AVAHO

LAKE TAHOE, CALIF. – Children experience a wide range of cutaneous manifestations of immunosuppression, including atopic dermatitis (AD), skin cancer, and side effects of vemurafenib treatment.

In a presentation on the cutaneous sequelae of different immunosuppressive regimens at the annual meeting of the Society for Pediatric Dermatology, Carrie C. Coughlin, MD, opened with a discussion of AD triggered by the tumor necrosis factor (TNF) blocker infliximab, especially in the setting of therapy for Crohn’s disease. “In this patient population you often think of psoriasis as a consequence of infliximab and other TNF therapies,” said Dr. Coughlin, a pediatric dermatologist at Washington University, St. Louis. “But you can also get true atopic dermatitis with infliximab as well. Who’s more at risk for this? Patients with Crohn’s disease seem to be. Most of the literature is in adults, but there are a few series of children. In a series of children looking at cutaneous sequelae of infliximab therapy, about 20% of cutaneous eruptions were atopic dermatitis. I think it’s a great opportunity for us in dermatology to do a more research in this area.”

Some researchers have proposed that atopic disease could be a marker of over-suppression of TNF-alpha in young Crohn’s disease patients on infliximab (Inflamm Bowel Dis. 2014; 20[8]:1309-15). “One question you could ask is, could these patients actually tolerate a dose reduction?” Dr. Coughlin said. She promoted the role of dermatologists in working at managing side effects to keep patients on medications helping their GI disease, but acknowledged this is not always possible.

Doug Brunk/MDedge News

dbrunk@mdedge.com

LAKE TAHOE, CALIF. – Children experience a wide range of cutaneous manifestations of immunosuppression, including atopic dermatitis (AD), skin cancer, and side effects of vemurafenib treatment.

In a presentation on the cutaneous sequelae of different immunosuppressive regimens at the annual meeting of the Society for Pediatric Dermatology, Carrie C. Coughlin, MD, opened with a discussion of AD triggered by the tumor necrosis factor (TNF) blocker infliximab, especially in the setting of therapy for Crohn’s disease. “In this patient population you often think of psoriasis as a consequence of infliximab and other TNF therapies,” said Dr. Coughlin, a pediatric dermatologist at Washington University, St. Louis. “But you can also get true atopic dermatitis with infliximab as well. Who’s more at risk for this? Patients with Crohn’s disease seem to be. Most of the literature is in adults, but there are a few series of children. In a series of children looking at cutaneous sequelae of infliximab therapy, about 20% of cutaneous eruptions were atopic dermatitis. I think it’s a great opportunity for us in dermatology to do a more research in this area.”

Some researchers have proposed that atopic disease could be a marker of over-suppression of TNF-alpha in young Crohn’s disease patients on infliximab (Inflamm Bowel Dis. 2014; 20[8]:1309-15). “One question you could ask is, could these patients actually tolerate a dose reduction?” Dr. Coughlin said. She promoted the role of dermatologists in working at managing side effects to keep patients on medications helping their GI disease, but acknowledged this is not always possible.

Doug Brunk/MDedge News

dbrunk@mdedge.com

LAKE TAHOE, CALIF. – Children experience a wide range of cutaneous manifestations of immunosuppression, including atopic dermatitis (AD), skin cancer, and side effects of vemurafenib treatment.

In a presentation on the cutaneous sequelae of different immunosuppressive regimens at the annual meeting of the Society for Pediatric Dermatology, Carrie C. Coughlin, MD, opened with a discussion of AD triggered by the tumor necrosis factor (TNF) blocker infliximab, especially in the setting of therapy for Crohn’s disease. “In this patient population you often think of psoriasis as a consequence of infliximab and other TNF therapies,” said Dr. Coughlin, a pediatric dermatologist at Washington University, St. Louis. “But you can also get true atopic dermatitis with infliximab as well. Who’s more at risk for this? Patients with Crohn’s disease seem to be. Most of the literature is in adults, but there are a few series of children. In a series of children looking at cutaneous sequelae of infliximab therapy, about 20% of cutaneous eruptions were atopic dermatitis. I think it’s a great opportunity for us in dermatology to do a more research in this area.”

Some researchers have proposed that atopic disease could be a marker of over-suppression of TNF-alpha in young Crohn’s disease patients on infliximab (Inflamm Bowel Dis. 2014; 20[8]:1309-15). “One question you could ask is, could these patients actually tolerate a dose reduction?” Dr. Coughlin said. She promoted the role of dermatologists in working at managing side effects to keep patients on medications helping their GI disease, but acknowledged this is not always possible.

Doug Brunk/MDedge News

dbrunk@mdedge.com

About Research in Context

In this article, the authors of recent scholarship have been asked to discuss the implications of their research on federal health care providers and specifically the veteran and active-duty service member patient populations. Because the article does not include new research and cannot be blinded, it has undergone an abbreviated peer review process. The original article can be found at Sullivan DR, Forsberg CW, Ganzini L, et al. Longitudinal changes in depression symptoms and survival among patients with lung cancer: a national cohort assessment. J Clin Oncol. 2016;34(33):3984-3991.

Although depression is common among patients with cancer, patients with lung cancer are at particularly high risk. The prevalence of major depressive disorder (MDD) among patients with cancer can be as high as 13%, whereas up to 44% of patients with lung cancer experience depression symptoms at some point following their cancer diagnosis.^1-3 These estimates are consistently higher than those of other types of cancer, possibly related to the stigma of the disease and the associated morbidity and mortality that are its hallmarks.^4-8 This potentially life-threatening cancer diagnosis often evokes psychological distress; however, additional stressors contribute to the development of depression, including the effects of chemotherapeutic agents, surgical procedures, radiotherapy, and the consequences of physical symptoms and paraneoplastic syndromes.

In addition to the crippling effects of comorbid depression on patients’ quality of life (QOL), severe and persistent depression among patients with cancer is associated with prolonged hospital stays, worse treatment adherence, physical distress and pain, and increased desire for hastened death.^9-11 During treatment, depression can amplify physical symptoms and interfere with effective coping.^12,13

Depression also is likely a significant factor for the risk of suicide, which is 4 times higher in patients with lung cancer than that of the general population.¹⁴ Most important, as our recent study demonstrated, depression that develops at cancer diagnosis or during cancer treatment may contribute to worse survival. This effect was strongest among patients with early stage disease, in other words, the patients who are most likely to achieve cure.³ This association with early stage disease also has been observed in a strictly veteran population from the northwest U.S.¹⁵

Another key finding of our study was the similar survival among patients who experienced a remission of their depression and those who were never depressed. This finding reinforces the importance of effective depression treatment, which has the potential to reduce depression-related mortality; however, depression treatment was not fully captured and could not be directly compared in our study. Unfortunately, comorbid depression often goes undiagnosed and untreated in cancer patients as they report unmet emotional needs and a desire for psychological support during and after completion of cancer treatment.^16,17

Given the general lack of depression treatment that occurs in patients with cancer, the negative consequences of depression can be sustained well into survivorship—defined clinically as someone who is free of any sign of cancer for 5 years. Cancer survivors frequently report fatigue, mood disturbance, sleep disruption, pain, and cognitive limitations that significantly impact QOL and are associated with disability and increased health care use.¹⁸ These symptoms likely are intertwined with and contribute to the development and persistence of depression. The ramifications of untreated depression on long-term cancer survivor outcomes are not completely understood, as few high-quality studies of depression in cancer survivors exist. However, in a mixed group of patients with cancer, there was a 2-fold risk of mortality in survivors with depression symptoms when these patients were assessed from 1 to 10 years into survivorship.¹⁹ The impact of depression on cancer survivorship is an important aspect of cancer care that deserves significantly more attention from both a research and clinical perspective.

Special Considerations for Veterans

There is a higher prevalence of mental health diagnoses in veterans than that in the general population, and depressive disorders are the most common.^20-22 According to the VA National Registry for Depression, 11% of veterans aged ≥ 65 years have a diagnosis of MDD, a rate more than twice that in the general population of a similar age.²³ However, the actual rate of depression among veterans may be even higher, as studies suggest depression is underdiagnosed in the veteran population.²⁴ In addition to depression, veterans experience other disabling psychological illnesses, such as posttraumatic stress disorder (PTSD) related to deployment and combat duty or combat-related injuries, such as traumatic brain injuries. The negative consequences of PTSD on cancer outcomes are largely unexplored, but PTSD can contribute to increased health care utilization and costs.^25,26 A similar psychological construct, cancer-related posttraumatic stress (PTS), which develops as a result of a cancer diagnosis or treatment, is associated with missed medical appointments and procedures, which could impact survival.²⁷

Depression Screening and Treatment

Given the negative consequences of comorbid mental illness, professional oncology societies have started developing guidelines regarding the assessments and care of patients with cancer who are experiencing symptoms of depression and/or anxiety.^11,28,29 Among these, the American Society of Clinical Oncology (ASCO) has adapted the Pan-Canadian Practice Guideline on Screening, Assessment, and Care of Psychosocial Distress (Depression, Anxiety) in Adults With Cancer.²⁸ Per ASCO, the target audience for these guidelines is health care providers (eg, medical, surgical, and radiation oncologists; psychiatrists; psychologists; primary care providers; nurses; and others involved in the delivery of care for adults with cancer) as well as patients with cancer and their family members and caregivers.²⁸ These guidelines address the optimum screening, assessment, and psychosocial-supportive care interventions for adults with cancer who are identified as experiencing symptoms of depression. Among the most imperative recommendations are periodic assessments across the trajectory of cancer care, including after cure, as well as employing institutional and community resources for depression treatment.

In clinical practice in a VA setting, implementing these guidelines might involve various interventions. First, it is vital for providers to conduct depression screening during periodic health care encounters. Given the high prevalence of depression in patients with lung cancer, we suggest using the 9-item Patient Health Questionnaire (PHQ-9) as an initial screening tool.³⁰ Unlike the abridged 2-item PHQ-2 commonly used in the VA, the PHQ-9 provides an assessment of the full range of depressive symptoms. An elevated PHQ-9 score (≥ 10) is consistent with a major depressive episode and should trigger next steps.³⁰

Once clinically significant depression is identified, initiation of treatment should occur next. The VA is well suited to assist and support non-mental health clinicians—particularly primary care—in treatment initiation and monitoring. This model of partnership is frequently called collaborative care, or integrated care, and it is well positioned to help patients with lung cancer with concomitant depression. In the VA, this model of care is called primary care-mental healthintegration (PC-MHI). One PC-MHI resource is called TIDES (Translating Initiatives for Depression into Effective Solutions), and when a patient is referred, a mental health nurse care manager helps to track the patients’ antidepressant adherence and treatment response while reporting results to primary care clinicians, who are generally responsible for initiating and continuing the antidepressant prescription. For patients preferring nonpharmacologic approaches or for whom an antidepressant may be contraindicated, PC-MHI can provide other assistance. For example, psychologists working in PC-MHI are equipped to provide a brief course of cognitive behavioral therapy sessions, another first-line, evidence-based treatment for clinical depression.

Clinician follow-up to ensure patient adherence, response, and satisfaction, and to adjust treatment as needed is essential. Besides ongoing coordination with PC-MHI services, including mental health clinicians as part of multidisciplinary cancer clinics could offer substantial added value to patients’ comprehensive cancer care. Indeed, the initiation of multicomponent depression care has been shown to improve QOL and role functioning in patients with cancer.³¹ Besides the established benefits on QOL, patients with lung cancer who achieve depression symptom remission also may enjoy a significant survival benefit over patients whose depression symptoms remain untreated during lung cancer treatment as our study suggests.³

Conclusion

Depression is a common comorbid disease among patients with lung cancer with important negative implications for QOL and survival. When it occurs after a cancer diagnosis, depression is expected to impact all phases of a patient’s life through treatment and survivorshi —ultimately affecting long-term survival. Veterans may be at particularly high risk given the increased prevalence of mental illness, including depression and PTSD in this group compared with that of the general population. Early detection and prompt treatment can promote depression remission, prevent relapse, and reduce the eventual emotional and financial burden of the disease. This approach may ultimately diminish the prevalence and persistence of depression symptoms and decrease the associated negative effects of this disease on patients with lung cancer.

