11%) had elevated PSA levels, of which 85% had a prostate biopsy. In the control group, it was estimated that contamination (PSA testing in the control group) occurred at a rate of approximately 10%–15% over 10 years. After a median follow-up of 10 years, 549 men died of prostate cancer–related causes in the intervention group, at a rate of 0.3 per 1000 person-years, and 647 men died of prostate cancer–related causes in the control group, at a rate of 0.31 per 1000 person-years. The rate difference was 0.013 per 1000 person-years with a risk ratio (RR) of 0.96 (95% confidence interval [CI], 0.85–1.08), P = 0.50), which was not statistically significant. The number of men diagnosed with prostate cancer was higher in the intervention group than in the control group (4.3% vs. 3.6%, RR 1.19 (95% CI 1.14–1.25), P < 0.001). The incidence rate was 4.45 per 1000 person-years in the intervention group and 3.80 per 1000 person-years in the control group. The prostate cancer tumors in the intervention group were less likely to be high grade or advanced stage when compared to the control group. There were 25,459 deaths in the intervention group and 28,306 deaths in the control group. There was no significant difference in the rates of all-cause mortality between the two groups.

Conclusion. The study found that a single PSA screening among men aged 50–69 did not reduce prostate cancer mortality at 10 years follow-up, but led to the increase in the detection of low-risk prostate cancer cases. This result does not support the screening strategy of a single PSA testing for population-based screening for prostate cancer.

Commentary

The use of a PSA test for population-based screening for prostate cancer is controversial; the United States Preventive Services Task Force (USPSTF) recommended against the routine use of PSA test for screening for prostate cancer because the evidence of its benefit is weak and because of the potential risks of unintended consequences of PSA screening [2]. This study is the largest study to date on PSA screening and it found that a low-intensity screening approach—a single PSA test—was not effective in reducing prostate cancer deaths, but rather identified early-stage prostate cancer cases. This result contrasts with previous large scale studies that found that screening led to an increased rate of prostate cancer diagnosis and reduced prostate cancer mortality in one trial [3] and no effect on diagnosis or mortality in another [4].

The rationale for USPSTF recommendation has a lot to do with the unintended consequences of PSA screening; PSA is a rather nonspecific test and elevated levels can be caused by a number of different prostate pathologies. Screening can often lead to procedures and treatments that cause harm to individuals who may not have prostate cancer to begin with or have slow-growing cancer that would otherwise not impact their overall health status over time [5]. This is particularly relevant for older adults that may have other comorbid diseases that impact their health. The selection of a single PSA test as the screening strategy in this study is an attempt to reduce the potential burden of repeated testing and thereby reduce risk of unintended harms. The tradeoff is that it is less effective in identifying prostate cancer over time and may partly explain why this study’s result contrasts with prior studies.

Applications for Clinical Practice

PSA test as a diagnostic tool for prostate cancer has significant drawbacks, and population screening strategies using this test will need to grapple with issues of misdiagnosis, overdiagnosis, and treatment that can have potential harmful consequences. The alternative of not screening is that prostate cancer may be diagnosed at later stages and more men may suffer morbidity and mortality from the disease. A better test and screening strategy are needed to balance the benefits and harms of screening so that older men may benefit from early diagnosis of prostate cancer.

Study Overview

Objective. To determine the effect of a single prostate-specific antigen (PSA) screening and standardized diagnostic pathway on prostate cancer–specific mortality when compared with no screening.

Design. Cluster randomized controlled trial.

Setting and participants. The study was conducted at 573 primary care clinics in the United Kingdom. 419,582 men, 50 to 69 years of age, were recruited between 2001 and 2009 and follow-up ended in 2016. Primary care clinics were randomized to intervention or control. Men in intervention group primary care clinics received an invitation to a single PSA test followed by standardized prostate biopsy in men with PSA levels of 3 ng/mL or greater. A trial that compared radical prostatectomy, radiotherapy, and androgen deprivation therapy and active monitoring was embedded within the screening trial [1]. The control group practices provided standard treatment and PSA testing was provided only to men who requested it. The majority of primary practices were in urban areas (88%–90%) and with multiple partners within the practice (88%–89%). Cases of prostate cancer that were detected in the intervention or control groups during the course of the study were managed by the same clinicians.

Main outcome measures. Main study outcome measures were definite, probable, or intervention-related prostate cancer mortality at a median follow-up of 10 years. An independent cause of death evaluation committee that was blinded to group assignment determined the cause of death in each case. The secondary outcomes included all-cause mortality and prostate cancer stage and Gleason grade at cancer diagnosis. The analysis was an intention-to-screen analysis. Survival analysis using Kaplan-Meier plots were done to demonstrate cumulative incidence of outcomes discussed above. Mixed effects Poisson regression models were used to compare prostate cancer incidence and mortality in intervention vs. control practices accounting for clustering.

Main results. A total of 189,386 men were in the intervention group, 40% attended the PSA testing clinic, and 67,313 (36%) had a blood sample taken for PSA testing, resulting in 64,436 valid PSA test result. 6857 (11%) had elevated PSA levels, of which 85% had a prostate biopsy. In the control group, it was estimated that contamination (PSA testing in the control group) occurred at a rate of approximately 10%–15% over 10 years. After a median follow-up of 10 years, 549 men died of prostate cancer–related causes in the intervention group, at a rate of 0.3 per 1000 person-years, and 647 men died of prostate cancer–related causes in the control group, at a rate of 0.31 per 1000 person-years. The rate difference was 0.013 per 1000 person-years with a risk ratio (RR) of 0.96 (95% confidence interval [CI], 0.85–1.08), P = 0.50), which was not statistically significant. The number of men diagnosed with prostate cancer was higher in the intervention group than in the control group (4.3% vs. 3.6%, RR 1.19 (95% CI 1.14–1.25), P < 0.001). The incidence rate was 4.45 per 1000 person-years in the intervention group and 3.80 per 1000 person-years in the control group. The prostate cancer tumors in the intervention group were less likely to be high grade or advanced stage when compared to the control group. There were 25,459 deaths in the intervention group and 28,306 deaths in the control group. There was no significant difference in the rates of all-cause mortality between the two groups.

Conclusion. The study found that a single PSA screening among men aged 50–69 did not reduce prostate cancer mortality at 10 years follow-up, but led to the increase in the detection of low-risk prostate cancer cases. This result does not support the screening strategy of a single PSA testing for population-based screening for prostate cancer.

Commentary

The use of a PSA test for population-based screening for prostate cancer is controversial; the United States Preventive Services Task Force (USPSTF) recommended against the routine use of PSA test for screening for prostate cancer because the evidence of its benefit is weak and because of the potential risks of unintended consequences of PSA screening [2]. This study is the largest study to date on PSA screening and it found that a low-intensity screening approach—a single PSA test—was not effective in reducing prostate cancer deaths, but rather identified early-stage prostate cancer cases. This result contrasts with previous large scale studies that found that screening led to an increased rate of prostate cancer diagnosis and reduced prostate cancer mortality in one trial [3] and no effect on diagnosis or mortality in another [4].

The rationale for USPSTF recommendation has a lot to do with the unintended consequences of PSA screening; PSA is a rather nonspecific test and elevated levels can be caused by a number of different prostate pathologies. Screening can often lead to procedures and treatments that cause harm to individuals who may not have prostate cancer to begin with or have slow-growing cancer that would otherwise not impact their overall health status over time [5]. This is particularly relevant for older adults that may have other comorbid diseases that impact their health. The selection of a single PSA test as the screening strategy in this study is an attempt to reduce the potential burden of repeated testing and thereby reduce risk of unintended harms. The tradeoff is that it is less effective in identifying prostate cancer over time and may partly explain why this study’s result contrasts with prior studies.

Applications for Clinical Practice

PSA test as a diagnostic tool for prostate cancer has significant drawbacks, and population screening strategies using this test will need to grapple with issues of misdiagnosis, overdiagnosis, and treatment that can have potential harmful consequences. The alternative of not screening is that prostate cancer may be diagnosed at later stages and more men may suffer morbidity and mortality from the disease. A better test and screening strategy are needed to balance the benefits and harms of screening so that older men may benefit from early diagnosis of prostate cancer.

Study Overview

Objective. To determine the effect of a single prostate-specific antigen (PSA) screening and standardized diagnostic pathway on prostate cancer–specific mortality when compared with no screening.

Design. Cluster randomized controlled trial.

Setting and participants. The study was conducted at 573 primary care clinics in the United Kingdom. 419,582 men, 50 to 69 years of age, were recruited between 2001 and 2009 and follow-up ended in 2016. Primary care clinics were randomized to intervention or control. Men in intervention group primary care clinics received an invitation to a single PSA test followed by standardized prostate biopsy in men with PSA levels of 3 ng/mL or greater. A trial that compared radical prostatectomy, radiotherapy, and androgen deprivation therapy and active monitoring was embedded within the screening trial [1]. The control group practices provided standard treatment and PSA testing was provided only to men who requested it. The majority of primary practices were in urban areas (88%–90%) and with multiple partners within the practice (88%–89%). Cases of prostate cancer that were detected in the intervention or control groups during the course of the study were managed by the same clinicians.

