SAN ANTONIO – Although there has been a general decline in transfusion-related anaphylaxis and acute infections over time among hospitalized older adults in the United States, incidence rates for both transfusion-related acute lung injury and transfusion-associated circulatory overload have risen over the last decade, according to researchers from the Food and Drug Administration.

Mikhail Menis, PharmD, an epidemiologist at the FDA Center for Biologics Evaluation and Research (CBER) and colleagues queried large Medicare databases to assess trends in transfusion-related adverse events among adults aged 65 years and older.

The investigators saw “substantially higher risk of all outcomes among immunocompromised beneficiaries, which could be related to higher blood use of all blood components, especially platelets, underlying conditions such as malignancies, and treatments such as chemotherapy or radiation, which need further investigation,” Dr. Menis said at the annual meeting of AABB, the group formerly known as the American Association of Blood Banks.

He reported data from a series of studies on four categories of transfusion-related events that may be life-threatening or fatal: transfusion-related anaphylaxis (TRA), transfusion-related acute lung injury (TRALI), transfusion-associated circulatory overload (TACO), and acute infection following transfusion (AIFT).

For each type of event, the researchers looked at overall incidence and the incidence by immune status, calendar year, blood components transfused, number of units transfused, age, sex, and race.
 

Anaphylaxis (TRA)

TRA may be caused by preformed immunoglobin E (IgE) antibodies to proteins in the plasma in transfused blood products or by preformed IgA antibodies in patients who are likely IgA deficient, Dr. Menis said.

The overall incidence of TRA among 8,833,817 inpatient transfusions stays for elderly beneficiaries from 2012 through 2018 was 7.1 per 100,000 stays. The rate was higher for immunocompromised patients, at 9.6, than it was among nonimmunocompromised patients, at 6.5.

The rates varied by every subgroup measured except immune status. Annual rates showed a downward trend, from 8.7 per 100,000 in 2012, to 5.1 in 2017 and 6.4 in 2018. The decline in occurrence may be caused by a decline in inpatient blood utilization during the study period, particularly among immunocompromised patients.

TRA rates increased with five or more units transfused. The risk was significantly reduced in the oldest group of patients versus the youngest (P less than .001), which supports the immune-based mechanism of action of anaphylaxis, Dr. Menis said.

They also found that TRA rates were substantially higher among patients who had received platelet and/or plasma transfusions, compared with patients who received only red blood cells (RBCs).

Additionally, risk for TRA was significantly higher among men than it was among women (9.3 vs. 5.4) and among white versus nonwhite patients (7.8 vs. 3.8).

The evidence suggested TRA cases are likely to be severe in this population, with inpatient mortality of 7.1%, and hospital stays of 7 days or longer in about 58% of cases, indicating the importance of TRA prevention, Dr. Menis said.

The investigators plan to perform multivariate regression analyses to assess potential risk factors, including underlying comorbidities and health histories for TRA occurrence for both the overall population and by immune status.
 

Acute lung injury (TRALI)

TRALI is a rare but serious adverse event, a clinical syndrome with onset within 6 hours of transfusion that presents as acute hypoxemia, respiratory distress, and noncardiogenic pulmonary edema.

Among 17,771,193 total inpatient transfusion stays, the overall incidence of TRALI was 33.2 per 100,000. The rate was 55.9 for immunocompromised patients versus 28.4 for nonimmunocompromised patients. The rate ratio was 2.0 (P less than .001).

The difference by immune status may be caused by higher blood utilizations with more units transfused per stay among immunocompromised patients, a higher incidence of prior transfusions among these patients, higher use of irradiated blood components that may lead to accumulation of proinflammatory mediators in blood products during storage, or underlying comorbidities.

The overall rate increased from 14.3 in 2007 to 56.4 in 2018. The rates increased proportionally among both immunocompromised and nonimmunocompromised patients.

As with TRA, the incidence of TRALI was higher in patients with five or more units transfused, while the incidence declined with age, likely caused by declining blood use and age-related changes in neutrophil function, Dr. Menis said.

TRALI rates were slightly higher among men than among women, as well as higher among white patients than among nonwhite patients.

Overall, TRALI rates were higher for patients who received platelets either alone or in combination with RBCs and/or plasma. The highest rates were among patients who received RBCs, plasma and platelets.

Dr. Menis called for studies to determine what effects the processing and storage of blood components may have on TRALI occurrence; he and his colleagues also are planning regression analyses to assess potential risk factors for this complication.
 

Circulatory overload (TACO)

TACO is one of the leading reported causes of transfusion-related fatalities in the U.S., with onset usually occurring within 6 hours of transfusion, presenting as acute respiratory distress with dyspnea, orthopnea, increased blood pressure, and cardiogenic pulmonary edema.

The overall incidence of TACO among hospitalized patients aged 65 years and older from 2011 through 2018 was 86.3 per 100,000 stays. The incidences were 128.3 in immunocompromised and 76.0 in nonimmunocompromised patients. The rate ratio for TACO in immunocompromised versus nonimmunocompromised patients was 1.70 (P less than .001).

Overall incidence rates of TACO rose from 62 per 100,000 stays in 2011 to 119.8 in 2018. As with other adverse events, incident rates rose with the number of units transfused.

Rates of TACO were significantly higher among women than they were among men (94.6 vs. 75.9 per 100,000; P less than .001), which could be caused by the higher mean age of women and/or a lower tolerance for increased blood volume from transfusion.

The study results also suggested that TACO and TRALI may coexist, based on evidence that 3.5% of all TACO stays also had diagnostic codes for TRALI. The frequency of co-occurrence of these two adverse events also increased over time, which may be caused by improved awareness, Dr. Menis said.
 

Infections (AIFT)

Acute infections following transfusion can lead to prolonged hospitalizations, sepsis, septic shock, and death. Those most at risk include elderly and immunocompromised patients because of high utilization of blood products, comorbidities, and decreased immune function.

Among 8,833,817 stays, the overall rate per 100,000 stays was 2.1. The rate for immunocompromised patients was 5.4, compared with 1.2 for nonimmunocompromised patients, for a rate ratio of 4.4 (P less than .001).

The incidence rate declined significantly (P = .03) over the study period, with the 3 latest years having the lowest rates.

Rates increased substantially among immunocompromised patients by the number of units transfused, but remained relatively stable among nonimmunocompromised patients.

Infection rates declined with age, from 2.7 per 100,000 stays for patients aged 65-68 years to 1.2 per 100,000 for those aged 85 years and older.

As with other adverse events, AIFT rates were likely related to the blood components transfused, with substantially higher rates for stays during which platelets were transfused either alone or with RBCs, compared with RBCs alone. This could be caused by the room-temperature storage of platelets and higher number of platelets units transfused, compared with RBCs alone, especially among immunocompromised patients.

In all, 51.9% of AIFT cases also had sepsis noted in the medical record, indicating high severity and emphasizing the importance of AIFT prevention, Dr. Menis said.

The studies were funded by the FDA, and Dr. Menis is an FDA employee. He reported having no conflicts of interest.

SAN ANTONIO – Although there has been a general decline in transfusion-related anaphylaxis and acute infections over time among hospitalized older adults in the United States, incidence rates for both transfusion-related acute lung injury and transfusion-associated circulatory overload have risen over the last decade, according to researchers from the Food and Drug Administration.

Mikhail Menis, PharmD, an epidemiologist at the FDA Center for Biologics Evaluation and Research (CBER) and colleagues queried large Medicare databases to assess trends in transfusion-related adverse events among adults aged 65 years and older.

The investigators saw “substantially higher risk of all outcomes among immunocompromised beneficiaries, which could be related to higher blood use of all blood components, especially platelets, underlying conditions such as malignancies, and treatments such as chemotherapy or radiation, which need further investigation,” Dr. Menis said at the annual meeting of AABB, the group formerly known as the American Association of Blood Banks.

He reported data from a series of studies on four categories of transfusion-related events that may be life-threatening or fatal: transfusion-related anaphylaxis (TRA), transfusion-related acute lung injury (TRALI), transfusion-associated circulatory overload (TACO), and acute infection following transfusion (AIFT).

For each type of event, the researchers looked at overall incidence and the incidence by immune status, calendar year, blood components transfused, number of units transfused, age, sex, and race.
 

Anaphylaxis (TRA)

TRA may be caused by preformed immunoglobin E (IgE) antibodies to proteins in the plasma in transfused blood products or by preformed IgA antibodies in patients who are likely IgA deficient, Dr. Menis said.

The overall incidence of TRA among 8,833,817 inpatient transfusions stays for elderly beneficiaries from 2012 through 2018 was 7.1 per 100,000 stays. The rate was higher for immunocompromised patients, at 9.6, than it was among nonimmunocompromised patients, at 6.5.

The rates varied by every subgroup measured except immune status. Annual rates showed a downward trend, from 8.7 per 100,000 in 2012, to 5.1 in 2017 and 6.4 in 2018. The decline in occurrence may be caused by a decline in inpatient blood utilization during the study period, particularly among immunocompromised patients.

TRA rates increased with five or more units transfused. The risk was significantly reduced in the oldest group of patients versus the youngest (P less than .001), which supports the immune-based mechanism of action of anaphylaxis, Dr. Menis said.

They also found that TRA rates were substantially higher among patients who had received platelet and/or plasma transfusions, compared with patients who received only red blood cells (RBCs).

Additionally, risk for TRA was significantly higher among men than it was among women (9.3 vs. 5.4) and among white versus nonwhite patients (7.8 vs. 3.8).

The evidence suggested TRA cases are likely to be severe in this population, with inpatient mortality of 7.1%, and hospital stays of 7 days or longer in about 58% of cases, indicating the importance of TRA prevention, Dr. Menis said.

The investigators plan to perform multivariate regression analyses to assess potential risk factors, including underlying comorbidities and health histories for TRA occurrence for both the overall population and by immune status.
 

Acute lung injury (TRALI)

TRALI is a rare but serious adverse event, a clinical syndrome with onset within 6 hours of transfusion that presents as acute hypoxemia, respiratory distress, and noncardiogenic pulmonary edema.

Among 17,771,193 total inpatient transfusion stays, the overall incidence of TRALI was 33.2 per 100,000. The rate was 55.9 for immunocompromised patients versus 28.4 for nonimmunocompromised patients. The rate ratio was 2.0 (P less than .001).

The difference by immune status may be caused by higher blood utilizations with more units transfused per stay among immunocompromised patients, a higher incidence of prior transfusions among these patients, higher use of irradiated blood components that may lead to accumulation of proinflammatory mediators in blood products during storage, or underlying comorbidities.

The overall rate increased from 14.3 in 2007 to 56.4 in 2018. The rates increased proportionally among both immunocompromised and nonimmunocompromised patients.

As with TRA, the incidence of TRALI was higher in patients with five or more units transfused, while the incidence declined with age, likely caused by declining blood use and age-related changes in neutrophil function, Dr. Menis said.

TRALI rates were slightly higher among men than among women, as well as higher among white patients than among nonwhite patients.

Overall, TRALI rates were higher for patients who received platelets either alone or in combination with RBCs and/or plasma. The highest rates were among patients who received RBCs, plasma and platelets.

Dr. Menis called for studies to determine what effects the processing and storage of blood components may have on TRALI occurrence; he and his colleagues also are planning regression analyses to assess potential risk factors for this complication.
 

Circulatory overload (TACO)

TACO is one of the leading reported causes of transfusion-related fatalities in the U.S., with onset usually occurring within 6 hours of transfusion, presenting as acute respiratory distress with dyspnea, orthopnea, increased blood pressure, and cardiogenic pulmonary edema.

The overall incidence of TACO among hospitalized patients aged 65 years and older from 2011 through 2018 was 86.3 per 100,000 stays. The incidences were 128.3 in immunocompromised and 76.0 in nonimmunocompromised patients. The rate ratio for TACO in immunocompromised versus nonimmunocompromised patients was 1.70 (P less than .001).

Overall incidence rates of TACO rose from 62 per 100,000 stays in 2011 to 119.8 in 2018. As with other adverse events, incident rates rose with the number of units transfused.

Rates of TACO were significantly higher among women than they were among men (94.6 vs. 75.9 per 100,000; P less than .001), which could be caused by the higher mean age of women and/or a lower tolerance for increased blood volume from transfusion.

The study results also suggested that TACO and TRALI may coexist, based on evidence that 3.5% of all TACO stays also had diagnostic codes for TRALI. The frequency of co-occurrence of these two adverse events also increased over time, which may be caused by improved awareness, Dr. Menis said.
 

Infections (AIFT)

Acute infections following transfusion can lead to prolonged hospitalizations, sepsis, septic shock, and death. Those most at risk include elderly and immunocompromised patients because of high utilization of blood products, comorbidities, and decreased immune function.

Among 8,833,817 stays, the overall rate per 100,000 stays was 2.1. The rate for immunocompromised patients was 5.4, compared with 1.2 for nonimmunocompromised patients, for a rate ratio of 4.4 (P less than .001).

The incidence rate declined significantly (P = .03) over the study period, with the 3 latest years having the lowest rates.

Rates increased substantially among immunocompromised patients by the number of units transfused, but remained relatively stable among nonimmunocompromised patients.

Infection rates declined with age, from 2.7 per 100,000 stays for patients aged 65-68 years to 1.2 per 100,000 for those aged 85 years and older.

As with other adverse events, AIFT rates were likely related to the blood components transfused, with substantially higher rates for stays during which platelets were transfused either alone or with RBCs, compared with RBCs alone. This could be caused by the room-temperature storage of platelets and higher number of platelets units transfused, compared with RBCs alone, especially among immunocompromised patients.

In all, 51.9% of AIFT cases also had sepsis noted in the medical record, indicating high severity and emphasizing the importance of AIFT prevention, Dr. Menis said.

The studies were funded by the FDA, and Dr. Menis is an FDA employee. He reported having no conflicts of interest.

SAN ANTONIO – Although there has been a general decline in transfusion-related anaphylaxis and acute infections over time among hospitalized older adults in the United States, incidence rates for both transfusion-related acute lung injury and transfusion-associated circulatory overload have risen over the last decade, according to researchers from the Food and Drug Administration.

Mikhail Menis, PharmD, an epidemiologist at the FDA Center for Biologics Evaluation and Research (CBER) and colleagues queried large Medicare databases to assess trends in transfusion-related adverse events among adults aged 65 years and older.

The investigators saw “substantially higher risk of all outcomes among immunocompromised beneficiaries, which could be related to higher blood use of all blood components, especially platelets, underlying conditions such as malignancies, and treatments such as chemotherapy or radiation, which need further investigation,” Dr. Menis said at the annual meeting of AABB, the group formerly known as the American Association of Blood Banks.

He reported data from a series of studies on four categories of transfusion-related events that may be life-threatening or fatal: transfusion-related anaphylaxis (TRA), transfusion-related acute lung injury (TRALI), transfusion-associated circulatory overload (TACO), and acute infection following transfusion (AIFT).

For each type of event, the researchers looked at overall incidence and the incidence by immune status, calendar year, blood components transfused, number of units transfused, age, sex, and race.
 

Anaphylaxis (TRA)

TRA may be caused by preformed immunoglobin E (IgE) antibodies to proteins in the plasma in transfused blood products or by preformed IgA antibodies in patients who are likely IgA deficient, Dr. Menis said.

The overall incidence of TRA among 8,833,817 inpatient transfusions stays for elderly beneficiaries from 2012 through 2018 was 7.1 per 100,000 stays. The rate was higher for immunocompromised patients, at 9.6, than it was among nonimmunocompromised patients, at 6.5.

The rates varied by every subgroup measured except immune status. Annual rates showed a downward trend, from 8.7 per 100,000 in 2012, to 5.1 in 2017 and 6.4 in 2018. The decline in occurrence may be caused by a decline in inpatient blood utilization during the study period, particularly among immunocompromised patients.

TRA rates increased with five or more units transfused. The risk was significantly reduced in the oldest group of patients versus the youngest (P less than .001), which supports the immune-based mechanism of action of anaphylaxis, Dr. Menis said.

They also found that TRA rates were substantially higher among patients who had received platelet and/or plasma transfusions, compared with patients who received only red blood cells (RBCs).

Additionally, risk for TRA was significantly higher among men than it was among women (9.3 vs. 5.4) and among white versus nonwhite patients (7.8 vs. 3.8).

The evidence suggested TRA cases are likely to be severe in this population, with inpatient mortality of 7.1%, and hospital stays of 7 days or longer in about 58% of cases, indicating the importance of TRA prevention, Dr. Menis said.

The investigators plan to perform multivariate regression analyses to assess potential risk factors, including underlying comorbidities and health histories for TRA occurrence for both the overall population and by immune status.
 

Acute lung injury (TRALI)

TRALI is a rare but serious adverse event, a clinical syndrome with onset within 6 hours of transfusion that presents as acute hypoxemia, respiratory distress, and noncardiogenic pulmonary edema.

Among 17,771,193 total inpatient transfusion stays, the overall incidence of TRALI was 33.2 per 100,000. The rate was 55.9 for immunocompromised patients versus 28.4 for nonimmunocompromised patients. The rate ratio was 2.0 (P less than .001).

The difference by immune status may be caused by higher blood utilizations with more units transfused per stay among immunocompromised patients, a higher incidence of prior transfusions among these patients, higher use of irradiated blood components that may lead to accumulation of proinflammatory mediators in blood products during storage, or underlying comorbidities.

The overall rate increased from 14.3 in 2007 to 56.4 in 2018. The rates increased proportionally among both immunocompromised and nonimmunocompromised patients.

As with TRA, the incidence of TRALI was higher in patients with five or more units transfused, while the incidence declined with age, likely caused by declining blood use and age-related changes in neutrophil function, Dr. Menis said.

TRALI rates were slightly higher among men than among women, as well as higher among white patients than among nonwhite patients.

Overall, TRALI rates were higher for patients who received platelets either alone or in combination with RBCs and/or plasma. The highest rates were among patients who received RBCs, plasma and platelets.

Dr. Menis called for studies to determine what effects the processing and storage of blood components may have on TRALI occurrence; he and his colleagues also are planning regression analyses to assess potential risk factors for this complication.
 

Circulatory overload (TACO)

TACO is one of the leading reported causes of transfusion-related fatalities in the U.S., with onset usually occurring within 6 hours of transfusion, presenting as acute respiratory distress with dyspnea, orthopnea, increased blood pressure, and cardiogenic pulmonary edema.

The overall incidence of TACO among hospitalized patients aged 65 years and older from 2011 through 2018 was 86.3 per 100,000 stays. The incidences were 128.3 in immunocompromised and 76.0 in nonimmunocompromised patients. The rate ratio for TACO in immunocompromised versus nonimmunocompromised patients was 1.70 (P less than .001).