The importance of integrated systems of depression treatment for patients with cancer as part of comprehensive cancer care cannot be overstated. Development and implementation of these systems should be a priority of lung cancer clinicians and treatment centers. The integrated system within the VA is well positioned to be a leader in this area, and VA clinicians who care for patients with lung cancer are encouraged to take advantage of available mental health resources. Additional research is urgently needed to explore optimal implementation of depression screening and subsequent treatment delivery to improve cancer patient outcomes in VA and non-VA health care settings.

Acknowledgments
This project was supported in part by the National Cancer Institute of the National Institutes of Health under award K07CA190706 to Dr. Sullivan, a Career Development Award from the Veterans Health Administration Health Service Research and Development (CDA 14-428) to Dr. Teo and the HSR&D Center to Improve Veteran Involvement in Care (CIVIC) (CIN 13-404) at the VA Portland Health Care System.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The VA had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies.

Click here to read the digital edition. 

About Research in Context

In this article, the authors of recent scholarship have been asked to discuss the implications of their research on federal health care providers and specifically the veteran and active-duty service member patient populations. Because the article does not include new research and cannot be blinded, it has undergone an abbreviated peer review process. The original article can be found at Sullivan DR, Forsberg CW, Ganzini L, et al. Longitudinal changes in depression symptoms and survival among patients with lung cancer: a national cohort assessment. J Clin Oncol. 2016;34(33):3984-3991.

Although depression is common among patients with cancer, patients with lung cancer are at particularly high risk. The prevalence of major depressive disorder (MDD) among patients with cancer can be as high as 13%, whereas up to 44% of patients with lung cancer experience depression symptoms at some point following their cancer diagnosis.^1-3 These estimates are consistently higher than those of other types of cancer, possibly related to the stigma of the disease and the associated morbidity and mortality that are its hallmarks.^4-8 This potentially life-threatening cancer diagnosis often evokes psychological distress; however, additional stressors contribute to the development of depression, including the effects of chemotherapeutic agents, surgical procedures, radiotherapy, and the consequences of physical symptoms and paraneoplastic syndromes.

In addition to the crippling effects of comorbid depression on patients’ quality of life (QOL), severe and persistent depression among patients with cancer is associated with prolonged hospital stays, worse treatment adherence, physical distress and pain, and increased desire for hastened death.^9-11 During treatment, depression can amplify physical symptoms and interfere with effective coping.^12,13

Depression also is likely a significant factor for the risk of suicide, which is 4 times higher in patients with lung cancer than that of the general population.¹⁴ Most important, as our recent study demonstrated, depression that develops at cancer diagnosis or during cancer treatment may contribute to worse survival. This effect was strongest among patients with early stage disease, in other words, the patients who are most likely to achieve cure.³ This association with early stage disease also has been observed in a strictly veteran population from the northwest U.S.¹⁵

Another key finding of our study was the similar survival among patients who experienced a remission of their depression and those who were never depressed. This finding reinforces the importance of effective depression treatment, which has the potential to reduce depression-related mortality; however, depression treatment was not fully captured and could not be directly compared in our study. Unfortunately, comorbid depression often goes undiagnosed and untreated in cancer patients as they report unmet emotional needs and a desire for psychological support during and after completion of cancer treatment.^16,17

Given the general lack of depression treatment that occurs in patients with cancer, the negative consequences of depression can be sustained well into survivorship—defined clinically as someone who is free of any sign of cancer for 5 years. Cancer survivors frequently report fatigue, mood disturbance, sleep disruption, pain, and cognitive limitations that significantly impact QOL and are associated with disability and increased health care use.¹⁸ These symptoms likely are intertwined with and contribute to the development and persistence of depression. The ramifications of untreated depression on long-term cancer survivor outcomes are not completely understood, as few high-quality studies of depression in cancer survivors exist. However, in a mixed group of patients with cancer, there was a 2-fold risk of mortality in survivors with depression symptoms when these patients were assessed from 1 to 10 years into survivorship.¹⁹ The impact of depression on cancer survivorship is an important aspect of cancer care that deserves significantly more attention from both a research and clinical perspective.

Special Considerations for Veterans

There is a higher prevalence of mental health diagnoses in veterans than that in the general population, and depressive disorders are the most common.^20-22 According to the VA National Registry for Depression, 11% of veterans aged ≥ 65 years have a diagnosis of MDD, a rate more than twice that in the general population of a similar age.²³ However, the actual rate of depression among veterans may be even higher, as studies suggest depression is underdiagnosed in the veteran population.²⁴ In addition to depression, veterans experience other disabling psychological illnesses, such as posttraumatic stress disorder (PTSD) related to deployment and combat duty or combat-related injuries, such as traumatic brain injuries. The negative consequences of PTSD on cancer outcomes are largely unexplored, but PTSD can contribute to increased health care utilization and costs.^25,26 A similar psychological construct, cancer-related posttraumatic stress (PTS), which develops as a result of a cancer diagnosis or treatment, is associated with missed medical appointments and procedures, which could impact survival.²⁷

Depression Screening and Treatment

Given the negative consequences of comorbid mental illness, professional oncology societies have started developing guidelines regarding the assessments and care of patients with cancer who are experiencing symptoms of depression and/or anxiety.^11,28,29 Among these, the American Society of Clinical Oncology (ASCO) has adapted the Pan-Canadian Practice Guideline on Screening, Assessment, and Care of Psychosocial Distress (Depression, Anxiety) in Adults With Cancer.²⁸ Per ASCO, the target audience for these guidelines is health care providers (eg, medical, surgical, and radiation oncologists; psychiatrists; psychologists; primary care providers; nurses; and others involved in the delivery of care for adults with cancer) as well as patients with cancer and their family members and caregivers.²⁸ These guidelines address the optimum screening, assessment, and psychosocial-supportive care interventions for adults with cancer who are identified as experiencing symptoms of depression. Among the most imperative recommendations are periodic assessments across the trajectory of cancer care, including after cure, as well as employing institutional and community resources for depression treatment.

In clinical practice in a VA setting, implementing these guidelines might involve various interventions. First, it is vital for providers to conduct depression screening during periodic health care encounters. Given the high prevalence of depression in patients with lung cancer, we suggest using the 9-item Patient Health Questionnaire (PHQ-9) as an initial screening tool.³⁰ Unlike the abridged 2-item PHQ-2 commonly used in the VA, the PHQ-9 provides an assessment of the full range of depressive symptoms. An elevated PHQ-9 score (≥ 10) is consistent with a major depressive episode and should trigger next steps.³⁰

Once clinically significant depression is identified, initiation of treatment should occur next. The VA is well suited to assist and support non-mental health clinicians—particularly primary care—in treatment initiation and monitoring. This model of partnership is frequently called collaborative care, or integrated care, and it is well positioned to help patients with lung cancer with concomitant depression. In the VA, this model of care is called primary care-mental healthintegration (PC-MHI). One PC-MHI resource is called TIDES (Translating Initiatives for Depression into Effective Solutions), and when a patient is referred, a mental health nurse care manager helps to track the patients’ antidepressant adherence and treatment response while reporting results to primary care clinicians, who are generally responsible for initiating and continuing the antidepressant prescription. For patients preferring nonpharmacologic approaches or for whom an antidepressant may be contraindicated, PC-MHI can provide other assistance. For example, psychologists working in PC-MHI are equipped to provide a brief course of cognitive behavioral therapy sessions, another first-line, evidence-based treatment for clinical depression.

Clinician follow-up to ensure patient adherence, response, and satisfaction, and to adjust treatment as needed is essential. Besides ongoing coordination with PC-MHI services, including mental health clinicians as part of multidisciplinary cancer clinics could offer substantial added value to patients’ comprehensive cancer care. Indeed, the initiation of multicomponent depression care has been shown to improve QOL and role functioning in patients with cancer.³¹ Besides the established benefits on QOL, patients with lung cancer who achieve depression symptom remission also may enjoy a significant survival benefit over patients whose depression symptoms remain untreated during lung cancer treatment as our study suggests.³

Conclusion

Depression is a common comorbid disease among patients with lung cancer with important negative implications for QOL and survival. When it occurs after a cancer diagnosis, depression is expected to impact all phases of a patient’s life through treatment and survivorshi —ultimately affecting long-term survival. Veterans may be at particularly high risk given the increased prevalence of mental illness, including depression and PTSD in this group compared with that of the general population. Early detection and prompt treatment can promote depression remission, prevent relapse, and reduce the eventual emotional and financial burden of the disease. This approach may ultimately diminish the prevalence and persistence of depression symptoms and decrease the associated negative effects of this disease on patients with lung cancer.

The importance of integrated systems of depression treatment for patients with cancer as part of comprehensive cancer care cannot be overstated. Development and implementation of these systems should be a priority of lung cancer clinicians and treatment centers. The integrated system within the VA is well positioned to be a leader in this area, and VA clinicians who care for patients with lung cancer are encouraged to take advantage of available mental health resources. Additional research is urgently needed to explore optimal implementation of depression screening and subsequent treatment delivery to improve cancer patient outcomes in VA and non-VA health care settings.

Acknowledgments
This project was supported in part by the National Cancer Institute of the National Institutes of Health under award K07CA190706 to Dr. Sullivan, a Career Development Award from the Veterans Health Administration Health Service Research and Development (CDA 14-428) to Dr. Teo and the HSR&D Center to Improve Veteran Involvement in Care (CIVIC) (CIN 13-404) at the VA Portland Health Care System.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The VA had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies.

Click here to read the digital edition. 

About Research in Context

In this article, the authors of recent scholarship have been asked to discuss the implications of their research on federal health care providers and specifically the veteran and active-duty service member patient populations. Because the article does not include new research and cannot be blinded, it has undergone an abbreviated peer review process. The original article can be found at Sullivan DR, Forsberg CW, Ganzini L, et al. Longitudinal changes in depression symptoms and survival among patients with lung cancer: a national cohort assessment. J Clin Oncol. 2016;34(33):3984-3991.

Although depression is common among patients with cancer, patients with lung cancer are at particularly high risk. The prevalence of major depressive disorder (MDD) among patients with cancer can be as high as 13%, whereas up to 44% of patients with lung cancer experience depression symptoms at some point following their cancer diagnosis.^1-3 These estimates are consistently higher than those of other types of cancer, possibly related to the stigma of the disease and the associated morbidity and mortality that are its hallmarks.^4-8 This potentially life-threatening cancer diagnosis often evokes psychological distress; however, additional stressors contribute to the development of depression, including the effects of chemotherapeutic agents, surgical procedures, radiotherapy, and the consequences of physical symptoms and paraneoplastic syndromes.

