NEW YORK – For the first time, the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis is preparing evidence-based treatment recommendations for the diagnosis and management of the comorbidities associated with psoriatic arthritis.

"I am really excited that we are taking the initiative to treat and manage the psoriatic arthritis [PsA] patient as a whole," reported Dr. Elaine Husni, director of the Arthritis and Musculoskeletal Center at the Cleveland Clinic. The guidelines are meant to be a "platform on which to raise awareness" and foster education.

An initial set of guidelines on comorbidities was drafted at the joint meetings of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) and the Spondyloarthritis Research & Treatment Network (SPARTAN). Dr. Husni led the consensus group and fielded questions about key recommendations.

The first of these recommendations, which will undergo a process of discussion and review prior to formal adoption, states that all patients with PsA should be evaluated for cardiovascular (CV) disease. The consensus group labeled this recommendation "strong" even while conferring it with grade D evidence.

"The grade D was based on the fact that there are no outcomes data specifically in patients with psoriatic arthritis," observed Dr. Alexis R. Ogdie-Beatty, director of the Penn Psoriatic Arthritis Clinic at the University of Pennsylvania, Philadelphia. A member of the consensus group, Dr. Ogdie-Beatty suggested that benefit from CV screening is still a reasonable expectation "given the growing evidence that patients with PsA are at increased risk."

Similar "strong" recommendations but grade D evidence were given for screening for ophthalmic complications and inflammatory bowel disease. In these cases, there is good evidence for an association with PsA but limited evidence that screening will lead to improved outcome. The exception was obesity for which the group gave a B rating to the evidence for benefit from diagnosis and treatment.

Screening for diabetes was also included among recommendations, but it was given a "weak" rating and a grade D for supportive evidence.

Most of the other recommendations involved screening for various infections, such as hepatitis C virus (HCV), HIV, and tuberculosis, prior to initiating immunosuppressant therapies, particularly biologics. The level of evidence for these recommendations typically ranged between B and C even though all were given strong recommendations.

The consensus recommendations are not expected to include much detail about the specific management of comorbidities. The reason is concern about their applicability across various settings of care. It was thought that GRAPPA, as an international organization, should accommodate different types of practice. For example, the group cautioned against outlining steps of CV risk management, which may be managed by rheumatologists in some areas of the world but by specialists in others.

"We want to stay away from being minicardiologists," Dr. Husni explained. She indicated that the goal of the recommendations is to simply identify the specific types of comorbidity screening that should be considered "core recommendations" in the approach to PsA.

However, there is interest in creating a table regarding the use of specific medications for PsA treatment in the context of comorbidities. In a color-coded draft presented at the GRAPPA and SPARTAN meeting, some examples included caution in the use of NSAIDs in patients with CV disease, a need for monitoring when using cyclosporine in patients with chronic kidney disease, and a preference for etanercept over other tumor necrosis factor inhibitors in patients with HCV infection.

Overall, recommendations for comorbidities were identified as an important step in defining optimal care for PsA. According to Dr. Ogdie-Beatty, "the most important point may be to raise awareness." As these recommendations wend their way through an approval process at the organizational level, Dr. Ogdie-Beatty expressed hope that the final wording is specific enough to encourage attention to comorbidities without restricting a variety of valid approaches.

Dr. Husni reported a financial relationship with Celgene. Dr. Ogdie-Beatty had no potential conflicts of interest to report.

NEW YORK – For the first time, the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis is preparing evidence-based treatment recommendations for the diagnosis and management of the comorbidities associated with psoriatic arthritis.

"I am really excited that we are taking the initiative to treat and manage the psoriatic arthritis [PsA] patient as a whole," reported Dr. Elaine Husni, director of the Arthritis and Musculoskeletal Center at the Cleveland Clinic. The guidelines are meant to be a "platform on which to raise awareness" and foster education.

An initial set of guidelines on comorbidities was drafted at the joint meetings of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) and the Spondyloarthritis Research & Treatment Network (SPARTAN). Dr. Husni led the consensus group and fielded questions about key recommendations.

The first of these recommendations, which will undergo a process of discussion and review prior to formal adoption, states that all patients with PsA should be evaluated for cardiovascular (CV) disease. The consensus group labeled this recommendation "strong" even while conferring it with grade D evidence.

"The grade D was based on the fact that there are no outcomes data specifically in patients with psoriatic arthritis," observed Dr. Alexis R. Ogdie-Beatty, director of the Penn Psoriatic Arthritis Clinic at the University of Pennsylvania, Philadelphia. A member of the consensus group, Dr. Ogdie-Beatty suggested that benefit from CV screening is still a reasonable expectation "given the growing evidence that patients with PsA are at increased risk."

Similar "strong" recommendations but grade D evidence were given for screening for ophthalmic complications and inflammatory bowel disease. In these cases, there is good evidence for an association with PsA but limited evidence that screening will lead to improved outcome. The exception was obesity for which the group gave a B rating to the evidence for benefit from diagnosis and treatment.

Screening for diabetes was also included among recommendations, but it was given a "weak" rating and a grade D for supportive evidence.

Most of the other recommendations involved screening for various infections, such as hepatitis C virus (HCV), HIV, and tuberculosis, prior to initiating immunosuppressant therapies, particularly biologics. The level of evidence for these recommendations typically ranged between B and C even though all were given strong recommendations.

The consensus recommendations are not expected to include much detail about the specific management of comorbidities. The reason is concern about their applicability across various settings of care. It was thought that GRAPPA, as an international organization, should accommodate different types of practice. For example, the group cautioned against outlining steps of CV risk management, which may be managed by rheumatologists in some areas of the world but by specialists in others.

"We want to stay away from being minicardiologists," Dr. Husni explained. She indicated that the goal of the recommendations is to simply identify the specific types of comorbidity screening that should be considered "core recommendations" in the approach to PsA.

However, there is interest in creating a table regarding the use of specific medications for PsA treatment in the context of comorbidities. In a color-coded draft presented at the GRAPPA and SPARTAN meeting, some examples included caution in the use of NSAIDs in patients with CV disease, a need for monitoring when using cyclosporine in patients with chronic kidney disease, and a preference for etanercept over other tumor necrosis factor inhibitors in patients with HCV infection.

Overall, recommendations for comorbidities were identified as an important step in defining optimal care for PsA. According to Dr. Ogdie-Beatty, "the most important point may be to raise awareness." As these recommendations wend their way through an approval process at the organizational level, Dr. Ogdie-Beatty expressed hope that the final wording is specific enough to encourage attention to comorbidities without restricting a variety of valid approaches.

Dr. Husni reported a financial relationship with Celgene. Dr. Ogdie-Beatty had no potential conflicts of interest to report.

NEW YORK – For the first time, the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis is preparing evidence-based treatment recommendations for the diagnosis and management of the comorbidities associated with psoriatic arthritis.

"I am really excited that we are taking the initiative to treat and manage the psoriatic arthritis [PsA] patient as a whole," reported Dr. Elaine Husni, director of the Arthritis and Musculoskeletal Center at the Cleveland Clinic. The guidelines are meant to be a "platform on which to raise awareness" and foster education.

An initial set of guidelines on comorbidities was drafted at the joint meetings of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) and the Spondyloarthritis Research & Treatment Network (SPARTAN). Dr. Husni led the consensus group and fielded questions about key recommendations.

The first of these recommendations, which will undergo a process of discussion and review prior to formal adoption, states that all patients with PsA should be evaluated for cardiovascular (CV) disease. The consensus group labeled this recommendation "strong" even while conferring it with grade D evidence.

"The grade D was based on the fact that there are no outcomes data specifically in patients with psoriatic arthritis," observed Dr. Alexis R. Ogdie-Beatty, director of the Penn Psoriatic Arthritis Clinic at the University of Pennsylvania, Philadelphia. A member of the consensus group, Dr. Ogdie-Beatty suggested that benefit from CV screening is still a reasonable expectation "given the growing evidence that patients with PsA are at increased risk."

Similar "strong" recommendations but grade D evidence were given for screening for ophthalmic complications and inflammatory bowel disease. In these cases, there is good evidence for an association with PsA but limited evidence that screening will lead to improved outcome. The exception was obesity for which the group gave a B rating to the evidence for benefit from diagnosis and treatment.

Screening for diabetes was also included among recommendations, but it was given a "weak" rating and a grade D for supportive evidence.

Most of the other recommendations involved screening for various infections, such as hepatitis C virus (HCV), HIV, and tuberculosis, prior to initiating immunosuppressant therapies, particularly biologics. The level of evidence for these recommendations typically ranged between B and C even though all were given strong recommendations.

The consensus recommendations are not expected to include much detail about the specific management of comorbidities. The reason is concern about their applicability across various settings of care. It was thought that GRAPPA, as an international organization, should accommodate different types of practice. For example, the group cautioned against outlining steps of CV risk management, which may be managed by rheumatologists in some areas of the world but by specialists in others.

"We want to stay away from being minicardiologists," Dr. Husni explained. She indicated that the goal of the recommendations is to simply identify the specific types of comorbidity screening that should be considered "core recommendations" in the approach to PsA.

However, there is interest in creating a table regarding the use of specific medications for PsA treatment in the context of comorbidities. In a color-coded draft presented at the GRAPPA and SPARTAN meeting, some examples included caution in the use of NSAIDs in patients with CV disease, a need for monitoring when using cyclosporine in patients with chronic kidney disease, and a preference for etanercept over other tumor necrosis factor inhibitors in patients with HCV infection.

Overall, recommendations for comorbidities were identified as an important step in defining optimal care for PsA. According to Dr. Ogdie-Beatty, "the most important point may be to raise awareness." As these recommendations wend their way through an approval process at the organizational level, Dr. Ogdie-Beatty expressed hope that the final wording is specific enough to encourage attention to comorbidities without restricting a variety of valid approaches.

Dr. Husni reported a financial relationship with Celgene. Dr. Ogdie-Beatty had no potential conflicts of interest to report.

Case Forgetful and depressed
Mr. B, age 55, has been a patient at our clinic for 8 years, where he has been under our care for treatment-resistant depression and opi­oid addiction [read about earlier events in his case in “A life of drugs and ‘downtime’” Current Psychiatry, August 2007, p. 98-103].¹ He reports feeling intermittently depressed since his teens and has had 3 near-fatal suicide attempts.

Three years ago, Mr. B reported severe depressive symptoms and short-term memory loss, which undermined his job performance and contributed to interpersonal conflict with his wife. The episode has been continuously severe for 10 months. He was taking sertra­line, 150 mg/d, and duloxetine, 60 mg/d, for major depressive disorder (MDD) and sublin­gual buprenorphine/naloxone, 20 mg/d, for opioid dependence, which was in sustained full remission.² Mr. B scored 24/30 in the Mini- Mental State Examination, indicating mild cognitive deficit. Negative results of a com­plete routine laboratory workup rule out an organic cause for his deteriorating cognition.

How would you diagnose Mr. B’s condition at this point?
   a) treatment-resistant MDD
   b) cognitive disorder not otherwise specified
   c) opioid use disorder
   d) a and c

The authors' observations
Relapse is a core feature of substance use dis­orders (SUDs) that contributes significantly to the longstanding functional impairment in patients with a mood disorder. With the relapse rate following substance use treat­ment estimated at more than 60%,³ SUDs often are described as chronic relapsing conditions. In chronic stress, corticotropin-releasing factor (CRF) is over-sensitized; we believe that acute stress can cause an unhealthy response to an over-expressed CRF system.

To prevent relapse in patients with an over-expressed CRF system, it is crucial to manage stress. One treatment option to con­sider in preventing relapse is mindfulness-based interventions (MBI). Mindfulness has been described as “paying attention in a particular way: on purpose, in the present moment, and non-judgmentally.” In the event of a relapse, awareness and acceptance fostered by mindfulness may aid in recogniz­ing and minimizing unhealthy responses, such as negative thinking that can increase the risk of relapse.

History Remission, then relapse
Mr. B was admitted to inpatient psychiatric unit after a near-fatal suicide attempt 8 years ago and given a diagnosis of MDD recurrent, severe with­out psychotic features. Trials of sertraline, bupro­pion, trazodone, quetiapine, and aripiprazole were ineffective.

Before he presented to our clinic 8 years ago, Mr. B had been taking venlafaxine, 75 mg/d, and mirtazapine, 30 mg at bedtime. His previous outpatient psychiatrist added methylphenidate, 40 mg/d, to augment the antidepressants, but this did not alleviate Mr. B’s depression.

At age 40, he entered a methadone pro­gram, began working steadily, and got married. Five years later, he stopped methadone (it is unclear from the chart if his psychiatrist initiated this change). Mr. B’s depression persisted while using opioids and became worse after stopping methadone.

We considered electroconvulsive therapy (ECT) at the time, but switching the anti­depressant or starting ECT would address only the persistent depression; buprenor­phine/naloxone would target opioid crav­ing. We started a trial of buprenorphine/ naloxone, a partial μ opioid agonist and ĸ opioid antagonist; ĸ receptor antagonism serves as an antidepressant. He responded well to augmentation of his current regimen (mirtazapine, 30 mg at bedtime, and venlafax­ine, 225 mg/d) with buprenorphine/naloxone, 16 mg/d.^4,5 he reported no anergia and said he felt more motivated and productive.

Mr. B took buprenorphine/naloxone, 32 mg/d, for 4 years until, because of concern for daytime sedation, his outpatient psychia­trist reduced the dose to 20 mg/d. With the lower dosage of buprenorphine/naloxone ini­tiated 4 years ago, Mr. B reported irritability, anhedonia, insomnia, increased self-criticism, and decreased self-care.

