Editor’s note: SHM occasionally puts the spotlight on our most active members who are making substantial contributions to hospital medicine. Visit www.hospitalmedicine.org for more information on how you can lend your expertise to help improve the care of hospitalized patients.

This month, The Hospitalist spotlights Ramin Yazdanfar, MD, hospitalist and Harrisburg (Pa.) site medical director at UPMC Pinnacle. Dr. Ramin has been a member of SHM since 2016, has attended two annual conferences as well as Leadership Academy, and together with his team received SHM’s Award of Excellence in Teamwork.
 

How did you learn about SHM and why did you become a member?

I first heard about SHM during my initial job out of residency. At that time, our medical director encouraged engagement in the field of hospital medicine, and he was quite involved in local meetings and national conferences. I became a member because I felt it would be a good way to connect with other hospitalists who might have been going through similar experiences and struggles, and in the hopes of gaining something I could take back to use in my daily practice.

Which SHM conferences have you attended and why?

I have attended two national conferences thus far. The first was the 2016 SHM Annual Conference in San Diego, where our hospitalist team won the Excellence in Teamwork and Quality Improvement Award for our active bed management program under Mary Ellen Pfeiffer, MD, and William “Tex” Landis, MD, among others. I also attended the 2017 Leadership Academy in Scottsdale, Ariz. As a new site director for a new hospitalist group, I thought it would be a valuable learning experience, with the goal of improving my communication as a leader. I also will be attending the 2018 SHM Leadership Academy in Vancouver. I am excited to reconnect with peers I met last year and to advance my leadership skills further.

What were the main takeaways from Leadership: Mastering Teamwork, and how have you applied them in your practice?

My most vivid and actionable memory of Leadership: Mastering Teamwork was the initial session around the five dysfunctions of a team and how to build a cohesive leadership team. Allowing ourselves to be vulnerable and open creates the foundation of trust, on which we can build everything else, such as handling conflict and creating commitment, accountability, and results. I have tried to use these principles in our own practice, at UPMC Pinnacle Health in Harrisburg, Pa. We have an ever-growing health system with an expanding regional leadership team. We base our foundation on trust in one another, and in our vision, so the rest follows suit.

As a separate takeaway, I really enjoyed sessions with Leonard Marcus, PhD, on SWARM Intelligence and Meta-Leadership. He is a very engaging speaker whom I would recommend to anyone considering the Mastering Teamwork session.
 

What advice do you have for early-career hospitalists looking to advance their career in hospital medicine?

My advice to early-career hospitalists is to be open to opportunity. There is so much change and development in the field of hospital medicine. While the foundation of our job is in the patient care realm, many of us find a niche that interests us. My advice is pursue it and be open to what follows, without forgetting that we do this for our patients and community.

Ms. Steele is a marketing communications specialist at the Society of Hospital Medicine.

Editor’s note: SHM occasionally puts the spotlight on our most active members who are making substantial contributions to hospital medicine. Visit www.hospitalmedicine.org for more information on how you can lend your expertise to help improve the care of hospitalized patients.

This month, The Hospitalist spotlights Ramin Yazdanfar, MD, hospitalist and Harrisburg (Pa.) site medical director at UPMC Pinnacle. Dr. Ramin has been a member of SHM since 2016, has attended two annual conferences as well as Leadership Academy, and together with his team received SHM’s Award of Excellence in Teamwork.
 

How did you learn about SHM and why did you become a member?

I first heard about SHM during my initial job out of residency. At that time, our medical director encouraged engagement in the field of hospital medicine, and he was quite involved in local meetings and national conferences. I became a member because I felt it would be a good way to connect with other hospitalists who might have been going through similar experiences and struggles, and in the hopes of gaining something I could take back to use in my daily practice.

Which SHM conferences have you attended and why?

I have attended two national conferences thus far. The first was the 2016 SHM Annual Conference in San Diego, where our hospitalist team won the Excellence in Teamwork and Quality Improvement Award for our active bed management program under Mary Ellen Pfeiffer, MD, and William “Tex” Landis, MD, among others. I also attended the 2017 Leadership Academy in Scottsdale, Ariz. As a new site director for a new hospitalist group, I thought it would be a valuable learning experience, with the goal of improving my communication as a leader. I also will be attending the 2018 SHM Leadership Academy in Vancouver. I am excited to reconnect with peers I met last year and to advance my leadership skills further.

What were the main takeaways from Leadership: Mastering Teamwork, and how have you applied them in your practice?

My most vivid and actionable memory of Leadership: Mastering Teamwork was the initial session around the five dysfunctions of a team and how to build a cohesive leadership team. Allowing ourselves to be vulnerable and open creates the foundation of trust, on which we can build everything else, such as handling conflict and creating commitment, accountability, and results. I have tried to use these principles in our own practice, at UPMC Pinnacle Health in Harrisburg, Pa. We have an ever-growing health system with an expanding regional leadership team. We base our foundation on trust in one another, and in our vision, so the rest follows suit.

As a separate takeaway, I really enjoyed sessions with Leonard Marcus, PhD, on SWARM Intelligence and Meta-Leadership. He is a very engaging speaker whom I would recommend to anyone considering the Mastering Teamwork session.
 

What advice do you have for early-career hospitalists looking to advance their career in hospital medicine?

My advice to early-career hospitalists is to be open to opportunity. There is so much change and development in the field of hospital medicine. While the foundation of our job is in the patient care realm, many of us find a niche that interests us. My advice is pursue it and be open to what follows, without forgetting that we do this for our patients and community.

Ms. Steele is a marketing communications specialist at the Society of Hospital Medicine.

Editor’s note: SHM occasionally puts the spotlight on our most active members who are making substantial contributions to hospital medicine. Visit www.hospitalmedicine.org for more information on how you can lend your expertise to help improve the care of hospitalized patients.

This month, The Hospitalist spotlights Ramin Yazdanfar, MD, hospitalist and Harrisburg (Pa.) site medical director at UPMC Pinnacle. Dr. Ramin has been a member of SHM since 2016, has attended two annual conferences as well as Leadership Academy, and together with his team received SHM’s Award of Excellence in Teamwork.
 

How did you learn about SHM and why did you become a member?

I first heard about SHM during my initial job out of residency. At that time, our medical director encouraged engagement in the field of hospital medicine, and he was quite involved in local meetings and national conferences. I became a member because I felt it would be a good way to connect with other hospitalists who might have been going through similar experiences and struggles, and in the hopes of gaining something I could take back to use in my daily practice.

Which SHM conferences have you attended and why?

I have attended two national conferences thus far. The first was the 2016 SHM Annual Conference in San Diego, where our hospitalist team won the Excellence in Teamwork and Quality Improvement Award for our active bed management program under Mary Ellen Pfeiffer, MD, and William “Tex” Landis, MD, among others. I also attended the 2017 Leadership Academy in Scottsdale, Ariz. As a new site director for a new hospitalist group, I thought it would be a valuable learning experience, with the goal of improving my communication as a leader. I also will be attending the 2018 SHM Leadership Academy in Vancouver. I am excited to reconnect with peers I met last year and to advance my leadership skills further.

What were the main takeaways from Leadership: Mastering Teamwork, and how have you applied them in your practice?

My most vivid and actionable memory of Leadership: Mastering Teamwork was the initial session around the five dysfunctions of a team and how to build a cohesive leadership team. Allowing ourselves to be vulnerable and open creates the foundation of trust, on which we can build everything else, such as handling conflict and creating commitment, accountability, and results. I have tried to use these principles in our own practice, at UPMC Pinnacle Health in Harrisburg, Pa. We have an ever-growing health system with an expanding regional leadership team. We base our foundation on trust in one another, and in our vision, so the rest follows suit.

As a separate takeaway, I really enjoyed sessions with Leonard Marcus, PhD, on SWARM Intelligence and Meta-Leadership. He is a very engaging speaker whom I would recommend to anyone considering the Mastering Teamwork session.
 

What advice do you have for early-career hospitalists looking to advance their career in hospital medicine?

My advice to early-career hospitalists is to be open to opportunity. There is so much change and development in the field of hospital medicine. While the foundation of our job is in the patient care realm, many of us find a niche that interests us. My advice is pursue it and be open to what follows, without forgetting that we do this for our patients and community.

Ms. Steele is a marketing communications specialist at the Society of Hospital Medicine.

Compared with patients who underwent drainage for treatment of symptomatic malignant pleural effusions that was guided by symptoms, patients who underwent once-daily drainage had similar breathless scores but an increased rate of spontaneous pleurodesis and better quality of life scores, according to recent research published in the Lancet Respiratory Medicine.

Nephron/Wikimedia Commons/CC-BY-SA-3.0

“In patients in whom pleurodesis is an important goal (e.g., those undertaking strategies involving an indwelling pleural catheter plus pleurodesing agents), aggressive drainage should be done for at least 60 days,” Sanjeevan Muruganandan, FRACP, MBBS, from Sir Charles Gairdner Hospital in Perth, Australia, and his colleagues wrote in their study. “Future studies will need to establish if more aggressive (e.g., twice daily) regimens for the initial phase could further enhance success rates.”

Dr. Muruganandan and his colleagues evaluated 87 patients with symptomatic malignant pleural effusions between July 2015 and January 2017 from 11 centers in Australia, New Zealand, Hong Kong, and Malaysia in the randomized controlled AMPLE-2 trial, in which patients received either once daily (43 patients) or symptom-guided (44 patients) drainage for 60 days with a 6-month follow-up. Patients were excluded if they had a pleural infection, were pregnant, had a previous pneumonectomy or ipsilateral lobectomy, had “significant loculations likely to preclude effective fluid drainage,” or had an estimated survival of less than 3 months. Patients were identified and grouped based on whether they had mesothelioma- or nonmesothelioma-type cancer, with cancer type being minimalized during randomization.

At 60 days, patients in the aggressive daily drainage group had a mean daily breathless score of 13.1 mm (geometric means; 95% confidence interval, 9.8-17.4), compared with a mean of 17.3 mm (95% CI, 13.0-22.0) in the symptom-guided drainage group. In the aggressive drainage group, 16 of 43 patients (37.2%) achieved spontaneous pleurodesis at 60 days, compared with 11 of 44 patients (11.4%) in the symptom-guided drainage group (P = .0049). At 6 months, 19 of 43 (44.2%) patients in the aggressive drainage group had spontaneous pleurodesis, compared with 7 of 44 patients (15.9%; P = .004) in the symptom-guided drainage group (hazard ratio, 3.287; 95% CI, 1.396-7.740; P = .0065).

In each group, the investigators noted adverse events: 11 of 43 (25.6%) patients in the aggressive drainage group and 12 of 44 patients (27.3%) in the symptom-guided drainage group reported a severe adverse event. There were no significant differences in mortality, pain scores, and hospital stay between the groups. Regarding quality of life, the investigators found patients in the aggressive drainage group reported better scores using the EuroQoL-5 Dimensions-5 Levels assessment (estimated means, 0.713; 95% CI, 0.647-0.779) than did patients in the symptom-guided group (0.601; 95% CI, 0.536-0.667), with an estimated difference in means of 0.112 (95% CI, 0.0198-0.204; P = .0174).

The investigators suggested that aggressive drainage may have some unmeasured benefits. “Daily removal of the fluid might have provided benefits in symptoms not captured with our breathlessness and pain measurements. The higher pleurodesis rate, with resultant freedom from fluid (and symptom) recurrence and of the catheter, might have contributed to the better reported quality of life. Additionally, it has been suggested that indwelling pleural catheter drainage gives patients an important sense of control when they are feeling helpless with their advancing cancer.”

They concluded, “For patients whose primary care aim is palliation (e.g., those with very limited life expectancy or significant trapped lung where pleurodesis is unlikely), our data show that symptom-guided drainage offers an effective means of breathlessness control without the inconvenience and costs of daily drainages. The ability to predict the likelihood of pleurodesis will help guide the choice of regimen and should be a topic of future studies.”

Three authors reported serving on the advisory board of CareFusion/BD, two authors reported an educational grant from Rocket Medical (UK), and one author reported an educational grant from CareFusion/BD. The other authors reported no relevant conflicts of interest.

SOURCE: Muruganandan S et al. Lancet Respir Med. 2018 July 20. doi: 10.1016/S2213-2600(18)30288-1.

Compared with patients who underwent drainage for treatment of symptomatic malignant pleural effusions that was guided by symptoms, patients who underwent once-daily drainage had similar breathless scores but an increased rate of spontaneous pleurodesis and better quality of life scores, according to recent research published in the Lancet Respiratory Medicine.

Nephron/Wikimedia Commons/CC-BY-SA-3.0

“In patients in whom pleurodesis is an important goal (e.g., those undertaking strategies involving an indwelling pleural catheter plus pleurodesing agents), aggressive drainage should be done for at least 60 days,” Sanjeevan Muruganandan, FRACP, MBBS, from Sir Charles Gairdner Hospital in Perth, Australia, and his colleagues wrote in their study. “Future studies will need to establish if more aggressive (e.g., twice daily) regimens for the initial phase could further enhance success rates.”

Dr. Muruganandan and his colleagues evaluated 87 patients with symptomatic malignant pleural effusions between July 2015 and January 2017 from 11 centers in Australia, New Zealand, Hong Kong, and Malaysia in the randomized controlled AMPLE-2 trial, in which patients received either once daily (43 patients) or symptom-guided (44 patients) drainage for 60 days with a 6-month follow-up. Patients were excluded if they had a pleural infection, were pregnant, had a previous pneumonectomy or ipsilateral lobectomy, had “significant loculations likely to preclude effective fluid drainage,” or had an estimated survival of less than 3 months. Patients were identified and grouped based on whether they had mesothelioma- or nonmesothelioma-type cancer, with cancer type being minimalized during randomization.

At 60 days, patients in the aggressive daily drainage group had a mean daily breathless score of 13.1 mm (geometric means; 95% confidence interval, 9.8-17.4), compared with a mean of 17.3 mm (95% CI, 13.0-22.0) in the symptom-guided drainage group. In the aggressive drainage group, 16 of 43 patients (37.2%) achieved spontaneous pleurodesis at 60 days, compared with 11 of 44 patients (11.4%) in the symptom-guided drainage group (P = .0049). At 6 months, 19 of 43 (44.2%) patients in the aggressive drainage group had spontaneous pleurodesis, compared with 7 of 44 patients (15.9%; P = .004) in the symptom-guided drainage group (hazard ratio, 3.287; 95% CI, 1.396-7.740; P = .0065).