In addition to the crippling effects of comorbid depression on patients’ quality of life (QOL), severe and persistent depression among patients with cancer is associated with prolonged hospital stays, worse treatment adherence, physical distress and pain, and increased desire for hastened death.^9-11 During treatment, depression can amplify physical symptoms and interfere with effective coping.^12,13

Depression also is likely a significant factor for the risk of suicide, which is 4 times higher in patients with lung cancer than that of the general population.¹⁴ Most important, as our recent study demonstrated, depression that develops at cancer diagnosis or during cancer treatment may contribute to worse survival. This effect was strongest among patients with early stage disease, in other words, the patients who are most likely to achieve cure.³ This association with early stage disease also has been observed in a strictly veteran population from the northwest U.S.¹⁵

Another key finding of our study was the similar survival among patients who experienced a remission of their depression and those who were never depressed. This finding reinforces the importance of effective depression treatment, which has the potential to reduce depression-related mortality; however, depression treatment was not fully captured and could not be directly compared in our study. Unfortunately, comorbid depression often goes undiagnosed and untreated in cancer patients as they report unmet emotional needs and a desire for psychological support during and after completion of cancer treatment.^16,17

Given the general lack of depression treatment that occurs in patients with cancer, the negative consequences of depression can be sustained well into survivorship—defined clinically as someone who is free of any sign of cancer for 5 years. Cancer survivors frequently report fatigue, mood disturbance, sleep disruption, pain, and cognitive limitations that significantly impact QOL and are associated with disability and increased health care use.¹⁸ These symptoms likely are intertwined with and contribute to the development and persistence of depression. The ramifications of untreated depression on long-term cancer survivor outcomes are not completely understood, as few high-quality studies of depression in cancer survivors exist. However, in a mixed group of patients with cancer, there was a 2-fold risk of mortality in survivors with depression symptoms when these patients were assessed from 1 to 10 years into survivorship.¹⁹ The impact of depression on cancer survivorship is an important aspect of cancer care that deserves significantly more attention from both a research and clinical perspective.

Special Considerations for Veterans

There is a higher prevalence of mental health diagnoses in veterans than that in the general population, and depressive disorders are the most common.^20-22 According to the VA National Registry for Depression, 11% of veterans aged ≥ 65 years have a diagnosis of MDD, a rate more than twice that in the general population of a similar age.²³ However, the actual rate of depression among veterans may be even higher, as studies suggest depression is underdiagnosed in the veteran population.²⁴ In addition to depression, veterans experience other disabling psychological illnesses, such as posttraumatic stress disorder (PTSD) related to deployment and combat duty or combat-related injuries, such as traumatic brain injuries. The negative consequences of PTSD on cancer outcomes are largely unexplored, but PTSD can contribute to increased health care utilization and costs.^25,26 A similar psychological construct, cancer-related posttraumatic stress (PTS), which develops as a result of a cancer diagnosis or treatment, is associated with missed medical appointments and procedures, which could impact survival.²⁷

Depression Screening and Treatment

Given the negative consequences of comorbid mental illness, professional oncology societies have started developing guidelines regarding the assessments and care of patients with cancer who are experiencing symptoms of depression and/or anxiety.^11,28,29 Among these, the American Society of Clinical Oncology (ASCO) has adapted the Pan-Canadian Practice Guideline on Screening, Assessment, and Care of Psychosocial Distress (Depression, Anxiety) in Adults With Cancer.²⁸ Per ASCO, the target audience for these guidelines is health care providers (eg, medical, surgical, and radiation oncologists; psychiatrists; psychologists; primary care providers; nurses; and others involved in the delivery of care for adults with cancer) as well as patients with cancer and their family members and caregivers.²⁸ These guidelines address the optimum screening, assessment, and psychosocial-supportive care interventions for adults with cancer who are identified as experiencing symptoms of depression. Among the most imperative recommendations are periodic assessments across the trajectory of cancer care, including after cure, as well as employing institutional and community resources for depression treatment.

In clinical practice in a VA setting, implementing these guidelines might involve various interventions. First, it is vital for providers to conduct depression screening during periodic health care encounters. Given the high prevalence of depression in patients with lung cancer, we suggest using the 9-item Patient Health Questionnaire (PHQ-9) as an initial screening tool.³⁰ Unlike the abridged 2-item PHQ-2 commonly used in the VA, the PHQ-9 provides an assessment of the full range of depressive symptoms. An elevated PHQ-9 score (≥ 10) is consistent with a major depressive episode and should trigger next steps.³⁰

Once clinically significant depression is identified, initiation of treatment should occur next. The VA is well suited to assist and support non-mental health clinicians—particularly primary care—in treatment initiation and monitoring. This model of partnership is frequently called collaborative care, or integrated care, and it is well positioned to help patients with lung cancer with concomitant depression. In the VA, this model of care is called primary care-mental healthintegration (PC-MHI). One PC-MHI resource is called TIDES (Translating Initiatives for Depression into Effective Solutions), and when a patient is referred, a mental health nurse care manager helps to track the patients’ antidepressant adherence and treatment response while reporting results to primary care clinicians, who are generally responsible for initiating and continuing the antidepressant prescription. For patients preferring nonpharmacologic approaches or for whom an antidepressant may be contraindicated, PC-MHI can provide other assistance. For example, psychologists working in PC-MHI are equipped to provide a brief course of cognitive behavioral therapy sessions, another first-line, evidence-based treatment for clinical depression.

Clinician follow-up to ensure patient adherence, response, and satisfaction, and to adjust treatment as needed is essential. Besides ongoing coordination with PC-MHI services, including mental health clinicians as part of multidisciplinary cancer clinics could offer substantial added value to patients’ comprehensive cancer care. Indeed, the initiation of multicomponent depression care has been shown to improve QOL and role functioning in patients with cancer.³¹ Besides the established benefits on QOL, patients with lung cancer who achieve depression symptom remission also may enjoy a significant survival benefit over patients whose depression symptoms remain untreated during lung cancer treatment as our study suggests.³

Conclusion

Depression is a common comorbid disease among patients with lung cancer with important negative implications for QOL and survival. When it occurs after a cancer diagnosis, depression is expected to impact all phases of a patient’s life through treatment and survivorshi —ultimately affecting long-term survival. Veterans may be at particularly high risk given the increased prevalence of mental illness, including depression and PTSD in this group compared with that of the general population. Early detection and prompt treatment can promote depression remission, prevent relapse, and reduce the eventual emotional and financial burden of the disease. This approach may ultimately diminish the prevalence and persistence of depression symptoms and decrease the associated negative effects of this disease on patients with lung cancer.

The importance of integrated systems of depression treatment for patients with cancer as part of comprehensive cancer care cannot be overstated. Development and implementation of these systems should be a priority of lung cancer clinicians and treatment centers. The integrated system within the VA is well positioned to be a leader in this area, and VA clinicians who care for patients with lung cancer are encouraged to take advantage of available mental health resources. Additional research is urgently needed to explore optimal implementation of depression screening and subsequent treatment delivery to improve cancer patient outcomes in VA and non-VA health care settings.

Acknowledgments
This project was supported in part by the National Cancer Institute of the National Institutes of Health under award K07CA190706 to Dr. Sullivan, a Career Development Award from the Veterans Health Administration Health Service Research and Development (CDA 14-428) to Dr. Teo and the HSR&D Center to Improve Veteran Involvement in Care (CIVIC) (CIN 13-404) at the VA Portland Health Care System.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The VA had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies.

Click here to read the digital edition. 

When the American Medical Association – one of the nation’s most powerful health care groups – met in Chicago this June, its medical student caucus seized an opportunity for change.

Though they had tried for years to advance a resolution calling on the organization to drop its decades-long opposition to single-payer health care, this was the first time it got a full hearing. The debate grew heated – older physicians warned their pay would decrease, calling younger advocates naive to single-payer’s consequences. But this time, by the meeting’s end, the AMA’s older members had agreed to at least study the possibility of changing its stance.

“We believe health care is a human right, maybe more so than past generations,” said Brad Zehr, MD, a pathology resident at Ohio State University, who was part of the debate. “There’s a generational shift happening, where we see universal health care as a requirement.”

The ins and outs of the AMA’s policymaking may sound like inside baseball. But this year’s youth uprising at the nexus of the medical establishment speaks to a cultural shift in the medical profession, and one with big political implications.

Amid Republican attacks on the Affordable Care Act, an increasing number of Democrats – both candidates and Congress members – are putting forth proposals that would vastly increase the government’s role in running the health system. These include single-payer, Medicare-for-all, or an option for anyone to buy in to the Medicare program. At least 70 House Democrats have signed on to the new “Medicare-for-all” caucus.

Organized medicine, and previous generations of doctors, had for the most part staunchly opposed any such plan. The AMA has thwarted public health insurance proposals since the 1930s and long been considered one of the policy’s most powerful opponents.

But the battle lines are shifting as younger doctors flip their views, a change that will likely assume greater significance as the next generation of physicians takes on leadership roles. The AMA did not make anyone available for comment.

Many younger physicians are “accepting of single-payer,” said Christian Pean, MD, a third-year orthopedic surgery resident at New York University.

In prior generations, “intelligent, motivated, quantitative” students pursued medicine, both for the income and because of the workplace independence – running practices with minimal government interference, said Steven Schroeder, MD, professor of medicine at the University of California, San Francisco.

In his 50 years of teaching, students’ attitudes have changed, he said. “The ‘Oh, keep government out of my work’ feeling is not as strong as it was with maybe older cohorts,” said Dr. Schroeder. “Students come in saying, ‘We want to make a difference through social justice. That’s why we’re here.’ ”

Though single-payer health care long has been dismissed as a left-wing pipe dream, polling suggests a slim majority of Americans now support the idea – though it is not clear people know what the term means.

A full single-payer system means everyone gets coverage from the same insurance plan, usually sponsored by the government. “Medicare for all,” a phrase that gained currency with the presidential campaign of Sen. Bernie Sanders (I-Vt.), means everyone gets Medicare, but, depending on the proposal, it may or may not allow private insurers to offer Medicare as well. (Sen. Sanders’ plan, which eliminates deductibles and expands benefits, would get rid of private insurers.)

Meanwhile, lots of countries achieve universal health care – everyone is covered somehow – but the method can vary. For example, France requires all citizens purchase coverage, which is sold through nonprofits. In Germany, most people get insurance from a government-run “public option,” while others purchase private plans. In England, health care is provided through the tax-funded National Health System.

American skeptics often use the phrase “socialized medicine” pejoratively to describe all of these models.

“Few really understand what you mean when you say single-payer,” said Frank Opelka, MD, medical director of quality and health policy for the American College of Surgeons, which opposes such a policy. “What they mean is, ‘I don’t think the current system is working.’ ”

But the willingness to explore previously unthinkable ideas is evident in young doctors’ ranks.

Recent surveys through LinkedIn, Merritt Hawkins, and NEJM Catalyst indicate growing support. In the March NEJM Catalyst survey, 61% of 607 respondents said single-payer would make it easier to deliver cost-effective, quality health care.

Delving further, that survey shows support is stronger among younger physicians, said Namita Mohta, MD, a hospitalist at Brigham and Women’s Hospital, Boston, and clinical editor at NEJM Catalyst.

But it’s unclear whether these findings reflect young doctors’ feelings about the policy or whether they are tapping in to broader frustrations with the American health system.

Much like the general public, doctors often use terms like single-payer, Medicare for all, and universal health care interchangeably.

“Our younger generation is less afraid to come out and say we want universal health care,” said Anna Yap, MD, an emergency medicine resident at UCLA, who served as a medical student delegate to the AMA until this past June. “But how? It’s different in what forms we see.”

Younger doctors also pointed to growing concern about how best to keep patients healthy. They cited research that broadly suggests having health insurance tracks with better health outcomes.

“Medical students, I would say, are very interested in public health and improving social determinants of health – one of them being access to health insurance,” said Jerome Jeevarajan, MD, a neurology resident at the University of Texas–Houston, referring to nonmedical factors that improve health, such as food or housing.

Some of the shift in opinion has to do with the changing realities of medical practice. Doctors now are more likely to end up working for large health systems or hospitals, rather than starting a practice. Combined with the increasing complexity of billing private insurance, many said, that means contracting with the government may feel like less of an intrusion.

The debate is, at this point, still theoretical. Republicans – who control the White House and both houses of Congress – sharply oppose single-payer. Meanwhile, single-state efforts in California, Colorado, and New York have fallen flat.