How would you treat Mr. B’s depression at this point?
   a) switch to a daytime antidepressant
   b) adjust the dosage of buprenorphine/ naloxone
   c) try ECT
   d) try mindfulness-based cognitive therapy

The authors’ observations
Mindfulness meditation (MM) is a medi­tation practice that cultivates awareness. While learning MM, the practitioner inten­tionally focuses on awareness—a way of purposely paying attention to the present moment, non-judgmentally, to nurture calmness and self-acceptance. Being con­scious of what the practitioner is doing while he is doing it is the core of mindful­ness practice.⁶

Mindfulness-based interventions. We rec­ommended the following forms of MBI to treat Mr. B:  
   • Mindfulness-based cognitive therapy (MBCT). MBCT is designed to help people who suffer repeated bouts of depression and chronic unhappiness. It combines the ideas of cognitive-behavioral therapy (CBT) with MM practices and attitudes based on culti­vating mindfulness.⁷  
   • Mindfulness-based stress reduction (MBSR). MBSR brings together MM and physical/breathing exercises to relax body and mind.⁶

Chronic stress and drug addiction
The literature demonstrates a significant association between acute and chronic stress and motivation to abuse substances. Stress mobilizes the CRF system to stimulate the hypothalamic-pituitary-adrenal (HPA) axis, and extra-hypothalamic actions of CRF can kindle the neuronal circuits responsible for stress-induced anxiety, dysphoria, and drug abuse behaviors.⁸

A study to evaluate effects of mindful­ness on young adult romantic partners’ HPA responses to conflict stress showed that MM has sex-specific effects on neu­roendocrine response to interpersonal stress.⁹ Research has shown that MM practice can decrease stress, increase well-being, and affect brain structure and func­tion.¹⁰ Meta-analysis of studies of animal models and humans described how spe­cific interventions intended to encourage pro-social behavior and well-being might produce plasticity-related changes in the brain.¹¹ This work concluded that, by tak­ing responsibility for the mind and the brain by participating in regular mental exercise, plastic changes in the brain pro­moted could produce lasting beneficial consequences for social and emotional behavior.¹¹

What could be perpetuating Mr. B’s depression?
   a) psychosocial stressors
   b) over-expression of CRF gene due to psychosocial stressors
   c) a and b

Treatment Mindfulness practice
Mr. B was started on CBT to manage anxiety symptoms and cognitive distortions. After 2 months, he reports no improvements in anx­iety, depression, or cognitive distortions.

We consider MBI for Mr. B, which was devel­oped by Segal et al⁷ to help prevent relapse of depression and gain the benefits of MM. There is evidence that MBI can prevent relapse of SUDs.¹² Mr. B’s MBI practice is based on MBCT, as outlined by Segal et al.⁷ He attends biweekly, 45-minute therapy sessions at our outpatient clinic. During these sessions, MM is practiced for 10 minutes under a psychiatrist’s supervision. The MBCT manual calls for 45 minutes of MM practice but, during the 10-minute ses­sion, we instruct Mr. B to independently prac­tice MM at home. Mr. B is assessed for relapses, and drug cravings; a urine toxicology screen is performed every 6 months.

We score Mr. B’s day-to-day level of mindful­ness experience, depression, and anxiety symp­toms before starting MBI and after 8 weeks of practicing MBI (Figure 1). Mindfulness is scored with the Mindful Attention Awareness Scale (MAAS), a valid, reliable scale.¹³ The MAAS comprises 15 items designed to reflect mindfulness in everyday experiences, includ­ing awareness and attention to thoughts, emotions, actions, and physical states. Items are rated on a 6-point Likert-type scale of 1 (“almost never”) to 6 (“almost always”). A typ­ical item on MAAS is “I find myself doing things without paying attention.”

Depression and anxiety symptoms are mea­sured using the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder Scale-7 (GAD-7) Item Scale. Mr. B scores a 23 on PHQ-9, indicating severe depression (he reports that he finds it ‘‘extremely difficult” to function) (Figure 2).

There is evidence to support the use of PHQ-9 for measurement-based care in the psychiatric population.¹⁴ PHQ-9 does not capture anxiety, which is a strong predicator of suicidal behavior; therefore, we use GAD-7 to measure the sever­ity of Mr. B’s subjective anxiety.¹⁵ He scores a 14 on GAD-7 and reports that it is “very difficult” for him to function.

Mr. B is retested after 8 weeks. During those 8 weeks, he was instructed by audio guidance in body scan technique. He practices MBI tech­niques for 45 minutes every morning between 5 AM and 6 AM.⁶

After 3 months of MBI, Mr. B is promoted at work and reports that he is handling more responsibilities. He is stressed at his new job and, subsequently, experiences a relapse of anxiety symptoms and insomnia. Partly, this is because Mr. B is not able to consistently practice MBI and misses a few outpatient appointments. In the meantime, he has difficulties with sleep and con­centration and anxiety symptoms.

The treating psychiatrist reassures Mr. B and provides support to restart MBI. He man­ages to attend outpatient clinic appointments consistently and shows interest in practicing MBI daily. Later, he reports practicing MBI con­sistently along with his routine treatment at our clinic. The timeline of Mr. B’s history and treatment are summarized in Figure 3.

The authors’ observations
Mr. B’s CRF may have been down-regulated by MBI. This, in turn, decreased his depres­sive and anxiety symptoms, thereby helping to prevent relapse of depression and sub­stance abuse. He benefited from MBI prac­tices in several areas of his life, which can be described with the acronym FACES.¹⁰

Flexible. Mr. B became more cogni­tively flexible. He started to realize that “thoughts are not facts.”⁷ This change was reflected in his relationship with his wife. His wife came to one of our sessions because she noticed significant change in his attitude toward her. Their marriage of 15 years was riddled with conflict and his wife was excited to see the improvement he achieved within the short time of prac­ticing MBI.

Adaptive. He became more adaptive to changes at the work place and reported that he is enjoying his work. This is a change from his feeling that his job was a burden, as he observed in our earlier sessions.

Coherent. He became more cognitively rational. He reported improvement in his memory and concentration. Five months after initiation of MBI and MM training, he was promoted and could cope with the stress at work.

Energized. Initially, he had said that he never wanted to be part of his extended family. During a session toward the end of the treatment, he mentioned that he made an effort to contact his extended family and reported that he found it more meaningful now to be reconnected with them.

Stable. He became more emotionally stable. He did not have the urge to use drugs and he did not relapse.

As we hypothesized, for Mr. B, practic­ing MBI was associated with abstinence from substance use, increased mindfulness, acceptance of mental health problems, and remission of psychiatric symptoms.

Bottom Line
Mindfulness-based interventions provide patients with tools to target symptoms such as poor affect regulation, poor impulse control, and rumination. Evidence supports that using MBI in addition to the usual treatment can prevent relapse of a substance use disorder.

Related Resources
• Sipe WE, Eisendrath SJ. Mindfulness-based cognitive therapy: theory and practice. Can J Psychiatry. 2012;57(2):63-69.• Lau MA, Grabovac AD. Mindfulness-based interventions: Effective for depression and anxiety. Current Psychiatry. 2009;8(12):39-55.

Drug Brand Names
Aripiprazole • Abilify                               Mirtazapine • Remeron
Buprenorphine/naloxone •                       Quetiapine • Seroquel
Suboxone              
Bupropion • Wellbutrin                            Sertraline • Zoloft
Duloxetine • Cymbalta                            Trazodone • Desyrel
Methadone • Dolophine                           Venlafaxine • Effexor
Methylphenidate • Ritalin, Concerta

Acknowledgement
The manuscript preparation of Maju Mathew Koola, MD, DPM was supported by the NIMH T32 grant MH067533-07 (PI: William T. Carpenter, MD) and the American Psychiatric Association/Kempf Fund Award for Research Development in Psychobiological Psychiatry (PI: Koola). The treating Psychiatrist PGY-5 (2011-2012) Addiction Psychiatry fellow (Dr. Varghese) was supervised by Dr. Eiger. Drs. Koola and Varghese contributed equally with the manuscript preparation and are joint first authors. Dr. Varghese received a second prize for a poster presentation of this case re­port at the 34th Indo American Psychiatric Association meeting in San Francisco, CA, May 19, 2013. Christina Mathew, MD, also contributed with manuscript preparation.

Disclosures
The authors report no financial relationship with any company whose products are mentioned in this article or with manufactures of competing products.

Case Forgetful and depressed
Mr. B, age 55, has been a patient at our clinic for 8 years, where he has been under our care for treatment-resistant depression and opi­oid addiction [read about earlier events in his case in “A life of drugs and ‘downtime’” Current Psychiatry, August 2007, p. 98-103].¹ He reports feeling intermittently depressed since his teens and has had 3 near-fatal suicide attempts.

Three years ago, Mr. B reported severe depressive symptoms and short-term memory loss, which undermined his job performance and contributed to interpersonal conflict with his wife. The episode has been continuously severe for 10 months. He was taking sertra­line, 150 mg/d, and duloxetine, 60 mg/d, for major depressive disorder (MDD) and sublin­gual buprenorphine/naloxone, 20 mg/d, for opioid dependence, which was in sustained full remission.² Mr. B scored 24/30 in the Mini- Mental State Examination, indicating mild cognitive deficit. Negative results of a com­plete routine laboratory workup rule out an organic cause for his deteriorating cognition.

How would you diagnose Mr. B’s condition at this point?
   a) treatment-resistant MDD
   b) cognitive disorder not otherwise specified
   c) opioid use disorder
   d) a and c

The authors' observations
Relapse is a core feature of substance use dis­orders (SUDs) that contributes significantly to the longstanding functional impairment in patients with a mood disorder. With the relapse rate following substance use treat­ment estimated at more than 60%,³ SUDs often are described as chronic relapsing conditions. In chronic stress, corticotropin-releasing factor (CRF) is over-sensitized; we believe that acute stress can cause an unhealthy response to an over-expressed CRF system.

To prevent relapse in patients with an over-expressed CRF system, it is crucial to manage stress. One treatment option to con­sider in preventing relapse is mindfulness-based interventions (MBI). Mindfulness has been described as “paying attention in a particular way: on purpose, in the present moment, and non-judgmentally.” In the event of a relapse, awareness and acceptance fostered by mindfulness may aid in recogniz­ing and minimizing unhealthy responses, such as negative thinking that can increase the risk of relapse.

History Remission, then relapse
Mr. B was admitted to inpatient psychiatric unit after a near-fatal suicide attempt 8 years ago and given a diagnosis of MDD recurrent, severe with­out psychotic features. Trials of sertraline, bupro­pion, trazodone, quetiapine, and aripiprazole were ineffective.

Before he presented to our clinic 8 years ago, Mr. B had been taking venlafaxine, 75 mg/d, and mirtazapine, 30 mg at bedtime. His previous outpatient psychiatrist added methylphenidate, 40 mg/d, to augment the antidepressants, but this did not alleviate Mr. B’s depression.

At age 40, he entered a methadone pro­gram, began working steadily, and got married. Five years later, he stopped methadone (it is unclear from the chart if his psychiatrist initiated this change). Mr. B’s depression persisted while using opioids and became worse after stopping methadone.

We considered electroconvulsive therapy (ECT) at the time, but switching the anti­depressant or starting ECT would address only the persistent depression; buprenor­phine/naloxone would target opioid crav­ing. We started a trial of buprenorphine/ naloxone, a partial μ opioid agonist and ĸ opioid antagonist; ĸ receptor antagonism serves as an antidepressant. He responded well to augmentation of his current regimen (mirtazapine, 30 mg at bedtime, and venlafax­ine, 225 mg/d) with buprenorphine/naloxone, 16 mg/d.^4,5 he reported no anergia and said he felt more motivated and productive.

Mr. B took buprenorphine/naloxone, 32 mg/d, for 4 years until, because of concern for daytime sedation, his outpatient psychia­trist reduced the dose to 20 mg/d. With the lower dosage of buprenorphine/naloxone ini­tiated 4 years ago, Mr. B reported irritability, anhedonia, insomnia, increased self-criticism, and decreased self-care.

How would you treat Mr. B’s depression at this point?
   a) switch to a daytime antidepressant
   b) adjust the dosage of buprenorphine/ naloxone
   c) try ECT
   d) try mindfulness-based cognitive therapy

The authors’ observations
Mindfulness meditation (MM) is a medi­tation practice that cultivates awareness. While learning MM, the practitioner inten­tionally focuses on awareness—a way of purposely paying attention to the present moment, non-judgmentally, to nurture calmness and self-acceptance. Being con­scious of what the practitioner is doing while he is doing it is the core of mindful­ness practice.⁶

Mindfulness-based interventions. We rec­ommended the following forms of MBI to treat Mr. B:  
   • Mindfulness-based cognitive therapy (MBCT). MBCT is designed to help people who suffer repeated bouts of depression and chronic unhappiness. It combines the ideas of cognitive-behavioral therapy (CBT) with MM practices and attitudes based on culti­vating mindfulness.⁷  
   • Mindfulness-based stress reduction (MBSR). MBSR brings together MM and physical/breathing exercises to relax body and mind.⁶

Chronic stress and drug addiction
The literature demonstrates a significant association between acute and chronic stress and motivation to abuse substances. Stress mobilizes the CRF system to stimulate the hypothalamic-pituitary-adrenal (HPA) axis, and extra-hypothalamic actions of CRF can kindle the neuronal circuits responsible for stress-induced anxiety, dysphoria, and drug abuse behaviors.⁸

A study to evaluate effects of mindful­ness on young adult romantic partners’ HPA responses to conflict stress showed that MM has sex-specific effects on neu­roendocrine response to interpersonal stress.⁹ Research has shown that MM practice can decrease stress, increase well-being, and affect brain structure and func­tion.¹⁰ Meta-analysis of studies of animal models and humans described how spe­cific interventions intended to encourage pro-social behavior and well-being might produce plasticity-related changes in the brain.¹¹ This work concluded that, by tak­ing responsibility for the mind and the brain by participating in regular mental exercise, plastic changes in the brain pro­moted could produce lasting beneficial consequences for social and emotional behavior.¹¹

What could be perpetuating Mr. B’s depression?
   a) psychosocial stressors
   b) over-expression of CRF gene due to psychosocial stressors
   c) a and b

Treatment Mindfulness practice
Mr. B was started on CBT to manage anxiety symptoms and cognitive distortions. After 2 months, he reports no improvements in anx­iety, depression, or cognitive distortions.

We consider MBI for Mr. B, which was devel­oped by Segal et al⁷ to help prevent relapse of depression and gain the benefits of MM. There is evidence that MBI can prevent relapse of SUDs.¹² Mr. B’s MBI practice is based on MBCT, as outlined by Segal et al.⁷ He attends biweekly, 45-minute therapy sessions at our outpatient clinic. During these sessions, MM is practiced for 10 minutes under a psychiatrist’s supervision. The MBCT manual calls for 45 minutes of MM practice but, during the 10-minute ses­sion, we instruct Mr. B to independently prac­tice MM at home. Mr. B is assessed for relapses, and drug cravings; a urine toxicology screen is performed every 6 months.