In each group, the investigators noted adverse events: 11 of 43 (25.6%) patients in the aggressive drainage group and 12 of 44 patients (27.3%) in the symptom-guided drainage group reported a severe adverse event. There were no significant differences in mortality, pain scores, and hospital stay between the groups. Regarding quality of life, the investigators found patients in the aggressive drainage group reported better scores using the EuroQoL-5 Dimensions-5 Levels assessment (estimated means, 0.713; 95% CI, 0.647-0.779) than did patients in the symptom-guided group (0.601; 95% CI, 0.536-0.667), with an estimated difference in means of 0.112 (95% CI, 0.0198-0.204; P = .0174).

The investigators suggested that aggressive drainage may have some unmeasured benefits. “Daily removal of the fluid might have provided benefits in symptoms not captured with our breathlessness and pain measurements. The higher pleurodesis rate, with resultant freedom from fluid (and symptom) recurrence and of the catheter, might have contributed to the better reported quality of life. Additionally, it has been suggested that indwelling pleural catheter drainage gives patients an important sense of control when they are feeling helpless with their advancing cancer.”

They concluded, “For patients whose primary care aim is palliation (e.g., those with very limited life expectancy or significant trapped lung where pleurodesis is unlikely), our data show that symptom-guided drainage offers an effective means of breathlessness control without the inconvenience and costs of daily drainages. The ability to predict the likelihood of pleurodesis will help guide the choice of regimen and should be a topic of future studies.”

Three authors reported serving on the advisory board of CareFusion/BD, two authors reported an educational grant from Rocket Medical (UK), and one author reported an educational grant from CareFusion/BD. The other authors reported no relevant conflicts of interest.

SOURCE: Muruganandan S et al. Lancet Respir Med. 2018 July 20. doi: 10.1016/S2213-2600(18)30288-1.

Compared with patients who underwent drainage for treatment of symptomatic malignant pleural effusions that was guided by symptoms, patients who underwent once-daily drainage had similar breathless scores but an increased rate of spontaneous pleurodesis and better quality of life scores, according to recent research published in the Lancet Respiratory Medicine.

Nephron/Wikimedia Commons/CC-BY-SA-3.0

“In patients in whom pleurodesis is an important goal (e.g., those undertaking strategies involving an indwelling pleural catheter plus pleurodesing agents), aggressive drainage should be done for at least 60 days,” Sanjeevan Muruganandan, FRACP, MBBS, from Sir Charles Gairdner Hospital in Perth, Australia, and his colleagues wrote in their study. “Future studies will need to establish if more aggressive (e.g., twice daily) regimens for the initial phase could further enhance success rates.”

Dr. Muruganandan and his colleagues evaluated 87 patients with symptomatic malignant pleural effusions between July 2015 and January 2017 from 11 centers in Australia, New Zealand, Hong Kong, and Malaysia in the randomized controlled AMPLE-2 trial, in which patients received either once daily (43 patients) or symptom-guided (44 patients) drainage for 60 days with a 6-month follow-up. Patients were excluded if they had a pleural infection, were pregnant, had a previous pneumonectomy or ipsilateral lobectomy, had “significant loculations likely to preclude effective fluid drainage,” or had an estimated survival of less than 3 months. Patients were identified and grouped based on whether they had mesothelioma- or nonmesothelioma-type cancer, with cancer type being minimalized during randomization.

At 60 days, patients in the aggressive daily drainage group had a mean daily breathless score of 13.1 mm (geometric means; 95% confidence interval, 9.8-17.4), compared with a mean of 17.3 mm (95% CI, 13.0-22.0) in the symptom-guided drainage group. In the aggressive drainage group, 16 of 43 patients (37.2%) achieved spontaneous pleurodesis at 60 days, compared with 11 of 44 patients (11.4%) in the symptom-guided drainage group (P = .0049). At 6 months, 19 of 43 (44.2%) patients in the aggressive drainage group had spontaneous pleurodesis, compared with 7 of 44 patients (15.9%; P = .004) in the symptom-guided drainage group (hazard ratio, 3.287; 95% CI, 1.396-7.740; P = .0065).

In each group, the investigators noted adverse events: 11 of 43 (25.6%) patients in the aggressive drainage group and 12 of 44 patients (27.3%) in the symptom-guided drainage group reported a severe adverse event. There were no significant differences in mortality, pain scores, and hospital stay between the groups. Regarding quality of life, the investigators found patients in the aggressive drainage group reported better scores using the EuroQoL-5 Dimensions-5 Levels assessment (estimated means, 0.713; 95% CI, 0.647-0.779) than did patients in the symptom-guided group (0.601; 95% CI, 0.536-0.667), with an estimated difference in means of 0.112 (95% CI, 0.0198-0.204; P = .0174).

The investigators suggested that aggressive drainage may have some unmeasured benefits. “Daily removal of the fluid might have provided benefits in symptoms not captured with our breathlessness and pain measurements. The higher pleurodesis rate, with resultant freedom from fluid (and symptom) recurrence and of the catheter, might have contributed to the better reported quality of life. Additionally, it has been suggested that indwelling pleural catheter drainage gives patients an important sense of control when they are feeling helpless with their advancing cancer.”

They concluded, “For patients whose primary care aim is palliation (e.g., those with very limited life expectancy or significant trapped lung where pleurodesis is unlikely), our data show that symptom-guided drainage offers an effective means of breathlessness control without the inconvenience and costs of daily drainages. The ability to predict the likelihood of pleurodesis will help guide the choice of regimen and should be a topic of future studies.”

Three authors reported serving on the advisory board of CareFusion/BD, two authors reported an educational grant from Rocket Medical (UK), and one author reported an educational grant from CareFusion/BD. The other authors reported no relevant conflicts of interest.

SOURCE: Muruganandan S et al. Lancet Respir Med. 2018 July 20. doi: 10.1016/S2213-2600(18)30288-1.

Elementary school girls with particular emotional and behavioral symptoms, including irritability, were significantly more likely to experience anxiety disorders in adolescence and young adulthood, based on data from a network analysis of 932 girls.

Data from previous studies suggest that targeting emotional problems in early childhood might prevent mental health disorders in young adults, wrote Alexandra Rouquette, MD, PhD, of Paris-Saclay University, Paris, and her colleagues. “However, these interventions are challenging to implement because we lack knowledge on which specific childhood symptoms have predictive associations with adult psychopathologic disorders,” they said.

In the study, published in JAMA Psychiatry, the researchers used data from an ongoing longitudinal prospective analysis of kindergarten children in the Canadian province of Quebec to assess potential “bridge symptoms,” defined as those that might affect the development of anxiety later in life. The study population included 932 girls whose parents completed the Social Behavior Questionnaire (SBQ) at baseline when the girls were 6 years old, and again at ages 8 and 10 years. Of these, 780 participants underwent screening for mental health disorders at age 15 and/or 22 years.

Of the 780 participants assessed at follow-up, 270 (35%) had developed at least one anxiety disorder, and 128 (16%) had developed at least one diagnosis of major depression or another depressive disorder.

The researchers used a network analysis technique to review 33 items in the SBQ and how they related to future anxiety disorders. They identified five bridge symptoms – irritability, blaming others, not being liked by others, frequent crying, and solitary behavior – as having “a distinctive position in the network because most of the direct relationships between the disruptive and internalized communities transited through them.”

In addition, children who were disobedient, irritable, and not liked by others had the strongest and earliest association with anxiety disorders over time, the researchers said. By contrast, the kicks disruptive symptom in early childhood was a negative predictor of anxiety disorders at follow-up.

The study findings were limited by several factors, including the relatively small study population, the number of statistical tests performed, and the challenges of identifying anxiety disorders at follow-up. However, the results support the potential role of childhood bridge symptoms in later life anxiety, the researchers said. “Clinicians may wish to focus on these bridge symptoms when assessing patients,” they noted, because those symptoms could be “early targets in disease-prevention and health-promotion interventions.”

The researchers had no financial conflicts to disclose. The study was funded by a grant to Dr. Rouquette from the OpenHealth Institute.

SOURCE: Rouquette A et al. JAMA Psychiatry. 2018 Aug 15. doi: 10.1001/jamapsychiatry.2018.2119.

Elementary school girls with particular emotional and behavioral symptoms, including irritability, were significantly more likely to experience anxiety disorders in adolescence and young adulthood, based on data from a network analysis of 932 girls.

Data from previous studies suggest that targeting emotional problems in early childhood might prevent mental health disorders in young adults, wrote Alexandra Rouquette, MD, PhD, of Paris-Saclay University, Paris, and her colleagues. “However, these interventions are challenging to implement because we lack knowledge on which specific childhood symptoms have predictive associations with adult psychopathologic disorders,” they said.

In the study, published in JAMA Psychiatry, the researchers used data from an ongoing longitudinal prospective analysis of kindergarten children in the Canadian province of Quebec to assess potential “bridge symptoms,” defined as those that might affect the development of anxiety later in life. The study population included 932 girls whose parents completed the Social Behavior Questionnaire (SBQ) at baseline when the girls were 6 years old, and again at ages 8 and 10 years. Of these, 780 participants underwent screening for mental health disorders at age 15 and/or 22 years.

Of the 780 participants assessed at follow-up, 270 (35%) had developed at least one anxiety disorder, and 128 (16%) had developed at least one diagnosis of major depression or another depressive disorder.

The researchers used a network analysis technique to review 33 items in the SBQ and how they related to future anxiety disorders. They identified five bridge symptoms – irritability, blaming others, not being liked by others, frequent crying, and solitary behavior – as having “a distinctive position in the network because most of the direct relationships between the disruptive and internalized communities transited through them.”

In addition, children who were disobedient, irritable, and not liked by others had the strongest and earliest association with anxiety disorders over time, the researchers said. By contrast, the kicks disruptive symptom in early childhood was a negative predictor of anxiety disorders at follow-up.

The study findings were limited by several factors, including the relatively small study population, the number of statistical tests performed, and the challenges of identifying anxiety disorders at follow-up. However, the results support the potential role of childhood bridge symptoms in later life anxiety, the researchers said. “Clinicians may wish to focus on these bridge symptoms when assessing patients,” they noted, because those symptoms could be “early targets in disease-prevention and health-promotion interventions.”

The researchers had no financial conflicts to disclose. The study was funded by a grant to Dr. Rouquette from the OpenHealth Institute.

SOURCE: Rouquette A et al. JAMA Psychiatry. 2018 Aug 15. doi: 10.1001/jamapsychiatry.2018.2119.

Elementary school girls with particular emotional and behavioral symptoms, including irritability, were significantly more likely to experience anxiety disorders in adolescence and young adulthood, based on data from a network analysis of 932 girls.

Data from previous studies suggest that targeting emotional problems in early childhood might prevent mental health disorders in young adults, wrote Alexandra Rouquette, MD, PhD, of Paris-Saclay University, Paris, and her colleagues. “However, these interventions are challenging to implement because we lack knowledge on which specific childhood symptoms have predictive associations with adult psychopathologic disorders,” they said.

In the study, published in JAMA Psychiatry, the researchers used data from an ongoing longitudinal prospective analysis of kindergarten children in the Canadian province of Quebec to assess potential “bridge symptoms,” defined as those that might affect the development of anxiety later in life. The study population included 932 girls whose parents completed the Social Behavior Questionnaire (SBQ) at baseline when the girls were 6 years old, and again at ages 8 and 10 years. Of these, 780 participants underwent screening for mental health disorders at age 15 and/or 22 years.

Of the 780 participants assessed at follow-up, 270 (35%) had developed at least one anxiety disorder, and 128 (16%) had developed at least one diagnosis of major depression or another depressive disorder.

The researchers used a network analysis technique to review 33 items in the SBQ and how they related to future anxiety disorders. They identified five bridge symptoms – irritability, blaming others, not being liked by others, frequent crying, and solitary behavior – as having “a distinctive position in the network because most of the direct relationships between the disruptive and internalized communities transited through them.”

In addition, children who were disobedient, irritable, and not liked by others had the strongest and earliest association with anxiety disorders over time, the researchers said. By contrast, the kicks disruptive symptom in early childhood was a negative predictor of anxiety disorders at follow-up.

The study findings were limited by several factors, including the relatively small study population, the number of statistical tests performed, and the challenges of identifying anxiety disorders at follow-up. However, the results support the potential role of childhood bridge symptoms in later life anxiety, the researchers said. “Clinicians may wish to focus on these bridge symptoms when assessing patients,” they noted, because those symptoms could be “early targets in disease-prevention and health-promotion interventions.”

The researchers had no financial conflicts to disclose. The study was funded by a grant to Dr. Rouquette from the OpenHealth Institute.

SOURCE: Rouquette A et al. JAMA Psychiatry. 2018 Aug 15. doi: 10.1001/jamapsychiatry.2018.2119.

The relationship between the immune system and tumors is complex and dynamic, and for immunotherapy to reach its full potential it will likely need to attack on multiple fronts. Here, we discuss some of the latest and most promising developments in the immuno-oncology field designed to build on the successes and address limitations.

The anti-tumor immune response

Cancer is a disease of genomic instability, whereby genetic alterations ranging from a single nucleotide to the whole chromosome level frequently occur. Although cancers derive from a patient’s own tissues, these genetic differences can mark the cancer cell as non-self, triggering an immune response to eliminate these cells.

The first hints of this anti-tumor immunity date back more than a century and a half and sparked the concept of mobilizing the immune system to treat patients.^1-3 Although early pioneers achieved little progress in this regard, their efforts provided invaluable insights into the complex and dynamic relationship between a tumor and the immune system that are now translating into real clinical successes.

