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Technology lowers stress among pediatric patients
Credit: Logan Tuttle
A new study suggests videoconferencing with family and friends can lower stress for pediatric patients who are hospitalized for an extended period.
UC Davis Children’s Hospital provides these patients with laptops, webcams, and secure Internet connections for videoconferencing.
And anecdotal accounts have suggested the service, called Family-Link, benefits patients. But researchers wanted more concrete evidence that Family-Link can reduce anxiety.
To that end, James Marcin, MD, and his colleagues studied 367 children who were hospitalized at UC Davis for at least 4 days.
Two hundred and thirty-two patients took advantage of the videoconferencing service, and 135 did not. The researchers used the Parent-Guardian Stress Survey to assess the children’s anxiety levels, both at admission and discharge.
The survey included 4 question groups centered on each child’s behavior and emotions, staff communication, sights and sounds, and the child’s appearance. Parents/guardians were asked whether the child exhibited a variety of behaviors, such as being demanding, frightened, angry, or confused.
The survey also included questions about the impact of monitoring equipment on stress levels and the staff’s ability to communicate important details about the child’s care.
Overall, children who used Family-Link experienced a greater reduction in stress than children who did not use the service.
The researchers were surprised to find this effect was even more pronounced for children who lived closer to the hospital and had shorter hospitalizations. This group experienced a 37% stress reduction when using Family-Link.
“This study shows that we have another tool to help children during their hospital stays,” said Nikki Yang, first author on the study. “The improvement in stress scores shows that Family-Link is really helping many children and might possibly be improving outcomes.”
Yang and her colleagues reported these findings in Pediatrics. 
Credit: Logan Tuttle
A new study suggests videoconferencing with family and friends can lower stress for pediatric patients who are hospitalized for an extended period.
UC Davis Children’s Hospital provides these patients with laptops, webcams, and secure Internet connections for videoconferencing.
And anecdotal accounts have suggested the service, called Family-Link, benefits patients. But researchers wanted more concrete evidence that Family-Link can reduce anxiety.
To that end, James Marcin, MD, and his colleagues studied 367 children who were hospitalized at UC Davis for at least 4 days.
Two hundred and thirty-two patients took advantage of the videoconferencing service, and 135 did not. The researchers used the Parent-Guardian Stress Survey to assess the children’s anxiety levels, both at admission and discharge.
The survey included 4 question groups centered on each child’s behavior and emotions, staff communication, sights and sounds, and the child’s appearance. Parents/guardians were asked whether the child exhibited a variety of behaviors, such as being demanding, frightened, angry, or confused.
The survey also included questions about the impact of monitoring equipment on stress levels and the staff’s ability to communicate important details about the child’s care.
Overall, children who used Family-Link experienced a greater reduction in stress than children who did not use the service.
The researchers were surprised to find this effect was even more pronounced for children who lived closer to the hospital and had shorter hospitalizations. This group experienced a 37% stress reduction when using Family-Link.
“This study shows that we have another tool to help children during their hospital stays,” said Nikki Yang, first author on the study. “The improvement in stress scores shows that Family-Link is really helping many children and might possibly be improving outcomes.”
Yang and her colleagues reported these findings in Pediatrics.
Credit: Logan Tuttle
A new study suggests videoconferencing with family and friends can lower stress for pediatric patients who are hospitalized for an extended period.
UC Davis Children’s Hospital provides these patients with laptops, webcams, and secure Internet connections for videoconferencing.
And anecdotal accounts have suggested the service, called Family-Link, benefits patients. But researchers wanted more concrete evidence that Family-Link can reduce anxiety.
To that end, James Marcin, MD, and his colleagues studied 367 children who were hospitalized at UC Davis for at least 4 days.
Two hundred and thirty-two patients took advantage of the videoconferencing service, and 135 did not. The researchers used the Parent-Guardian Stress Survey to assess the children’s anxiety levels, both at admission and discharge.
The survey included 4 question groups centered on each child’s behavior and emotions, staff communication, sights and sounds, and the child’s appearance. Parents/guardians were asked whether the child exhibited a variety of behaviors, such as being demanding, frightened, angry, or confused.
The survey also included questions about the impact of monitoring equipment on stress levels and the staff’s ability to communicate important details about the child’s care.
Overall, children who used Family-Link experienced a greater reduction in stress than children who did not use the service.
The researchers were surprised to find this effect was even more pronounced for children who lived closer to the hospital and had shorter hospitalizations. This group experienced a 37% stress reduction when using Family-Link.
“This study shows that we have another tool to help children during their hospital stays,” said Nikki Yang, first author on the study. “The improvement in stress scores shows that Family-Link is really helping many children and might possibly be improving outcomes.”
Yang and her colleagues reported these findings in Pediatrics.
Differentiating DNI From DNR
Since the introduction of defibrillation and closed chest cardiopulmonary resuscitation (CPR) in the 1950s, the ability to revive an arrested heart has been a realized possibility. Around the same time, endotracheal intubation with mechanical ventilation (MV) came into wide practice, allowing doctors to augment or even replace their patients' breathing. But just as the 1950s and 1960s saw the rise of these enhanced medical techniques, they also saw the increased importance of medical ethicsin particular, patient autonomy. A natural reaction to medicine's use of CPR and MV was the advent of advance directives and more specific do‐not‐resuscitate (DNR) and do‐not‐intubate (DNI) orders meant to protect a patient's ability to remain autonomous with their end of life decisions.[1]
Unfortunately, the code status discussions that lead to these orders often collapse cardiac arrest with prearrest respiratory failure and CPR with MV.[2, 3] This is a problem for a number of reasons. First, cardiac arrest and prearrest respiratory failure are unique end points, and though their respective treatments (CPR and MV) are often required simultaneously for an individual patient, they are distinct medical interventions with different goals, indications, and associated disease states. Although MV is typically a part of the cadre of interventions meant to ensure continued tissue oxygenation in the setting of a cardiac arrest, this accounts for 2% of indications for MV.[4] The vast majority of MV is used to treat prearrest causes of respiratory failure, such as pneumonia, congestive heart failure, acute exacerbations of chronic obstructive pulmonary disease, and following surgery.[4]
We do not believe these differences are adequately reflected in typical code status discussions.[2, 3] One study using audio‐recorded admission encounters included transcripts of hospitalist‐led code status discussions that all resembled the following: Physician: [I]f an emergency were to happenand your heart would (stop) or your breathing became so difficult that you needed to be attached to machines, would you want the nurses and doctors to attempt heroic measures to try to restart your heart and attach you to a breathing machine?[2] It would come as little surprise if a patient hearing this assumed that just 1 question were being asked and that decisions relating to any cause of respiratory failure (including prearrest causes) were being made. In practice, many physicians then extrapolate DNR orders to other treatment decision (including MV) and interpret them as precluding intubation, even for prearrest states.[5, 6, 7]
A second issue is that the mortality associated with cardiopulmonary arrest requiring CPR and prearrest respiratory failure requiring MV are not equal. Though the mortality after in‐hospital cardiac arrest has decreased over the last decade, it remains >75%.[8] The outcomes for MV for isolated respiratory failure, on the other hand, are not as grim; studies of the general population typically report mortality rates 40%. Despite this, descriptions of outcomes are often left out of goals of care discussions.[9, 10] For example, Sharma et al. recently reported that only one‐third of residents, including those who had undergone training on goals of care discussions, discussed outcomes.[9] And when outcomes are included, they are typically for CPR but not MV as an independent intervention for prearrest respiratory failure.[10] Given that many of the conditions that lead to respiratory failure are among the most common reasons for hospitalization,[11] distinguishing between decisions regarding CPR and prearrest MV with discussion of their associated outcomes is of particular importance to hospitalists. Failing to do so impedes patients from making informed autonomous decisions that incorporate an accurate understanding of the treatments being discussed.
Imagine you are caring for a 75‐year‐old man with a history of coronary artery disease and congestive heart failure now admitted with pneumonia. Given his age, admitting diagnosis, and comorbidities, you feel it would be appropriate to engage him in a discussion of goals of care. His chances of survival with near return to baseline after a cardiac arrest requiring CPR are not the same as his chances of surviving an episode of worsening pneumonia requiring MV. To discuss cardiac arrest and prearrest respiratory failure in the same breath, without acknowledging the differences, is misleading. Based on his goals and values, this patient may see a trial of MV as acceptable. One recent study supports this hypothesis, as 28% of hospitalized patients with a combined DNR/DNI order would accept a trial of MV for pneumonia.[12] If the genesis of these orders was our desire to ensure that patients' autonomous preferences are respected, we must actually know those preferences, and those preferences should be based on adequate information about the expected outcomes, highlighting the differences outlined above.
Some may consider separating CPR from MVtherefore allowing for more clearly separate DNR and DNI ordersproblematic, as it may result in a menu of choices for patients. However, although CPR and MV may be performed at the same time for the same patient, they do not overlap in 100% of their occurrences. This is conceptually different from discussing whether to use epinephrine versus vasopressin, for example, or offering options such as chest compressions alone. More clearly separating CPR from MV would not be dissimilar to what is done with renal dialysis; a patient may wish to be DNR while still electing to undergo dialysis for failing kidneys. Though the discussions surrounding renal dialysis are less urgent, this alone does not adequately explain why the topic is not routinely collapsed into the discussion of CPR. Instead, renal dialysis is an intervention with unique indications, goals, and outcomes; this is what prompts the separation. The same is true of MV.
No matter the situation, code status discussions should focus on determining an individual patient's values and goals of care and should guide physicians in provision (or omission) of certain interventions. For the patient with pneumonia described above, his goal may be to promote quality of life over extension of life. Although this may prompt a recommendation to forego CPR, (if it were felt that his quality of life, even after successful return of spontaneous circulation, would be low), it may not be inconsistent for him to accept a trial of MV were his pneumonia to get worse (if it were felt that he could quickly improve and return to a quality of life close to what he experienced before the episode of pneumonia). We recommend that when discussing options with patients, the indications for and outcomes of CPR and MV be more clearly separated. It may be as simple as saying, there are 2 different situations I would like to discuss with you, followed by a discussion of the associated scenarios and likely outcomes in the best judgment of the care team. For a hospitalist, framing the discussion of MV around anticipated causes of pre‐arrest respiratory failure (eg, pneumonia, acute pulmonary edema) is essential.
In conclusion, if DNR and DNI orders are going to meet their promise of ensuring patients make informed decisions congruent with their goals, then the discussions from which they follow will need to more clearly acknowledge the important differences in indications and outcomes. Although a patient's goals should still be the framework upon which decisions regarding interventions are made, an important distinction should be made between cardiopulmonary arrest and prearrest respiratory failure, with a more explicit accompanying discussion of how the corresponding interventions fit within the patient's overall goals of care.