We score Mr. B’s day-to-day level of mindful­ness experience, depression, and anxiety symp­toms before starting MBI and after 8 weeks of practicing MBI (Figure 1). Mindfulness is scored with the Mindful Attention Awareness Scale (MAAS), a valid, reliable scale.¹³ The MAAS comprises 15 items designed to reflect mindfulness in everyday experiences, includ­ing awareness and attention to thoughts, emotions, actions, and physical states. Items are rated on a 6-point Likert-type scale of 1 (“almost never”) to 6 (“almost always”). A typ­ical item on MAAS is “I find myself doing things without paying attention.”

Depression and anxiety symptoms are mea­sured using the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder Scale-7 (GAD-7) Item Scale. Mr. B scores a 23 on PHQ-9, indicating severe depression (he reports that he finds it ‘‘extremely difficult” to function) (Figure 2).

There is evidence to support the use of PHQ-9 for measurement-based care in the psychiatric population.¹⁴ PHQ-9 does not capture anxiety, which is a strong predicator of suicidal behavior; therefore, we use GAD-7 to measure the sever­ity of Mr. B’s subjective anxiety.¹⁵ He scores a 14 on GAD-7 and reports that it is “very difficult” for him to function.

Mr. B is retested after 8 weeks. During those 8 weeks, he was instructed by audio guidance in body scan technique. He practices MBI tech­niques for 45 minutes every morning between 5 AM and 6 AM.⁶

After 3 months of MBI, Mr. B is promoted at work and reports that he is handling more responsibilities. He is stressed at his new job and, subsequently, experiences a relapse of anxiety symptoms and insomnia. Partly, this is because Mr. B is not able to consistently practice MBI and misses a few outpatient appointments. In the meantime, he has difficulties with sleep and con­centration and anxiety symptoms.

The treating psychiatrist reassures Mr. B and provides support to restart MBI. He man­ages to attend outpatient clinic appointments consistently and shows interest in practicing MBI daily. Later, he reports practicing MBI con­sistently along with his routine treatment at our clinic. The timeline of Mr. B’s history and treatment are summarized in Figure 3.

The authors’ observations
Mr. B’s CRF may have been down-regulated by MBI. This, in turn, decreased his depres­sive and anxiety symptoms, thereby helping to prevent relapse of depression and sub­stance abuse. He benefited from MBI prac­tices in several areas of his life, which can be described with the acronym FACES.¹⁰

Flexible. Mr. B became more cogni­tively flexible. He started to realize that “thoughts are not facts.”⁷ This change was reflected in his relationship with his wife. His wife came to one of our sessions because she noticed significant change in his attitude toward her. Their marriage of 15 years was riddled with conflict and his wife was excited to see the improvement he achieved within the short time of prac­ticing MBI.

Adaptive. He became more adaptive to changes at the work place and reported that he is enjoying his work. This is a change from his feeling that his job was a burden, as he observed in our earlier sessions.

Coherent. He became more cognitively rational. He reported improvement in his memory and concentration. Five months after initiation of MBI and MM training, he was promoted and could cope with the stress at work.

Energized. Initially, he had said that he never wanted to be part of his extended family. During a session toward the end of the treatment, he mentioned that he made an effort to contact his extended family and reported that he found it more meaningful now to be reconnected with them.

Stable. He became more emotionally stable. He did not have the urge to use drugs and he did not relapse.

As we hypothesized, for Mr. B, practic­ing MBI was associated with abstinence from substance use, increased mindfulness, acceptance of mental health problems, and remission of psychiatric symptoms.

Bottom Line
Mindfulness-based interventions provide patients with tools to target symptoms such as poor affect regulation, poor impulse control, and rumination. Evidence supports that using MBI in addition to the usual treatment can prevent relapse of a substance use disorder.

Related Resources
• Sipe WE, Eisendrath SJ. Mindfulness-based cognitive therapy: theory and practice. Can J Psychiatry. 2012;57(2):63-69.• Lau MA, Grabovac AD. Mindfulness-based interventions: Effective for depression and anxiety. Current Psychiatry. 2009;8(12):39-55.

Drug Brand Names
Aripiprazole • Abilify                               Mirtazapine • Remeron
Buprenorphine/naloxone •                       Quetiapine • Seroquel
Suboxone              
Bupropion • Wellbutrin                            Sertraline • Zoloft
Duloxetine • Cymbalta                            Trazodone • Desyrel
Methadone • Dolophine                           Venlafaxine • Effexor
Methylphenidate • Ritalin, Concerta

Acknowledgement
The manuscript preparation of Maju Mathew Koola, MD, DPM was supported by the NIMH T32 grant MH067533-07 (PI: William T. Carpenter, MD) and the American Psychiatric Association/Kempf Fund Award for Research Development in Psychobiological Psychiatry (PI: Koola). The treating Psychiatrist PGY-5 (2011-2012) Addiction Psychiatry fellow (Dr. Varghese) was supervised by Dr. Eiger. Drs. Koola and Varghese contributed equally with the manuscript preparation and are joint first authors. Dr. Varghese received a second prize for a poster presentation of this case re­port at the 34th Indo American Psychiatric Association meeting in San Francisco, CA, May 19, 2013. Christina Mathew, MD, also contributed with manuscript preparation.

Disclosures
The authors report no financial relationship with any company whose products are mentioned in this article or with manufactures of competing products.

Case Forgetful and depressed
Mr. B, age 55, has been a patient at our clinic for 8 years, where he has been under our care for treatment-resistant depression and opi­oid addiction [read about earlier events in his case in “A life of drugs and ‘downtime’” Current Psychiatry, August 2007, p. 98-103].¹ He reports feeling intermittently depressed since his teens and has had 3 near-fatal suicide attempts.

Three years ago, Mr. B reported severe depressive symptoms and short-term memory loss, which undermined his job performance and contributed to interpersonal conflict with his wife. The episode has been continuously severe for 10 months. He was taking sertra­line, 150 mg/d, and duloxetine, 60 mg/d, for major depressive disorder (MDD) and sublin­gual buprenorphine/naloxone, 20 mg/d, for opioid dependence, which was in sustained full remission.² Mr. B scored 24/30 in the Mini- Mental State Examination, indicating mild cognitive deficit. Negative results of a com­plete routine laboratory workup rule out an organic cause for his deteriorating cognition.

How would you diagnose Mr. B’s condition at this point?
   a) treatment-resistant MDD
   b) cognitive disorder not otherwise specified
   c) opioid use disorder
   d) a and c

The authors' observations
Relapse is a core feature of substance use dis­orders (SUDs) that contributes significantly to the longstanding functional impairment in patients with a mood disorder. With the relapse rate following substance use treat­ment estimated at more than 60%,³ SUDs often are described as chronic relapsing conditions. In chronic stress, corticotropin-releasing factor (CRF) is over-sensitized; we believe that acute stress can cause an unhealthy response to an over-expressed CRF system.

To prevent relapse in patients with an over-expressed CRF system, it is crucial to manage stress. One treatment option to con­sider in preventing relapse is mindfulness-based interventions (MBI). Mindfulness has been described as “paying attention in a particular way: on purpose, in the present moment, and non-judgmentally.” In the event of a relapse, awareness and acceptance fostered by mindfulness may aid in recogniz­ing and minimizing unhealthy responses, such as negative thinking that can increase the risk of relapse.

History Remission, then relapse
Mr. B was admitted to inpatient psychiatric unit after a near-fatal suicide attempt 8 years ago and given a diagnosis of MDD recurrent, severe with­out psychotic features. Trials of sertraline, bupro­pion, trazodone, quetiapine, and aripiprazole were ineffective.

Before he presented to our clinic 8 years ago, Mr. B had been taking venlafaxine, 75 mg/d, and mirtazapine, 30 mg at bedtime. His previous outpatient psychiatrist added methylphenidate, 40 mg/d, to augment the antidepressants, but this did not alleviate Mr. B’s depression.

At age 40, he entered a methadone pro­gram, began working steadily, and got married. Five years later, he stopped methadone (it is unclear from the chart if his psychiatrist initiated this change). Mr. B’s depression persisted while using opioids and became worse after stopping methadone.

We considered electroconvulsive therapy (ECT) at the time, but switching the anti­depressant or starting ECT would address only the persistent depression; buprenor­phine/naloxone would target opioid crav­ing. We started a trial of buprenorphine/ naloxone, a partial μ opioid agonist and ĸ opioid antagonist; ĸ receptor antagonism serves as an antidepressant. He responded well to augmentation of his current regimen (mirtazapine, 30 mg at bedtime, and venlafax­ine, 225 mg/d) with buprenorphine/naloxone, 16 mg/d.^4,5 he reported no anergia and said he felt more motivated and productive.

Mr. B took buprenorphine/naloxone, 32 mg/d, for 4 years until, because of concern for daytime sedation, his outpatient psychia­trist reduced the dose to 20 mg/d. With the lower dosage of buprenorphine/naloxone ini­tiated 4 years ago, Mr. B reported irritability, anhedonia, insomnia, increased self-criticism, and decreased self-care.

How would you treat Mr. B’s depression at this point?
   a) switch to a daytime antidepressant
   b) adjust the dosage of buprenorphine/ naloxone
   c) try ECT
   d) try mindfulness-based cognitive therapy

The authors’ observations
Mindfulness meditation (MM) is a medi­tation practice that cultivates awareness. While learning MM, the practitioner inten­tionally focuses on awareness—a way of purposely paying attention to the present moment, non-judgmentally, to nurture calmness and self-acceptance. Being con­scious of what the practitioner is doing while he is doing it is the core of mindful­ness practice.⁶

Mindfulness-based interventions. We rec­ommended the following forms of MBI to treat Mr. B:  
   • Mindfulness-based cognitive therapy (MBCT). MBCT is designed to help people who suffer repeated bouts of depression and chronic unhappiness. It combines the ideas of cognitive-behavioral therapy (CBT) with MM practices and attitudes based on culti­vating mindfulness.⁷  
   • Mindfulness-based stress reduction (MBSR). MBSR brings together MM and physical/breathing exercises to relax body and mind.⁶

Chronic stress and drug addiction
The literature demonstrates a significant association between acute and chronic stress and motivation to abuse substances. Stress mobilizes the CRF system to stimulate the hypothalamic-pituitary-adrenal (HPA) axis, and extra-hypothalamic actions of CRF can kindle the neuronal circuits responsible for stress-induced anxiety, dysphoria, and drug abuse behaviors.⁸

A study to evaluate effects of mindful­ness on young adult romantic partners’ HPA responses to conflict stress showed that MM has sex-specific effects on neu­roendocrine response to interpersonal stress.⁹ Research has shown that MM practice can decrease stress, increase well-being, and affect brain structure and func­tion.¹⁰ Meta-analysis of studies of animal models and humans described how spe­cific interventions intended to encourage pro-social behavior and well-being might produce plasticity-related changes in the brain.¹¹ This work concluded that, by tak­ing responsibility for the mind and the brain by participating in regular mental exercise, plastic changes in the brain pro­moted could produce lasting beneficial consequences for social and emotional behavior.¹¹

What could be perpetuating Mr. B’s depression?
   a) psychosocial stressors
   b) over-expression of CRF gene due to psychosocial stressors
   c) a and b

Treatment Mindfulness practice
Mr. B was started on CBT to manage anxiety symptoms and cognitive distortions. After 2 months, he reports no improvements in anx­iety, depression, or cognitive distortions.

We consider MBI for Mr. B, which was devel­oped by Segal et al⁷ to help prevent relapse of depression and gain the benefits of MM. There is evidence that MBI can prevent relapse of SUDs.¹² Mr. B’s MBI practice is based on MBCT, as outlined by Segal et al.⁷ He attends biweekly, 45-minute therapy sessions at our outpatient clinic. During these sessions, MM is practiced for 10 minutes under a psychiatrist’s supervision. The MBCT manual calls for 45 minutes of MM practice but, during the 10-minute ses­sion, we instruct Mr. B to independently prac­tice MM at home. Mr. B is assessed for relapses, and drug cravings; a urine toxicology screen is performed every 6 months.

We score Mr. B’s day-to-day level of mindful­ness experience, depression, and anxiety symp­toms before starting MBI and after 8 weeks of practicing MBI (Figure 1). Mindfulness is scored with the Mindful Attention Awareness Scale (MAAS), a valid, reliable scale.¹³ The MAAS comprises 15 items designed to reflect mindfulness in everyday experiences, includ­ing awareness and attention to thoughts, emotions, actions, and physical states. Items are rated on a 6-point Likert-type scale of 1 (“almost never”) to 6 (“almost always”). A typ­ical item on MAAS is “I find myself doing things without paying attention.”

Depression and anxiety symptoms are mea­sured using the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder Scale-7 (GAD-7) Item Scale. Mr. B scores a 23 on PHQ-9, indicating severe depression (he reports that he finds it ‘‘extremely difficult” to function) (Figure 2).

There is evidence to support the use of PHQ-9 for measurement-based care in the psychiatric population.¹⁴ PHQ-9 does not capture anxiety, which is a strong predicator of suicidal behavior; therefore, we use GAD-7 to measure the sever­ity of Mr. B’s subjective anxiety.¹⁵ He scores a 14 on GAD-7 and reports that it is “very difficult” for him to function.

Mr. B is retested after 8 weeks. During those 8 weeks, he was instructed by audio guidance in body scan technique. He practices MBI tech­niques for 45 minutes every morning between 5 AM and 6 AM.⁶

After 3 months of MBI, Mr. B is promoted at work and reports that he is handling more responsibilities. He is stressed at his new job and, subsequently, experiences a relapse of anxiety symptoms and insomnia. Partly, this is because Mr. B is not able to consistently practice MBI and misses a few outpatient appointments. In the meantime, he has difficulties with sleep and con­centration and anxiety symptoms.

The treating psychiatrist reassures Mr. B and provides support to restart MBI. He man­ages to attend outpatient clinic appointments consistently and shows interest in practicing MBI daily. Later, he reports practicing MBI con­sistently along with his routine treatment at our clinic. The timeline of Mr. B’s history and treatment are summarized in Figure 3.

The authors’ observations
Mr. B’s CRF may have been down-regulated by MBI. This, in turn, decreased his depres­sive and anxiety symptoms, thereby helping to prevent relapse of depression and sub­stance abuse. He benefited from MBI prac­tices in several areas of his life, which can be described with the acronym FACES.¹⁰

Flexible. Mr. B became more cogni­tively flexible. He started to realize that “thoughts are not facts.”⁷ This change was reflected in his relationship with his wife. His wife came to one of our sessions because she noticed significant change in his attitude toward her. Their marriage of 15 years was riddled with conflict and his wife was excited to see the improvement he achieved within the short time of prac­ticing MBI.