We now understand that the immune system has a dual role in both restraining and promoting cancer development and have translated this understanding into the theory of cancer immunoediting. Immunoediting has three stages: elimination, wherein the tumor is seemingly destroyed by the innate and adaptive immune response; equilibrium, in which cancer cells that were able to escape elimination are selected for growth; and escape, whereby these resistant cancer cells overwhelm the immune system and develop into a symptomatic lesion.^4,5

Immuno-oncologists have also described the cancer immunity cycle to capture the steps that are required for an effective anti-tumor immune response and defects in this cycle form the basis of the most common mechanisms used by cancer cells to subvert the anti-tumor immune response. Much like the cancer hallmarks did for molecularly targeted cancer drugs, the cancer immunity cycle serves as the intellectual framework for cancer immunotherapy.^6,7

Exploiting nature’s weapon of mass destruction

Initially, attempts at immunotherapy focused on boosting the immune response using adjuvants and cytokines. The characterization of subtle differences between tumor cells and normal cells led to the development of vaccines and cell-based therapies that exploited these tumor-associated antigens (TAAs).^1-6

Despite the approval of a therapeutic vaccine, sipuleucel-T, in 2010 for the treatment of metastatic prostate cancer, in general the success of vaccines has been limited. Marketing authorization for sipuleucel-T was recently withdrawn in Europe, and although it is still available in the United States, it is not widely used because of issues with production and administration. Other vaccines, such as GVAX, which looked particularly promising in early-stage clinical trials, failed to show clinical efficacy in subsequent testing.^8,9

Cell-based therapies, such as adoptive cellular therapy (ACT), in which immune cells are removed from the host, primed to attack cancer cells, and then reinfused back into the patient, have focused on T cells because they are the major effectors of the adaptive immune response. Clinical success with the most common approach, tumor-infiltrating lymphocyte (TIL) therapy, has so far been limited to only one type of cancer – metastatic melanoma – but ACT may be inching closer to the mainstream with the development of techniques that allow genetic manipulation of the T cells before they are infused back into the patient.

Two key techniques have been developed (Figure 1). T-cell receptor (TCR) therapy involves genetically modifying the receptor on the surface of T cells that is responsible for recognizing antigens bound to major histocompatibility complex (MHC) molecules on the surface of antigen-presenting cells (APCs). The TCR can be altered to recognize a specific TAA or modified to improve its antigen recognition and binding capabilities. This type of therapy is limited by the fact that the TCRs need to be genetically matched to the patient’s immune type.

Releasing the brakes

To ensure that it is only activated at the appropriate time and not in response to the antigens expressed on the surface of the host’s own tissues or harmless materials, the immune system has developed numerous mechanisms for immunological tolerance. Cancer cells are able to exploit these mechanisms to allow them to evade the anti-tumor immune response. One of the main ways in which they do this is by manipulating the signaling pathways involved in T-cell activation, which play a vital role in tolerance.¹²

To become fully activated, T cells require a primary signal generated by an interaction between the TCR and the antigen-MHC complex on the surface of an APC, followed by secondary costimulatory signals generated by a range of different receptors present on the T-cell surface binding to their ligands on the APC.

If the second signal is inhibitory rather than stimulatory, then the T cell is deactivated instead of becoming activated. Two key coinhibitory receptors are programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) and tumor cells are able to overcome the anti-tumor immune response in part by expressing the ligands that bind these receptors to dampen the activity of tumor-infiltrating T cells and induce tolerance.¹³

The development of inhibitors of CTLA-4 and PD-1 and their respective ligands has driven some of the most dramatic successes with cancer immunotherapy, particularly with PD-1-targeting drugs which have fewer side effects. Targeting of this pathway has resulted in durable responses, revolutionizing the treatment of metastatic melanoma, with recently published long-term survival data for pembrolizumab showing that 40% of patients were alive 3 years after initiating treatment and, in a separate study, 34% of nivolumab-treated patients were still alive after 5 years.^14,15 More recently, PD-1 inhibitors have been slowly expanding into a range of other cancer types and 4 immune checkpoint inhibitors are now approved by the United States Food and Drug Administration (FDA): ipilimumab (Yervoy), nivolumab (Opdivo), pembrolizumab (Keytruda) and atezolizumab (Tecentriq).

Six years on from the first approval in this drug class and an extensive network of coinhibitory receptors has been uncovered – so-called immune checkpoints – many of which are now also serving as therapeutic targets (Table, Figure 2).¹⁶ Lymphocyte activation gene 3 (LAG-3) is a member of the immunoglobulin superfamily of receptors that is expressed on a number of different types of immune cell. In addition to negatively regulating cytotoxic T-cell activation like PD-1 and CTLA-4, it is also thought to regulate the immunosuppressive functions of regulatory T cells and the maturation and activation of dendritic cells. T-cell immunoglobulin and mucin domain-containing 3 (TIM-3) is found on the surface of helper and cytotoxic T cells and regulates T-cell inhibition as well as macrophage activation. Inhibitors of both proteins have been developed that are being evaluated in phase 1 or 2 clinical trials in a variety of tumor types.17

Indeed, although T cells have commanded the most attention, there is growing appreciation of the potential for targeting other types of immune cell that play a role in the anti-tumor immune response or in fostering an immunosuppressive microenvironment. NK cells have been a particular focus, since they represent the body’s first line of immune defense and they appear to have analogous inhibitory and activating receptors expressed on their surface that regulate their cytotoxic activity.

The best-defined NK cell receptors are the killer cell immunoglobulin-like receptors (KIRs) that bind to the MHC class I proteins found on the surface of all cells that distinguish them as ‘self’ or ‘non-self’. KIRs can be either activating or inhibitory, depending upon their structure and the ligands to which they bind.¹⁹ To date, 2 antibodies targeting inhibitory KIRs have been developed. Though there has been some disappointment with these drugs, most recently a phase 2 trial of lirilumab in elderly patients with acute myeloid leukemia, which missed its primary endpoint, they continue to be evaluated in clinical trials.²⁰

The inhibitory immune checkpoint field has also expanded to include molecules that regulate T-cell activity in other ways. Most prominently, this includes enzymes like indoleamine-2,3 dioxygenase (IDO), which is involved in the metabolism of the essential amino acid tryptophan. IDO-induced depletion of tryptophan and generation of tryptophan metabolites is toxic to cytotoxic T cells, and IDO is also thought to directly activate regulatory T cells, thus the net effect of IDO is immunosuppression. Two IDO inhibitors are currently being developed.²¹

Stepping on the gas

Despite their unprecedented success, immune checkpoint inhibitors are not effective in all patients or in all tumor types. Their efficacy is limited in large part by the requirement for a pre-existing anti-tumor immune response. If there are no T cells within the tumor microenvironment then releasing the brakes on the immune system won’t help.

More recently, researchers have returned to the idea of stimulating an anti-tumor immune response, this time by targeting the other side of the immune checkpoint coin, the costimulatory molecules. These drugs could prove more effective as they aren’t reliant on a pre-existing anti-tumor immune response. A number of agonist antibodies designed to target these receptors have now been developed and are undergoing clinical evaluation.²²

Furthest along in development are those targeting OX40, a costimulatory molecule that is upregulated on the surface of T cells once they have been fully activated by the TCR signal and an initial costimulatory signal. OX40 is thought to be involved in a more long-term immune response and in the formation of a memory response. A mouse monoclonal antibody had a potent immune-stimulating effect accompanied by the regression of at least 1 metastatic lesion in 30% of patients treated in a phase 1 clinical trial, but was limited by the generation of anti-mouse antibodies. 7 OX40 agonists are now in clinical development, 6 fully human monoclonal antibodies and 1 OX40 ligand-Fc fusion protein, MEDI-6383.²³

Combinations are key

Many researchers are now reaching the conclusion that combination therapy is likely to be key in expanding the scope of immunotherapy into currently unresponsive patient populations. Investigating rational combinations is already becoming a burgeoning area of the immuno-oncology field, with a variety of different strategies being tested.

Now the question becomes what are the optimal combinations and the timing and sequencing of combination therapy is likely to be a paramount consideration. Developing combinations that have distinct mechanisms of action or target multiple steps in the cancer immunity cycle offers the greatest potential for therapeutic synergy since this is most likely to address potential mechanisms of resistance by blocking other paths to immune evasion for cancer cells (Figure 3).

Given the expanding network of immune-checkpoint inhibitors and agonists, the focal point of combination therapy has been combining immune checkpoint-targeting drugs with different mechanisms of action, including those that would simultaneously release the brakes and step on the gas pedal. The vast majority of ongoing clinical trials of approved checkpoint inhibitors and the drugs in development listed in the table are combination trials.

These efforts yielded the first FDA-approved combination immunotherapy regimen in 2015; nivolumab and ipilimumab for the treatment of metastatic melanoma. Approval was based on the demonstration of improved ORR, prolonged response duration, and improved progression-free survival among 142 patients treated with the combination, compared to either drug alone.²⁴

The results of a phase 1/2 trial evaluating the combination of a 4-1BB receptor agonist urelumab with nivolumab in hematologic malignancies and solid tumors found the combination to be safe and particularly effective in patients with advanced/metastatic melanoma, with an ORR of 50%.²⁵ Nivolumab was also combined with the CD27 agonist varlilumab in a phase 1/2 clinical trial of patients with solid tumors, for which data was also recently released. Among 46 patients enrolled, primarily those with colorectal and ovarian cancer the combination had an acceptable safety profile and favorable changes in intratumoral immune biomarkers were observed. The phase 2 portion of the trial is ongoing.²⁶

Meanwhile, Incyte’s IDO inhibitor epacadostat has recently been making waves in combination with pembrolizumab in patients with advanced solid tumors. It demonstrated particularly promising clinical activity in patients with metastatic melanoma, with an overall response rate (ORR) of 57%, including 2 complete responses (CRs), prompting initiation of a phase 3 trial of this combination (NCT02752074).²⁷

The relationship between the immune system and tumors is complex and dynamic, and for immunotherapy to reach its full potential it will likely need to attack on multiple fronts. Here, we discuss some of the latest and most promising developments in the immuno-oncology field designed to build on the successes and address limitations.

The anti-tumor immune response

Cancer is a disease of genomic instability, whereby genetic alterations ranging from a single nucleotide to the whole chromosome level frequently occur. Although cancers derive from a patient’s own tissues, these genetic differences can mark the cancer cell as non-self, triggering an immune response to eliminate these cells.

The first hints of this anti-tumor immunity date back more than a century and a half and sparked the concept of mobilizing the immune system to treat patients.^1-3 Although early pioneers achieved little progress in this regard, their efforts provided invaluable insights into the complex and dynamic relationship between a tumor and the immune system that are now translating into real clinical successes.

We now understand that the immune system has a dual role in both restraining and promoting cancer development and have translated this understanding into the theory of cancer immunoediting. Immunoediting has three stages: elimination, wherein the tumor is seemingly destroyed by the innate and adaptive immune response; equilibrium, in which cancer cells that were able to escape elimination are selected for growth; and escape, whereby these resistant cancer cells overwhelm the immune system and develop into a symptomatic lesion.^4,5

Immuno-oncologists have also described the cancer immunity cycle to capture the steps that are required for an effective anti-tumor immune response and defects in this cycle form the basis of the most common mechanisms used by cancer cells to subvert the anti-tumor immune response. Much like the cancer hallmarks did for molecularly targeted cancer drugs, the cancer immunity cycle serves as the intellectual framework for cancer immunotherapy.^6,7

Exploiting nature’s weapon of mass destruction

Initially, attempts at immunotherapy focused on boosting the immune response using adjuvants and cytokines. The characterization of subtle differences between tumor cells and normal cells led to the development of vaccines and cell-based therapies that exploited these tumor-associated antigens (TAAs).^1-6

Despite the approval of a therapeutic vaccine, sipuleucel-T, in 2010 for the treatment of metastatic prostate cancer, in general the success of vaccines has been limited. Marketing authorization for sipuleucel-T was recently withdrawn in Europe, and although it is still available in the United States, it is not widely used because of issues with production and administration. Other vaccines, such as GVAX, which looked particularly promising in early-stage clinical trials, failed to show clinical efficacy in subsequent testing.^8,9

Cell-based therapies, such as adoptive cellular therapy (ACT), in which immune cells are removed from the host, primed to attack cancer cells, and then reinfused back into the patient, have focused on T cells because they are the major effectors of the adaptive immune response. Clinical success with the most common approach, tumor-infiltrating lymphocyte (TIL) therapy, has so far been limited to only one type of cancer – metastatic melanoma – but ACT may be inching closer to the mainstream with the development of techniques that allow genetic manipulation of the T cells before they are infused back into the patient.

Two key techniques have been developed (Figure 1). T-cell receptor (TCR) therapy involves genetically modifying the receptor on the surface of T cells that is responsible for recognizing antigens bound to major histocompatibility complex (MHC) molecules on the surface of antigen-presenting cells (APCs). The TCR can be altered to recognize a specific TAA or modified to improve its antigen recognition and binding capabilities. This type of therapy is limited by the fact that the TCRs need to be genetically matched to the patient’s immune type.

Releasing the brakes

To ensure that it is only activated at the appropriate time and not in response to the antigens expressed on the surface of the host’s own tissues or harmless materials, the immune system has developed numerous mechanisms for immunological tolerance. Cancer cells are able to exploit these mechanisms to allow them to evade the anti-tumor immune response. One of the main ways in which they do this is by manipulating the signaling pathways involved in T-cell activation, which play a vital role in tolerance.¹²

To become fully activated, T cells require a primary signal generated by an interaction between the TCR and the antigen-MHC complex on the surface of an APC, followed by secondary costimulatory signals generated by a range of different receptors present on the T-cell surface binding to their ligands on the APC.

If the second signal is inhibitory rather than stimulatory, then the T cell is deactivated instead of becoming activated. Two key coinhibitory receptors are programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) and tumor cells are able to overcome the anti-tumor immune response in part by expressing the ligands that bind these receptors to dampen the activity of tumor-infiltrating T cells and induce tolerance.¹³

The development of inhibitors of CTLA-4 and PD-1 and their respective ligands has driven some of the most dramatic successes with cancer immunotherapy, particularly with PD-1-targeting drugs which have fewer side effects. Targeting of this pathway has resulted in durable responses, revolutionizing the treatment of metastatic melanoma, with recently published long-term survival data for pembrolizumab showing that 40% of patients were alive 3 years after initiating treatment and, in a separate study, 34% of nivolumab-treated patients were still alive after 5 years.^14,15 More recently, PD-1 inhibitors have been slowly expanding into a range of other cancer types and 4 immune checkpoint inhibitors are now approved by the United States Food and Drug Administration (FDA): ipilimumab (Yervoy), nivolumab (Opdivo), pembrolizumab (Keytruda) and atezolizumab (Tecentriq).