Also, doctors represent only one part of the sprawling health care industrial complex. Other health care interests – including private insurance, the drug industry, and hospital trade groups – have been slower to warm to catchphrases like single-payer or universal health care, all of which would likely mean a drop in income.

But increasingly physicians seem to be switching sides in the debate, and young physicians want to be part of the discussion.

“There’s tremendous potential ... to be at the table if single-payer becomes a significant part of the political discourse, and create a system that is more equitable,” Dr. Pean said.

Kaiser Health News is a nonprofit national health policy news service. It is an editorially independent program of the Henry J. Kaiser Family Foundation that is not affiliated with Kaiser Permanente.

When the American Medical Association – one of the nation’s most powerful health care groups – met in Chicago this June, its medical student caucus seized an opportunity for change.

Though they had tried for years to advance a resolution calling on the organization to drop its decades-long opposition to single-payer health care, this was the first time it got a full hearing. The debate grew heated – older physicians warned their pay would decrease, calling younger advocates naive to single-payer’s consequences. But this time, by the meeting’s end, the AMA’s older members had agreed to at least study the possibility of changing its stance.

“We believe health care is a human right, maybe more so than past generations,” said Brad Zehr, MD, a pathology resident at Ohio State University, who was part of the debate. “There’s a generational shift happening, where we see universal health care as a requirement.”

The ins and outs of the AMA’s policymaking may sound like inside baseball. But this year’s youth uprising at the nexus of the medical establishment speaks to a cultural shift in the medical profession, and one with big political implications.

Amid Republican attacks on the Affordable Care Act, an increasing number of Democrats – both candidates and Congress members – are putting forth proposals that would vastly increase the government’s role in running the health system. These include single-payer, Medicare-for-all, or an option for anyone to buy in to the Medicare program. At least 70 House Democrats have signed on to the new “Medicare-for-all” caucus.

Organized medicine, and previous generations of doctors, had for the most part staunchly opposed any such plan. The AMA has thwarted public health insurance proposals since the 1930s and long been considered one of the policy’s most powerful opponents.

But the battle lines are shifting as younger doctors flip their views, a change that will likely assume greater significance as the next generation of physicians takes on leadership roles. The AMA did not make anyone available for comment.

Many younger physicians are “accepting of single-payer,” said Christian Pean, MD, a third-year orthopedic surgery resident at New York University.

In prior generations, “intelligent, motivated, quantitative” students pursued medicine, both for the income and because of the workplace independence – running practices with minimal government interference, said Steven Schroeder, MD, professor of medicine at the University of California, San Francisco.

In his 50 years of teaching, students’ attitudes have changed, he said. “The ‘Oh, keep government out of my work’ feeling is not as strong as it was with maybe older cohorts,” said Dr. Schroeder. “Students come in saying, ‘We want to make a difference through social justice. That’s why we’re here.’ ”

Though single-payer health care long has been dismissed as a left-wing pipe dream, polling suggests a slim majority of Americans now support the idea – though it is not clear people know what the term means.

A full single-payer system means everyone gets coverage from the same insurance plan, usually sponsored by the government. “Medicare for all,” a phrase that gained currency with the presidential campaign of Sen. Bernie Sanders (I-Vt.), means everyone gets Medicare, but, depending on the proposal, it may or may not allow private insurers to offer Medicare as well. (Sen. Sanders’ plan, which eliminates deductibles and expands benefits, would get rid of private insurers.)

Meanwhile, lots of countries achieve universal health care – everyone is covered somehow – but the method can vary. For example, France requires all citizens purchase coverage, which is sold through nonprofits. In Germany, most people get insurance from a government-run “public option,” while others purchase private plans. In England, health care is provided through the tax-funded National Health System.

American skeptics often use the phrase “socialized medicine” pejoratively to describe all of these models.

“Few really understand what you mean when you say single-payer,” said Frank Opelka, MD, medical director of quality and health policy for the American College of Surgeons, which opposes such a policy. “What they mean is, ‘I don’t think the current system is working.’ ”

But the willingness to explore previously unthinkable ideas is evident in young doctors’ ranks.

Recent surveys through LinkedIn, Merritt Hawkins, and NEJM Catalyst indicate growing support. In the March NEJM Catalyst survey, 61% of 607 respondents said single-payer would make it easier to deliver cost-effective, quality health care.

Delving further, that survey shows support is stronger among younger physicians, said Namita Mohta, MD, a hospitalist at Brigham and Women’s Hospital, Boston, and clinical editor at NEJM Catalyst.

But it’s unclear whether these findings reflect young doctors’ feelings about the policy or whether they are tapping in to broader frustrations with the American health system.

Much like the general public, doctors often use terms like single-payer, Medicare for all, and universal health care interchangeably.

“Our younger generation is less afraid to come out and say we want universal health care,” said Anna Yap, MD, an emergency medicine resident at UCLA, who served as a medical student delegate to the AMA until this past June. “But how? It’s different in what forms we see.”

Younger doctors also pointed to growing concern about how best to keep patients healthy. They cited research that broadly suggests having health insurance tracks with better health outcomes.

“Medical students, I would say, are very interested in public health and improving social determinants of health – one of them being access to health insurance,” said Jerome Jeevarajan, MD, a neurology resident at the University of Texas–Houston, referring to nonmedical factors that improve health, such as food or housing.

Some of the shift in opinion has to do with the changing realities of medical practice. Doctors now are more likely to end up working for large health systems or hospitals, rather than starting a practice. Combined with the increasing complexity of billing private insurance, many said, that means contracting with the government may feel like less of an intrusion.

The debate is, at this point, still theoretical. Republicans – who control the White House and both houses of Congress – sharply oppose single-payer. Meanwhile, single-state efforts in California, Colorado, and New York have fallen flat.

Also, doctors represent only one part of the sprawling health care industrial complex. Other health care interests – including private insurance, the drug industry, and hospital trade groups – have been slower to warm to catchphrases like single-payer or universal health care, all of which would likely mean a drop in income.

But increasingly physicians seem to be switching sides in the debate, and young physicians want to be part of the discussion.

“There’s tremendous potential ... to be at the table if single-payer becomes a significant part of the political discourse, and create a system that is more equitable,” Dr. Pean said.

Kaiser Health News is a nonprofit national health policy news service. It is an editorially independent program of the Henry J. Kaiser Family Foundation that is not affiliated with Kaiser Permanente.

When the American Medical Association – one of the nation’s most powerful health care groups – met in Chicago this June, its medical student caucus seized an opportunity for change.

Though they had tried for years to advance a resolution calling on the organization to drop its decades-long opposition to single-payer health care, this was the first time it got a full hearing. The debate grew heated – older physicians warned their pay would decrease, calling younger advocates naive to single-payer’s consequences. But this time, by the meeting’s end, the AMA’s older members had agreed to at least study the possibility of changing its stance.

“We believe health care is a human right, maybe more so than past generations,” said Brad Zehr, MD, a pathology resident at Ohio State University, who was part of the debate. “There’s a generational shift happening, where we see universal health care as a requirement.”

The ins and outs of the AMA’s policymaking may sound like inside baseball. But this year’s youth uprising at the nexus of the medical establishment speaks to a cultural shift in the medical profession, and one with big political implications.

Amid Republican attacks on the Affordable Care Act, an increasing number of Democrats – both candidates and Congress members – are putting forth proposals that would vastly increase the government’s role in running the health system. These include single-payer, Medicare-for-all, or an option for anyone to buy in to the Medicare program. At least 70 House Democrats have signed on to the new “Medicare-for-all” caucus.

Organized medicine, and previous generations of doctors, had for the most part staunchly opposed any such plan. The AMA has thwarted public health insurance proposals since the 1930s and long been considered one of the policy’s most powerful opponents.

But the battle lines are shifting as younger doctors flip their views, a change that will likely assume greater significance as the next generation of physicians takes on leadership roles. The AMA did not make anyone available for comment.

Many younger physicians are “accepting of single-payer,” said Christian Pean, MD, a third-year orthopedic surgery resident at New York University.

In prior generations, “intelligent, motivated, quantitative” students pursued medicine, both for the income and because of the workplace independence – running practices with minimal government interference, said Steven Schroeder, MD, professor of medicine at the University of California, San Francisco.

In his 50 years of teaching, students’ attitudes have changed, he said. “The ‘Oh, keep government out of my work’ feeling is not as strong as it was with maybe older cohorts,” said Dr. Schroeder. “Students come in saying, ‘We want to make a difference through social justice. That’s why we’re here.’ ”

Though single-payer health care long has been dismissed as a left-wing pipe dream, polling suggests a slim majority of Americans now support the idea – though it is not clear people know what the term means.

A full single-payer system means everyone gets coverage from the same insurance plan, usually sponsored by the government. “Medicare for all,” a phrase that gained currency with the presidential campaign of Sen. Bernie Sanders (I-Vt.), means everyone gets Medicare, but, depending on the proposal, it may or may not allow private insurers to offer Medicare as well. (Sen. Sanders’ plan, which eliminates deductibles and expands benefits, would get rid of private insurers.)

Meanwhile, lots of countries achieve universal health care – everyone is covered somehow – but the method can vary. For example, France requires all citizens purchase coverage, which is sold through nonprofits. In Germany, most people get insurance from a government-run “public option,” while others purchase private plans. In England, health care is provided through the tax-funded National Health System.

American skeptics often use the phrase “socialized medicine” pejoratively to describe all of these models.

“Few really understand what you mean when you say single-payer,” said Frank Opelka, MD, medical director of quality and health policy for the American College of Surgeons, which opposes such a policy. “What they mean is, ‘I don’t think the current system is working.’ ”

But the willingness to explore previously unthinkable ideas is evident in young doctors’ ranks.

Recent surveys through LinkedIn, Merritt Hawkins, and NEJM Catalyst indicate growing support. In the March NEJM Catalyst survey, 61% of 607 respondents said single-payer would make it easier to deliver cost-effective, quality health care.

Delving further, that survey shows support is stronger among younger physicians, said Namita Mohta, MD, a hospitalist at Brigham and Women’s Hospital, Boston, and clinical editor at NEJM Catalyst.

But it’s unclear whether these findings reflect young doctors’ feelings about the policy or whether they are tapping in to broader frustrations with the American health system.

Much like the general public, doctors often use terms like single-payer, Medicare for all, and universal health care interchangeably.

“Our younger generation is less afraid to come out and say we want universal health care,” said Anna Yap, MD, an emergency medicine resident at UCLA, who served as a medical student delegate to the AMA until this past June. “But how? It’s different in what forms we see.”

Younger doctors also pointed to growing concern about how best to keep patients healthy. They cited research that broadly suggests having health insurance tracks with better health outcomes.

“Medical students, I would say, are very interested in public health and improving social determinants of health – one of them being access to health insurance,” said Jerome Jeevarajan, MD, a neurology resident at the University of Texas–Houston, referring to nonmedical factors that improve health, such as food or housing.

Some of the shift in opinion has to do with the changing realities of medical practice. Doctors now are more likely to end up working for large health systems or hospitals, rather than starting a practice. Combined with the increasing complexity of billing private insurance, many said, that means contracting with the government may feel like less of an intrusion.

The debate is, at this point, still theoretical. Republicans – who control the White House and both houses of Congress – sharply oppose single-payer. Meanwhile, single-state efforts in California, Colorado, and New York have fallen flat.

Also, doctors represent only one part of the sprawling health care industrial complex. Other health care interests – including private insurance, the drug industry, and hospital trade groups – have been slower to warm to catchphrases like single-payer or universal health care, all of which would likely mean a drop in income.

But increasingly physicians seem to be switching sides in the debate, and young physicians want to be part of the discussion.

“There’s tremendous potential ... to be at the table if single-payer becomes a significant part of the political discourse, and create a system that is more equitable,” Dr. Pean said.