Main outcome measures. Main study outcome measures were definite, probable, or intervention-related prostate cancer mortality at a median follow-up of 10 years. An independent cause of death evaluation committee that was blinded to group assignment determined the cause of death in each case. The secondary outcomes included all-cause mortality and prostate cancer stage and Gleason grade at cancer diagnosis. The analysis was an intention-to-screen analysis. Survival analysis using Kaplan-Meier plots were done to demonstrate cumulative incidence of outcomes discussed above. Mixed effects Poisson regression models were used to compare prostate cancer incidence and mortality in intervention vs. control practices accounting for clustering.

Main results. A total of 189,386 men were in the intervention group, 40% attended the PSA testing clinic, and 67,313 (36%) had a blood sample taken for PSA testing, resulting in 64,436 valid PSA test result. 6857 (11%) had elevated PSA levels, of which 85% had a prostate biopsy. In the control group, it was estimated that contamination (PSA testing in the control group) occurred at a rate of approximately 10%–15% over 10 years. After a median follow-up of 10 years, 549 men died of prostate cancer–related causes in the intervention group, at a rate of 0.3 per 1000 person-years, and 647 men died of prostate cancer–related causes in the control group, at a rate of 0.31 per 1000 person-years. The rate difference was 0.013 per 1000 person-years with a risk ratio (RR) of 0.96 (95% confidence interval [CI], 0.85–1.08), P = 0.50), which was not statistically significant. The number of men diagnosed with prostate cancer was higher in the intervention group than in the control group (4.3% vs. 3.6%, RR 1.19 (95% CI 1.14–1.25), P < 0.001). The incidence rate was 4.45 per 1000 person-years in the intervention group and 3.80 per 1000 person-years in the control group. The prostate cancer tumors in the intervention group were less likely to be high grade or advanced stage when compared to the control group. There were 25,459 deaths in the intervention group and 28,306 deaths in the control group. There was no significant difference in the rates of all-cause mortality between the two groups.

Conclusion. The study found that a single PSA screening among men aged 50–69 did not reduce prostate cancer mortality at 10 years follow-up, but led to the increase in the detection of low-risk prostate cancer cases. This result does not support the screening strategy of a single PSA testing for population-based screening for prostate cancer.

Commentary

The use of a PSA test for population-based screening for prostate cancer is controversial; the United States Preventive Services Task Force (USPSTF) recommended against the routine use of PSA test for screening for prostate cancer because the evidence of its benefit is weak and because of the potential risks of unintended consequences of PSA screening [2]. This study is the largest study to date on PSA screening and it found that a low-intensity screening approach—a single PSA test—was not effective in reducing prostate cancer deaths, but rather identified early-stage prostate cancer cases. This result contrasts with previous large scale studies that found that screening led to an increased rate of prostate cancer diagnosis and reduced prostate cancer mortality in one trial [3] and no effect on diagnosis or mortality in another [4].

The rationale for USPSTF recommendation has a lot to do with the unintended consequences of PSA screening; PSA is a rather nonspecific test and elevated levels can be caused by a number of different prostate pathologies. Screening can often lead to procedures and treatments that cause harm to individuals who may not have prostate cancer to begin with or have slow-growing cancer that would otherwise not impact their overall health status over time [5]. This is particularly relevant for older adults that may have other comorbid diseases that impact their health. The selection of a single PSA test as the screening strategy in this study is an attempt to reduce the potential burden of repeated testing and thereby reduce risk of unintended harms. The tradeoff is that it is less effective in identifying prostate cancer over time and may partly explain why this study’s result contrasts with prior studies.

Applications for Clinical Practice

PSA test as a diagnostic tool for prostate cancer has significant drawbacks, and population screening strategies using this test will need to grapple with issues of misdiagnosis, overdiagnosis, and treatment that can have potential harmful consequences. The alternative of not screening is that prostate cancer may be diagnosed at later stages and more men may suffer morbidity and mortality from the disease. A better test and screening strategy are needed to balance the benefits and harms of screening so that older men may benefit from early diagnosis of prostate cancer.

Study Overview

Objective. To evaluate the efficacy and safety of the anti-CD19 chimeric antigen receptor (CAR) T-cell, axicabtagene ciloleucel (axi-cel), in patients with refractory large B-cell lymphoma.

Design. The ZUMA-1 trial was a phase 1-2 multicenter study. The results of the primary analysis and updated analysis with 1-year follow up of the phase 2 portion of ZUMA-1 are reported here.

Setting and participants. The phase 2 portion of the ZUMA-1 trial enrolled 111 patients from 22 centers in the United States (21) and Israel (1) from November 2015 through September 2016. Eligible patients included those with histologically confirmed large B-cell lymphoma, primary mediastinal B-cell lymphoma or transformed follicular lymphoma. Patients were required to have refractory disease, defined as disease progression or stable disease as the best response to chemotherapy or disease progression within 12 months following autologous stem cell transplantation. All patients were required to have adequate organ function, an absolute neutrophil count > 1000, absolute lymphocyte count > 100 and platelet count > 75,000.

Intervention. Patients first underwent leukapheresis and CAR T-cell manufacturing. Following this patients were admitted to the hospital and received a low-dose conditioning regimen consisting of fludarabine 30 mg/m² and cyclophosphamide 500 mg/m² given on days –5, –4 and –3. On day 0 the patient was infused with their manufactured CAR T-cell product at a target dose of 2 x10⁶ CAR T cells per kilogram of body weight. Patients could not receive “bridging chemotherapy” between leukapheresis and infusion of axi-cel product. Patients could be retreated with axi-cel if they experienced disease progression at least 3 months after their first dose.

Main outcome measures. The primary endpoint of this study was objective response rate, which was defined as the combined rate of complete response (CR) and partial response (PR). The secondary endpoints were duration of response, progression-free survival (PFS), overall survival (OS), and adverse events. Blood levels of CAR T cells and serum cytokine levels were followed.

Main results. A total of 111 patients were enrolled. Axi-cel was administered to 101 patients included in the intention to treat analysis. Of these, 77 had diffuse large B-cell lymphoma and 24 had primary mediastinal B-cell lymphoma or transformed follicular lymphoma. The median follow-up was 8.7 months for the primary analysis and updated analysis median follow-up was 15.4 months. The median time from leukapheresis to delivery of the product was 17 days. Only 1 patient had unsuccessful manufacturing. The median age of the treated patients was 58 years. Most of the patients (77%) had disease resistant to second-line or later therapy and 21% had disease relapse after autologous stem cell transplant.

Primary analysis results. The objective response rate was 82% with a 54% CR rate. The median time to response was 1 month and median duration of response was 8.1 months. The response rates were consistent across all subgroups including age, disease stage, IPI score, presence or absence of bulky disease, cell-of-origin subtype, and the use of tocilizumab or glucocorticoids. High response rates were maintained in those with primary refractory disease (response rate 88%) and those with prior autologous stem cell transplant (response rate 76%). The response rate was not influenced by CD19 expression. At the time of the primary analysis 52 patients died from disease progression and 3 died from adverse events during treatment. Forty-four patients remained in remission, 39 of whom maintained a CR.

Updated analysis results. At the time of the updated analysis 108 patients in the phase 1 and phase 2 portions had been followed for at least 12 months. The objective response rate was 82% with a CR rate of 58%. At the data cut-off, 42% remained in response with 40% maintaining a CR. Again, response rates were consistent across all previously mentioned subgroups. The median duration of response was 11.1 months. The median PFS was 5.8 months with PFS rate of 41% at 15 months. The median OS was not reached. A total of 56% of patients remained alive at the time of this analysis.

Safety. During treatment 100% of patients had adverse events (AEs), which were grade 3 or higher in 95%. Fevers (85%), neutropenia (84%) and anemia (66%) were the most common AEs. Myelosuppression was the most common grade 3 or higher AE. Cytokine release syndrome occurred in 93% of patients of which 13% were grade 3 or higher (9% grade 3, 3% grade 4 and 1% grade 5). 17% of patients required vasopressor support. The median time from infusion to the onset of cytokine release syndrome was 2 days (range, 1–12). The median time to resolution was 8 days. One grade 5 event of hemophagocytic lymphohistiocytosis and one grade 5 cardiac arrest occurred. Grade 3 or higher neurological events occurred in 28% of patients, with encephalopathy occurring in 21%. Neurological events occurred at a median of 5 days after infusion and lasted for a median of 17 days after infusion. Forty-three percent of patients received tocilizumab and 27% received glucocorticoids.

Biomarkers. CAR T levels peaked within 14 days after infusion. Three patients with a CR at 24 months still had detectable levels in the blood. CAR T cell expansion as significantly associated with disease response. Interleukin -6, -10, -15 and -2Ra levels were significantly associated with neurological events and cytokine release syndrome of grade 3 or higher. Anti-CAR antibodies were not detected in any patient.

Commentary

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma with 5-year survival rates of ~60% following conventional chemoimmunotherapy in the first-line setting. Following relapse, salvage therapy followed by high-dose chemotherapy with autologous stem-cell transplantation can result in long-term remissions; however, those who relapse have a poor prognosis. The recently published SCHOLAR-1 study retrospectively analyzed the outcomes of patients with relapsed or refractory DLBCL and found that for patients with refractory disease the objective response to salvage therapy was only 26% (7% CR) with a median OS of 6.3 months [1]. CAR-engineered T cells offer a novel and revolutionary therapy for these patients, whom otherwise have very poor outcomes.