Overall incidence rates of TACO rose from 62 per 100,000 stays in 2011 to 119.8 in 2018. As with other adverse events, incident rates rose with the number of units transfused.

Rates of TACO were significantly higher among women than they were among men (94.6 vs. 75.9 per 100,000; P less than .001), which could be caused by the higher mean age of women and/or a lower tolerance for increased blood volume from transfusion.

The study results also suggested that TACO and TRALI may coexist, based on evidence that 3.5% of all TACO stays also had diagnostic codes for TRALI. The frequency of co-occurrence of these two adverse events also increased over time, which may be caused by improved awareness, Dr. Menis said.
 

Infections (AIFT)

Acute infections following transfusion can lead to prolonged hospitalizations, sepsis, septic shock, and death. Those most at risk include elderly and immunocompromised patients because of high utilization of blood products, comorbidities, and decreased immune function.

Among 8,833,817 stays, the overall rate per 100,000 stays was 2.1. The rate for immunocompromised patients was 5.4, compared with 1.2 for nonimmunocompromised patients, for a rate ratio of 4.4 (P less than .001).

The incidence rate declined significantly (P = .03) over the study period, with the 3 latest years having the lowest rates.

Rates increased substantially among immunocompromised patients by the number of units transfused, but remained relatively stable among nonimmunocompromised patients.

Infection rates declined with age, from 2.7 per 100,000 stays for patients aged 65-68 years to 1.2 per 100,000 for those aged 85 years and older.

As with other adverse events, AIFT rates were likely related to the blood components transfused, with substantially higher rates for stays during which platelets were transfused either alone or with RBCs, compared with RBCs alone. This could be caused by the room-temperature storage of platelets and higher number of platelets units transfused, compared with RBCs alone, especially among immunocompromised patients.

In all, 51.9% of AIFT cases also had sepsis noted in the medical record, indicating high severity and emphasizing the importance of AIFT prevention, Dr. Menis said.

The studies were funded by the FDA, and Dr. Menis is an FDA employee. He reported having no conflicts of interest.

BOSTON – The combination of nivolumab and ipilimumab provided a “robust” clinical benefit and had manageable hepatic adverse events in a phase 2 study of sorafenib-treated patients with advanced hepatocellular carcinoma (HCC), an investigator said at the annual meeting of the American Association for the Study of Liver Diseases.

Response rates for the combination treatment exceeded 30% in CheckMate 040, with median overall survival approaching 23 months in one arm of this randomized trial, said Bruno Sangro, MD, PhD, of Clinica Universidad de Navarra, Pamplona, Spain.

The combination had a manageable safety profile with no new safety signals, and most immune-mediated adverse events resolved, including hepatic events, Dr. Sango said in an oral abstract session.

“The favorable benefit/risk profile observed we believe warrants further investigation in patients with HCC,” Dr. Sangro said in his presentation to attendees, adding that a phase 3 study of the combination is already ongoing.

On Nov. 11, 2019, Bristol-Myers Squibb announced its application for nivolumab plus ipilimumab for previously treated advanced HCC had been accepted for priority review by the Food and Drug Administration, which had furthermore granted breakthrough therapy designation for that potential indication.

In September 2017, the FDA approved nivolumab as monotherapy for patients with HCC previously treated with sorafenib. That action was based on results from CheckMate 040 showing on overall response rate of 14% and a median overall survival of 15 months, Dr. Sangro said.

The combination of the programmed death–1 inhibitor nivolumab and the CTLA-4 inhibitor ipilimumab, which has shown durable responses in other tumor types, may promote synergistic immune activity in HCC through their distinct but complementary mechanisms, according to the investigator.

The first report on the combination of nivolumab plus ipilimumab in CheckMate 040, reported earlier this year at the annual meeting of the American Society of Clinical Oncology, indicated that the combination produced responses that were robust and durable.

Dr. Sangro reported data on 148 patients with advanced HCC previously treated with sorafenib randomized to one of three different dosing regimens with nivolumab plus ipilimumab.

Response rates ranged from 31% to 32% in the three arms, while one particular dosing regimen given every 3 weeks for four cycles had a median overall survival of 22.8 months.

“Just to give a perspective, let me remind you that patients receiving placebo post sorafenib in a number of phase 3 trials have very consistently shown median overall survivals of around 8 months,” Dr. Sangro told attendees.

Hepatic treatment-related adverse events of any grade reported within 30 days of the last dose were seen in 39% of patients in that arm, Dr. Sangro said.

Hepatic events thought to be immune mediated were typically managed with a short course of high-dose corticosteroids, according to Dr. Sangro, who said no patients rechallenged with treatment experienced a recurrence of the event.

Most of the hepatic adverse events occurred early, with a median time to onset of 5.6-8.1 weeks, he said, and most resolved at a median of 6.1-7.9 weeks.

In the ongoing phase 3 CheckMate 9DW study, patients with advanced HCC who are naive to systemic therapy are being randomized to the combination of nivolumab plus ipilimumab, or to the investigators’ choice of either sorafenib or lenvatinib, with a primary endpoint of overall survival, Dr. Sangro said.

The study was supported by Bristol-Myers Squibb and ONO Pharmaceutical. Dr. Sangro reported disclosures related to Adaptimmune, AstraZeneca, Bayer, Bristol-Myers Squibb, BTG, Merck, Onxeo, Sirtex Medical, Terumo, H3 Biomedicine, Ipsen, Lilly, Exelixis, Roche, and Ipsen.

SOURCE: Sangro B et al. The Liver Meeting 2019, Abstract 200.

BOSTON – The combination of nivolumab and ipilimumab provided a “robust” clinical benefit and had manageable hepatic adverse events in a phase 2 study of sorafenib-treated patients with advanced hepatocellular carcinoma (HCC), an investigator said at the annual meeting of the American Association for the Study of Liver Diseases.

Response rates for the combination treatment exceeded 30% in CheckMate 040, with median overall survival approaching 23 months in one arm of this randomized trial, said Bruno Sangro, MD, PhD, of Clinica Universidad de Navarra, Pamplona, Spain.

The combination had a manageable safety profile with no new safety signals, and most immune-mediated adverse events resolved, including hepatic events, Dr. Sango said in an oral abstract session.

“The favorable benefit/risk profile observed we believe warrants further investigation in patients with HCC,” Dr. Sangro said in his presentation to attendees, adding that a phase 3 study of the combination is already ongoing.

On Nov. 11, 2019, Bristol-Myers Squibb announced its application for nivolumab plus ipilimumab for previously treated advanced HCC had been accepted for priority review by the Food and Drug Administration, which had furthermore granted breakthrough therapy designation for that potential indication.

In September 2017, the FDA approved nivolumab as monotherapy for patients with HCC previously treated with sorafenib. That action was based on results from CheckMate 040 showing on overall response rate of 14% and a median overall survival of 15 months, Dr. Sangro said.

The combination of the programmed death–1 inhibitor nivolumab and the CTLA-4 inhibitor ipilimumab, which has shown durable responses in other tumor types, may promote synergistic immune activity in HCC through their distinct but complementary mechanisms, according to the investigator.

The first report on the combination of nivolumab plus ipilimumab in CheckMate 040, reported earlier this year at the annual meeting of the American Society of Clinical Oncology, indicated that the combination produced responses that were robust and durable.

Dr. Sangro reported data on 148 patients with advanced HCC previously treated with sorafenib randomized to one of three different dosing regimens with nivolumab plus ipilimumab.

Response rates ranged from 31% to 32% in the three arms, while one particular dosing regimen given every 3 weeks for four cycles had a median overall survival of 22.8 months.

“Just to give a perspective, let me remind you that patients receiving placebo post sorafenib in a number of phase 3 trials have very consistently shown median overall survivals of around 8 months,” Dr. Sangro told attendees.

Hepatic treatment-related adverse events of any grade reported within 30 days of the last dose were seen in 39% of patients in that arm, Dr. Sangro said.

Hepatic events thought to be immune mediated were typically managed with a short course of high-dose corticosteroids, according to Dr. Sangro, who said no patients rechallenged with treatment experienced a recurrence of the event.

Most of the hepatic adverse events occurred early, with a median time to onset of 5.6-8.1 weeks, he said, and most resolved at a median of 6.1-7.9 weeks.

In the ongoing phase 3 CheckMate 9DW study, patients with advanced HCC who are naive to systemic therapy are being randomized to the combination of nivolumab plus ipilimumab, or to the investigators’ choice of either sorafenib or lenvatinib, with a primary endpoint of overall survival, Dr. Sangro said.

The study was supported by Bristol-Myers Squibb and ONO Pharmaceutical. Dr. Sangro reported disclosures related to Adaptimmune, AstraZeneca, Bayer, Bristol-Myers Squibb, BTG, Merck, Onxeo, Sirtex Medical, Terumo, H3 Biomedicine, Ipsen, Lilly, Exelixis, Roche, and Ipsen.

SOURCE: Sangro B et al. The Liver Meeting 2019, Abstract 200.

BOSTON – The combination of nivolumab and ipilimumab provided a “robust” clinical benefit and had manageable hepatic adverse events in a phase 2 study of sorafenib-treated patients with advanced hepatocellular carcinoma (HCC), an investigator said at the annual meeting of the American Association for the Study of Liver Diseases.

Response rates for the combination treatment exceeded 30% in CheckMate 040, with median overall survival approaching 23 months in one arm of this randomized trial, said Bruno Sangro, MD, PhD, of Clinica Universidad de Navarra, Pamplona, Spain.

The combination had a manageable safety profile with no new safety signals, and most immune-mediated adverse events resolved, including hepatic events, Dr. Sango said in an oral abstract session.

“The favorable benefit/risk profile observed we believe warrants further investigation in patients with HCC,” Dr. Sangro said in his presentation to attendees, adding that a phase 3 study of the combination is already ongoing.

On Nov. 11, 2019, Bristol-Myers Squibb announced its application for nivolumab plus ipilimumab for previously treated advanced HCC had been accepted for priority review by the Food and Drug Administration, which had furthermore granted breakthrough therapy designation for that potential indication.

In September 2017, the FDA approved nivolumab as monotherapy for patients with HCC previously treated with sorafenib. That action was based on results from CheckMate 040 showing on overall response rate of 14% and a median overall survival of 15 months, Dr. Sangro said.

The combination of the programmed death–1 inhibitor nivolumab and the CTLA-4 inhibitor ipilimumab, which has shown durable responses in other tumor types, may promote synergistic immune activity in HCC through their distinct but complementary mechanisms, according to the investigator.

The first report on the combination of nivolumab plus ipilimumab in CheckMate 040, reported earlier this year at the annual meeting of the American Society of Clinical Oncology, indicated that the combination produced responses that were robust and durable.

Dr. Sangro reported data on 148 patients with advanced HCC previously treated with sorafenib randomized to one of three different dosing regimens with nivolumab plus ipilimumab.

Response rates ranged from 31% to 32% in the three arms, while one particular dosing regimen given every 3 weeks for four cycles had a median overall survival of 22.8 months.

“Just to give a perspective, let me remind you that patients receiving placebo post sorafenib in a number of phase 3 trials have very consistently shown median overall survivals of around 8 months,” Dr. Sangro told attendees.

Hepatic treatment-related adverse events of any grade reported within 30 days of the last dose were seen in 39% of patients in that arm, Dr. Sangro said.

Hepatic events thought to be immune mediated were typically managed with a short course of high-dose corticosteroids, according to Dr. Sangro, who said no patients rechallenged with treatment experienced a recurrence of the event.

Most of the hepatic adverse events occurred early, with a median time to onset of 5.6-8.1 weeks, he said, and most resolved at a median of 6.1-7.9 weeks.

In the ongoing phase 3 CheckMate 9DW study, patients with advanced HCC who are naive to systemic therapy are being randomized to the combination of nivolumab plus ipilimumab, or to the investigators’ choice of either sorafenib or lenvatinib, with a primary endpoint of overall survival, Dr. Sangro said.

The study was supported by Bristol-Myers Squibb and ONO Pharmaceutical. Dr. Sangro reported disclosures related to Adaptimmune, AstraZeneca, Bayer, Bristol-Myers Squibb, BTG, Merck, Onxeo, Sirtex Medical, Terumo, H3 Biomedicine, Ipsen, Lilly, Exelixis, Roche, and Ipsen.

SOURCE: Sangro B et al. The Liver Meeting 2019, Abstract 200.

AUSTIN, TEX. – Neuromuscular complications from immunotherapy for cancer are rare, but they occur often enough that it is helpful to know which ones can result from different immunotherapies and how to distinguish them from non–adverse event conditions, according to Christopher Trevino, MD, a neuro-oncologist at Tulane University in New Orleans.

At the annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine, Dr. Trevino reviewed immunotherapy types, particularly immune checkpoint inhibitors, and the most common neuromuscular complications – primarily neuropathy, myasthenia gravis (MG), myositis, and encephalitis or meningitis.

“Timing of onset is a critical component to assist in identifying immune checkpoint inhibitor–associated versus non–immune checkpoint inhibitor–associated neuromuscular disease,” Dr. Trevino told attendees. Prompt recognition can be particularly urgent for MG because crisis and death rates are higher when induced by immunotherapy and require quick treatment. “Understanding the mechanisms of action sets a foundation for treatment approach,” he added.

Any part of the nervous system can be affected by immunotherapy toxicity, he said, and syndromes often overlap, with the peripheral nervous system typically more often affected than the central nervous system. Neurologic immune-related adverse events typically occur within four cycles of therapy – about 12 weeks after therapy initiation – but should always involve a work-up to exclude effects from the cancer itself, other neuromuscular diagnoses unrelated to therapy, and other toxicities from chemotherapy.

Recommended first-line treatment is halting immunotherapy with or without corticosteroids, after which most patients improve, often with “rapid, complete resolution of symptoms,” Dr. Trevino said. Restarting immunotherapy treatment is possible in some patients, though.
 

CAR T-cell and dendritic cell vaccine therapies

Four main types of immunotherapy exist: viral therapy, vaccine therapy, immune checkpoint inhibitors, and adoptive cell transfer, such as chimeric antigen receptor (CAR) T-cell therapy. Dr. Trevino focused on checkpoint inhibitors and adoptive cell transfer.

CAR T-cell therapy is a multistep treatment process that involves first removing blood from the patient to obtain their T cells. These are used to create and grow CAR T cells in the lab so that they can be infused back into the patient. The cells then bind to cancer cells and destroy them. Examples of approved CAR T-cell therapy include Yescarta (axicabtagene ciloleucel) for some types of non-Hodgkin lymphoma and Kymriah (tisagenlecleucel) for acute lymphoblastic leukemia (ALL).

Dendritic cell vaccines are similar to CAR T-cell therapy in that they also use the patient’s own immune cells to create cancer-killing cells that the patient then receives back. The only currently approved dendritic cell vaccine is Provenge (sipuleucel-T) for advanced prostate cancer.

The main toxicity to watch for from CAR T-cell therapy and dendritic cell vaccines is cytokine release syndrome (CRS). It can begin anywhere from 1-14 days after the infusion and involves T-cell expansion in the body that leads to a cytokine storm. Symptoms are wide ranging, including fatigue, fever, loss of appetite, tachycardia, hypotension, pain, rash, diarrhea, headache, confusion, seizures, muscle and joint pain, tachypnea, hypoxia and hallucinations, among others.

Specific central neurotoxicities that can result from CAR T-cell therapy include encephalopathy, cerebral edema, seizures and status epilepticus, cerebral vasospasm, and aphasia.
 

Immune checkpoint inhibitor toxicities

Immune checkpoint inhibitors are drugs that interrupt a cancer’s ability to hijack the immune system; they block the proteins that hold back T-cells from attacking the cancer, thereby releasing the immune system to go after the malignant cells.

The two most common types of immune checkpoint inhibitors are those targeting the programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) pathways. The three currently approved PD-1 inhibitors are pembrolizumab (Keytruda), nivolumab (Opdivo), and cemiplimab (Libtayo), which can treat nearly a dozen malignancies affecting different organs. Atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi) are the three currently approved PD-L1 inhibitors, indicated for urothelial carcinoma and a handful of other cancers, such as small-cell and non–small cell lung cancer and triple negative breast cancer.

The only other type of approved checkpoint inhibitor is ipilimumab (Yervoy), which targets the CTLA-4 protein. A number of other checkpoint inhibitors are in trials, however, such as ones targeting pathways involving OX40, ICOS, TIM3, and LAG-3 (J Hematol Oncol. 2018. doi: 10.1186/s13045-018-0582-8).

Immune-related adverse events are less common with PD-1 or PD-L1 inhibitors – a rate of 5%-10% – compared with adverse events from CTLA-4 inhibitors, which occur in about 15% of patients. Neurologic complications occur even more rarely – about 1%-4% of all immune checkpoint inhibitor therapies – and primarily include MG, Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), and inflammatory myositis (Muscle Nerve. 2018;58[1]:10-22).

Treatment with multiple checkpoint inhibitors increases the likelihood of severe adverse events, with rates of up to 30%-50% of patients with dual treatment.
 

Distinguishing features of neuromuscular immunotherapy-related adverse events

MG is the most common neuromuscular immune-related adverse event from immune checkpoint inhibitors and tends to occur 3-12 weeks after beginning treatment, frequently comorbid with inflammatory myopathy or cardiomyopathy, Dr. Trevino said. About two-thirds of cases are de novo, while the remaining one-third involve preexisting MG; no reports of Lambert-Eaton myasthenic syndrome have been linked to checkpoint inhibitors.

Several characteristics distinguish checkpoint inhibitor–associated MG from standard MG. Standard MG can be ocular with or without bulbar or appendicular weakness, whereas immunotherapy-related MG is rarely only ocular (about 18% of cases). Immunotherapy-related MG involves an MG crisis at diagnosis in up to 50% of cases and has high mortality, both of which are rarer with standard MG.

While standard MG can be seronegative or involve AChR, MuSK, or LRP4 antibodies, about two-thirds of immunotherapy-related MG cases are positive for AChR antibodies. LRP4 antibodies are rare with MG from checkpoint inhibitors, and no MuSK antibodies have been reported in these cases. Creatine kinase (CK) or troponin I (TnI) elevation occurs in about 87% of patients with checkpoint inhibitor-induced MG, but standard MG doesn’t typically involve increased CK levels.

Inflammatory myositis (IM), the second most common neuromuscular adverse event from immunotherapy, tends to occur 2-15 weeks after immune checkpoint inhibitor therapy and can involve polymyositis, necrotizing autoimmune myopathy, dermatomyositis, granulomatous myositis, or other nonspecific myositis and myopathies.

Though proximal weakness occurs with IM both associated with immunotherapy and not, ocular symptoms are unique to cases associated with therapy and occur in about half of them. Myalgia, dyspnea, and dysphagia can all occur with checkpoint inhibitor–associated IM but don’t generally occur with standard IM. Immunotherapy-related IM is usually seronegative for myositis antibodies and doesn’t generally cause abnormalities in electromyography, compared with increased exertional activity and early recruitment of myopathic motor units in electromyography with standard IM.

