Two years ago, a panel appointed by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine, referred to as a consensus conference, proposed a new definition for sepsis and new diagnostic criteria for sepsis and septic shock, known as Sepsis-3 (Singer M, et al. JAMA. 2016;315[8]:801). The panel proposed that sepsis be defined as life-threatening organ dysfunction due to a dysregulated host response to infection. Upon reflection, one could see that what we had called definitions of sepsis, severe sepsis, and septic shock for over 2 decades actually represented diagnostic criteria more than concise definitions. In that regard, a concise definition is a useful addition in the tool kit for training all health-care professionals to recognize sepsis and to treat it early and aggressively.

However, the diagnostic criteria leave something to be desired, in terms of both practicality and sensitivity for detecting patients whose infection has made them seriously ill. Those who participate in quality improvement efforts in their own hospitals will recognize that to promote change and to achieve a goal of better, higher quality care, it is important to remove obstacles in the system and to structure it so that doing the right thing is easier than not doing it. For sepsis, the first step in the process, recognizing that sepsis is present, has always been complex enough that it has been the bane of the enterprise. As many as two-thirds of patients with sepsis presenting to the ED with severe sepsis never receive that diagnosis while in the hospital. (Deis AS, et al. Chest. 2018;153[1]:39). As any sepsis core measure coordinator can attest, diagnostic criteria that are readily visible on retrospective examination are often unnoticed or misinterpreted in real time.

The crux of this issue is that the very entity of sepsis is not a definite thing but a not-quite-focused idea. Much is known of pathophysiologic features that seem to be important, but there is no one unifying pathologic condition. Contrast that with another critical illness, myocardial infarction. The very name states the unifying pathology. Our predecessors were able to work backward from an understanding that acute blockage of a small artery led to ischemia and infarction, in order to identify methods to detect it while it is happening—measuring enzymes and evaluating an ECG. For sepsis, we don’t even understand why patients are sick or why they die. There is a complex interaction of inflammation, microcirculatory thrombosis, mitochondrial dysfunction, immune suppression, but there is no one combination of those things that is yet understood in a way that lends itself to diagnostic testing. The best we can say is that the patient reacted to their infection in a way that was detrimental to their own body’s functioning. Rather than recognizing a few symptoms and sending a confirmatory test, with sepsis, we must tote up the signs and symptoms in the domains of recognizing infection and recognizing organ dysfunction, then determine whether they are present in sufficient amounts; it is an exercise that requires mental discipline.

If the diagnostic criteria we use, whether Sepsis-1, 2, or 3, are all gross descriptions of complex internal interactions that are not specific, then the syndrome that any of these criteria identifies is also not specific for anything particular. It falls to the medical community, as a whole, to determine exactly what it is that we desire a given syndrome to be indicative of. The Sepsis-3 authors decided that the appropriate syndrome should predict death or prolonged ICU stay. They used several large data sets to develop and validate infection-associated variables that would have good predictive ability for that outcome, and they compared what they found with sepsis by the Sepsis-1 definition, infection plus SIRS (Seymour C, et al. JAMA. 2016;315[8]:762). Infection + SIRS is a strawman in this comparison, because they tested its predictive ability for the outcome against that of the Sequential Organ Failure Assessment (SOFA) and the Logistic Organ Dysfunction Score (LODS). These two scoring systems were developed as severity of injury scales and validated as mortality predictors; the higher the score, the likelier mortality, whereas SIRS clearly contains no information about organ dysfunction. The comparator of interest for this outcome is actually severe sepsis, infection plus SIRS plus organ dysfunction.

Although the criteria the Sepsis-3 investigators used for defining patients with suspected infection were novel and reasonable, we lack additional important information about the patients they studied. They did not report the spectrum of treatments for sepsis in their cohort, whether early or late, adequate or inadequate, so it is impossible to determine whether the criteria address patients who are undertreated, patients who are treated late, patients who will die regardless of adequate therapy, or some combination. In other words, there is no way to tell whether patients who were recognized early in their course via Sepsis-1 criteria and treated aggressively and effectively may have avoided shock, ICU admission, and death. It is, of course, the business of physicians and nurses to help patients avoid exactly those things. Multiple studies have now demonstrated that SIRS criteria are more sensitive than SOFA-based screens, specifically qSOFA, for identifying infection with organ dysfunction, and that qSOFA is more specific for mortality (Serafim, et al. Chest. 2017; http://dx.doi.org/10.1016/j.chest.2017.12.015).

In contrast, the Sepsis-1 authors proposed infection plus SIRS as a sensitive screening tool that could warn of the possibility of an associated organ dysfunction (Sprung, et al. Crit Care Med. 2017;45[9]:1564). Previous to the Sepsis-1 conference, Bone and colleagues had defined the sepsis syndrome, which incorporated both SIRS and organ dysfunction (Bone, et al. Crit Care Med. 1989;17[5]:389). It was the collective insight of the Sepsis-1 participants to recognize that SIRS induced by infection could be a harbinger of organ failure. The Sepsis-3 authors believe that SIRS is a “normal and adaptive” part of infection and that it is “not useful” in the diagnosis of sepsis. That analysis neglects a couple of important things about SIRS. First, numerous studies demonstrate that infection with SIRS is associated with a mortality rate of 7% to 9%, which is by no means trivial (Rangel-Frausto MS, et al. JAMA. 1995;273[2]:117). Second, the components of SIRS have been recognized as representative of serious illness for millennia; the assertion that the Sepsis-1 definitions are not evidence-based is mistaken and discounts the collective experience of the medical profession.

Finally, SIRS is criticized on the basis of being nonspecific. “If I climb a flight of stairs, I get SIRS.” This is clearly a true statement. In fact, one could propose that the name could more accurately be Systemic Stress Response Syndrome, though “scissors” is certainly less catchy than “sirs” when one says it aloud. However, the critique neglects an important concept, encapsulated in Bayes’ Theorem. The value of any positive test result is largely dependent on the prevalence of the disease being tested for in the population being tested. It is unlikely that the prevalence of sepsis is very high among patients whose SIRS is induced by climbing a flight of stairs. On the other hand, tachycardia and tachypnea in a patient who is indulging in no activity while lying on a bed feeling miserable should prompt a search for both the infection that could be causing it and the organ dysfunction that could be associated with it. The specificity of SIRS derives from the population in which it is witnessed, and its sensitivity is to be respected.

To quote a friend, the remarkable CEO of a small Kansas hospital, “If a patient with an infection feels bad enough that they climb up on that gurney and place themselves at our mercy, we owe it to them to prove why they don’t have sepsis, rather than why they do.”

Editor’s Comment

The progress made in the last several years emphasizes the importance of early identification and aggressive treatment of sepsis. The Third International Consensus Definitions (Sepsis-3) have sparked great controversy in the sepsis community, because they delay the recognition of sepsis until organ damage occurs. In this Critical Care Commentary, Dr. Steven Q. Simpson asserts with solid arguments that the use of a screening tool with higher specificity for mortality, at the expense of sensitivity, is not a step in the right direction. Moving away from criteria that have been widely adopted in clinical trials and quality improvement initiatives throughout the world can be a setback in the battle to improve sepsis outcomes. Until prospectively validated criteria that allow earlier identification of sepsis are developed, there is no compelling reason for change.

Angel Coz, MD, FCCP
Section Editor

Dr. Simpson is Professor, Interim Director; Division of Pulmonary and Critical Care Medicine, University of Kansas, Kansas City, Kansas.

Two years ago, a panel appointed by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine, referred to as a consensus conference, proposed a new definition for sepsis and new diagnostic criteria for sepsis and septic shock, known as Sepsis-3 (Singer M, et al. JAMA. 2016;315[8]:801). The panel proposed that sepsis be defined as life-threatening organ dysfunction due to a dysregulated host response to infection. Upon reflection, one could see that what we had called definitions of sepsis, severe sepsis, and septic shock for over 2 decades actually represented diagnostic criteria more than concise definitions. In that regard, a concise definition is a useful addition in the tool kit for training all health-care professionals to recognize sepsis and to treat it early and aggressively.

However, the diagnostic criteria leave something to be desired, in terms of both practicality and sensitivity for detecting patients whose infection has made them seriously ill. Those who participate in quality improvement efforts in their own hospitals will recognize that to promote change and to achieve a goal of better, higher quality care, it is important to remove obstacles in the system and to structure it so that doing the right thing is easier than not doing it. For sepsis, the first step in the process, recognizing that sepsis is present, has always been complex enough that it has been the bane of the enterprise. As many as two-thirds of patients with sepsis presenting to the ED with severe sepsis never receive that diagnosis while in the hospital. (Deis AS, et al. Chest. 2018;153[1]:39). As any sepsis core measure coordinator can attest, diagnostic criteria that are readily visible on retrospective examination are often unnoticed or misinterpreted in real time.