Early CAR T-cell trials by Bretjens and colleagues first documented a CR in a subset of patients with refractory hematologic malignancies [2]. Since that time there has been tremendous advancement in CAR T development and clinical application. In the December 2017 issue of the New England Journal of Medicine there were 2 studies published validating the efficacy of CD19-targeted CAR T-cell therapy in relapsed/refractory lymphoma, the current ZUMA-1 study as well as another small case-series by Schuster and colleagues. Schuster et al evaluated the CD19-directed CAR, CTL019, in 28 patients with relapsed/refractory DLBCL or follicular lymphoma. The ORR noted in this study was 64% with a CR rate of 57% [3]. Similarly, in the current ZUMA-1 study the CR rate was 54% in 101 patients with relapsed and refractory large B-cell lymphomas. In addition, with a median follow-up of 15.4 months responses were ongoing in 42% of patients including 40% who had a CR. The durability of such responses has been demonstrated in 3 of 7 patients from the phase 1 portion of this study at 24 months. Durable responses have also been reported with anti-CD19 CAR T-cell therapy in 4 of 5 patients who had a CR and remain in remission after 3-4 years of follow-up [4]. While promising, the durability of responses remains unclear. While CAR therapy represents an exciting therapeutic strategy, it should be noted that in this study approximately 50% of patients will not achieve a durable response and the reason for this is not completely understood.

One of the most discussed aspects of CAR therapy has been the unique toxicity profile, which was again noted in the ZUMA-1 study. As noted, 95% of patients in this study experienced a grade 3 or higher AE. Of interest, cytokine release syndrome occurred in 93% of patients with 13% being grade 3 or higher. There were 2 deaths attributed to such. Neurological toxicity was also noted in 64% of patients in this trial. While the vast majority of these AEs were reversible, they clearly represent high treatment-related morbidity.

The results of the ZUMA-1 study lead to the FDA approval of anti-CD19 CAR T-cell therapy for relapsed or refractory large B-cell lymphoma in October 2017 and represents a pivotal advancement in the management of these patients with otherwise limited treatment options and overall poor outcomes. The ZUMA-1 trial not only demonstrates the efficacy of such agents but also demonstrates the feasibility of incorporating them into clinical practice with a 99% manufacturing success rate and short (median 17 days) product delivery time. The economic burden of such therapies warrant particular consideration as the indications for CAR therapy will continue to expand, driving the cost of care higher. Nevertheless, this represents an exciting step forward in personalized medicine.

Applications for Clinical Practice

CAR T-cell therapy with the CD-19 targeted CAR axicabtagene ciloleucel (axi-cel) results in a high rate of objective and durable responses in patients with relapsed or refractory large B-cell lymphomas. While such treatment does carry a high rate of toxicity in regards to cytokine release and neurological complications, this represents an important treatment option in patients with refractory disease with a historically poor prognosis. However, there will be a need to develop policies to address the economic challenges associated with such treatments.

Study Overview

Objective. To evaluate the efficacy and safety of the anti-CD19 chimeric antigen receptor (CAR) T-cell, axicabtagene ciloleucel (axi-cel), in patients with refractory large B-cell lymphoma.

Design. The ZUMA-1 trial was a phase 1-2 multicenter study. The results of the primary analysis and updated analysis with 1-year follow up of the phase 2 portion of ZUMA-1 are reported here.

Setting and participants. The phase 2 portion of the ZUMA-1 trial enrolled 111 patients from 22 centers in the United States (21) and Israel (1) from November 2015 through September 2016. Eligible patients included those with histologically confirmed large B-cell lymphoma, primary mediastinal B-cell lymphoma or transformed follicular lymphoma. Patients were required to have refractory disease, defined as disease progression or stable disease as the best response to chemotherapy or disease progression within 12 months following autologous stem cell transplantation. All patients were required to have adequate organ function, an absolute neutrophil count > 1000, absolute lymphocyte count > 100 and platelet count > 75,000.

Intervention. Patients first underwent leukapheresis and CAR T-cell manufacturing. Following this patients were admitted to the hospital and received a low-dose conditioning regimen consisting of fludarabine 30 mg/m² and cyclophosphamide 500 mg/m² given on days –5, –4 and –3. On day 0 the patient was infused with their manufactured CAR T-cell product at a target dose of 2 x10⁶ CAR T cells per kilogram of body weight. Patients could not receive “bridging chemotherapy” between leukapheresis and infusion of axi-cel product. Patients could be retreated with axi-cel if they experienced disease progression at least 3 months after their first dose.

Main outcome measures. The primary endpoint of this study was objective response rate, which was defined as the combined rate of complete response (CR) and partial response (PR). The secondary endpoints were duration of response, progression-free survival (PFS), overall survival (OS), and adverse events. Blood levels of CAR T cells and serum cytokine levels were followed.

Main results. A total of 111 patients were enrolled. Axi-cel was administered to 101 patients included in the intention to treat analysis. Of these, 77 had diffuse large B-cell lymphoma and 24 had primary mediastinal B-cell lymphoma or transformed follicular lymphoma. The median follow-up was 8.7 months for the primary analysis and updated analysis median follow-up was 15.4 months. The median time from leukapheresis to delivery of the product was 17 days. Only 1 patient had unsuccessful manufacturing. The median age of the treated patients was 58 years. Most of the patients (77%) had disease resistant to second-line or later therapy and 21% had disease relapse after autologous stem cell transplant.

Primary analysis results. The objective response rate was 82% with a 54% CR rate. The median time to response was 1 month and median duration of response was 8.1 months. The response rates were consistent across all subgroups including age, disease stage, IPI score, presence or absence of bulky disease, cell-of-origin subtype, and the use of tocilizumab or glucocorticoids. High response rates were maintained in those with primary refractory disease (response rate 88%) and those with prior autologous stem cell transplant (response rate 76%). The response rate was not influenced by CD19 expression. At the time of the primary analysis 52 patients died from disease progression and 3 died from adverse events during treatment. Forty-four patients remained in remission, 39 of whom maintained a CR.

Updated analysis results. At the time of the updated analysis 108 patients in the phase 1 and phase 2 portions had been followed for at least 12 months. The objective response rate was 82% with a CR rate of 58%. At the data cut-off, 42% remained in response with 40% maintaining a CR. Again, response rates were consistent across all previously mentioned subgroups. The median duration of response was 11.1 months. The median PFS was 5.8 months with PFS rate of 41% at 15 months. The median OS was not reached. A total of 56% of patients remained alive at the time of this analysis.

Safety. During treatment 100% of patients had adverse events (AEs), which were grade 3 or higher in 95%. Fevers (85%), neutropenia (84%) and anemia (66%) were the most common AEs. Myelosuppression was the most common grade 3 or higher AE. Cytokine release syndrome occurred in 93% of patients of which 13% were grade 3 or higher (9% grade 3, 3% grade 4 and 1% grade 5). 17% of patients required vasopressor support. The median time from infusion to the onset of cytokine release syndrome was 2 days (range, 1–12). The median time to resolution was 8 days. One grade 5 event of hemophagocytic lymphohistiocytosis and one grade 5 cardiac arrest occurred. Grade 3 or higher neurological events occurred in 28% of patients, with encephalopathy occurring in 21%. Neurological events occurred at a median of 5 days after infusion and lasted for a median of 17 days after infusion. Forty-three percent of patients received tocilizumab and 27% received glucocorticoids.

Biomarkers. CAR T levels peaked within 14 days after infusion. Three patients with a CR at 24 months still had detectable levels in the blood. CAR T cell expansion as significantly associated with disease response. Interleukin -6, -10, -15 and -2Ra levels were significantly associated with neurological events and cytokine release syndrome of grade 3 or higher. Anti-CAR antibodies were not detected in any patient.

Commentary

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma with 5-year survival rates of ~60% following conventional chemoimmunotherapy in the first-line setting. Following relapse, salvage therapy followed by high-dose chemotherapy with autologous stem-cell transplantation can result in long-term remissions; however, those who relapse have a poor prognosis. The recently published SCHOLAR-1 study retrospectively analyzed the outcomes of patients with relapsed or refractory DLBCL and found that for patients with refractory disease the objective response to salvage therapy was only 26% (7% CR) with a median OS of 6.3 months [1]. CAR-engineered T cells offer a novel and revolutionary therapy for these patients, whom otherwise have very poor outcomes.

Early CAR T-cell trials by Bretjens and colleagues first documented a CR in a subset of patients with refractory hematologic malignancies [2]. Since that time there has been tremendous advancement in CAR T development and clinical application. In the December 2017 issue of the New England Journal of Medicine there were 2 studies published validating the efficacy of CD19-targeted CAR T-cell therapy in relapsed/refractory lymphoma, the current ZUMA-1 study as well as another small case-series by Schuster and colleagues. Schuster et al evaluated the CD19-directed CAR, CTL019, in 28 patients with relapsed/refractory DLBCL or follicular lymphoma. The ORR noted in this study was 64% with a CR rate of 57% [3]. Similarly, in the current ZUMA-1 study the CR rate was 54% in 101 patients with relapsed and refractory large B-cell lymphomas. In addition, with a median follow-up of 15.4 months responses were ongoing in 42% of patients including 40% who had a CR. The durability of such responses has been demonstrated in 3 of 7 patients from the phase 1 portion of this study at 24 months. Durable responses have also been reported with anti-CD19 CAR T-cell therapy in 4 of 5 patients who had a CR and remain in remission after 3-4 years of follow-up [4]. While promising, the durability of responses remains unclear. While CAR therapy represents an exciting therapeutic strategy, it should be noted that in this study approximately 50% of patients will not achieve a durable response and the reason for this is not completely understood.