Adaptive. He became more adaptive to changes at the work place and reported that he is enjoying his work. This is a change from his feeling that his job was a burden, as he observed in our earlier sessions.

Coherent. He became more cognitively rational. He reported improvement in his memory and concentration. Five months after initiation of MBI and MM training, he was promoted and could cope with the stress at work.

Energized. Initially, he had said that he never wanted to be part of his extended family. During a session toward the end of the treatment, he mentioned that he made an effort to contact his extended family and reported that he found it more meaningful now to be reconnected with them.

Stable. He became more emotionally stable. He did not have the urge to use drugs and he did not relapse.

As we hypothesized, for Mr. B, practic­ing MBI was associated with abstinence from substance use, increased mindfulness, acceptance of mental health problems, and remission of psychiatric symptoms.

Bottom Line
Mindfulness-based interventions provide patients with tools to target symptoms such as poor affect regulation, poor impulse control, and rumination. Evidence supports that using MBI in addition to the usual treatment can prevent relapse of a substance use disorder.

Related Resources
• Sipe WE, Eisendrath SJ. Mindfulness-based cognitive therapy: theory and practice. Can J Psychiatry. 2012;57(2):63-69.• Lau MA, Grabovac AD. Mindfulness-based interventions: Effective for depression and anxiety. Current Psychiatry. 2009;8(12):39-55.

Drug Brand Names
Aripiprazole • Abilify                               Mirtazapine • Remeron
Buprenorphine/naloxone •                       Quetiapine • Seroquel
Suboxone              
Bupropion • Wellbutrin                            Sertraline • Zoloft
Duloxetine • Cymbalta                            Trazodone • Desyrel
Methadone • Dolophine                           Venlafaxine • Effexor
Methylphenidate • Ritalin, Concerta

Acknowledgement
The manuscript preparation of Maju Mathew Koola, MD, DPM was supported by the NIMH T32 grant MH067533-07 (PI: William T. Carpenter, MD) and the American Psychiatric Association/Kempf Fund Award for Research Development in Psychobiological Psychiatry (PI: Koola). The treating Psychiatrist PGY-5 (2011-2012) Addiction Psychiatry fellow (Dr. Varghese) was supervised by Dr. Eiger. Drs. Koola and Varghese contributed equally with the manuscript preparation and are joint first authors. Dr. Varghese received a second prize for a poster presentation of this case re­port at the 34th Indo American Psychiatric Association meeting in San Francisco, CA, May 19, 2013. Christina Mathew, MD, also contributed with manuscript preparation.

Disclosures
The authors report no financial relationship with any company whose products are mentioned in this article or with manufactures of competing products.

Mild cognitive impairment (MCI) is a transitional clinical stage between normal aging and demen­tia. Together with aging, it is considered the most significant risk factor for developing dementia, often the Alzheimer’s type.¹

MCI is a challenging neuropsychiat­ric diagnosis to discuss with patients and their family because it is characterized by overlapping features of normal aging and because of its heterogeneity of etiol­ogy, clinical presentation, and outcome.^2,3 The evolution to dementia and the lack of effective treatments for preventing or forestalling this outcome can be difficult to address—particularly when the patient is in good health and has been leading a productive life.

Successful communication is key
You can take steps to communicate in a helpful way, build a strong treatment alli­ance, and reduce the potential for the iat­rogenic effects of disclosing this diagnosis and its prognostic implications.

Clarify that your findings are consistent with the patient’s or family’s report of sustained and concerning change in cog­nition and, depending on the patient, concurrent alterations in affect, behavior, or both. Emphasize that these changes are disproportionately severe relative to expectations for the patient’s age and are not caused by psychiatric or clear-cut medical factors.

Highlight contexts in which the patient’s symptoms are likely to become more dis­ruptive and impaired, and situations in which the patient can be expected to func­tion more effectively.

Provide evidence-based support for the rate of progression of symptoms and func­tional impairment.³

Emphasize that major lifestyle adjust­ments usually are unnecessary in the absence of progression, especially for patients who are retired or not involved in endeavors that involve significant cogni­tive and executive functioning demands.

Discuss the role that cognition-enhancing medications might play in managing symptoms.⁴

Address indications for additional services, including formal psychiatric care for patients who have concomitant affec­tive or behavioral symptoms and who are highly distressed by the diagnosis. Pair these services with longitudinal monitor­ing for possible exacerbation of symptoms.

Identify psychiatric, medical, and life­style factors that can increase the risk of dementia. Depending on the patient’s history, this might include diabetes, hypertension, elevated lipid levels, obe­sity, smoking, head trauma, depres­sion, physical inactivity, and lack of intellectual stimulation.

Review compensatory strategies. In MCI predominantly amnestic type, for example, having the patient make system­atic lists for shopping and other activities of daily living, as well as establishing rou­tines for organizaton, can bolster success­ful coping.

If psychometric testing was not utilized to establish the diagnosis, discussion can include the value of performing such an assessment for a more finely tuned profile of preserved and impaired neurobehavioral functions. Such a profile can include test patterns that 1) have prognostic value with regard to the likelihood of progression to dementia and 2) establish a baseline against which you can assess stability or progression over time.⁵

Disclosure
Dr. Pollak reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Mild cognitive impairment (MCI) is a transitional clinical stage between normal aging and demen­tia. Together with aging, it is considered the most significant risk factor for developing dementia, often the Alzheimer’s type.¹

MCI is a challenging neuropsychiat­ric diagnosis to discuss with patients and their family because it is characterized by overlapping features of normal aging and because of its heterogeneity of etiol­ogy, clinical presentation, and outcome.^2,3 The evolution to dementia and the lack of effective treatments for preventing or forestalling this outcome can be difficult to address—particularly when the patient is in good health and has been leading a productive life.

Successful communication is key
You can take steps to communicate in a helpful way, build a strong treatment alli­ance, and reduce the potential for the iat­rogenic effects of disclosing this diagnosis and its prognostic implications.

Clarify that your findings are consistent with the patient’s or family’s report of sustained and concerning change in cog­nition and, depending on the patient, concurrent alterations in affect, behavior, or both. Emphasize that these changes are disproportionately severe relative to expectations for the patient’s age and are not caused by psychiatric or clear-cut medical factors.

Highlight contexts in which the patient’s symptoms are likely to become more dis­ruptive and impaired, and situations in which the patient can be expected to func­tion more effectively.

Provide evidence-based support for the rate of progression of symptoms and func­tional impairment.³

Emphasize that major lifestyle adjust­ments usually are unnecessary in the absence of progression, especially for patients who are retired or not involved in endeavors that involve significant cogni­tive and executive functioning demands.

Discuss the role that cognition-enhancing medications might play in managing symptoms.⁴

Address indications for additional services, including formal psychiatric care for patients who have concomitant affec­tive or behavioral symptoms and who are highly distressed by the diagnosis. Pair these services with longitudinal monitor­ing for possible exacerbation of symptoms.

Identify psychiatric, medical, and life­style factors that can increase the risk of dementia. Depending on the patient’s history, this might include diabetes, hypertension, elevated lipid levels, obe­sity, smoking, head trauma, depres­sion, physical inactivity, and lack of intellectual stimulation.

Review compensatory strategies. In MCI predominantly amnestic type, for example, having the patient make system­atic lists for shopping and other activities of daily living, as well as establishing rou­tines for organizaton, can bolster success­ful coping.

If psychometric testing was not utilized to establish the diagnosis, discussion can include the value of performing such an assessment for a more finely tuned profile of preserved and impaired neurobehavioral functions. Such a profile can include test patterns that 1) have prognostic value with regard to the likelihood of progression to dementia and 2) establish a baseline against which you can assess stability or progression over time.⁵

Disclosure
Dr. Pollak reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Mild cognitive impairment (MCI) is a transitional clinical stage between normal aging and demen­tia. Together with aging, it is considered the most significant risk factor for developing dementia, often the Alzheimer’s type.¹

MCI is a challenging neuropsychiat­ric diagnosis to discuss with patients and their family because it is characterized by overlapping features of normal aging and because of its heterogeneity of etiol­ogy, clinical presentation, and outcome.^2,3 The evolution to dementia and the lack of effective treatments for preventing or forestalling this outcome can be difficult to address—particularly when the patient is in good health and has been leading a productive life.

Successful communication is key
You can take steps to communicate in a helpful way, build a strong treatment alli­ance, and reduce the potential for the iat­rogenic effects of disclosing this diagnosis and its prognostic implications.

Clarify that your findings are consistent with the patient’s or family’s report of sustained and concerning change in cog­nition and, depending on the patient, concurrent alterations in affect, behavior, or both. Emphasize that these changes are disproportionately severe relative to expectations for the patient’s age and are not caused by psychiatric or clear-cut medical factors.

Highlight contexts in which the patient’s symptoms are likely to become more dis­ruptive and impaired, and situations in which the patient can be expected to func­tion more effectively.

Provide evidence-based support for the rate of progression of symptoms and func­tional impairment.³

Emphasize that major lifestyle adjust­ments usually are unnecessary in the absence of progression, especially for patients who are retired or not involved in endeavors that involve significant cogni­tive and executive functioning demands.

Discuss the role that cognition-enhancing medications might play in managing symptoms.⁴

Address indications for additional services, including formal psychiatric care for patients who have concomitant affec­tive or behavioral symptoms and who are highly distressed by the diagnosis. Pair these services with longitudinal monitor­ing for possible exacerbation of symptoms.

Identify psychiatric, medical, and life­style factors that can increase the risk of dementia. Depending on the patient’s history, this might include diabetes, hypertension, elevated lipid levels, obe­sity, smoking, head trauma, depres­sion, physical inactivity, and lack of intellectual stimulation.

Review compensatory strategies. In MCI predominantly amnestic type, for example, having the patient make system­atic lists for shopping and other activities of daily living, as well as establishing rou­tines for organizaton, can bolster success­ful coping.

If psychometric testing was not utilized to establish the diagnosis, discussion can include the value of performing such an assessment for a more finely tuned profile of preserved and impaired neurobehavioral functions. Such a profile can include test patterns that 1) have prognostic value with regard to the likelihood of progression to dementia and 2) establish a baseline against which you can assess stability or progression over time.⁵

Disclosure
Dr. Pollak reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Severe and enduring anorexia ner­vosa (SE-AN) is persistent anorexia nervosa (AN) lasting for ≥7 years with or without a history of treat­ment. Evidence points to the effec­tiveness of a patient-tailored plan for treating SE-AN over any universal fix. Proper medication, therapeutic alliance, and strategic discharge planning are the ingre­dients for treating SE-AN that avoids re-hospitalization (Table).

Nutritional support and pharmacotherapy required
Comprehensive metabolic analysis and initiating nutrition should be the first pri­ority for the medical team. Starved-state patients can have electrolyte and metabolic derangements that place them at risk of fatal arrhythmias or multi-system organ failure. Do not hesitate to initiate nasogastric tube feeding under the observation of a certified nutritionist when necessary for survival. A double-blind, randomized controlled trial demonstrated the benefit of olanzap­ine compared with placebo to increase body mass index (BMI) of hospitalized AN patients. Olanzapine was titrated from 2.5 to 10 mg/d over a 13-week period, and was associated with higher patient achieve­ment of a BMI > 18.5 kg/m2.¹

Although the patient is receiving nutri­tional support in conjunction with psycho­tropic medication, the road to BMI recovery can be long. Don’t forget that SE-AN can be incapacitating. In SE-AN, the fear of gaining weight is so severe that the idea of starvation-induced death initially might seem more palatable. Although counterintuitive, as the patient recovers metabolically, self-image deteriorates. Statements praising any new weight gain can derail any therapeutic relationship.

Therapeutic alliance is key
Establishing high-quality therapeutic alliance, as measured by the Helping Relationships Questionnaire, has been shown to have a positive outcome on eating disorder symptoms and comorbid depressed mood in later phases of SE-AN treatment.^2,3 Although therapeutic alliance is individual­ized, maintaining open communication and reiterating how it is the patient’s decision to consume whole food at a level at which the feeding tube can be discontinued are good places to start treatment.

Proper discharge timing and transition to outpatient care for SE-AN patients is paramount. In multicenter studies, treat­ment ends too early in 57.8% of patients; discharge at sub-ideal BMI is linked to rehospitalization.³ Slower weight gain and delayed establishment of therapeutic alli­ance are predictors of patients who exit treatment programs too early.³ Clinicians who remain vigilant for the above metrics are less likely to feed into the unacceptably high rate of treatment failure for SE-AN.

Disclosures
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Severe and enduring anorexia ner­vosa (SE-AN) is persistent anorexia nervosa (AN) lasting for ≥7 years with or without a history of treat­ment. Evidence points to the effec­tiveness of a patient-tailored plan for treating SE-AN over any universal fix. Proper medication, therapeutic alliance, and strategic discharge planning are the ingre­dients for treating SE-AN that avoids re-hospitalization (Table).

Nutritional support and pharmacotherapy required
Comprehensive metabolic analysis and initiating nutrition should be the first pri­ority for the medical team. Starved-state patients can have electrolyte and metabolic derangements that place them at risk of fatal arrhythmias or multi-system organ failure. Do not hesitate to initiate nasogastric tube feeding under the observation of a certified nutritionist when necessary for survival. A double-blind, randomized controlled trial demonstrated the benefit of olanzap­ine compared with placebo to increase body mass index (BMI) of hospitalized AN patients. Olanzapine was titrated from 2.5 to 10 mg/d over a 13-week period, and was associated with higher patient achieve­ment of a BMI > 18.5 kg/m2.¹

Although the patient is receiving nutri­tional support in conjunction with psycho­tropic medication, the road to BMI recovery can be long. Don’t forget that SE-AN can be incapacitating. In SE-AN, the fear of gaining weight is so severe that the idea of starvation-induced death initially might seem more palatable. Although counterintuitive, as the patient recovers metabolically, self-image deteriorates. Statements praising any new weight gain can derail any therapeutic relationship.

Therapeutic alliance is key
Establishing high-quality therapeutic alliance, as measured by the Helping Relationships Questionnaire, has been shown to have a positive outcome on eating disorder symptoms and comorbid depressed mood in later phases of SE-AN treatment.^2,3 Although therapeutic alliance is individual­ized, maintaining open communication and reiterating how it is the patient’s decision to consume whole food at a level at which the feeding tube can be discontinued are good places to start treatment.