Kaiser Health News is a nonprofit national health policy news service. It is an editorially independent program of the Henry J. Kaiser Family Foundation that is not affiliated with Kaiser Permanente.

Many patients with primary central nervous system lymphoma (PCNSL) experience rapid, aggressive progression of CNS malignancy. It is “accepted,” say researchers from Chonnam National University Hwasun Hospital in the Republic of Korea, that salvage therapy is beneficial and significantly improves survival in comparison to palliative care, but therapy options remain limited—mainly because few trials have been done. Several case reports have suggested that bendamustine has modest clinical activity against relapsed PCNSL, the researchers note, but its effect as part of combination salvage therapy in these patients has not been established. The study offers some validation of previous findings and new information about the benefits of a bendamustine-based combination regimen.

The researchers enrolled 10 patients, of whom 7 had refractory disease. All had previously been on high-dose methotrexate. Of the 3 relapsed patients, 1 entered the study at second relapse. The patients received either R-B(O)AD or R-BAD (rituximab, vincristine, bendamustine, cytarabine, dexamethasone) every 4 weeks for up to 4 cycles. Vincristine was omitted in 4 regimens, and dosages of bendamustine and cytarabine were reduced for 4 patients who were over 70.

The overall response rate for R-B(O)AD was 50%. One patient achieved complete response and 4 achieved partial response. The researchers observed “remarkable effects” on imaging in patients who responded. They attribute the activity to the anticipated synergy of bendamustine combined with cytarabine—even though disease in the majority of the patients had progressed despite previous treatment with cytarabine.

However, the synergistic effects also led to significant marrow depression; hematologic toxicity with R-B(O)AD was “considerable,” with grade 3 or 4 neutropenia and thrombocytopenia seen in more than 85% of treatment cycles. Moreover, 3 patients developed severe infection, all with involvement of the lungs. The researchers therefore amended the study protocol to reduce cytarabine dosage. While the toxicity is significant, the researchers say, it is manageable with the dose reduction and supportive care.

Bendamustine cerebrospinal fluid levels were minimal, but corresponded to plasma exposure and response to treatment in deep tumor locations.

Although the study is small, it supports the use of the bendamustine-based regimen as an effective salvage option, the researchers conclude, especially for patients who are no longer responding to methotrexate or have developed cumulative renal or neurotoxicity from treatment.

Source:
Kim T, Choi HY, Lee HS, et al. BMC Cancer. 2018;18(1):729

Many patients with primary central nervous system lymphoma (PCNSL) experience rapid, aggressive progression of CNS malignancy. It is “accepted,” say researchers from Chonnam National University Hwasun Hospital in the Republic of Korea, that salvage therapy is beneficial and significantly improves survival in comparison to palliative care, but therapy options remain limited—mainly because few trials have been done. Several case reports have suggested that bendamustine has modest clinical activity against relapsed PCNSL, the researchers note, but its effect as part of combination salvage therapy in these patients has not been established. The study offers some validation of previous findings and new information about the benefits of a bendamustine-based combination regimen.

The researchers enrolled 10 patients, of whom 7 had refractory disease. All had previously been on high-dose methotrexate. Of the 3 relapsed patients, 1 entered the study at second relapse. The patients received either R-B(O)AD or R-BAD (rituximab, vincristine, bendamustine, cytarabine, dexamethasone) every 4 weeks for up to 4 cycles. Vincristine was omitted in 4 regimens, and dosages of bendamustine and cytarabine were reduced for 4 patients who were over 70.

The overall response rate for R-B(O)AD was 50%. One patient achieved complete response and 4 achieved partial response. The researchers observed “remarkable effects” on imaging in patients who responded. They attribute the activity to the anticipated synergy of bendamustine combined with cytarabine—even though disease in the majority of the patients had progressed despite previous treatment with cytarabine.

However, the synergistic effects also led to significant marrow depression; hematologic toxicity with R-B(O)AD was “considerable,” with grade 3 or 4 neutropenia and thrombocytopenia seen in more than 85% of treatment cycles. Moreover, 3 patients developed severe infection, all with involvement of the lungs. The researchers therefore amended the study protocol to reduce cytarabine dosage. While the toxicity is significant, the researchers say, it is manageable with the dose reduction and supportive care.

Bendamustine cerebrospinal fluid levels were minimal, but corresponded to plasma exposure and response to treatment in deep tumor locations.

Although the study is small, it supports the use of the bendamustine-based regimen as an effective salvage option, the researchers conclude, especially for patients who are no longer responding to methotrexate or have developed cumulative renal or neurotoxicity from treatment.

Source:
Kim T, Choi HY, Lee HS, et al. BMC Cancer. 2018;18(1):729

Many patients with primary central nervous system lymphoma (PCNSL) experience rapid, aggressive progression of CNS malignancy. It is “accepted,” say researchers from Chonnam National University Hwasun Hospital in the Republic of Korea, that salvage therapy is beneficial and significantly improves survival in comparison to palliative care, but therapy options remain limited—mainly because few trials have been done. Several case reports have suggested that bendamustine has modest clinical activity against relapsed PCNSL, the researchers note, but its effect as part of combination salvage therapy in these patients has not been established. The study offers some validation of previous findings and new information about the benefits of a bendamustine-based combination regimen.

The researchers enrolled 10 patients, of whom 7 had refractory disease. All had previously been on high-dose methotrexate. Of the 3 relapsed patients, 1 entered the study at second relapse. The patients received either R-B(O)AD or R-BAD (rituximab, vincristine, bendamustine, cytarabine, dexamethasone) every 4 weeks for up to 4 cycles. Vincristine was omitted in 4 regimens, and dosages of bendamustine and cytarabine were reduced for 4 patients who were over 70.

The overall response rate for R-B(O)AD was 50%. One patient achieved complete response and 4 achieved partial response. The researchers observed “remarkable effects” on imaging in patients who responded. They attribute the activity to the anticipated synergy of bendamustine combined with cytarabine—even though disease in the majority of the patients had progressed despite previous treatment with cytarabine.

However, the synergistic effects also led to significant marrow depression; hematologic toxicity with R-B(O)AD was “considerable,” with grade 3 or 4 neutropenia and thrombocytopenia seen in more than 85% of treatment cycles. Moreover, 3 patients developed severe infection, all with involvement of the lungs. The researchers therefore amended the study protocol to reduce cytarabine dosage. While the toxicity is significant, the researchers say, it is manageable with the dose reduction and supportive care.

Bendamustine cerebrospinal fluid levels were minimal, but corresponded to plasma exposure and response to treatment in deep tumor locations.

Although the study is small, it supports the use of the bendamustine-based regimen as an effective salvage option, the researchers conclude, especially for patients who are no longer responding to methotrexate or have developed cumulative renal or neurotoxicity from treatment.

Source:
Kim T, Choi HY, Lee HS, et al. BMC Cancer. 2018;18(1):729

In this interview, Dr David Henry and Dr Maura Sammon discuss some of the most common immunotherapy-related side effects – lung, gastrointestinal, rash, and endocrine-related problems – and Dr Sammon describes in detail how physicians in the ED would triage and treat the patient. However, the overarching takeaway is the importance of communication: first, between the oncologist and patient, so that the patient is aware of these nuances in advance of an emergency, and second, between the ED physician and the treating oncologist soon after the patient has presented and undergone an initial assessment.

Dr Henry is Editor-in-Chief of  the JCSO, and Dr Sammon is at the Lewis Katz School of Medicine, Temple University, in Philadelphia, Pennsylvania

Listen here:

In this interview, Dr David Henry and Dr Maura Sammon discuss some of the most common immunotherapy-related side effects – lung, gastrointestinal, rash, and endocrine-related problems – and Dr Sammon describes in detail how physicians in the ED would triage and treat the patient. However, the overarching takeaway is the importance of communication: first, between the oncologist and patient, so that the patient is aware of these nuances in advance of an emergency, and second, between the ED physician and the treating oncologist soon after the patient has presented and undergone an initial assessment.

Dr Henry is Editor-in-Chief of  the JCSO, and Dr Sammon is at the Lewis Katz School of Medicine, Temple University, in Philadelphia, Pennsylvania

Listen here:

In this interview, Dr David Henry and Dr Maura Sammon discuss some of the most common immunotherapy-related side effects – lung, gastrointestinal, rash, and endocrine-related problems – and Dr Sammon describes in detail how physicians in the ED would triage and treat the patient. However, the overarching takeaway is the importance of communication: first, between the oncologist and patient, so that the patient is aware of these nuances in advance of an emergency, and second, between the ED physician and the treating oncologist soon after the patient has presented and undergone an initial assessment.

Dr Henry is Editor-in-Chief of  the JCSO, and Dr Sammon is at the Lewis Katz School of Medicine, Temple University, in Philadelphia, Pennsylvania

Listen here:

Case Presentation. A 64-year-old US Army veteran with a history of colorectal cancer, melanoma, and fibrinolytic presented with dyspnea to VA Boston Healthcare System (VABHS). Seven years prior to the current presentation, at the time of her diagnosis of colorectal cancer, the patient was found to be HIV negative but to have a positive purified protein derivative (PPD) test. She was treated with isoniazid (INH) therapy for 9 months. Sputum cultures collected prior to initiation of therapy grew Mycobacterium avium complex (MAC) in 1 of 3 samples, with these results reported several months after initiation of therapy. She was a never smoker with no known travel or exposure. At the time of the current presentation, her medications included bupropion, levothyroxine, capsaicin, cyclobenzaprine, ibuprofen, and acetaminophen.

►Lakshmana Swamy, MD, Chief Medical Resident, VABHS and Boston Medical Center. Dr. Monach, this patient is on a variety of pain medications and has a diagnosis of fibromyalgia. This diagnosis often frustrates doctors and patients alike. Can you tell us about fibromyalgia from the rheumatologist’s perspective and what you think of her current treatment regimen?

►Paul A. Monach, MD, PhD, Chief, Section of Rheumatology, VABHS and Associate Professor of Medicine, Boston University School of Medicine. Fibromyalgia is a syndrome of chronic widespread pain without known pathology in the musculoskeletal system. It is thought to be caused by chronic dysfunction of pain-processing pathways in the central nervous system (CNS). It is often accompanied by other somatic symptoms such as chronic fatigue, irritable bowel syndrome, and bladder pain. It is a common condition, affecting up to 5% of otherwise healthy women. It is particularly common in persons with chronic nonrestorative sleep or posttraumatic stress disorder from a wide range of causes. However, it also is more common in persons with autoimmune inflammatory diseases, such as lupus, Sjögren syndrome, or rheumatoid arthritis. Concern for one of these diseases is the main reason to consider referring a patient for evaluation by a rheumatologist. Often rheumatologists participate in the management of fibromyalgia. A patient should be given appropriate expectations by the referring physician.

Effectiveness of treatment varies widely among patients. Nonpharmacologic approaches such as aerobic exercise, cognitive behavioral therapy, and tai chi have support from clinical trials, and yoga and aquatherapy also are widely used.^1,2 The classes of drugs used are the same as for neuropathic pain: tricyclics, including cyclobenzaprine; serotonin and norepinephrine reuptake inhibitors (SNRIs); and gabapentinoids. In contrast, nonsteroidal anti-inflammatory drugs and opioids are ineffective unless there is a superimposed mechanical or inflammatory cause in the periphery. The key point is that continuation of any treatment should be based entirely on the patient’s own assessment of benefit.

►Dr. Swamy. Seven years later, the patient returned to her primary care provider, reporting increased dyspnea on exertion as well as significant fatigue. She was referred to the pulmonary department and had repeat computed tomography (CT) scans of the chest, which indicated persistent right middle lobe (RML) bronchiectasis. She then underwent bronchoscopy with a subsequent bronchoalveolar lavage (BAL) culture growing MAC. Dr. Fine, please interpret the baseline and follow-up CT scans and help us understand the significance of the MAC on sputum and BAL cultures.