Six years on from the first approval in this drug class and an extensive network of coinhibitory receptors has been uncovered – so-called immune checkpoints – many of which are now also serving as therapeutic targets (Table, Figure 2).¹⁶ Lymphocyte activation gene 3 (LAG-3) is a member of the immunoglobulin superfamily of receptors that is expressed on a number of different types of immune cell. In addition to negatively regulating cytotoxic T-cell activation like PD-1 and CTLA-4, it is also thought to regulate the immunosuppressive functions of regulatory T cells and the maturation and activation of dendritic cells. T-cell immunoglobulin and mucin domain-containing 3 (TIM-3) is found on the surface of helper and cytotoxic T cells and regulates T-cell inhibition as well as macrophage activation. Inhibitors of both proteins have been developed that are being evaluated in phase 1 or 2 clinical trials in a variety of tumor types.17

Indeed, although T cells have commanded the most attention, there is growing appreciation of the potential for targeting other types of immune cell that play a role in the anti-tumor immune response or in fostering an immunosuppressive microenvironment. NK cells have been a particular focus, since they represent the body’s first line of immune defense and they appear to have analogous inhibitory and activating receptors expressed on their surface that regulate their cytotoxic activity.

The best-defined NK cell receptors are the killer cell immunoglobulin-like receptors (KIRs) that bind to the MHC class I proteins found on the surface of all cells that distinguish them as ‘self’ or ‘non-self’. KIRs can be either activating or inhibitory, depending upon their structure and the ligands to which they bind.¹⁹ To date, 2 antibodies targeting inhibitory KIRs have been developed. Though there has been some disappointment with these drugs, most recently a phase 2 trial of lirilumab in elderly patients with acute myeloid leukemia, which missed its primary endpoint, they continue to be evaluated in clinical trials.²⁰

The inhibitory immune checkpoint field has also expanded to include molecules that regulate T-cell activity in other ways. Most prominently, this includes enzymes like indoleamine-2,3 dioxygenase (IDO), which is involved in the metabolism of the essential amino acid tryptophan. IDO-induced depletion of tryptophan and generation of tryptophan metabolites is toxic to cytotoxic T cells, and IDO is also thought to directly activate regulatory T cells, thus the net effect of IDO is immunosuppression. Two IDO inhibitors are currently being developed.²¹

Stepping on the gas

Despite their unprecedented success, immune checkpoint inhibitors are not effective in all patients or in all tumor types. Their efficacy is limited in large part by the requirement for a pre-existing anti-tumor immune response. If there are no T cells within the tumor microenvironment then releasing the brakes on the immune system won’t help.

More recently, researchers have returned to the idea of stimulating an anti-tumor immune response, this time by targeting the other side of the immune checkpoint coin, the costimulatory molecules. These drugs could prove more effective as they aren’t reliant on a pre-existing anti-tumor immune response. A number of agonist antibodies designed to target these receptors have now been developed and are undergoing clinical evaluation.²²

Furthest along in development are those targeting OX40, a costimulatory molecule that is upregulated on the surface of T cells once they have been fully activated by the TCR signal and an initial costimulatory signal. OX40 is thought to be involved in a more long-term immune response and in the formation of a memory response. A mouse monoclonal antibody had a potent immune-stimulating effect accompanied by the regression of at least 1 metastatic lesion in 30% of patients treated in a phase 1 clinical trial, but was limited by the generation of anti-mouse antibodies. 7 OX40 agonists are now in clinical development, 6 fully human monoclonal antibodies and 1 OX40 ligand-Fc fusion protein, MEDI-6383.²³

Combinations are key

Many researchers are now reaching the conclusion that combination therapy is likely to be key in expanding the scope of immunotherapy into currently unresponsive patient populations. Investigating rational combinations is already becoming a burgeoning area of the immuno-oncology field, with a variety of different strategies being tested.

Now the question becomes what are the optimal combinations and the timing and sequencing of combination therapy is likely to be a paramount consideration. Developing combinations that have distinct mechanisms of action or target multiple steps in the cancer immunity cycle offers the greatest potential for therapeutic synergy since this is most likely to address potential mechanisms of resistance by blocking other paths to immune evasion for cancer cells (Figure 3).

Given the expanding network of immune-checkpoint inhibitors and agonists, the focal point of combination therapy has been combining immune checkpoint-targeting drugs with different mechanisms of action, including those that would simultaneously release the brakes and step on the gas pedal. The vast majority of ongoing clinical trials of approved checkpoint inhibitors and the drugs in development listed in the table are combination trials.

These efforts yielded the first FDA-approved combination immunotherapy regimen in 2015; nivolumab and ipilimumab for the treatment of metastatic melanoma. Approval was based on the demonstration of improved ORR, prolonged response duration, and improved progression-free survival among 142 patients treated with the combination, compared to either drug alone.²⁴

The results of a phase 1/2 trial evaluating the combination of a 4-1BB receptor agonist urelumab with nivolumab in hematologic malignancies and solid tumors found the combination to be safe and particularly effective in patients with advanced/metastatic melanoma, with an ORR of 50%.²⁵ Nivolumab was also combined with the CD27 agonist varlilumab in a phase 1/2 clinical trial of patients with solid tumors, for which data was also recently released. Among 46 patients enrolled, primarily those with colorectal and ovarian cancer the combination had an acceptable safety profile and favorable changes in intratumoral immune biomarkers were observed. The phase 2 portion of the trial is ongoing.²⁶

Meanwhile, Incyte’s IDO inhibitor epacadostat has recently been making waves in combination with pembrolizumab in patients with advanced solid tumors. It demonstrated particularly promising clinical activity in patients with metastatic melanoma, with an overall response rate (ORR) of 57%, including 2 complete responses (CRs), prompting initiation of a phase 3 trial of this combination (NCT02752074).²⁷

The relationship between the immune system and tumors is complex and dynamic, and for immunotherapy to reach its full potential it will likely need to attack on multiple fronts. Here, we discuss some of the latest and most promising developments in the immuno-oncology field designed to build on the successes and address limitations.

The anti-tumor immune response

Cancer is a disease of genomic instability, whereby genetic alterations ranging from a single nucleotide to the whole chromosome level frequently occur. Although cancers derive from a patient’s own tissues, these genetic differences can mark the cancer cell as non-self, triggering an immune response to eliminate these cells.

The first hints of this anti-tumor immunity date back more than a century and a half and sparked the concept of mobilizing the immune system to treat patients.^1-3 Although early pioneers achieved little progress in this regard, their efforts provided invaluable insights into the complex and dynamic relationship between a tumor and the immune system that are now translating into real clinical successes.

We now understand that the immune system has a dual role in both restraining and promoting cancer development and have translated this understanding into the theory of cancer immunoediting. Immunoediting has three stages: elimination, wherein the tumor is seemingly destroyed by the innate and adaptive immune response; equilibrium, in which cancer cells that were able to escape elimination are selected for growth; and escape, whereby these resistant cancer cells overwhelm the immune system and develop into a symptomatic lesion.^4,5

Immuno-oncologists have also described the cancer immunity cycle to capture the steps that are required for an effective anti-tumor immune response and defects in this cycle form the basis of the most common mechanisms used by cancer cells to subvert the anti-tumor immune response. Much like the cancer hallmarks did for molecularly targeted cancer drugs, the cancer immunity cycle serves as the intellectual framework for cancer immunotherapy.^6,7

Exploiting nature’s weapon of mass destruction

Initially, attempts at immunotherapy focused on boosting the immune response using adjuvants and cytokines. The characterization of subtle differences between tumor cells and normal cells led to the development of vaccines and cell-based therapies that exploited these tumor-associated antigens (TAAs).^1-6

Despite the approval of a therapeutic vaccine, sipuleucel-T, in 2010 for the treatment of metastatic prostate cancer, in general the success of vaccines has been limited. Marketing authorization for sipuleucel-T was recently withdrawn in Europe, and although it is still available in the United States, it is not widely used because of issues with production and administration. Other vaccines, such as GVAX, which looked particularly promising in early-stage clinical trials, failed to show clinical efficacy in subsequent testing.^8,9

Cell-based therapies, such as adoptive cellular therapy (ACT), in which immune cells are removed from the host, primed to attack cancer cells, and then reinfused back into the patient, have focused on T cells because they are the major effectors of the adaptive immune response. Clinical success with the most common approach, tumor-infiltrating lymphocyte (TIL) therapy, has so far been limited to only one type of cancer – metastatic melanoma – but ACT may be inching closer to the mainstream with the development of techniques that allow genetic manipulation of the T cells before they are infused back into the patient.

Two key techniques have been developed (Figure 1). T-cell receptor (TCR) therapy involves genetically modifying the receptor on the surface of T cells that is responsible for recognizing antigens bound to major histocompatibility complex (MHC) molecules on the surface of antigen-presenting cells (APCs). The TCR can be altered to recognize a specific TAA or modified to improve its antigen recognition and binding capabilities. This type of therapy is limited by the fact that the TCRs need to be genetically matched to the patient’s immune type.

Releasing the brakes

To ensure that it is only activated at the appropriate time and not in response to the antigens expressed on the surface of the host’s own tissues or harmless materials, the immune system has developed numerous mechanisms for immunological tolerance. Cancer cells are able to exploit these mechanisms to allow them to evade the anti-tumor immune response. One of the main ways in which they do this is by manipulating the signaling pathways involved in T-cell activation, which play a vital role in tolerance.¹²

To become fully activated, T cells require a primary signal generated by an interaction between the TCR and the antigen-MHC complex on the surface of an APC, followed by secondary costimulatory signals generated by a range of different receptors present on the T-cell surface binding to their ligands on the APC.

If the second signal is inhibitory rather than stimulatory, then the T cell is deactivated instead of becoming activated. Two key coinhibitory receptors are programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) and tumor cells are able to overcome the anti-tumor immune response in part by expressing the ligands that bind these receptors to dampen the activity of tumor-infiltrating T cells and induce tolerance.¹³

The development of inhibitors of CTLA-4 and PD-1 and their respective ligands has driven some of the most dramatic successes with cancer immunotherapy, particularly with PD-1-targeting drugs which have fewer side effects. Targeting of this pathway has resulted in durable responses, revolutionizing the treatment of metastatic melanoma, with recently published long-term survival data for pembrolizumab showing that 40% of patients were alive 3 years after initiating treatment and, in a separate study, 34% of nivolumab-treated patients were still alive after 5 years.^14,15 More recently, PD-1 inhibitors have been slowly expanding into a range of other cancer types and 4 immune checkpoint inhibitors are now approved by the United States Food and Drug Administration (FDA): ipilimumab (Yervoy), nivolumab (Opdivo), pembrolizumab (Keytruda) and atezolizumab (Tecentriq).

Six years on from the first approval in this drug class and an extensive network of coinhibitory receptors has been uncovered – so-called immune checkpoints – many of which are now also serving as therapeutic targets (Table, Figure 2).¹⁶ Lymphocyte activation gene 3 (LAG-3) is a member of the immunoglobulin superfamily of receptors that is expressed on a number of different types of immune cell. In addition to negatively regulating cytotoxic T-cell activation like PD-1 and CTLA-4, it is also thought to regulate the immunosuppressive functions of regulatory T cells and the maturation and activation of dendritic cells. T-cell immunoglobulin and mucin domain-containing 3 (TIM-3) is found on the surface of helper and cytotoxic T cells and regulates T-cell inhibition as well as macrophage activation. Inhibitors of both proteins have been developed that are being evaluated in phase 1 or 2 clinical trials in a variety of tumor types.17

Indeed, although T cells have commanded the most attention, there is growing appreciation of the potential for targeting other types of immune cell that play a role in the anti-tumor immune response or in fostering an immunosuppressive microenvironment. NK cells have been a particular focus, since they represent the body’s first line of immune defense and they appear to have analogous inhibitory and activating receptors expressed on their surface that regulate their cytotoxic activity.

The best-defined NK cell receptors are the killer cell immunoglobulin-like receptors (KIRs) that bind to the MHC class I proteins found on the surface of all cells that distinguish them as ‘self’ or ‘non-self’. KIRs can be either activating or inhibitory, depending upon their structure and the ligands to which they bind.¹⁹ To date, 2 antibodies targeting inhibitory KIRs have been developed. Though there has been some disappointment with these drugs, most recently a phase 2 trial of lirilumab in elderly patients with acute myeloid leukemia, which missed its primary endpoint, they continue to be evaluated in clinical trials.²⁰

The inhibitory immune checkpoint field has also expanded to include molecules that regulate T-cell activity in other ways. Most prominently, this includes enzymes like indoleamine-2,3 dioxygenase (IDO), which is involved in the metabolism of the essential amino acid tryptophan. IDO-induced depletion of tryptophan and generation of tryptophan metabolites is toxic to cytotoxic T cells, and IDO is also thought to directly activate regulatory T cells, thus the net effect of IDO is immunosuppression. Two IDO inhibitors are currently being developed.²¹

Stepping on the gas

Despite their unprecedented success, immune checkpoint inhibitors are not effective in all patients or in all tumor types. Their efficacy is limited in large part by the requirement for a pre-existing anti-tumor immune response. If there are no T cells within the tumor microenvironment then releasing the brakes on the immune system won’t help.

More recently, researchers have returned to the idea of stimulating an anti-tumor immune response, this time by targeting the other side of the immune checkpoint coin, the costimulatory molecules. These drugs could prove more effective as they aren’t reliant on a pre-existing anti-tumor immune response. A number of agonist antibodies designed to target these receptors have now been developed and are undergoing clinical evaluation.²²

Furthest along in development are those targeting OX40, a costimulatory molecule that is upregulated on the surface of T cells once they have been fully activated by the TCR signal and an initial costimulatory signal. OX40 is thought to be involved in a more long-term immune response and in the formation of a memory response. A mouse monoclonal antibody had a potent immune-stimulating effect accompanied by the regression of at least 1 metastatic lesion in 30% of patients treated in a phase 1 clinical trial, but was limited by the generation of anti-mouse antibodies. 7 OX40 agonists are now in clinical development, 6 fully human monoclonal antibodies and 1 OX40 ligand-Fc fusion protein, MEDI-6383.²³

Combinations are key

Many researchers are now reaching the conclusion that combination therapy is likely to be key in expanding the scope of immunotherapy into currently unresponsive patient populations. Investigating rational combinations is already becoming a burgeoning area of the immuno-oncology field, with a variety of different strategies being tested.