The crux of this issue is that the very entity of sepsis is not a definite thing but a not-quite-focused idea. Much is known of pathophysiologic features that seem to be important, but there is no one unifying pathologic condition. Contrast that with another critical illness, myocardial infarction. The very name states the unifying pathology. Our predecessors were able to work backward from an understanding that acute blockage of a small artery led to ischemia and infarction, in order to identify methods to detect it while it is happening—measuring enzymes and evaluating an ECG. For sepsis, we don’t even understand why patients are sick or why they die. There is a complex interaction of inflammation, microcirculatory thrombosis, mitochondrial dysfunction, immune suppression, but there is no one combination of those things that is yet understood in a way that lends itself to diagnostic testing. The best we can say is that the patient reacted to their infection in a way that was detrimental to their own body’s functioning. Rather than recognizing a few symptoms and sending a confirmatory test, with sepsis, we must tote up the signs and symptoms in the domains of recognizing infection and recognizing organ dysfunction, then determine whether they are present in sufficient amounts; it is an exercise that requires mental discipline.

If the diagnostic criteria we use, whether Sepsis-1, 2, or 3, are all gross descriptions of complex internal interactions that are not specific, then the syndrome that any of these criteria identifies is also not specific for anything particular. It falls to the medical community, as a whole, to determine exactly what it is that we desire a given syndrome to be indicative of. The Sepsis-3 authors decided that the appropriate syndrome should predict death or prolonged ICU stay. They used several large data sets to develop and validate infection-associated variables that would have good predictive ability for that outcome, and they compared what they found with sepsis by the Sepsis-1 definition, infection plus SIRS (Seymour C, et al. JAMA. 2016;315[8]:762). Infection + SIRS is a strawman in this comparison, because they tested its predictive ability for the outcome against that of the Sequential Organ Failure Assessment (SOFA) and the Logistic Organ Dysfunction Score (LODS). These two scoring systems were developed as severity of injury scales and validated as mortality predictors; the higher the score, the likelier mortality, whereas SIRS clearly contains no information about organ dysfunction. The comparator of interest for this outcome is actually severe sepsis, infection plus SIRS plus organ dysfunction.

Although the criteria the Sepsis-3 investigators used for defining patients with suspected infection were novel and reasonable, we lack additional important information about the patients they studied. They did not report the spectrum of treatments for sepsis in their cohort, whether early or late, adequate or inadequate, so it is impossible to determine whether the criteria address patients who are undertreated, patients who are treated late, patients who will die regardless of adequate therapy, or some combination. In other words, there is no way to tell whether patients who were recognized early in their course via Sepsis-1 criteria and treated aggressively and effectively may have avoided shock, ICU admission, and death. It is, of course, the business of physicians and nurses to help patients avoid exactly those things. Multiple studies have now demonstrated that SIRS criteria are more sensitive than SOFA-based screens, specifically qSOFA, for identifying infection with organ dysfunction, and that qSOFA is more specific for mortality (Serafim, et al. Chest. 2017; http://dx.doi.org/10.1016/j.chest.2017.12.015).

In contrast, the Sepsis-1 authors proposed infection plus SIRS as a sensitive screening tool that could warn of the possibility of an associated organ dysfunction (Sprung, et al. Crit Care Med. 2017;45[9]:1564). Previous to the Sepsis-1 conference, Bone and colleagues had defined the sepsis syndrome, which incorporated both SIRS and organ dysfunction (Bone, et al. Crit Care Med. 1989;17[5]:389). It was the collective insight of the Sepsis-1 participants to recognize that SIRS induced by infection could be a harbinger of organ failure. The Sepsis-3 authors believe that SIRS is a “normal and adaptive” part of infection and that it is “not useful” in the diagnosis of sepsis. That analysis neglects a couple of important things about SIRS. First, numerous studies demonstrate that infection with SIRS is associated with a mortality rate of 7% to 9%, which is by no means trivial (Rangel-Frausto MS, et al. JAMA. 1995;273[2]:117). Second, the components of SIRS have been recognized as representative of serious illness for millennia; the assertion that the Sepsis-1 definitions are not evidence-based is mistaken and discounts the collective experience of the medical profession.

Finally, SIRS is criticized on the basis of being nonspecific. “If I climb a flight of stairs, I get SIRS.” This is clearly a true statement. In fact, one could propose that the name could more accurately be Systemic Stress Response Syndrome, though “scissors” is certainly less catchy than “sirs” when one says it aloud. However, the critique neglects an important concept, encapsulated in Bayes’ Theorem. The value of any positive test result is largely dependent on the prevalence of the disease being tested for in the population being tested. It is unlikely that the prevalence of sepsis is very high among patients whose SIRS is induced by climbing a flight of stairs. On the other hand, tachycardia and tachypnea in a patient who is indulging in no activity while lying on a bed feeling miserable should prompt a search for both the infection that could be causing it and the organ dysfunction that could be associated with it. The specificity of SIRS derives from the population in which it is witnessed, and its sensitivity is to be respected.

To quote a friend, the remarkable CEO of a small Kansas hospital, “If a patient with an infection feels bad enough that they climb up on that gurney and place themselves at our mercy, we owe it to them to prove why they don’t have sepsis, rather than why they do.”

Editor’s Comment

The progress made in the last several years emphasizes the importance of early identification and aggressive treatment of sepsis. The Third International Consensus Definitions (Sepsis-3) have sparked great controversy in the sepsis community, because they delay the recognition of sepsis until organ damage occurs. In this Critical Care Commentary, Dr. Steven Q. Simpson asserts with solid arguments that the use of a screening tool with higher specificity for mortality, at the expense of sensitivity, is not a step in the right direction. Moving away from criteria that have been widely adopted in clinical trials and quality improvement initiatives throughout the world can be a setback in the battle to improve sepsis outcomes. Until prospectively validated criteria that allow earlier identification of sepsis are developed, there is no compelling reason for change.

Angel Coz, MD, FCCP
Section Editor

Dr. Simpson is Professor, Interim Director; Division of Pulmonary and Critical Care Medicine, University of Kansas, Kansas City, Kansas.

Two years ago, a panel appointed by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine, referred to as a consensus conference, proposed a new definition for sepsis and new diagnostic criteria for sepsis and septic shock, known as Sepsis-3 (Singer M, et al. JAMA. 2016;315[8]:801). The panel proposed that sepsis be defined as life-threatening organ dysfunction due to a dysregulated host response to infection. Upon reflection, one could see that what we had called definitions of sepsis, severe sepsis, and septic shock for over 2 decades actually represented diagnostic criteria more than concise definitions. In that regard, a concise definition is a useful addition in the tool kit for training all health-care professionals to recognize sepsis and to treat it early and aggressively.

However, the diagnostic criteria leave something to be desired, in terms of both practicality and sensitivity for detecting patients whose infection has made them seriously ill. Those who participate in quality improvement efforts in their own hospitals will recognize that to promote change and to achieve a goal of better, higher quality care, it is important to remove obstacles in the system and to structure it so that doing the right thing is easier than not doing it. For sepsis, the first step in the process, recognizing that sepsis is present, has always been complex enough that it has been the bane of the enterprise. As many as two-thirds of patients with sepsis presenting to the ED with severe sepsis never receive that diagnosis while in the hospital. (Deis AS, et al. Chest. 2018;153[1]:39). As any sepsis core measure coordinator can attest, diagnostic criteria that are readily visible on retrospective examination are often unnoticed or misinterpreted in real time.

The crux of this issue is that the very entity of sepsis is not a definite thing but a not-quite-focused idea. Much is known of pathophysiologic features that seem to be important, but there is no one unifying pathologic condition. Contrast that with another critical illness, myocardial infarction. The very name states the unifying pathology. Our predecessors were able to work backward from an understanding that acute blockage of a small artery led to ischemia and infarction, in order to identify methods to detect it while it is happening—measuring enzymes and evaluating an ECG. For sepsis, we don’t even understand why patients are sick or why they die. There is a complex interaction of inflammation, microcirculatory thrombosis, mitochondrial dysfunction, immune suppression, but there is no one combination of those things that is yet understood in a way that lends itself to diagnostic testing. The best we can say is that the patient reacted to their infection in a way that was detrimental to their own body’s functioning. Rather than recognizing a few symptoms and sending a confirmatory test, with sepsis, we must tote up the signs and symptoms in the domains of recognizing infection and recognizing organ dysfunction, then determine whether they are present in sufficient amounts; it is an exercise that requires mental discipline.