GBS and CIDP are the third most common cause of neuromuscular complications from checkpoint inhibitors. The main distinguishing feature of these conditions from those not related to immunotherapy is that they occur anywhere from 4 to 68 weeks after therapy begins. Presentation is otherwise similar whether related to checkpoint inhibitors or not.

Aside from GBS and CIDP, other neuropathies that can result from immunotherapy complications include acute cranial neuropathies, axonal or demyelinating neuropathies, motor polyradiculopathy, vasculitic neuropathy, and plexopathy.

Neuromuscular complications other than those described above can also occur from checkpoint inhibitor therapy, such as enteric neuropathy, polyradiculitis, and meningo-radiculo-neuritis, but these are much rarer.

Four organizations have developed consensus guidelines for immune checkpoint inhibitor toxicities: the European Society for Medical Oncology (ESMO, 2017), Society for Immunotherapy of Cancer (SITC, 2017), American Society of Clinical Oncology (ASCO, 2018), and National Comprehensive Cancer Network (NCCN, 2019).

Dr Trevino had no disclosures.

AUSTIN, TEX. – Neuromuscular complications from immunotherapy for cancer are rare, but they occur often enough that it is helpful to know which ones can result from different immunotherapies and how to distinguish them from non–adverse event conditions, according to Christopher Trevino, MD, a neuro-oncologist at Tulane University in New Orleans.

At the annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine, Dr. Trevino reviewed immunotherapy types, particularly immune checkpoint inhibitors, and the most common neuromuscular complications – primarily neuropathy, myasthenia gravis (MG), myositis, and encephalitis or meningitis.

“Timing of onset is a critical component to assist in identifying immune checkpoint inhibitor–associated versus non–immune checkpoint inhibitor–associated neuromuscular disease,” Dr. Trevino told attendees. Prompt recognition can be particularly urgent for MG because crisis and death rates are higher when induced by immunotherapy and require quick treatment. “Understanding the mechanisms of action sets a foundation for treatment approach,” he added.

Any part of the nervous system can be affected by immunotherapy toxicity, he said, and syndromes often overlap, with the peripheral nervous system typically more often affected than the central nervous system. Neurologic immune-related adverse events typically occur within four cycles of therapy – about 12 weeks after therapy initiation – but should always involve a work-up to exclude effects from the cancer itself, other neuromuscular diagnoses unrelated to therapy, and other toxicities from chemotherapy.

Recommended first-line treatment is halting immunotherapy with or without corticosteroids, after which most patients improve, often with “rapid, complete resolution of symptoms,” Dr. Trevino said. Restarting immunotherapy treatment is possible in some patients, though.
 

CAR T-cell and dendritic cell vaccine therapies

Four main types of immunotherapy exist: viral therapy, vaccine therapy, immune checkpoint inhibitors, and adoptive cell transfer, such as chimeric antigen receptor (CAR) T-cell therapy. Dr. Trevino focused on checkpoint inhibitors and adoptive cell transfer.

CAR T-cell therapy is a multistep treatment process that involves first removing blood from the patient to obtain their T cells. These are used to create and grow CAR T cells in the lab so that they can be infused back into the patient. The cells then bind to cancer cells and destroy them. Examples of approved CAR T-cell therapy include Yescarta (axicabtagene ciloleucel) for some types of non-Hodgkin lymphoma and Kymriah (tisagenlecleucel) for acute lymphoblastic leukemia (ALL).

Dendritic cell vaccines are similar to CAR T-cell therapy in that they also use the patient’s own immune cells to create cancer-killing cells that the patient then receives back. The only currently approved dendritic cell vaccine is Provenge (sipuleucel-T) for advanced prostate cancer.

The main toxicity to watch for from CAR T-cell therapy and dendritic cell vaccines is cytokine release syndrome (CRS). It can begin anywhere from 1-14 days after the infusion and involves T-cell expansion in the body that leads to a cytokine storm. Symptoms are wide ranging, including fatigue, fever, loss of appetite, tachycardia, hypotension, pain, rash, diarrhea, headache, confusion, seizures, muscle and joint pain, tachypnea, hypoxia and hallucinations, among others.

Specific central neurotoxicities that can result from CAR T-cell therapy include encephalopathy, cerebral edema, seizures and status epilepticus, cerebral vasospasm, and aphasia.
 

Immune checkpoint inhibitor toxicities

Immune checkpoint inhibitors are drugs that interrupt a cancer’s ability to hijack the immune system; they block the proteins that hold back T-cells from attacking the cancer, thereby releasing the immune system to go after the malignant cells.

The two most common types of immune checkpoint inhibitors are those targeting the programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) pathways. The three currently approved PD-1 inhibitors are pembrolizumab (Keytruda), nivolumab (Opdivo), and cemiplimab (Libtayo), which can treat nearly a dozen malignancies affecting different organs. Atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi) are the three currently approved PD-L1 inhibitors, indicated for urothelial carcinoma and a handful of other cancers, such as small-cell and non–small cell lung cancer and triple negative breast cancer.

The only other type of approved checkpoint inhibitor is ipilimumab (Yervoy), which targets the CTLA-4 protein. A number of other checkpoint inhibitors are in trials, however, such as ones targeting pathways involving OX40, ICOS, TIM3, and LAG-3 (J Hematol Oncol. 2018. doi: 10.1186/s13045-018-0582-8).

Immune-related adverse events are less common with PD-1 or PD-L1 inhibitors – a rate of 5%-10% – compared with adverse events from CTLA-4 inhibitors, which occur in about 15% of patients. Neurologic complications occur even more rarely – about 1%-4% of all immune checkpoint inhibitor therapies – and primarily include MG, Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), and inflammatory myositis (Muscle Nerve. 2018;58[1]:10-22).

Treatment with multiple checkpoint inhibitors increases the likelihood of severe adverse events, with rates of up to 30%-50% of patients with dual treatment.
 

Distinguishing features of neuromuscular immunotherapy-related adverse events

MG is the most common neuromuscular immune-related adverse event from immune checkpoint inhibitors and tends to occur 3-12 weeks after beginning treatment, frequently comorbid with inflammatory myopathy or cardiomyopathy, Dr. Trevino said. About two-thirds of cases are de novo, while the remaining one-third involve preexisting MG; no reports of Lambert-Eaton myasthenic syndrome have been linked to checkpoint inhibitors.

Several characteristics distinguish checkpoint inhibitor–associated MG from standard MG. Standard MG can be ocular with or without bulbar or appendicular weakness, whereas immunotherapy-related MG is rarely only ocular (about 18% of cases). Immunotherapy-related MG involves an MG crisis at diagnosis in up to 50% of cases and has high mortality, both of which are rarer with standard MG.

While standard MG can be seronegative or involve AChR, MuSK, or LRP4 antibodies, about two-thirds of immunotherapy-related MG cases are positive for AChR antibodies. LRP4 antibodies are rare with MG from checkpoint inhibitors, and no MuSK antibodies have been reported in these cases. Creatine kinase (CK) or troponin I (TnI) elevation occurs in about 87% of patients with checkpoint inhibitor-induced MG, but standard MG doesn’t typically involve increased CK levels.

Inflammatory myositis (IM), the second most common neuromuscular adverse event from immunotherapy, tends to occur 2-15 weeks after immune checkpoint inhibitor therapy and can involve polymyositis, necrotizing autoimmune myopathy, dermatomyositis, granulomatous myositis, or other nonspecific myositis and myopathies.

Though proximal weakness occurs with IM both associated with immunotherapy and not, ocular symptoms are unique to cases associated with therapy and occur in about half of them. Myalgia, dyspnea, and dysphagia can all occur with checkpoint inhibitor–associated IM but don’t generally occur with standard IM. Immunotherapy-related IM is usually seronegative for myositis antibodies and doesn’t generally cause abnormalities in electromyography, compared with increased exertional activity and early recruitment of myopathic motor units in electromyography with standard IM.

GBS and CIDP are the third most common cause of neuromuscular complications from checkpoint inhibitors. The main distinguishing feature of these conditions from those not related to immunotherapy is that they occur anywhere from 4 to 68 weeks after therapy begins. Presentation is otherwise similar whether related to checkpoint inhibitors or not.

Aside from GBS and CIDP, other neuropathies that can result from immunotherapy complications include acute cranial neuropathies, axonal or demyelinating neuropathies, motor polyradiculopathy, vasculitic neuropathy, and plexopathy.

Neuromuscular complications other than those described above can also occur from checkpoint inhibitor therapy, such as enteric neuropathy, polyradiculitis, and meningo-radiculo-neuritis, but these are much rarer.

Four organizations have developed consensus guidelines for immune checkpoint inhibitor toxicities: the European Society for Medical Oncology (ESMO, 2017), Society for Immunotherapy of Cancer (SITC, 2017), American Society of Clinical Oncology (ASCO, 2018), and National Comprehensive Cancer Network (NCCN, 2019).

Dr Trevino had no disclosures.

AUSTIN, TEX. – Neuromuscular complications from immunotherapy for cancer are rare, but they occur often enough that it is helpful to know which ones can result from different immunotherapies and how to distinguish them from non–adverse event conditions, according to Christopher Trevino, MD, a neuro-oncologist at Tulane University in New Orleans.

At the annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine, Dr. Trevino reviewed immunotherapy types, particularly immune checkpoint inhibitors, and the most common neuromuscular complications – primarily neuropathy, myasthenia gravis (MG), myositis, and encephalitis or meningitis.

“Timing of onset is a critical component to assist in identifying immune checkpoint inhibitor–associated versus non–immune checkpoint inhibitor–associated neuromuscular disease,” Dr. Trevino told attendees. Prompt recognition can be particularly urgent for MG because crisis and death rates are higher when induced by immunotherapy and require quick treatment. “Understanding the mechanisms of action sets a foundation for treatment approach,” he added.

Any part of the nervous system can be affected by immunotherapy toxicity, he said, and syndromes often overlap, with the peripheral nervous system typically more often affected than the central nervous system. Neurologic immune-related adverse events typically occur within four cycles of therapy – about 12 weeks after therapy initiation – but should always involve a work-up to exclude effects from the cancer itself, other neuromuscular diagnoses unrelated to therapy, and other toxicities from chemotherapy.

Recommended first-line treatment is halting immunotherapy with or without corticosteroids, after which most patients improve, often with “rapid, complete resolution of symptoms,” Dr. Trevino said. Restarting immunotherapy treatment is possible in some patients, though.
 

CAR T-cell and dendritic cell vaccine therapies

Four main types of immunotherapy exist: viral therapy, vaccine therapy, immune checkpoint inhibitors, and adoptive cell transfer, such as chimeric antigen receptor (CAR) T-cell therapy. Dr. Trevino focused on checkpoint inhibitors and adoptive cell transfer.

CAR T-cell therapy is a multistep treatment process that involves first removing blood from the patient to obtain their T cells. These are used to create and grow CAR T cells in the lab so that they can be infused back into the patient. The cells then bind to cancer cells and destroy them. Examples of approved CAR T-cell therapy include Yescarta (axicabtagene ciloleucel) for some types of non-Hodgkin lymphoma and Kymriah (tisagenlecleucel) for acute lymphoblastic leukemia (ALL).

Dendritic cell vaccines are similar to CAR T-cell therapy in that they also use the patient’s own immune cells to create cancer-killing cells that the patient then receives back. The only currently approved dendritic cell vaccine is Provenge (sipuleucel-T) for advanced prostate cancer.

The main toxicity to watch for from CAR T-cell therapy and dendritic cell vaccines is cytokine release syndrome (CRS). It can begin anywhere from 1-14 days after the infusion and involves T-cell expansion in the body that leads to a cytokine storm. Symptoms are wide ranging, including fatigue, fever, loss of appetite, tachycardia, hypotension, pain, rash, diarrhea, headache, confusion, seizures, muscle and joint pain, tachypnea, hypoxia and hallucinations, among others.

Specific central neurotoxicities that can result from CAR T-cell therapy include encephalopathy, cerebral edema, seizures and status epilepticus, cerebral vasospasm, and aphasia.
 

Immune checkpoint inhibitor toxicities

Immune checkpoint inhibitors are drugs that interrupt a cancer’s ability to hijack the immune system; they block the proteins that hold back T-cells from attacking the cancer, thereby releasing the immune system to go after the malignant cells.

The two most common types of immune checkpoint inhibitors are those targeting the programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) pathways. The three currently approved PD-1 inhibitors are pembrolizumab (Keytruda), nivolumab (Opdivo), and cemiplimab (Libtayo), which can treat nearly a dozen malignancies affecting different organs. Atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi) are the three currently approved PD-L1 inhibitors, indicated for urothelial carcinoma and a handful of other cancers, such as small-cell and non–small cell lung cancer and triple negative breast cancer.

The only other type of approved checkpoint inhibitor is ipilimumab (Yervoy), which targets the CTLA-4 protein. A number of other checkpoint inhibitors are in trials, however, such as ones targeting pathways involving OX40, ICOS, TIM3, and LAG-3 (J Hematol Oncol. 2018. doi: 10.1186/s13045-018-0582-8).

Immune-related adverse events are less common with PD-1 or PD-L1 inhibitors – a rate of 5%-10% – compared with adverse events from CTLA-4 inhibitors, which occur in about 15% of patients. Neurologic complications occur even more rarely – about 1%-4% of all immune checkpoint inhibitor therapies – and primarily include MG, Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), and inflammatory myositis (Muscle Nerve. 2018;58[1]:10-22).

Treatment with multiple checkpoint inhibitors increases the likelihood of severe adverse events, with rates of up to 30%-50% of patients with dual treatment.
 

Distinguishing features of neuromuscular immunotherapy-related adverse events

MG is the most common neuromuscular immune-related adverse event from immune checkpoint inhibitors and tends to occur 3-12 weeks after beginning treatment, frequently comorbid with inflammatory myopathy or cardiomyopathy, Dr. Trevino said. About two-thirds of cases are de novo, while the remaining one-third involve preexisting MG; no reports of Lambert-Eaton myasthenic syndrome have been linked to checkpoint inhibitors.

Several characteristics distinguish checkpoint inhibitor–associated MG from standard MG. Standard MG can be ocular with or without bulbar or appendicular weakness, whereas immunotherapy-related MG is rarely only ocular (about 18% of cases). Immunotherapy-related MG involves an MG crisis at diagnosis in up to 50% of cases and has high mortality, both of which are rarer with standard MG.

While standard MG can be seronegative or involve AChR, MuSK, or LRP4 antibodies, about two-thirds of immunotherapy-related MG cases are positive for AChR antibodies. LRP4 antibodies are rare with MG from checkpoint inhibitors, and no MuSK antibodies have been reported in these cases. Creatine kinase (CK) or troponin I (TnI) elevation occurs in about 87% of patients with checkpoint inhibitor-induced MG, but standard MG doesn’t typically involve increased CK levels.

Inflammatory myositis (IM), the second most common neuromuscular adverse event from immunotherapy, tends to occur 2-15 weeks after immune checkpoint inhibitor therapy and can involve polymyositis, necrotizing autoimmune myopathy, dermatomyositis, granulomatous myositis, or other nonspecific myositis and myopathies.

Though proximal weakness occurs with IM both associated with immunotherapy and not, ocular symptoms are unique to cases associated with therapy and occur in about half of them. Myalgia, dyspnea, and dysphagia can all occur with checkpoint inhibitor–associated IM but don’t generally occur with standard IM. Immunotherapy-related IM is usually seronegative for myositis antibodies and doesn’t generally cause abnormalities in electromyography, compared with increased exertional activity and early recruitment of myopathic motor units in electromyography with standard IM.

GBS and CIDP are the third most common cause of neuromuscular complications from checkpoint inhibitors. The main distinguishing feature of these conditions from those not related to immunotherapy is that they occur anywhere from 4 to 68 weeks after therapy begins. Presentation is otherwise similar whether related to checkpoint inhibitors or not.

Aside from GBS and CIDP, other neuropathies that can result from immunotherapy complications include acute cranial neuropathies, axonal or demyelinating neuropathies, motor polyradiculopathy, vasculitic neuropathy, and plexopathy.

Neuromuscular complications other than those described above can also occur from checkpoint inhibitor therapy, such as enteric neuropathy, polyradiculitis, and meningo-radiculo-neuritis, but these are much rarer.

Four organizations have developed consensus guidelines for immune checkpoint inhibitor toxicities: the European Society for Medical Oncology (ESMO, 2017), Society for Immunotherapy of Cancer (SITC, 2017), American Society of Clinical Oncology (ASCO, 2018), and National Comprehensive Cancer Network (NCCN, 2019).

Dr Trevino had no disclosures.

A novel 17-gene expression signature may help guide the choice of initial treatment in patients with IGHV-unmutated chronic lymphocytic leukemia (CLL), according to findings of a retrospective dual cohort study.

copyright Kativ/iStockphoto

“[Fludarabine, cyclophosphamide, and rituximab] was the first regimen to improve progression-free survival and overall survival in patients with chronic lymphocytic leukaemia, and has become a gold-standard chemoimmunotherapy regimen in physically fit patients,” wrote the investigators, who were led by Carmen D. Herling, MD, of the Center for Integrated Oncology, Cologne, Germany; and Kevin R. Coombes, PhD, of Ohio State University, Columbus.

While several studies demonstrate that young, fit patients with mutated IGHV gene and no high-risk cytogenetic abnormalities achieve durable remission with the FCR (fludarabine, cyclophosphamide, and rituximab) regimen, there have been no studies to identify if this is true for patients with unmutated IGHV gene, they reported in the Lancet Oncology.

The investigators performed transcriptional profiling using peripheral blood samples collected from two cohorts of patients with CLL who were treated with frontline FCR.

The discovery and training cohort consisted of 101 patients (65% with IGHV-unmutated disease) treated at the MD Anderson Cancer Center who had a median follow-up of about 12 years. The validation cohort consisted of 109 patients with IGHV-unmutated disease treated on the German CLL8 single-arm trial who had a median follow-up of about 6 years.

A total of 1,136 genes showed a significant univariate association with time to progression. Ultimately, 17 of these genes – most of them involved in purine metabolism and oxidative phosphorylation – were included in the expression signature.

Among patients with IGHV-unmutated CLL, the 17-gene signature discriminated between two groups having differing time to progression after their frontline FCR chemoimmunotherapy: an unfavorable prognosis group and an intermediate prognosis group.

The unfavorable prognosis group had a significantly higher relative risk of progression in both the discovery/training cohort (hazard ratio, 3.83; P less than .0001) and the validation cohort (HR, 1.90; P = .008). In the validation cohort, the median time to progression was 39 months among patients with a signature-defined unfavorable prognosis, compared with 59 months among patients with a signature-defined intermediate prognosis.