One of the most discussed aspects of CAR therapy has been the unique toxicity profile, which was again noted in the ZUMA-1 study. As noted, 95% of patients in this study experienced a grade 3 or higher AE. Of interest, cytokine release syndrome occurred in 93% of patients with 13% being grade 3 or higher. There were 2 deaths attributed to such. Neurological toxicity was also noted in 64% of patients in this trial. While the vast majority of these AEs were reversible, they clearly represent high treatment-related morbidity.

The results of the ZUMA-1 study lead to the FDA approval of anti-CD19 CAR T-cell therapy for relapsed or refractory large B-cell lymphoma in October 2017 and represents a pivotal advancement in the management of these patients with otherwise limited treatment options and overall poor outcomes. The ZUMA-1 trial not only demonstrates the efficacy of such agents but also demonstrates the feasibility of incorporating them into clinical practice with a 99% manufacturing success rate and short (median 17 days) product delivery time. The economic burden of such therapies warrant particular consideration as the indications for CAR therapy will continue to expand, driving the cost of care higher. Nevertheless, this represents an exciting step forward in personalized medicine.

Applications for Clinical Practice

CAR T-cell therapy with the CD-19 targeted CAR axicabtagene ciloleucel (axi-cel) results in a high rate of objective and durable responses in patients with relapsed or refractory large B-cell lymphomas. While such treatment does carry a high rate of toxicity in regards to cytokine release and neurological complications, this represents an important treatment option in patients with refractory disease with a historically poor prognosis. However, there will be a need to develop policies to address the economic challenges associated with such treatments.

Study Overview

Objective. To evaluate the efficacy and safety of the anti-CD19 chimeric antigen receptor (CAR) T-cell, axicabtagene ciloleucel (axi-cel), in patients with refractory large B-cell lymphoma.

Design. The ZUMA-1 trial was a phase 1-2 multicenter study. The results of the primary analysis and updated analysis with 1-year follow up of the phase 2 portion of ZUMA-1 are reported here.

Setting and participants. The phase 2 portion of the ZUMA-1 trial enrolled 111 patients from 22 centers in the United States (21) and Israel (1) from November 2015 through September 2016. Eligible patients included those with histologically confirmed large B-cell lymphoma, primary mediastinal B-cell lymphoma or transformed follicular lymphoma. Patients were required to have refractory disease, defined as disease progression or stable disease as the best response to chemotherapy or disease progression within 12 months following autologous stem cell transplantation. All patients were required to have adequate organ function, an absolute neutrophil count > 1000, absolute lymphocyte count > 100 and platelet count > 75,000.

Intervention. Patients first underwent leukapheresis and CAR T-cell manufacturing. Following this patients were admitted to the hospital and received a low-dose conditioning regimen consisting of fludarabine 30 mg/m² and cyclophosphamide 500 mg/m² given on days –5, –4 and –3. On day 0 the patient was infused with their manufactured CAR T-cell product at a target dose of 2 x10⁶ CAR T cells per kilogram of body weight. Patients could not receive “bridging chemotherapy” between leukapheresis and infusion of axi-cel product. Patients could be retreated with axi-cel if they experienced disease progression at least 3 months after their first dose.

Main outcome measures. The primary endpoint of this study was objective response rate, which was defined as the combined rate of complete response (CR) and partial response (PR). The secondary endpoints were duration of response, progression-free survival (PFS), overall survival (OS), and adverse events. Blood levels of CAR T cells and serum cytokine levels were followed.

Main results. A total of 111 patients were enrolled. Axi-cel was administered to 101 patients included in the intention to treat analysis. Of these, 77 had diffuse large B-cell lymphoma and 24 had primary mediastinal B-cell lymphoma or transformed follicular lymphoma. The median follow-up was 8.7 months for the primary analysis and updated analysis median follow-up was 15.4 months. The median time from leukapheresis to delivery of the product was 17 days. Only 1 patient had unsuccessful manufacturing. The median age of the treated patients was 58 years. Most of the patients (77%) had disease resistant to second-line or later therapy and 21% had disease relapse after autologous stem cell transplant.

Primary analysis results. The objective response rate was 82% with a 54% CR rate. The median time to response was 1 month and median duration of response was 8.1 months. The response rates were consistent across all subgroups including age, disease stage, IPI score, presence or absence of bulky disease, cell-of-origin subtype, and the use of tocilizumab or glucocorticoids. High response rates were maintained in those with primary refractory disease (response rate 88%) and those with prior autologous stem cell transplant (response rate 76%). The response rate was not influenced by CD19 expression. At the time of the primary analysis 52 patients died from disease progression and 3 died from adverse events during treatment. Forty-four patients remained in remission, 39 of whom maintained a CR.

Updated analysis results. At the time of the updated analysis 108 patients in the phase 1 and phase 2 portions had been followed for at least 12 months. The objective response rate was 82% with a CR rate of 58%. At the data cut-off, 42% remained in response with 40% maintaining a CR. Again, response rates were consistent across all previously mentioned subgroups. The median duration of response was 11.1 months. The median PFS was 5.8 months with PFS rate of 41% at 15 months. The median OS was not reached. A total of 56% of patients remained alive at the time of this analysis.

Safety. During treatment 100% of patients had adverse events (AEs), which were grade 3 or higher in 95%. Fevers (85%), neutropenia (84%) and anemia (66%) were the most common AEs. Myelosuppression was the most common grade 3 or higher AE. Cytokine release syndrome occurred in 93% of patients of which 13% were grade 3 or higher (9% grade 3, 3% grade 4 and 1% grade 5). 17% of patients required vasopressor support. The median time from infusion to the onset of cytokine release syndrome was 2 days (range, 1–12). The median time to resolution was 8 days. One grade 5 event of hemophagocytic lymphohistiocytosis and one grade 5 cardiac arrest occurred. Grade 3 or higher neurological events occurred in 28% of patients, with encephalopathy occurring in 21%. Neurological events occurred at a median of 5 days after infusion and lasted for a median of 17 days after infusion. Forty-three percent of patients received tocilizumab and 27% received glucocorticoids.

Biomarkers. CAR T levels peaked within 14 days after infusion. Three patients with a CR at 24 months still had detectable levels in the blood. CAR T cell expansion as significantly associated with disease response. Interleukin -6, -10, -15 and -2Ra levels were significantly associated with neurological events and cytokine release syndrome of grade 3 or higher. Anti-CAR antibodies were not detected in any patient.

Commentary

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma with 5-year survival rates of ~60% following conventional chemoimmunotherapy in the first-line setting. Following relapse, salvage therapy followed by high-dose chemotherapy with autologous stem-cell transplantation can result in long-term remissions; however, those who relapse have a poor prognosis. The recently published SCHOLAR-1 study retrospectively analyzed the outcomes of patients with relapsed or refractory DLBCL and found that for patients with refractory disease the objective response to salvage therapy was only 26% (7% CR) with a median OS of 6.3 months [1]. CAR-engineered T cells offer a novel and revolutionary therapy for these patients, whom otherwise have very poor outcomes.

Early CAR T-cell trials by Bretjens and colleagues first documented a CR in a subset of patients with refractory hematologic malignancies [2]. Since that time there has been tremendous advancement in CAR T development and clinical application. In the December 2017 issue of the New England Journal of Medicine there were 2 studies published validating the efficacy of CD19-targeted CAR T-cell therapy in relapsed/refractory lymphoma, the current ZUMA-1 study as well as another small case-series by Schuster and colleagues. Schuster et al evaluated the CD19-directed CAR, CTL019, in 28 patients with relapsed/refractory DLBCL or follicular lymphoma. The ORR noted in this study was 64% with a CR rate of 57% [3]. Similarly, in the current ZUMA-1 study the CR rate was 54% in 101 patients with relapsed and refractory large B-cell lymphomas. In addition, with a median follow-up of 15.4 months responses were ongoing in 42% of patients including 40% who had a CR. The durability of such responses has been demonstrated in 3 of 7 patients from the phase 1 portion of this study at 24 months. Durable responses have also been reported with anti-CD19 CAR T-cell therapy in 4 of 5 patients who had a CR and remain in remission after 3-4 years of follow-up [4]. While promising, the durability of responses remains unclear. While CAR therapy represents an exciting therapeutic strategy, it should be noted that in this study approximately 50% of patients will not achieve a durable response and the reason for this is not completely understood.

One of the most discussed aspects of CAR therapy has been the unique toxicity profile, which was again noted in the ZUMA-1 study. As noted, 95% of patients in this study experienced a grade 3 or higher AE. Of interest, cytokine release syndrome occurred in 93% of patients with 13% being grade 3 or higher. There were 2 deaths attributed to such. Neurological toxicity was also noted in 64% of patients in this trial. While the vast majority of these AEs were reversible, they clearly represent high treatment-related morbidity.

The results of the ZUMA-1 study lead to the FDA approval of anti-CD19 CAR T-cell therapy for relapsed or refractory large B-cell lymphoma in October 2017 and represents a pivotal advancement in the management of these patients with otherwise limited treatment options and overall poor outcomes. The ZUMA-1 trial not only demonstrates the efficacy of such agents but also demonstrates the feasibility of incorporating them into clinical practice with a 99% manufacturing success rate and short (median 17 days) product delivery time. The economic burden of such therapies warrant particular consideration as the indications for CAR therapy will continue to expand, driving the cost of care higher. Nevertheless, this represents an exciting step forward in personalized medicine.