If the diagnostic criteria we use, whether Sepsis-1, 2, or 3, are all gross descriptions of complex internal interactions that are not specific, then the syndrome that any of these criteria identifies is also not specific for anything particular. It falls to the medical community, as a whole, to determine exactly what it is that we desire a given syndrome to be indicative of. The Sepsis-3 authors decided that the appropriate syndrome should predict death or prolonged ICU stay. They used several large data sets to develop and validate infection-associated variables that would have good predictive ability for that outcome, and they compared what they found with sepsis by the Sepsis-1 definition, infection plus SIRS (Seymour C, et al. JAMA. 2016;315[8]:762). Infection + SIRS is a strawman in this comparison, because they tested its predictive ability for the outcome against that of the Sequential Organ Failure Assessment (SOFA) and the Logistic Organ Dysfunction Score (LODS). These two scoring systems were developed as severity of injury scales and validated as mortality predictors; the higher the score, the likelier mortality, whereas SIRS clearly contains no information about organ dysfunction. The comparator of interest for this outcome is actually severe sepsis, infection plus SIRS plus organ dysfunction.

Although the criteria the Sepsis-3 investigators used for defining patients with suspected infection were novel and reasonable, we lack additional important information about the patients they studied. They did not report the spectrum of treatments for sepsis in their cohort, whether early or late, adequate or inadequate, so it is impossible to determine whether the criteria address patients who are undertreated, patients who are treated late, patients who will die regardless of adequate therapy, or some combination. In other words, there is no way to tell whether patients who were recognized early in their course via Sepsis-1 criteria and treated aggressively and effectively may have avoided shock, ICU admission, and death. It is, of course, the business of physicians and nurses to help patients avoid exactly those things. Multiple studies have now demonstrated that SIRS criteria are more sensitive than SOFA-based screens, specifically qSOFA, for identifying infection with organ dysfunction, and that qSOFA is more specific for mortality (Serafim, et al. Chest. 2017; http://dx.doi.org/10.1016/j.chest.2017.12.015).

In contrast, the Sepsis-1 authors proposed infection plus SIRS as a sensitive screening tool that could warn of the possibility of an associated organ dysfunction (Sprung, et al. Crit Care Med. 2017;45[9]:1564). Previous to the Sepsis-1 conference, Bone and colleagues had defined the sepsis syndrome, which incorporated both SIRS and organ dysfunction (Bone, et al. Crit Care Med. 1989;17[5]:389). It was the collective insight of the Sepsis-1 participants to recognize that SIRS induced by infection could be a harbinger of organ failure. The Sepsis-3 authors believe that SIRS is a “normal and adaptive” part of infection and that it is “not useful” in the diagnosis of sepsis. That analysis neglects a couple of important things about SIRS. First, numerous studies demonstrate that infection with SIRS is associated with a mortality rate of 7% to 9%, which is by no means trivial (Rangel-Frausto MS, et al. JAMA. 1995;273[2]:117). Second, the components of SIRS have been recognized as representative of serious illness for millennia; the assertion that the Sepsis-1 definitions are not evidence-based is mistaken and discounts the collective experience of the medical profession.

Finally, SIRS is criticized on the basis of being nonspecific. “If I climb a flight of stairs, I get SIRS.” This is clearly a true statement. In fact, one could propose that the name could more accurately be Systemic Stress Response Syndrome, though “scissors” is certainly less catchy than “sirs” when one says it aloud. However, the critique neglects an important concept, encapsulated in Bayes’ Theorem. The value of any positive test result is largely dependent on the prevalence of the disease being tested for in the population being tested. It is unlikely that the prevalence of sepsis is very high among patients whose SIRS is induced by climbing a flight of stairs. On the other hand, tachycardia and tachypnea in a patient who is indulging in no activity while lying on a bed feeling miserable should prompt a search for both the infection that could be causing it and the organ dysfunction that could be associated with it. The specificity of SIRS derives from the population in which it is witnessed, and its sensitivity is to be respected.

To quote a friend, the remarkable CEO of a small Kansas hospital, “If a patient with an infection feels bad enough that they climb up on that gurney and place themselves at our mercy, we owe it to them to prove why they don’t have sepsis, rather than why they do.”

Editor’s Comment

The progress made in the last several years emphasizes the importance of early identification and aggressive treatment of sepsis. The Third International Consensus Definitions (Sepsis-3) have sparked great controversy in the sepsis community, because they delay the recognition of sepsis until organ damage occurs. In this Critical Care Commentary, Dr. Steven Q. Simpson asserts with solid arguments that the use of a screening tool with higher specificity for mortality, at the expense of sensitivity, is not a step in the right direction. Moving away from criteria that have been widely adopted in clinical trials and quality improvement initiatives throughout the world can be a setback in the battle to improve sepsis outcomes. Until prospectively validated criteria that allow earlier identification of sepsis are developed, there is no compelling reason for change.

Angel Coz, MD, FCCP
Section Editor

Dr. Simpson is Professor, Interim Director; Division of Pulmonary and Critical Care Medicine, University of Kansas, Kansas City, Kansas.

Have you shopped at the CHEST Store lately? We’ve recently updated our merchandise to include several new items perfect for staff gifts or for yourself. Along with our old standbys, including lab coats and scrubs, we now feature CHEST-branded scarves, knit caps (perfect for winter), and insulated hot and cold drink mugs. And don’t forget, most items are customizable for a small, additional fee. For the more education-inclined, the store also features the best in CHEST print, including CHEST SEEK^TM volumes, Coding for Chest Medicine, patient education guides, and much more.

Products can be ordered online, and most items are sold on-site at our live learning and board review courses and at the CHEST Annual Meeting. If you can’t purchase in person, visit the store at chestnet.org/store to stock up.

Have you shopped at the CHEST Store lately? We’ve recently updated our merchandise to include several new items perfect for staff gifts or for yourself. Along with our old standbys, including lab coats and scrubs, we now feature CHEST-branded scarves, knit caps (perfect for winter), and insulated hot and cold drink mugs. And don’t forget, most items are customizable for a small, additional fee. For the more education-inclined, the store also features the best in CHEST print, including CHEST SEEK^TM volumes, Coding for Chest Medicine, patient education guides, and much more.

Products can be ordered online, and most items are sold on-site at our live learning and board review courses and at the CHEST Annual Meeting. If you can’t purchase in person, visit the store at chestnet.org/store to stock up.

Have you shopped at the CHEST Store lately? We’ve recently updated our merchandise to include several new items perfect for staff gifts or for yourself. Along with our old standbys, including lab coats and scrubs, we now feature CHEST-branded scarves, knit caps (perfect for winter), and insulated hot and cold drink mugs. And don’t forget, most items are customizable for a small, additional fee. For the more education-inclined, the store also features the best in CHEST print, including CHEST SEEK^TM volumes, Coding for Chest Medicine, patient education guides, and much more.

Products can be ordered online, and most items are sold on-site at our live learning and board review courses and at the CHEST Annual Meeting. If you can’t purchase in person, visit the store at chestnet.org/store to stock up.

CHEST has been informed of the following members’ deaths.

We extend our sincere condolences.

Nagesh V Salian, MD, FCCP (2016)

Ted A Calinog, MD, FCCP (2017)

Azam Ansari, MD (2017)

Arthur E. Schmidt, MD, FCCP (2017)

CHEST has been informed of the following members’ deaths.

We extend our sincere condolences.

Nagesh V Salian, MD, FCCP (2016)

Ted A Calinog, MD, FCCP (2017)

Azam Ansari, MD (2017)

Arthur E. Schmidt, MD, FCCP (2017)

CHEST has been informed of the following members’ deaths.

We extend our sincere condolences.

Nagesh V Salian, MD, FCCP (2016)

Ted A Calinog, MD, FCCP (2017)

Azam Ansari, MD (2017)

Arthur E. Schmidt, MD, FCCP (2017)

Giants In Chest Medicine Professor Nan-shan Zhong, MD.

By Wei-jie Guan.

Original Research

Long-term Use of Inhaled Corticosteroids in COPD and the Risk of Fracture. By Dr. A. V. Gonzalez, et al.

Cardiac Troponin Values in Patients With Acute Coronary Syndrome and Sleep Apnea: A Pilot Study. By Dr. A. Sánchez-de-la-Torre, et al.

CA-125 in Disease Progression and Treatment of Lymphangioleiomyomatosis. By Dr. C. G. Glasgow, et al.

Evidence-Based Medicine

Cough Due to TB and Other Chronic Infections: CHEST Guideline and Expert Panel Report. By Dr. S. K. Field, et al, on behalf of the CHEST Expert Cough Panel.

Giants In Chest Medicine Professor Nan-shan Zhong, MD.