“We would recommend testing the value of the 17-gene signature in a prospective study that compares FCR treatment with alternative therapies, such as ibrutinib, as part of a randomised clinical trial,” the investigators wrote.

Dr. Herling reported financial disclosures related to Hoffmann-La Roche, and Dr. Coombes reported grants from the National Institutes of Health. The study was funded by the Chronic Lymphocytic Leukaemia Global Research Foundation and the National Institutes of Health/National Cancer Institute.

SOURCE: Herling CD et al. Lancet Oncol. 2019;20(11):1576-86.

A novel 17-gene expression signature may help guide the choice of initial treatment in patients with IGHV-unmutated chronic lymphocytic leukemia (CLL), according to findings of a retrospective dual cohort study.

copyright Kativ/iStockphoto

“[Fludarabine, cyclophosphamide, and rituximab] was the first regimen to improve progression-free survival and overall survival in patients with chronic lymphocytic leukaemia, and has become a gold-standard chemoimmunotherapy regimen in physically fit patients,” wrote the investigators, who were led by Carmen D. Herling, MD, of the Center for Integrated Oncology, Cologne, Germany; and Kevin R. Coombes, PhD, of Ohio State University, Columbus.

While several studies demonstrate that young, fit patients with mutated IGHV gene and no high-risk cytogenetic abnormalities achieve durable remission with the FCR (fludarabine, cyclophosphamide, and rituximab) regimen, there have been no studies to identify if this is true for patients with unmutated IGHV gene, they reported in the Lancet Oncology.

The investigators performed transcriptional profiling using peripheral blood samples collected from two cohorts of patients with CLL who were treated with frontline FCR.

The discovery and training cohort consisted of 101 patients (65% with IGHV-unmutated disease) treated at the MD Anderson Cancer Center who had a median follow-up of about 12 years. The validation cohort consisted of 109 patients with IGHV-unmutated disease treated on the German CLL8 single-arm trial who had a median follow-up of about 6 years.

A total of 1,136 genes showed a significant univariate association with time to progression. Ultimately, 17 of these genes – most of them involved in purine metabolism and oxidative phosphorylation – were included in the expression signature.

Among patients with IGHV-unmutated CLL, the 17-gene signature discriminated between two groups having differing time to progression after their frontline FCR chemoimmunotherapy: an unfavorable prognosis group and an intermediate prognosis group.

The unfavorable prognosis group had a significantly higher relative risk of progression in both the discovery/training cohort (hazard ratio, 3.83; P less than .0001) and the validation cohort (HR, 1.90; P = .008). In the validation cohort, the median time to progression was 39 months among patients with a signature-defined unfavorable prognosis, compared with 59 months among patients with a signature-defined intermediate prognosis.

“We would recommend testing the value of the 17-gene signature in a prospective study that compares FCR treatment with alternative therapies, such as ibrutinib, as part of a randomised clinical trial,” the investigators wrote.

Dr. Herling reported financial disclosures related to Hoffmann-La Roche, and Dr. Coombes reported grants from the National Institutes of Health. The study was funded by the Chronic Lymphocytic Leukaemia Global Research Foundation and the National Institutes of Health/National Cancer Institute.

SOURCE: Herling CD et al. Lancet Oncol. 2019;20(11):1576-86.

A novel 17-gene expression signature may help guide the choice of initial treatment in patients with IGHV-unmutated chronic lymphocytic leukemia (CLL), according to findings of a retrospective dual cohort study.

copyright Kativ/iStockphoto

“[Fludarabine, cyclophosphamide, and rituximab] was the first regimen to improve progression-free survival and overall survival in patients with chronic lymphocytic leukaemia, and has become a gold-standard chemoimmunotherapy regimen in physically fit patients,” wrote the investigators, who were led by Carmen D. Herling, MD, of the Center for Integrated Oncology, Cologne, Germany; and Kevin R. Coombes, PhD, of Ohio State University, Columbus.

While several studies demonstrate that young, fit patients with mutated IGHV gene and no high-risk cytogenetic abnormalities achieve durable remission with the FCR (fludarabine, cyclophosphamide, and rituximab) regimen, there have been no studies to identify if this is true for patients with unmutated IGHV gene, they reported in the Lancet Oncology.

The investigators performed transcriptional profiling using peripheral blood samples collected from two cohorts of patients with CLL who were treated with frontline FCR.

The discovery and training cohort consisted of 101 patients (65% with IGHV-unmutated disease) treated at the MD Anderson Cancer Center who had a median follow-up of about 12 years. The validation cohort consisted of 109 patients with IGHV-unmutated disease treated on the German CLL8 single-arm trial who had a median follow-up of about 6 years.

A total of 1,136 genes showed a significant univariate association with time to progression. Ultimately, 17 of these genes – most of them involved in purine metabolism and oxidative phosphorylation – were included in the expression signature.

Among patients with IGHV-unmutated CLL, the 17-gene signature discriminated between two groups having differing time to progression after their frontline FCR chemoimmunotherapy: an unfavorable prognosis group and an intermediate prognosis group.

The unfavorable prognosis group had a significantly higher relative risk of progression in both the discovery/training cohort (hazard ratio, 3.83; P less than .0001) and the validation cohort (HR, 1.90; P = .008). In the validation cohort, the median time to progression was 39 months among patients with a signature-defined unfavorable prognosis, compared with 59 months among patients with a signature-defined intermediate prognosis.

“We would recommend testing the value of the 17-gene signature in a prospective study that compares FCR treatment with alternative therapies, such as ibrutinib, as part of a randomised clinical trial,” the investigators wrote.

Dr. Herling reported financial disclosures related to Hoffmann-La Roche, and Dr. Coombes reported grants from the National Institutes of Health. The study was funded by the Chronic Lymphocytic Leukaemia Global Research Foundation and the National Institutes of Health/National Cancer Institute.

SOURCE: Herling CD et al. Lancet Oncol. 2019;20(11):1576-86.

NEW ORLEANS – Social media and electronics aren’t the only barriers to a good night’s sleep for teens, according to Adiaha I. A. Spinks-Franklin, MD, MPH, a pediatrician at Texas Children’s Hospital in Houston.

junpinzon/Thinkstock

Another half-dozen “sleep enemies” interfere with adolescents’ sleep and can contribute to insomnia or other sleep disorders, she told attendees at the annual meeting of the American Academy of Pediatrics.

Knowing what normal sleep physiology looks like in youth and understanding the most common sleep enemies and sleep-behavior problems can help you use effective interventions to help your patients get the sleep they need, she said.

Infants need the most sleep, about 12-16 hours each 24-hour period, including naps, for those aged 4-12 months. As they grow into toddlerhood and preschool age, children gradually need less: Children aged 1-2 years need 11-14 hours and children aged 3-5 years need 10-13 hours, including naps. By the time children are in school, ages 6-12, they should have dropped their naps and need 9-12 hours a night.

Parents may expect teens can get by with only as much sleep as adults need, but teens actually need 8-10 hours of sleep a night, and many don’t get that much. In fact, 75% of high school seniors get less than 8 hours of sleep a day and live with a chronic sleep debt, Dr. Spinks-Franklin said.

Although social media use and electronics in the bedroom – TVs, computers, cell phones, and video games – can certainly contribute to inadequate sleep, a heavy academic load and extracurricular activities can be just as problematic, Dr. Spinks-Franklin said. Teens who work after school also may have difficulty getting enough sleep, especially if they also have to balance a heavier academic load or even one or two extracurricular activities.

Socializing with friends also can interfere with sleep, especially when get-togethers run late; drinking caffeinated drinks in the afternoon onward can make it difficult for adolescents to get the sleep they need as well. Less-modifiable contributors to too little sleep are stress and early school start times, Dr. Spinks-Franklin said.

The two most common sleep problems seen in teens are insomnia and delayed sleep phase syndrome. Addressing these is important because the effects of chronic insufficient sleep can have far-reaching consequences. Obesity and related chronic health conditions are associated with inadequate sleep, as are poor academic performance, poor judgment, poor executive functioning, and mental health disorders like depression.

Short-term effects of insufficient sleep also can be problematic and can exacerbate existing sleep problems, such as sleeping in on the weekends to “catch up” on sleep or drinking more caffeine to try to stay awake during the day. Increased caffeine intake can interfere with non-REM deep sleep, Dr. Spinks-Franklin said, and therefore reduce the quality of sleep even if the person gets the total hours they need.

Insomnia in adolescents

Insomnia can refer to difficulty falling asleep, staying asleep, sleeping for long enough, or getting enough sleep in one period of time even when the opportunity is there. Some people may have no trouble falling asleep, but they wake up too early – before they have had gotten the sleep they need – and cannot return to sleep.

To be insomnia, the problem must occur “despite having enough time available for sleep,” Dr. Spinks-Franklin said. “Patient who restrict the amount of time for sleep due to work or social commitments may have trouble sleeping and daytime sleepiness but do not have insomnia.”

Daytime impairment also is part of the American Academy of Sleep Medicine’s definition of insomnia. The rare teen who doesn’t need as much sleep as average and functions without difficulty during the day does not necessarily have insomnia.

But the impairment may not necessarily just be fatigue or sleepiness. In fact, many of the symptoms are the same as those seen with ADHD.

Daytime consequences of insomnia can include the following:

• Depression, feeling sad or “blue,” or emotional hypersensitivity.
• Mood swings, crankiness, or irritability.
• Difficulty concentrating or paying attention, poor memory, mind wandering, or even inability to sit still.
• Job or school problems, such as not being able to finish homework, not finishing tasks they start, or forgetfulness.
• Difficulty in social situations, such as discomfort with others or problems with friends.
• Daytime sleepiness, even when unable to actually take a nap.
• Behavioral problems, such as hyperactivity, impulsivity, or aggression.
• Frequent mistakes, especially at work, at school, or while driving (often “errors of omission,” such as not seeing a street sign or not hearing an instruction).
• Lower levels of motivation or initiative, feeling less energetic.
• Excessive worry about sleep.

Evaluation of insomnia can be framed with “the three-factor model,” which includes predisposing factors, precipitating factors, and perpetuating factors.

Predisposing factors – those that indicate a person already may be at risk for insomnia – include potential genetic influences as well as their typical response to stress. “Do they sleep more or less?” Dr. Spinks-Franklin said. Even teens predisposed to insomnia may not develop it, however, without a precipitating trigger.

These triggers could include stress, anxiety, poor initial sleep hygiene that becomes a pattern, dietary intake or behaviors (such as drinking caffeine or eating too much or too late in the evening), changes to their schedule, or side effects of medications.

Once insomnia begins, various factors can then perpetuate the cycle, including some of those that triggered it, such as anxiety or a school or work schedule. Sometimes it can be difficult to pinpoint the factor prolonging insomnia, such as the unconscious reward of going to work or school late with few or no consequences.

Delayed sleep phase syndrome

Delayed sleep phase syndrome occurs when someone has a delayed onset of melatonin secretion that pushes back the time when they can fall asleep. Melatonin is the neurotransmitter produced by the pineal gland that signals the start of nighttime. Although it has a hereditary component, delayed sleep phase syndrome also can result from a pattern of poor sleep onset and sleeping in on the weekends.

Dr. Spinks-Franklin described the typical cycle: A teen doesn’t go to sleep until after midnight and then wants to sleep in later in the morning. Because they have to wake up early for school, they sleep in on the weekends to try to regain the sleep they lost. Sleeping in pushes their circadian rhythm even later, perpetuating the problem.

Interventions for sleep disorders

The recommended treatment for insomnia is cognitive-behavior therapy for insomnia, for which strong evidence exists. Before seeking cognitive-behavior therapy, however, families can work to improve sleep hygiene and reduce stimuli that contribute to insomnia.

Teens should avoid screens for at least 1 hour before bedtime and avoid caffeine and exercise for at least 4 hours before going to bed. They also need to develop a schedule with a consistent bedtime and wake-up time, including on the weekends. They should avoid sleeping in on the weekends or taking naps during the day, Dr. Spinks-Franklin said.

Delayed sleep phase syndrome is more resistant to treatment and has a high recurrence rate, she said, and it requires commitment from the parent and their child to address it successfully. Teens with this condition also can start with sleep hygiene practices: a consistent wake-up time that they maintain on the weekends and no daytime naps. Phototherapy in the morning can be added to hopefully induce an earlier onset of melatonin release in the evening.

The next step is making changes to the youth’s schedule, particularly evening and/or weekend activities. They can try to gradually advance their biological clock by changing their sleep schedule.

Dr. Spinks-Franklin also briefly addressed the use of over-the-counter melatonin supplements for treating sleep problems. Melatonin can be effective for treating insomnia by improving sleep onset and sleep quality, particularly in children and teens with autism spectrum disorder or ADHD.

Dr. Spinks-Franklin had no disclosures, and her presentation used no outside funding.

NEW ORLEANS – Social media and electronics aren’t the only barriers to a good night’s sleep for teens, according to Adiaha I. A. Spinks-Franklin, MD, MPH, a pediatrician at Texas Children’s Hospital in Houston.

junpinzon/Thinkstock

Another half-dozen “sleep enemies” interfere with adolescents’ sleep and can contribute to insomnia or other sleep disorders, she told attendees at the annual meeting of the American Academy of Pediatrics.

Knowing what normal sleep physiology looks like in youth and understanding the most common sleep enemies and sleep-behavior problems can help you use effective interventions to help your patients get the sleep they need, she said.

Infants need the most sleep, about 12-16 hours each 24-hour period, including naps, for those aged 4-12 months. As they grow into toddlerhood and preschool age, children gradually need less: Children aged 1-2 years need 11-14 hours and children aged 3-5 years need 10-13 hours, including naps. By the time children are in school, ages 6-12, they should have dropped their naps and need 9-12 hours a night.

Parents may expect teens can get by with only as much sleep as adults need, but teens actually need 8-10 hours of sleep a night, and many don’t get that much. In fact, 75% of high school seniors get less than 8 hours of sleep a day and live with a chronic sleep debt, Dr. Spinks-Franklin said.

Although social media use and electronics in the bedroom – TVs, computers, cell phones, and video games – can certainly contribute to inadequate sleep, a heavy academic load and extracurricular activities can be just as problematic, Dr. Spinks-Franklin said. Teens who work after school also may have difficulty getting enough sleep, especially if they also have to balance a heavier academic load or even one or two extracurricular activities.

Socializing with friends also can interfere with sleep, especially when get-togethers run late; drinking caffeinated drinks in the afternoon onward can make it difficult for adolescents to get the sleep they need as well. Less-modifiable contributors to too little sleep are stress and early school start times, Dr. Spinks-Franklin said.

The two most common sleep problems seen in teens are insomnia and delayed sleep phase syndrome. Addressing these is important because the effects of chronic insufficient sleep can have far-reaching consequences. Obesity and related chronic health conditions are associated with inadequate sleep, as are poor academic performance, poor judgment, poor executive functioning, and mental health disorders like depression.

Short-term effects of insufficient sleep also can be problematic and can exacerbate existing sleep problems, such as sleeping in on the weekends to “catch up” on sleep or drinking more caffeine to try to stay awake during the day. Increased caffeine intake can interfere with non-REM deep sleep, Dr. Spinks-Franklin said, and therefore reduce the quality of sleep even if the person gets the total hours they need.

Insomnia in adolescents

Insomnia can refer to difficulty falling asleep, staying asleep, sleeping for long enough, or getting enough sleep in one period of time even when the opportunity is there. Some people may have no trouble falling asleep, but they wake up too early – before they have had gotten the sleep they need – and cannot return to sleep.

To be insomnia, the problem must occur “despite having enough time available for sleep,” Dr. Spinks-Franklin said. “Patient who restrict the amount of time for sleep due to work or social commitments may have trouble sleeping and daytime sleepiness but do not have insomnia.”

Daytime impairment also is part of the American Academy of Sleep Medicine’s definition of insomnia. The rare teen who doesn’t need as much sleep as average and functions without difficulty during the day does not necessarily have insomnia.

But the impairment may not necessarily just be fatigue or sleepiness. In fact, many of the symptoms are the same as those seen with ADHD.

Daytime consequences of insomnia can include the following:

• Depression, feeling sad or “blue,” or emotional hypersensitivity.
• Mood swings, crankiness, or irritability.
• Difficulty concentrating or paying attention, poor memory, mind wandering, or even inability to sit still.
• Job or school problems, such as not being able to finish homework, not finishing tasks they start, or forgetfulness.
• Difficulty in social situations, such as discomfort with others or problems with friends.
• Daytime sleepiness, even when unable to actually take a nap.
• Behavioral problems, such as hyperactivity, impulsivity, or aggression.
• Frequent mistakes, especially at work, at school, or while driving (often “errors of omission,” such as not seeing a street sign or not hearing an instruction).
• Lower levels of motivation or initiative, feeling less energetic.
• Excessive worry about sleep.

Evaluation of insomnia can be framed with “the three-factor model,” which includes predisposing factors, precipitating factors, and perpetuating factors.

Predisposing factors – those that indicate a person already may be at risk for insomnia – include potential genetic influences as well as their typical response to stress. “Do they sleep more or less?” Dr. Spinks-Franklin said. Even teens predisposed to insomnia may not develop it, however, without a precipitating trigger.

These triggers could include stress, anxiety, poor initial sleep hygiene that becomes a pattern, dietary intake or behaviors (such as drinking caffeine or eating too much or too late in the evening), changes to their schedule, or side effects of medications.

Once insomnia begins, various factors can then perpetuate the cycle, including some of those that triggered it, such as anxiety or a school or work schedule. Sometimes it can be difficult to pinpoint the factor prolonging insomnia, such as the unconscious reward of going to work or school late with few or no consequences.

Delayed sleep phase syndrome

Delayed sleep phase syndrome occurs when someone has a delayed onset of melatonin secretion that pushes back the time when they can fall asleep. Melatonin is the neurotransmitter produced by the pineal gland that signals the start of nighttime. Although it has a hereditary component, delayed sleep phase syndrome also can result from a pattern of poor sleep onset and sleeping in on the weekends.

Dr. Spinks-Franklin described the typical cycle: A teen doesn’t go to sleep until after midnight and then wants to sleep in later in the morning. Because they have to wake up early for school, they sleep in on the weekends to try to regain the sleep they lost. Sleeping in pushes their circadian rhythm even later, perpetuating the problem.

Interventions for sleep disorders

The recommended treatment for insomnia is cognitive-behavior therapy for insomnia, for which strong evidence exists. Before seeking cognitive-behavior therapy, however, families can work to improve sleep hygiene and reduce stimuli that contribute to insomnia.