Acknowledgements
The authors thank Rafael Campo, MD, and Sharon H. Chou, MD, for their suggestions and critical reading of this manuscript.
Disclosures:
Dr. Herzig was funded by grant number K23AG042459 from the National Institute on Aging.
- , , . Orders not to resuscitate. N Engl J Med. 1976;295(7):364–366.
- , , , , . Code status discussions between attending hospitalist physicians and medical patients at hospital admission. J Gen Intern Med. 2010;26(4):359–366.
- , , . How do medical residents discuss resuscitation with patients? J Gen Intern Med. 1995;10(8):436–442.
- , , , et al. Characteristics and outcomes in adult patients receiving mechanical ventilation: a 28‐day international study. JAMA. 2002;287(3):345–355.
- , . The effect of do‐not‐resuscitate orders on physician decision‐making. J Am Geriatr Soc. 2002;50(12):2057–2061.
- , , . Hospital do‐not‐resuscitate orders: why they have failed and how to fix them. J Gen Intern Med. 2011;26(7):791–797.
- , , . Clinician perspectives regarding the do‐not‐resuscitate order. JAMA Pediatr. 2013;167(10):954–958.
- , , , , , . Trends in survival after in‐hospital cardiac arrest. N Engl J Med. 2012;367(20):1912–1920.
- , , , , , . Unpacking resident‐led code status discussions: results from a mixed methods study. J Gen Intern Med. 2014;29(5):750–7.
- , , , et al. If asked, hospitalized patients will choose whether to receive life‐sustaining therapies. J Hosp Med. 2006;1(3):161–167.
- Healthcare Cost and Utilization Project (HCUP). HCUP Facts and Figures: Statistics on Hospital‐Based Care in the United States, 2009. Rockville, MD: Agency for Healthcare Research and Quality; 2011.
- , , , et al. Preferences for resuscitation and intubation among patients with do‐not‐resuscitate/do‐not‐intubate orders. Mayo Clin Proceed. 2013;88(7):658–665.
Since the introduction of defibrillation and closed chest cardiopulmonary resuscitation (CPR) in the 1950s, the ability to revive an arrested heart has been a realized possibility. Around the same time, endotracheal intubation with mechanical ventilation (MV) came into wide practice, allowing doctors to augment or even replace their patients' breathing. But just as the 1950s and 1960s saw the rise of these enhanced medical techniques, they also saw the increased importance of medical ethicsin particular, patient autonomy. A natural reaction to medicine's use of CPR and MV was the advent of advance directives and more specific do‐not‐resuscitate (DNR) and do‐not‐intubate (DNI) orders meant to protect a patient's ability to remain autonomous with their end of life decisions.[1]
Unfortunately, the code status discussions that lead to these orders often collapse cardiac arrest with prearrest respiratory failure and CPR with MV.[2, 3] This is a problem for a number of reasons. First, cardiac arrest and prearrest respiratory failure are unique end points, and though their respective treatments (CPR and MV) are often required simultaneously for an individual patient, they are distinct medical interventions with different goals, indications, and associated disease states. Although MV is typically a part of the cadre of interventions meant to ensure continued tissue oxygenation in the setting of a cardiac arrest, this accounts for 2% of indications for MV.[4] The vast majority of MV is used to treat prearrest causes of respiratory failure, such as pneumonia, congestive heart failure, acute exacerbations of chronic obstructive pulmonary disease, and following surgery.[4]
We do not believe these differences are adequately reflected in typical code status discussions.[2, 3] One study using audio‐recorded admission encounters included transcripts of hospitalist‐led code status discussions that all resembled the following: Physician: [I]f an emergency were to happenand your heart would (stop) or your breathing became so difficult that you needed to be attached to machines, would you want the nurses and doctors to attempt heroic measures to try to restart your heart and attach you to a breathing machine?[2] It would come as little surprise if a patient hearing this assumed that just 1 question were being asked and that decisions relating to any cause of respiratory failure (including prearrest causes) were being made. In practice, many physicians then extrapolate DNR orders to other treatment decision (including MV) and interpret them as precluding intubation, even for prearrest states.[5, 6, 7]
A second issue is that the mortality associated with cardiopulmonary arrest requiring CPR and prearrest respiratory failure requiring MV are not equal. Though the mortality after in‐hospital cardiac arrest has decreased over the last decade, it remains >75%.[8] The outcomes for MV for isolated respiratory failure, on the other hand, are not as grim; studies of the general population typically report mortality rates 40%. Despite this, descriptions of outcomes are often left out of goals of care discussions.[9, 10] For example, Sharma et al. recently reported that only one‐third of residents, including those who had undergone training on goals of care discussions, discussed outcomes.[9] And when outcomes are included, they are typically for CPR but not MV as an independent intervention for prearrest respiratory failure.[10] Given that many of the conditions that lead to respiratory failure are among the most common reasons for hospitalization,[11] distinguishing between decisions regarding CPR and prearrest MV with discussion of their associated outcomes is of particular importance to hospitalists. Failing to do so impedes patients from making informed autonomous decisions that incorporate an accurate understanding of the treatments being discussed.
Imagine you are caring for a 75‐year‐old man with a history of coronary artery disease and congestive heart failure now admitted with pneumonia. Given his age, admitting diagnosis, and comorbidities, you feel it would be appropriate to engage him in a discussion of goals of care. His chances of survival with near return to baseline after a cardiac arrest requiring CPR are not the same as his chances of surviving an episode of worsening pneumonia requiring MV. To discuss cardiac arrest and prearrest respiratory failure in the same breath, without acknowledging the differences, is misleading. Based on his goals and values, this patient may see a trial of MV as acceptable. One recent study supports this hypothesis, as 28% of hospitalized patients with a combined DNR/DNI order would accept a trial of MV for pneumonia.[12] If the genesis of these orders was our desire to ensure that patients' autonomous preferences are respected, we must actually know those preferences, and those preferences should be based on adequate information about the expected outcomes, highlighting the differences outlined above.
Some may consider separating CPR from MVtherefore allowing for more clearly separate DNR and DNI ordersproblematic, as it may result in a menu of choices for patients. However, although CPR and MV may be performed at the same time for the same patient, they do not overlap in 100% of their occurrences. This is conceptually different from discussing whether to use epinephrine versus vasopressin, for example, or offering options such as chest compressions alone. More clearly separating CPR from MV would not be dissimilar to what is done with renal dialysis; a patient may wish to be DNR while still electing to undergo dialysis for failing kidneys. Though the discussions surrounding renal dialysis are less urgent, this alone does not adequately explain why the topic is not routinely collapsed into the discussion of CPR. Instead, renal dialysis is an intervention with unique indications, goals, and outcomes; this is what prompts the separation. The same is true of MV.
No matter the situation, code status discussions should focus on determining an individual patient's values and goals of care and should guide physicians in provision (or omission) of certain interventions. For the patient with pneumonia described above, his goal may be to promote quality of life over extension of life. Although this may prompt a recommendation to forego CPR, (if it were felt that his quality of life, even after successful return of spontaneous circulation, would be low), it may not be inconsistent for him to accept a trial of MV were his pneumonia to get worse (if it were felt that he could quickly improve and return to a quality of life close to what he experienced before the episode of pneumonia). We recommend that when discussing options with patients, the indications for and outcomes of CPR and MV be more clearly separated. It may be as simple as saying, there are 2 different situations I would like to discuss with you, followed by a discussion of the associated scenarios and likely outcomes in the best judgment of the care team. For a hospitalist, framing the discussion of MV around anticipated causes of pre‐arrest respiratory failure (eg, pneumonia, acute pulmonary edema) is essential.
In conclusion, if DNR and DNI orders are going to meet their promise of ensuring patients make informed decisions congruent with their goals, then the discussions from which they follow will need to more clearly acknowledge the important differences in indications and outcomes. Although a patient's goals should still be the framework upon which decisions regarding interventions are made, an important distinction should be made between cardiopulmonary arrest and prearrest respiratory failure, with a more explicit accompanying discussion of how the corresponding interventions fit within the patient's overall goals of care.
Acknowledgements
The authors thank Rafael Campo, MD, and Sharon H. Chou, MD, for their suggestions and critical reading of this manuscript.
Disclosures:
Dr. Herzig was funded by grant number K23AG042459 from the National Institute on Aging.
Since the introduction of defibrillation and closed chest cardiopulmonary resuscitation (CPR) in the 1950s, the ability to revive an arrested heart has been a realized possibility. Around the same time, endotracheal intubation with mechanical ventilation (MV) came into wide practice, allowing doctors to augment or even replace their patients' breathing. But just as the 1950s and 1960s saw the rise of these enhanced medical techniques, they also saw the increased importance of medical ethicsin particular, patient autonomy. A natural reaction to medicine's use of CPR and MV was the advent of advance directives and more specific do‐not‐resuscitate (DNR) and do‐not‐intubate (DNI) orders meant to protect a patient's ability to remain autonomous with their end of life decisions.[1]
Unfortunately, the code status discussions that lead to these orders often collapse cardiac arrest with prearrest respiratory failure and CPR with MV.[2, 3] This is a problem for a number of reasons. First, cardiac arrest and prearrest respiratory failure are unique end points, and though their respective treatments (CPR and MV) are often required simultaneously for an individual patient, they are distinct medical interventions with different goals, indications, and associated disease states. Although MV is typically a part of the cadre of interventions meant to ensure continued tissue oxygenation in the setting of a cardiac arrest, this accounts for 2% of indications for MV.[4] The vast majority of MV is used to treat prearrest causes of respiratory failure, such as pneumonia, congestive heart failure, acute exacerbations of chronic obstructive pulmonary disease, and following surgery.[4]
We do not believe these differences are adequately reflected in typical code status discussions.[2, 3] One study using audio‐recorded admission encounters included transcripts of hospitalist‐led code status discussions that all resembled the following: Physician: [I]f an emergency were to happenand your heart would (stop) or your breathing became so difficult that you needed to be attached to machines, would you want the nurses and doctors to attempt heroic measures to try to restart your heart and attach you to a breathing machine?[2] It would come as little surprise if a patient hearing this assumed that just 1 question were being asked and that decisions relating to any cause of respiratory failure (including prearrest causes) were being made. In practice, many physicians then extrapolate DNR orders to other treatment decision (including MV) and interpret them as precluding intubation, even for prearrest states.[5, 6, 7]
A second issue is that the mortality associated with cardiopulmonary arrest requiring CPR and prearrest respiratory failure requiring MV are not equal. Though the mortality after in‐hospital cardiac arrest has decreased over the last decade, it remains >75%.[8] The outcomes for MV for isolated respiratory failure, on the other hand, are not as grim; studies of the general population typically report mortality rates 40%. Despite this, descriptions of outcomes are often left out of goals of care discussions.[9, 10] For example, Sharma et al. recently reported that only one‐third of residents, including those who had undergone training on goals of care discussions, discussed outcomes.[9] And when outcomes are included, they are typically for CPR but not MV as an independent intervention for prearrest respiratory failure.[10] Given that many of the conditions that lead to respiratory failure are among the most common reasons for hospitalization,[11] distinguishing between decisions regarding CPR and prearrest MV with discussion of their associated outcomes is of particular importance to hospitalists. Failing to do so impedes patients from making informed autonomous decisions that incorporate an accurate understanding of the treatments being discussed.