Now the question becomes what are the optimal combinations and the timing and sequencing of combination therapy is likely to be a paramount consideration. Developing combinations that have distinct mechanisms of action or target multiple steps in the cancer immunity cycle offers the greatest potential for therapeutic synergy since this is most likely to address potential mechanisms of resistance by blocking other paths to immune evasion for cancer cells (Figure 3).

Given the expanding network of immune-checkpoint inhibitors and agonists, the focal point of combination therapy has been combining immune checkpoint-targeting drugs with different mechanisms of action, including those that would simultaneously release the brakes and step on the gas pedal. The vast majority of ongoing clinical trials of approved checkpoint inhibitors and the drugs in development listed in the table are combination trials.

These efforts yielded the first FDA-approved combination immunotherapy regimen in 2015; nivolumab and ipilimumab for the treatment of metastatic melanoma. Approval was based on the demonstration of improved ORR, prolonged response duration, and improved progression-free survival among 142 patients treated with the combination, compared to either drug alone.²⁴

The results of a phase 1/2 trial evaluating the combination of a 4-1BB receptor agonist urelumab with nivolumab in hematologic malignancies and solid tumors found the combination to be safe and particularly effective in patients with advanced/metastatic melanoma, with an ORR of 50%.²⁵ Nivolumab was also combined with the CD27 agonist varlilumab in a phase 1/2 clinical trial of patients with solid tumors, for which data was also recently released. Among 46 patients enrolled, primarily those with colorectal and ovarian cancer the combination had an acceptable safety profile and favorable changes in intratumoral immune biomarkers were observed. The phase 2 portion of the trial is ongoing.²⁶

Meanwhile, Incyte’s IDO inhibitor epacadostat has recently been making waves in combination with pembrolizumab in patients with advanced solid tumors. It demonstrated particularly promising clinical activity in patients with metastatic melanoma, with an overall response rate (ORR) of 57%, including 2 complete responses (CRs), prompting initiation of a phase 3 trial of this combination (NCT02752074).²⁷

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of mature T- and natural killer-cell neoplasms that comprise about 10%-15% of all non-Hodgkin lymphomas in the United States.^1,2 The development of effective therapies for PTCL has been challenging because of the rare nature and heterogeneity of these lymphomas. Most therapies are a derivative of aggressive B-cell lymphoma therapies, including CHOP (cyclophosphamide, hydroxydaunorubicin, vinicristine, prednisone) and CHOEP (cyclophosphamide, hydroxydaunorubicin, vinicristine, etoposide, prednisone).¹ Many centers use autologous or allogeneic stem cell transplant in this setting,¹ but outcomes remain poor and progress in developing effective treatments has been slow.

Pralatrexate is the first drug to have been approved by the US Food and Drug Administration specifically for treating patients with relapsed or refractory PTCL.³ As a folate analog metabolic inhibitor, pralatrexate competitively inhibits dihydrofolate reductase and reduces cellular levels of thymidine monophosphate, which prevents the cell from synthesizing genetic material and triggers it to undergo apoptosis.⁴ The agency’s approval of pralatrexate was based on results from the PROPEL study, which is possibly the largest prospective study conducted in patients with relapsed or refractory PTCL (109 evaluable patients).² Findings from the study showed an overall response rate (ORR) of 29%, and a median duration of response (DoR) of 10 months.²

Pralatrexate is administered intravenously at 30 mg/m2 once weekly for 6 weeks of a 7-week treatment cycle. It is generally continued until disease progression or an unacceptable level of toxicity.² Alternative dosing schedules have been described, including 15 mg/m2 once weekly for 3 weeks of a 4-week treatment cycle for cutaneous T-cell lymphomas.⁵

In this case series, we examine the outcomes of 2 patients with particularly aggressive subtypes of PTCL who were treated with pralatrexate. The significance of this report is in describing the long duration of response and reporting on a PTCL subtype – subcutaneous panniculitis-like T-cell lymphoma, alpha/beta type – that was underrepresented in the PROPEL study and is underreported in the literature.
 

Case presentations and summaries

Case 1

A 23-year-old Asian American man with a medical history of osteogenesis imperfecta presented to Emergency Department at the Hospital of University of Pennsylvania with bilateral lower extremity edema, low-grade fevers, a weight loss of 25 lb, and flat hyperpigmented scaly skin patches across his torso. Symptoms had started manifesting around five months prior to the visit. A punch biopsy of a skin lesion revealed skin tissue with focal infiltrate of small- to medium-sized, atypical lymphocytes infiltrating subcutaneous adipose tissue (panniculitis-like) and adnexa. Immunohistochemical stains showed that the abnormal lymphocytes were positive for CD3, CD8, perforin, granzyme B, TIA-1 (minor subset), and TCR beta; and negative for CD4, CD56, and CD30. Proliferation index (Ki67) was 70%. The findings were consistent with primary subcutaneous panniculitis-like T-cell lymphoma, alpha/beta type (Figure 1). A staging positron-emission tomography–computed tomography (PET–CT) scan demonstrated stage IVB lymphoma with subcutaneous involvement without nodal disease.

He was initially treated with aggressive combination regimens including EPOCH (etoposide, prednisolone, vincristine, cyclophosphamide, hydroxydaunorubicin) and ICE (ifosfamide, carboplatin, etoposide), but he had no response and his disease was primary refractory. Because of his osteogenesis imperfecta, he was not a candidate for allogenic stem cell transplant.

He responded to hyperCVAD B combination therapy (methotrexate and cytarabine), but the course was complicated by cytarabine-induced ataxia and dysarthia. He was then treated with 3 months of intravenous alemtuzumab without response. Intravenous methotrexate (2,000 mg/m²) was then used for 3 cycles, but this exacerbated his previous cytarabine-induced neurological symptoms and resulted in only partial response with persistent fluorine-18-deoxyglucose (FDG) avid lesions on a subsequent PET–CT scan.

At that point, the patient was started on pralatrexate at 15 mg/m² weekly for 3 weeks on a 4-week cycle schedule. This was his fifth line of therapy and at 16 months from his initial diagnosis. This dosage was continued for 6 months, and he tolerated the therapy well. He reported no exacerbations of his dysarthia, and by the second month, he had achieved clinical and radiographic remission with complete resolution of B symptoms (fevers, night sweats, and weight loss). The dosing was modified to 15 mg/m² every 2 weeks for 3 months. A whole body PET–CT scan showed resolution of previously FDG avid lesions.

The patient was then continued on 15 mg/m² pralatrexate every 3 weeks for 1 year and he has been maintained on once-a-month dosing for a second and now third year of therapy. He continues to tolerate the therapy and remains disease free at nearly 2 years since starting pralatrexate.
 

Case 2

A 64-year-old white man with a medical history of myasthenia gravis (in remission) and invasive thymoma (after thymectomy) presented with diffuse bulky lymphadenopathy and lung lesions to outpatient clinic at the Abramson Cancer Center at the University of Pennsylvania. His LDH was elevated (278 U/L, reference range 98-192 U/L). Excisional biopsy of a left inguinal lymph node revealed sheets of mitotically active large cells with oval to irregular nuclei, clumped chromatin, conspicuous and sometimes multiple nucleoli, and ample eosinophilic cytoplasm. Immunohistochemical staining showed that the neoplastic cells were positive for CD3, CD4, CD30, BCL2 (variable), and MUM1; and negative for ALK 1, CD5, CD8, CD15, CD43, and CD56. Proliferation index (Ki67) was 90% (Figure 2). PET-CT scan showed widespread hypermetabolic lymphoma in the chest, neck, abdomen, and pelvis with pulmonary metastases. Imaging also demonstrated FDG-avid lesions in the gastric and sinus area. The findings were consistent with ALK-negative, anaplastic large cell lymphoma. He was stage IVA; had gastric, lung, and sinus involvement; and disease above and below the diaphragm.

The patient was initially treated with 6 cycles of CHOP and intrathecal methotrexate injections. His post-treatment PET–CT scan showed persistent FDG-avid disease and his LDH level remained elevated. He underwent 1 cycle of ICE and then BCV (busulfan, cyclophosphamide, etoposide) autologous stem cell transplant. Post-transplant PET–CT scan showed improvement from previous 2 scans but still showed several hypermetabolic lymph nodes consistent with persistent disease.

The patient was started on a pralatrexate regimen of 30 mg/m² once weekly for 6 weeks of a 7-week treatment cycle. After 5 doses, he developed thrombocytopenia and mucositis, which were deemed pralatrexate related. The dosage was reduced to 20 mg/m² once weekly with variable frequency depending on tolerability. His response assessment with PET–CT scan demonstrated radiographic complete response with resolution of hypermetabolic lesions (Figure 3B).

Discussion

PTCL is a rare and heterogeneous lymphoma with poor prognosis. Only 3 agents – pralatrexate, belinostat, and romidespin – have been approved specifically for the treatment of PTCL and all of them have an ORR of less than 30%, based on findings from phase 2 studies.^2,6,7 In the PROPEL study, pralatrexate showed an ORR of 29% and a median DoR of 10 months.² Those results could be considered discouraging, but some PTCL patients may have durable response to pralatrexate monotherapy.

In this case series, each of the patients presented with a particularly aggressive subtype of PTCL, and 1 suffered from a notably rare subtype for which there was scant clinical data to guide treatment. Both patients went through several lines of aggressive treatment that were ineffective and resulted in minimal response. However, both were able to achieve complete resolution of their disease and maintained remission for a significant duration of time after treatment with pralatrexate. In addition, each patient has maintained his remission – one for 6 years after the last dose. These are noteworthy results, and give both patients and clinicians hope that this therapy can be highly effective in some settings.

A better understanding at the molecular level of the oncogenic mechanisms in PTCL patients will be necessary to guide our therapy choices. In these 2 cases, it is likely that the tumor demonstrated superior sensitivity to dihydrofolate reductase inhibition by pralatrexate. In the future, we hope that analysis of the tumor tissue from PTCL patients will allow us to better categorize the tumor sensitivities to particular therapeutic agents. We believe that individualized treatment will lead to better overall outcomes in this challenging group of lymphomas.

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of mature T- and natural killer-cell neoplasms that comprise about 10%-15% of all non-Hodgkin lymphomas in the United States.^1,2 The development of effective therapies for PTCL has been challenging because of the rare nature and heterogeneity of these lymphomas. Most therapies are a derivative of aggressive B-cell lymphoma therapies, including CHOP (cyclophosphamide, hydroxydaunorubicin, vinicristine, prednisone) and CHOEP (cyclophosphamide, hydroxydaunorubicin, vinicristine, etoposide, prednisone).¹ Many centers use autologous or allogeneic stem cell transplant in this setting,¹ but outcomes remain poor and progress in developing effective treatments has been slow.

Pralatrexate is the first drug to have been approved by the US Food and Drug Administration specifically for treating patients with relapsed or refractory PTCL.³ As a folate analog metabolic inhibitor, pralatrexate competitively inhibits dihydrofolate reductase and reduces cellular levels of thymidine monophosphate, which prevents the cell from synthesizing genetic material and triggers it to undergo apoptosis.⁴ The agency’s approval of pralatrexate was based on results from the PROPEL study, which is possibly the largest prospective study conducted in patients with relapsed or refractory PTCL (109 evaluable patients).² Findings from the study showed an overall response rate (ORR) of 29%, and a median duration of response (DoR) of 10 months.²

Pralatrexate is administered intravenously at 30 mg/m2 once weekly for 6 weeks of a 7-week treatment cycle. It is generally continued until disease progression or an unacceptable level of toxicity.² Alternative dosing schedules have been described, including 15 mg/m2 once weekly for 3 weeks of a 4-week treatment cycle for cutaneous T-cell lymphomas.⁵

In this case series, we examine the outcomes of 2 patients with particularly aggressive subtypes of PTCL who were treated with pralatrexate. The significance of this report is in describing the long duration of response and reporting on a PTCL subtype – subcutaneous panniculitis-like T-cell lymphoma, alpha/beta type – that was underrepresented in the PROPEL study and is underreported in the literature.
 

Case presentations and summaries

Case 1

A 23-year-old Asian American man with a medical history of osteogenesis imperfecta presented to Emergency Department at the Hospital of University of Pennsylvania with bilateral lower extremity edema, low-grade fevers, a weight loss of 25 lb, and flat hyperpigmented scaly skin patches across his torso. Symptoms had started manifesting around five months prior to the visit. A punch biopsy of a skin lesion revealed skin tissue with focal infiltrate of small- to medium-sized, atypical lymphocytes infiltrating subcutaneous adipose tissue (panniculitis-like) and adnexa. Immunohistochemical stains showed that the abnormal lymphocytes were positive for CD3, CD8, perforin, granzyme B, TIA-1 (minor subset), and TCR beta; and negative for CD4, CD56, and CD30. Proliferation index (Ki67) was 70%. The findings were consistent with primary subcutaneous panniculitis-like T-cell lymphoma, alpha/beta type (Figure 1). A staging positron-emission tomography–computed tomography (PET–CT) scan demonstrated stage IVB lymphoma with subcutaneous involvement without nodal disease.

He was initially treated with aggressive combination regimens including EPOCH (etoposide, prednisolone, vincristine, cyclophosphamide, hydroxydaunorubicin) and ICE (ifosfamide, carboplatin, etoposide), but he had no response and his disease was primary refractory. Because of his osteogenesis imperfecta, he was not a candidate for allogenic stem cell transplant.

He responded to hyperCVAD B combination therapy (methotrexate and cytarabine), but the course was complicated by cytarabine-induced ataxia and dysarthia. He was then treated with 3 months of intravenous alemtuzumab without response. Intravenous methotrexate (2,000 mg/m²) was then used for 3 cycles, but this exacerbated his previous cytarabine-induced neurological symptoms and resulted in only partial response with persistent fluorine-18-deoxyglucose (FDG) avid lesions on a subsequent PET–CT scan.