Teens should avoid screens for at least 1 hour before bedtime and avoid caffeine and exercise for at least 4 hours before going to bed. They also need to develop a schedule with a consistent bedtime and wake-up time, including on the weekends. They should avoid sleeping in on the weekends or taking naps during the day, Dr. Spinks-Franklin said.

Delayed sleep phase syndrome is more resistant to treatment and has a high recurrence rate, she said, and it requires commitment from the parent and their child to address it successfully. Teens with this condition also can start with sleep hygiene practices: a consistent wake-up time that they maintain on the weekends and no daytime naps. Phototherapy in the morning can be added to hopefully induce an earlier onset of melatonin release in the evening.

The next step is making changes to the youth’s schedule, particularly evening and/or weekend activities. They can try to gradually advance their biological clock by changing their sleep schedule.

Dr. Spinks-Franklin also briefly addressed the use of over-the-counter melatonin supplements for treating sleep problems. Melatonin can be effective for treating insomnia by improving sleep onset and sleep quality, particularly in children and teens with autism spectrum disorder or ADHD.

Dr. Spinks-Franklin had no disclosures, and her presentation used no outside funding.

NEW ORLEANS – Social media and electronics aren’t the only barriers to a good night’s sleep for teens, according to Adiaha I. A. Spinks-Franklin, MD, MPH, a pediatrician at Texas Children’s Hospital in Houston.

junpinzon/Thinkstock

Another half-dozen “sleep enemies” interfere with adolescents’ sleep and can contribute to insomnia or other sleep disorders, she told attendees at the annual meeting of the American Academy of Pediatrics.

Knowing what normal sleep physiology looks like in youth and understanding the most common sleep enemies and sleep-behavior problems can help you use effective interventions to help your patients get the sleep they need, she said.

Infants need the most sleep, about 12-16 hours each 24-hour period, including naps, for those aged 4-12 months. As they grow into toddlerhood and preschool age, children gradually need less: Children aged 1-2 years need 11-14 hours and children aged 3-5 years need 10-13 hours, including naps. By the time children are in school, ages 6-12, they should have dropped their naps and need 9-12 hours a night.

Parents may expect teens can get by with only as much sleep as adults need, but teens actually need 8-10 hours of sleep a night, and many don’t get that much. In fact, 75% of high school seniors get less than 8 hours of sleep a day and live with a chronic sleep debt, Dr. Spinks-Franklin said.

Although social media use and electronics in the bedroom – TVs, computers, cell phones, and video games – can certainly contribute to inadequate sleep, a heavy academic load and extracurricular activities can be just as problematic, Dr. Spinks-Franklin said. Teens who work after school also may have difficulty getting enough sleep, especially if they also have to balance a heavier academic load or even one or two extracurricular activities.

Socializing with friends also can interfere with sleep, especially when get-togethers run late; drinking caffeinated drinks in the afternoon onward can make it difficult for adolescents to get the sleep they need as well. Less-modifiable contributors to too little sleep are stress and early school start times, Dr. Spinks-Franklin said.

The two most common sleep problems seen in teens are insomnia and delayed sleep phase syndrome. Addressing these is important because the effects of chronic insufficient sleep can have far-reaching consequences. Obesity and related chronic health conditions are associated with inadequate sleep, as are poor academic performance, poor judgment, poor executive functioning, and mental health disorders like depression.

Short-term effects of insufficient sleep also can be problematic and can exacerbate existing sleep problems, such as sleeping in on the weekends to “catch up” on sleep or drinking more caffeine to try to stay awake during the day. Increased caffeine intake can interfere with non-REM deep sleep, Dr. Spinks-Franklin said, and therefore reduce the quality of sleep even if the person gets the total hours they need.

Insomnia in adolescents

Insomnia can refer to difficulty falling asleep, staying asleep, sleeping for long enough, or getting enough sleep in one period of time even when the opportunity is there. Some people may have no trouble falling asleep, but they wake up too early – before they have had gotten the sleep they need – and cannot return to sleep.

To be insomnia, the problem must occur “despite having enough time available for sleep,” Dr. Spinks-Franklin said. “Patient who restrict the amount of time for sleep due to work or social commitments may have trouble sleeping and daytime sleepiness but do not have insomnia.”

Daytime impairment also is part of the American Academy of Sleep Medicine’s definition of insomnia. The rare teen who doesn’t need as much sleep as average and functions without difficulty during the day does not necessarily have insomnia.

But the impairment may not necessarily just be fatigue or sleepiness. In fact, many of the symptoms are the same as those seen with ADHD.

Daytime consequences of insomnia can include the following:

• Depression, feeling sad or “blue,” or emotional hypersensitivity.
• Mood swings, crankiness, or irritability.
• Difficulty concentrating or paying attention, poor memory, mind wandering, or even inability to sit still.
• Job or school problems, such as not being able to finish homework, not finishing tasks they start, or forgetfulness.
• Difficulty in social situations, such as discomfort with others or problems with friends.
• Daytime sleepiness, even when unable to actually take a nap.
• Behavioral problems, such as hyperactivity, impulsivity, or aggression.
• Frequent mistakes, especially at work, at school, or while driving (often “errors of omission,” such as not seeing a street sign or not hearing an instruction).
• Lower levels of motivation or initiative, feeling less energetic.
• Excessive worry about sleep.

Evaluation of insomnia can be framed with “the three-factor model,” which includes predisposing factors, precipitating factors, and perpetuating factors.

Predisposing factors – those that indicate a person already may be at risk for insomnia – include potential genetic influences as well as their typical response to stress. “Do they sleep more or less?” Dr. Spinks-Franklin said. Even teens predisposed to insomnia may not develop it, however, without a precipitating trigger.

These triggers could include stress, anxiety, poor initial sleep hygiene that becomes a pattern, dietary intake or behaviors (such as drinking caffeine or eating too much or too late in the evening), changes to their schedule, or side effects of medications.

Once insomnia begins, various factors can then perpetuate the cycle, including some of those that triggered it, such as anxiety or a school or work schedule. Sometimes it can be difficult to pinpoint the factor prolonging insomnia, such as the unconscious reward of going to work or school late with few or no consequences.

Delayed sleep phase syndrome

Delayed sleep phase syndrome occurs when someone has a delayed onset of melatonin secretion that pushes back the time when they can fall asleep. Melatonin is the neurotransmitter produced by the pineal gland that signals the start of nighttime. Although it has a hereditary component, delayed sleep phase syndrome also can result from a pattern of poor sleep onset and sleeping in on the weekends.

Dr. Spinks-Franklin described the typical cycle: A teen doesn’t go to sleep until after midnight and then wants to sleep in later in the morning. Because they have to wake up early for school, they sleep in on the weekends to try to regain the sleep they lost. Sleeping in pushes their circadian rhythm even later, perpetuating the problem.

Interventions for sleep disorders

The recommended treatment for insomnia is cognitive-behavior therapy for insomnia, for which strong evidence exists. Before seeking cognitive-behavior therapy, however, families can work to improve sleep hygiene and reduce stimuli that contribute to insomnia.

Teens should avoid screens for at least 1 hour before bedtime and avoid caffeine and exercise for at least 4 hours before going to bed. They also need to develop a schedule with a consistent bedtime and wake-up time, including on the weekends. They should avoid sleeping in on the weekends or taking naps during the day, Dr. Spinks-Franklin said.

Delayed sleep phase syndrome is more resistant to treatment and has a high recurrence rate, she said, and it requires commitment from the parent and their child to address it successfully. Teens with this condition also can start with sleep hygiene practices: a consistent wake-up time that they maintain on the weekends and no daytime naps. Phototherapy in the morning can be added to hopefully induce an earlier onset of melatonin release in the evening.

The next step is making changes to the youth’s schedule, particularly evening and/or weekend activities. They can try to gradually advance their biological clock by changing their sleep schedule.

Dr. Spinks-Franklin also briefly addressed the use of over-the-counter melatonin supplements for treating sleep problems. Melatonin can be effective for treating insomnia by improving sleep onset and sleep quality, particularly in children and teens with autism spectrum disorder or ADHD.

Dr. Spinks-Franklin had no disclosures, and her presentation used no outside funding.

CHARLOTTE, N.C. – Approximately one-fifth of pediatric stroke activations are for ischemic stroke or transient ischemic attack (TIA), according to research presented at the annual meeting of the Child Neurology Society. Ischemic stroke and TIA were the second leading diagnoses among the stroke activations examined in the study, after seizure and Todd’s paralysis. “These data, in conjunction with previous studies, highlight the importance of developing protocols for early recognition and evaluation of children who present with strokelike symptoms,” said Tiffany Barkley, DO, a child neurology resident at Children’s Mercy Hospital in Kansas City, Mo., and colleagues.

Dr. Barkley and colleagues conducted their research to describe the demographic and other characteristics of patients who present with strokelike symptoms to their hospital. They undertook a descriptive, retrospective chart review of patients who came to Children’s Mercy Hospital from Sept. 1, 2016, to August 31, 2018, with concern for acute stroke. The investigators examined only patients for whom the Stroke Alert Process and power plan were activated.

“Power plans were created at Children’s Mercy Hospital to streamline and standardize care for children,” said Dr. Barkley. “While stroke order sets tend to be common practice in many adult hospitals, stroke order sets in pediatric hospitals are new.”

In all, 61 stroke activations occurred during the study period. Twelve patients (20%) had a final diagnosis of ischemic stroke or TIA. Among the patients with a final diagnosis of ischemic stroke, the most common presenting symptom was unilateral weakness. Two of these patients were candidates for intervention with mechanical thrombectomy, and none received tissue plasminogen activator. The average age of patients in all activations was 14 years, and the average age of patients with a final diagnosis of ischemic stroke or TIA was 4 years. About 37 (61%) subjects of activations were female, and the most common racial demographic was Caucasian.

Ischemic stroke or TIA was the second most common diagnosis of all activations (12 patients; 20%). Seizure or Todd’s paralysis (14 patients; 23%) was the leading diagnosis. Other common diagnoses included migraine (18%), psychogenic or conversion disorder (15%), oncologic process (3.0%), and complications of meningitis or encephalitis (1.6%). Children who presented with ischemic stroke secondary to Moyamoya disease were classified separately (two patients or 3%). It can be difficult to distinguish between stroke and stroke mimics based on neurologic examination alone, and imaging such as MRI often is needed, said Dr. Barkley. The researchers did not identify any intracranial hemorrhages in this patient population.

These findings are consistent with current reported literature, said the researchers. “Our study is one of the first to look at the demographics of children who present with strokelike symptoms,” said Dr. Barkley. “We hope that our study will not only help identify children who present with symptoms concerning for stroke, but also help us identify children who may be at risk for ischemic stroke before the stroke happens.”

The investigators did not have funding for this study and did not report any disclosures.

[email protected]

SOURCE: Barkley T et al. CNS 2019. Abstract 235.

CHARLOTTE, N.C. – Approximately one-fifth of pediatric stroke activations are for ischemic stroke or transient ischemic attack (TIA), according to research presented at the annual meeting of the Child Neurology Society. Ischemic stroke and TIA were the second leading diagnoses among the stroke activations examined in the study, after seizure and Todd’s paralysis. “These data, in conjunction with previous studies, highlight the importance of developing protocols for early recognition and evaluation of children who present with strokelike symptoms,” said Tiffany Barkley, DO, a child neurology resident at Children’s Mercy Hospital in Kansas City, Mo., and colleagues.

Dr. Barkley and colleagues conducted their research to describe the demographic and other characteristics of patients who present with strokelike symptoms to their hospital. They undertook a descriptive, retrospective chart review of patients who came to Children’s Mercy Hospital from Sept. 1, 2016, to August 31, 2018, with concern for acute stroke. The investigators examined only patients for whom the Stroke Alert Process and power plan were activated.

“Power plans were created at Children’s Mercy Hospital to streamline and standardize care for children,” said Dr. Barkley. “While stroke order sets tend to be common practice in many adult hospitals, stroke order sets in pediatric hospitals are new.”

In all, 61 stroke activations occurred during the study period. Twelve patients (20%) had a final diagnosis of ischemic stroke or TIA. Among the patients with a final diagnosis of ischemic stroke, the most common presenting symptom was unilateral weakness. Two of these patients were candidates for intervention with mechanical thrombectomy, and none received tissue plasminogen activator. The average age of patients in all activations was 14 years, and the average age of patients with a final diagnosis of ischemic stroke or TIA was 4 years. About 37 (61%) subjects of activations were female, and the most common racial demographic was Caucasian.

Ischemic stroke or TIA was the second most common diagnosis of all activations (12 patients; 20%). Seizure or Todd’s paralysis (14 patients; 23%) was the leading diagnosis. Other common diagnoses included migraine (18%), psychogenic or conversion disorder (15%), oncologic process (3.0%), and complications of meningitis or encephalitis (1.6%). Children who presented with ischemic stroke secondary to Moyamoya disease were classified separately (two patients or 3%). It can be difficult to distinguish between stroke and stroke mimics based on neurologic examination alone, and imaging such as MRI often is needed, said Dr. Barkley. The researchers did not identify any intracranial hemorrhages in this patient population.

These findings are consistent with current reported literature, said the researchers. “Our study is one of the first to look at the demographics of children who present with strokelike symptoms,” said Dr. Barkley. “We hope that our study will not only help identify children who present with symptoms concerning for stroke, but also help us identify children who may be at risk for ischemic stroke before the stroke happens.”

The investigators did not have funding for this study and did not report any disclosures.

[email protected]

SOURCE: Barkley T et al. CNS 2019. Abstract 235.

CHARLOTTE, N.C. – Approximately one-fifth of pediatric stroke activations are for ischemic stroke or transient ischemic attack (TIA), according to research presented at the annual meeting of the Child Neurology Society. Ischemic stroke and TIA were the second leading diagnoses among the stroke activations examined in the study, after seizure and Todd’s paralysis. “These data, in conjunction with previous studies, highlight the importance of developing protocols for early recognition and evaluation of children who present with strokelike symptoms,” said Tiffany Barkley, DO, a child neurology resident at Children’s Mercy Hospital in Kansas City, Mo., and colleagues.

Dr. Barkley and colleagues conducted their research to describe the demographic and other characteristics of patients who present with strokelike symptoms to their hospital. They undertook a descriptive, retrospective chart review of patients who came to Children’s Mercy Hospital from Sept. 1, 2016, to August 31, 2018, with concern for acute stroke. The investigators examined only patients for whom the Stroke Alert Process and power plan were activated.

“Power plans were created at Children’s Mercy Hospital to streamline and standardize care for children,” said Dr. Barkley. “While stroke order sets tend to be common practice in many adult hospitals, stroke order sets in pediatric hospitals are new.”

In all, 61 stroke activations occurred during the study period. Twelve patients (20%) had a final diagnosis of ischemic stroke or TIA. Among the patients with a final diagnosis of ischemic stroke, the most common presenting symptom was unilateral weakness. Two of these patients were candidates for intervention with mechanical thrombectomy, and none received tissue plasminogen activator. The average age of patients in all activations was 14 years, and the average age of patients with a final diagnosis of ischemic stroke or TIA was 4 years. About 37 (61%) subjects of activations were female, and the most common racial demographic was Caucasian.

Ischemic stroke or TIA was the second most common diagnosis of all activations (12 patients; 20%). Seizure or Todd’s paralysis (14 patients; 23%) was the leading diagnosis. Other common diagnoses included migraine (18%), psychogenic or conversion disorder (15%), oncologic process (3.0%), and complications of meningitis or encephalitis (1.6%). Children who presented with ischemic stroke secondary to Moyamoya disease were classified separately (two patients or 3%). It can be difficult to distinguish between stroke and stroke mimics based on neurologic examination alone, and imaging such as MRI often is needed, said Dr. Barkley. The researchers did not identify any intracranial hemorrhages in this patient population.

These findings are consistent with current reported literature, said the researchers. “Our study is one of the first to look at the demographics of children who present with strokelike symptoms,” said Dr. Barkley. “We hope that our study will not only help identify children who present with symptoms concerning for stroke, but also help us identify children who may be at risk for ischemic stroke before the stroke happens.”

The investigators did not have funding for this study and did not report any disclosures.

[email protected]

SOURCE: Barkley T et al. CNS 2019. Abstract 235.

NATIONAL HARBOR, MD. – Trial results suggest a personalized vaccination approach is feasible and safe, and the vaccine can produce clinical responses in patients with non–small cell lung cancer (NSCLC).

Jennifer Smith/MDedge News

The neoantigen vaccine produced only grade 1 adverse events, yielded responses in patients with epidermal growth factor receptor (EGFR) mutations, and proved particularly effective in patients who were also receiving an EGFR inhibitor.

“EGFR inhibitors seemed to reduce tumor immunosuppression barriers and may enhance antitumor immune responses before and during immunization, suggesting there may be a potential synergy of EGFR with immunotherapies,” Gregory A. Lizee, PhD, of University of Texas MD Anderson Cancer Center, Houston, said at the annual meeting of the Society for Immunotherapy of Cancer.

The research began with an elderly patient who had heavily pretreated NSCLC (Oncoimmunology. 2016;5[12]:e1238539). Dr. Lizee and colleagues used tumor mutational profiling and human leukocyte antigen (HLA) typing to develop a personalized peptide vaccine for the patient. He received the vaccine along with topical imiquimod and had multiple lung tumor nodules regress. However, the patient also had liver metastasis that remained refractory to treatment, and he ultimately died.

To investigate this treatment approach in a larger group, Dr. Lizee and colleagues began a phase 1b trial of patients with advanced NSCLC (ChiCTR-IIR-16009867). As with the prior patient, the researchers designed personalized peptide vaccines for the trial subjects based on mutational profiling of 508 cancer-associated genes and high-resolution HLA typing. The peptides were selected based on nonsynonymous somatic tumor–associated mutations with variant allele frequency greater than 0.04 and the highest predicted neoantigen peptide binding to each patient’s HLA class I and II molecules. The vaccines targeted up to eight independent somatic mutations (mean, 3.75 mutations).

In all, 31 patients provided lung tumor biopsies and peripheral blood for mutational and HLA analyses. The researchers designed 27 personalized neoantigen vaccines, and 24 patients were ultimately vaccinated. This translates to a vaccination rate of 77%, which suggests this treatment approach is feasible, Dr. Lizee said.

Of the 24 vaccinated patients, 18 had adenocarcinoma, and 6 had squamous cell carcinoma. All patients had received multiple prior therapies, including surgery, chemotherapy, radiation, and EGFR inhibitors.

Each patient was vaccinated with a personalized mixture of short and long neoantigen peptides (mean, 9.4 peptides) dissolved in isotonic saline. Patients received at least 12 weekly immunizations and had topical imiquimod applied over the injection site for costimulation through toll-like receptor 7. The 16 patients with EGFR mutations were given the option of continuing on an EGFR inhibitor, and 9 patients elected to do so.
 