Imagine you are caring for a 75‐year‐old man with a history of coronary artery disease and congestive heart failure now admitted with pneumonia. Given his age, admitting diagnosis, and comorbidities, you feel it would be appropriate to engage him in a discussion of goals of care. His chances of survival with near return to baseline after a cardiac arrest requiring CPR are not the same as his chances of surviving an episode of worsening pneumonia requiring MV. To discuss cardiac arrest and prearrest respiratory failure in the same breath, without acknowledging the differences, is misleading. Based on his goals and values, this patient may see a trial of MV as acceptable. One recent study supports this hypothesis, as 28% of hospitalized patients with a combined DNR/DNI order would accept a trial of MV for pneumonia.[12] If the genesis of these orders was our desire to ensure that patients' autonomous preferences are respected, we must actually know those preferences, and those preferences should be based on adequate information about the expected outcomes, highlighting the differences outlined above.
Some may consider separating CPR from MVtherefore allowing for more clearly separate DNR and DNI ordersproblematic, as it may result in a menu of choices for patients. However, although CPR and MV may be performed at the same time for the same patient, they do not overlap in 100% of their occurrences. This is conceptually different from discussing whether to use epinephrine versus vasopressin, for example, or offering options such as chest compressions alone. More clearly separating CPR from MV would not be dissimilar to what is done with renal dialysis; a patient may wish to be DNR while still electing to undergo dialysis for failing kidneys. Though the discussions surrounding renal dialysis are less urgent, this alone does not adequately explain why the topic is not routinely collapsed into the discussion of CPR. Instead, renal dialysis is an intervention with unique indications, goals, and outcomes; this is what prompts the separation. The same is true of MV.
No matter the situation, code status discussions should focus on determining an individual patient's values and goals of care and should guide physicians in provision (or omission) of certain interventions. For the patient with pneumonia described above, his goal may be to promote quality of life over extension of life. Although this may prompt a recommendation to forego CPR, (if it were felt that his quality of life, even after successful return of spontaneous circulation, would be low), it may not be inconsistent for him to accept a trial of MV were his pneumonia to get worse (if it were felt that he could quickly improve and return to a quality of life close to what he experienced before the episode of pneumonia). We recommend that when discussing options with patients, the indications for and outcomes of CPR and MV be more clearly separated. It may be as simple as saying, there are 2 different situations I would like to discuss with you, followed by a discussion of the associated scenarios and likely outcomes in the best judgment of the care team. For a hospitalist, framing the discussion of MV around anticipated causes of pre‐arrest respiratory failure (eg, pneumonia, acute pulmonary edema) is essential.
In conclusion, if DNR and DNI orders are going to meet their promise of ensuring patients make informed decisions congruent with their goals, then the discussions from which they follow will need to more clearly acknowledge the important differences in indications and outcomes. Although a patient's goals should still be the framework upon which decisions regarding interventions are made, an important distinction should be made between cardiopulmonary arrest and prearrest respiratory failure, with a more explicit accompanying discussion of how the corresponding interventions fit within the patient's overall goals of care.
Acknowledgements
The authors thank Rafael Campo, MD, and Sharon H. Chou, MD, for their suggestions and critical reading of this manuscript.
Disclosures:
Dr. Herzig was funded by grant number K23AG042459 from the National Institute on Aging.
- , , . Orders not to resuscitate. N Engl J Med. 1976;295(7):364–366.
- , , , , . Code status discussions between attending hospitalist physicians and medical patients at hospital admission. J Gen Intern Med. 2010;26(4):359–366.
- , , . How do medical residents discuss resuscitation with patients? J Gen Intern Med. 1995;10(8):436–442.
- , , , et al. Characteristics and outcomes in adult patients receiving mechanical ventilation: a 28‐day international study. JAMA. 2002;287(3):345–355.
- , . The effect of do‐not‐resuscitate orders on physician decision‐making. J Am Geriatr Soc. 2002;50(12):2057–2061.
- , , . Hospital do‐not‐resuscitate orders: why they have failed and how to fix them. J Gen Intern Med. 2011;26(7):791–797.
- , , . Clinician perspectives regarding the do‐not‐resuscitate order. JAMA Pediatr. 2013;167(10):954–958.
- , , , , , . Trends in survival after in‐hospital cardiac arrest. N Engl J Med. 2012;367(20):1912–1920.
- , , , , , . Unpacking resident‐led code status discussions: results from a mixed methods study. J Gen Intern Med. 2014;29(5):750–7.
- , , , et al. If asked, hospitalized patients will choose whether to receive life‐sustaining therapies. J Hosp Med. 2006;1(3):161–167.
- Healthcare Cost and Utilization Project (HCUP). HCUP Facts and Figures: Statistics on Hospital‐Based Care in the United States, 2009. Rockville, MD: Agency for Healthcare Research and Quality; 2011.
- , , , et al. Preferences for resuscitation and intubation among patients with do‐not‐resuscitate/do‐not‐intubate orders. Mayo Clin Proceed. 2013;88(7):658–665.
- , , . Orders not to resuscitate. N Engl J Med. 1976;295(7):364–366.
- , , , , . Code status discussions between attending hospitalist physicians and medical patients at hospital admission. J Gen Intern Med. 2010;26(4):359–366.
- , , . How do medical residents discuss resuscitation with patients? J Gen Intern Med. 1995;10(8):436–442.
- , , , et al. Characteristics and outcomes in adult patients receiving mechanical ventilation: a 28‐day international study. JAMA. 2002;287(3):345–355.
- , . The effect of do‐not‐resuscitate orders on physician decision‐making. J Am Geriatr Soc. 2002;50(12):2057–2061.
- , , . Hospital do‐not‐resuscitate orders: why they have failed and how to fix them. J Gen Intern Med. 2011;26(7):791–797.
- , , . Clinician perspectives regarding the do‐not‐resuscitate order. JAMA Pediatr. 2013;167(10):954–958.
- , , , , , . Trends in survival after in‐hospital cardiac arrest. N Engl J Med. 2012;367(20):1912–1920.
- , , , , , . Unpacking resident‐led code status discussions: results from a mixed methods study. J Gen Intern Med. 2014;29(5):750–7.
- , , , et al. If asked, hospitalized patients will choose whether to receive life‐sustaining therapies. J Hosp Med. 2006;1(3):161–167.
- Healthcare Cost and Utilization Project (HCUP). HCUP Facts and Figures: Statistics on Hospital‐Based Care in the United States, 2009. Rockville, MD: Agency for Healthcare Research and Quality; 2011.
- , , , et al. Preferences for resuscitation and intubation among patients with do‐not‐resuscitate/do‐not‐intubate orders. Mayo Clin Proceed. 2013;88(7):658–665.
Ofatumumab falls short in CLL, DLBCL
Credit: Linda Bartlett
The anti-CD20 antibody ofatumumab (Arzerra) has failed to meet the primary endpoint in two phase 3 trials, according to the companies developing the drug.
Ofatumumab failed to improve progression-free survival (PFS) when compared to physicians’ choice in patients with bulky, fludarabine-refractory chronic lymphocytic leukemia (CLL).
Likewise, ofatumumab plus chemotherapy failed to improve PFS when compared to rituximab plus chemotherapy in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).
GlaxoSmithKline (GSK) and Genmab recently announced these headline results but said the full analyses of safety and efficacy data are underway and will be completed in the coming months.
However, based on these early results, the companies said they are unlikely to pursue regulatory filings for ofatumumab in either indication.
CLL trial
In the OMB114242 study, researchers enrolled 122 patients with bulky, fludarabine-refractory CLL. Patients were randomized to receive ofatumumab or physicians’ choice (2:1).
Patients randomized to ofatumumab received an initial dose of 300 mg, followed 1 week later by 2000 mg once weekly for 7 weeks, followed 4 weeks later by 1 infusion of 2000 mg every 4 weeks, for a total treatment duration of 6 to 12 months. Patients in the physicians’ choice arm received a treatment regimen chosen by a physician for up to 6 months.
The primary endpoint was PFS, and secondary objectives were to evaluate response, overall survival, safety, tolerability, and health-related quality of life.
The median PFS, as assessed by an independent review committee, was 5.36 months for ofatumumab and 3.61 months for physicians’ choice (hazard ratio 0.79, P=0.267).
“It was our priority to share this result with the scientific community as soon it became available,” said Rafael Amado, MD, Head of Oncology R&D at GSK. “We will now work to further analyze the data and to better understand the totality of the efficacy and safety findings.”
This study was conducted to meet the requirements from the European Commission for the conditional approval of ofatumumab for the treatment of CLL in patients who are refractory to fludarabine and alemtuzumab. The current indications in the European Union and the United States do not include bulky, fludarabine-refractory CLL patients.
“Although ofatumumab performed broadly in line with previous data, today’s result is disappointing,” said Jan van de Winkel, PhD, Chief Executive Officer of Genmab. “Based on this result, we do not anticipate applying for a label expansion for ofatumumab in this specific refractory CLL population.”
DLBCL trial
The ORCHARRD study included 447 patients who were refractory to, or had relapsed following, first-line treatment with rituximab in combination with a chemotherapy regimen containing anthracycline or anthracenedione. Patients were also eligible for autologous stem cell transplant.
Patients were randomized 1:1 to receive 3 cycles of either ofatumumab or rituximab in combination with DHAP (dexamethasone, cytarabine, and cisplatin) salvage chemotherapy. After the third treatment cycle, patients who obtained a complete or partial response received high-dose chemotherapy followed by transplant.
The primary endpoint was PFS. But GSK and Genmab reported no statistically significant difference in PFS between the treatment arms.
There were no differences in adverse events (AEs) leading to treatment discontinuation, grade 3 or higher AEs, or severe AEs between the treatment arms. However, there were more dose interruptions and delays due to infusion reactions and increased serum creatinine in the ofatumumab-plus-chemotherapy arm, which require further analysis.