►Alan Fine, MD, Section of Pulmonary and Critical Care, VABHS and Professor of Medicine, Boston University School of Medicine. Prior to this presentation, the patient had a pleural-based area of fibrosis with possible associated RML bronchiectasis. This appears to be a postinflammatory process without classic features of malignant or metastatic disease. She then had a sputum, which grew MAC in only 1 of 3 samples and in liquid media only. Importantly, the sputum was not smear positive. All of this suggests a low organism burden. One possibility is that this could reflect colonization with MAC; it is not uncommon for patients with underlying chronic changes in their lung to grow MAC, and it is often difficult to tell whether it is indicative of active disease. Structural lung disease, such as bronchiectasis, predisposes a patient to MAC, but chronic MAC also may cause bronchiectasis. This chicken-and-egg scenario comes up frequently. She may have a MAC infection, but as she is HIV negative and asymptomatic, there is no urgent indication to treat, especially as the burden of therapy is not insignificant.

►Dr. Swamy. Do we need to worry about Mycobacterium tuberculosis (MTB)?

►Dr. Fine. Although she was previously PPD positive, she had already completed 1 year of isoniazid (INH) therapy, making active MTB less likely. From an infection control standpoint, it is important to distinguish MAC from MTB. The former is not contagious, and there is no need for airborne isolation.

►Dr. Swamy. Dr. Fine, where does MAC come from? Does it commonly cause disease?

►Dr. Fine. In the environment, MAC is nearly ubiquitous , especially in water and soil. In one study, 20% of showerheads were positive for MAC; when patients are infected, we may suggest changing/bleaching the showerhead, but there are no definitive recommendations.³ Because MAC is so common in the environment, it is unlikely that measures to target MAC colonization will be clinically meaningful. On the other hand, the incidence of nontuberculous mycobacterial infections is increasing across the US, and it may be a common and frequently underdiagnosed cause of chronic cough, especially in postmenopausal women.

►Dr. Swamy. Four years prior to the current presentation, the patient developed a cough after an upper respiratory tract infection that persisted for more than 2 weeks. Given her history, she underwent a repeat chest CT, which noted a slight increase in nodularity and ground-glass opacity restricted to the RML. She also reported dyspnea on exertion and was referred to the pulmonary medicine department. By the time she arrived, her dyspnea had largely resolved, but she reported persistent fatigue without other systemic symptoms, such as fevers or chills. Dr. Fine, does MAC explain this patient’s dyspnea?

►Dr. Fine. As her pulmonary symptoms resolved in a short period of time with only azithromycin, it is very unlikely that her symptoms were related to her prior disease. The MAC infection is not likely to cause dyspnea on exertion and fatigue and should be worked up more broadly before attributing it to MAC. In view of this, it would not be unreasonable to follow her clinically and see her again in 6 to 8 weeks. In this context, we also should consider the untoward impact of repeated radiation exposure derived from multiple CT scans. When a patient has an abnormality on CT scan, it often leads to further scans even if the symptoms do not match the previous findings, as in this case.

►Dr. Swamy. Given her ongoing fatigue and systemic symptoms (morning stiffness of the shoulders, legs, and thighs, and leg cramps), she was referred to the rheumatology department where the physical examination revealed muscle tenderness in her proximal arms and legs with normal strength, tender points at the elbows and medial side of the bilateral knees, significant tenderness of lower legs, and no synovitis.

Dr. Monach, can you walk us through your approach to this patient? Are we seeing manifestations of fibromyalgia? What diagnoses concerns you and how would you proceed?

►Dr. Monach. The history and exam are most helpful in raising or reducing suspicion for an underlying inflammatory disease. Areas of tenderness described in her case are typical of fibromyalgia, although it can be difficult to interpret symptoms in the hip girdle and shoulder girdle because objective findings are often absent on exam in patients with inflammatory arthritis or bursitis. Similarly, tenderness at sites of tendon insertion (enthuses) without objective abnormalities is common in different forms of spondyloarthritis, so tenderness at the elbow, knee, lateral hip, and low back can be difficult to interpret. What this patient is lacking is prominent subjective or objective findings in the joints most commonly affected in rheumatoid arthritis and lupus: wrists, hands, ankles, and feet.

►Dr. Swamy. Initial laboratory data include an erythrocyte sedimentation rate of 79 with a normal C-reactive protein. A tentative diagnosis of polymyalgia rheumatic is made with consideration of a trial treatment of prednisone.

Dr. Monach, this patient has an indolent infection and is about to be given glucocorticoids. Could you describe the situations in which you feel that glucocorticoids cause a relative immunosuppression?

►Dr. Monach. Glucocorticoids are considered safe in a patient whose infection is not intrinsically dangerous or who has started appropriate antibiotics for that infection. Although all toxicities of glucocorticoids are dose dependent, the long-standing assertion that doses below 10 mg to 15 mg do not increase risk of infection is contradicted by data published in the past 10 to 15 years, with the caveat that these patients were on long-term treatment.

►Dr. Swamy. The patient was started on prednisone 15 mg per day for 15 days. She returned to the clinic after 1 week of prednisone troutment and noted “significant improvement in fatigue, morning stiffness of shoulders, thighs, leg, back is better, leg cramps resolved, shooting pain in many joints resolved.” Further laboratory results were notable for a negative rheumatoid factor, negative antinuclear antibody, and a cyclic citrullinated peptide of 60. A presumptive diagnosis of rheumatoid arthritis (RA) was made and plaquenil 200 mg twice daily was started.

Dr. Monach, can you explain why RA comes up now on serology but was not considered initially? Why does this presentation fit RA, and was her response to treatment typical? How does this fit in with her previous diagnosis of fibromyalgia? Was that just an atypical, indolent presentation of RA?

►Dr. Monach. Though her presentation is atypical for RA, in elderly patients, RA can present with symptoms resembling polymyalgia rheumatica. The question is whether she had RA all along (in which case “elderly onset” would not apply) or had fibromyalgia and developed RA more recently. The response to empiric glucocorticoid therapy is helpful, since fibromyalgia should not improve with prednisone even in a patient with RA unless treatment of RA would allow better sleep and ability to exercise. Rheumatoid arthritis typically responds very well to prednisone in the 5-mg to 15-mg range.

►Dr. Swamy. Given the new diagnosis of an inflammatory arthritis requiring immunosuppression, bronchoscopy with BAL is performed to evaluate for the presence of MAC. These cultures were positive for MAC.

Dr. Fine, does the positive BAL culture indicate an active MAC infection?

►Dr. Fine. Yes, based on these updated data, the patient has an active MAC infection. Active infection is defined as symptoms or imaging consistent with the diagnosis, supporting microbiology data (either 2 sputum or 1 BAL sample growing MAC) and the exclusion of other causes. Previously, this patient grew MAC in just one expectorated sputum; this did not meet the microbiologic criteria. Now sputum has grown in the BAL sample; along with the CT imaging, this is enough to diagnosis active MAC infection.

Treatment for MAC must consider the details of each case. First, this is not an emergency; treatment decisions should be made with the rheumatologist to consider the planned immunosuppression. For example, we must consider potential drug interactions. A specific point should be made of the use of tumor necrosis factor (TNF)-α inhibition, which data indicate can reactivate TB and may inhibit mechanisms that restrain mycobacterial disease. Serious cases of MAC infection have been reported in the literature in the setting of TNF-α inhibition.^5,6 Despite these concerns, there is not a contraindication to using these therapies from the perspective of the active MAC disease. All of these decisions will impact the need to commit the patient to MAC therapy.

►Dr. Swamy. Dr. Fine, what do you consider prior to initiating MAC therapy?

► Dr. Fine. The decision to pursue MAC therapy should not be taken lightly. Therapy often entails prolonged multidrug regimens, usually spanning more than a year, with frequent adverse effects. Outside of very specific cases, such as TNF-β inhibition, MAC is rarely a life-threatening disease, so the benefit may be limited. Treatment for MAC is certainly unlikely to be fruitful without a diligent and motivated patient able to handle the high and prolonged pill burden. Of note, it is also important to keep this patient up-to-date with influenza and pneumonia vaccination given her structural lung disease.

►Dr. Swamy. The decision is made to treat MAC with azithromycin, rifampin, and ethambutol. The disease is noted to be nonfibrocavitary. The patient underwent monthly liver function test monitoring and visual acuity testing, which were unremarkable. Dr. Fine, can you describe the phenotypes of nontuberculous mycobacterial (NTM) disease?

►Dr. Fine. There are 3 main phenotypes of NTM.³ First, we see the elderly man with preexisting lung disease—usually chronic obstructive pulmonary disease—with fibrocavitary and/or reticulonodular appearance. Second, we see the slim, elderly woman often without any preexisting lung disease presenting with focal bronchiectasis and nodular lesions in right middle lobe and lingula—the Lady Windermere syndrome. This eponym is derived from Oscar Wilde’s play “Lady Windermere’s Fan, a Play About a Good Woman,” and was first associated with this disease in 1992.⁷ At the time, it was thought that the voluntary suppression of cough led to poorly draining lung regions, vulnerable to engraftment by atypical mycobacteria. Infection with atypical mycobacteria are associated with this population; however, it is no longer thought to be due to the voluntary suppression of cough.^7,8 Third, we do occasionally see atypical presentations, such as focal masses and solitary nodules.

►Dr. Swamy. At 1-year follow-up she successfully completed MAC therapy and noted ongoing control of rheumatoid symptoms.

Case Presentation. A 64-year-old US Army veteran with a history of colorectal cancer, melanoma, and fibrinolytic presented with dyspnea to VA Boston Healthcare System (VABHS). Seven years prior to the current presentation, at the time of her diagnosis of colorectal cancer, the patient was found to be HIV negative but to have a positive purified protein derivative (PPD) test. She was treated with isoniazid (INH) therapy for 9 months. Sputum cultures collected prior to initiation of therapy grew Mycobacterium avium complex (MAC) in 1 of 3 samples, with these results reported several months after initiation of therapy. She was a never smoker with no known travel or exposure. At the time of the current presentation, her medications included bupropion, levothyroxine, capsaicin, cyclobenzaprine, ibuprofen, and acetaminophen.

►Lakshmana Swamy, MD, Chief Medical Resident, VABHS and Boston Medical Center. Dr. Monach, this patient is on a variety of pain medications and has a diagnosis of fibromyalgia. This diagnosis often frustrates doctors and patients alike. Can you tell us about fibromyalgia from the rheumatologist’s perspective and what you think of her current treatment regimen?

►Paul A. Monach, MD, PhD, Chief, Section of Rheumatology, VABHS and Associate Professor of Medicine, Boston University School of Medicine. Fibromyalgia is a syndrome of chronic widespread pain without known pathology in the musculoskeletal system. It is thought to be caused by chronic dysfunction of pain-processing pathways in the central nervous system (CNS). It is often accompanied by other somatic symptoms such as chronic fatigue, irritable bowel syndrome, and bladder pain. It is a common condition, affecting up to 5% of otherwise healthy women. It is particularly common in persons with chronic nonrestorative sleep or posttraumatic stress disorder from a wide range of causes. However, it also is more common in persons with autoimmune inflammatory diseases, such as lupus, Sjögren syndrome, or rheumatoid arthritis. Concern for one of these diseases is the main reason to consider referring a patient for evaluation by a rheumatologist. Often rheumatologists participate in the management of fibromyalgia. A patient should be given appropriate expectations by the referring physician.