Results

Dr. Lizee said this treatment approach was “very safe,” with only grade 1 treatment-related adverse events. The events were fatigue (n = 2), rash (n = 1), and fever (n = 1).

Seven patients achieved a response after vaccination, and one patient achieved a complete response. All seven responders had EGFR mutations, and four of them were receiving an EGFR inhibitor.

The patients on an EGFR inhibitor had significantly better overall survival than that of EGFR-mutated patients who had stopped taking an EGFR inhibitor – 13.8 months and 7.6 months, respectively (P = .038).

Immune profiling revealed that neoantigen-specific T-cell reactivity was associated with clinical responses. The researchers observed EGFR neoantigen-specific T-cell responses in five responders. In three responders, the strongest response was against a peptide encompassing the L858R driver mutation.

The researchers also found evidence of synergy between EGFR inhibitor therapy and the peptide vaccine. EGFR inhibition caused immunomodulatory pathways in EGFR-mutated cancer cells to favor immune-cell infiltration and HLA-mediated antigen presentation.

“Our mechanistic working model is that, in the circulation, the personalized vaccine increased the T-cell frequency,” Dr. Lizee said. “The EGFR inhibitor increased chemokines and antigen presentation at the tumor site, which then attracted those T cells to migrate to the tumor. Then, recognition of the antigen caused interferon gamma [to increase], which caused, potentially, a feed-forward loop by increasing chemokines and antigen presentation further.”

This research is sponsored by Tianjin Beichen Hospital and funded by Tianjin HengJia Biotechnology Development Co. Ltd. Dr. Lizee disclosed a consulting relationship with Tianjin HengJia Biotechnology Development Co. Ltd.

SOURCE: Lizee G et al. SITC 2019. Abstract O18.

NATIONAL HARBOR, MD. – Trial results suggest a personalized vaccination approach is feasible and safe, and the vaccine can produce clinical responses in patients with non–small cell lung cancer (NSCLC).

Jennifer Smith/MDedge News

The neoantigen vaccine produced only grade 1 adverse events, yielded responses in patients with epidermal growth factor receptor (EGFR) mutations, and proved particularly effective in patients who were also receiving an EGFR inhibitor.

“EGFR inhibitors seemed to reduce tumor immunosuppression barriers and may enhance antitumor immune responses before and during immunization, suggesting there may be a potential synergy of EGFR with immunotherapies,” Gregory A. Lizee, PhD, of University of Texas MD Anderson Cancer Center, Houston, said at the annual meeting of the Society for Immunotherapy of Cancer.

The research began with an elderly patient who had heavily pretreated NSCLC (Oncoimmunology. 2016;5[12]:e1238539). Dr. Lizee and colleagues used tumor mutational profiling and human leukocyte antigen (HLA) typing to develop a personalized peptide vaccine for the patient. He received the vaccine along with topical imiquimod and had multiple lung tumor nodules regress. However, the patient also had liver metastasis that remained refractory to treatment, and he ultimately died.

To investigate this treatment approach in a larger group, Dr. Lizee and colleagues began a phase 1b trial of patients with advanced NSCLC (ChiCTR-IIR-16009867). As with the prior patient, the researchers designed personalized peptide vaccines for the trial subjects based on mutational profiling of 508 cancer-associated genes and high-resolution HLA typing. The peptides were selected based on nonsynonymous somatic tumor–associated mutations with variant allele frequency greater than 0.04 and the highest predicted neoantigen peptide binding to each patient’s HLA class I and II molecules. The vaccines targeted up to eight independent somatic mutations (mean, 3.75 mutations).

In all, 31 patients provided lung tumor biopsies and peripheral blood for mutational and HLA analyses. The researchers designed 27 personalized neoantigen vaccines, and 24 patients were ultimately vaccinated. This translates to a vaccination rate of 77%, which suggests this treatment approach is feasible, Dr. Lizee said.

Of the 24 vaccinated patients, 18 had adenocarcinoma, and 6 had squamous cell carcinoma. All patients had received multiple prior therapies, including surgery, chemotherapy, radiation, and EGFR inhibitors.

Each patient was vaccinated with a personalized mixture of short and long neoantigen peptides (mean, 9.4 peptides) dissolved in isotonic saline. Patients received at least 12 weekly immunizations and had topical imiquimod applied over the injection site for costimulation through toll-like receptor 7. The 16 patients with EGFR mutations were given the option of continuing on an EGFR inhibitor, and 9 patients elected to do so.
 

Results

Dr. Lizee said this treatment approach was “very safe,” with only grade 1 treatment-related adverse events. The events were fatigue (n = 2), rash (n = 1), and fever (n = 1).

Seven patients achieved a response after vaccination, and one patient achieved a complete response. All seven responders had EGFR mutations, and four of them were receiving an EGFR inhibitor.

The patients on an EGFR inhibitor had significantly better overall survival than that of EGFR-mutated patients who had stopped taking an EGFR inhibitor – 13.8 months and 7.6 months, respectively (P = .038).

Immune profiling revealed that neoantigen-specific T-cell reactivity was associated with clinical responses. The researchers observed EGFR neoantigen-specific T-cell responses in five responders. In three responders, the strongest response was against a peptide encompassing the L858R driver mutation.

The researchers also found evidence of synergy between EGFR inhibitor therapy and the peptide vaccine. EGFR inhibition caused immunomodulatory pathways in EGFR-mutated cancer cells to favor immune-cell infiltration and HLA-mediated antigen presentation.

“Our mechanistic working model is that, in the circulation, the personalized vaccine increased the T-cell frequency,” Dr. Lizee said. “The EGFR inhibitor increased chemokines and antigen presentation at the tumor site, which then attracted those T cells to migrate to the tumor. Then, recognition of the antigen caused interferon gamma [to increase], which caused, potentially, a feed-forward loop by increasing chemokines and antigen presentation further.”

This research is sponsored by Tianjin Beichen Hospital and funded by Tianjin HengJia Biotechnology Development Co. Ltd. Dr. Lizee disclosed a consulting relationship with Tianjin HengJia Biotechnology Development Co. Ltd.

SOURCE: Lizee G et al. SITC 2019. Abstract O18.

NATIONAL HARBOR, MD. – Trial results suggest a personalized vaccination approach is feasible and safe, and the vaccine can produce clinical responses in patients with non–small cell lung cancer (NSCLC).

Jennifer Smith/MDedge News

The neoantigen vaccine produced only grade 1 adverse events, yielded responses in patients with epidermal growth factor receptor (EGFR) mutations, and proved particularly effective in patients who were also receiving an EGFR inhibitor.

“EGFR inhibitors seemed to reduce tumor immunosuppression barriers and may enhance antitumor immune responses before and during immunization, suggesting there may be a potential synergy of EGFR with immunotherapies,” Gregory A. Lizee, PhD, of University of Texas MD Anderson Cancer Center, Houston, said at the annual meeting of the Society for Immunotherapy of Cancer.

The research began with an elderly patient who had heavily pretreated NSCLC (Oncoimmunology. 2016;5[12]:e1238539). Dr. Lizee and colleagues used tumor mutational profiling and human leukocyte antigen (HLA) typing to develop a personalized peptide vaccine for the patient. He received the vaccine along with topical imiquimod and had multiple lung tumor nodules regress. However, the patient also had liver metastasis that remained refractory to treatment, and he ultimately died.

To investigate this treatment approach in a larger group, Dr. Lizee and colleagues began a phase 1b trial of patients with advanced NSCLC (ChiCTR-IIR-16009867). As with the prior patient, the researchers designed personalized peptide vaccines for the trial subjects based on mutational profiling of 508 cancer-associated genes and high-resolution HLA typing. The peptides were selected based on nonsynonymous somatic tumor–associated mutations with variant allele frequency greater than 0.04 and the highest predicted neoantigen peptide binding to each patient’s HLA class I and II molecules. The vaccines targeted up to eight independent somatic mutations (mean, 3.75 mutations).

In all, 31 patients provided lung tumor biopsies and peripheral blood for mutational and HLA analyses. The researchers designed 27 personalized neoantigen vaccines, and 24 patients were ultimately vaccinated. This translates to a vaccination rate of 77%, which suggests this treatment approach is feasible, Dr. Lizee said.

Of the 24 vaccinated patients, 18 had adenocarcinoma, and 6 had squamous cell carcinoma. All patients had received multiple prior therapies, including surgery, chemotherapy, radiation, and EGFR inhibitors.

Each patient was vaccinated with a personalized mixture of short and long neoantigen peptides (mean, 9.4 peptides) dissolved in isotonic saline. Patients received at least 12 weekly immunizations and had topical imiquimod applied over the injection site for costimulation through toll-like receptor 7. The 16 patients with EGFR mutations were given the option of continuing on an EGFR inhibitor, and 9 patients elected to do so.
 

Results

Dr. Lizee said this treatment approach was “very safe,” with only grade 1 treatment-related adverse events. The events were fatigue (n = 2), rash (n = 1), and fever (n = 1).

Seven patients achieved a response after vaccination, and one patient achieved a complete response. All seven responders had EGFR mutations, and four of them were receiving an EGFR inhibitor.

The patients on an EGFR inhibitor had significantly better overall survival than that of EGFR-mutated patients who had stopped taking an EGFR inhibitor – 13.8 months and 7.6 months, respectively (P = .038).

Immune profiling revealed that neoantigen-specific T-cell reactivity was associated with clinical responses. The researchers observed EGFR neoantigen-specific T-cell responses in five responders. In three responders, the strongest response was against a peptide encompassing the L858R driver mutation.

The researchers also found evidence of synergy between EGFR inhibitor therapy and the peptide vaccine. EGFR inhibition caused immunomodulatory pathways in EGFR-mutated cancer cells to favor immune-cell infiltration and HLA-mediated antigen presentation.

“Our mechanistic working model is that, in the circulation, the personalized vaccine increased the T-cell frequency,” Dr. Lizee said. “The EGFR inhibitor increased chemokines and antigen presentation at the tumor site, which then attracted those T cells to migrate to the tumor. Then, recognition of the antigen caused interferon gamma [to increase], which caused, potentially, a feed-forward loop by increasing chemokines and antigen presentation further.”

This research is sponsored by Tianjin Beichen Hospital and funded by Tianjin HengJia Biotechnology Development Co. Ltd. Dr. Lizee disclosed a consulting relationship with Tianjin HengJia Biotechnology Development Co. Ltd.

SOURCE: Lizee G et al. SITC 2019. Abstract O18.

“You and I are living in a time when some miracle drugs no longer perform miracles and families are being ripped apart by a microscopic enemy. The time for action is now and we can be part of the solution,” said Robert R. Redfield, MD, director of the Centers for Disease Control and Prevention in his foreword to the new CDC report on antibiotic resistance.

In this update of the previous 2013 report, the CDC details how antibiotic-resistant bacteria and fungi cause more than 2.8 million infections and 35,000 deaths in the United States each year. The current report uses EHRs and other data sources obtained by the CDC for relevant infections extrapolated to develop national disease incidence. The report focuses on “the top 18 pathogens that require attention now,” advises specific steps be taken to address these pathogens, and puts into perspective the future of antibiotic development, their use and abuse, and the continuing threat of antibiotic resistance.

The CDC categorizes these 18 pathogens as either an urgent, serious, or concerning threat.

Urgent Threats

• Carbapenem-resistant Acinetobacter, which cause pneumonia and wound, bloodstream, and urinary tract infections; they tend to affect patients in ICUs. Of particular concern, some Acinetobacter are resistant to nearly all antibiotics, with few new drugs in development (8,500 hospital infections in 2017; 700 deaths).
• Candida auris, a drug-resistant fungus that was first identified in 2009 in Asia and has quickly become a cause of severe infections around the world; it is extremely difficult to eradicate from health care settings. It began spreading in the United States in 2015, with 323 cases reported in 2018 (90% resistant to at least one antifungal, and 30% resistant to at least two antifungals).
• Clostridioides difficile, which can cause life-threatening diarrhea, most often in people who have taken antibiotics for other conditions. It is the most common health care–associated infection, and although decreasing in the health care system, it has not decreased in community settings (223,900 hospital infections in 2017, and 12,800 estimated deaths).
• Carbapenem-resistant Enterobacteriaceae, which most frequently infect patients who require devices such as catheters and those taking long courses of some antibiotics. Of particular concern is the fact that these bacteria contain a transmissible plasmid that can transfer their drug resistance to other pathogens (13,100 hospital infections in 2017, and 1,100 estimated deaths).
• Drug-resistant Neisseria gonorrhoeae, which is a sexually transmitted disease that can result in life-threatening ectopic pregnancy, lead to infertility, and can increase the risk of getting and giving HIV; it can also cause cardiovascular and neurological problems. It is resistant to all but one class of antibiotics, and half of all infections are resistant to at least one antibiotic (550,000 drug-resistant infections yearly).

Serious Threats

• Drug-resistant Campylobacter.
• Drug-resistant Candida.
• Extended spectrum beta-lactamase–producing Enterobacteriaceae.
• Vancomycin-resistant Enterococci.
• Multidrug-resistant Pseudomonas aeruginosa.
• Drug-resistant nontyphoidal Salmonella.
• Drug-resistant Salmonella serotype Typhi.
• Drug-resistant Shigella.
• Methicillin-resistant Staphylococcus aureus (MRSA).
• Drug-resistant Streptococcus pneumoniae.
• Drug-resistant Tuberculosis.

Concerning Threats

These comprise erythromycin-resistant group A Streptococcus and clindamycin-resistant group B Streptococcus.

In addition, the CDC has established a Watch List of three pathogens to be wary of: azole-resistant Aspergillus fumigatus, drug-resistant Mycoplasma genitalium, and drug-resistant Bordetella pertussis.

Because antibiotic resistance is a global phenomenon caused by and affecting everyone, the CDC provided solutions to the problem of antibiotic resistance at every level of society. This “comprehensive and coordinated response implements the U.S. National Action Plan for Combating Antibiotic-Resistant Bacteria” and includes cooperation with the Department of Health and Human Services, Department of Veterans Affairs, Department of Defense, Department of State, and Department of Agriculture, according to the report.

The key components of this response include using data and new technologies to detect and track antibiotic resistance; infection prevention and containment, especially in terms of outbreak response; improving antibiotic use across populations (one successful example being a 16% decrease of outpatient antibiotic prescribing to children during 2011-2017); improvements in the identification and intervention in the environment including water and soil and in sanitation; and a significant investment in vaccines, diagnostics, and novel therapeutics (the CDC provided nearly $110 million to 96 institutions for work in these areas).

The report also details some hope in the development of new antibiotics. As of June 2019, there were 42 new antibiotics in development, including 4 with new drug applications submitted, 17 with the potential to treat serious gram negative bacteria, and 11 that could address the urgent threats of gonorrhea or C. difficile. Overall, a quarter of these new antibiotics represent a novel drug class or use a novel mechanism of action.

Furthermore, 84% of U.S. hospitals report a stewardship program meeting all seven of CDC’s Core Elements of Hospital Antibiotic Stewardship. Proper stewardship is at the core of preventing the development of new antibiotic resistant pathogen strains.

In addition, the CDC noted a 5% overall decline in antibiotic prescribing in outpatient settings during 2011-2016.

“The problem will get worse if we do not act now, but we can make a difference,” according to Dr. Redfield. “Simply, here’s what works. Preventing infections protects everyone. Improving antibiotic use in people and animals slows the threat and helps preserve today’s drugs and those yet to come. Detecting threats and implementing interventions to keep germs from becoming widespread saves lives.”

In response to the release of the report, the AMA issued a supporting statement and cited its collection of educational resources for physicians focused on antibiotic use, resistance, and stewardship.

Similarly, the Society for Healthcare Epidemiology of America (SHEA) stated that hospitals were “a bright spot” in the CDC report and offered tools and resources available to educate and inform health care professionals about best practices in infection prevention and control, as well as antibiotic stewardship.

[email protected]

SOURCE: CDC. Antibiotic Resistance Threats in the United States 2019.

“You and I are living in a time when some miracle drugs no longer perform miracles and families are being ripped apart by a microscopic enemy. The time for action is now and we can be part of the solution,” said Robert R. Redfield, MD, director of the Centers for Disease Control and Prevention in his foreword to the new CDC report on antibiotic resistance.

In this update of the previous 2013 report, the CDC details how antibiotic-resistant bacteria and fungi cause more than 2.8 million infections and 35,000 deaths in the United States each year. The current report uses EHRs and other data sources obtained by the CDC for relevant infections extrapolated to develop national disease incidence. The report focuses on “the top 18 pathogens that require attention now,” advises specific steps be taken to address these pathogens, and puts into perspective the future of antibiotic development, their use and abuse, and the continuing threat of antibiotic resistance.

The CDC categorizes these 18 pathogens as either an urgent, serious, or concerning threat.

Urgent Threats

• Carbapenem-resistant Acinetobacter, which cause pneumonia and wound, bloodstream, and urinary tract infections; they tend to affect patients in ICUs. Of particular concern, some Acinetobacter are resistant to nearly all antibiotics, with few new drugs in development (8,500 hospital infections in 2017; 700 deaths).
• Candida auris, a drug-resistant fungus that was first identified in 2009 in Asia and has quickly become a cause of severe infections around the world; it is extremely difficult to eradicate from health care settings. It began spreading in the United States in 2015, with 323 cases reported in 2018 (90% resistant to at least one antifungal, and 30% resistant to at least two antifungals).
• Clostridioides difficile, which can cause life-threatening diarrhea, most often in people who have taken antibiotics for other conditions. It is the most common health care–associated infection, and although decreasing in the health care system, it has not decreased in community settings (223,900 hospital infections in 2017, and 12,800 estimated deaths).
• Carbapenem-resistant Enterobacteriaceae, which most frequently infect patients who require devices such as catheters and those taking long courses of some antibiotics. Of particular concern is the fact that these bacteria contain a transmissible plasmid that can transfer their drug resistance to other pathogens (13,100 hospital infections in 2017, and 1,100 estimated deaths).
• Drug-resistant Neisseria gonorrhoeae, which is a sexually transmitted disease that can result in life-threatening ectopic pregnancy, lead to infertility, and can increase the risk of getting and giving HIV; it can also cause cardiovascular and neurological problems. It is resistant to all but one class of antibiotics, and half of all infections are resistant to at least one antibiotic (550,000 drug-resistant infections yearly).

Serious Threats

• Drug-resistant Campylobacter.
• Drug-resistant Candida.
• Extended spectrum beta-lactamase–producing Enterobacteriaceae.
• Vancomycin-resistant Enterococci.
• Multidrug-resistant Pseudomonas aeruginosa.
• Drug-resistant nontyphoidal Salmonella.
• Drug-resistant Salmonella serotype Typhi.
• Drug-resistant Shigella.
• Methicillin-resistant Staphylococcus aureus (MRSA).
• Drug-resistant Streptococcus pneumoniae.
• Drug-resistant Tuberculosis.