“We plan to submit detailed data from the ofatumumab ORCHARRD study in DLBCL for presentation at a medical conference later this year, which we hope will provide further clarity on today’s headline results,” Dr van de Winkel said. “Based on [these early] results, we are unlikely to move forward with a regulatory filing.” 
Credit: Linda Bartlett
The anti-CD20 antibody ofatumumab (Arzerra) has failed to meet the primary endpoint in two phase 3 trials, according to the companies developing the drug.
Ofatumumab failed to improve progression-free survival (PFS) when compared to physicians’ choice in patients with bulky, fludarabine-refractory chronic lymphocytic leukemia (CLL).
Likewise, ofatumumab plus chemotherapy failed to improve PFS when compared to rituximab plus chemotherapy in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).
GlaxoSmithKline (GSK) and Genmab recently announced these headline results but said the full analyses of safety and efficacy data are underway and will be completed in the coming months.
However, based on these early results, the companies said they are unlikely to pursue regulatory filings for ofatumumab in either indication.
CLL trial
In the OMB114242 study, researchers enrolled 122 patients with bulky, fludarabine-refractory CLL. Patients were randomized to receive ofatumumab or physicians’ choice (2:1).
Patients randomized to ofatumumab received an initial dose of 300 mg, followed 1 week later by 2000 mg once weekly for 7 weeks, followed 4 weeks later by 1 infusion of 2000 mg every 4 weeks, for a total treatment duration of 6 to 12 months. Patients in the physicians’ choice arm received a treatment regimen chosen by a physician for up to 6 months.
The primary endpoint was PFS, and secondary objectives were to evaluate response, overall survival, safety, tolerability, and health-related quality of life.
The median PFS, as assessed by an independent review committee, was 5.36 months for ofatumumab and 3.61 months for physicians’ choice (hazard ratio 0.79, P=0.267).
“It was our priority to share this result with the scientific community as soon it became available,” said Rafael Amado, MD, Head of Oncology R&D at GSK. “We will now work to further analyze the data and to better understand the totality of the efficacy and safety findings.”
This study was conducted to meet the requirements from the European Commission for the conditional approval of ofatumumab for the treatment of CLL in patients who are refractory to fludarabine and alemtuzumab. The current indications in the European Union and the United States do not include bulky, fludarabine-refractory CLL patients.
“Although ofatumumab performed broadly in line with previous data, today’s result is disappointing,” said Jan van de Winkel, PhD, Chief Executive Officer of Genmab. “Based on this result, we do not anticipate applying for a label expansion for ofatumumab in this specific refractory CLL population.”
DLBCL trial
The ORCHARRD study included 447 patients who were refractory to, or had relapsed following, first-line treatment with rituximab in combination with a chemotherapy regimen containing anthracycline or anthracenedione. Patients were also eligible for autologous stem cell transplant.
Patients were randomized 1:1 to receive 3 cycles of either ofatumumab or rituximab in combination with DHAP (dexamethasone, cytarabine, and cisplatin) salvage chemotherapy. After the third treatment cycle, patients who obtained a complete or partial response received high-dose chemotherapy followed by transplant.
The primary endpoint was PFS. But GSK and Genmab reported no statistically significant difference in PFS between the treatment arms.
There were no differences in adverse events (AEs) leading to treatment discontinuation, grade 3 or higher AEs, or severe AEs between the treatment arms. However, there were more dose interruptions and delays due to infusion reactions and increased serum creatinine in the ofatumumab-plus-chemotherapy arm, which require further analysis.
“We plan to submit detailed data from the ofatumumab ORCHARRD study in DLBCL for presentation at a medical conference later this year, which we hope will provide further clarity on today’s headline results,” Dr van de Winkel said. “Based on [these early] results, we are unlikely to move forward with a regulatory filing.”
Credit: Linda Bartlett
The anti-CD20 antibody ofatumumab (Arzerra) has failed to meet the primary endpoint in two phase 3 trials, according to the companies developing the drug.
Ofatumumab failed to improve progression-free survival (PFS) when compared to physicians’ choice in patients with bulky, fludarabine-refractory chronic lymphocytic leukemia (CLL).
Likewise, ofatumumab plus chemotherapy failed to improve PFS when compared to rituximab plus chemotherapy in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).
GlaxoSmithKline (GSK) and Genmab recently announced these headline results but said the full analyses of safety and efficacy data are underway and will be completed in the coming months.
However, based on these early results, the companies said they are unlikely to pursue regulatory filings for ofatumumab in either indication.
CLL trial
In the OMB114242 study, researchers enrolled 122 patients with bulky, fludarabine-refractory CLL. Patients were randomized to receive ofatumumab or physicians’ choice (2:1).
Patients randomized to ofatumumab received an initial dose of 300 mg, followed 1 week later by 2000 mg once weekly for 7 weeks, followed 4 weeks later by 1 infusion of 2000 mg every 4 weeks, for a total treatment duration of 6 to 12 months. Patients in the physicians’ choice arm received a treatment regimen chosen by a physician for up to 6 months.
The primary endpoint was PFS, and secondary objectives were to evaluate response, overall survival, safety, tolerability, and health-related quality of life.
The median PFS, as assessed by an independent review committee, was 5.36 months for ofatumumab and 3.61 months for physicians’ choice (hazard ratio 0.79, P=0.267).
“It was our priority to share this result with the scientific community as soon it became available,” said Rafael Amado, MD, Head of Oncology R&D at GSK. “We will now work to further analyze the data and to better understand the totality of the efficacy and safety findings.”
This study was conducted to meet the requirements from the European Commission for the conditional approval of ofatumumab for the treatment of CLL in patients who are refractory to fludarabine and alemtuzumab. The current indications in the European Union and the United States do not include bulky, fludarabine-refractory CLL patients.
“Although ofatumumab performed broadly in line with previous data, today’s result is disappointing,” said Jan van de Winkel, PhD, Chief Executive Officer of Genmab. “Based on this result, we do not anticipate applying for a label expansion for ofatumumab in this specific refractory CLL population.”
DLBCL trial
The ORCHARRD study included 447 patients who were refractory to, or had relapsed following, first-line treatment with rituximab in combination with a chemotherapy regimen containing anthracycline or anthracenedione. Patients were also eligible for autologous stem cell transplant.
Patients were randomized 1:1 to receive 3 cycles of either ofatumumab or rituximab in combination with DHAP (dexamethasone, cytarabine, and cisplatin) salvage chemotherapy. After the third treatment cycle, patients who obtained a complete or partial response received high-dose chemotherapy followed by transplant.
The primary endpoint was PFS. But GSK and Genmab reported no statistically significant difference in PFS between the treatment arms.
There were no differences in adverse events (AEs) leading to treatment discontinuation, grade 3 or higher AEs, or severe AEs between the treatment arms. However, there were more dose interruptions and delays due to infusion reactions and increased serum creatinine in the ofatumumab-plus-chemotherapy arm, which require further analysis.
“We plan to submit detailed data from the ofatumumab ORCHARRD study in DLBCL for presentation at a medical conference later this year, which we hope will provide further clarity on today’s headline results,” Dr van de Winkel said. “Based on [these early] results, we are unlikely to move forward with a regulatory filing.”
CHMP recommends apixaban for VTE
Credit: Andre E.X. Brown
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended that apixaban (Eliquis) be granted marketing authorization for the treatment and prevention of venous thromboembolism (VTE) in adults.
The European Commission will take the CHMP’s opinion into account when deciding whether to approve the drug for this indication in all 28 European Union member states, plus Iceland and Norway.
The CHMP’s recommendation of apixaban was based on results from the AMPLIFY and AMPLIFY-EXTENSION studies.
The phase 3 AMPLIFY trial enrolled 5395 patients with confirmed, symptomatic deep vein thrombosis (DVT) or pulmonary embolism (PE) requiring treatment for 6 months.
About half of patients (n=2691) were randomized to apixaban, and the other half (n=2704) were randomized to standard of care, which was initial enoxaparin treatment overlapped by warfarin therapy.
The primary efficacy outcome was the composite endpoint of recurrent, symptomatic VTE or VTE-related death. This occurred in 59 patients in the apixaban arm (2.3%) and 71 patients (2.7%) in the standard-therapy arm (P<0.0001 for noninferiority).
The composite endpoint of major bleeding and clinically relevant, nonmajor bleeding occurred in 4.3% of patients in the apixaban arm and 9.7% of patients in the standard-therapy arm (P<0.001).
The phase 3 AMPLIFY-EXTENSION trial included 2486 patients with prior VTE who had completed 6 to 12 months of anticoagulation treatment for DVT or PE.
Eight hundred and forty-two patients were randomized to apixaban at 2.5 mg, 815 were randomized to apixaban at 5 mg, and 829 were randomized to placebo.
The study’s primary efficacy endpoint was recurrent VTE or all-cause death. During the 12-month active study period, these events occurred in 32 patients (3.8%) in the 2.5-mg arm, 34 patients (4.2%) in the 5-mg arm, and 96 patients (11.6%) in the placebo arm. Both apixaban doses were significantly superior to placebo (P<0.001).
The primary safety endpoint was the incidence of major bleeding, which occurred in 2 patients (0.2%) in the 2.5-mg arm, 1 patient (0.1%) in the 5-mg arm, and 4 patients (0.5%) in the placebo arm.
Credit: Andre E.X. Brown
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended that apixaban (Eliquis) be granted marketing authorization for the treatment and prevention of venous thromboembolism (VTE) in adults.
The European Commission will take the CHMP’s opinion into account when deciding whether to approve the drug for this indication in all 28 European Union member states, plus Iceland and Norway.
The CHMP’s recommendation of apixaban was based on results from the AMPLIFY and AMPLIFY-EXTENSION studies.
The phase 3 AMPLIFY trial enrolled 5395 patients with confirmed, symptomatic deep vein thrombosis (DVT) or pulmonary embolism (PE) requiring treatment for 6 months.
About half of patients (n=2691) were randomized to apixaban, and the other half (n=2704) were randomized to standard of care, which was initial enoxaparin treatment overlapped by warfarin therapy.
The primary efficacy outcome was the composite endpoint of recurrent, symptomatic VTE or VTE-related death. This occurred in 59 patients in the apixaban arm (2.3%) and 71 patients (2.7%) in the standard-therapy arm (P<0.0001 for noninferiority).
The composite endpoint of major bleeding and clinically relevant, nonmajor bleeding occurred in 4.3% of patients in the apixaban arm and 9.7% of patients in the standard-therapy arm (P<0.001).
The phase 3 AMPLIFY-EXTENSION trial included 2486 patients with prior VTE who had completed 6 to 12 months of anticoagulation treatment for DVT or PE.