Applications for Clinical Practice

CAR T-cell therapy with the CD-19 targeted CAR axicabtagene ciloleucel (axi-cel) results in a high rate of objective and durable responses in patients with relapsed or refractory large B-cell lymphomas. While such treatment does carry a high rate of toxicity in regards to cytokine release and neurological complications, this represents an important treatment option in patients with refractory disease with a historically poor prognosis. However, there will be a need to develop policies to address the economic challenges associated with such treatments.

Loud noise is one of the most common workplace hazards in the US. One-quarter of US workers (an estimated 41 million people) report a history of noise exposure at work—and that may put them at risk for heart disease. According to a Centers for Disease Control and Prevention (CDC) study, high blood pressure and high cholesterol are more common among workers exposed to loud noise at work.

The National Institute for Occupational Safety and Health (NIOSH) researchers analyzed data from the 2014 National Health Interview Survey to estimate the prevalence of occupational noise exposure, hearing difficulty, and heart conditions within US industries and occupations. They also looked at the association between workplace noise exposure and heart disease. Their analysis showed:

• 25% of current workers had a history of work-related noise exposure, 14% were exposed in the last year;
• 12% of current workers had hearing difficulty, 24% had high blood pressure, 28% had high cholesterol; and
• Of those cases 58%, 14%, and 9%, respectively, can be attributed to occupational noise exposure.

Study coauthor Liz Masterson, PhD, says, “If noise could be reduced to safer levels in the workplace, more than 5 million cases of hearing difficulty among noise-exposed workers could potentially be prevented.”

Loud noise is one of the most common workplace hazards in the US. One-quarter of US workers (an estimated 41 million people) report a history of noise exposure at work—and that may put them at risk for heart disease. According to a Centers for Disease Control and Prevention (CDC) study, high blood pressure and high cholesterol are more common among workers exposed to loud noise at work.

The National Institute for Occupational Safety and Health (NIOSH) researchers analyzed data from the 2014 National Health Interview Survey to estimate the prevalence of occupational noise exposure, hearing difficulty, and heart conditions within US industries and occupations. They also looked at the association between workplace noise exposure and heart disease. Their analysis showed:

• 25% of current workers had a history of work-related noise exposure, 14% were exposed in the last year;
• 12% of current workers had hearing difficulty, 24% had high blood pressure, 28% had high cholesterol; and
• Of those cases 58%, 14%, and 9%, respectively, can be attributed to occupational noise exposure.

Study coauthor Liz Masterson, PhD, says, “If noise could be reduced to safer levels in the workplace, more than 5 million cases of hearing difficulty among noise-exposed workers could potentially be prevented.”

Loud noise is one of the most common workplace hazards in the US. One-quarter of US workers (an estimated 41 million people) report a history of noise exposure at work—and that may put them at risk for heart disease. According to a Centers for Disease Control and Prevention (CDC) study, high blood pressure and high cholesterol are more common among workers exposed to loud noise at work.

The National Institute for Occupational Safety and Health (NIOSH) researchers analyzed data from the 2014 National Health Interview Survey to estimate the prevalence of occupational noise exposure, hearing difficulty, and heart conditions within US industries and occupations. They also looked at the association between workplace noise exposure and heart disease. Their analysis showed:

• 25% of current workers had a history of work-related noise exposure, 14% were exposed in the last year;
• 12% of current workers had hearing difficulty, 24% had high blood pressure, 28% had high cholesterol; and
• Of those cases 58%, 14%, and 9%, respectively, can be attributed to occupational noise exposure.

Study coauthor Liz Masterson, PhD, says, “If noise could be reduced to safer levels in the workplace, more than 5 million cases of hearing difficulty among noise-exposed workers could potentially be prevented.”

About 10% to 15% of women in the US have postpartum depression (PPD)—but that estimate is based mostly on women of European ancestry. In black women the rates are doubled, and among Latinas the prevalence is 30% to 43%. But those 2 groups have been inadequately studied, say researchers from University of North Carolina. To help remedy the lack of information, they conducted a study with the largest and “most robustly phenotyped” cohort of minority women with PPD. Their study also is the first to examine genetic ancestry as it contributes to PPD risk.

The researchers recruited 549 women with PPD and 968 without PPD who were within 6 weeks of having given birth. Of those, 67.4% were black, 14.4% were Latina, and 18.2% were white. The median age was 26.7; nearly half of the participants were married. Only 3.6% had given birth for the first time.

The women completed a battery of tests, including the Abuse and Trauma Inventory, Everyday Stressors Index (ESI), Edinburgh Postnatal Depression Scale (EPDS), and Postpartum Bonding Questionnaire. The researchers also assessed estradiol, progesterone, brain-derived neurotrophic factor, oxytocin, and allopregnanolone.

The women with PPD had significantly higher rates of previous psychiatric diagnoses, significantly higher EPDS total scores, and higher rates of family history of PPD. They also had significantly higher rates of previous diagnoses of major depressive disorder (MDD) (53% vs 15%), although 47% were experiencing their first episode of MDD. Dramatically higher numbers of women with PPD vs without PPD had suicidal thoughts in the month prior to assessment: 36% vs 2%, respectively.

Genetic ancestry was not predictive of case status, nor were hormonal influences any different between the 2 groups. Instead, psychiatric history and exposure to adverse life events were significant predictors. Nearly half of all the women with PPD had a lifetime anxiety disorder diagnosis compared with 7% of the controls. And although 67% of all participants reported a history of ≥ 1 traumatic event, women with PPD had double the proportion of multiple events of abuse and trauma. Women who had experienced multiple adverse life events were 3 times more likely to have PPD. Childhood and adult sexual abuse and life-threatening attack were among the most predictive.

The women with PPD had an ESI score > 3 times higher than that of the controls (19% vs 6%, respectively). The researchers note that cumulative lifetime stress may lead to epigenetic modification, and thus to PPD. Women with PPD also had a significantly higher proportion of dysfunctional mother-infant relationships, although the numbers were low in both groups (7% vs 0.35%, respectively).

The researchers say that although genetic ancestry did not play a role in determining case status, there are important ethnic and cultural differences that do play a role in treatment. For instance, Latinas and black women may be less likely to accept antidepressants as therapy. And because socioeconomic status is a determinant of health care access, they also face major barriers to mental health care. However, neither insurance nor education status (markers of socioeconomic status) distinguished cases from controls, even when the researchers controlled for genetic ancestry.

Their data provide a set of risk factors that can be used in screening new mothers, the researchers say. A brief, single assessment for previous psychiatric and abuse/trauma history during the perinatal period, along with regular mood monitoring, could increase a clinician’s ability to predict the onset of PPD.

Source:
Guintivano J, Sullivan PF, Stuebe AM. Psychol Med. 2018;48(7):1190-1200.
doi: 10.1017/S0033291717002641.

About 10% to 15% of women in the US have postpartum depression (PPD)—but that estimate is based mostly on women of European ancestry. In black women the rates are doubled, and among Latinas the prevalence is 30% to 43%. But those 2 groups have been inadequately studied, say researchers from University of North Carolina. To help remedy the lack of information, they conducted a study with the largest and “most robustly phenotyped” cohort of minority women with PPD. Their study also is the first to examine genetic ancestry as it contributes to PPD risk.

The researchers recruited 549 women with PPD and 968 without PPD who were within 6 weeks of having given birth. Of those, 67.4% were black, 14.4% were Latina, and 18.2% were white. The median age was 26.7; nearly half of the participants were married. Only 3.6% had given birth for the first time.

The women completed a battery of tests, including the Abuse and Trauma Inventory, Everyday Stressors Index (ESI), Edinburgh Postnatal Depression Scale (EPDS), and Postpartum Bonding Questionnaire. The researchers also assessed estradiol, progesterone, brain-derived neurotrophic factor, oxytocin, and allopregnanolone.

The women with PPD had significantly higher rates of previous psychiatric diagnoses, significantly higher EPDS total scores, and higher rates of family history of PPD. They also had significantly higher rates of previous diagnoses of major depressive disorder (MDD) (53% vs 15%), although 47% were experiencing their first episode of MDD. Dramatically higher numbers of women with PPD vs without PPD had suicidal thoughts in the month prior to assessment: 36% vs 2%, respectively.

Genetic ancestry was not predictive of case status, nor were hormonal influences any different between the 2 groups. Instead, psychiatric history and exposure to adverse life events were significant predictors. Nearly half of all the women with PPD had a lifetime anxiety disorder diagnosis compared with 7% of the controls. And although 67% of all participants reported a history of ≥ 1 traumatic event, women with PPD had double the proportion of multiple events of abuse and trauma. Women who had experienced multiple adverse life events were 3 times more likely to have PPD. Childhood and adult sexual abuse and life-threatening attack were among the most predictive.

The women with PPD had an ESI score > 3 times higher than that of the controls (19% vs 6%, respectively). The researchers note that cumulative lifetime stress may lead to epigenetic modification, and thus to PPD. Women with PPD also had a significantly higher proportion of dysfunctional mother-infant relationships, although the numbers were low in both groups (7% vs 0.35%, respectively).