Concerning Threats

These comprise erythromycin-resistant group A Streptococcus and clindamycin-resistant group B Streptococcus.

In addition, the CDC has established a Watch List of three pathogens to be wary of: azole-resistant Aspergillus fumigatus, drug-resistant Mycoplasma genitalium, and drug-resistant Bordetella pertussis.

Because antibiotic resistance is a global phenomenon caused by and affecting everyone, the CDC provided solutions to the problem of antibiotic resistance at every level of society. This “comprehensive and coordinated response implements the U.S. National Action Plan for Combating Antibiotic-Resistant Bacteria” and includes cooperation with the Department of Health and Human Services, Department of Veterans Affairs, Department of Defense, Department of State, and Department of Agriculture, according to the report.

The key components of this response include using data and new technologies to detect and track antibiotic resistance; infection prevention and containment, especially in terms of outbreak response; improving antibiotic use across populations (one successful example being a 16% decrease of outpatient antibiotic prescribing to children during 2011-2017); improvements in the identification and intervention in the environment including water and soil and in sanitation; and a significant investment in vaccines, diagnostics, and novel therapeutics (the CDC provided nearly $110 million to 96 institutions for work in these areas).

The report also details some hope in the development of new antibiotics. As of June 2019, there were 42 new antibiotics in development, including 4 with new drug applications submitted, 17 with the potential to treat serious gram negative bacteria, and 11 that could address the urgent threats of gonorrhea or C. difficile. Overall, a quarter of these new antibiotics represent a novel drug class or use a novel mechanism of action.

Furthermore, 84% of U.S. hospitals report a stewardship program meeting all seven of CDC’s Core Elements of Hospital Antibiotic Stewardship. Proper stewardship is at the core of preventing the development of new antibiotic resistant pathogen strains.

In addition, the CDC noted a 5% overall decline in antibiotic prescribing in outpatient settings during 2011-2016.

“The problem will get worse if we do not act now, but we can make a difference,” according to Dr. Redfield. “Simply, here’s what works. Preventing infections protects everyone. Improving antibiotic use in people and animals slows the threat and helps preserve today’s drugs and those yet to come. Detecting threats and implementing interventions to keep germs from becoming widespread saves lives.”

In response to the release of the report, the AMA issued a supporting statement and cited its collection of educational resources for physicians focused on antibiotic use, resistance, and stewardship.

Similarly, the Society for Healthcare Epidemiology of America (SHEA) stated that hospitals were “a bright spot” in the CDC report and offered tools and resources available to educate and inform health care professionals about best practices in infection prevention and control, as well as antibiotic stewardship.

[email protected]

SOURCE: CDC. Antibiotic Resistance Threats in the United States 2019.

“You and I are living in a time when some miracle drugs no longer perform miracles and families are being ripped apart by a microscopic enemy. The time for action is now and we can be part of the solution,” said Robert R. Redfield, MD, director of the Centers for Disease Control and Prevention in his foreword to the new CDC report on antibiotic resistance.

In this update of the previous 2013 report, the CDC details how antibiotic-resistant bacteria and fungi cause more than 2.8 million infections and 35,000 deaths in the United States each year. The current report uses EHRs and other data sources obtained by the CDC for relevant infections extrapolated to develop national disease incidence. The report focuses on “the top 18 pathogens that require attention now,” advises specific steps be taken to address these pathogens, and puts into perspective the future of antibiotic development, their use and abuse, and the continuing threat of antibiotic resistance.

The CDC categorizes these 18 pathogens as either an urgent, serious, or concerning threat.

Urgent Threats

• Carbapenem-resistant Acinetobacter, which cause pneumonia and wound, bloodstream, and urinary tract infections; they tend to affect patients in ICUs. Of particular concern, some Acinetobacter are resistant to nearly all antibiotics, with few new drugs in development (8,500 hospital infections in 2017; 700 deaths).
• Candida auris, a drug-resistant fungus that was first identified in 2009 in Asia and has quickly become a cause of severe infections around the world; it is extremely difficult to eradicate from health care settings. It began spreading in the United States in 2015, with 323 cases reported in 2018 (90% resistant to at least one antifungal, and 30% resistant to at least two antifungals).
• Clostridioides difficile, which can cause life-threatening diarrhea, most often in people who have taken antibiotics for other conditions. It is the most common health care–associated infection, and although decreasing in the health care system, it has not decreased in community settings (223,900 hospital infections in 2017, and 12,800 estimated deaths).
• Carbapenem-resistant Enterobacteriaceae, which most frequently infect patients who require devices such as catheters and those taking long courses of some antibiotics. Of particular concern is the fact that these bacteria contain a transmissible plasmid that can transfer their drug resistance to other pathogens (13,100 hospital infections in 2017, and 1,100 estimated deaths).
• Drug-resistant Neisseria gonorrhoeae, which is a sexually transmitted disease that can result in life-threatening ectopic pregnancy, lead to infertility, and can increase the risk of getting and giving HIV; it can also cause cardiovascular and neurological problems. It is resistant to all but one class of antibiotics, and half of all infections are resistant to at least one antibiotic (550,000 drug-resistant infections yearly).

Serious Threats

• Drug-resistant Campylobacter.
• Drug-resistant Candida.
• Extended spectrum beta-lactamase–producing Enterobacteriaceae.
• Vancomycin-resistant Enterococci.
• Multidrug-resistant Pseudomonas aeruginosa.
• Drug-resistant nontyphoidal Salmonella.
• Drug-resistant Salmonella serotype Typhi.
• Drug-resistant Shigella.
• Methicillin-resistant Staphylococcus aureus (MRSA).
• Drug-resistant Streptococcus pneumoniae.
• Drug-resistant Tuberculosis.

Concerning Threats

These comprise erythromycin-resistant group A Streptococcus and clindamycin-resistant group B Streptococcus.

In addition, the CDC has established a Watch List of three pathogens to be wary of: azole-resistant Aspergillus fumigatus, drug-resistant Mycoplasma genitalium, and drug-resistant Bordetella pertussis.

Because antibiotic resistance is a global phenomenon caused by and affecting everyone, the CDC provided solutions to the problem of antibiotic resistance at every level of society. This “comprehensive and coordinated response implements the U.S. National Action Plan for Combating Antibiotic-Resistant Bacteria” and includes cooperation with the Department of Health and Human Services, Department of Veterans Affairs, Department of Defense, Department of State, and Department of Agriculture, according to the report.

The key components of this response include using data and new technologies to detect and track antibiotic resistance; infection prevention and containment, especially in terms of outbreak response; improving antibiotic use across populations (one successful example being a 16% decrease of outpatient antibiotic prescribing to children during 2011-2017); improvements in the identification and intervention in the environment including water and soil and in sanitation; and a significant investment in vaccines, diagnostics, and novel therapeutics (the CDC provided nearly $110 million to 96 institutions for work in these areas).

The report also details some hope in the development of new antibiotics. As of June 2019, there were 42 new antibiotics in development, including 4 with new drug applications submitted, 17 with the potential to treat serious gram negative bacteria, and 11 that could address the urgent threats of gonorrhea or C. difficile. Overall, a quarter of these new antibiotics represent a novel drug class or use a novel mechanism of action.

Furthermore, 84% of U.S. hospitals report a stewardship program meeting all seven of CDC’s Core Elements of Hospital Antibiotic Stewardship. Proper stewardship is at the core of preventing the development of new antibiotic resistant pathogen strains.

In addition, the CDC noted a 5% overall decline in antibiotic prescribing in outpatient settings during 2011-2016.

“The problem will get worse if we do not act now, but we can make a difference,” according to Dr. Redfield. “Simply, here’s what works. Preventing infections protects everyone. Improving antibiotic use in people and animals slows the threat and helps preserve today’s drugs and those yet to come. Detecting threats and implementing interventions to keep germs from becoming widespread saves lives.”

In response to the release of the report, the AMA issued a supporting statement and cited its collection of educational resources for physicians focused on antibiotic use, resistance, and stewardship.

Similarly, the Society for Healthcare Epidemiology of America (SHEA) stated that hospitals were “a bright spot” in the CDC report and offered tools and resources available to educate and inform health care professionals about best practices in infection prevention and control, as well as antibiotic stewardship.

[email protected]

SOURCE: CDC. Antibiotic Resistance Threats in the United States 2019.

NEW ORLEANS – In the opinion of Jason E. Reynolds, MD, PhD,, primary care pediatricians are uniquely qualified to treat adolescents with opioid use disorder (OUD).

Doug Brunk/MDedge News

“One of the real benefits of treatment in primary care is that it removes the stigma so that these patients aren’t isolated into addiction clinics; they’re being treated by providers that they know well and that their family knows well,” Dr. Reynolds, a pediatrician who practices in Wareham, Mass., said at the annual meeting of the American Academy of Pediatrics. “That feels a lot better to them, and I think it makes a statement in the community that these people don’t need to be isolated. Anything we can do to reduce the stigma of opioid use disorder is important. We in primary care are well suited to manage chronic disease over the continuum.”

In 2016, the AAP released a policy statement advocating for pediatricians to consider providing medication-assisted treatment to patients with OUD (Pediatrics. 2016;138[3]e20161893). The statement cited results from a nationally representative sample of 345 addiction treatment programs serving adolescents and adults. It found that fewer than 50% of those programs used medication-assisted treatment (J Addict Med. 2011;5[1]:21-7). “When they looked at patients who actually had opioid dependence, the numbers were even lower,” said Dr. Reynolds, who was not involved with the study. “In fact, 34% of opioid-dependent patients received medication-assisted treatment. When they stratified it by age, the younger you were, the less likely you were to be treated. Only 11.5% of youth under 18 are actually being treated. We know that youth with opioid use disorders have very bad health outcomes over their lifetime. The fact that such few patients receive what is considered to be a gold-standard treatment is really alarming.”

Dr. Reynolds acknowledged that many perceived barriers exist to providing treatment of OUD in pediatric primary care, including the fact that patients with addiction are not easy to treat. “They can be manipulative and can make you feel both sad for them and angry at them within the same visit,” he said. “They also have complex needs. For many of these patients, it’s not just that they use opiates; they have medical problems and psychological diagnoses, and oftentimes they have social issues such as being in foster care. They also may have issues with their parents, employer, or their school, so there are many needs that need to be juggled. That can be overwhelming.”

However, he said that such patients “are actually in our wheelhouse, because as primary care physicians we’re used to coordinating care. These are the perfect patients to have a medical home. We manage chronic disease over the continuum of care. This is a chronic disease, and we have to help patients.”

Another perceived barrier for treating adolescents with OUD relates to reimbursement. While most patients with OUD have insurance, Dr. Reynolds finds that the requirement for prior authorizations can result in delay of treatment and poses an unnecessary burden on care providers. “It’s an administrative task that either the physician or the office staff has to take care of,” he said. “Interestingly, reimbursement ranks as a low concern in studies of buprenorphine providers. That tells me that this is not a major hurdle.”

Pediatricians also cite a lack of knowledge as a reason they’re leery of providing OUD treatment in their office. “They wonder: ‘How do I do this? What’s the right way to do it? Are there best practices?’ ” Dr. Reynolds said. “There’s a feeling that it must be dangerous, the idea that if I don’t do it right I’m going to hurt somebody. The reality is, buprenorphine is no more dangerous than any of the other opiates. Technically, because it’s a partial agonist, it’s probably less dangerous than some of the opiates that we prescribe. It’s no more dangerous than prescribing amitriptyline for chronic pain.”

One key resource, the Providers Clinical Support System (www.pcssnow.org), provides resources for clinicians and family members, education and training, and access to mentoring. Another resource, the American Society of Addiction Medicine (www.asam.org), includes clinical practice guidelines, online courses and training on the treatment of OUD, and sample consent and opioid-withdrawal forms. Dr. Reynolds characterized learning how to treat patients with OUD as no different than learning step therapy for asthma. “Once you look into it, you realize that there’s no sort of magic behind this,” he said. “It’s something that any of us can do. Staff can be trained. There are modules to train your staff into the protocols. Learn the knowledge and put it into action. Have the confidence and the knowledge.”

The Drug Addiction and Treatment Act of 2000 set up the waiver process by which physicians can obtain a waiver from the Drug Enforcement Agency after completing an 8-hour CME course on substance abuse disorder and buprenorphine prescribing. To receive a waiver to practice opioid dependency treatment with approved buprenorphine medications, a clinician must notify the SAMHSA Center for Substance Abuse Treatment of their intent to practice this form of medication-assisted treatment.

Dr. Reynolds acknowledged that not every practice is equipped to provide psychosocial support for complex patients with OUD. “When I first started this in 2017, I wanted to make sure that my patients were in some form of counseling,” he said. “However, the medical literature shows that you can treat OUD without counseling, and some of those patients will be fine, too. There have been reports that just going to Narcotics Anonymous meetings weekly has been shown to improve the effectiveness of medication-assisted treatment.”

For clinicians concerned about having backup when they face challenging cases, data shows that having more than one waivered provider in a practice is associated with completing waiver training. “This makes sense,” Dr. Reynolds said. “We like to be able to discuss our cases with colleagues, but a lot of us don’t want to be on call 365 days a year for our patients. Shared responsibility makes it easier. Access to specialty telemedicine consult has also been identified as a facilitator to physicians prescribing medical-assisted therapy.”

He concluded his presentation by noting that increasing numbers of OUD patients are initiating buprenorphine treatment in the ED. “That takes advantage of the fact that most of these patients present to the emergency room after receiving Narcan for an overdose,” Dr. Reynolds said. “In the emergency room, they’re counseled and instructed on how to start buprenorphine, they’re given the first dose, and they’re told to go home and avoid using any other opiates for 24 hours, start the buprenorphine, and follow up with their primary care doctor or an addiction medicine specialist in 3 days. In my community, this is what our local emergency department is doing for adult patients, except they’re not referring back to primary care. They’re referring to a hospital-based addiction medicine specialist. This is a way to increase access and get people started on buprenorphine treatment.”

Dr. Reynolds reported having no financial disclosures.

[email protected]

NEW ORLEANS – In the opinion of Jason E. Reynolds, MD, PhD,, primary care pediatricians are uniquely qualified to treat adolescents with opioid use disorder (OUD).

Doug Brunk/MDedge News

“One of the real benefits of treatment in primary care is that it removes the stigma so that these patients aren’t isolated into addiction clinics; they’re being treated by providers that they know well and that their family knows well,” Dr. Reynolds, a pediatrician who practices in Wareham, Mass., said at the annual meeting of the American Academy of Pediatrics. “That feels a lot better to them, and I think it makes a statement in the community that these people don’t need to be isolated. Anything we can do to reduce the stigma of opioid use disorder is important. We in primary care are well suited to manage chronic disease over the continuum.”

In 2016, the AAP released a policy statement advocating for pediatricians to consider providing medication-assisted treatment to patients with OUD (Pediatrics. 2016;138[3]e20161893). The statement cited results from a nationally representative sample of 345 addiction treatment programs serving adolescents and adults. It found that fewer than 50% of those programs used medication-assisted treatment (J Addict Med. 2011;5[1]:21-7). “When they looked at patients who actually had opioid dependence, the numbers were even lower,” said Dr. Reynolds, who was not involved with the study. “In fact, 34% of opioid-dependent patients received medication-assisted treatment. When they stratified it by age, the younger you were, the less likely you were to be treated. Only 11.5% of youth under 18 are actually being treated. We know that youth with opioid use disorders have very bad health outcomes over their lifetime. The fact that such few patients receive what is considered to be a gold-standard treatment is really alarming.”

Dr. Reynolds acknowledged that many perceived barriers exist to providing treatment of OUD in pediatric primary care, including the fact that patients with addiction are not easy to treat. “They can be manipulative and can make you feel both sad for them and angry at them within the same visit,” he said. “They also have complex needs. For many of these patients, it’s not just that they use opiates; they have medical problems and psychological diagnoses, and oftentimes they have social issues such as being in foster care. They also may have issues with their parents, employer, or their school, so there are many needs that need to be juggled. That can be overwhelming.”

However, he said that such patients “are actually in our wheelhouse, because as primary care physicians we’re used to coordinating care. These are the perfect patients to have a medical home. We manage chronic disease over the continuum of care. This is a chronic disease, and we have to help patients.”

Another perceived barrier for treating adolescents with OUD relates to reimbursement. While most patients with OUD have insurance, Dr. Reynolds finds that the requirement for prior authorizations can result in delay of treatment and poses an unnecessary burden on care providers. “It’s an administrative task that either the physician or the office staff has to take care of,” he said. “Interestingly, reimbursement ranks as a low concern in studies of buprenorphine providers. That tells me that this is not a major hurdle.”

Pediatricians also cite a lack of knowledge as a reason they’re leery of providing OUD treatment in their office. “They wonder: ‘How do I do this? What’s the right way to do it? Are there best practices?’ ” Dr. Reynolds said. “There’s a feeling that it must be dangerous, the idea that if I don’t do it right I’m going to hurt somebody. The reality is, buprenorphine is no more dangerous than any of the other opiates. Technically, because it’s a partial agonist, it’s probably less dangerous than some of the opiates that we prescribe. It’s no more dangerous than prescribing amitriptyline for chronic pain.”

One key resource, the Providers Clinical Support System (www.pcssnow.org), provides resources for clinicians and family members, education and training, and access to mentoring. Another resource, the American Society of Addiction Medicine (www.asam.org), includes clinical practice guidelines, online courses and training on the treatment of OUD, and sample consent and opioid-withdrawal forms. Dr. Reynolds characterized learning how to treat patients with OUD as no different than learning step therapy for asthma. “Once you look into it, you realize that there’s no sort of magic behind this,” he said. “It’s something that any of us can do. Staff can be trained. There are modules to train your staff into the protocols. Learn the knowledge and put it into action. Have the confidence and the knowledge.”

The Drug Addiction and Treatment Act of 2000 set up the waiver process by which physicians can obtain a waiver from the Drug Enforcement Agency after completing an 8-hour CME course on substance abuse disorder and buprenorphine prescribing. To receive a waiver to practice opioid dependency treatment with approved buprenorphine medications, a clinician must notify the SAMHSA Center for Substance Abuse Treatment of their intent to practice this form of medication-assisted treatment.

Dr. Reynolds acknowledged that not every practice is equipped to provide psychosocial support for complex patients with OUD. “When I first started this in 2017, I wanted to make sure that my patients were in some form of counseling,” he said. “However, the medical literature shows that you can treat OUD without counseling, and some of those patients will be fine, too. There have been reports that just going to Narcotics Anonymous meetings weekly has been shown to improve the effectiveness of medication-assisted treatment.”