Eight hundred and forty-two patients were randomized to apixaban at 2.5 mg, 815 were randomized to apixaban at 5 mg, and 829 were randomized to placebo.
The study’s primary efficacy endpoint was recurrent VTE or all-cause death. During the 12-month active study period, these events occurred in 32 patients (3.8%) in the 2.5-mg arm, 34 patients (4.2%) in the 5-mg arm, and 96 patients (11.6%) in the placebo arm. Both apixaban doses were significantly superior to placebo (P<0.001).
The primary safety endpoint was the incidence of major bleeding, which occurred in 2 patients (0.2%) in the 2.5-mg arm, 1 patient (0.1%) in the 5-mg arm, and 4 patients (0.5%) in the placebo arm.
Credit: Andre E.X. Brown
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended that apixaban (Eliquis) be granted marketing authorization for the treatment and prevention of venous thromboembolism (VTE) in adults.
The European Commission will take the CHMP’s opinion into account when deciding whether to approve the drug for this indication in all 28 European Union member states, plus Iceland and Norway.
The CHMP’s recommendation of apixaban was based on results from the AMPLIFY and AMPLIFY-EXTENSION studies.
The phase 3 AMPLIFY trial enrolled 5395 patients with confirmed, symptomatic deep vein thrombosis (DVT) or pulmonary embolism (PE) requiring treatment for 6 months.
About half of patients (n=2691) were randomized to apixaban, and the other half (n=2704) were randomized to standard of care, which was initial enoxaparin treatment overlapped by warfarin therapy.
The primary efficacy outcome was the composite endpoint of recurrent, symptomatic VTE or VTE-related death. This occurred in 59 patients in the apixaban arm (2.3%) and 71 patients (2.7%) in the standard-therapy arm (P<0.0001 for noninferiority).
The composite endpoint of major bleeding and clinically relevant, nonmajor bleeding occurred in 4.3% of patients in the apixaban arm and 9.7% of patients in the standard-therapy arm (P<0.001).
The phase 3 AMPLIFY-EXTENSION trial included 2486 patients with prior VTE who had completed 6 to 12 months of anticoagulation treatment for DVT or PE.
Eight hundred and forty-two patients were randomized to apixaban at 2.5 mg, 815 were randomized to apixaban at 5 mg, and 829 were randomized to placebo.
The study’s primary efficacy endpoint was recurrent VTE or all-cause death. During the 12-month active study period, these events occurred in 32 patients (3.8%) in the 2.5-mg arm, 34 patients (4.2%) in the 5-mg arm, and 96 patients (11.6%) in the placebo arm. Both apixaban doses were significantly superior to placebo (P<0.001).
The primary safety endpoint was the incidence of major bleeding, which occurred in 2 patients (0.2%) in the 2.5-mg arm, 1 patient (0.1%) in the 5-mg arm, and 4 patients (0.5%) in the placebo arm.
Impending stroke chalked up to carpal tunnel syndrome
Impending stroke chalked up to carpal tunnel syndrome
A WOMAN WENT TO HER PHYSICIAN COMPLAINING OF DIZZINESS, blurred vision, numbness, tingling in her hands and feet, and other symptoms. The physician diagnosed carpal tunnel syndrome. The patient visited her physician a second time, and a day later, suffered a stroke and died.
PLAINTIFF The patient specifically asked her physician if she was having a stroke and her physician told her No.
THE DEFENSE No information about the defense is available.
VERDICT $907,486 Kansas verdict.
COMMENT Certainly carpal tunnel syndrome is not sufficient to explain all of this patient’s symptoms—especially dizziness and blurred vision—but the details on this case are limited. If the patient did in fact express concern about a possible stroke, it was incumbent upon the physician to evaluate carefully and either diagnose that condition or rule it out.
Rather than coming too late, Rx for methadone came too soon
A 34-YEAR-OLD MAN ADDICTED TO OXYCODONE AND OTHER PAIN MEDICATIONS as the result of a work-related injury 10 years earlier sought treatment for his addiction from a family physician (FP) while visiting Kentucky. The patient also was abusing alprazolam. The FP administered a drug test but prescribed methadone, 180 10-mg pills, before receiving the results. The next day, the drug screen returned positive for multiple drugs, including opiates and cannabinoids. The FP’s staff tried to reach the patient, but was unsuccessful. The patient was found dead a few hours later after overdosing on a combination of methadone and alprazolam. Although 64 methadone pills were missing, the patient could not have taken all of them because only a therapeutic level of methadone was found in his system.
PLAINTIFF’S CLAIM The physician should have waited to receive the results of the drug screen before prescribing methadone. Drug Enforcement Administration guidelines allow prescription of methadone for addiction only if a patient is in withdrawal and in the process of being admitted to a treatment facility. There was no proof of withdrawal symptoms.
THE DEFENSE The treatment was reasonable and compassionate. The patient was at fault for abusing narcotics.
VERDICT $204,500 Kentucky verdict.
Could a proper history have spared this patient multiple surgeries?
A 13-YEAR-OLD CAME TO THE EMERGENCY DEPARTMENT (ED) with left knee pain and fever. He was diagnosed with a quadriceps strain and discharged. The next morning the patient still had knee pain and sought treatment from an FP, who diagnosed a sprained knee. At this visit, the patient’s temperature was normal. Three days later, the patient went to another ED with a high fever and knee pain so severe that he couldn’t walk. Blood culture revealed methicillin-resistant Staphylococcus aureus (MRSA) in the knee, which quickly spread. The patient was hospitalized and required 17 surgeries.
PLAINTIFF’S CLAIM The FP should have ordered blood work and recognized the signs of infection. MRSA had been present at least 4 days before it was diagnosed.
THE DEFENSE The patient did not have a diagnosable infection the day the physician saw him and his condition had progressed over the following 3 days.
VERDICT $2.1 million Illinois verdict.
COMMENT This case reminds me of the necessity of obtaining a history of the mechanism of injury for joint pain. Absence of a definite cause should have led to a wider differential diagnosis.
Impending stroke chalked up to carpal tunnel syndrome
A WOMAN WENT TO HER PHYSICIAN COMPLAINING OF DIZZINESS, blurred vision, numbness, tingling in her hands and feet, and other symptoms. The physician diagnosed carpal tunnel syndrome. The patient visited her physician a second time, and a day later, suffered a stroke and died.
PLAINTIFF The patient specifically asked her physician if she was having a stroke and her physician told her No.
THE DEFENSE No information about the defense is available.
VERDICT $907,486 Kansas verdict.
COMMENT Certainly carpal tunnel syndrome is not sufficient to explain all of this patient’s symptoms—especially dizziness and blurred vision—but the details on this case are limited. If the patient did in fact express concern about a possible stroke, it was incumbent upon the physician to evaluate carefully and either diagnose that condition or rule it out.
Rather than coming too late, Rx for methadone came too soon
A 34-YEAR-OLD MAN ADDICTED TO OXYCODONE AND OTHER PAIN MEDICATIONS as the result of a work-related injury 10 years earlier sought treatment for his addiction from a family physician (FP) while visiting Kentucky. The patient also was abusing alprazolam. The FP administered a drug test but prescribed methadone, 180 10-mg pills, before receiving the results. The next day, the drug screen returned positive for multiple drugs, including opiates and cannabinoids. The FP’s staff tried to reach the patient, but was unsuccessful. The patient was found dead a few hours later after overdosing on a combination of methadone and alprazolam. Although 64 methadone pills were missing, the patient could not have taken all of them because only a therapeutic level of methadone was found in his system.
PLAINTIFF’S CLAIM The physician should have waited to receive the results of the drug screen before prescribing methadone. Drug Enforcement Administration guidelines allow prescription of methadone for addiction only if a patient is in withdrawal and in the process of being admitted to a treatment facility. There was no proof of withdrawal symptoms.
THE DEFENSE The treatment was reasonable and compassionate. The patient was at fault for abusing narcotics.
VERDICT $204,500 Kentucky verdict.
Could a proper history have spared this patient multiple surgeries?
A 13-YEAR-OLD CAME TO THE EMERGENCY DEPARTMENT (ED) with left knee pain and fever. He was diagnosed with a quadriceps strain and discharged. The next morning the patient still had knee pain and sought treatment from an FP, who diagnosed a sprained knee. At this visit, the patient’s temperature was normal. Three days later, the patient went to another ED with a high fever and knee pain so severe that he couldn’t walk. Blood culture revealed methicillin-resistant Staphylococcus aureus (MRSA) in the knee, which quickly spread. The patient was hospitalized and required 17 surgeries.
PLAINTIFF’S CLAIM The FP should have ordered blood work and recognized the signs of infection. MRSA had been present at least 4 days before it was diagnosed.
THE DEFENSE The patient did not have a diagnosable infection the day the physician saw him and his condition had progressed over the following 3 days.
VERDICT $2.1 million Illinois verdict.
COMMENT This case reminds me of the necessity of obtaining a history of the mechanism of injury for joint pain. Absence of a definite cause should have led to a wider differential diagnosis.
Impending stroke chalked up to carpal tunnel syndrome
A WOMAN WENT TO HER PHYSICIAN COMPLAINING OF DIZZINESS, blurred vision, numbness, tingling in her hands and feet, and other symptoms. The physician diagnosed carpal tunnel syndrome. The patient visited her physician a second time, and a day later, suffered a stroke and died.
PLAINTIFF The patient specifically asked her physician if she was having a stroke and her physician told her No.
THE DEFENSE No information about the defense is available.
VERDICT $907,486 Kansas verdict.
COMMENT Certainly carpal tunnel syndrome is not sufficient to explain all of this patient’s symptoms—especially dizziness and blurred vision—but the details on this case are limited. If the patient did in fact express concern about a possible stroke, it was incumbent upon the physician to evaluate carefully and either diagnose that condition or rule it out.
Rather than coming too late, Rx for methadone came too soon
A 34-YEAR-OLD MAN ADDICTED TO OXYCODONE AND OTHER PAIN MEDICATIONS as the result of a work-related injury 10 years earlier sought treatment for his addiction from a family physician (FP) while visiting Kentucky. The patient also was abusing alprazolam. The FP administered a drug test but prescribed methadone, 180 10-mg pills, before receiving the results. The next day, the drug screen returned positive for multiple drugs, including opiates and cannabinoids. The FP’s staff tried to reach the patient, but was unsuccessful. The patient was found dead a few hours later after overdosing on a combination of methadone and alprazolam. Although 64 methadone pills were missing, the patient could not have taken all of them because only a therapeutic level of methadone was found in his system.