Proper discharge timing and transition to outpatient care for SE-AN patients is paramount. In multicenter studies, treat­ment ends too early in 57.8% of patients; discharge at sub-ideal BMI is linked to rehospitalization.³ Slower weight gain and delayed establishment of therapeutic alli­ance are predictors of patients who exit treatment programs too early.³ Clinicians who remain vigilant for the above metrics are less likely to feed into the unacceptably high rate of treatment failure for SE-AN.

Disclosures
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Severe and enduring anorexia ner­vosa (SE-AN) is persistent anorexia nervosa (AN) lasting for ≥7 years with or without a history of treat­ment. Evidence points to the effec­tiveness of a patient-tailored plan for treating SE-AN over any universal fix. Proper medication, therapeutic alliance, and strategic discharge planning are the ingre­dients for treating SE-AN that avoids re-hospitalization (Table).

Nutritional support and pharmacotherapy required
Comprehensive metabolic analysis and initiating nutrition should be the first pri­ority for the medical team. Starved-state patients can have electrolyte and metabolic derangements that place them at risk of fatal arrhythmias or multi-system organ failure. Do not hesitate to initiate nasogastric tube feeding under the observation of a certified nutritionist when necessary for survival. A double-blind, randomized controlled trial demonstrated the benefit of olanzap­ine compared with placebo to increase body mass index (BMI) of hospitalized AN patients. Olanzapine was titrated from 2.5 to 10 mg/d over a 13-week period, and was associated with higher patient achieve­ment of a BMI > 18.5 kg/m2.¹

Although the patient is receiving nutri­tional support in conjunction with psycho­tropic medication, the road to BMI recovery can be long. Don’t forget that SE-AN can be incapacitating. In SE-AN, the fear of gaining weight is so severe that the idea of starvation-induced death initially might seem more palatable. Although counterintuitive, as the patient recovers metabolically, self-image deteriorates. Statements praising any new weight gain can derail any therapeutic relationship.

Therapeutic alliance is key
Establishing high-quality therapeutic alliance, as measured by the Helping Relationships Questionnaire, has been shown to have a positive outcome on eating disorder symptoms and comorbid depressed mood in later phases of SE-AN treatment.^2,3 Although therapeutic alliance is individual­ized, maintaining open communication and reiterating how it is the patient’s decision to consume whole food at a level at which the feeding tube can be discontinued are good places to start treatment.

Proper discharge timing and transition to outpatient care for SE-AN patients is paramount. In multicenter studies, treat­ment ends too early in 57.8% of patients; discharge at sub-ideal BMI is linked to rehospitalization.³ Slower weight gain and delayed establishment of therapeutic alli­ance are predictors of patients who exit treatment programs too early.³ Clinicians who remain vigilant for the above metrics are less likely to feed into the unacceptably high rate of treatment failure for SE-AN.

Disclosures
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Doctor and patient in hospital

Credit: CDC

New research indicates that anticoagulant therapy alone may be safer than catheter-directed thrombolysis (CDT) for treating deep vein thrombosis (DVT).

The study revealed similar rates of in-hospital mortality among patients treated with CDT and those receiving anticoagulation alone.

However, patients who received CDT were more likely to develop pulmonary emboli, experience intracranial hemorrhaging, and require blood transfusions.

Several previous studies have suggested that CDT can reduce the incidence of post-thrombotic syndrome in DVT patients. But CDT is controversial, with conflicting directives on its use because of inconclusive comparative safety outcomes.

So Riyaz Bashir, MD, of Temple University School of Medicine in Philadelphia, Pennsylvania, and his colleagues set out to compare CDT with anticoagulation alone.

They reported their findings in JAMA Internal Medicine.

The researchers examined in-hospital mortality, as well as secondary outcomes of bleeding complications, length of stay, and hospital charges, in a group of 90,618 patients hospitalized for DVT from 2005 through 2010 as part of the Nationwide Inpatient Sample database.

In all, 3649 patients (4.1%) underwent CDT. The CDT utilization rate increased from 2.3% in 2005 to 5.9% in 2010.

The in-hospital mortality rates were not significantly different in the CDT and anticoagulation-only groups, at 1.2% and 0.9%, respectively (P=0.15).

However, rates of adverse events were higher among patients treated with CDT. This included blood transfusion (11.1% vs 6.5%, P<0.001), pulmonary embolism (17.9% vs 11.4%, P<0.001), intracranial hemorrhage (0.9% vs 0.3%, P=0.03), and vena cava filter placement (34.8% vs 15.6%, P<0.001).

Patients in the CDT group also had longer average lengths of stay (7.2 vs 5 days, P<0.001) and higher hospital charges ($85,094 vs $28,164, P<0.001) compared with the anticoagulation-only group.

The researchers pointed out that their results are based on observational data, so the findings could be subject to residual confounding. Therefore, randomized trials are needed to better evaluate the effects of CDT.

However, the team also said that, as we don’t yet have this information, it may be reasonable to restrict CDT use to those patients who have a low bleeding risk and a high risk for post-thrombotic syndrome.

Doctor and patient in hospital

Credit: CDC

New research indicates that anticoagulant therapy alone may be safer than catheter-directed thrombolysis (CDT) for treating deep vein thrombosis (DVT).

The study revealed similar rates of in-hospital mortality among patients treated with CDT and those receiving anticoagulation alone.

However, patients who received CDT were more likely to develop pulmonary emboli, experience intracranial hemorrhaging, and require blood transfusions.

Several previous studies have suggested that CDT can reduce the incidence of post-thrombotic syndrome in DVT patients. But CDT is controversial, with conflicting directives on its use because of inconclusive comparative safety outcomes.

So Riyaz Bashir, MD, of Temple University School of Medicine in Philadelphia, Pennsylvania, and his colleagues set out to compare CDT with anticoagulation alone.

They reported their findings in JAMA Internal Medicine.

The researchers examined in-hospital mortality, as well as secondary outcomes of bleeding complications, length of stay, and hospital charges, in a group of 90,618 patients hospitalized for DVT from 2005 through 2010 as part of the Nationwide Inpatient Sample database.

In all, 3649 patients (4.1%) underwent CDT. The CDT utilization rate increased from 2.3% in 2005 to 5.9% in 2010.

The in-hospital mortality rates were not significantly different in the CDT and anticoagulation-only groups, at 1.2% and 0.9%, respectively (P=0.15).

However, rates of adverse events were higher among patients treated with CDT. This included blood transfusion (11.1% vs 6.5%, P<0.001), pulmonary embolism (17.9% vs 11.4%, P<0.001), intracranial hemorrhage (0.9% vs 0.3%, P=0.03), and vena cava filter placement (34.8% vs 15.6%, P<0.001).

Patients in the CDT group also had longer average lengths of stay (7.2 vs 5 days, P<0.001) and higher hospital charges ($85,094 vs $28,164, P<0.001) compared with the anticoagulation-only group.

The researchers pointed out that their results are based on observational data, so the findings could be subject to residual confounding. Therefore, randomized trials are needed to better evaluate the effects of CDT.

However, the team also said that, as we don’t yet have this information, it may be reasonable to restrict CDT use to those patients who have a low bleeding risk and a high risk for post-thrombotic syndrome.

Doctor and patient in hospital

Credit: CDC

New research indicates that anticoagulant therapy alone may be safer than catheter-directed thrombolysis (CDT) for treating deep vein thrombosis (DVT).

The study revealed similar rates of in-hospital mortality among patients treated with CDT and those receiving anticoagulation alone.

However, patients who received CDT were more likely to develop pulmonary emboli, experience intracranial hemorrhaging, and require blood transfusions.

Several previous studies have suggested that CDT can reduce the incidence of post-thrombotic syndrome in DVT patients. But CDT is controversial, with conflicting directives on its use because of inconclusive comparative safety outcomes.

So Riyaz Bashir, MD, of Temple University School of Medicine in Philadelphia, Pennsylvania, and his colleagues set out to compare CDT with anticoagulation alone.

They reported their findings in JAMA Internal Medicine.

The researchers examined in-hospital mortality, as well as secondary outcomes of bleeding complications, length of stay, and hospital charges, in a group of 90,618 patients hospitalized for DVT from 2005 through 2010 as part of the Nationwide Inpatient Sample database.

In all, 3649 patients (4.1%) underwent CDT. The CDT utilization rate increased from 2.3% in 2005 to 5.9% in 2010.

The in-hospital mortality rates were not significantly different in the CDT and anticoagulation-only groups, at 1.2% and 0.9%, respectively (P=0.15).

However, rates of adverse events were higher among patients treated with CDT. This included blood transfusion (11.1% vs 6.5%, P<0.001), pulmonary embolism (17.9% vs 11.4%, P<0.001), intracranial hemorrhage (0.9% vs 0.3%, P=0.03), and vena cava filter placement (34.8% vs 15.6%, P<0.001).

Patients in the CDT group also had longer average lengths of stay (7.2 vs 5 days, P<0.001) and higher hospital charges ($85,094 vs $28,164, P<0.001) compared with the anticoagulation-only group.

The researchers pointed out that their results are based on observational data, so the findings could be subject to residual confounding. Therefore, randomized trials are needed to better evaluate the effects of CDT.

However, the team also said that, as we don’t yet have this information, it may be reasonable to restrict CDT use to those patients who have a low bleeding risk and a high risk for post-thrombotic syndrome.

Blood for transfusion

Credit: UAB Hospital

A change in transfusion protocol has resulted in fewer potentially preventable deaths among soldiers, researchers have reported in JAMA Surgery.

In 2006, hospitals treating soldiers from Iraq and Afghanistan implemented a protocol called damage control resuscitation (DCR).

It involves administering blood products early and in a balanced ratio, using an aggressive approach to correct coagulopathy, and minimizing the use of crystalloid fluids.

The research showed that soldiers who died in the hospital after DCR was implemented were more likely than their predecessors to be severely injured and have a severe brain injury.

And this is consistent with a decrease in potentially preventable deaths, according to study author Nicholas R. Langan, MD, of the Madigan Army Medical Center in Tacoma, Washington, and his colleagues.

To conduct the study, the researchers reviewed data from the Joint Theater Trauma Registry of US forward combat hospitals. This included 57,179 soldiers, 2565 (4.5%) of whom died in the hospital. Seventy-four percent of these patients were severely injured, and 80% died within 24 hours of admission.

To assess the impact of DCR, the researchers divided patients into 2 groups: those treated before DCR implementation, from 2002 through 2005, and those treated with the DCR protocol, from 2006 through 2011.

The analysis showed that DCR policies were successfully implemented. There was a significant decrease in mean crystalloid infusion volume in the first 24 hours after hospitalization, from 6.1 L to 3.2 L (P<0.05).

There was a significant increase in fresh-frozen plasma use—from 3.2 U to 10.1 U (P=0.01)—and packed red blood cell use—from 8.4 U to 11.4 U (P=0.01)—in the first 24 hours after hospitalization.

And the mean ratio of packed red blood cells to fresh-frozen plasma changed from 2.6:1 in the pre-DCR period to 1.4:1 during the DCR period (P<0.01).

On the other hand, there was no significant difference in cryoprecipitate use, platelet use, or the ratio of packed red blood cells to cryoprecipitate or platelets.

The change in treatment protocol was associated with a change in the incidence of early and late, but not intermediate, deaths. The incidence of early death (within the first 24 hours) increased from 77% pre-DCR to 80% during DCR (P=0.02).

The incidence of late death (more than 7 days after injury) decreased from 10% pre-DCR to 6% during DCR (P<0.01). And the rate of intermediate death (1-7 days after injury) measured 13% for both periods (P=0.95).

The percentage of patients with any severe injury increased significantly from the pre-DCR period to the DCR period, from 64% to 80% (P<0.05). And the percentage of patients with severe head injuries increased significantly, from 57% to 73% (P<0.05).

As patients who died during the DCR period were more likely to have such “nonsurvivable” wounds, the researchers said this suggests that DCR is associated with a decrease in deaths among potentially salvageable patients.

Blood for transfusion

Credit: UAB Hospital

A change in transfusion protocol has resulted in fewer potentially preventable deaths among soldiers, researchers have reported in JAMA Surgery.

In 2006, hospitals treating soldiers from Iraq and Afghanistan implemented a protocol called damage control resuscitation (DCR).

It involves administering blood products early and in a balanced ratio, using an aggressive approach to correct coagulopathy, and minimizing the use of crystalloid fluids.

The research showed that soldiers who died in the hospital after DCR was implemented were more likely than their predecessors to be severely injured and have a severe brain injury.

And this is consistent with a decrease in potentially preventable deaths, according to study author Nicholas R. Langan, MD, of the Madigan Army Medical Center in Tacoma, Washington, and his colleagues.

To conduct the study, the researchers reviewed data from the Joint Theater Trauma Registry of US forward combat hospitals. This included 57,179 soldiers, 2565 (4.5%) of whom died in the hospital. Seventy-four percent of these patients were severely injured, and 80% died within 24 hours of admission.

To assess the impact of DCR, the researchers divided patients into 2 groups: those treated before DCR implementation, from 2002 through 2005, and those treated with the DCR protocol, from 2006 through 2011.

The analysis showed that DCR policies were successfully implemented. There was a significant decrease in mean crystalloid infusion volume in the first 24 hours after hospitalization, from 6.1 L to 3.2 L (P<0.05).

There was a significant increase in fresh-frozen plasma use—from 3.2 U to 10.1 U (P=0.01)—and packed red blood cell use—from 8.4 U to 11.4 U (P=0.01)—in the first 24 hours after hospitalization.

And the mean ratio of packed red blood cells to fresh-frozen plasma changed from 2.6:1 in the pre-DCR period to 1.4:1 during the DCR period (P<0.01).

On the other hand, there was no significant difference in cryoprecipitate use, platelet use, or the ratio of packed red blood cells to cryoprecipitate or platelets.

The change in treatment protocol was associated with a change in the incidence of early and late, but not intermediate, deaths. The incidence of early death (within the first 24 hours) increased from 77% pre-DCR to 80% during DCR (P=0.02).

The incidence of late death (more than 7 days after injury) decreased from 10% pre-DCR to 6% during DCR (P<0.01). And the rate of intermediate death (1-7 days after injury) measured 13% for both periods (P=0.95).

The percentage of patients with any severe injury increased significantly from the pre-DCR period to the DCR period, from 64% to 80% (P<0.05). And the percentage of patients with severe head injuries increased significantly, from 57% to 73% (P<0.05).