By Wei-jie Guan.

Original Research

Long-term Use of Inhaled Corticosteroids in COPD and the Risk of Fracture. By Dr. A. V. Gonzalez, et al.

Cardiac Troponin Values in Patients With Acute Coronary Syndrome and Sleep Apnea: A Pilot Study. By Dr. A. Sánchez-de-la-Torre, et al.

CA-125 in Disease Progression and Treatment of Lymphangioleiomyomatosis. By Dr. C. G. Glasgow, et al.

Evidence-Based Medicine

Cough Due to TB and Other Chronic Infections: CHEST Guideline and Expert Panel Report. By Dr. S. K. Field, et al, on behalf of the CHEST Expert Cough Panel.

Giants In Chest Medicine Professor Nan-shan Zhong, MD.

By Wei-jie Guan.

Original Research

Long-term Use of Inhaled Corticosteroids in COPD and the Risk of Fracture. By Dr. A. V. Gonzalez, et al.

Cardiac Troponin Values in Patients With Acute Coronary Syndrome and Sleep Apnea: A Pilot Study. By Dr. A. Sánchez-de-la-Torre, et al.

CA-125 in Disease Progression and Treatment of Lymphangioleiomyomatosis. By Dr. C. G. Glasgow, et al.

Evidence-Based Medicine

Cough Due to TB and Other Chronic Infections: CHEST Guideline and Expert Panel Report. By Dr. S. K. Field, et al, on behalf of the CHEST Expert Cough Panel.

KAUAI, HAWAII – Imiquimod on the lip can be extremely painful, but it works wonders for actinic cheilitis, sometimes with only a few treatments.

Also, photodynamic therapy for actinic keratoses (AKs) doesn’t have to hurt. You just have to adjust the aminolevulinic acid incubation time and how long patients stay under the lamp, advised Theodore Rosen, MD, professor of dermatology at Baylor College of Medicine, Houston.

These are just a few of the tips Dr. Rosen shared in a presentation about AKs at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.

In a video interview after his talk, he went into detail about the use of imiquimod for actinic cheilitis – AKs of the lip – and painless PDT, as well as how to discuss AKs with patients – and a quick, clever way to help distinguish AKs from squamous cell carcinoma.

Dr. Rosen is an adviser to Aclaris, Cipher, Pfizer, and Valeant.

SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.

aotto@frontlinemedcom.com

KAUAI, HAWAII – Imiquimod on the lip can be extremely painful, but it works wonders for actinic cheilitis, sometimes with only a few treatments.

Also, photodynamic therapy for actinic keratoses (AKs) doesn’t have to hurt. You just have to adjust the aminolevulinic acid incubation time and how long patients stay under the lamp, advised Theodore Rosen, MD, professor of dermatology at Baylor College of Medicine, Houston.

These are just a few of the tips Dr. Rosen shared in a presentation about AKs at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.

In a video interview after his talk, he went into detail about the use of imiquimod for actinic cheilitis – AKs of the lip – and painless PDT, as well as how to discuss AKs with patients – and a quick, clever way to help distinguish AKs from squamous cell carcinoma.

Dr. Rosen is an adviser to Aclaris, Cipher, Pfizer, and Valeant.

SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.

aotto@frontlinemedcom.com

KAUAI, HAWAII – Imiquimod on the lip can be extremely painful, but it works wonders for actinic cheilitis, sometimes with only a few treatments.

Also, photodynamic therapy for actinic keratoses (AKs) doesn’t have to hurt. You just have to adjust the aminolevulinic acid incubation time and how long patients stay under the lamp, advised Theodore Rosen, MD, professor of dermatology at Baylor College of Medicine, Houston.

These are just a few of the tips Dr. Rosen shared in a presentation about AKs at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.

In a video interview after his talk, he went into detail about the use of imiquimod for actinic cheilitis – AKs of the lip – and painless PDT, as well as how to discuss AKs with patients – and a quick, clever way to help distinguish AKs from squamous cell carcinoma.

Dr. Rosen is an adviser to Aclaris, Cipher, Pfizer, and Valeant.

SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.

aotto@frontlinemedcom.com

SAN FRANCISCO – The order in which targeted therapies are given to patients with previously treated metastatic colorectal cancer can have a marked impact on overall survival, according to results of the REVERCE trial reported at the 2018 GI Cancers Symposium.

Investigators led by Kohei Shitara, MD, National Cancer Center Hospital East, Kashiwa, Japan, enrolled in the multicenter, phase 2, randomized trial 101 patients with mainly KRAS wild-type metastatic colorectal cancer who had previously received fluoropyrimidine, oxaliplatin, and irinotecan, but not any therapy targeting epidermal growth factor receptor (EGFR).

Clinical implications

“The amount of difference in overall survival [between sequences] was pretty striking. These were patients in second line and third line,” commented session chair Michael J. Hall, MD, of Fox Chase Cancer Center, Philadelphia.

Study details

The REVERCE investigators planned to enroll 180 patients in the trial but stopped after 101 patients because of slow accrual. Most of those studied had previously received bevacizumab.

About 70% of patients in the regorafenib-first group needed a dose reduction at some point, compared with about 30% in the cetuximab-first group, a difference likely related to the longer duration of treatment for the former, Dr. Shitara speculated.

Median overall survival was 17.4 months when regorafenib was given first and 11.6 months when cetuximab was give first (hazard ratio, 0.61; P = .029), according to data reported at the symposium, which was sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

In subgroup analyses, the regorafenib-first strategy yielded significantly better overall survival among patients with left-sided tumors (HR, 0.51; P = .011), but not among those with right-sided tumors (HR, 0.88).

The regorafenib-first strategy had similar benefit when restricted to patients with RAS/RAF wild-type tumors (18.2 vs. 12.7 months; HR, 0.60; P = .036).

Analysis of blood samples collected after the first agent indicated that 26% of patients had emergence of a RAS mutation after receiving cetuximab. However, these patients did not appear to have worse overall survival, according to Dr. Shitara.

Progression-free survival on the first agent was 2.4 months in the regorafenib-first group and 4.2 months in the cetuximab-first group, a nonsignificant difference. In contrast, for the second treatment, it was 5.2 months in the regorafenib-first group and just 1.8 months in the cetuximab-first group (HR, 0.29; P less than .0001).

Dr. Shitara disclosed that he receives honoraria from Abbvie, Novartis, Ono Pharmaceutical, and Yakult; has a consulting or advisory role with Astellas Pharma, Bristol-Myers Squibb, Lilly, Pfizer, and Takeda; and that his institution receives research funding from Chugai Pharma, Daiichi Sankyo, Dainippon Sumitomo Pharma, Lilly, MSD, Taiho Pharmaceutical, and Yakult. The trial was funded by Bayer Yahin.

SOURCE: Shitara et al. GI Cancers Symposium Abstract 557

SAN FRANCISCO – The order in which targeted therapies are given to patients with previously treated metastatic colorectal cancer can have a marked impact on overall survival, according to results of the REVERCE trial reported at the 2018 GI Cancers Symposium.

Investigators led by Kohei Shitara, MD, National Cancer Center Hospital East, Kashiwa, Japan, enrolled in the multicenter, phase 2, randomized trial 101 patients with mainly KRAS wild-type metastatic colorectal cancer who had previously received fluoropyrimidine, oxaliplatin, and irinotecan, but not any therapy targeting epidermal growth factor receptor (EGFR).

Clinical implications

“The amount of difference in overall survival [between sequences] was pretty striking. These were patients in second line and third line,” commented session chair Michael J. Hall, MD, of Fox Chase Cancer Center, Philadelphia.

Study details

The REVERCE investigators planned to enroll 180 patients in the trial but stopped after 101 patients because of slow accrual. Most of those studied had previously received bevacizumab.

About 70% of patients in the regorafenib-first group needed a dose reduction at some point, compared with about 30% in the cetuximab-first group, a difference likely related to the longer duration of treatment for the former, Dr. Shitara speculated.

Median overall survival was 17.4 months when regorafenib was given first and 11.6 months when cetuximab was give first (hazard ratio, 0.61; P = .029), according to data reported at the symposium, which was sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

In subgroup analyses, the regorafenib-first strategy yielded significantly better overall survival among patients with left-sided tumors (HR, 0.51; P = .011), but not among those with right-sided tumors (HR, 0.88).

The regorafenib-first strategy had similar benefit when restricted to patients with RAS/RAF wild-type tumors (18.2 vs. 12.7 months; HR, 0.60; P = .036).

Analysis of blood samples collected after the first agent indicated that 26% of patients had emergence of a RAS mutation after receiving cetuximab. However, these patients did not appear to have worse overall survival, according to Dr. Shitara.