Effectiveness of treatment varies widely among patients. Nonpharmacologic approaches such as aerobic exercise, cognitive behavioral therapy, and tai chi have support from clinical trials, and yoga and aquatherapy also are widely used.^1,2 The classes of drugs used are the same as for neuropathic pain: tricyclics, including cyclobenzaprine; serotonin and norepinephrine reuptake inhibitors (SNRIs); and gabapentinoids. In contrast, nonsteroidal anti-inflammatory drugs and opioids are ineffective unless there is a superimposed mechanical or inflammatory cause in the periphery. The key point is that continuation of any treatment should be based entirely on the patient’s own assessment of benefit.

►Dr. Swamy. Seven years later, the patient returned to her primary care provider, reporting increased dyspnea on exertion as well as significant fatigue. She was referred to the pulmonary department and had repeat computed tomography (CT) scans of the chest, which indicated persistent right middle lobe (RML) bronchiectasis. She then underwent bronchoscopy with a subsequent bronchoalveolar lavage (BAL) culture growing MAC. Dr. Fine, please interpret the baseline and follow-up CT scans and help us understand the significance of the MAC on sputum and BAL cultures.

►Alan Fine, MD, Section of Pulmonary and Critical Care, VABHS and Professor of Medicine, Boston University School of Medicine. Prior to this presentation, the patient had a pleural-based area of fibrosis with possible associated RML bronchiectasis. This appears to be a postinflammatory process without classic features of malignant or metastatic disease. She then had a sputum, which grew MAC in only 1 of 3 samples and in liquid media only. Importantly, the sputum was not smear positive. All of this suggests a low organism burden. One possibility is that this could reflect colonization with MAC; it is not uncommon for patients with underlying chronic changes in their lung to grow MAC, and it is often difficult to tell whether it is indicative of active disease. Structural lung disease, such as bronchiectasis, predisposes a patient to MAC, but chronic MAC also may cause bronchiectasis. This chicken-and-egg scenario comes up frequently. She may have a MAC infection, but as she is HIV negative and asymptomatic, there is no urgent indication to treat, especially as the burden of therapy is not insignificant.

►Dr. Swamy. Do we need to worry about Mycobacterium tuberculosis (MTB)?

►Dr. Fine. Although she was previously PPD positive, she had already completed 1 year of isoniazid (INH) therapy, making active MTB less likely. From an infection control standpoint, it is important to distinguish MAC from MTB. The former is not contagious, and there is no need for airborne isolation.

►Dr. Swamy. Dr. Fine, where does MAC come from? Does it commonly cause disease?

►Dr. Fine. In the environment, MAC is nearly ubiquitous , especially in water and soil. In one study, 20% of showerheads were positive for MAC; when patients are infected, we may suggest changing/bleaching the showerhead, but there are no definitive recommendations.³ Because MAC is so common in the environment, it is unlikely that measures to target MAC colonization will be clinically meaningful. On the other hand, the incidence of nontuberculous mycobacterial infections is increasing across the US, and it may be a common and frequently underdiagnosed cause of chronic cough, especially in postmenopausal women.

►Dr. Swamy. Four years prior to the current presentation, the patient developed a cough after an upper respiratory tract infection that persisted for more than 2 weeks. Given her history, she underwent a repeat chest CT, which noted a slight increase in nodularity and ground-glass opacity restricted to the RML. She also reported dyspnea on exertion and was referred to the pulmonary medicine department. By the time she arrived, her dyspnea had largely resolved, but she reported persistent fatigue without other systemic symptoms, such as fevers or chills. Dr. Fine, does MAC explain this patient’s dyspnea?

►Dr. Fine. As her pulmonary symptoms resolved in a short period of time with only azithromycin, it is very unlikely that her symptoms were related to her prior disease. The MAC infection is not likely to cause dyspnea on exertion and fatigue and should be worked up more broadly before attributing it to MAC. In view of this, it would not be unreasonable to follow her clinically and see her again in 6 to 8 weeks. In this context, we also should consider the untoward impact of repeated radiation exposure derived from multiple CT scans. When a patient has an abnormality on CT scan, it often leads to further scans even if the symptoms do not match the previous findings, as in this case.

►Dr. Swamy. Given her ongoing fatigue and systemic symptoms (morning stiffness of the shoulders, legs, and thighs, and leg cramps), she was referred to the rheumatology department where the physical examination revealed muscle tenderness in her proximal arms and legs with normal strength, tender points at the elbows and medial side of the bilateral knees, significant tenderness of lower legs, and no synovitis.

Dr. Monach, can you walk us through your approach to this patient? Are we seeing manifestations of fibromyalgia? What diagnoses concerns you and how would you proceed?

►Dr. Monach. The history and exam are most helpful in raising or reducing suspicion for an underlying inflammatory disease. Areas of tenderness described in her case are typical of fibromyalgia, although it can be difficult to interpret symptoms in the hip girdle and shoulder girdle because objective findings are often absent on exam in patients with inflammatory arthritis or bursitis. Similarly, tenderness at sites of tendon insertion (enthuses) without objective abnormalities is common in different forms of spondyloarthritis, so tenderness at the elbow, knee, lateral hip, and low back can be difficult to interpret. What this patient is lacking is prominent subjective or objective findings in the joints most commonly affected in rheumatoid arthritis and lupus: wrists, hands, ankles, and feet.

►Dr. Swamy. Initial laboratory data include an erythrocyte sedimentation rate of 79 with a normal C-reactive protein. A tentative diagnosis of polymyalgia rheumatic is made with consideration of a trial treatment of prednisone.

Dr. Monach, this patient has an indolent infection and is about to be given glucocorticoids. Could you describe the situations in which you feel that glucocorticoids cause a relative immunosuppression?

►Dr. Monach. Glucocorticoids are considered safe in a patient whose infection is not intrinsically dangerous or who has started appropriate antibiotics for that infection. Although all toxicities of glucocorticoids are dose dependent, the long-standing assertion that doses below 10 mg to 15 mg do not increase risk of infection is contradicted by data published in the past 10 to 15 years, with the caveat that these patients were on long-term treatment.

►Dr. Swamy. The patient was started on prednisone 15 mg per day for 15 days. She returned to the clinic after 1 week of prednisone troutment and noted “significant improvement in fatigue, morning stiffness of shoulders, thighs, leg, back is better, leg cramps resolved, shooting pain in many joints resolved.” Further laboratory results were notable for a negative rheumatoid factor, negative antinuclear antibody, and a cyclic citrullinated peptide of 60. A presumptive diagnosis of rheumatoid arthritis (RA) was made and plaquenil 200 mg twice daily was started.

Dr. Monach, can you explain why RA comes up now on serology but was not considered initially? Why does this presentation fit RA, and was her response to treatment typical? How does this fit in with her previous diagnosis of fibromyalgia? Was that just an atypical, indolent presentation of RA?

►Dr. Monach. Though her presentation is atypical for RA, in elderly patients, RA can present with symptoms resembling polymyalgia rheumatica. The question is whether she had RA all along (in which case “elderly onset” would not apply) or had fibromyalgia and developed RA more recently. The response to empiric glucocorticoid therapy is helpful, since fibromyalgia should not improve with prednisone even in a patient with RA unless treatment of RA would allow better sleep and ability to exercise. Rheumatoid arthritis typically responds very well to prednisone in the 5-mg to 15-mg range.

►Dr. Swamy. Given the new diagnosis of an inflammatory arthritis requiring immunosuppression, bronchoscopy with BAL is performed to evaluate for the presence of MAC. These cultures were positive for MAC.

Dr. Fine, does the positive BAL culture indicate an active MAC infection?

►Dr. Fine. Yes, based on these updated data, the patient has an active MAC infection. Active infection is defined as symptoms or imaging consistent with the diagnosis, supporting microbiology data (either 2 sputum or 1 BAL sample growing MAC) and the exclusion of other causes. Previously, this patient grew MAC in just one expectorated sputum; this did not meet the microbiologic criteria. Now sputum has grown in the BAL sample; along with the CT imaging, this is enough to diagnosis active MAC infection.

Treatment for MAC must consider the details of each case. First, this is not an emergency; treatment decisions should be made with the rheumatologist to consider the planned immunosuppression. For example, we must consider potential drug interactions. A specific point should be made of the use of tumor necrosis factor (TNF)-α inhibition, which data indicate can reactivate TB and may inhibit mechanisms that restrain mycobacterial disease. Serious cases of MAC infection have been reported in the literature in the setting of TNF-α inhibition.^5,6 Despite these concerns, there is not a contraindication to using these therapies from the perspective of the active MAC disease. All of these decisions will impact the need to commit the patient to MAC therapy.

►Dr. Swamy. Dr. Fine, what do you consider prior to initiating MAC therapy?

► Dr. Fine. The decision to pursue MAC therapy should not be taken lightly. Therapy often entails prolonged multidrug regimens, usually spanning more than a year, with frequent adverse effects. Outside of very specific cases, such as TNF-β inhibition, MAC is rarely a life-threatening disease, so the benefit may be limited. Treatment for MAC is certainly unlikely to be fruitful without a diligent and motivated patient able to handle the high and prolonged pill burden. Of note, it is also important to keep this patient up-to-date with influenza and pneumonia vaccination given her structural lung disease.

►Dr. Swamy. The decision is made to treat MAC with azithromycin, rifampin, and ethambutol. The disease is noted to be nonfibrocavitary. The patient underwent monthly liver function test monitoring and visual acuity testing, which were unremarkable. Dr. Fine, can you describe the phenotypes of nontuberculous mycobacterial (NTM) disease?

►Dr. Fine. There are 3 main phenotypes of NTM.³ First, we see the elderly man with preexisting lung disease—usually chronic obstructive pulmonary disease—with fibrocavitary and/or reticulonodular appearance. Second, we see the slim, elderly woman often without any preexisting lung disease presenting with focal bronchiectasis and nodular lesions in right middle lobe and lingula—the Lady Windermere syndrome. This eponym is derived from Oscar Wilde’s play “Lady Windermere’s Fan, a Play About a Good Woman,” and was first associated with this disease in 1992.⁷ At the time, it was thought that the voluntary suppression of cough led to poorly draining lung regions, vulnerable to engraftment by atypical mycobacteria. Infection with atypical mycobacteria are associated with this population; however, it is no longer thought to be due to the voluntary suppression of cough.^7,8 Third, we do occasionally see atypical presentations, such as focal masses and solitary nodules.

►Dr. Swamy. At 1-year follow-up she successfully completed MAC therapy and noted ongoing control of rheumatoid symptoms.

Case Presentation. A 64-year-old US Army veteran with a history of colorectal cancer, melanoma, and fibrinolytic presented with dyspnea to VA Boston Healthcare System (VABHS). Seven years prior to the current presentation, at the time of her diagnosis of colorectal cancer, the patient was found to be HIV negative but to have a positive purified protein derivative (PPD) test. She was treated with isoniazid (INH) therapy for 9 months. Sputum cultures collected prior to initiation of therapy grew Mycobacterium avium complex (MAC) in 1 of 3 samples, with these results reported several months after initiation of therapy. She was a never smoker with no known travel or exposure. At the time of the current presentation, her medications included bupropion, levothyroxine, capsaicin, cyclobenzaprine, ibuprofen, and acetaminophen.

►Lakshmana Swamy, MD, Chief Medical Resident, VABHS and Boston Medical Center. Dr. Monach, this patient is on a variety of pain medications and has a diagnosis of fibromyalgia. This diagnosis often frustrates doctors and patients alike. Can you tell us about fibromyalgia from the rheumatologist’s perspective and what you think of her current treatment regimen?