As patients who died during the DCR period were more likely to have such “nonsurvivable” wounds, the researchers said this suggests that DCR is associated with a decrease in deaths among potentially salvageable patients.

Blood for transfusion

Credit: UAB Hospital

A change in transfusion protocol has resulted in fewer potentially preventable deaths among soldiers, researchers have reported in JAMA Surgery.

In 2006, hospitals treating soldiers from Iraq and Afghanistan implemented a protocol called damage control resuscitation (DCR).

It involves administering blood products early and in a balanced ratio, using an aggressive approach to correct coagulopathy, and minimizing the use of crystalloid fluids.

The research showed that soldiers who died in the hospital after DCR was implemented were more likely than their predecessors to be severely injured and have a severe brain injury.

And this is consistent with a decrease in potentially preventable deaths, according to study author Nicholas R. Langan, MD, of the Madigan Army Medical Center in Tacoma, Washington, and his colleagues.

To conduct the study, the researchers reviewed data from the Joint Theater Trauma Registry of US forward combat hospitals. This included 57,179 soldiers, 2565 (4.5%) of whom died in the hospital. Seventy-four percent of these patients were severely injured, and 80% died within 24 hours of admission.

To assess the impact of DCR, the researchers divided patients into 2 groups: those treated before DCR implementation, from 2002 through 2005, and those treated with the DCR protocol, from 2006 through 2011.

The analysis showed that DCR policies were successfully implemented. There was a significant decrease in mean crystalloid infusion volume in the first 24 hours after hospitalization, from 6.1 L to 3.2 L (P<0.05).

There was a significant increase in fresh-frozen plasma use—from 3.2 U to 10.1 U (P=0.01)—and packed red blood cell use—from 8.4 U to 11.4 U (P=0.01)—in the first 24 hours after hospitalization.

And the mean ratio of packed red blood cells to fresh-frozen plasma changed from 2.6:1 in the pre-DCR period to 1.4:1 during the DCR period (P<0.01).

On the other hand, there was no significant difference in cryoprecipitate use, platelet use, or the ratio of packed red blood cells to cryoprecipitate or platelets.

The change in treatment protocol was associated with a change in the incidence of early and late, but not intermediate, deaths. The incidence of early death (within the first 24 hours) increased from 77% pre-DCR to 80% during DCR (P=0.02).

The incidence of late death (more than 7 days after injury) decreased from 10% pre-DCR to 6% during DCR (P<0.01). And the rate of intermediate death (1-7 days after injury) measured 13% for both periods (P=0.95).

The percentage of patients with any severe injury increased significantly from the pre-DCR period to the DCR period, from 64% to 80% (P<0.05). And the percentage of patients with severe head injuries increased significantly, from 57% to 73% (P<0.05).

As patients who died during the DCR period were more likely to have such “nonsurvivable” wounds, the researchers said this suggests that DCR is associated with a decrease in deaths among potentially salvageable patients.

Image showing mitosis, with

the endoplasmic reticulum

in green, mitochondria in red,

and chromosomes in blue

Credit: Wellcome Images

Researchers say they’ve uncovered the structure of one of the most important protein complexes involved in cell division, and their finding has implications for cancer treatment.

The team mapped the anaphase-promoting complex (APC/C), which performs a wide range of tasks associated with mitosis.

The researchers believe that seeing APC/C in unprecedented detail could transform our understanding of how cells divide and reveal binding sites for future cancer drugs.

“It’s very rewarding to finally tie down the detailed structure of this important protein, which is both one of the most important and most complicated found in all of nature,” said David Barford, DPhil, of the Medical Research Council Laboratory of Molecular Biology in Cambridge, UK.

“We hope our discovery will open up whole new avenues of research that increase our understanding of the process of mitosis and ultimately lead to the discovery of new cancer drugs.”

Dr Barford and his colleagues detailed their discovery in Nature.

The researchers reconstituted human APC/C and used a combination of electron microscopy and imaging software to visualize it at a resolution of less than a billionth of a meter.

The resolution was so fine that it allowed the team to see the secondary structure—the set of basic building blocks that combine to form every protein. Alpha-helix rods and folded beta-sheet constructions were clearly visible within the 20 subunits of the APC/C, defining the overall architecture of the complex.

Previous studies led by the same team had shown a globular structure for APC/C in much lower resolution, but the secondary structure had not been mapped.

Each of the APC/C’s subunits bond and mesh with other units at different points in the cell cycle, allowing it to control a range of mitotic processes, including the initiation of DNA replication, the segregation of chromosomes along spindles, and cytokinesis. Disrupting each of these processes could selectively kill cancer cells or prevent them from dividing.

“The fantastic insights into molecular structure provided by this study are a vivid illustration of the critical role played by fundamental cell biology in cancer research,” said Paul Workman, PhD, of The Institute of Cancer Research, London.

“The new study is a major step forward in our understanding of cell division. When this process goes awry, it is a critical difference that separates cancer cells from their healthy counterparts. Understanding exactly how cancer cells divide inappropriately is crucial to the discovery of innovative cancer treatments to improve outcomes for cancer patients.”

Image showing mitosis, with

the endoplasmic reticulum

in green, mitochondria in red,

and chromosomes in blue

Credit: Wellcome Images

Researchers say they’ve uncovered the structure of one of the most important protein complexes involved in cell division, and their finding has implications for cancer treatment.

The team mapped the anaphase-promoting complex (APC/C), which performs a wide range of tasks associated with mitosis.

The researchers believe that seeing APC/C in unprecedented detail could transform our understanding of how cells divide and reveal binding sites for future cancer drugs.

“It’s very rewarding to finally tie down the detailed structure of this important protein, which is both one of the most important and most complicated found in all of nature,” said David Barford, DPhil, of the Medical Research Council Laboratory of Molecular Biology in Cambridge, UK.

“We hope our discovery will open up whole new avenues of research that increase our understanding of the process of mitosis and ultimately lead to the discovery of new cancer drugs.”

Dr Barford and his colleagues detailed their discovery in Nature.

The researchers reconstituted human APC/C and used a combination of electron microscopy and imaging software to visualize it at a resolution of less than a billionth of a meter.

The resolution was so fine that it allowed the team to see the secondary structure—the set of basic building blocks that combine to form every protein. Alpha-helix rods and folded beta-sheet constructions were clearly visible within the 20 subunits of the APC/C, defining the overall architecture of the complex.

Previous studies led by the same team had shown a globular structure for APC/C in much lower resolution, but the secondary structure had not been mapped.

Each of the APC/C’s subunits bond and mesh with other units at different points in the cell cycle, allowing it to control a range of mitotic processes, including the initiation of DNA replication, the segregation of chromosomes along spindles, and cytokinesis. Disrupting each of these processes could selectively kill cancer cells or prevent them from dividing.

“The fantastic insights into molecular structure provided by this study are a vivid illustration of the critical role played by fundamental cell biology in cancer research,” said Paul Workman, PhD, of The Institute of Cancer Research, London.

“The new study is a major step forward in our understanding of cell division. When this process goes awry, it is a critical difference that separates cancer cells from their healthy counterparts. Understanding exactly how cancer cells divide inappropriately is crucial to the discovery of innovative cancer treatments to improve outcomes for cancer patients.”

Image showing mitosis, with

the endoplasmic reticulum

in green, mitochondria in red,

and chromosomes in blue

Credit: Wellcome Images

Researchers say they’ve uncovered the structure of one of the most important protein complexes involved in cell division, and their finding has implications for cancer treatment.

The team mapped the anaphase-promoting complex (APC/C), which performs a wide range of tasks associated with mitosis.

The researchers believe that seeing APC/C in unprecedented detail could transform our understanding of how cells divide and reveal binding sites for future cancer drugs.

“It’s very rewarding to finally tie down the detailed structure of this important protein, which is both one of the most important and most complicated found in all of nature,” said David Barford, DPhil, of the Medical Research Council Laboratory of Molecular Biology in Cambridge, UK.

“We hope our discovery will open up whole new avenues of research that increase our understanding of the process of mitosis and ultimately lead to the discovery of new cancer drugs.”

Dr Barford and his colleagues detailed their discovery in Nature.

The researchers reconstituted human APC/C and used a combination of electron microscopy and imaging software to visualize it at a resolution of less than a billionth of a meter.

The resolution was so fine that it allowed the team to see the secondary structure—the set of basic building blocks that combine to form every protein. Alpha-helix rods and folded beta-sheet constructions were clearly visible within the 20 subunits of the APC/C, defining the overall architecture of the complex.

Previous studies led by the same team had shown a globular structure for APC/C in much lower resolution, but the secondary structure had not been mapped.

Each of the APC/C’s subunits bond and mesh with other units at different points in the cell cycle, allowing it to control a range of mitotic processes, including the initiation of DNA replication, the segregation of chromosomes along spindles, and cytokinesis. Disrupting each of these processes could selectively kill cancer cells or prevent them from dividing.

“The fantastic insights into molecular structure provided by this study are a vivid illustration of the critical role played by fundamental cell biology in cancer research,” said Paul Workman, PhD, of The Institute of Cancer Research, London.

“The new study is a major step forward in our understanding of cell division. When this process goes awry, it is a critical difference that separates cancer cells from their healthy counterparts. Understanding exactly how cancer cells divide inappropriately is crucial to the discovery of innovative cancer treatments to improve outcomes for cancer patients.”

Platelets (blue) in a thrombus

Credit: Andre E.X. Brown

A next-generation bioreactor can produce fully functional platelets, according to research published in Blood.

The bioreactor recapitulates human bone marrow and blood vessel microenvironments.

And when the researchers introduced megakaryocytes derived from human induced pluripotent stem cell cultures (hiPSC-MKs), the bioreactor produced platelets with the structural and functional properties of natural platelets.

The team said this work is a major advancement that could help address blood transfusion needs worldwide.

“The ability to generate an alternative source of functional human platelets with virtually no disease transmission represents a paradigm shift in how we collect platelets that may allow us to meet the growing need for blood transfusions,” said lead study author Jonathan Thon, PhD, of Brigham and Women’s Hospital in Boston.

His group’s bioreactor uses biologically inspired engineering to fully integrate the major components of bone marrow, modeling both its composition and blood flow characteristics.

The bioreactor recapitulates features such as bone marrow stiffness, extracellular matrix composition, micro-channel size, and blood flow stability under high-resolution live-cell microscopy to make human platelets.

“[B]eing able to develop a device that successfully models bone marrow represents a crucial bridge connecting our understanding of the physiological triggers of platelet formation to support drug development and scale platelet production,” said senior study author Joseph Italiano, Jr, PhD, also of Brigham and Women’s Hospital.

He and his colleagues showed that physiological shear stresses in the bioreactor triggered proplatelet initiation, reproduced ex vivo bone marrow proplatelet production, and generated functional platelets.

In static culture, hiPSC-MKs began producing proplatelets at 6 hours post-isolation and reached maximal production at 18 hours. However, hiPSC-MKs under physiological shear stress began producing proplatelets immediately upon trapping and extended/released proplatelets within the first 2 hours of culture.

About 90% of hiPSC-MKs under shear stress produced proplatelets, compared to 10% of hiPSC-MKs in static cultures.

The hiPSC-MK-derived bioreactor platelets displayed forward scatter, side scatter, and surface biomarker expression characteristic of human platelets. Electron microscopy showed the 2 types of platelets were ultrastructurally indistinguishable from one another.

Furthermore, bioreactor platelets displayed morphology and microtubule expression comparable to human platelets. And bioreactor platelets spread normally upon contact-activation with glass, forming both filpodia and lamellipodia.

“Bioreactor-derived platelets theoretically have several advantages over conventional, donor-derived platelets in terms of safety and resource utilization,” said William Savage, MD, PhD, medical director at Kraft Family Blood Donor Center at Brigham and Women’s Hospital, who did not contribute to the study.

“A major factor that has limited our ability to compare bioreactor platelets to donor platelets is the inefficiency of growing platelets, a problem that slows progress of clinical research. This study addresses that gap, while contributing to our understanding of platelet biology at the same time.”

Based on the promising results of this study, the researchers would like to begin clinical trials testing the bioreactor platelets in 2017.

“The regulatory bar is appropriately set high for blood products,” Dr Thon said. “And it is important to us that we show platelet quality, function, and safety over these next 3 years, since we’ll likely be recipients of these platelets ourselves at some point.”

Platelets (blue) in a thrombus

Credit: Andre E.X. Brown

A next-generation bioreactor can produce fully functional platelets, according to research published in Blood.

The bioreactor recapitulates human bone marrow and blood vessel microenvironments.

And when the researchers introduced megakaryocytes derived from human induced pluripotent stem cell cultures (hiPSC-MKs), the bioreactor produced platelets with the structural and functional properties of natural platelets.

The team said this work is a major advancement that could help address blood transfusion needs worldwide.

“The ability to generate an alternative source of functional human platelets with virtually no disease transmission represents a paradigm shift in how we collect platelets that may allow us to meet the growing need for blood transfusions,” said lead study author Jonathan Thon, PhD, of Brigham and Women’s Hospital in Boston.

His group’s bioreactor uses biologically inspired engineering to fully integrate the major components of bone marrow, modeling both its composition and blood flow characteristics.

The bioreactor recapitulates features such as bone marrow stiffness, extracellular matrix composition, micro-channel size, and blood flow stability under high-resolution live-cell microscopy to make human platelets.

“[B]eing able to develop a device that successfully models bone marrow represents a crucial bridge connecting our understanding of the physiological triggers of platelet formation to support drug development and scale platelet production,” said senior study author Joseph Italiano, Jr, PhD, also of Brigham and Women’s Hospital.

He and his colleagues showed that physiological shear stresses in the bioreactor triggered proplatelet initiation, reproduced ex vivo bone marrow proplatelet production, and generated functional platelets.

In static culture, hiPSC-MKs began producing proplatelets at 6 hours post-isolation and reached maximal production at 18 hours. However, hiPSC-MKs under physiological shear stress began producing proplatelets immediately upon trapping and extended/released proplatelets within the first 2 hours of culture.

About 90% of hiPSC-MKs under shear stress produced proplatelets, compared to 10% of hiPSC-MKs in static cultures.

The hiPSC-MK-derived bioreactor platelets displayed forward scatter, side scatter, and surface biomarker expression characteristic of human platelets. Electron microscopy showed the 2 types of platelets were ultrastructurally indistinguishable from one another.