The researchers say that although genetic ancestry did not play a role in determining case status, there are important ethnic and cultural differences that do play a role in treatment. For instance, Latinas and black women may be less likely to accept antidepressants as therapy. And because socioeconomic status is a determinant of health care access, they also face major barriers to mental health care. However, neither insurance nor education status (markers of socioeconomic status) distinguished cases from controls, even when the researchers controlled for genetic ancestry.

Their data provide a set of risk factors that can be used in screening new mothers, the researchers say. A brief, single assessment for previous psychiatric and abuse/trauma history during the perinatal period, along with regular mood monitoring, could increase a clinician’s ability to predict the onset of PPD.

Source:
Guintivano J, Sullivan PF, Stuebe AM. Psychol Med. 2018;48(7):1190-1200.
doi: 10.1017/S0033291717002641.

About 10% to 15% of women in the US have postpartum depression (PPD)—but that estimate is based mostly on women of European ancestry. In black women the rates are doubled, and among Latinas the prevalence is 30% to 43%. But those 2 groups have been inadequately studied, say researchers from University of North Carolina. To help remedy the lack of information, they conducted a study with the largest and “most robustly phenotyped” cohort of minority women with PPD. Their study also is the first to examine genetic ancestry as it contributes to PPD risk.

The researchers recruited 549 women with PPD and 968 without PPD who were within 6 weeks of having given birth. Of those, 67.4% were black, 14.4% were Latina, and 18.2% were white. The median age was 26.7; nearly half of the participants were married. Only 3.6% had given birth for the first time.

The women completed a battery of tests, including the Abuse and Trauma Inventory, Everyday Stressors Index (ESI), Edinburgh Postnatal Depression Scale (EPDS), and Postpartum Bonding Questionnaire. The researchers also assessed estradiol, progesterone, brain-derived neurotrophic factor, oxytocin, and allopregnanolone.

The women with PPD had significantly higher rates of previous psychiatric diagnoses, significantly higher EPDS total scores, and higher rates of family history of PPD. They also had significantly higher rates of previous diagnoses of major depressive disorder (MDD) (53% vs 15%), although 47% were experiencing their first episode of MDD. Dramatically higher numbers of women with PPD vs without PPD had suicidal thoughts in the month prior to assessment: 36% vs 2%, respectively.

Genetic ancestry was not predictive of case status, nor were hormonal influences any different between the 2 groups. Instead, psychiatric history and exposure to adverse life events were significant predictors. Nearly half of all the women with PPD had a lifetime anxiety disorder diagnosis compared with 7% of the controls. And although 67% of all participants reported a history of ≥ 1 traumatic event, women with PPD had double the proportion of multiple events of abuse and trauma. Women who had experienced multiple adverse life events were 3 times more likely to have PPD. Childhood and adult sexual abuse and life-threatening attack were among the most predictive.

The women with PPD had an ESI score > 3 times higher than that of the controls (19% vs 6%, respectively). The researchers note that cumulative lifetime stress may lead to epigenetic modification, and thus to PPD. Women with PPD also had a significantly higher proportion of dysfunctional mother-infant relationships, although the numbers were low in both groups (7% vs 0.35%, respectively).

The researchers say that although genetic ancestry did not play a role in determining case status, there are important ethnic and cultural differences that do play a role in treatment. For instance, Latinas and black women may be less likely to accept antidepressants as therapy. And because socioeconomic status is a determinant of health care access, they also face major barriers to mental health care. However, neither insurance nor education status (markers of socioeconomic status) distinguished cases from controls, even when the researchers controlled for genetic ancestry.

Their data provide a set of risk factors that can be used in screening new mothers, the researchers say. A brief, single assessment for previous psychiatric and abuse/trauma history during the perinatal period, along with regular mood monitoring, could increase a clinician’s ability to predict the onset of PPD.

Source:
Guintivano J, Sullivan PF, Stuebe AM. Psychol Med. 2018;48(7):1190-1200.
doi: 10.1017/S0033291717002641.

Photo by Patrick Pelletier

The availability of generic imatinib has had limited effects on costs of the drug, according to research published in Health Affairs.

Data suggest the cost of Gleevec in the US has more than doubled since the drug was approved in 2001, and the introduction of generic imatinib has reduced costs only slightly.

Two years after generic imatinib hit the market, a month’s supply of Gleevec cost about $9000, and the cost for generic imatinib was about $8000.

“Patients and providers have all looked forward to generic entry, expecting major price reductions,” said study author Stacie Dusetzina, PhD, of Vanderbilt University School of Medicine in Nashville, Tennessee.

“Unfortunately, we don’t see prices drop as quickly and as low as we would hope when generics are available.”

For this study, Dr Dusetzina and a colleague analyzed data from the MarketScan Commercial Research Database. The database contained records of 139,233 prescription fills for imatinib, which were made by 7201 patients from May 2001 through September 2017.

The researchers noted that Gleevec was priced at nearly $4000 for a 1-month (400 mg) supply when it came on the market in 2001. That price escalated to nearly $10,000 by 2015 before a generic competitor entered the market.

However, prices for Gleevec and generic imatinib remained high 2 years later. In 2017, a month’s supply of Gleevec cost about $9000, and the cost of generic imatinib was about $8000.

The researchers said the Gleevec case demonstrates several potential barriers to effective generic price competition, including shifts in prescribing toward more expensive brand-name treatments and smaller-than-expected price reductions.

Twenty-four percent of imatinib (Gleevec) prescriptions claims were for “dispense as written,” according to the researchers. This suggests that patients or providers specifically wanted to stay on the brand-name drug instead of switching to the generic.

“The more than doubling of the drug price over time and the lack of price reductions observed with nearly 2 years of generic drug competition is concerning,” Dr Dusetzina said.

“It begs the question whether we can rely on generic entry as a primary approach to address drug pricing for high-priced specialty medications. We need robust competition to move prices in this space.”

Photo by Patrick Pelletier

The availability of generic imatinib has had limited effects on costs of the drug, according to research published in Health Affairs.

Data suggest the cost of Gleevec in the US has more than doubled since the drug was approved in 2001, and the introduction of generic imatinib has reduced costs only slightly.

Two years after generic imatinib hit the market, a month’s supply of Gleevec cost about $9000, and the cost for generic imatinib was about $8000.

“Patients and providers have all looked forward to generic entry, expecting major price reductions,” said study author Stacie Dusetzina, PhD, of Vanderbilt University School of Medicine in Nashville, Tennessee.

“Unfortunately, we don’t see prices drop as quickly and as low as we would hope when generics are available.”

For this study, Dr Dusetzina and a colleague analyzed data from the MarketScan Commercial Research Database. The database contained records of 139,233 prescription fills for imatinib, which were made by 7201 patients from May 2001 through September 2017.

The researchers noted that Gleevec was priced at nearly $4000 for a 1-month (400 mg) supply when it came on the market in 2001. That price escalated to nearly $10,000 by 2015 before a generic competitor entered the market.

However, prices for Gleevec and generic imatinib remained high 2 years later. In 2017, a month’s supply of Gleevec cost about $9000, and the cost of generic imatinib was about $8000.

The researchers said the Gleevec case demonstrates several potential barriers to effective generic price competition, including shifts in prescribing toward more expensive brand-name treatments and smaller-than-expected price reductions.

Twenty-four percent of imatinib (Gleevec) prescriptions claims were for “dispense as written,” according to the researchers. This suggests that patients or providers specifically wanted to stay on the brand-name drug instead of switching to the generic.

“The more than doubling of the drug price over time and the lack of price reductions observed with nearly 2 years of generic drug competition is concerning,” Dr Dusetzina said.

“It begs the question whether we can rely on generic entry as a primary approach to address drug pricing for high-priced specialty medications. We need robust competition to move prices in this space.”

Photo by Patrick Pelletier

The availability of generic imatinib has had limited effects on costs of the drug, according to research published in Health Affairs.

Data suggest the cost of Gleevec in the US has more than doubled since the drug was approved in 2001, and the introduction of generic imatinib has reduced costs only slightly.

Two years after generic imatinib hit the market, a month’s supply of Gleevec cost about $9000, and the cost for generic imatinib was about $8000.

“Patients and providers have all looked forward to generic entry, expecting major price reductions,” said study author Stacie Dusetzina, PhD, of Vanderbilt University School of Medicine in Nashville, Tennessee.

“Unfortunately, we don’t see prices drop as quickly and as low as we would hope when generics are available.”

For this study, Dr Dusetzina and a colleague analyzed data from the MarketScan Commercial Research Database. The database contained records of 139,233 prescription fills for imatinib, which were made by 7201 patients from May 2001 through September 2017.

The researchers noted that Gleevec was priced at nearly $4000 for a 1-month (400 mg) supply when it came on the market in 2001. That price escalated to nearly $10,000 by 2015 before a generic competitor entered the market.

However, prices for Gleevec and generic imatinib remained high 2 years later. In 2017, a month’s supply of Gleevec cost about $9000, and the cost of generic imatinib was about $8000.

The researchers said the Gleevec case demonstrates several potential barriers to effective generic price competition, including shifts in prescribing toward more expensive brand-name treatments and smaller-than-expected price reductions.

Twenty-four percent of imatinib (Gleevec) prescriptions claims were for “dispense as written,” according to the researchers. This suggests that patients or providers specifically wanted to stay on the brand-name drug instead of switching to the generic.

“The more than doubling of the drug price over time and the lack of price reductions observed with nearly 2 years of generic drug competition is concerning,” Dr Dusetzina said.