At that point, the patient was started on pralatrexate at 15 mg/m² weekly for 3 weeks on a 4-week cycle schedule. This was his fifth line of therapy and at 16 months from his initial diagnosis. This dosage was continued for 6 months, and he tolerated the therapy well. He reported no exacerbations of his dysarthia, and by the second month, he had achieved clinical and radiographic remission with complete resolution of B symptoms (fevers, night sweats, and weight loss). The dosing was modified to 15 mg/m² every 2 weeks for 3 months. A whole body PET–CT scan showed resolution of previously FDG avid lesions.

The patient was then continued on 15 mg/m² pralatrexate every 3 weeks for 1 year and he has been maintained on once-a-month dosing for a second and now third year of therapy. He continues to tolerate the therapy and remains disease free at nearly 2 years since starting pralatrexate.
 

Case 2

A 64-year-old white man with a medical history of myasthenia gravis (in remission) and invasive thymoma (after thymectomy) presented with diffuse bulky lymphadenopathy and lung lesions to outpatient clinic at the Abramson Cancer Center at the University of Pennsylvania. His LDH was elevated (278 U/L, reference range 98-192 U/L). Excisional biopsy of a left inguinal lymph node revealed sheets of mitotically active large cells with oval to irregular nuclei, clumped chromatin, conspicuous and sometimes multiple nucleoli, and ample eosinophilic cytoplasm. Immunohistochemical staining showed that the neoplastic cells were positive for CD3, CD4, CD30, BCL2 (variable), and MUM1; and negative for ALK 1, CD5, CD8, CD15, CD43, and CD56. Proliferation index (Ki67) was 90% (Figure 2). PET-CT scan showed widespread hypermetabolic lymphoma in the chest, neck, abdomen, and pelvis with pulmonary metastases. Imaging also demonstrated FDG-avid lesions in the gastric and sinus area. The findings were consistent with ALK-negative, anaplastic large cell lymphoma. He was stage IVA; had gastric, lung, and sinus involvement; and disease above and below the diaphragm.

The patient was initially treated with 6 cycles of CHOP and intrathecal methotrexate injections. His post-treatment PET–CT scan showed persistent FDG-avid disease and his LDH level remained elevated. He underwent 1 cycle of ICE and then BCV (busulfan, cyclophosphamide, etoposide) autologous stem cell transplant. Post-transplant PET–CT scan showed improvement from previous 2 scans but still showed several hypermetabolic lymph nodes consistent with persistent disease.

The patient was started on a pralatrexate regimen of 30 mg/m² once weekly for 6 weeks of a 7-week treatment cycle. After 5 doses, he developed thrombocytopenia and mucositis, which were deemed pralatrexate related. The dosage was reduced to 20 mg/m² once weekly with variable frequency depending on tolerability. His response assessment with PET–CT scan demonstrated radiographic complete response with resolution of hypermetabolic lesions (Figure 3B).

Discussion

PTCL is a rare and heterogeneous lymphoma with poor prognosis. Only 3 agents – pralatrexate, belinostat, and romidespin – have been approved specifically for the treatment of PTCL and all of them have an ORR of less than 30%, based on findings from phase 2 studies.^2,6,7 In the PROPEL study, pralatrexate showed an ORR of 29% and a median DoR of 10 months.² Those results could be considered discouraging, but some PTCL patients may have durable response to pralatrexate monotherapy.

In this case series, each of the patients presented with a particularly aggressive subtype of PTCL, and 1 suffered from a notably rare subtype for which there was scant clinical data to guide treatment. Both patients went through several lines of aggressive treatment that were ineffective and resulted in minimal response. However, both were able to achieve complete resolution of their disease and maintained remission for a significant duration of time after treatment with pralatrexate. In addition, each patient has maintained his remission – one for 6 years after the last dose. These are noteworthy results, and give both patients and clinicians hope that this therapy can be highly effective in some settings.

A better understanding at the molecular level of the oncogenic mechanisms in PTCL patients will be necessary to guide our therapy choices. In these 2 cases, it is likely that the tumor demonstrated superior sensitivity to dihydrofolate reductase inhibition by pralatrexate. In the future, we hope that analysis of the tumor tissue from PTCL patients will allow us to better categorize the tumor sensitivities to particular therapeutic agents. We believe that individualized treatment will lead to better overall outcomes in this challenging group of lymphomas.

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of mature T- and natural killer-cell neoplasms that comprise about 10%-15% of all non-Hodgkin lymphomas in the United States.^1,2 The development of effective therapies for PTCL has been challenging because of the rare nature and heterogeneity of these lymphomas. Most therapies are a derivative of aggressive B-cell lymphoma therapies, including CHOP (cyclophosphamide, hydroxydaunorubicin, vinicristine, prednisone) and CHOEP (cyclophosphamide, hydroxydaunorubicin, vinicristine, etoposide, prednisone).¹ Many centers use autologous or allogeneic stem cell transplant in this setting,¹ but outcomes remain poor and progress in developing effective treatments has been slow.

Pralatrexate is the first drug to have been approved by the US Food and Drug Administration specifically for treating patients with relapsed or refractory PTCL.³ As a folate analog metabolic inhibitor, pralatrexate competitively inhibits dihydrofolate reductase and reduces cellular levels of thymidine monophosphate, which prevents the cell from synthesizing genetic material and triggers it to undergo apoptosis.⁴ The agency’s approval of pralatrexate was based on results from the PROPEL study, which is possibly the largest prospective study conducted in patients with relapsed or refractory PTCL (109 evaluable patients).² Findings from the study showed an overall response rate (ORR) of 29%, and a median duration of response (DoR) of 10 months.²

Pralatrexate is administered intravenously at 30 mg/m2 once weekly for 6 weeks of a 7-week treatment cycle. It is generally continued until disease progression or an unacceptable level of toxicity.² Alternative dosing schedules have been described, including 15 mg/m2 once weekly for 3 weeks of a 4-week treatment cycle for cutaneous T-cell lymphomas.⁵

In this case series, we examine the outcomes of 2 patients with particularly aggressive subtypes of PTCL who were treated with pralatrexate. The significance of this report is in describing the long duration of response and reporting on a PTCL subtype – subcutaneous panniculitis-like T-cell lymphoma, alpha/beta type – that was underrepresented in the PROPEL study and is underreported in the literature.
 

Case presentations and summaries

Case 1

A 23-year-old Asian American man with a medical history of osteogenesis imperfecta presented to Emergency Department at the Hospital of University of Pennsylvania with bilateral lower extremity edema, low-grade fevers, a weight loss of 25 lb, and flat hyperpigmented scaly skin patches across his torso. Symptoms had started manifesting around five months prior to the visit. A punch biopsy of a skin lesion revealed skin tissue with focal infiltrate of small- to medium-sized, atypical lymphocytes infiltrating subcutaneous adipose tissue (panniculitis-like) and adnexa. Immunohistochemical stains showed that the abnormal lymphocytes were positive for CD3, CD8, perforin, granzyme B, TIA-1 (minor subset), and TCR beta; and negative for CD4, CD56, and CD30. Proliferation index (Ki67) was 70%. The findings were consistent with primary subcutaneous panniculitis-like T-cell lymphoma, alpha/beta type (Figure 1). A staging positron-emission tomography–computed tomography (PET–CT) scan demonstrated stage IVB lymphoma with subcutaneous involvement without nodal disease.

He was initially treated with aggressive combination regimens including EPOCH (etoposide, prednisolone, vincristine, cyclophosphamide, hydroxydaunorubicin) and ICE (ifosfamide, carboplatin, etoposide), but he had no response and his disease was primary refractory. Because of his osteogenesis imperfecta, he was not a candidate for allogenic stem cell transplant.

He responded to hyperCVAD B combination therapy (methotrexate and cytarabine), but the course was complicated by cytarabine-induced ataxia and dysarthia. He was then treated with 3 months of intravenous alemtuzumab without response. Intravenous methotrexate (2,000 mg/m²) was then used for 3 cycles, but this exacerbated his previous cytarabine-induced neurological symptoms and resulted in only partial response with persistent fluorine-18-deoxyglucose (FDG) avid lesions on a subsequent PET–CT scan.

At that point, the patient was started on pralatrexate at 15 mg/m² weekly for 3 weeks on a 4-week cycle schedule. This was his fifth line of therapy and at 16 months from his initial diagnosis. This dosage was continued for 6 months, and he tolerated the therapy well. He reported no exacerbations of his dysarthia, and by the second month, he had achieved clinical and radiographic remission with complete resolution of B symptoms (fevers, night sweats, and weight loss). The dosing was modified to 15 mg/m² every 2 weeks for 3 months. A whole body PET–CT scan showed resolution of previously FDG avid lesions.

The patient was then continued on 15 mg/m² pralatrexate every 3 weeks for 1 year and he has been maintained on once-a-month dosing for a second and now third year of therapy. He continues to tolerate the therapy and remains disease free at nearly 2 years since starting pralatrexate.
 

Case 2

A 64-year-old white man with a medical history of myasthenia gravis (in remission) and invasive thymoma (after thymectomy) presented with diffuse bulky lymphadenopathy and lung lesions to outpatient clinic at the Abramson Cancer Center at the University of Pennsylvania. His LDH was elevated (278 U/L, reference range 98-192 U/L). Excisional biopsy of a left inguinal lymph node revealed sheets of mitotically active large cells with oval to irregular nuclei, clumped chromatin, conspicuous and sometimes multiple nucleoli, and ample eosinophilic cytoplasm. Immunohistochemical staining showed that the neoplastic cells were positive for CD3, CD4, CD30, BCL2 (variable), and MUM1; and negative for ALK 1, CD5, CD8, CD15, CD43, and CD56. Proliferation index (Ki67) was 90% (Figure 2). PET-CT scan showed widespread hypermetabolic lymphoma in the chest, neck, abdomen, and pelvis with pulmonary metastases. Imaging also demonstrated FDG-avid lesions in the gastric and sinus area. The findings were consistent with ALK-negative, anaplastic large cell lymphoma. He was stage IVA; had gastric, lung, and sinus involvement; and disease above and below the diaphragm.

The patient was initially treated with 6 cycles of CHOP and intrathecal methotrexate injections. His post-treatment PET–CT scan showed persistent FDG-avid disease and his LDH level remained elevated. He underwent 1 cycle of ICE and then BCV (busulfan, cyclophosphamide, etoposide) autologous stem cell transplant. Post-transplant PET–CT scan showed improvement from previous 2 scans but still showed several hypermetabolic lymph nodes consistent with persistent disease.

The patient was started on a pralatrexate regimen of 30 mg/m² once weekly for 6 weeks of a 7-week treatment cycle. After 5 doses, he developed thrombocytopenia and mucositis, which were deemed pralatrexate related. The dosage was reduced to 20 mg/m² once weekly with variable frequency depending on tolerability. His response assessment with PET–CT scan demonstrated radiographic complete response with resolution of hypermetabolic lesions (Figure 3B).

Discussion

PTCL is a rare and heterogeneous lymphoma with poor prognosis. Only 3 agents – pralatrexate, belinostat, and romidespin – have been approved specifically for the treatment of PTCL and all of them have an ORR of less than 30%, based on findings from phase 2 studies.^2,6,7 In the PROPEL study, pralatrexate showed an ORR of 29% and a median DoR of 10 months.² Those results could be considered discouraging, but some PTCL patients may have durable response to pralatrexate monotherapy.

In this case series, each of the patients presented with a particularly aggressive subtype of PTCL, and 1 suffered from a notably rare subtype for which there was scant clinical data to guide treatment. Both patients went through several lines of aggressive treatment that were ineffective and resulted in minimal response. However, both were able to achieve complete resolution of their disease and maintained remission for a significant duration of time after treatment with pralatrexate. In addition, each patient has maintained his remission – one for 6 years after the last dose. These are noteworthy results, and give both patients and clinicians hope that this therapy can be highly effective in some settings.

A better understanding at the molecular level of the oncogenic mechanisms in PTCL patients will be necessary to guide our therapy choices. In these 2 cases, it is likely that the tumor demonstrated superior sensitivity to dihydrofolate reductase inhibition by pralatrexate. In the future, we hope that analysis of the tumor tissue from PTCL patients will allow us to better categorize the tumor sensitivities to particular therapeutic agents. We believe that individualized treatment will lead to better overall outcomes in this challenging group of lymphomas.

In this edition of the MDedge Psychcast Laura Marsh, MD, returns to discuss Parkinson’s disease. And later, Dr. RK gives Part 2 on her talk on HIPAA.

In this edition of the MDedge Psychcast Laura Marsh, MD, returns to discuss Parkinson’s disease. And later, Dr. RK gives Part 2 on her talk on HIPAA.

In this edition of the MDedge Psychcast Laura Marsh, MD, returns to discuss Parkinson’s disease. And later, Dr. RK gives Part 2 on her talk on HIPAA.

Lenalidomide may be the best maintenance treatment option for patients with newly diagnosed multiple myeloma, say the authors of a systematic review and meta-analysis.

Francesca M. Gay, MD, from the division of hematology at the University of Torino (Italy), and her coauthors wrote that despite the well-recognized importance of novel agent–based maintenance therapy for multiple myeloma, there is a lack of direct or indirect comparisons between the available regimens.

In a paper published online in JAMA Oncology, the researchers reported the results of the systematic review and meta-analysis of 11 prospective, phase 3 randomized, controlled trials of eight varieties of maintenance therapy, in 5,073 participants with newly diagnosed multiple myeloma.

Their analysis found that lenalidomide-based regimens showed the best progression-free survival rates (hazard ratio, 0.39 for lenalidomide plus prednisone; HR, 0.47 for lenalidomide alone), compared with placebo, and in 74% of the network meta-analysis simulations, they were the most effective options.

Four other maintenance treatment options - thalidomide-interferon, thalidomide-bortezomib, bortezomib-prednisone, and thalidomide alone – also showed progression-free survival gains – but interferon therapy failed to show any benefit.

However, for overall survival, lenalidomide alone was the best option, followed by thalidomide-bortezomib and bortezomib-prednisone. None of the other regimens considered showed benefits for overall survival.

“Long-term use of lenalidomide undoubtedly has advantages, owing to the lack of neuropathy, which is the main factor limiting the long-term use of both thalidomide and bortezomib,” the authors wrote.