►Paul A. Monach, MD, PhD, Chief, Section of Rheumatology, VABHS and Associate Professor of Medicine, Boston University School of Medicine. Fibromyalgia is a syndrome of chronic widespread pain without known pathology in the musculoskeletal system. It is thought to be caused by chronic dysfunction of pain-processing pathways in the central nervous system (CNS). It is often accompanied by other somatic symptoms such as chronic fatigue, irritable bowel syndrome, and bladder pain. It is a common condition, affecting up to 5% of otherwise healthy women. It is particularly common in persons with chronic nonrestorative sleep or posttraumatic stress disorder from a wide range of causes. However, it also is more common in persons with autoimmune inflammatory diseases, such as lupus, Sjögren syndrome, or rheumatoid arthritis. Concern for one of these diseases is the main reason to consider referring a patient for evaluation by a rheumatologist. Often rheumatologists participate in the management of fibromyalgia. A patient should be given appropriate expectations by the referring physician.

Effectiveness of treatment varies widely among patients. Nonpharmacologic approaches such as aerobic exercise, cognitive behavioral therapy, and tai chi have support from clinical trials, and yoga and aquatherapy also are widely used.^1,2 The classes of drugs used are the same as for neuropathic pain: tricyclics, including cyclobenzaprine; serotonin and norepinephrine reuptake inhibitors (SNRIs); and gabapentinoids. In contrast, nonsteroidal anti-inflammatory drugs and opioids are ineffective unless there is a superimposed mechanical or inflammatory cause in the periphery. The key point is that continuation of any treatment should be based entirely on the patient’s own assessment of benefit.

►Dr. Swamy. Seven years later, the patient returned to her primary care provider, reporting increased dyspnea on exertion as well as significant fatigue. She was referred to the pulmonary department and had repeat computed tomography (CT) scans of the chest, which indicated persistent right middle lobe (RML) bronchiectasis. She then underwent bronchoscopy with a subsequent bronchoalveolar lavage (BAL) culture growing MAC. Dr. Fine, please interpret the baseline and follow-up CT scans and help us understand the significance of the MAC on sputum and BAL cultures.

►Alan Fine, MD, Section of Pulmonary and Critical Care, VABHS and Professor of Medicine, Boston University School of Medicine. Prior to this presentation, the patient had a pleural-based area of fibrosis with possible associated RML bronchiectasis. This appears to be a postinflammatory process without classic features of malignant or metastatic disease. She then had a sputum, which grew MAC in only 1 of 3 samples and in liquid media only. Importantly, the sputum was not smear positive. All of this suggests a low organism burden. One possibility is that this could reflect colonization with MAC; it is not uncommon for patients with underlying chronic changes in their lung to grow MAC, and it is often difficult to tell whether it is indicative of active disease. Structural lung disease, such as bronchiectasis, predisposes a patient to MAC, but chronic MAC also may cause bronchiectasis. This chicken-and-egg scenario comes up frequently. She may have a MAC infection, but as she is HIV negative and asymptomatic, there is no urgent indication to treat, especially as the burden of therapy is not insignificant.

►Dr. Swamy. Do we need to worry about Mycobacterium tuberculosis (MTB)?

►Dr. Fine. Although she was previously PPD positive, she had already completed 1 year of isoniazid (INH) therapy, making active MTB less likely. From an infection control standpoint, it is important to distinguish MAC from MTB. The former is not contagious, and there is no need for airborne isolation.

►Dr. Swamy. Dr. Fine, where does MAC come from? Does it commonly cause disease?

►Dr. Fine. In the environment, MAC is nearly ubiquitous , especially in water and soil. In one study, 20% of showerheads were positive for MAC; when patients are infected, we may suggest changing/bleaching the showerhead, but there are no definitive recommendations.³ Because MAC is so common in the environment, it is unlikely that measures to target MAC colonization will be clinically meaningful. On the other hand, the incidence of nontuberculous mycobacterial infections is increasing across the US, and it may be a common and frequently underdiagnosed cause of chronic cough, especially in postmenopausal women.

►Dr. Swamy. Four years prior to the current presentation, the patient developed a cough after an upper respiratory tract infection that persisted for more than 2 weeks. Given her history, she underwent a repeat chest CT, which noted a slight increase in nodularity and ground-glass opacity restricted to the RML. She also reported dyspnea on exertion and was referred to the pulmonary medicine department. By the time she arrived, her dyspnea had largely resolved, but she reported persistent fatigue without other systemic symptoms, such as fevers or chills. Dr. Fine, does MAC explain this patient’s dyspnea?

►Dr. Fine. As her pulmonary symptoms resolved in a short period of time with only azithromycin, it is very unlikely that her symptoms were related to her prior disease. The MAC infection is not likely to cause dyspnea on exertion and fatigue and should be worked up more broadly before attributing it to MAC. In view of this, it would not be unreasonable to follow her clinically and see her again in 6 to 8 weeks. In this context, we also should consider the untoward impact of repeated radiation exposure derived from multiple CT scans. When a patient has an abnormality on CT scan, it often leads to further scans even if the symptoms do not match the previous findings, as in this case.

►Dr. Swamy. Given her ongoing fatigue and systemic symptoms (morning stiffness of the shoulders, legs, and thighs, and leg cramps), she was referred to the rheumatology department where the physical examination revealed muscle tenderness in her proximal arms and legs with normal strength, tender points at the elbows and medial side of the bilateral knees, significant tenderness of lower legs, and no synovitis.

Dr. Monach, can you walk us through your approach to this patient? Are we seeing manifestations of fibromyalgia? What diagnoses concerns you and how would you proceed?

►Dr. Monach. The history and exam are most helpful in raising or reducing suspicion for an underlying inflammatory disease. Areas of tenderness described in her case are typical of fibromyalgia, although it can be difficult to interpret symptoms in the hip girdle and shoulder girdle because objective findings are often absent on exam in patients with inflammatory arthritis or bursitis. Similarly, tenderness at sites of tendon insertion (enthuses) without objective abnormalities is common in different forms of spondyloarthritis, so tenderness at the elbow, knee, lateral hip, and low back can be difficult to interpret. What this patient is lacking is prominent subjective or objective findings in the joints most commonly affected in rheumatoid arthritis and lupus: wrists, hands, ankles, and feet.

►Dr. Swamy. Initial laboratory data include an erythrocyte sedimentation rate of 79 with a normal C-reactive protein. A tentative diagnosis of polymyalgia rheumatic is made with consideration of a trial treatment of prednisone.

Dr. Monach, this patient has an indolent infection and is about to be given glucocorticoids. Could you describe the situations in which you feel that glucocorticoids cause a relative immunosuppression?

►Dr. Monach. Glucocorticoids are considered safe in a patient whose infection is not intrinsically dangerous or who has started appropriate antibiotics for that infection. Although all toxicities of glucocorticoids are dose dependent, the long-standing assertion that doses below 10 mg to 15 mg do not increase risk of infection is contradicted by data published in the past 10 to 15 years, with the caveat that these patients were on long-term treatment.

►Dr. Swamy. The patient was started on prednisone 15 mg per day for 15 days. She returned to the clinic after 1 week of prednisone troutment and noted “significant improvement in fatigue, morning stiffness of shoulders, thighs, leg, back is better, leg cramps resolved, shooting pain in many joints resolved.” Further laboratory results were notable for a negative rheumatoid factor, negative antinuclear antibody, and a cyclic citrullinated peptide of 60. A presumptive diagnosis of rheumatoid arthritis (RA) was made and plaquenil 200 mg twice daily was started.

Dr. Monach, can you explain why RA comes up now on serology but was not considered initially? Why does this presentation fit RA, and was her response to treatment typical? How does this fit in with her previous diagnosis of fibromyalgia? Was that just an atypical, indolent presentation of RA?

►Dr. Monach. Though her presentation is atypical for RA, in elderly patients, RA can present with symptoms resembling polymyalgia rheumatica. The question is whether she had RA all along (in which case “elderly onset” would not apply) or had fibromyalgia and developed RA more recently. The response to empiric glucocorticoid therapy is helpful, since fibromyalgia should not improve with prednisone even in a patient with RA unless treatment of RA would allow better sleep and ability to exercise. Rheumatoid arthritis typically responds very well to prednisone in the 5-mg to 15-mg range.

►Dr. Swamy. Given the new diagnosis of an inflammatory arthritis requiring immunosuppression, bronchoscopy with BAL is performed to evaluate for the presence of MAC. These cultures were positive for MAC.

Dr. Fine, does the positive BAL culture indicate an active MAC infection?

►Dr. Fine. Yes, based on these updated data, the patient has an active MAC infection. Active infection is defined as symptoms or imaging consistent with the diagnosis, supporting microbiology data (either 2 sputum or 1 BAL sample growing MAC) and the exclusion of other causes. Previously, this patient grew MAC in just one expectorated sputum; this did not meet the microbiologic criteria. Now sputum has grown in the BAL sample; along with the CT imaging, this is enough to diagnosis active MAC infection.

Treatment for MAC must consider the details of each case. First, this is not an emergency; treatment decisions should be made with the rheumatologist to consider the planned immunosuppression. For example, we must consider potential drug interactions. A specific point should be made of the use of tumor necrosis factor (TNF)-α inhibition, which data indicate can reactivate TB and may inhibit mechanisms that restrain mycobacterial disease. Serious cases of MAC infection have been reported in the literature in the setting of TNF-α inhibition.^5,6 Despite these concerns, there is not a contraindication to using these therapies from the perspective of the active MAC disease. All of these decisions will impact the need to commit the patient to MAC therapy.

►Dr. Swamy. Dr. Fine, what do you consider prior to initiating MAC therapy?

► Dr. Fine. The decision to pursue MAC therapy should not be taken lightly. Therapy often entails prolonged multidrug regimens, usually spanning more than a year, with frequent adverse effects. Outside of very specific cases, such as TNF-β inhibition, MAC is rarely a life-threatening disease, so the benefit may be limited. Treatment for MAC is certainly unlikely to be fruitful without a diligent and motivated patient able to handle the high and prolonged pill burden. Of note, it is also important to keep this patient up-to-date with influenza and pneumonia vaccination given her structural lung disease.

►Dr. Swamy. The decision is made to treat MAC with azithromycin, rifampin, and ethambutol. The disease is noted to be nonfibrocavitary. The patient underwent monthly liver function test monitoring and visual acuity testing, which were unremarkable. Dr. Fine, can you describe the phenotypes of nontuberculous mycobacterial (NTM) disease?

►Dr. Fine. There are 3 main phenotypes of NTM.³ First, we see the elderly man with preexisting lung disease—usually chronic obstructive pulmonary disease—with fibrocavitary and/or reticulonodular appearance. Second, we see the slim, elderly woman often without any preexisting lung disease presenting with focal bronchiectasis and nodular lesions in right middle lobe and lingula—the Lady Windermere syndrome. This eponym is derived from Oscar Wilde’s play “Lady Windermere’s Fan, a Play About a Good Woman,” and was first associated with this disease in 1992.⁷ At the time, it was thought that the voluntary suppression of cough led to poorly draining lung regions, vulnerable to engraftment by atypical mycobacteria. Infection with atypical mycobacteria are associated with this population; however, it is no longer thought to be due to the voluntary suppression of cough.^7,8 Third, we do occasionally see atypical presentations, such as focal masses and solitary nodules.

►Dr. Swamy. At 1-year follow-up she successfully completed MAC therapy and noted ongoing control of rheumatoid symptoms.

The Food and Drug Administration has issued a safety alert warning against long-term use of azithromycin to prevent bronchiolitis obliterans syndrome in patients with blood or lymph node cancers who have received donor stem cell transplants.

cpalmer@mdedge.com

The Food and Drug Administration has issued a safety alert warning against long-term use of azithromycin to prevent bronchiolitis obliterans syndrome in patients with blood or lymph node cancers who have received donor stem cell transplants.

cpalmer@mdedge.com

The Food and Drug Administration has issued a safety alert warning against long-term use of azithromycin to prevent bronchiolitis obliterans syndrome in patients with blood or lymph node cancers who have received donor stem cell transplants.

cpalmer@mdedge.com