“It begs the question whether we can rely on generic entry as a primary approach to address drug pricing for high-priced specialty medications. We need robust competition to move prices in this space.”

Henrique Orlandi Mourao

Researchers have discovered the first leukemia-protective gene that is specific to the Y chromosome, according to an article published in Nature Genetics.

The researchers were investigating how loss of the X-chromosome gene UTX hastens the development of acute myeloid leukemia (AML).

However, they found that UTY, a related gene on the Y chromosome, protected male mice lacking UTX from developing AML.

The researchers then found that, in AML and other cancers, loss of UTX is accompanied by loss of UTY.

“This is the first Y chromosome-specific gene that protects against AML,” said study author Malgorzata Gozdecka, PhD, of the Wellcome Sanger Institute in Hinxton, UK.

“Previously, it had been suggested that the only function of the Y chromosome is in creating male sexual characteristics, but our results indicate that the Y chromosome could also protect against AML and other cancers.”

For this work, Dr Gozdecka and her colleagues studied the UTX gene in human cells and mice.

In addition to their discovery that UTY acts as a tumor suppressor gene, the researchers uncovered a new mechanism for how loss of UTX leads to AML.

They discovered that UTX acts as a common scaffold, bringing together a large number of regulatory proteins that control access to DNA and gene expression, a function that can also be carried out by UTY.

Specifically, the team said UTX suppresses AML by repressing oncogenic ETS and upregulating tumor-suppressive GATA programs. And loss of UTX leads to “altered patterns of gene expression that induce and maintain” AML.

“Treatments for AML have not changed in decades, and there is a large unmet need for new therapies,” said study author George Vassiliou, PhD, of the Wellcome Sanger Institute.

“This study helps us understand the development of AML and gives us clues for developing new drug targets to disrupt leukemia-causing processes. We hope this study will enable new lines of research for the development of previously unforeseen treatments and improve the lives of patients with AML.”

Henrique Orlandi Mourao

Researchers have discovered the first leukemia-protective gene that is specific to the Y chromosome, according to an article published in Nature Genetics.

The researchers were investigating how loss of the X-chromosome gene UTX hastens the development of acute myeloid leukemia (AML).

However, they found that UTY, a related gene on the Y chromosome, protected male mice lacking UTX from developing AML.

The researchers then found that, in AML and other cancers, loss of UTX is accompanied by loss of UTY.

“This is the first Y chromosome-specific gene that protects against AML,” said study author Malgorzata Gozdecka, PhD, of the Wellcome Sanger Institute in Hinxton, UK.

“Previously, it had been suggested that the only function of the Y chromosome is in creating male sexual characteristics, but our results indicate that the Y chromosome could also protect against AML and other cancers.”

For this work, Dr Gozdecka and her colleagues studied the UTX gene in human cells and mice.

In addition to their discovery that UTY acts as a tumor suppressor gene, the researchers uncovered a new mechanism for how loss of UTX leads to AML.

They discovered that UTX acts as a common scaffold, bringing together a large number of regulatory proteins that control access to DNA and gene expression, a function that can also be carried out by UTY.

Specifically, the team said UTX suppresses AML by repressing oncogenic ETS and upregulating tumor-suppressive GATA programs. And loss of UTX leads to “altered patterns of gene expression that induce and maintain” AML.

“Treatments for AML have not changed in decades, and there is a large unmet need for new therapies,” said study author George Vassiliou, PhD, of the Wellcome Sanger Institute.

“This study helps us understand the development of AML and gives us clues for developing new drug targets to disrupt leukemia-causing processes. We hope this study will enable new lines of research for the development of previously unforeseen treatments and improve the lives of patients with AML.”

Henrique Orlandi Mourao

Researchers have discovered the first leukemia-protective gene that is specific to the Y chromosome, according to an article published in Nature Genetics.

The researchers were investigating how loss of the X-chromosome gene UTX hastens the development of acute myeloid leukemia (AML).

However, they found that UTY, a related gene on the Y chromosome, protected male mice lacking UTX from developing AML.

The researchers then found that, in AML and other cancers, loss of UTX is accompanied by loss of UTY.

“This is the first Y chromosome-specific gene that protects against AML,” said study author Malgorzata Gozdecka, PhD, of the Wellcome Sanger Institute in Hinxton, UK.

“Previously, it had been suggested that the only function of the Y chromosome is in creating male sexual characteristics, but our results indicate that the Y chromosome could also protect against AML and other cancers.”

For this work, Dr Gozdecka and her colleagues studied the UTX gene in human cells and mice.

In addition to their discovery that UTY acts as a tumor suppressor gene, the researchers uncovered a new mechanism for how loss of UTX leads to AML.

They discovered that UTX acts as a common scaffold, bringing together a large number of regulatory proteins that control access to DNA and gene expression, a function that can also be carried out by UTY.

Specifically, the team said UTX suppresses AML by repressing oncogenic ETS and upregulating tumor-suppressive GATA programs. And loss of UTX leads to “altered patterns of gene expression that induce and maintain” AML.

“Treatments for AML have not changed in decades, and there is a large unmet need for new therapies,” said study author George Vassiliou, PhD, of the Wellcome Sanger Institute.

“This study helps us understand the development of AML and gives us clues for developing new drug targets to disrupt leukemia-causing processes. We hope this study will enable new lines of research for the development of previously unforeseen treatments and improve the lives of patients with AML.”

Image courtesy of AFIP

Preclinical research helps explain how the JAK1/2 inhibitor ruxolitinib can reduce thrombosis in patients with myeloproliferative neoplasms (MPNs).

Experiments revealed a link between JAK2^V617F and the formation of neutrophil extracellular traps (NETs), which have been implicated in thrombosis.

Researchers found that ruxolitinib reduced NET formation and decreased thrombosis in JAK2-mutant mice.

Benjamin L. Ebert, MD, PhD, of Brigham and Women’s Hospital in Boston, Massachusetts, and his colleagues reported these findings in Science Translational Medicine.

The researchers noted that patients with MPNs have an increased risk of thrombosis, and previous research linked thrombosis to the formation of NETs. NETs are structures that help trap pathogens but may also promote autoimmune responses and excessive blood clotting.

With the current study, Dr Ebert and his colleagues examined whether NET formation could promote thrombosis in patients with MPNs.

The team found that neutrophils from MPN patients were more likely to form NETs than neutrophils from healthy individuals. However, incubating neutrophils with ruxolitinib reduced NET formation.

The researchers also found that mice with JAK2^V617F were more likely to form NETs and develop thrombosis when compared to wild-type mice. However, treatment with ruxolitinib reduced rates of thrombosis and prevented NET formation in the mice.

The researchers noted that expression of PAD4, a protein required for NET formation, is increased in JAK2^V617F-expressing neutrophils. And the team found that PAD4 is required for JAK2^V617F-driven NET formation and thrombosis in mouse models of MPNs.

Lastly, the researchers looked at data from 10,893 human subjects. None of these subjects had MPNs, but some had JAK2^V617F.

Subjects who were JAK2^V617F-positive had a significantly higher risk of thrombotic events than subjects without the mutation (P=0.0003).

Taken together, these findings suggest that JAK2 inhibition can reduce NET formation and ameliorate thrombosis in patients with MPNs or the JAK2^V617F mutation.

The researchers noted that, in the phase 3 RESPONSE trial, patients with polycythemia vera had a lower rate of thromboembolic events if they received ruxolitinib rather than standard therapy.

Image courtesy of AFIP

Preclinical research helps explain how the JAK1/2 inhibitor ruxolitinib can reduce thrombosis in patients with myeloproliferative neoplasms (MPNs).

Experiments revealed a link between JAK2^V617F and the formation of neutrophil extracellular traps (NETs), which have been implicated in thrombosis.

Researchers found that ruxolitinib reduced NET formation and decreased thrombosis in JAK2-mutant mice.

Benjamin L. Ebert, MD, PhD, of Brigham and Women’s Hospital in Boston, Massachusetts, and his colleagues reported these findings in Science Translational Medicine.

The researchers noted that patients with MPNs have an increased risk of thrombosis, and previous research linked thrombosis to the formation of NETs. NETs are structures that help trap pathogens but may also promote autoimmune responses and excessive blood clotting.

With the current study, Dr Ebert and his colleagues examined whether NET formation could promote thrombosis in patients with MPNs.

The team found that neutrophils from MPN patients were more likely to form NETs than neutrophils from healthy individuals. However, incubating neutrophils with ruxolitinib reduced NET formation.

The researchers also found that mice with JAK2^V617F were more likely to form NETs and develop thrombosis when compared to wild-type mice. However, treatment with ruxolitinib reduced rates of thrombosis and prevented NET formation in the mice.

The researchers noted that expression of PAD4, a protein required for NET formation, is increased in JAK2^V617F-expressing neutrophils. And the team found that PAD4 is required for JAK2^V617F-driven NET formation and thrombosis in mouse models of MPNs.

Lastly, the researchers looked at data from 10,893 human subjects. None of these subjects had MPNs, but some had JAK2^V617F.

Subjects who were JAK2^V617F-positive had a significantly higher risk of thrombotic events than subjects without the mutation (P=0.0003).

Taken together, these findings suggest that JAK2 inhibition can reduce NET formation and ameliorate thrombosis in patients with MPNs or the JAK2^V617F mutation.