PLAINTIFF’S CLAIM The physician should have waited to receive the results of the drug screen before prescribing methadone. Drug Enforcement Administration guidelines allow prescription of methadone for addiction only if a patient is in withdrawal and in the process of being admitted to a treatment facility. There was no proof of withdrawal symptoms.
THE DEFENSE The treatment was reasonable and compassionate. The patient was at fault for abusing narcotics.
VERDICT $204,500 Kentucky verdict.
Could a proper history have spared this patient multiple surgeries?
A 13-YEAR-OLD CAME TO THE EMERGENCY DEPARTMENT (ED) with left knee pain and fever. He was diagnosed with a quadriceps strain and discharged. The next morning the patient still had knee pain and sought treatment from an FP, who diagnosed a sprained knee. At this visit, the patient’s temperature was normal. Three days later, the patient went to another ED with a high fever and knee pain so severe that he couldn’t walk. Blood culture revealed methicillin-resistant Staphylococcus aureus (MRSA) in the knee, which quickly spread. The patient was hospitalized and required 17 surgeries.
PLAINTIFF’S CLAIM The FP should have ordered blood work and recognized the signs of infection. MRSA had been present at least 4 days before it was diagnosed.
THE DEFENSE The patient did not have a diagnosable infection the day the physician saw him and his condition had progressed over the following 3 days.
VERDICT $2.1 million Illinois verdict.
COMMENT This case reminds me of the necessity of obtaining a history of the mechanism of injury for joint pain. Absence of a definite cause should have led to a wider differential diagnosis.
VSTs can target up to 5 viruses
for Cell and Gene Therapy
at Baylor College of Medicine
New virus-specific T-cells (VSTs) can effectively target multiple viruses, thereby clearing and preventing infections in transplant recipients, researchers have reported in Science Translational Medicine.
VSTs have proven effective in previous studies, but they are typically costly, can take months to produce, and often target a single virus.
The new VSTs took about 10 days to produce, are more cost-effective than standard therapy, and can target up to 5 viruses, according to the researchers.
Ann Leen, PhD, of the Baylor College of Medicine in Houston, and her colleagues developed the technique to produce the VSTs, which can target Epstein-Barr virus (EBV), adenovirus (ADV), cytomegalovirus (CMV), BK virus (BKV), and human herpesvirus 6 (HHV6).
“Unlike conventional antiviral drugs, our therapy improves virus-specific T-cell immunity—the root cause of post-transplant viral infections—providing both an effective and safe strategy to treat viruses,” Dr Leen said.
“Additionally, we can readily produce both individualized products and T-cell banks for third-party use, facilitating the extension of T-cell therapy to a standard of care for transplant recipients.”
The researchers generated 48 VST cell lines by stimulating peripheral blood mononuclear cells from allogeneic donors with overlapping peptide libraries that incorporate EBV, CMV, ADV, BKV, and HHV6 antigens.
The team then tested these VSTs in 11 patients who had received allogeneic transplants to treat leukemia, lymphoma, sickle cell disease, and other hematologic and immunodeficient disorders.
Eight of the patients had up to 4 active infections with the targeted viruses. Three patients received the VSTs to prevent infection.
The VSTs produced an overall 94% virological and clinical response that was sustained long-term. Of the 3 patients who received VSTs prophylactically, all remained free of infection for more than 3 months after infusion.
There were no immediate infusion-related toxicities. One patient developed de novo graft-vs-host disease of the skin that improved with topical steroids.
Two patients who received VSTs as prophylaxis developed transplant-associated microangiopathy, but the researchers considered this to be unrelated to VST infusion.
They noted that this is the first time BKV and HHV6 reactivations have been controlled using VSTs. Dr Leen’s team had previously reported promising results with VSTs targeting EBV, CMV, and ADV.
“This study translated improved manufacturing techniques developed in Dr Leen’s laboratory to the clinic and showed that virus-specific T cells produced with the new method could target new viruses and be ready for clinical use after 10 days,” said Helen Heslop, MD, also of Baylor College of Medicine.
“These advances mean that this therapy could be available for more patients to treat viral infections and provide long-lasting protection.”
for Cell and Gene Therapy
at Baylor College of Medicine
New virus-specific T-cells (VSTs) can effectively target multiple viruses, thereby clearing and preventing infections in transplant recipients, researchers have reported in Science Translational Medicine.
VSTs have proven effective in previous studies, but they are typically costly, can take months to produce, and often target a single virus.
The new VSTs took about 10 days to produce, are more cost-effective than standard therapy, and can target up to 5 viruses, according to the researchers.
Ann Leen, PhD, of the Baylor College of Medicine in Houston, and her colleagues developed the technique to produce the VSTs, which can target Epstein-Barr virus (EBV), adenovirus (ADV), cytomegalovirus (CMV), BK virus (BKV), and human herpesvirus 6 (HHV6).
“Unlike conventional antiviral drugs, our therapy improves virus-specific T-cell immunity—the root cause of post-transplant viral infections—providing both an effective and safe strategy to treat viruses,” Dr Leen said.
“Additionally, we can readily produce both individualized products and T-cell banks for third-party use, facilitating the extension of T-cell therapy to a standard of care for transplant recipients.”
The researchers generated 48 VST cell lines by stimulating peripheral blood mononuclear cells from allogeneic donors with overlapping peptide libraries that incorporate EBV, CMV, ADV, BKV, and HHV6 antigens.
The team then tested these VSTs in 11 patients who had received allogeneic transplants to treat leukemia, lymphoma, sickle cell disease, and other hematologic and immunodeficient disorders.
Eight of the patients had up to 4 active infections with the targeted viruses. Three patients received the VSTs to prevent infection.
The VSTs produced an overall 94% virological and clinical response that was sustained long-term. Of the 3 patients who received VSTs prophylactically, all remained free of infection for more than 3 months after infusion.
There were no immediate infusion-related toxicities. One patient developed de novo graft-vs-host disease of the skin that improved with topical steroids.
Two patients who received VSTs as prophylaxis developed transplant-associated microangiopathy, but the researchers considered this to be unrelated to VST infusion.
They noted that this is the first time BKV and HHV6 reactivations have been controlled using VSTs. Dr Leen’s team had previously reported promising results with VSTs targeting EBV, CMV, and ADV.
“This study translated improved manufacturing techniques developed in Dr Leen’s laboratory to the clinic and showed that virus-specific T cells produced with the new method could target new viruses and be ready for clinical use after 10 days,” said Helen Heslop, MD, also of Baylor College of Medicine.
“These advances mean that this therapy could be available for more patients to treat viral infections and provide long-lasting protection.”
for Cell and Gene Therapy
at Baylor College of Medicine
New virus-specific T-cells (VSTs) can effectively target multiple viruses, thereby clearing and preventing infections in transplant recipients, researchers have reported in Science Translational Medicine.
VSTs have proven effective in previous studies, but they are typically costly, can take months to produce, and often target a single virus.
The new VSTs took about 10 days to produce, are more cost-effective than standard therapy, and can target up to 5 viruses, according to the researchers.
Ann Leen, PhD, of the Baylor College of Medicine in Houston, and her colleagues developed the technique to produce the VSTs, which can target Epstein-Barr virus (EBV), adenovirus (ADV), cytomegalovirus (CMV), BK virus (BKV), and human herpesvirus 6 (HHV6).
“Unlike conventional antiviral drugs, our therapy improves virus-specific T-cell immunity—the root cause of post-transplant viral infections—providing both an effective and safe strategy to treat viruses,” Dr Leen said.
“Additionally, we can readily produce both individualized products and T-cell banks for third-party use, facilitating the extension of T-cell therapy to a standard of care for transplant recipients.”
The researchers generated 48 VST cell lines by stimulating peripheral blood mononuclear cells from allogeneic donors with overlapping peptide libraries that incorporate EBV, CMV, ADV, BKV, and HHV6 antigens.
The team then tested these VSTs in 11 patients who had received allogeneic transplants to treat leukemia, lymphoma, sickle cell disease, and other hematologic and immunodeficient disorders.
Eight of the patients had up to 4 active infections with the targeted viruses. Three patients received the VSTs to prevent infection.
The VSTs produced an overall 94% virological and clinical response that was sustained long-term. Of the 3 patients who received VSTs prophylactically, all remained free of infection for more than 3 months after infusion.
There were no immediate infusion-related toxicities. One patient developed de novo graft-vs-host disease of the skin that improved with topical steroids.
Two patients who received VSTs as prophylaxis developed transplant-associated microangiopathy, but the researchers considered this to be unrelated to VST infusion.
They noted that this is the first time BKV and HHV6 reactivations have been controlled using VSTs. Dr Leen’s team had previously reported promising results with VSTs targeting EBV, CMV, and ADV.
“This study translated improved manufacturing techniques developed in Dr Leen’s laboratory to the clinic and showed that virus-specific T cells produced with the new method could target new viruses and be ready for clinical use after 10 days,” said Helen Heslop, MD, also of Baylor College of Medicine.
“These advances mean that this therapy could be available for more patients to treat viral infections and provide long-lasting protection.”
System can attenuate thrombin generation
Credit: Kevin MacKenzie
Results of a phase 1 trial suggest the REG2 anticoagulation system can attenuate thrombin generation and then restore thrombin following reversal.
The REG2 system consists of pegnivacogin, a subcutaneously administered aptamer factor IXa inhibitor, and its intravenous active control agent, anivamersen.
REG2 is formulated to provide a controllable level of anticoagulation for up to 2 weeks for sub-acute uses, especially in cases where a patient may be unable to swallow an oral anticoagulant.
Results observed with REG2 were published in the Journal of Thrombosis and Thrombolysis. The study was sponsored by Regado Biosciences, Inc, the company developing the REG2 system.
The study included 32 healthy volunteers who were enrolled sequentially into 4 cohorts. Patients in cohorts 1-3 were randomized (3:1) to ascending doses of pegnivacogin—from 0.5 mg/kg to 3 mg/kg—or placebo, with no anivamersen administered.
In cohort 4, all patients received 2 mg/kg of pegnivacogin and were randomized (1:1) to reversal by 1 dose or multiple doses over time of 1 mg/kg of anivamersen.
The researchers drew blood samples in the presence or absence of corn trypsin inhibitor at specified times within each dosing cohort. They initiated thrombin generation with tissue factor and measured thrombin generation kinetics using the calibrated automated thrombogram (CAT).
The team found that REG2 attenuated thrombin generation in a dose-dependent manner. All parameters of the CAT assay, except for lag time, showed a dose- and concentration-dependent response to pegnivacogin.
Specifically, there was a decrease in velocity index (VIx) from baseline to 24 hours after pegnivacogin administration. The largest percent change in VIx was in cohort 3 (3 mg/kg). There was a 90% decrease at 24 hours post-dose. This remained stable up to 48 hours in cohort 1 and up to 96 hours in cohorts 2 and 3.