When the authors restricted their analysis to trials conducted in the setting of autologous stem cell transplantation they found similar results, with lenalidomide-based regimens having the best progression-free and overall survival.

Patients with a good prognosis and standard-risk chromosomal abnormalities also did best with lenalidomide-based maintenance, while those with a poor prognosis – for example, with ISS stage III disease – benefited more from bortezomib-based maintenance. However patients with high-risk chromosomal abnormalities gained no advantage from any regimen, which the authors suggested may relate to small sample size, different cut-off points or their extremely poor prognosis.

The authors noted that their analysis did not take into account adverse events, drug discontinuations, or quality of life but focused solely on progression-free survival and overall survival.

“An increase in second primary malignant disease with prolonged lenalidomide therapy has been reported, but the survival benefit overcame the risk in all the trials,” they wrote.

They also commented that better treatment options are needed for patients with aggressive disease, and there are ongoing trials looking at second-generation proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies for maintenance therapy.

Most authors declared research funding, advisory board positions, fees and honoraria from the pharmaceutical industry, including lenalidomide manufacturer Celgene.

SOURCE: Gay F et al. 2018 Aug 9. doi:10.1001/jamaoncol.2018.2961.

Lenalidomide may be the best maintenance treatment option for patients with newly diagnosed multiple myeloma, say the authors of a systematic review and meta-analysis.

Francesca M. Gay, MD, from the division of hematology at the University of Torino (Italy), and her coauthors wrote that despite the well-recognized importance of novel agent–based maintenance therapy for multiple myeloma, there is a lack of direct or indirect comparisons between the available regimens.

In a paper published online in JAMA Oncology, the researchers reported the results of the systematic review and meta-analysis of 11 prospective, phase 3 randomized, controlled trials of eight varieties of maintenance therapy, in 5,073 participants with newly diagnosed multiple myeloma.

Their analysis found that lenalidomide-based regimens showed the best progression-free survival rates (hazard ratio, 0.39 for lenalidomide plus prednisone; HR, 0.47 for lenalidomide alone), compared with placebo, and in 74% of the network meta-analysis simulations, they were the most effective options.

Four other maintenance treatment options - thalidomide-interferon, thalidomide-bortezomib, bortezomib-prednisone, and thalidomide alone – also showed progression-free survival gains – but interferon therapy failed to show any benefit.

However, for overall survival, lenalidomide alone was the best option, followed by thalidomide-bortezomib and bortezomib-prednisone. None of the other regimens considered showed benefits for overall survival.

“Long-term use of lenalidomide undoubtedly has advantages, owing to the lack of neuropathy, which is the main factor limiting the long-term use of both thalidomide and bortezomib,” the authors wrote.

When the authors restricted their analysis to trials conducted in the setting of autologous stem cell transplantation they found similar results, with lenalidomide-based regimens having the best progression-free and overall survival.

Patients with a good prognosis and standard-risk chromosomal abnormalities also did best with lenalidomide-based maintenance, while those with a poor prognosis – for example, with ISS stage III disease – benefited more from bortezomib-based maintenance. However patients with high-risk chromosomal abnormalities gained no advantage from any regimen, which the authors suggested may relate to small sample size, different cut-off points or their extremely poor prognosis.

The authors noted that their analysis did not take into account adverse events, drug discontinuations, or quality of life but focused solely on progression-free survival and overall survival.

“An increase in second primary malignant disease with prolonged lenalidomide therapy has been reported, but the survival benefit overcame the risk in all the trials,” they wrote.

They also commented that better treatment options are needed for patients with aggressive disease, and there are ongoing trials looking at second-generation proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies for maintenance therapy.

Most authors declared research funding, advisory board positions, fees and honoraria from the pharmaceutical industry, including lenalidomide manufacturer Celgene.

SOURCE: Gay F et al. 2018 Aug 9. doi:10.1001/jamaoncol.2018.2961.

Lenalidomide may be the best maintenance treatment option for patients with newly diagnosed multiple myeloma, say the authors of a systematic review and meta-analysis.

Francesca M. Gay, MD, from the division of hematology at the University of Torino (Italy), and her coauthors wrote that despite the well-recognized importance of novel agent–based maintenance therapy for multiple myeloma, there is a lack of direct or indirect comparisons between the available regimens.

In a paper published online in JAMA Oncology, the researchers reported the results of the systematic review and meta-analysis of 11 prospective, phase 3 randomized, controlled trials of eight varieties of maintenance therapy, in 5,073 participants with newly diagnosed multiple myeloma.

Their analysis found that lenalidomide-based regimens showed the best progression-free survival rates (hazard ratio, 0.39 for lenalidomide plus prednisone; HR, 0.47 for lenalidomide alone), compared with placebo, and in 74% of the network meta-analysis simulations, they were the most effective options.

Four other maintenance treatment options - thalidomide-interferon, thalidomide-bortezomib, bortezomib-prednisone, and thalidomide alone – also showed progression-free survival gains – but interferon therapy failed to show any benefit.

However, for overall survival, lenalidomide alone was the best option, followed by thalidomide-bortezomib and bortezomib-prednisone. None of the other regimens considered showed benefits for overall survival.

“Long-term use of lenalidomide undoubtedly has advantages, owing to the lack of neuropathy, which is the main factor limiting the long-term use of both thalidomide and bortezomib,” the authors wrote.

When the authors restricted their analysis to trials conducted in the setting of autologous stem cell transplantation they found similar results, with lenalidomide-based regimens having the best progression-free and overall survival.

Patients with a good prognosis and standard-risk chromosomal abnormalities also did best with lenalidomide-based maintenance, while those with a poor prognosis – for example, with ISS stage III disease – benefited more from bortezomib-based maintenance. However patients with high-risk chromosomal abnormalities gained no advantage from any regimen, which the authors suggested may relate to small sample size, different cut-off points or their extremely poor prognosis.

The authors noted that their analysis did not take into account adverse events, drug discontinuations, or quality of life but focused solely on progression-free survival and overall survival.

“An increase in second primary malignant disease with prolonged lenalidomide therapy has been reported, but the survival benefit overcame the risk in all the trials,” they wrote.

They also commented that better treatment options are needed for patients with aggressive disease, and there are ongoing trials looking at second-generation proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies for maintenance therapy.

Most authors declared research funding, advisory board positions, fees and honoraria from the pharmaceutical industry, including lenalidomide manufacturer Celgene.

SOURCE: Gay F et al. 2018 Aug 9. doi:10.1001/jamaoncol.2018.2961.

PARIS – The so-called hybrid strategy is now the preferred approach to percutaneous coronary intervention (PCI) for chronic total occlusions (CTO), 12-month outcomes of the multicenter observational CONSISTENT CTO trial suggest, according to Simon J. Walsh, MD, an interventional cardiologist at Belfast Health and Social Care Trust.

Bruce Jancin/MDedge News

The hybrid algorithm-based PCI strategy utilizes an individual’s CTO anatomy to dictate the initial choice of approach. The goal is to pick the strategy that is most likely to achieve successful outcome efficiently, with minimal contrast and radiation doses for that particular type of CTO. The hybrid algorithm begins with dual-catheter injection and intravascular ultrasound aimed at determining whether four key anatomic features are present: an ambiguous proximal cap, a poor distal target, good interventional collaterals, and a major side branch at the distal cap.

If those four features are absent and the CTO lesion is less than 20-mm long, the algorithm dictates that the initial approach is antegrade wire escalation; if the lesion is 20 mm or more, the first approach is antegrade dissection reentry. However, if those anatomic features are present, the initial strategy is retrograde wire escalation if the lesion is less than 20 mm, and retrograde dissection reentry for longer lesions. When the initial approach fails, structured protocols dictate the selection of second and third approaches (JACC Cardiovasc Interv. 2012 Apr;5[4]:367-79).

The right coronary artery was the site of the CTO in 70% of study participants. Dual-catheter access was utilized in 79% of patients; only 10% had exclusively radial access. An average of 2.8 Synergy stents were deployed, with a whopping mean total stent length of 96.6 mm in the 48% of patients with dissection and 75.4 mm in those without. Mean procedure time was 122 minutes, with a fluoroscopy time of 44.6 minutes.

The primary efficacy endpoint was the rate of target vessel failure (TVF) at 12 months, defined as cardiac death, MI related to the target vessel, or any ischemia-driven revascularization of the target vessel. The rate was 5.24%.

“We were pleasantly surprised by that,” Dr. Walsh admitted.

Indeed, based upon studies of PCI for CTO published by other investigators, he and his colleagues had initially projected a 13% TVF rate, then bumped it up to 15% because of the high degree of lesion complexity.

Diabetes was the main predictor of target vessel revascularization.

At the time of the index PCI, 19% of patients were scheduled to return for an early optimization procedure within 3 months. This was arranged when operators anticipated significant positive remodeling would occur as the target vessel readjusted to blood flow or distal disease of borderline severity was noted beyond the CTO segment. These were not counted as adverse events. Half of the returnees underwent angiography and no further action was undertaken. The others underwent postdilation of their Synergy stents or new stenting of distal disease.

Complete revascularization of the target territory was achieved in 98.6% of patients. Key complications consisted of 5 perforations, 10 hematomas at vascular access sites, 2 cases of pericardiocentesis, and 4 instances of bleeding requiring transfusion.

The final successful CTO revascularization strategy was antegrade dissection reentry in 18% of patients, retrograde dissection reentry in 30%, antegrade wire escalation in 34%, and retrograde wire escalation in 18%. A switch from the initial algorithm-based strategy to a second strategy occurred in 41% of patients, and a third strategy was employed in 9%.

“I think the key message is you need to have more than one option to treat complicated disease. Half of patients had a switch in strategy,” Dr. Walsh observed.

Intravascular ultrasound (IVUS) adjudication in the central core lab showed a humbling rate of discordance between the operators’ impression of how their procedures were proceeding and what was really going on.

“There’s a bit of a mantra [that says] if you’re wiring stuff you’re always in the lumen, and if you’re using dissection techniques you’re always not in the lumen. In fact, that’s nonsense. You get it wrong one in six times. When you use IVUS adjudication to see if you’re outside the lumen or not, with wire-based retrograde escalation you’re out of the lumen and in the subintimal space 27% of the time. And with dissection strategies you’re wrong in about 15%,” according to the cardiologist.

He described the study participants as “extremely limited” at baseline as evidenced by their scores on the Seattle Angina Questionnaire Physical Limitation, Angina Stability, and Angina Frequency domains. At 12 months of follow-up, patients averaged 20- to 40-point improvements across all three domains.

One member of the discussion panel expressed a wish that the study had included a sham PCI arm. He raised the possibility that PCI had exerted an enormous placebo effect that could conceivably account for the substantial quality of life benefits documented in the study. But another panelist scoffed at this notion. This wasn’t a modest improvement in quality of life, nor was it measured after a mere 6 weeks, as was the case in the sham-controlled ORBITA trial.

“It’s really difficult to imagine a sham effect that persists out to a year,” he argued.

Dr. Walsh reported receiving research grants from and serving as a consultant to Boston Scientific, which funded the CONSISTENT CTO Study.

[email protected]

PARIS – The so-called hybrid strategy is now the preferred approach to percutaneous coronary intervention (PCI) for chronic total occlusions (CTO), 12-month outcomes of the multicenter observational CONSISTENT CTO trial suggest, according to Simon J. Walsh, MD, an interventional cardiologist at Belfast Health and Social Care Trust.

Bruce Jancin/MDedge News

The hybrid algorithm-based PCI strategy utilizes an individual’s CTO anatomy to dictate the initial choice of approach. The goal is to pick the strategy that is most likely to achieve successful outcome efficiently, with minimal contrast and radiation doses for that particular type of CTO. The hybrid algorithm begins with dual-catheter injection and intravascular ultrasound aimed at determining whether four key anatomic features are present: an ambiguous proximal cap, a poor distal target, good interventional collaterals, and a major side branch at the distal cap.

If those four features are absent and the CTO lesion is less than 20-mm long, the algorithm dictates that the initial approach is antegrade wire escalation; if the lesion is 20 mm or more, the first approach is antegrade dissection reentry. However, if those anatomic features are present, the initial strategy is retrograde wire escalation if the lesion is less than 20 mm, and retrograde dissection reentry for longer lesions. When the initial approach fails, structured protocols dictate the selection of second and third approaches (JACC Cardiovasc Interv. 2012 Apr;5[4]:367-79).

The right coronary artery was the site of the CTO in 70% of study participants. Dual-catheter access was utilized in 79% of patients; only 10% had exclusively radial access. An average of 2.8 Synergy stents were deployed, with a whopping mean total stent length of 96.6 mm in the 48% of patients with dissection and 75.4 mm in those without. Mean procedure time was 122 minutes, with a fluoroscopy time of 44.6 minutes.

The primary efficacy endpoint was the rate of target vessel failure (TVF) at 12 months, defined as cardiac death, MI related to the target vessel, or any ischemia-driven revascularization of the target vessel. The rate was 5.24%.

“We were pleasantly surprised by that,” Dr. Walsh admitted.

Indeed, based upon studies of PCI for CTO published by other investigators, he and his colleagues had initially projected a 13% TVF rate, then bumped it up to 15% because of the high degree of lesion complexity.

Diabetes was the main predictor of target vessel revascularization.

At the time of the index PCI, 19% of patients were scheduled to return for an early optimization procedure within 3 months. This was arranged when operators anticipated significant positive remodeling would occur as the target vessel readjusted to blood flow or distal disease of borderline severity was noted beyond the CTO segment. These were not counted as adverse events. Half of the returnees underwent angiography and no further action was undertaken. The others underwent postdilation of their Synergy stents or new stenting of distal disease.

Complete revascularization of the target territory was achieved in 98.6% of patients. Key complications consisted of 5 perforations, 10 hematomas at vascular access sites, 2 cases of pericardiocentesis, and 4 instances of bleeding requiring transfusion.

The final successful CTO revascularization strategy was antegrade dissection reentry in 18% of patients, retrograde dissection reentry in 30%, antegrade wire escalation in 34%, and retrograde wire escalation in 18%. A switch from the initial algorithm-based strategy to a second strategy occurred in 41% of patients, and a third strategy was employed in 9%.

“I think the key message is you need to have more than one option to treat complicated disease. Half of patients had a switch in strategy,” Dr. Walsh observed.