The researchers noted that, in the phase 3 RESPONSE trial, patients with polycythemia vera had a lower rate of thromboembolic events if they received ruxolitinib rather than standard therapy.

Image courtesy of AFIP

Preclinical research helps explain how the JAK1/2 inhibitor ruxolitinib can reduce thrombosis in patients with myeloproliferative neoplasms (MPNs).

Experiments revealed a link between JAK2^V617F and the formation of neutrophil extracellular traps (NETs), which have been implicated in thrombosis.

Researchers found that ruxolitinib reduced NET formation and decreased thrombosis in JAK2-mutant mice.

Benjamin L. Ebert, MD, PhD, of Brigham and Women’s Hospital in Boston, Massachusetts, and his colleagues reported these findings in Science Translational Medicine.

The researchers noted that patients with MPNs have an increased risk of thrombosis, and previous research linked thrombosis to the formation of NETs. NETs are structures that help trap pathogens but may also promote autoimmune responses and excessive blood clotting.

With the current study, Dr Ebert and his colleagues examined whether NET formation could promote thrombosis in patients with MPNs.

The team found that neutrophils from MPN patients were more likely to form NETs than neutrophils from healthy individuals. However, incubating neutrophils with ruxolitinib reduced NET formation.

The researchers also found that mice with JAK2^V617F were more likely to form NETs and develop thrombosis when compared to wild-type mice. However, treatment with ruxolitinib reduced rates of thrombosis and prevented NET formation in the mice.

The researchers noted that expression of PAD4, a protein required for NET formation, is increased in JAK2^V617F-expressing neutrophils. And the team found that PAD4 is required for JAK2^V617F-driven NET formation and thrombosis in mouse models of MPNs.

Lastly, the researchers looked at data from 10,893 human subjects. None of these subjects had MPNs, but some had JAK2^V617F.

Subjects who were JAK2^V617F-positive had a significantly higher risk of thrombotic events than subjects without the mutation (P=0.0003).

Taken together, these findings suggest that JAK2 inhibition can reduce NET formation and ameliorate thrombosis in patients with MPNs or the JAK2^V617F mutation.

The researchers noted that, in the phase 3 RESPONSE trial, patients with polycythemia vera had a lower rate of thromboembolic events if they received ruxolitinib rather than standard therapy.

TORONTO – Almost half of adolescents (45%) reported that their primary care providers (PCPs) do not routinely ask them about sex, and only 13% report they’ve been offered screening for sexually transmitted infections (STIs), according to a survey study presented at the Pediatric Academic Societies meeting.

And it appears the teenagers aren’t even listening to much of what their parents are saying on the subject: The survey also found that 90% of parents reported that they talk to their adolescents about sex, but only 39% of adolescents reported the same.

Rawpixel/iStock/Getty Images

“I think that primary care physicians have a lot to cover when doing preventive health visits with adolescents, and talking about sex is not necessarily an easy or comfortable thing to do and so may be something that falls to a lower priority. And it certainly doesn’t help if parents are not supportive of the concept of confidential adolescent care,” Dr. Schneider related.

“We were very surprised to see that 25% of parents did not feel that PCPs should be discussing sex with their child. I think that we need to next work on getting the parents on board and building an expectation that adolescents, when visiting their PCP, will have confidential discussions about sexual health,” she said.

TORONTO – Almost half of adolescents (45%) reported that their primary care providers (PCPs) do not routinely ask them about sex, and only 13% report they’ve been offered screening for sexually transmitted infections (STIs), according to a survey study presented at the Pediatric Academic Societies meeting.

And it appears the teenagers aren’t even listening to much of what their parents are saying on the subject: The survey also found that 90% of parents reported that they talk to their adolescents about sex, but only 39% of adolescents reported the same.

Rawpixel/iStock/Getty Images

“I think that primary care physicians have a lot to cover when doing preventive health visits with adolescents, and talking about sex is not necessarily an easy or comfortable thing to do and so may be something that falls to a lower priority. And it certainly doesn’t help if parents are not supportive of the concept of confidential adolescent care,” Dr. Schneider related.

“We were very surprised to see that 25% of parents did not feel that PCPs should be discussing sex with their child. I think that we need to next work on getting the parents on board and building an expectation that adolescents, when visiting their PCP, will have confidential discussions about sexual health,” she said.

TORONTO – Almost half of adolescents (45%) reported that their primary care providers (PCPs) do not routinely ask them about sex, and only 13% report they’ve been offered screening for sexually transmitted infections (STIs), according to a survey study presented at the Pediatric Academic Societies meeting.

And it appears the teenagers aren’t even listening to much of what their parents are saying on the subject: The survey also found that 90% of parents reported that they talk to their adolescents about sex, but only 39% of adolescents reported the same.

Rawpixel/iStock/Getty Images

“I think that primary care physicians have a lot to cover when doing preventive health visits with adolescents, and talking about sex is not necessarily an easy or comfortable thing to do and so may be something that falls to a lower priority. And it certainly doesn’t help if parents are not supportive of the concept of confidential adolescent care,” Dr. Schneider related.

“We were very surprised to see that 25% of parents did not feel that PCPs should be discussing sex with their child. I think that we need to next work on getting the parents on board and building an expectation that adolescents, when visiting their PCP, will have confidential discussions about sexual health,” she said.

NEW YORK – Veterans are not a homogeneous group, and when treating them for posttraumatic stress, it helps to consider their specific cohort, according to Elspeth Cameron Ritchie, MD.

Veterans from the first Gulf War, for example, have lingering concerns regarding medical illness (Gulf War syndrome); those from Vietnam are aging and might have medical problems or find that while they did well while working, now they are experiencing PTSD symptoms for the first time; and those returning from the conflicts in Iraq and Afghanistan might have physical injuries from blasts – the “signature weapon” of those wars. Such blasts can cause amputations, genital injuries, head trauma, and PTSD, said Dr. Ritchie, of the Uniformed Services University of the Health Sciences, Bethesda, Md.

In this video interview, Dr. Ritchie discusses these and other issues related to the treatment of PTSD among veterans as presented during a workshop entitled “Psychiatry and U.S. Veterans,” which she chaired at the annual meeting of the American Psychiatric Association.

The workshop covered the spectrum of treatments that might be helpful for veterans.

“One thing I find with veterans is that they really want to have control over their treatment. They don’t want it to just be the doctor giving them a pill,” she said. “Veterans are resilient; they’re tough; they don’t like to be thought of as victims ... and when you’re working with them, it’s very important to link into that dynamic resilient piece and capitalize on their strengths.”

Dr. Ritchie reported having no disclosures.

[email protected]

SOURCE: Ritchie EC et al. APA Workshop.

NEW YORK – Veterans are not a homogeneous group, and when treating them for posttraumatic stress, it helps to consider their specific cohort, according to Elspeth Cameron Ritchie, MD.

Veterans from the first Gulf War, for example, have lingering concerns regarding medical illness (Gulf War syndrome); those from Vietnam are aging and might have medical problems or find that while they did well while working, now they are experiencing PTSD symptoms for the first time; and those returning from the conflicts in Iraq and Afghanistan might have physical injuries from blasts – the “signature weapon” of those wars. Such blasts can cause amputations, genital injuries, head trauma, and PTSD, said Dr. Ritchie, of the Uniformed Services University of the Health Sciences, Bethesda, Md.

In this video interview, Dr. Ritchie discusses these and other issues related to the treatment of PTSD among veterans as presented during a workshop entitled “Psychiatry and U.S. Veterans,” which she chaired at the annual meeting of the American Psychiatric Association.

The workshop covered the spectrum of treatments that might be helpful for veterans.

“One thing I find with veterans is that they really want to have control over their treatment. They don’t want it to just be the doctor giving them a pill,” she said. “Veterans are resilient; they’re tough; they don’t like to be thought of as victims ... and when you’re working with them, it’s very important to link into that dynamic resilient piece and capitalize on their strengths.”

Dr. Ritchie reported having no disclosures.

[email protected]

SOURCE: Ritchie EC et al. APA Workshop.

NEW YORK – Veterans are not a homogeneous group, and when treating them for posttraumatic stress, it helps to consider their specific cohort, according to Elspeth Cameron Ritchie, MD.

Veterans from the first Gulf War, for example, have lingering concerns regarding medical illness (Gulf War syndrome); those from Vietnam are aging and might have medical problems or find that while they did well while working, now they are experiencing PTSD symptoms for the first time; and those returning from the conflicts in Iraq and Afghanistan might have physical injuries from blasts – the “signature weapon” of those wars. Such blasts can cause amputations, genital injuries, head trauma, and PTSD, said Dr. Ritchie, of the Uniformed Services University of the Health Sciences, Bethesda, Md.

In this video interview, Dr. Ritchie discusses these and other issues related to the treatment of PTSD among veterans as presented during a workshop entitled “Psychiatry and U.S. Veterans,” which she chaired at the annual meeting of the American Psychiatric Association.

The workshop covered the spectrum of treatments that might be helpful for veterans.

“One thing I find with veterans is that they really want to have control over their treatment. They don’t want it to just be the doctor giving them a pill,” she said. “Veterans are resilient; they’re tough; they don’t like to be thought of as victims ... and when you’re working with them, it’s very important to link into that dynamic resilient piece and capitalize on their strengths.”

Dr. Ritchie reported having no disclosures.

[email protected]

SOURCE: Ritchie EC et al. APA Workshop.