Similarly, mean peak thrombin generation (PTG) values decreased as pegnivacogin dose and plasma concentrations increased. Cohort 3 had an 80% decrease in PTG at 24 hours post-dose. The percent change in mean PTG was consistent and preserved for at least 24 hours for all pegnivacogin doses. In cohorts 2 and 3, it was stable for at least 96 hours.
Endogenous thrombin potential (ETP) levels also decreased after pegnivacogin administration. Again, the largest decrease occurred in cohort 3, which exhibited a 65% decrease at 24 hours. Beyond that, the percent change in ETP was stable within each dose group, up to the last recorded measurement at 96 hours.
Peak time (PTm) was positively correlated with pegnivacogin concentration and relative activated partial thromboplastin time values. The correlation between PTm and quartile of pegnivacogin concentration was statistically significant (P=0.04) but weaker than that of ETP (P=0.001), PTG (P<0.001), or VIx (P<0.001). The changes in PTm persisted for at least 96 hours after pegnivacogin administration.
Finally, the researchers found that anivamersen reversed the effects of pegnivacogin, restoring thrombin generation without rebound effect.
Credit: Kevin MacKenzie
Results of a phase 1 trial suggest the REG2 anticoagulation system can attenuate thrombin generation and then restore thrombin following reversal.
The REG2 system consists of pegnivacogin, a subcutaneously administered aptamer factor IXa inhibitor, and its intravenous active control agent, anivamersen.
REG2 is formulated to provide a controllable level of anticoagulation for up to 2 weeks for sub-acute uses, especially in cases where a patient may be unable to swallow an oral anticoagulant.
Results observed with REG2 were published in the Journal of Thrombosis and Thrombolysis. The study was sponsored by Regado Biosciences, Inc, the company developing the REG2 system.
The study included 32 healthy volunteers who were enrolled sequentially into 4 cohorts. Patients in cohorts 1-3 were randomized (3:1) to ascending doses of pegnivacogin—from 0.5 mg/kg to 3 mg/kg—or placebo, with no anivamersen administered.
In cohort 4, all patients received 2 mg/kg of pegnivacogin and were randomized (1:1) to reversal by 1 dose or multiple doses over time of 1 mg/kg of anivamersen.
The researchers drew blood samples in the presence or absence of corn trypsin inhibitor at specified times within each dosing cohort. They initiated thrombin generation with tissue factor and measured thrombin generation kinetics using the calibrated automated thrombogram (CAT).
The team found that REG2 attenuated thrombin generation in a dose-dependent manner. All parameters of the CAT assay, except for lag time, showed a dose- and concentration-dependent response to pegnivacogin.
Specifically, there was a decrease in velocity index (VIx) from baseline to 24 hours after pegnivacogin administration. The largest percent change in VIx was in cohort 3 (3 mg/kg). There was a 90% decrease at 24 hours post-dose. This remained stable up to 48 hours in cohort 1 and up to 96 hours in cohorts 2 and 3.
Similarly, mean peak thrombin generation (PTG) values decreased as pegnivacogin dose and plasma concentrations increased. Cohort 3 had an 80% decrease in PTG at 24 hours post-dose. The percent change in mean PTG was consistent and preserved for at least 24 hours for all pegnivacogin doses. In cohorts 2 and 3, it was stable for at least 96 hours.
Endogenous thrombin potential (ETP) levels also decreased after pegnivacogin administration. Again, the largest decrease occurred in cohort 3, which exhibited a 65% decrease at 24 hours. Beyond that, the percent change in ETP was stable within each dose group, up to the last recorded measurement at 96 hours.
Peak time (PTm) was positively correlated with pegnivacogin concentration and relative activated partial thromboplastin time values. The correlation between PTm and quartile of pegnivacogin concentration was statistically significant (P=0.04) but weaker than that of ETP (P=0.001), PTG (P<0.001), or VIx (P<0.001). The changes in PTm persisted for at least 96 hours after pegnivacogin administration.
Finally, the researchers found that anivamersen reversed the effects of pegnivacogin, restoring thrombin generation without rebound effect.
Credit: Kevin MacKenzie
Results of a phase 1 trial suggest the REG2 anticoagulation system can attenuate thrombin generation and then restore thrombin following reversal.
The REG2 system consists of pegnivacogin, a subcutaneously administered aptamer factor IXa inhibitor, and its intravenous active control agent, anivamersen.
REG2 is formulated to provide a controllable level of anticoagulation for up to 2 weeks for sub-acute uses, especially in cases where a patient may be unable to swallow an oral anticoagulant.
Results observed with REG2 were published in the Journal of Thrombosis and Thrombolysis. The study was sponsored by Regado Biosciences, Inc, the company developing the REG2 system.
The study included 32 healthy volunteers who were enrolled sequentially into 4 cohorts. Patients in cohorts 1-3 were randomized (3:1) to ascending doses of pegnivacogin—from 0.5 mg/kg to 3 mg/kg—or placebo, with no anivamersen administered.
In cohort 4, all patients received 2 mg/kg of pegnivacogin and were randomized (1:1) to reversal by 1 dose or multiple doses over time of 1 mg/kg of anivamersen.
The researchers drew blood samples in the presence or absence of corn trypsin inhibitor at specified times within each dosing cohort. They initiated thrombin generation with tissue factor and measured thrombin generation kinetics using the calibrated automated thrombogram (CAT).
The team found that REG2 attenuated thrombin generation in a dose-dependent manner. All parameters of the CAT assay, except for lag time, showed a dose- and concentration-dependent response to pegnivacogin.
Specifically, there was a decrease in velocity index (VIx) from baseline to 24 hours after pegnivacogin administration. The largest percent change in VIx was in cohort 3 (3 mg/kg). There was a 90% decrease at 24 hours post-dose. This remained stable up to 48 hours in cohort 1 and up to 96 hours in cohorts 2 and 3.
Similarly, mean peak thrombin generation (PTG) values decreased as pegnivacogin dose and plasma concentrations increased. Cohort 3 had an 80% decrease in PTG at 24 hours post-dose. The percent change in mean PTG was consistent and preserved for at least 24 hours for all pegnivacogin doses. In cohorts 2 and 3, it was stable for at least 96 hours.
Endogenous thrombin potential (ETP) levels also decreased after pegnivacogin administration. Again, the largest decrease occurred in cohort 3, which exhibited a 65% decrease at 24 hours. Beyond that, the percent change in ETP was stable within each dose group, up to the last recorded measurement at 96 hours.
Peak time (PTm) was positively correlated with pegnivacogin concentration and relative activated partial thromboplastin time values. The correlation between PTm and quartile of pegnivacogin concentration was statistically significant (P=0.04) but weaker than that of ETP (P=0.001), PTG (P<0.001), or VIx (P<0.001). The changes in PTm persisted for at least 96 hours after pegnivacogin administration.
Finally, the researchers found that anivamersen reversed the effects of pegnivacogin, restoring thrombin generation without rebound effect.
Study reveals new risk factors for bloodstream infections
Current guidelines to help prevent bloodstream infections during intravenous feeding may need revisions to strengthen protection for patients, a new study suggests.
These guidelines restrict how long a single bag of parenteral nutrition containing lipids can be used, due to the ability of lipids to encourage the growth of microorganisms.
But researchers found the guidelines do not account for other independent factors that can affect the growth of potentially deadly microorganisms.
Their findings appear in the Journal of Parenteral and Enteral Nutrition.
Peter David Austin, of the University of Southampton in the UK, and his colleagues looked at the growth of Escherichia coli and Enterococcus durans in parenteral nutrition to identify factors that can affect microbial growth.
They assessed the growth of E coli and E durans in quadruplicate in 12 different patients who received parenteral nutrition, with and without lipid, in varying glucose concentrations.
Results showed that glucose concentration, the proportion of glucose to lipid, and osmolarity all affected microbial growth, in addition to the presence of lipids.
The researchers therefore recommend these additional factors be considered when making clinical and policy decisions to limit the potential growth of microorganisms in parenteral nutrition.
Current guidelines to help prevent bloodstream infections during intravenous feeding may need revisions to strengthen protection for patients, a new study suggests.
These guidelines restrict how long a single bag of parenteral nutrition containing lipids can be used, due to the ability of lipids to encourage the growth of microorganisms.
But researchers found the guidelines do not account for other independent factors that can affect the growth of potentially deadly microorganisms.
Their findings appear in the Journal of Parenteral and Enteral Nutrition.
Peter David Austin, of the University of Southampton in the UK, and his colleagues looked at the growth of Escherichia coli and Enterococcus durans in parenteral nutrition to identify factors that can affect microbial growth.
They assessed the growth of E coli and E durans in quadruplicate in 12 different patients who received parenteral nutrition, with and without lipid, in varying glucose concentrations.
Results showed that glucose concentration, the proportion of glucose to lipid, and osmolarity all affected microbial growth, in addition to the presence of lipids.
The researchers therefore recommend these additional factors be considered when making clinical and policy decisions to limit the potential growth of microorganisms in parenteral nutrition.
Current guidelines to help prevent bloodstream infections during intravenous feeding may need revisions to strengthen protection for patients, a new study suggests.
These guidelines restrict how long a single bag of parenteral nutrition containing lipids can be used, due to the ability of lipids to encourage the growth of microorganisms.
But researchers found the guidelines do not account for other independent factors that can affect the growth of potentially deadly microorganisms.
Their findings appear in the Journal of Parenteral and Enteral Nutrition.
Peter David Austin, of the University of Southampton in the UK, and his colleagues looked at the growth of Escherichia coli and Enterococcus durans in parenteral nutrition to identify factors that can affect microbial growth.
They assessed the growth of E coli and E durans in quadruplicate in 12 different patients who received parenteral nutrition, with and without lipid, in varying glucose concentrations.
Results showed that glucose concentration, the proportion of glucose to lipid, and osmolarity all affected microbial growth, in addition to the presence of lipids.
The researchers therefore recommend these additional factors be considered when making clinical and policy decisions to limit the potential growth of microorganisms in parenteral nutrition.
Group finds master regulator of MYC
Credit: Juha Klefstrom
New research indicates that an unexpected partnership between the MYC oncogene and a non-coding RNA called PVT1 could be the key to understanding how MYC fuels cancers.
The researchers knew that MYC amplifications cause cancer, but MYC does not amplify alone. It often pairs with adjacent chromosomal regions.
“We wanted to know if the neighboring genes played a role,” said study author Anindya Bagchi, PhD, of the University of Minnesota in Minneapolis.