Furthermore, bioreactor platelets displayed morphology and microtubule expression comparable to human platelets. And bioreactor platelets spread normally upon contact-activation with glass, forming both filpodia and lamellipodia.

“Bioreactor-derived platelets theoretically have several advantages over conventional, donor-derived platelets in terms of safety and resource utilization,” said William Savage, MD, PhD, medical director at Kraft Family Blood Donor Center at Brigham and Women’s Hospital, who did not contribute to the study.

“A major factor that has limited our ability to compare bioreactor platelets to donor platelets is the inefficiency of growing platelets, a problem that slows progress of clinical research. This study addresses that gap, while contributing to our understanding of platelet biology at the same time.”

Based on the promising results of this study, the researchers would like to begin clinical trials testing the bioreactor platelets in 2017.

“The regulatory bar is appropriately set high for blood products,” Dr Thon said. “And it is important to us that we show platelet quality, function, and safety over these next 3 years, since we’ll likely be recipients of these platelets ourselves at some point.”

Platelets (blue) in a thrombus

Credit: Andre E.X. Brown

A next-generation bioreactor can produce fully functional platelets, according to research published in Blood.

The bioreactor recapitulates human bone marrow and blood vessel microenvironments.

And when the researchers introduced megakaryocytes derived from human induced pluripotent stem cell cultures (hiPSC-MKs), the bioreactor produced platelets with the structural and functional properties of natural platelets.

The team said this work is a major advancement that could help address blood transfusion needs worldwide.

“The ability to generate an alternative source of functional human platelets with virtually no disease transmission represents a paradigm shift in how we collect platelets that may allow us to meet the growing need for blood transfusions,” said lead study author Jonathan Thon, PhD, of Brigham and Women’s Hospital in Boston.

His group’s bioreactor uses biologically inspired engineering to fully integrate the major components of bone marrow, modeling both its composition and blood flow characteristics.

The bioreactor recapitulates features such as bone marrow stiffness, extracellular matrix composition, micro-channel size, and blood flow stability under high-resolution live-cell microscopy to make human platelets.

“[B]eing able to develop a device that successfully models bone marrow represents a crucial bridge connecting our understanding of the physiological triggers of platelet formation to support drug development and scale platelet production,” said senior study author Joseph Italiano, Jr, PhD, also of Brigham and Women’s Hospital.

He and his colleagues showed that physiological shear stresses in the bioreactor triggered proplatelet initiation, reproduced ex vivo bone marrow proplatelet production, and generated functional platelets.

In static culture, hiPSC-MKs began producing proplatelets at 6 hours post-isolation and reached maximal production at 18 hours. However, hiPSC-MKs under physiological shear stress began producing proplatelets immediately upon trapping and extended/released proplatelets within the first 2 hours of culture.

About 90% of hiPSC-MKs under shear stress produced proplatelets, compared to 10% of hiPSC-MKs in static cultures.

The hiPSC-MK-derived bioreactor platelets displayed forward scatter, side scatter, and surface biomarker expression characteristic of human platelets. Electron microscopy showed the 2 types of platelets were ultrastructurally indistinguishable from one another.

Furthermore, bioreactor platelets displayed morphology and microtubule expression comparable to human platelets. And bioreactor platelets spread normally upon contact-activation with glass, forming both filpodia and lamellipodia.

“Bioreactor-derived platelets theoretically have several advantages over conventional, donor-derived platelets in terms of safety and resource utilization,” said William Savage, MD, PhD, medical director at Kraft Family Blood Donor Center at Brigham and Women’s Hospital, who did not contribute to the study.

“A major factor that has limited our ability to compare bioreactor platelets to donor platelets is the inefficiency of growing platelets, a problem that slows progress of clinical research. This study addresses that gap, while contributing to our understanding of platelet biology at the same time.”

Based on the promising results of this study, the researchers would like to begin clinical trials testing the bioreactor platelets in 2017.

“The regulatory bar is appropriately set high for blood products,” Dr Thon said. “And it is important to us that we show platelet quality, function, and safety over these next 3 years, since we’ll likely be recipients of these platelets ourselves at some point.”

MILAN – A full 61.5% of patients with chronic myeloid leukemia in deep molecular remission for more than 1 year on long-term tyrosine kinase inhibitor therapy remained alive and free of relapse 6 months after stopping their TKI in the EURO-SKI trial.

Molecular relapse-free survival at 9 months was 58% and 55% at 12 months.

The preplanned interim analysis after 200 patients allowed the trialists to discard the study’s null hypothesis that molecular relapse-free survival at 6 months would be 40% or less (P less than .0001).

"With less strict inclusion and relapse criteria than the A-STIM study and other trials, stopping is safe and we can continue with the trial," Dr. Susanne Saussele said in a late-breaking abstract session at the annual meeting of the European Hematology Association.

Importantly, interim results from the EURO-SKI (European Stop TKI) study also suggest that the level of molecular response (MR) achieved prior to TKI withdrawal affects molecular relapse-free survival.

Among 197 patients with molecular laboratory results available for exact classification, 49% of patients in MR⁴ relapsed, compared with 39% in MR^4.5 and 39% in MR⁵.

"In the setting of standardized molecular testing within a CML [chronic myeloid leukemia] stopping trial, it seems that molecular remission has an impact on molecular free-survival," said Dr. Saussele of University Medical Centre Mannheim, Germany.

As no statistical test was performed and this was an interim analysis, MR^4.5 or MR⁵ cannot yet be used as a criterion to select patients to withdraw from treatment, she said in an interview.

The findings do confirm results from the recent A-STIM (According to Stop Imatinib) study showing that loss of major molecular response can be used as a practical criterion for restarting imatinib (J. Clin. Oncol. 2014;32:424-30).

Several studies including the STIM (Stop Imatinib) trial and the STOP 2G-TKI (Stop Second Generation Tyrosine Kinase Inhibitors) study have shown that imatinib (Gleevec), dasatinib (Sprycel), and nilotinib (Tasigna) can be safely withdrawn in a substantial proportion of patients with CML in deep MR.

A number of questions remain open, however, such as which molecular level has to be reached before stopping TKI therapy, the minimal duration of TKI pretreatment or MR⁴ before stopping, and which prognostic factors influence molecular relapse-free survival, she said.

EURO-SKI was set up to define prognostic markers to increase the rate of patients in durable deep MR after stopping TKI treatment. Other aims are to evaluate methods of molecular monitoring, quality of life, and saved treatment costs per country.

Patients with chronic-phase CML from eight countries were eligible if they were on a TKI for at least 3 years and had a confirmed deep MR, defined as more than a 4 log reduction in BCR-ABL (breakpoint cluster region–Abelson) transcripts for more than 12 months confirmed by three consecutive polymerase chain reaction results.

MR⁴ status also had to be confirmed in an MR⁴-standardized laboratory according to criteria by Cross et al. (Leukemia 2012;26:2172-5)

Patients with previous or planned allogeneic stem cell transplantation or a prior TKI failure were excluded.

A total of 103 patients received pretreatment before TKI therapy, mostly with hydroxyurea alone (n = 71) or with interferon (n = 22). Their median age was 53 years.

First-line TKI was imatinib in 194 patients, nilotinib in 3, and dasatinib in 3.

The median duration of TKI therapy was 8 years and median MR⁴ duration before stopping TKI therapy was 5 years.

Dr. Saussele cautioned that adverse events and quality of life must be taken into account when considering TKI withdrawal in these patients.

A total of 222 adverse events were reported in 98 patients, with 57 events in 37 patients related to treatment stop. None were grade 4.

The most common adverse event was musculoskeletal or joint pain (39 events of all grades and 6 grade 3/4 events). This was first described in the Swedish EURO-SKI patients in 15-20% of patients after TKI withdrawal, prompting the investigators to send an advisory letter to all participating physicians, she remarked.

Other adverse events included sweating, skin disorders, folliculitis, depressive episodes, fatigue, urticaria, and weight loss.

The EURO-SKI trial was recently expanded to enroll 700 patients, with a quality of life analysis expected later this year. The next report on the primary endpoint is expected at the American Society of Hematology annual meeting, Dr. Saussele said.

Dr. Saussele reported honoraria and research and travel support from BMS, Novartis, and Pfizer.

[email protected]

MILAN – A full 61.5% of patients with chronic myeloid leukemia in deep molecular remission for more than 1 year on long-term tyrosine kinase inhibitor therapy remained alive and free of relapse 6 months after stopping their TKI in the EURO-SKI trial.

Molecular relapse-free survival at 9 months was 58% and 55% at 12 months.

The preplanned interim analysis after 200 patients allowed the trialists to discard the study’s null hypothesis that molecular relapse-free survival at 6 months would be 40% or less (P less than .0001).

"With less strict inclusion and relapse criteria than the A-STIM study and other trials, stopping is safe and we can continue with the trial," Dr. Susanne Saussele said in a late-breaking abstract session at the annual meeting of the European Hematology Association.

Importantly, interim results from the EURO-SKI (European Stop TKI) study also suggest that the level of molecular response (MR) achieved prior to TKI withdrawal affects molecular relapse-free survival.

Among 197 patients with molecular laboratory results available for exact classification, 49% of patients in MR⁴ relapsed, compared with 39% in MR^4.5 and 39% in MR⁵.

"In the setting of standardized molecular testing within a CML [chronic myeloid leukemia] stopping trial, it seems that molecular remission has an impact on molecular free-survival," said Dr. Saussele of University Medical Centre Mannheim, Germany.

As no statistical test was performed and this was an interim analysis, MR^4.5 or MR⁵ cannot yet be used as a criterion to select patients to withdraw from treatment, she said in an interview.

The findings do confirm results from the recent A-STIM (According to Stop Imatinib) study showing that loss of major molecular response can be used as a practical criterion for restarting imatinib (J. Clin. Oncol. 2014;32:424-30).

Several studies including the STIM (Stop Imatinib) trial and the STOP 2G-TKI (Stop Second Generation Tyrosine Kinase Inhibitors) study have shown that imatinib (Gleevec), dasatinib (Sprycel), and nilotinib (Tasigna) can be safely withdrawn in a substantial proportion of patients with CML in deep MR.

A number of questions remain open, however, such as which molecular level has to be reached before stopping TKI therapy, the minimal duration of TKI pretreatment or MR⁴ before stopping, and which prognostic factors influence molecular relapse-free survival, she said.

EURO-SKI was set up to define prognostic markers to increase the rate of patients in durable deep MR after stopping TKI treatment. Other aims are to evaluate methods of molecular monitoring, quality of life, and saved treatment costs per country.

Patients with chronic-phase CML from eight countries were eligible if they were on a TKI for at least 3 years and had a confirmed deep MR, defined as more than a 4 log reduction in BCR-ABL (breakpoint cluster region–Abelson) transcripts for more than 12 months confirmed by three consecutive polymerase chain reaction results.

MR⁴ status also had to be confirmed in an MR⁴-standardized laboratory according to criteria by Cross et al. (Leukemia 2012;26:2172-5)

Patients with previous or planned allogeneic stem cell transplantation or a prior TKI failure were excluded.

A total of 103 patients received pretreatment before TKI therapy, mostly with hydroxyurea alone (n = 71) or with interferon (n = 22). Their median age was 53 years.

First-line TKI was imatinib in 194 patients, nilotinib in 3, and dasatinib in 3.

The median duration of TKI therapy was 8 years and median MR⁴ duration before stopping TKI therapy was 5 years.

Dr. Saussele cautioned that adverse events and quality of life must be taken into account when considering TKI withdrawal in these patients.

A total of 222 adverse events were reported in 98 patients, with 57 events in 37 patients related to treatment stop. None were grade 4.

The most common adverse event was musculoskeletal or joint pain (39 events of all grades and 6 grade 3/4 events). This was first described in the Swedish EURO-SKI patients in 15-20% of patients after TKI withdrawal, prompting the investigators to send an advisory letter to all participating physicians, she remarked.

Other adverse events included sweating, skin disorders, folliculitis, depressive episodes, fatigue, urticaria, and weight loss.

The EURO-SKI trial was recently expanded to enroll 700 patients, with a quality of life analysis expected later this year. The next report on the primary endpoint is expected at the American Society of Hematology annual meeting, Dr. Saussele said.

Dr. Saussele reported honoraria and research and travel support from BMS, Novartis, and Pfizer.

[email protected]

MILAN – A full 61.5% of patients with chronic myeloid leukemia in deep molecular remission for more than 1 year on long-term tyrosine kinase inhibitor therapy remained alive and free of relapse 6 months after stopping their TKI in the EURO-SKI trial.

Molecular relapse-free survival at 9 months was 58% and 55% at 12 months.

The preplanned interim analysis after 200 patients allowed the trialists to discard the study’s null hypothesis that molecular relapse-free survival at 6 months would be 40% or less (P less than .0001).

"With less strict inclusion and relapse criteria than the A-STIM study and other trials, stopping is safe and we can continue with the trial," Dr. Susanne Saussele said in a late-breaking abstract session at the annual meeting of the European Hematology Association.

Importantly, interim results from the EURO-SKI (European Stop TKI) study also suggest that the level of molecular response (MR) achieved prior to TKI withdrawal affects molecular relapse-free survival.

Among 197 patients with molecular laboratory results available for exact classification, 49% of patients in MR⁴ relapsed, compared with 39% in MR^4.5 and 39% in MR⁵.

"In the setting of standardized molecular testing within a CML [chronic myeloid leukemia] stopping trial, it seems that molecular remission has an impact on molecular free-survival," said Dr. Saussele of University Medical Centre Mannheim, Germany.

As no statistical test was performed and this was an interim analysis, MR^4.5 or MR⁵ cannot yet be used as a criterion to select patients to withdraw from treatment, she said in an interview.

The findings do confirm results from the recent A-STIM (According to Stop Imatinib) study showing that loss of major molecular response can be used as a practical criterion for restarting imatinib (J. Clin. Oncol. 2014;32:424-30).

Several studies including the STIM (Stop Imatinib) trial and the STOP 2G-TKI (Stop Second Generation Tyrosine Kinase Inhibitors) study have shown that imatinib (Gleevec), dasatinib (Sprycel), and nilotinib (Tasigna) can be safely withdrawn in a substantial proportion of patients with CML in deep MR.

A number of questions remain open, however, such as which molecular level has to be reached before stopping TKI therapy, the minimal duration of TKI pretreatment or MR⁴ before stopping, and which prognostic factors influence molecular relapse-free survival, she said.