For clinicians concerned about having backup when they face challenging cases, data shows that having more than one waivered provider in a practice is associated with completing waiver training. “This makes sense,” Dr. Reynolds said. “We like to be able to discuss our cases with colleagues, but a lot of us don’t want to be on call 365 days a year for our patients. Shared responsibility makes it easier. Access to specialty telemedicine consult has also been identified as a facilitator to physicians prescribing medical-assisted therapy.”

He concluded his presentation by noting that increasing numbers of OUD patients are initiating buprenorphine treatment in the ED. “That takes advantage of the fact that most of these patients present to the emergency room after receiving Narcan for an overdose,” Dr. Reynolds said. “In the emergency room, they’re counseled and instructed on how to start buprenorphine, they’re given the first dose, and they’re told to go home and avoid using any other opiates for 24 hours, start the buprenorphine, and follow up with their primary care doctor or an addiction medicine specialist in 3 days. In my community, this is what our local emergency department is doing for adult patients, except they’re not referring back to primary care. They’re referring to a hospital-based addiction medicine specialist. This is a way to increase access and get people started on buprenorphine treatment.”

Dr. Reynolds reported having no financial disclosures.

[email protected]

NEW ORLEANS – In the opinion of Jason E. Reynolds, MD, PhD,, primary care pediatricians are uniquely qualified to treat adolescents with opioid use disorder (OUD).

Doug Brunk/MDedge News

“One of the real benefits of treatment in primary care is that it removes the stigma so that these patients aren’t isolated into addiction clinics; they’re being treated by providers that they know well and that their family knows well,” Dr. Reynolds, a pediatrician who practices in Wareham, Mass., said at the annual meeting of the American Academy of Pediatrics. “That feels a lot better to them, and I think it makes a statement in the community that these people don’t need to be isolated. Anything we can do to reduce the stigma of opioid use disorder is important. We in primary care are well suited to manage chronic disease over the continuum.”

In 2016, the AAP released a policy statement advocating for pediatricians to consider providing medication-assisted treatment to patients with OUD (Pediatrics. 2016;138[3]e20161893). The statement cited results from a nationally representative sample of 345 addiction treatment programs serving adolescents and adults. It found that fewer than 50% of those programs used medication-assisted treatment (J Addict Med. 2011;5[1]:21-7). “When they looked at patients who actually had opioid dependence, the numbers were even lower,” said Dr. Reynolds, who was not involved with the study. “In fact, 34% of opioid-dependent patients received medication-assisted treatment. When they stratified it by age, the younger you were, the less likely you were to be treated. Only 11.5% of youth under 18 are actually being treated. We know that youth with opioid use disorders have very bad health outcomes over their lifetime. The fact that such few patients receive what is considered to be a gold-standard treatment is really alarming.”

Dr. Reynolds acknowledged that many perceived barriers exist to providing treatment of OUD in pediatric primary care, including the fact that patients with addiction are not easy to treat. “They can be manipulative and can make you feel both sad for them and angry at them within the same visit,” he said. “They also have complex needs. For many of these patients, it’s not just that they use opiates; they have medical problems and psychological diagnoses, and oftentimes they have social issues such as being in foster care. They also may have issues with their parents, employer, or their school, so there are many needs that need to be juggled. That can be overwhelming.”

However, he said that such patients “are actually in our wheelhouse, because as primary care physicians we’re used to coordinating care. These are the perfect patients to have a medical home. We manage chronic disease over the continuum of care. This is a chronic disease, and we have to help patients.”

Another perceived barrier for treating adolescents with OUD relates to reimbursement. While most patients with OUD have insurance, Dr. Reynolds finds that the requirement for prior authorizations can result in delay of treatment and poses an unnecessary burden on care providers. “It’s an administrative task that either the physician or the office staff has to take care of,” he said. “Interestingly, reimbursement ranks as a low concern in studies of buprenorphine providers. That tells me that this is not a major hurdle.”

Pediatricians also cite a lack of knowledge as a reason they’re leery of providing OUD treatment in their office. “They wonder: ‘How do I do this? What’s the right way to do it? Are there best practices?’ ” Dr. Reynolds said. “There’s a feeling that it must be dangerous, the idea that if I don’t do it right I’m going to hurt somebody. The reality is, buprenorphine is no more dangerous than any of the other opiates. Technically, because it’s a partial agonist, it’s probably less dangerous than some of the opiates that we prescribe. It’s no more dangerous than prescribing amitriptyline for chronic pain.”

One key resource, the Providers Clinical Support System (www.pcssnow.org), provides resources for clinicians and family members, education and training, and access to mentoring. Another resource, the American Society of Addiction Medicine (www.asam.org), includes clinical practice guidelines, online courses and training on the treatment of OUD, and sample consent and opioid-withdrawal forms. Dr. Reynolds characterized learning how to treat patients with OUD as no different than learning step therapy for asthma. “Once you look into it, you realize that there’s no sort of magic behind this,” he said. “It’s something that any of us can do. Staff can be trained. There are modules to train your staff into the protocols. Learn the knowledge and put it into action. Have the confidence and the knowledge.”

The Drug Addiction and Treatment Act of 2000 set up the waiver process by which physicians can obtain a waiver from the Drug Enforcement Agency after completing an 8-hour CME course on substance abuse disorder and buprenorphine prescribing. To receive a waiver to practice opioid dependency treatment with approved buprenorphine medications, a clinician must notify the SAMHSA Center for Substance Abuse Treatment of their intent to practice this form of medication-assisted treatment.

Dr. Reynolds acknowledged that not every practice is equipped to provide psychosocial support for complex patients with OUD. “When I first started this in 2017, I wanted to make sure that my patients were in some form of counseling,” he said. “However, the medical literature shows that you can treat OUD without counseling, and some of those patients will be fine, too. There have been reports that just going to Narcotics Anonymous meetings weekly has been shown to improve the effectiveness of medication-assisted treatment.”

For clinicians concerned about having backup when they face challenging cases, data shows that having more than one waivered provider in a practice is associated with completing waiver training. “This makes sense,” Dr. Reynolds said. “We like to be able to discuss our cases with colleagues, but a lot of us don’t want to be on call 365 days a year for our patients. Shared responsibility makes it easier. Access to specialty telemedicine consult has also been identified as a facilitator to physicians prescribing medical-assisted therapy.”

He concluded his presentation by noting that increasing numbers of OUD patients are initiating buprenorphine treatment in the ED. “That takes advantage of the fact that most of these patients present to the emergency room after receiving Narcan for an overdose,” Dr. Reynolds said. “In the emergency room, they’re counseled and instructed on how to start buprenorphine, they’re given the first dose, and they’re told to go home and avoid using any other opiates for 24 hours, start the buprenorphine, and follow up with their primary care doctor or an addiction medicine specialist in 3 days. In my community, this is what our local emergency department is doing for adult patients, except they’re not referring back to primary care. They’re referring to a hospital-based addiction medicine specialist. This is a way to increase access and get people started on buprenorphine treatment.”

Dr. Reynolds reported having no financial disclosures.

[email protected]

VANCOUVER – Two new randomized trials demonstrate that pain following minimally invasive gynecologic surgery can be successfully managed using reduced opioid prescriptions.

Ingram Publishing/Thinkstock

In each case, patients were randomized to receive higher or lower numbers of oxycodone tablets. In both trials, the lower amount was five 5-mg oxycodone tablets. The work should reassure surgeons who wish to change their prescribing patterns, but may worry about patient dissatisfaction, at least in the context of prolapse repair and benign minor gynecologic laparoscopy, which were the focus of the two studies.

The ob.gyn. literature cites rates of 4%-6% of persistent opioid use after surgery on opioid-naive patients, and that’s a risk that needs to be addressed. “If we look at this as a risk factor of our surgical process, this is much higher than any other risk in patients undergoing surgery, and it’s not something we routinely talk to patients about,” Kari Plewniak, MD, an ob.gyn. at Montefiore Medical Center, New York, said during her presentation on pain control during benign gynecologic laparoscopy at the meeting sponsored by AAGL.

The trials provide some welcome guidance. “They provide pretty concrete guidelines with strong evidence of safety, so this is really helpful,” said Sean Dowdy, MD, chair of gynecologic oncology at Mayo Clinic in Rochester, Minn., while speaking as a discussant for the presentations.

Emily Davidson, MD, and associates at the Cleveland Clinic conducted a single-institution, noninferiority trial of standard- versus reduced-prescription opioids in 116 women undergoing prolapse repair. Half were randomized to receive 28 tablets of 5 mg oxycodone (routine arm) and half were prescribed just 5 tablets (reduced arm). All patients also received multimodal pain therapy featuring acetaminophen and ibuprofen. The mean age of patients was 62 years, 91% were white, and 84% were post menopausal. The most common surgery was hysterectomy combined with native tissue repair (60.2%), followed by vaginal colpopexy (15.3%), hysteropexy (15.3%), and sacrocolpopexy (9.3%).

At their postsurgical visit, patients were asked about their satisfaction with their postoperative pain management; 93% in the reduced arm reported that they were very satisfied or somewhat satisfied, as did 93% in the routine arm, which met the standard for noninferiority with a 15% margin. About 15% of patients in the reduced arm used more opioids than originally prescribed, compared with 2% of patients in the routine arm (P less than .01). The reduced arm had an average of 4 unused opioid tablets, compared with 26 in the routine arm. On average, the reduced arm used one tablet, compared with three in the routine arm (P = .03).

The researchers suggested that clinicians should consider prescribing 5-10 tablets for most patients, and all patients should receive multimodal pain management.

The noninferiority nature of the design was welcome, according to Dr. Dowdy. “I think we need to do more noninferiority trial designs because it allows us to make more observations about other parts of the value equation, so if we have two interventions that are equivalent, we can pick the one that has the best patient experience and the lowest cost, so it simplifies a lot of our management.”

The other study, conducted at Montefiore Medical Center, set out to see if a similar regimen of 5 5-mg oxycodone tablets, combined with acetaminophen and ibuprofen, could adequately manage postoperative pain after minor benign gynecologic laparoscopy (excluding hysterectomy), compared with a 10-tablet regimen. All patients received 25 tablets of 600 mg ibuprofen (1 tablet every 6 hours or as needed), plus 50 tablets of 250 mg acetaminophen (1-2 tablets every 6 hours or as needed).

The median number of opioid tablets taken was 2.0 in the 5-tablet group and 2.5 in the 10-tablet group; 32% and 28% took no tablets, and 68% and 65% took three or fewer tablets in the respective groups. The median number of leftover opioid tablets was 3 in the 5-tablet group and 8 in the 10-tablet group, reported Dr. Plewniak.

The studies are a good first step, but more is needed, according to Dr. Dowdy. It’s important to begin looking at more-challenging patient groups, such as those who are not opioid naive, as well as patients taking buprenorphine. “That creates some unique challenges with postoperative pain management,” he said.

Dr. Dowdy, Dr. Davidson, and Dr. Plewniak have no relevant financial disclosures.*

* This article was updated 11/27/2019.

VANCOUVER – Two new randomized trials demonstrate that pain following minimally invasive gynecologic surgery can be successfully managed using reduced opioid prescriptions.

Ingram Publishing/Thinkstock

In each case, patients were randomized to receive higher or lower numbers of oxycodone tablets. In both trials, the lower amount was five 5-mg oxycodone tablets. The work should reassure surgeons who wish to change their prescribing patterns, but may worry about patient dissatisfaction, at least in the context of prolapse repair and benign minor gynecologic laparoscopy, which were the focus of the two studies.

The ob.gyn. literature cites rates of 4%-6% of persistent opioid use after surgery on opioid-naive patients, and that’s a risk that needs to be addressed. “If we look at this as a risk factor of our surgical process, this is much higher than any other risk in patients undergoing surgery, and it’s not something we routinely talk to patients about,” Kari Plewniak, MD, an ob.gyn. at Montefiore Medical Center, New York, said during her presentation on pain control during benign gynecologic laparoscopy at the meeting sponsored by AAGL.

The trials provide some welcome guidance. “They provide pretty concrete guidelines with strong evidence of safety, so this is really helpful,” said Sean Dowdy, MD, chair of gynecologic oncology at Mayo Clinic in Rochester, Minn., while speaking as a discussant for the presentations.

Emily Davidson, MD, and associates at the Cleveland Clinic conducted a single-institution, noninferiority trial of standard- versus reduced-prescription opioids in 116 women undergoing prolapse repair. Half were randomized to receive 28 tablets of 5 mg oxycodone (routine arm) and half were prescribed just 5 tablets (reduced arm). All patients also received multimodal pain therapy featuring acetaminophen and ibuprofen. The mean age of patients was 62 years, 91% were white, and 84% were post menopausal. The most common surgery was hysterectomy combined with native tissue repair (60.2%), followed by vaginal colpopexy (15.3%), hysteropexy (15.3%), and sacrocolpopexy (9.3%).

At their postsurgical visit, patients were asked about their satisfaction with their postoperative pain management; 93% in the reduced arm reported that they were very satisfied or somewhat satisfied, as did 93% in the routine arm, which met the standard for noninferiority with a 15% margin. About 15% of patients in the reduced arm used more opioids than originally prescribed, compared with 2% of patients in the routine arm (P less than .01). The reduced arm had an average of 4 unused opioid tablets, compared with 26 in the routine arm. On average, the reduced arm used one tablet, compared with three in the routine arm (P = .03).

The researchers suggested that clinicians should consider prescribing 5-10 tablets for most patients, and all patients should receive multimodal pain management.

The noninferiority nature of the design was welcome, according to Dr. Dowdy. “I think we need to do more noninferiority trial designs because it allows us to make more observations about other parts of the value equation, so if we have two interventions that are equivalent, we can pick the one that has the best patient experience and the lowest cost, so it simplifies a lot of our management.”

The other study, conducted at Montefiore Medical Center, set out to see if a similar regimen of 5 5-mg oxycodone tablets, combined with acetaminophen and ibuprofen, could adequately manage postoperative pain after minor benign gynecologic laparoscopy (excluding hysterectomy), compared with a 10-tablet regimen. All patients received 25 tablets of 600 mg ibuprofen (1 tablet every 6 hours or as needed), plus 50 tablets of 250 mg acetaminophen (1-2 tablets every 6 hours or as needed).

The median number of opioid tablets taken was 2.0 in the 5-tablet group and 2.5 in the 10-tablet group; 32% and 28% took no tablets, and 68% and 65% took three or fewer tablets in the respective groups. The median number of leftover opioid tablets was 3 in the 5-tablet group and 8 in the 10-tablet group, reported Dr. Plewniak.

The studies are a good first step, but more is needed, according to Dr. Dowdy. It’s important to begin looking at more-challenging patient groups, such as those who are not opioid naive, as well as patients taking buprenorphine. “That creates some unique challenges with postoperative pain management,” he said.

Dr. Dowdy, Dr. Davidson, and Dr. Plewniak have no relevant financial disclosures.*

* This article was updated 11/27/2019.

VANCOUVER – Two new randomized trials demonstrate that pain following minimally invasive gynecologic surgery can be successfully managed using reduced opioid prescriptions.

Ingram Publishing/Thinkstock

In each case, patients were randomized to receive higher or lower numbers of oxycodone tablets. In both trials, the lower amount was five 5-mg oxycodone tablets. The work should reassure surgeons who wish to change their prescribing patterns, but may worry about patient dissatisfaction, at least in the context of prolapse repair and benign minor gynecologic laparoscopy, which were the focus of the two studies.

The ob.gyn. literature cites rates of 4%-6% of persistent opioid use after surgery on opioid-naive patients, and that’s a risk that needs to be addressed. “If we look at this as a risk factor of our surgical process, this is much higher than any other risk in patients undergoing surgery, and it’s not something we routinely talk to patients about,” Kari Plewniak, MD, an ob.gyn. at Montefiore Medical Center, New York, said during her presentation on pain control during benign gynecologic laparoscopy at the meeting sponsored by AAGL.

The trials provide some welcome guidance. “They provide pretty concrete guidelines with strong evidence of safety, so this is really helpful,” said Sean Dowdy, MD, chair of gynecologic oncology at Mayo Clinic in Rochester, Minn., while speaking as a discussant for the presentations.

Emily Davidson, MD, and associates at the Cleveland Clinic conducted a single-institution, noninferiority trial of standard- versus reduced-prescription opioids in 116 women undergoing prolapse repair. Half were randomized to receive 28 tablets of 5 mg oxycodone (routine arm) and half were prescribed just 5 tablets (reduced arm). All patients also received multimodal pain therapy featuring acetaminophen and ibuprofen. The mean age of patients was 62 years, 91% were white, and 84% were post menopausal. The most common surgery was hysterectomy combined with native tissue repair (60.2%), followed by vaginal colpopexy (15.3%), hysteropexy (15.3%), and sacrocolpopexy (9.3%).

At their postsurgical visit, patients were asked about their satisfaction with their postoperative pain management; 93% in the reduced arm reported that they were very satisfied or somewhat satisfied, as did 93% in the routine arm, which met the standard for noninferiority with a 15% margin. About 15% of patients in the reduced arm used more opioids than originally prescribed, compared with 2% of patients in the routine arm (P less than .01). The reduced arm had an average of 4 unused opioid tablets, compared with 26 in the routine arm. On average, the reduced arm used one tablet, compared with three in the routine arm (P = .03).

The researchers suggested that clinicians should consider prescribing 5-10 tablets for most patients, and all patients should receive multimodal pain management.

The noninferiority nature of the design was welcome, according to Dr. Dowdy. “I think we need to do more noninferiority trial designs because it allows us to make more observations about other parts of the value equation, so if we have two interventions that are equivalent, we can pick the one that has the best patient experience and the lowest cost, so it simplifies a lot of our management.”

The other study, conducted at Montefiore Medical Center, set out to see if a similar regimen of 5 5-mg oxycodone tablets, combined with acetaminophen and ibuprofen, could adequately manage postoperative pain after minor benign gynecologic laparoscopy (excluding hysterectomy), compared with a 10-tablet regimen. All patients received 25 tablets of 600 mg ibuprofen (1 tablet every 6 hours or as needed), plus 50 tablets of 250 mg acetaminophen (1-2 tablets every 6 hours or as needed).

The median number of opioid tablets taken was 2.0 in the 5-tablet group and 2.5 in the 10-tablet group; 32% and 28% took no tablets, and 68% and 65% took three or fewer tablets in the respective groups. The median number of leftover opioid tablets was 3 in the 5-tablet group and 8 in the 10-tablet group, reported Dr. Plewniak.

The studies are a good first step, but more is needed, according to Dr. Dowdy. It’s important to begin looking at more-challenging patient groups, such as those who are not opioid naive, as well as patients taking buprenorphine. “That creates some unique challenges with postoperative pain management,” he said.

Dr. Dowdy, Dr. Davidson, and Dr. Plewniak have no relevant financial disclosures.*

* This article was updated 11/27/2019.