“We took a chance and were surprised to find this unexpected and counter-intuitive partnership between MYC and its neighbor, PVT1. Not only do these genes amplify together, PVT1 helps boost the MYC protein’s ability to carry out its dangerous activities in the cell.”
The researchers reported this finding in Nature.
Dr Bagchi and his team focused on a region of the genome, 8q24, which contains the MYC gene and is commonly expressed in cancer. The team separated MYC from the neighboring region containing the non-coding RNA PVT1.
Using chromosome engineering, the researchers developed mouse strains in 3 separate iterations: MYC only, the rest of the region containing PVT1 but without MYC, and the pairing of MYC with the regional genes.
The expected outcome, if MYC was the sole driver of the cancer, was tumor growth on the MYC line as well as the paired line. However, the researchers found growth only on the paired line. This suggests MYC is not acting alone and needs help from adjacent genes.
“The discovery of this partnership gives us a stronger understanding of how MYC amplification is fueled,” said David Largaespada, PhD, also of the University of Minnesota.
“When cancer promotes a cell to make more MYC, it also increases the PVT1 in the cell, which, in turn, boosts the amount of MYC. It’s a cycle, and now we’ve identified it, we can look for ways to uncouple this dangerous partnership.”
Testing this theory of uncoupling, the researchers looked closely at several breast and colorectal cancers that are driven by MYC. For example, in colorectal cancer lab models, where a mutation in the beta-catenin gene drives MYC to cancerous levels, eliminating PVT1 from these cells made the tumors nearly disappear.
“Finding the cooperation between MYC and PVT1 could be a game changer,” said Yuen-Yi Tseng, a graduate student at the University of Minnesota.
“We used to think MYC amplification is the major issue but ignored that other co-amplified genes, such as PVT1, can be significant. In this study, we show that PVT1 can be a key regulator of MYC protein, which can shift the paradigm in our understanding of MYC-amplified cancers.”
MYC has been notoriously elusive as a drug target. By uncoupling MYC and PVT1, the researchers suspect they could disable the cancer growth and limit MYC to precancerous levels. This would make PVT1 an ideal drug target to potentially control a major cancer gene.
“This is a thrilling discovery, but there are more questions that follow,” Dr Bagchi said. “Two major areas present themselves now for research. Will breaking the nexus between MYC and PVT1 perform the same in any MYC-driven cancer, even those not driven by this specific genetic location?”
“And how is PVT1 stabilizing or boosting MYC within the cells? This relationship will be a key to developing any drugs to target this mechanism.”
Credit: Juha Klefstrom
New research indicates that an unexpected partnership between the MYC oncogene and a non-coding RNA called PVT1 could be the key to understanding how MYC fuels cancers.
The researchers knew that MYC amplifications cause cancer, but MYC does not amplify alone. It often pairs with adjacent chromosomal regions.
“We wanted to know if the neighboring genes played a role,” said study author Anindya Bagchi, PhD, of the University of Minnesota in Minneapolis.
“We took a chance and were surprised to find this unexpected and counter-intuitive partnership between MYC and its neighbor, PVT1. Not only do these genes amplify together, PVT1 helps boost the MYC protein’s ability to carry out its dangerous activities in the cell.”
The researchers reported this finding in Nature.
Dr Bagchi and his team focused on a region of the genome, 8q24, which contains the MYC gene and is commonly expressed in cancer. The team separated MYC from the neighboring region containing the non-coding RNA PVT1.
Using chromosome engineering, the researchers developed mouse strains in 3 separate iterations: MYC only, the rest of the region containing PVT1 but without MYC, and the pairing of MYC with the regional genes.
The expected outcome, if MYC was the sole driver of the cancer, was tumor growth on the MYC line as well as the paired line. However, the researchers found growth only on the paired line. This suggests MYC is not acting alone and needs help from adjacent genes.
“The discovery of this partnership gives us a stronger understanding of how MYC amplification is fueled,” said David Largaespada, PhD, also of the University of Minnesota.
“When cancer promotes a cell to make more MYC, it also increases the PVT1 in the cell, which, in turn, boosts the amount of MYC. It’s a cycle, and now we’ve identified it, we can look for ways to uncouple this dangerous partnership.”
Testing this theory of uncoupling, the researchers looked closely at several breast and colorectal cancers that are driven by MYC. For example, in colorectal cancer lab models, where a mutation in the beta-catenin gene drives MYC to cancerous levels, eliminating PVT1 from these cells made the tumors nearly disappear.
“Finding the cooperation between MYC and PVT1 could be a game changer,” said Yuen-Yi Tseng, a graduate student at the University of Minnesota.
“We used to think MYC amplification is the major issue but ignored that other co-amplified genes, such as PVT1, can be significant. In this study, we show that PVT1 can be a key regulator of MYC protein, which can shift the paradigm in our understanding of MYC-amplified cancers.”
MYC has been notoriously elusive as a drug target. By uncoupling MYC and PVT1, the researchers suspect they could disable the cancer growth and limit MYC to precancerous levels. This would make PVT1 an ideal drug target to potentially control a major cancer gene.
“This is a thrilling discovery, but there are more questions that follow,” Dr Bagchi said. “Two major areas present themselves now for research. Will breaking the nexus between MYC and PVT1 perform the same in any MYC-driven cancer, even those not driven by this specific genetic location?”
“And how is PVT1 stabilizing or boosting MYC within the cells? This relationship will be a key to developing any drugs to target this mechanism.”
Credit: Juha Klefstrom
New research indicates that an unexpected partnership between the MYC oncogene and a non-coding RNA called PVT1 could be the key to understanding how MYC fuels cancers.
The researchers knew that MYC amplifications cause cancer, but MYC does not amplify alone. It often pairs with adjacent chromosomal regions.
“We wanted to know if the neighboring genes played a role,” said study author Anindya Bagchi, PhD, of the University of Minnesota in Minneapolis.
“We took a chance and were surprised to find this unexpected and counter-intuitive partnership between MYC and its neighbor, PVT1. Not only do these genes amplify together, PVT1 helps boost the MYC protein’s ability to carry out its dangerous activities in the cell.”
The researchers reported this finding in Nature.
Dr Bagchi and his team focused on a region of the genome, 8q24, which contains the MYC gene and is commonly expressed in cancer. The team separated MYC from the neighboring region containing the non-coding RNA PVT1.
Using chromosome engineering, the researchers developed mouse strains in 3 separate iterations: MYC only, the rest of the region containing PVT1 but without MYC, and the pairing of MYC with the regional genes.
The expected outcome, if MYC was the sole driver of the cancer, was tumor growth on the MYC line as well as the paired line. However, the researchers found growth only on the paired line. This suggests MYC is not acting alone and needs help from adjacent genes.
“The discovery of this partnership gives us a stronger understanding of how MYC amplification is fueled,” said David Largaespada, PhD, also of the University of Minnesota.
“When cancer promotes a cell to make more MYC, it also increases the PVT1 in the cell, which, in turn, boosts the amount of MYC. It’s a cycle, and now we’ve identified it, we can look for ways to uncouple this dangerous partnership.”
Testing this theory of uncoupling, the researchers looked closely at several breast and colorectal cancers that are driven by MYC. For example, in colorectal cancer lab models, where a mutation in the beta-catenin gene drives MYC to cancerous levels, eliminating PVT1 from these cells made the tumors nearly disappear.
“Finding the cooperation between MYC and PVT1 could be a game changer,” said Yuen-Yi Tseng, a graduate student at the University of Minnesota.
“We used to think MYC amplification is the major issue but ignored that other co-amplified genes, such as PVT1, can be significant. In this study, we show that PVT1 can be a key regulator of MYC protein, which can shift the paradigm in our understanding of MYC-amplified cancers.”
MYC has been notoriously elusive as a drug target. By uncoupling MYC and PVT1, the researchers suspect they could disable the cancer growth and limit MYC to precancerous levels. This would make PVT1 an ideal drug target to potentially control a major cancer gene.
“This is a thrilling discovery, but there are more questions that follow,” Dr Bagchi said. “Two major areas present themselves now for research. Will breaking the nexus between MYC and PVT1 perform the same in any MYC-driven cancer, even those not driven by this specific genetic location?”
“And how is PVT1 stabilizing or boosting MYC within the cells? This relationship will be a key to developing any drugs to target this mechanism.”
BEST PRACTICES IN: In Atopic Dermatitis
Medical Education Library
A Best Practices Supplement to Skin & Allergy News®. This supplement was sponsored by Valeant Pharmaceuticals North America LLC.
- Introduction
- Treatment with ELIDEL ® (pimecrolimus) Cream 1%
- IMPORTANT SAFETY INFORMATION
Faculty/Faculty Disclosure
Dr. Adelaide A. Hebert, MD
University of Texas Medical School at Houston
Houston, Texas
Dr. Hebert reported that she has served as a consultant and speaker for Astellas Pharma US, Inc.; Novartis Pharmaceuticals Corporation; and Valeant Pharmaceuticals, North America, LLC. Her employer, the University of Texas Health Sciences Center-Houston has received grant funding for research conducted by Dr. Hebert for Astellas and Novartis.
Copyright © by Frontline Medical Communications Inc.
Medical Education Library
A Best Practices Supplement to Skin & Allergy News®. This supplement was sponsored by Valeant Pharmaceuticals North America LLC.
- Introduction
- Treatment with ELIDEL ® (pimecrolimus) Cream 1%
- IMPORTANT SAFETY INFORMATION
Faculty/Faculty Disclosure
Dr. Adelaide A. Hebert, MD
University of Texas Medical School at Houston
Houston, Texas
Dr. Hebert reported that she has served as a consultant and speaker for Astellas Pharma US, Inc.; Novartis Pharmaceuticals Corporation; and Valeant Pharmaceuticals, North America, LLC. Her employer, the University of Texas Health Sciences Center-Houston has received grant funding for research conducted by Dr. Hebert for Astellas and Novartis.
Copyright © by Frontline Medical Communications Inc.
Medical Education Library
A Best Practices Supplement to Skin & Allergy News®. This supplement was sponsored by Valeant Pharmaceuticals North America LLC.
- Introduction
- Treatment with ELIDEL ® (pimecrolimus) Cream 1%
- IMPORTANT SAFETY INFORMATION
Faculty/Faculty Disclosure
Dr. Adelaide A. Hebert, MD
University of Texas Medical School at Houston
Houston, Texas
Dr. Hebert reported that she has served as a consultant and speaker for Astellas Pharma US, Inc.; Novartis Pharmaceuticals Corporation; and Valeant Pharmaceuticals, North America, LLC. Her employer, the University of Texas Health Sciences Center-Houston has received grant funding for research conducted by Dr. Hebert for Astellas and Novartis.
Copyright © by Frontline Medical Communications Inc.