Progression-free survival on the first agent was 2.4 months in the regorafenib-first group and 4.2 months in the cetuximab-first group, a nonsignificant difference. In contrast, for the second treatment, it was 5.2 months in the regorafenib-first group and just 1.8 months in the cetuximab-first group (HR, 0.29; P less than .0001).

Dr. Shitara disclosed that he receives honoraria from Abbvie, Novartis, Ono Pharmaceutical, and Yakult; has a consulting or advisory role with Astellas Pharma, Bristol-Myers Squibb, Lilly, Pfizer, and Takeda; and that his institution receives research funding from Chugai Pharma, Daiichi Sankyo, Dainippon Sumitomo Pharma, Lilly, MSD, Taiho Pharmaceutical, and Yakult. The trial was funded by Bayer Yahin.

SOURCE: Shitara et al. GI Cancers Symposium Abstract 557

SAN FRANCISCO – The order in which targeted therapies are given to patients with previously treated metastatic colorectal cancer can have a marked impact on overall survival, according to results of the REVERCE trial reported at the 2018 GI Cancers Symposium.

Investigators led by Kohei Shitara, MD, National Cancer Center Hospital East, Kashiwa, Japan, enrolled in the multicenter, phase 2, randomized trial 101 patients with mainly KRAS wild-type metastatic colorectal cancer who had previously received fluoropyrimidine, oxaliplatin, and irinotecan, but not any therapy targeting epidermal growth factor receptor (EGFR).

Clinical implications

“The amount of difference in overall survival [between sequences] was pretty striking. These were patients in second line and third line,” commented session chair Michael J. Hall, MD, of Fox Chase Cancer Center, Philadelphia.

Study details

The REVERCE investigators planned to enroll 180 patients in the trial but stopped after 101 patients because of slow accrual. Most of those studied had previously received bevacizumab.

About 70% of patients in the regorafenib-first group needed a dose reduction at some point, compared with about 30% in the cetuximab-first group, a difference likely related to the longer duration of treatment for the former, Dr. Shitara speculated.

Median overall survival was 17.4 months when regorafenib was given first and 11.6 months when cetuximab was give first (hazard ratio, 0.61; P = .029), according to data reported at the symposium, which was sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

In subgroup analyses, the regorafenib-first strategy yielded significantly better overall survival among patients with left-sided tumors (HR, 0.51; P = .011), but not among those with right-sided tumors (HR, 0.88).

The regorafenib-first strategy had similar benefit when restricted to patients with RAS/RAF wild-type tumors (18.2 vs. 12.7 months; HR, 0.60; P = .036).

Analysis of blood samples collected after the first agent indicated that 26% of patients had emergence of a RAS mutation after receiving cetuximab. However, these patients did not appear to have worse overall survival, according to Dr. Shitara.

Progression-free survival on the first agent was 2.4 months in the regorafenib-first group and 4.2 months in the cetuximab-first group, a nonsignificant difference. In contrast, for the second treatment, it was 5.2 months in the regorafenib-first group and just 1.8 months in the cetuximab-first group (HR, 0.29; P less than .0001).

Dr. Shitara disclosed that he receives honoraria from Abbvie, Novartis, Ono Pharmaceutical, and Yakult; has a consulting or advisory role with Astellas Pharma, Bristol-Myers Squibb, Lilly, Pfizer, and Takeda; and that his institution receives research funding from Chugai Pharma, Daiichi Sankyo, Dainippon Sumitomo Pharma, Lilly, MSD, Taiho Pharmaceutical, and Yakult. The trial was funded by Bayer Yahin.

SOURCE: Shitara et al. GI Cancers Symposium Abstract 557

Our first daughter was born during my last year in medical school, and our second was born as I was finishing my second year in residency. Seeing those two little darlings grow and develop was a critical supplement to my pediatric training. And, watching my wife initially struggle and then succeed with breastfeeding provided a very personal experience and education about lactation that my interactions in the hospital and outpatient clinics didn’t offer.

We considered ourselves lucky because my wife wasn’t facing the additional challenge of returning to an out-of-the-home job. However, our good fortune did not confer immunity against the anxiety, insecurity, discomfort, and sleep deprivation–induced frustrations of breastfeeding. Watching my wife navigate the choppy waters of lactation certainly influenced my approach to counseling new mothers over my subsequent 4 decades of practice. I think I was a more sympathetic and realistic adviser based on my first-hand observations.

©Lev Olkha/iStockphoto.com

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.”

Our first daughter was born during my last year in medical school, and our second was born as I was finishing my second year in residency. Seeing those two little darlings grow and develop was a critical supplement to my pediatric training. And, watching my wife initially struggle and then succeed with breastfeeding provided a very personal experience and education about lactation that my interactions in the hospital and outpatient clinics didn’t offer.

We considered ourselves lucky because my wife wasn’t facing the additional challenge of returning to an out-of-the-home job. However, our good fortune did not confer immunity against the anxiety, insecurity, discomfort, and sleep deprivation–induced frustrations of breastfeeding. Watching my wife navigate the choppy waters of lactation certainly influenced my approach to counseling new mothers over my subsequent 4 decades of practice. I think I was a more sympathetic and realistic adviser based on my first-hand observations.

©Lev Olkha/iStockphoto.com

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.”

Our first daughter was born during my last year in medical school, and our second was born as I was finishing my second year in residency. Seeing those two little darlings grow and develop was a critical supplement to my pediatric training. And, watching my wife initially struggle and then succeed with breastfeeding provided a very personal experience and education about lactation that my interactions in the hospital and outpatient clinics didn’t offer.

We considered ourselves lucky because my wife wasn’t facing the additional challenge of returning to an out-of-the-home job. However, our good fortune did not confer immunity against the anxiety, insecurity, discomfort, and sleep deprivation–induced frustrations of breastfeeding. Watching my wife navigate the choppy waters of lactation certainly influenced my approach to counseling new mothers over my subsequent 4 decades of practice. I think I was a more sympathetic and realistic adviser based on my first-hand observations.

©Lev Olkha/iStockphoto.com

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.”

SNOWMASS, COLO. – After years of dazzlingly declining mortality due to ST-elevation MI, progress has stalled, Ajay J. Kirtane, MD, declared at the Annual Cardiovascular Conference at Snowmass.

“We have to recognize the fact that our success has somewhat plateaued. We’ve made great strides in shortening door-to-balloon times, but further reductions in [that measure] are not translating into further reductions in adverse outcomes,” observed Dr. Kirtane of Columbia University, New York.

Bruce Jancin/Frontline Medical News

What about nonculprit lesions?

A hot topic in STEMI management is what to do about residual disease in nonculprit vessels after primary PCI.

“Some people have drawn upon trials like COURAGE to inform their decision making, saying ‘Now the patient is stabilized, we’ve treated the STEMI, so we could now treat the patient like a COURAGE patient [with optimal medical therapy alone].’ I would caution against extrapolating the results of COURAGE and other stable ischemic heart disease paradigms to these types of patients. They’ve already presented with a very high risk feature – STEMI – and in addition, in the COURAGE trial there were only 118 patients that had acute coronary syndrome of less than 2 weeks’ duration out of more than 2,000 subjects,” Dr. Kirtane said.

“Intravascular ultrasound studies show that nonculprit plaques in stable angina are very different from those in STEMI: They’re typically fibrotic and stable, while even the nonculprit plaques in STEMI or non-STEMI ACS are much more inflamed and vulnerable,” he added.

He predicted clarity regarding best management in this area will come from the ongoing COMPLETE trial, a multinational study of nearly 4,000 patients randomized to staged nonculprit lesion PCI versus medical therapy plus culprit lesion-only revascularization. The study is due to be completed late in 2018.

Improving pharmacotherapy

Rates of hospital discharge on guideline-directed optimal medical therapy after primary PCI have risen steadily in recent years. However, studies indicate a significant minority of patients drop from dual-antiplatelet therapy to aspirin alone within a month after leaving the hospital.

Also, it’s essential to effectively inhibit both platelets and thrombus in the catheterization lab. But is that happening consistently? There is now evidence of delayed absorption of the potent oral antiplatelet agents in STEMI patients. Moreover, that delay is exacerbated by having morphine or fentanyl on board.

“It’s been shown that even with ticagrelor and prasugrel, in STEMI patients at 2 hours, you still don’t have sufficient inhibition of platelet aggregation, whereas if I gave one of those drugs to any of us here in the audience now we’d have full effect within an hour or 2 max. That’s one of the reasons why there’s a rationale for using an intravenous agent such as cangrelor [Kengreal], a nonthienopyridine direct P2Y12 inhibitor,” Dr. Kirtane said.
 