Intravascular ultrasound (IVUS) adjudication in the central core lab showed a humbling rate of discordance between the operators’ impression of how their procedures were proceeding and what was really going on.

“There’s a bit of a mantra [that says] if you’re wiring stuff you’re always in the lumen, and if you’re using dissection techniques you’re always not in the lumen. In fact, that’s nonsense. You get it wrong one in six times. When you use IVUS adjudication to see if you’re outside the lumen or not, with wire-based retrograde escalation you’re out of the lumen and in the subintimal space 27% of the time. And with dissection strategies you’re wrong in about 15%,” according to the cardiologist.

He described the study participants as “extremely limited” at baseline as evidenced by their scores on the Seattle Angina Questionnaire Physical Limitation, Angina Stability, and Angina Frequency domains. At 12 months of follow-up, patients averaged 20- to 40-point improvements across all three domains.

One member of the discussion panel expressed a wish that the study had included a sham PCI arm. He raised the possibility that PCI had exerted an enormous placebo effect that could conceivably account for the substantial quality of life benefits documented in the study. But another panelist scoffed at this notion. This wasn’t a modest improvement in quality of life, nor was it measured after a mere 6 weeks, as was the case in the sham-controlled ORBITA trial.

“It’s really difficult to imagine a sham effect that persists out to a year,” he argued.

Dr. Walsh reported receiving research grants from and serving as a consultant to Boston Scientific, which funded the CONSISTENT CTO Study.

[email protected]

PARIS – The so-called hybrid strategy is now the preferred approach to percutaneous coronary intervention (PCI) for chronic total occlusions (CTO), 12-month outcomes of the multicenter observational CONSISTENT CTO trial suggest, according to Simon J. Walsh, MD, an interventional cardiologist at Belfast Health and Social Care Trust.

Bruce Jancin/MDedge News

The hybrid algorithm-based PCI strategy utilizes an individual’s CTO anatomy to dictate the initial choice of approach. The goal is to pick the strategy that is most likely to achieve successful outcome efficiently, with minimal contrast and radiation doses for that particular type of CTO. The hybrid algorithm begins with dual-catheter injection and intravascular ultrasound aimed at determining whether four key anatomic features are present: an ambiguous proximal cap, a poor distal target, good interventional collaterals, and a major side branch at the distal cap.

If those four features are absent and the CTO lesion is less than 20-mm long, the algorithm dictates that the initial approach is antegrade wire escalation; if the lesion is 20 mm or more, the first approach is antegrade dissection reentry. However, if those anatomic features are present, the initial strategy is retrograde wire escalation if the lesion is less than 20 mm, and retrograde dissection reentry for longer lesions. When the initial approach fails, structured protocols dictate the selection of second and third approaches (JACC Cardiovasc Interv. 2012 Apr;5[4]:367-79).

The right coronary artery was the site of the CTO in 70% of study participants. Dual-catheter access was utilized in 79% of patients; only 10% had exclusively radial access. An average of 2.8 Synergy stents were deployed, with a whopping mean total stent length of 96.6 mm in the 48% of patients with dissection and 75.4 mm in those without. Mean procedure time was 122 minutes, with a fluoroscopy time of 44.6 minutes.

The primary efficacy endpoint was the rate of target vessel failure (TVF) at 12 months, defined as cardiac death, MI related to the target vessel, or any ischemia-driven revascularization of the target vessel. The rate was 5.24%.

“We were pleasantly surprised by that,” Dr. Walsh admitted.

Indeed, based upon studies of PCI for CTO published by other investigators, he and his colleagues had initially projected a 13% TVF rate, then bumped it up to 15% because of the high degree of lesion complexity.

Diabetes was the main predictor of target vessel revascularization.

At the time of the index PCI, 19% of patients were scheduled to return for an early optimization procedure within 3 months. This was arranged when operators anticipated significant positive remodeling would occur as the target vessel readjusted to blood flow or distal disease of borderline severity was noted beyond the CTO segment. These were not counted as adverse events. Half of the returnees underwent angiography and no further action was undertaken. The others underwent postdilation of their Synergy stents or new stenting of distal disease.

Complete revascularization of the target territory was achieved in 98.6% of patients. Key complications consisted of 5 perforations, 10 hematomas at vascular access sites, 2 cases of pericardiocentesis, and 4 instances of bleeding requiring transfusion.

The final successful CTO revascularization strategy was antegrade dissection reentry in 18% of patients, retrograde dissection reentry in 30%, antegrade wire escalation in 34%, and retrograde wire escalation in 18%. A switch from the initial algorithm-based strategy to a second strategy occurred in 41% of patients, and a third strategy was employed in 9%.

“I think the key message is you need to have more than one option to treat complicated disease. Half of patients had a switch in strategy,” Dr. Walsh observed.

Intravascular ultrasound (IVUS) adjudication in the central core lab showed a humbling rate of discordance between the operators’ impression of how their procedures were proceeding and what was really going on.

“There’s a bit of a mantra [that says] if you’re wiring stuff you’re always in the lumen, and if you’re using dissection techniques you’re always not in the lumen. In fact, that’s nonsense. You get it wrong one in six times. When you use IVUS adjudication to see if you’re outside the lumen or not, with wire-based retrograde escalation you’re out of the lumen and in the subintimal space 27% of the time. And with dissection strategies you’re wrong in about 15%,” according to the cardiologist.

He described the study participants as “extremely limited” at baseline as evidenced by their scores on the Seattle Angina Questionnaire Physical Limitation, Angina Stability, and Angina Frequency domains. At 12 months of follow-up, patients averaged 20- to 40-point improvements across all three domains.

One member of the discussion panel expressed a wish that the study had included a sham PCI arm. He raised the possibility that PCI had exerted an enormous placebo effect that could conceivably account for the substantial quality of life benefits documented in the study. But another panelist scoffed at this notion. This wasn’t a modest improvement in quality of life, nor was it measured after a mere 6 weeks, as was the case in the sham-controlled ORBITA trial.

“It’s really difficult to imagine a sham effect that persists out to a year,” he argued.

Dr. Walsh reported receiving research grants from and serving as a consultant to Boston Scientific, which funded the CONSISTENT CTO Study.

[email protected]

Hundreds of reports since the 1980s have associated Alzheimer disease with bacteria and viruses. But researchers could not explain the connection. Now new research suggests that viral species, particularly herpes viruses, play a role in Alzheimer disease biology.

The hypotheses that link viruses to brain disease are not new, Richard Hodes, MD, director of the National Institute on Aging, says, but this is the first study to provide “strong evidence” based on unbiased approaches and large datasets.

The study, which was funded by National Institute of Aging (NIA) , originally was intended to find out whether drugs used to treat other diseases can be repurposed for treating Alzheimer. Researchers analyzed large datasets from postmortem brain samples to map and compare biological networks underlying Alzheimer disease. They found that the disease biology is impacted by a “complex constellation” of factors, including the ways the interrelated systems of DNA, RNA, proteins, and metabolites interact with molecular, genetic, and clinical aspects of Alzheimer disease.

Among the key findings: Human herpes virus 6A and 7 were more abundant in Alzheimer disease samples than in non-Alzheimer samples. Researchers also found multiple points of overlap between virus-host interactions and genes associated with Alzheimer risk.

The research “reinforces the complexity of Alzheimer disease,” Hode says, and “highlights the importance of sharing data freely and widely with the research community.”

Hundreds of reports since the 1980s have associated Alzheimer disease with bacteria and viruses. But researchers could not explain the connection. Now new research suggests that viral species, particularly herpes viruses, play a role in Alzheimer disease biology.

The hypotheses that link viruses to brain disease are not new, Richard Hodes, MD, director of the National Institute on Aging, says, but this is the first study to provide “strong evidence” based on unbiased approaches and large datasets.

The study, which was funded by National Institute of Aging (NIA) , originally was intended to find out whether drugs used to treat other diseases can be repurposed for treating Alzheimer. Researchers analyzed large datasets from postmortem brain samples to map and compare biological networks underlying Alzheimer disease. They found that the disease biology is impacted by a “complex constellation” of factors, including the ways the interrelated systems of DNA, RNA, proteins, and metabolites interact with molecular, genetic, and clinical aspects of Alzheimer disease.

Among the key findings: Human herpes virus 6A and 7 were more abundant in Alzheimer disease samples than in non-Alzheimer samples. Researchers also found multiple points of overlap between virus-host interactions and genes associated with Alzheimer risk.

The research “reinforces the complexity of Alzheimer disease,” Hode says, and “highlights the importance of sharing data freely and widely with the research community.”

Hundreds of reports since the 1980s have associated Alzheimer disease with bacteria and viruses. But researchers could not explain the connection. Now new research suggests that viral species, particularly herpes viruses, play a role in Alzheimer disease biology.

The hypotheses that link viruses to brain disease are not new, Richard Hodes, MD, director of the National Institute on Aging, says, but this is the first study to provide “strong evidence” based on unbiased approaches and large datasets.

The study, which was funded by National Institute of Aging (NIA) , originally was intended to find out whether drugs used to treat other diseases can be repurposed for treating Alzheimer. Researchers analyzed large datasets from postmortem brain samples to map and compare biological networks underlying Alzheimer disease. They found that the disease biology is impacted by a “complex constellation” of factors, including the ways the interrelated systems of DNA, RNA, proteins, and metabolites interact with molecular, genetic, and clinical aspects of Alzheimer disease.

Among the key findings: Human herpes virus 6A and 7 were more abundant in Alzheimer disease samples than in non-Alzheimer samples. Researchers also found multiple points of overlap between virus-host interactions and genes associated with Alzheimer risk.

The research “reinforces the complexity of Alzheimer disease,” Hode says, and “highlights the importance of sharing data freely and widely with the research community.”

Platelet-transmitted bacterial infections persist as a cause of transfusion-associated morbidity and mortality, according to researchers writing in Mortality and Morbidity Weekly Report. They describe 2 separate clusters of platelet transfusion-associated bacterial sepsis reported in Utah and California, in which 3 patients died.

Contamination of blood products most commonly happens when skin microbiota is introduced during needle insertion. Because most platelets are stored at room temperature, bacteria can proliferate to clinically important levels by the time the unit is transfused, the CDC says. About 1 in 5,000 platelet collections are contaminated; 1 in 100,000 platelet transfusions results in bacterial sepsis.

In Utah, 2 patients received contaminated apheresis platelet units. One developed rigors 30 minutes after infusion, but transfusion-transmitted bacterial infection was not considered because of the patient’s complex medical history. He died 4 days later.

Less than a day after the first patient’s infusion, the second patient received the other platelet unit. No immediate symptoms of sepsis followed but later that day routine laboratory testing revealed new intravascular hemolysis. She died 11 hours after transfusion.

In California, a patient developed vomiting, tachycardia, and hypotension within 15 minutes of an infusion that came from an apheresis blood donation. Although the transfusion was stopped, he died within 5 hours. A second patient developed septic shock approximately 9 hours after infusion but recovered.

Subsequent investigation found that both the Utah and California collection facilities followed current practices. However, the CDC report highlights that even when procedures are followed appropriately, the risk remains. The CDC says evidence-based strategies such as pathogen inactivation, rapid detection devices, and modified screen of bacterial culture protocols can help mitigate that risk.

Platelet-transmitted bacterial infections persist as a cause of transfusion-associated morbidity and mortality, according to researchers writing in Mortality and Morbidity Weekly Report. They describe 2 separate clusters of platelet transfusion-associated bacterial sepsis reported in Utah and California, in which 3 patients died.

Contamination of blood products most commonly happens when skin microbiota is introduced during needle insertion. Because most platelets are stored at room temperature, bacteria can proliferate to clinically important levels by the time the unit is transfused, the CDC says. About 1 in 5,000 platelet collections are contaminated; 1 in 100,000 platelet transfusions results in bacterial sepsis.

In Utah, 2 patients received contaminated apheresis platelet units. One developed rigors 30 minutes after infusion, but transfusion-transmitted bacterial infection was not considered because of the patient’s complex medical history. He died 4 days later.

Less than a day after the first patient’s infusion, the second patient received the other platelet unit. No immediate symptoms of sepsis followed but later that day routine laboratory testing revealed new intravascular hemolysis. She died 11 hours after transfusion.

In California, a patient developed vomiting, tachycardia, and hypotension within 15 minutes of an infusion that came from an apheresis blood donation. Although the transfusion was stopped, he died within 5 hours. A second patient developed septic shock approximately 9 hours after infusion but recovered.

Subsequent investigation found that both the Utah and California collection facilities followed current practices. However, the CDC report highlights that even when procedures are followed appropriately, the risk remains. The CDC says evidence-based strategies such as pathogen inactivation, rapid detection devices, and modified screen of bacterial culture protocols can help mitigate that risk.

Platelet-transmitted bacterial infections persist as a cause of transfusion-associated morbidity and mortality, according to researchers writing in Mortality and Morbidity Weekly Report. They describe 2 separate clusters of platelet transfusion-associated bacterial sepsis reported in Utah and California, in which 3 patients died.

Contamination of blood products most commonly happens when skin microbiota is introduced during needle insertion. Because most platelets are stored at room temperature, bacteria can proliferate to clinically important levels by the time the unit is transfused, the CDC says. About 1 in 5,000 platelet collections are contaminated; 1 in 100,000 platelet transfusions results in bacterial sepsis.

In Utah, 2 patients received contaminated apheresis platelet units. One developed rigors 30 minutes after infusion, but transfusion-transmitted bacterial infection was not considered because of the patient’s complex medical history. He died 4 days later.

Less than a day after the first patient’s infusion, the second patient received the other platelet unit. No immediate symptoms of sepsis followed but later that day routine laboratory testing revealed new intravascular hemolysis. She died 11 hours after transfusion.

In California, a patient developed vomiting, tachycardia, and hypotension within 15 minutes of an infusion that came from an apheresis blood donation. Although the transfusion was stopped, he died within 5 hours. A second patient developed septic shock approximately 9 hours after infusion but recovered.

Subsequent investigation found that both the Utah and California collection facilities followed current practices. However, the CDC report highlights that even when procedures are followed appropriately, the risk remains. The CDC says evidence-based strategies such as pathogen inactivation, rapid detection devices, and modified screen of bacterial culture protocols can help mitigate that risk.