EURO-SKI was set up to define prognostic markers to increase the rate of patients in durable deep MR after stopping TKI treatment. Other aims are to evaluate methods of molecular monitoring, quality of life, and saved treatment costs per country.

Patients with chronic-phase CML from eight countries were eligible if they were on a TKI for at least 3 years and had a confirmed deep MR, defined as more than a 4 log reduction in BCR-ABL (breakpoint cluster region–Abelson) transcripts for more than 12 months confirmed by three consecutive polymerase chain reaction results.

MR⁴ status also had to be confirmed in an MR⁴-standardized laboratory according to criteria by Cross et al. (Leukemia 2012;26:2172-5)

Patients with previous or planned allogeneic stem cell transplantation or a prior TKI failure were excluded.

A total of 103 patients received pretreatment before TKI therapy, mostly with hydroxyurea alone (n = 71) or with interferon (n = 22). Their median age was 53 years.

First-line TKI was imatinib in 194 patients, nilotinib in 3, and dasatinib in 3.

The median duration of TKI therapy was 8 years and median MR⁴ duration before stopping TKI therapy was 5 years.

Dr. Saussele cautioned that adverse events and quality of life must be taken into account when considering TKI withdrawal in these patients.

A total of 222 adverse events were reported in 98 patients, with 57 events in 37 patients related to treatment stop. None were grade 4.

The most common adverse event was musculoskeletal or joint pain (39 events of all grades and 6 grade 3/4 events). This was first described in the Swedish EURO-SKI patients in 15-20% of patients after TKI withdrawal, prompting the investigators to send an advisory letter to all participating physicians, she remarked.

Other adverse events included sweating, skin disorders, folliculitis, depressive episodes, fatigue, urticaria, and weight loss.

The EURO-SKI trial was recently expanded to enroll 700 patients, with a quality of life analysis expected later this year. The next report on the primary endpoint is expected at the American Society of Hematology annual meeting, Dr. Saussele said.

Dr. Saussele reported honoraria and research and travel support from BMS, Novartis, and Pfizer.

[email protected]

MILAN – A full 61.5% of patients with chronic myeloid leukemia in deep molecular remission for more than 1 year on long-term tyrosine kinase inhibitor therapy remained alive and free of relapse 6 months after stopping their TKI in the EURO-SKI trial.

Molecular relapse-free survival at 9 months was 58% and 55% at 12 months.

The preplanned interim analysis after 200 patients allowed the trialists to discard the study’s null hypothesis that molecular relapse-free survival at 6 months would be 40% or less (P less than .0001).

"With less strict inclusion and relapse criteria than the A-STIM study and other trials, stopping is safe and we can continue with the trial," Dr. Susanne Saussele said in a late-breaking abstract session at the annual meeting of the European Hematology Association.

Importantly, interim results from the EURO-SKI (European Stop TKI) study also suggest that the level of molecular response (MR) achieved prior to TKI withdrawal affects molecular relapse-free survival.

Among 197 patients with molecular laboratory results available for exact classification, 49% of patients in MR⁴ relapsed, compared with 39% in MR^4.5 and 39% in MR⁵.

"In the setting of standardized molecular testing within a CML [chronic myeloid leukemia] stopping trial, it seems that molecular remission has an impact on molecular free-survival," said Dr. Saussele of University Medical Centre Mannheim, Germany.

As no statistical test was performed and this was an interim analysis, MR^4.5 or MR⁵ cannot yet be used as a criterion to select patients to withdraw from treatment, she said in an interview.

The findings do confirm results from the recent A-STIM (According to Stop Imatinib) study showing that loss of major molecular response can be used as a practical criterion for restarting imatinib (J. Clin. Oncol. 2014;32:424-30).

Several studies including the STIM (Stop Imatinib) trial and the STOP 2G-TKI (Stop Second Generation Tyrosine Kinase Inhibitors) study have shown that imatinib (Gleevec), dasatinib (Sprycel), and nilotinib (Tasigna) can be safely withdrawn in a substantial proportion of patients with CML in deep MR.

A number of questions remain open, however, such as which molecular level has to be reached before stopping TKI therapy, the minimal duration of TKI pretreatment or MR⁴ before stopping, and which prognostic factors influence molecular relapse-free survival, she said.

EURO-SKI was set up to define prognostic markers to increase the rate of patients in durable deep MR after stopping TKI treatment. Other aims are to evaluate methods of molecular monitoring, quality of life, and saved treatment costs per country.

Patients with chronic-phase CML from eight countries were eligible if they were on a TKI for at least 3 years and had a confirmed deep MR, defined as more than a 4 log reduction in BCR-ABL (breakpoint cluster region–Abelson) transcripts for more than 12 months confirmed by three consecutive polymerase chain reaction results.

MR⁴ status also had to be confirmed in an MR⁴-standardized laboratory according to criteria by Cross et al. (Leukemia 2012;26:2172-5)

Patients with previous or planned allogeneic stem cell transplantation or a prior TKI failure were excluded.

A total of 103 patients received pretreatment before TKI therapy, mostly with hydroxyurea alone (n = 71) or with interferon (n = 22). Their median age was 53 years.

First-line TKI was imatinib in 194 patients, nilotinib in 3, and dasatinib in 3.

The median duration of TKI therapy was 8 years and median MR⁴ duration before stopping TKI therapy was 5 years.

Dr. Saussele cautioned that adverse events and quality of life must be taken into account when considering TKI withdrawal in these patients.

A total of 222 adverse events were reported in 98 patients, with 57 events in 37 patients related to treatment stop. None were grade 4.

The most common adverse event was musculoskeletal or joint pain (39 events of all grades and 6 grade 3/4 events). This was first described in the Swedish EURO-SKI patients in 15-20% of patients after TKI withdrawal, prompting the investigators to send an advisory letter to all participating physicians, she remarked.

Other adverse events included sweating, skin disorders, folliculitis, depressive episodes, fatigue, urticaria, and weight loss.

The EURO-SKI trial was recently expanded to enroll 700 patients, with a quality of life analysis expected later this year. The next report on the primary endpoint is expected at the American Society of Hematology annual meeting, Dr. Saussele said.

Dr. Saussele reported honoraria and research and travel support from BMS, Novartis, and Pfizer.

[email protected]

MILAN – A full 61.5% of patients with chronic myeloid leukemia in deep molecular remission for more than 1 year on long-term tyrosine kinase inhibitor therapy remained alive and free of relapse 6 months after stopping their TKI in the EURO-SKI trial.

Molecular relapse-free survival at 9 months was 58% and 55% at 12 months.

The preplanned interim analysis after 200 patients allowed the trialists to discard the study’s null hypothesis that molecular relapse-free survival at 6 months would be 40% or less (P less than .0001).

"With less strict inclusion and relapse criteria than the A-STIM study and other trials, stopping is safe and we can continue with the trial," Dr. Susanne Saussele said in a late-breaking abstract session at the annual meeting of the European Hematology Association.

Importantly, interim results from the EURO-SKI (European Stop TKI) study also suggest that the level of molecular response (MR) achieved prior to TKI withdrawal affects molecular relapse-free survival.

Among 197 patients with molecular laboratory results available for exact classification, 49% of patients in MR⁴ relapsed, compared with 39% in MR^4.5 and 39% in MR⁵.

"In the setting of standardized molecular testing within a CML [chronic myeloid leukemia] stopping trial, it seems that molecular remission has an impact on molecular free-survival," said Dr. Saussele of University Medical Centre Mannheim, Germany.

As no statistical test was performed and this was an interim analysis, MR^4.5 or MR⁵ cannot yet be used as a criterion to select patients to withdraw from treatment, she said in an interview.

The findings do confirm results from the recent A-STIM (According to Stop Imatinib) study showing that loss of major molecular response can be used as a practical criterion for restarting imatinib (J. Clin. Oncol. 2014;32:424-30).

Several studies including the STIM (Stop Imatinib) trial and the STOP 2G-TKI (Stop Second Generation Tyrosine Kinase Inhibitors) study have shown that imatinib (Gleevec), dasatinib (Sprycel), and nilotinib (Tasigna) can be safely withdrawn in a substantial proportion of patients with CML in deep MR.

A number of questions remain open, however, such as which molecular level has to be reached before stopping TKI therapy, the minimal duration of TKI pretreatment or MR⁴ before stopping, and which prognostic factors influence molecular relapse-free survival, she said.

EURO-SKI was set up to define prognostic markers to increase the rate of patients in durable deep MR after stopping TKI treatment. Other aims are to evaluate methods of molecular monitoring, quality of life, and saved treatment costs per country.

Patients with chronic-phase CML from eight countries were eligible if they were on a TKI for at least 3 years and had a confirmed deep MR, defined as more than a 4 log reduction in BCR-ABL (breakpoint cluster region–Abelson) transcripts for more than 12 months confirmed by three consecutive polymerase chain reaction results.

MR⁴ status also had to be confirmed in an MR⁴-standardized laboratory according to criteria by Cross et al. (Leukemia 2012;26:2172-5)

Patients with previous or planned allogeneic stem cell transplantation or a prior TKI failure were excluded.

A total of 103 patients received pretreatment before TKI therapy, mostly with hydroxyurea alone (n = 71) or with interferon (n = 22). Their median age was 53 years.

First-line TKI was imatinib in 194 patients, nilotinib in 3, and dasatinib in 3.

The median duration of TKI therapy was 8 years and median MR⁴ duration before stopping TKI therapy was 5 years.

Dr. Saussele cautioned that adverse events and quality of life must be taken into account when considering TKI withdrawal in these patients.

A total of 222 adverse events were reported in 98 patients, with 57 events in 37 patients related to treatment stop. None were grade 4.

The most common adverse event was musculoskeletal or joint pain (39 events of all grades and 6 grade 3/4 events). This was first described in the Swedish EURO-SKI patients in 15-20% of patients after TKI withdrawal, prompting the investigators to send an advisory letter to all participating physicians, she remarked.

Other adverse events included sweating, skin disorders, folliculitis, depressive episodes, fatigue, urticaria, and weight loss.

The EURO-SKI trial was recently expanded to enroll 700 patients, with a quality of life analysis expected later this year. The next report on the primary endpoint is expected at the American Society of Hematology annual meeting, Dr. Saussele said.

Dr. Saussele reported honoraria and research and travel support from BMS, Novartis, and Pfizer.

[email protected]

MILAN – A full 61.5% of patients with chronic myeloid leukemia in deep molecular remission for more than 1 year on long-term tyrosine kinase inhibitor therapy remained alive and free of relapse 6 months after stopping their TKI in the EURO-SKI trial.

Molecular relapse-free survival at 9 months was 58% and 55% at 12 months.

The preplanned interim analysis after 200 patients allowed the trialists to discard the study’s null hypothesis that molecular relapse-free survival at 6 months would be 40% or less (P less than .0001).

"With less strict inclusion and relapse criteria than the A-STIM study and other trials, stopping is safe and we can continue with the trial," Dr. Susanne Saussele said in a late-breaking abstract session at the annual meeting of the European Hematology Association.

Importantly, interim results from the EURO-SKI (European Stop TKI) study also suggest that the level of molecular response (MR) achieved prior to TKI withdrawal affects molecular relapse-free survival.

Among 197 patients with molecular laboratory results available for exact classification, 49% of patients in MR⁴ relapsed, compared with 39% in MR^4.5 and 39% in MR⁵.

"In the setting of standardized molecular testing within a CML [chronic myeloid leukemia] stopping trial, it seems that molecular remission has an impact on molecular free-survival," said Dr. Saussele of University Medical Centre Mannheim, Germany.

As no statistical test was performed and this was an interim analysis, MR^4.5 or MR⁵ cannot yet be used as a criterion to select patients to withdraw from treatment, she said in an interview.

The findings do confirm results from the recent A-STIM (According to Stop Imatinib) study showing that loss of major molecular response can be used as a practical criterion for restarting imatinib (J. Clin. Oncol. 2014;32:424-30).

Several studies including the STIM (Stop Imatinib) trial and the STOP 2G-TKI (Stop Second Generation Tyrosine Kinase Inhibitors) study have shown that imatinib (Gleevec), dasatinib (Sprycel), and nilotinib (Tasigna) can be safely withdrawn in a substantial proportion of patients with CML in deep MR.

A number of questions remain open, however, such as which molecular level has to be reached before stopping TKI therapy, the minimal duration of TKI pretreatment or MR⁴ before stopping, and which prognostic factors influence molecular relapse-free survival, she said.

EURO-SKI was set up to define prognostic markers to increase the rate of patients in durable deep MR after stopping TKI treatment. Other aims are to evaluate methods of molecular monitoring, quality of life, and saved treatment costs per country.

Patients with chronic-phase CML from eight countries were eligible if they were on a TKI for at least 3 years and had a confirmed deep MR, defined as more than a 4 log reduction in BCR-ABL (breakpoint cluster region–Abelson) transcripts for more than 12 months confirmed by three consecutive polymerase chain reaction results.

MR⁴ status also had to be confirmed in an MR⁴-standardized laboratory according to criteria by Cross et al. (Leukemia 2012;26:2172-5)

Patients with previous or planned allogeneic stem cell transplantation or a prior TKI failure were excluded.

A total of 103 patients received pretreatment before TKI therapy, mostly with hydroxyurea alone (n = 71) or with interferon (n = 22). Their median age was 53 years.

First-line TKI was imatinib in 194 patients, nilotinib in 3, and dasatinib in 3.

The median duration of TKI therapy was 8 years and median MR⁴ duration before stopping TKI therapy was 5 years.

Dr. Saussele cautioned that adverse events and quality of life must be taken into account when considering TKI withdrawal in these patients.

A total of 222 adverse events were reported in 98 patients, with 57 events in 37 patients related to treatment stop. None were grade 4.

The most common adverse event was musculoskeletal or joint pain (39 events of all grades and 6 grade 3/4 events). This was first described in the Swedish EURO-SKI patients in 15-20% of patients after TKI withdrawal, prompting the investigators to send an advisory letter to all participating physicians, she remarked.

Other adverse events included sweating, skin disorders, folliculitis, depressive episodes, fatigue, urticaria, and weight loss.

The EURO-SKI trial was recently expanded to enroll 700 patients, with a quality of life analysis expected later this year. The next report on the primary endpoint is expected at the American Society of Hematology annual meeting, Dr. Saussele said.

Dr. Saussele reported honoraria and research and travel support from BMS, Novartis, and Pfizer.

[email protected]