Transradial access for primary PCI

Dr. Kirtane argued in a recent editorial that widespread adoption of transradial PCI for STEMI will provide the next major advance in STEMI systems of care resulting in improved clinical outcomes (JAMA Cardiol. 2017 Oct 1;2[10]:1057-8).

This is a controversial issue, he acknowledged. “There are interventional cardiologists who say, ‘No way.’ ” But studies indicate that transradial PCI for STEMI reduces mortality by 16%-48% compared with transfemoral access, without a significant cost in terms of door-to-balloon time. For now, transfemoral access PCI remains the most common strategy for STEMI patients in the United States, although the use of transradial primary PCI is growing.

Dr. Kirtane reported receiving research grants from more than half a dozen medical device companies.

bjancin@frontlinemedcom.com

SNOWMASS, COLO. – After years of dazzlingly declining mortality due to ST-elevation MI, progress has stalled, Ajay J. Kirtane, MD, declared at the Annual Cardiovascular Conference at Snowmass.

“We have to recognize the fact that our success has somewhat plateaued. We’ve made great strides in shortening door-to-balloon times, but further reductions in [that measure] are not translating into further reductions in adverse outcomes,” observed Dr. Kirtane of Columbia University, New York.

Bruce Jancin/Frontline Medical News

What about nonculprit lesions?

A hot topic in STEMI management is what to do about residual disease in nonculprit vessels after primary PCI.

“Some people have drawn upon trials like COURAGE to inform their decision making, saying ‘Now the patient is stabilized, we’ve treated the STEMI, so we could now treat the patient like a COURAGE patient [with optimal medical therapy alone].’ I would caution against extrapolating the results of COURAGE and other stable ischemic heart disease paradigms to these types of patients. They’ve already presented with a very high risk feature – STEMI – and in addition, in the COURAGE trial there were only 118 patients that had acute coronary syndrome of less than 2 weeks’ duration out of more than 2,000 subjects,” Dr. Kirtane said.

“Intravascular ultrasound studies show that nonculprit plaques in stable angina are very different from those in STEMI: They’re typically fibrotic and stable, while even the nonculprit plaques in STEMI or non-STEMI ACS are much more inflamed and vulnerable,” he added.

He predicted clarity regarding best management in this area will come from the ongoing COMPLETE trial, a multinational study of nearly 4,000 patients randomized to staged nonculprit lesion PCI versus medical therapy plus culprit lesion-only revascularization. The study is due to be completed late in 2018.

Improving pharmacotherapy

Rates of hospital discharge on guideline-directed optimal medical therapy after primary PCI have risen steadily in recent years. However, studies indicate a significant minority of patients drop from dual-antiplatelet therapy to aspirin alone within a month after leaving the hospital.

Also, it’s essential to effectively inhibit both platelets and thrombus in the catheterization lab. But is that happening consistently? There is now evidence of delayed absorption of the potent oral antiplatelet agents in STEMI patients. Moreover, that delay is exacerbated by having morphine or fentanyl on board.

“It’s been shown that even with ticagrelor and prasugrel, in STEMI patients at 2 hours, you still don’t have sufficient inhibition of platelet aggregation, whereas if I gave one of those drugs to any of us here in the audience now we’d have full effect within an hour or 2 max. That’s one of the reasons why there’s a rationale for using an intravenous agent such as cangrelor [Kengreal], a nonthienopyridine direct P2Y12 inhibitor,” Dr. Kirtane said.
 

Transradial access for primary PCI

Dr. Kirtane argued in a recent editorial that widespread adoption of transradial PCI for STEMI will provide the next major advance in STEMI systems of care resulting in improved clinical outcomes (JAMA Cardiol. 2017 Oct 1;2[10]:1057-8).

This is a controversial issue, he acknowledged. “There are interventional cardiologists who say, ‘No way.’ ” But studies indicate that transradial PCI for STEMI reduces mortality by 16%-48% compared with transfemoral access, without a significant cost in terms of door-to-balloon time. For now, transfemoral access PCI remains the most common strategy for STEMI patients in the United States, although the use of transradial primary PCI is growing.

Dr. Kirtane reported receiving research grants from more than half a dozen medical device companies.

bjancin@frontlinemedcom.com

SNOWMASS, COLO. – After years of dazzlingly declining mortality due to ST-elevation MI, progress has stalled, Ajay J. Kirtane, MD, declared at the Annual Cardiovascular Conference at Snowmass.

“We have to recognize the fact that our success has somewhat plateaued. We’ve made great strides in shortening door-to-balloon times, but further reductions in [that measure] are not translating into further reductions in adverse outcomes,” observed Dr. Kirtane of Columbia University, New York.

Bruce Jancin/Frontline Medical News

What about nonculprit lesions?

A hot topic in STEMI management is what to do about residual disease in nonculprit vessels after primary PCI.

“Some people have drawn upon trials like COURAGE to inform their decision making, saying ‘Now the patient is stabilized, we’ve treated the STEMI, so we could now treat the patient like a COURAGE patient [with optimal medical therapy alone].’ I would caution against extrapolating the results of COURAGE and other stable ischemic heart disease paradigms to these types of patients. They’ve already presented with a very high risk feature – STEMI – and in addition, in the COURAGE trial there were only 118 patients that had acute coronary syndrome of less than 2 weeks’ duration out of more than 2,000 subjects,” Dr. Kirtane said.

“Intravascular ultrasound studies show that nonculprit plaques in stable angina are very different from those in STEMI: They’re typically fibrotic and stable, while even the nonculprit plaques in STEMI or non-STEMI ACS are much more inflamed and vulnerable,” he added.

He predicted clarity regarding best management in this area will come from the ongoing COMPLETE trial, a multinational study of nearly 4,000 patients randomized to staged nonculprit lesion PCI versus medical therapy plus culprit lesion-only revascularization. The study is due to be completed late in 2018.

Improving pharmacotherapy

Rates of hospital discharge on guideline-directed optimal medical therapy after primary PCI have risen steadily in recent years. However, studies indicate a significant minority of patients drop from dual-antiplatelet therapy to aspirin alone within a month after leaving the hospital.

Also, it’s essential to effectively inhibit both platelets and thrombus in the catheterization lab. But is that happening consistently? There is now evidence of delayed absorption of the potent oral antiplatelet agents in STEMI patients. Moreover, that delay is exacerbated by having morphine or fentanyl on board.

“It’s been shown that even with ticagrelor and prasugrel, in STEMI patients at 2 hours, you still don’t have sufficient inhibition of platelet aggregation, whereas if I gave one of those drugs to any of us here in the audience now we’d have full effect within an hour or 2 max. That’s one of the reasons why there’s a rationale for using an intravenous agent such as cangrelor [Kengreal], a nonthienopyridine direct P2Y12 inhibitor,” Dr. Kirtane said.
 

Transradial access for primary PCI

Dr. Kirtane argued in a recent editorial that widespread adoption of transradial PCI for STEMI will provide the next major advance in STEMI systems of care resulting in improved clinical outcomes (JAMA Cardiol. 2017 Oct 1;2[10]:1057-8).

This is a controversial issue, he acknowledged. “There are interventional cardiologists who say, ‘No way.’ ” But studies indicate that transradial PCI for STEMI reduces mortality by 16%-48% compared with transfemoral access, without a significant cost in terms of door-to-balloon time. For now, transfemoral access PCI remains the most common strategy for STEMI patients in the United States, although the use of transradial primary PCI is growing.

Dr. Kirtane reported receiving research grants from more than half a dozen medical device companies.

bjancin@frontlinemedcom.com

When we were invited to a family gathering to celebrate a 60th birthday, we expected to hear an abundance of news about grandchildren. They are natural, and seldom controversial, topics of discussion. If there is a child still waiting in utero and destined to be the first grandchild on one or both sides of the family, the impending adventure in parenthood will dominate the conversation.

To our great surprise, despite the presence of one very pregnant young woman, who in 6 weeks would be giving birth to the first grandchild in my nephew’s family, my wife and I can recall only one brief dialogue in which I was asked about how one might go about selecting a pediatrician.

Stockbyte/Thinkstock

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.”

When we were invited to a family gathering to celebrate a 60th birthday, we expected to hear an abundance of news about grandchildren. They are natural, and seldom controversial, topics of discussion. If there is a child still waiting in utero and destined to be the first grandchild on one or both sides of the family, the impending adventure in parenthood will dominate the conversation.

To our great surprise, despite the presence of one very pregnant young woman, who in 6 weeks would be giving birth to the first grandchild in my nephew’s family, my wife and I can recall only one brief dialogue in which I was asked about how one might go about selecting a pediatrician.

Stockbyte/Thinkstock

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.”

When we were invited to a family gathering to celebrate a 60th birthday, we expected to hear an abundance of news about grandchildren. They are natural, and seldom controversial, topics of discussion. If there is a child still waiting in utero and destined to be the first grandchild on one or both sides of the family, the impending adventure in parenthood will dominate the conversation.

To our great surprise, despite the presence of one very pregnant young woman, who in 6 weeks would be giving birth to the first grandchild in my nephew’s family, my wife and I can recall only one brief dialogue in which I was asked about how one might go about selecting a pediatrician.

Stockbyte/Thinkstock

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.”

SAN FRANCISCO – The CD19-directed 4-1BB chimeric antigen receptor (CAR) T-cell product JCAR017 demonstrated increased CAR T-cell expansion and persistence, and higher durability of response at higher dose levels – with manageable toxicities – in a pivotal phase 1 trial of relapsed/refractory B-cell non-Hodgkin lymphoma.

However, preliminary modeling data suggest that a therapeutic window exists for the CAR T-cell expansion, which means that development of strategies for pushing patients into that window could enhance efficacy and limit toxicity associated with JCAR017, Tanya Siddiqi, MD, of City of Hope Comprehensive Cancer Center, Duarte, Calif., reported at the ASCO-SITC Clinical Immuno-Oncology Symposium.

TRANSCEND NHL 001 is a multicenter, seamless design, pivotal trial, which started as a phase 1 first-in-human study of JCAR017, a defined composition CAR T-cell product also known as lisocabtagene maraleucel and administered at precise doses of CD4+ and CD8+ CAR T cells. Dose-finding and dose-expansion cohorts have been investigated, and currently the pivotal diffuse large B-cell lymphoma (DLBCL) cohort is enrolling, Dr. Saddiqi said, noting that dose level 2 (1 x 10⁸ cells given as a single dose) was selected for that cohort.

The current findings are based on the TRANSCEND core population – a set of patients selected from the dose-finding and dose-expansion cohorts. This population includes patients with DLBCL not otherwise specified, transformed follicular lymphoma, or high-grade double- or triple-hit lymphomas, she said, explaining that she and her colleagues looked at prelymphodepletion baseline patient characteristics and biomarkers to assess how they related to outcomes and toxicities. This precise dosing of JCAR017 reduces variability, enabling the identification of potential patient factors associated with clinical outcomes, she said.

Response rates among 27 patients who received dose level 2 were high, with an 81% overall response rate and a 63% complete response rate.

“Patients with complete remission seemed to have more of a durable response,” she said. “In the core population at dose level 2, 50% with 6 months of follow-up seemed to remain in complete response, so there’s a dose-response effect in these patients.”

It doesn’t appear that the dose affects development of cytokine release syndrome (CRS) or neurotoxicity (NT), as the rates of these (30% and 20%, respectively) did not differ by dose level or schedule, but certain baseline features, such as a lactate dehydrogenase (LDH) level above 500 U/L and tumor burden measured as the sum of the product of diameters of 50 cm or greater, do appear to affect the development of these toxicities.

For example, 10 of 13 (77%) of patients with both of those baseline characteristics developed CRS, and 7 of 13 (54%) developed NT; for those without these characteristics, the odds of developing CRS and NT were significantly lower, she said.

Of note, higher C_max, or peak expansion of CAR T cells in vivo, was seen at dose level 2, and exposure (area under the curve) was also higher, as was expected at that dose level, Dr. Siddiqi said.

“It also appears that there is a trend of patients with higher tumor burden to have higher expansion of their CAR T cells in vivo,” she said, noting that some of those patients were “superexpanders” with very high expansion of CAR T cells. “Similarly there were certain cytokines at the prelymphodepletion time point that seem to be higher … in patients who also go on to have higher expansion of their CAR T cells.”

These included interleukin-7, IL-15, MIP (macrophage inflammatory protein)–1alpha, and tumor necrosis factor (TNF)–alpha.

“Patients with certain higher inflammatory cytokines and biomarkers of inflammation also were noted to have higher events of CRS and neurotoxicity, so not just higher tumor burden, but also higher inflammatory state at baseline seems to affect patients in terms of getting any grade CRS or any grade neurotoxicity,” she said.

Those associated with CRS included ferritin, C-reactive protein (CRP), IL-10, IL-15, IL-16, TNF-alpha, and MIP-1beta levels, and those associated with NT included ferritin, CRP, d-dimer, IL-6, IL-15, TNF-alpha, and MIP-1alpha levels.

“Interestingly, there’s an inverse relationship between the expression of some of these biomarkers and inflammatory markers and the durability of response at 3 months,” she said.

Patients with higher tumor burden, LDH, and other markers either had no response at 3 months, or they had a very rapid response at the 1-month mark and then lost their response by 3 months, she noted.

“One of the theories could be that these patients with higher tumor burden, higher inflammatory state – they have such a high peak expansion rapidly after receiving their CAR T cells that potentially those CAR T cells may be getting exhausted or dying off very quickly, and therefore patients can lose their response,” she said.

When these data are considered together and modeled, there seems to be a therapeutic window where patients who have optimal expansion of CAR T cells in vivo may have lesser toxicity, higher overall response rates, and better durability of response, she said.

That is, on one end of the spectrum, there are patients with lower CAR T-cell expansion who have lower toxicities, but who also have lower overall response rates and lower durability of response, and on the other end, there are patients with superhigh expansion of CAR T cells, who have higher response rates, but also higher rates of toxicity, and who lose their response quickly.

“So if we can identify patients who would be in this window of optimal target expansion of CAR T cells, and if we could find strategies or mechanisms to move patients who are on either end of that spectrum into this window, we may be able to get patients with better efficacy and lower toxicities, and there could be combination strategies that could help get us there,” she said.

TRANSCEND NHL 001 is sponsored by Juno Therapeutics. Dr. Siddiqi reported serving as a consultant or adviser for Juno Therapeutics, and as a member of the speakers bureau for Pharmacyclics/Janssen and Seattle Genetics. Research funding was provided to her institution by Juno Therapeutics and several other companies.

sworcester@frontlinemedcom.com

SOURCE: Siddiqi T et al. ASCO-SITC, abstract 122.

SAN FRANCISCO – The CD19-directed 4-1BB chimeric antigen receptor (CAR) T-cell product JCAR017 demonstrated increased CAR T-cell expansion and persistence, and higher durability of response at higher dose levels – with manageable toxicities – in a pivotal phase 1 trial of relapsed/refractory B-cell non-Hodgkin lymphoma.

However, preliminary modeling data suggest that a therapeutic window exists for the CAR T-cell expansion, which means that development of strategies for pushing patients into that window could enhance efficacy and limit toxicity associated with JCAR017, Tanya Siddiqi, MD, of City of Hope Comprehensive Cancer Center, Duarte, Calif., reported at the ASCO-SITC Clinical Immuno-Oncology Symposium.

TRANSCEND NHL 001 is a multicenter, seamless design, pivotal trial, which started as a phase 1 first-in-human study of JCAR017, a defined composition CAR T-cell product also known as lisocabtagene maraleucel and administered at precise doses of CD4+ and CD8+ CAR T cells. Dose-finding and dose-expansion cohorts have been investigated, and currently the pivotal diffuse large B-cell lymphoma (DLBCL) cohort is enrolling, Dr. Saddiqi said, noting that dose level 2 (1 x 10⁸ cells given as a single dose) was selected for that cohort.

The current findings are based on the TRANSCEND core population – a set of patients selected from the dose-finding and dose-expansion cohorts. This population includes patients with DLBCL not otherwise specified, transformed follicular lymphoma, or high-grade double- or triple-hit lymphomas, she said, explaining that she and her colleagues looked at prelymphodepletion baseline patient characteristics and biomarkers to assess how they related to outcomes and toxicities. This precise dosing of JCAR017 reduces variability, enabling the identification of potential patient factors associated with clinical outcomes, she said.

Response rates among 27 patients who received dose level 2 were high, with an 81% overall response rate and a 63% complete response rate.

“Patients with complete remission seemed to have more of a durable response,” she said. “In the core population at dose level 2, 50% with 6 months of follow-up seemed to remain in complete response, so there’s a dose-response effect in these patients.”

It doesn’t appear that the dose affects development of cytokine release syndrome (CRS) or neurotoxicity (NT), as the rates of these (30% and 20%, respectively) did not differ by dose level or schedule, but certain baseline features, such as a lactate dehydrogenase (LDH) level above 500 U/L and tumor burden measured as the sum of the product of diameters of 50 cm or greater, do appear to affect the development of these toxicities.

For example, 10 of 13 (77%) of patients with both of those baseline characteristics developed CRS, and 7 of 13 (54%) developed NT; for those without these characteristics, the odds of developing CRS and NT were significantly lower, she said.

Of note, higher C_max, or peak expansion of CAR T cells in vivo, was seen at dose level 2, and exposure (area under the curve) was also higher, as was expected at that dose level, Dr. Siddiqi said.

“It also appears that there is a trend of patients with higher tumor burden to have higher expansion of their CAR T cells in vivo,” she said, noting that some of those patients were “superexpanders” with very high expansion of CAR T cells. “Similarly there were certain cytokines at the prelymphodepletion time point that seem to be higher … in patients who also go on to have higher expansion of their CAR T cells.”

These included interleukin-7, IL-15, MIP (macrophage inflammatory protein)–1alpha, and tumor necrosis factor (TNF)–alpha.

“Patients with certain higher inflammatory cytokines and biomarkers of inflammation also were noted to have higher events of CRS and neurotoxicity, so not just higher tumor burden, but also higher inflammatory state at baseline seems to affect patients in terms of getting any grade CRS or any grade neurotoxicity,” she said.

Those associated with CRS included ferritin, C-reactive protein (CRP), IL-10, IL-15, IL-16, TNF-alpha, and MIP-1beta levels, and those associated with NT included ferritin, CRP, d-dimer, IL-6, IL-15, TNF-alpha, and MIP-1alpha levels.

“Interestingly, there’s an inverse relationship between the expression of some of these biomarkers and inflammatory markers and the durability of response at 3 months,” she said.

Patients with higher tumor burden, LDH, and other markers either had no response at 3 months, or they had a very rapid response at the 1-month mark and then lost their response by 3 months, she noted.

“One of the theories could be that these patients with higher tumor burden, higher inflammatory state – they have such a high peak expansion rapidly after receiving their CAR T cells that potentially those CAR T cells may be getting exhausted or dying off very quickly, and therefore patients can lose their response,” she said.

When these data are considered together and modeled, there seems to be a therapeutic window where patients who have optimal expansion of CAR T cells in vivo may have lesser toxicity, higher overall response rates, and better durability of response, she said.

That is, on one end of the spectrum, there are patients with lower CAR T-cell expansion who have lower toxicities, but who also have lower overall response rates and lower durability of response, and on the other end, there are patients with superhigh expansion of CAR T cells, who have higher response rates, but also higher rates of toxicity, and who lose their response quickly.

“So if we can identify patients who would be in this window of optimal target expansion of CAR T cells, and if we could find strategies or mechanisms to move patients who are on either end of that spectrum into this window, we may be able to get patients with better efficacy and lower toxicities, and there could be combination strategies that could help get us there,” she said.

TRANSCEND NHL 001 is sponsored by Juno Therapeutics. Dr. Siddiqi reported serving as a consultant or adviser for Juno Therapeutics, and as a member of the speakers bureau for Pharmacyclics/Janssen and Seattle Genetics. Research funding was provided to her institution by Juno Therapeutics and several other companies.

sworcester@frontlinemedcom.com

SOURCE: Siddiqi T et al. ASCO-SITC, abstract 122.

SAN FRANCISCO – The CD19-directed 4-1BB chimeric antigen receptor (CAR) T-cell product JCAR017 demonstrated increased CAR T-cell expansion and persistence, and higher durability of response at higher dose levels – with manageable toxicities – in a pivotal phase 1 trial of relapsed/refractory B-cell non-Hodgkin lymphoma.

However, preliminary modeling data suggest that a therapeutic window exists for the CAR T-cell expansion, which means that development of strategies for pushing patients into that window could enhance efficacy and limit toxicity associated with JCAR017, Tanya Siddiqi, MD, of City of Hope Comprehensive Cancer Center, Duarte, Calif., reported at the ASCO-SITC Clinical Immuno-Oncology Symposium.

TRANSCEND NHL 001 is a multicenter, seamless design, pivotal trial, which started as a phase 1 first-in-human study of JCAR017, a defined composition CAR T-cell product also known as lisocabtagene maraleucel and administered at precise doses of CD4+ and CD8+ CAR T cells. Dose-finding and dose-expansion cohorts have been investigated, and currently the pivotal diffuse large B-cell lymphoma (DLBCL) cohort is enrolling, Dr. Saddiqi said, noting that dose level 2 (1 x 10⁸ cells given as a single dose) was selected for that cohort.

The current findings are based on the TRANSCEND core population – a set of patients selected from the dose-finding and dose-expansion cohorts. This population includes patients with DLBCL not otherwise specified, transformed follicular lymphoma, or high-grade double- or triple-hit lymphomas, she said, explaining that she and her colleagues looked at prelymphodepletion baseline patient characteristics and biomarkers to assess how they related to outcomes and toxicities. This precise dosing of JCAR017 reduces variability, enabling the identification of potential patient factors associated with clinical outcomes, she said.

Response rates among 27 patients who received dose level 2 were high, with an 81% overall response rate and a 63% complete response rate.

“Patients with complete remission seemed to have more of a durable response,” she said. “In the core population at dose level 2, 50% with 6 months of follow-up seemed to remain in complete response, so there’s a dose-response effect in these patients.”

It doesn’t appear that the dose affects development of cytokine release syndrome (CRS) or neurotoxicity (NT), as the rates of these (30% and 20%, respectively) did not differ by dose level or schedule, but certain baseline features, such as a lactate dehydrogenase (LDH) level above 500 U/L and tumor burden measured as the sum of the product of diameters of 50 cm or greater, do appear to affect the development of these toxicities.

For example, 10 of 13 (77%) of patients with both of those baseline characteristics developed CRS, and 7 of 13 (54%) developed NT; for those without these characteristics, the odds of developing CRS and NT were significantly lower, she said.

Of note, higher C_max, or peak expansion of CAR T cells in vivo, was seen at dose level 2, and exposure (area under the curve) was also higher, as was expected at that dose level, Dr. Siddiqi said.

“It also appears that there is a trend of patients with higher tumor burden to have higher expansion of their CAR T cells in vivo,” she said, noting that some of those patients were “superexpanders” with very high expansion of CAR T cells. “Similarly there were certain cytokines at the prelymphodepletion time point that seem to be higher … in patients who also go on to have higher expansion of their CAR T cells.”

These included interleukin-7, IL-15, MIP (macrophage inflammatory protein)–1alpha, and tumor necrosis factor (TNF)–alpha.

“Patients with certain higher inflammatory cytokines and biomarkers of inflammation also were noted to have higher events of CRS and neurotoxicity, so not just higher tumor burden, but also higher inflammatory state at baseline seems to affect patients in terms of getting any grade CRS or any grade neurotoxicity,” she said.

Those associated with CRS included ferritin, C-reactive protein (CRP), IL-10, IL-15, IL-16, TNF-alpha, and MIP-1beta levels, and those associated with NT included ferritin, CRP, d-dimer, IL-6, IL-15, TNF-alpha, and MIP-1alpha levels.

“Interestingly, there’s an inverse relationship between the expression of some of these biomarkers and inflammatory markers and the durability of response at 3 months,” she said.

Patients with higher tumor burden, LDH, and other markers either had no response at 3 months, or they had a very rapid response at the 1-month mark and then lost their response by 3 months, she noted.

“One of the theories could be that these patients with higher tumor burden, higher inflammatory state – they have such a high peak expansion rapidly after receiving their CAR T cells that potentially those CAR T cells may be getting exhausted or dying off very quickly, and therefore patients can lose their response,” she said.

When these data are considered together and modeled, there seems to be a therapeutic window where patients who have optimal expansion of CAR T cells in vivo may have lesser toxicity, higher overall response rates, and better durability of response, she said.

That is, on one end of the spectrum, there are patients with lower CAR T-cell expansion who have lower toxicities, but who also have lower overall response rates and lower durability of response, and on the other end, there are patients with superhigh expansion of CAR T cells, who have higher response rates, but also higher rates of toxicity, and who lose their response quickly.

“So if we can identify patients who would be in this window of optimal target expansion of CAR T cells, and if we could find strategies or mechanisms to move patients who are on either end of that spectrum into this window, we may be able to get patients with better efficacy and lower toxicities, and there could be combination strategies that could help get us there,” she said.

TRANSCEND NHL 001 is sponsored by Juno Therapeutics. Dr. Siddiqi reported serving as a consultant or adviser for Juno Therapeutics, and as a member of the speakers bureau for Pharmacyclics/Janssen and Seattle Genetics. Research funding was provided to her institution by Juno Therapeutics and several other companies.

sworcester@frontlinemedcom.com

SOURCE: Siddiqi T et al. ASCO-SITC, abstract 122.