PARIS – In a sham-controlled randomized trial that enrolled patients with moderate to severe chronic obstructive pulmonary disease (COPD), targeted lung denervation (TLD) was not only found safe, which was the primary goal of the study, but effective, according to data presented at the annual congress of the European Respiratory Society.

Ted Bosworth/MDedge News

Within the first year of follow-up, “the positive benefit in those randomized to TLD persisted with a more than 50% reduction in the number of patients hospitalized for respiratory complications,” reported Dirk-Jan Slebos, MD, department of lung diseases and tuberculosis, University of Gröningen, the Netherlands.

In this phase 2 trial, called AIRFLOW-2, 82 patients were randomized to receive TLD, which ablates nerves with radiofrequency energy, or a sham procedure. The study enrolled patients with moderate to severe COPD and forced expiratory volume in 1 second of 30%-60% predicted. All patients were treated with the long-acting muscarinic antagonist (LAMA) tiotropium.

The primary endpoint was a composite of respiratory-related adverse events, such as respiratory failure, worsening bronchitis, or worsening dyspnea. Secondary endpoints included serious adverse events of any kind as well as a variety of measures of efficacy, including changes in quality of life as measured with standardized tools such as the St. George’s Respiratory Questionnaire (SGRQ).

Within 6 months of the procedure, 71% of those randomized to the sham procedure and 32% of those treated with TLD experienced one of the predefined respiratory adverse events (P = .0008). At 1 year, 25% of patients in the sham group versus 12% in the TLD group were hospitalized for an exacerbation (P = .039). In addition to achieving greater improvement in several of the individual symptoms, such as dyspnea, those randomized to TLD also achieved numerical improvements in SGRQ scores (–8.3 vs. –3.8) at 12 months.

Gastrointestinal adverse events were more common in the TLD group (15% vs. 5%). Although the higher rate of GI events, which included nausea, bloating, and abdominal discomfort, did not reach statistical significance, it was attributed to off-target exposure of nerves in the GI system to the radiofrequency energy.

“We are improving our imaging process in order to implement additional measures to avoid these nerves,” said Dr. Slebos, who added that this potential risk can be modified. In this study, all of the GI symptoms resolved.

Dr. Slebos emphasized that the 12-month follow-up permitted the study to “confirm that TLD is safe and technically feasible with no late-onset safety signals.” It has set the stage for AIRFLOW-3, a phase 3 trial that is expected to lead to regulatory approval of the catheter if it shows similar safety and efficacy.

The principle of TLD is to deliver energy to ablate parasympathetic pulmonary nerves. The exact mechanism of benefit has not been proved, but it is believed that inhibiting release of acetylcholine that induces smooth muscle constriction has several beneficial downstream effects, including prevention of hyperinflation and reduced mucus production. AIRFLOW-3, like AIRFLOW-2, will evaluate a proprietary catheter developed for this purpose.

“TLD will not replace pharmaceutical therapy. Rather, it appears to have a synergistic effect,” explained Dr. Slebos, who said the procedure is performed on an outpatient basis. The average procedure time for TLD in AIRFLOW-2 was 42 minutes.

The first human study of TLD, also led by Dr. Slebos, was published in 2015. While several subsequent patient series support efficacy and benefit, Daiana Stolz, MD, Clinic for Respiratory Medicine and Pulmonary Cell Research, University of Basel (Switzerland), called the data from this sham-controlled trial “really exciting and important.” However, she said, the larger AIRFLOW-3 trial is needed “to confirm this is an effective and safe treatment.”
 

Dr. Slebos receives consultancy fees from Aeris Therapeutics, Boston Scientific, Broncus Technologies, CSA Medical. Olympus, Portaero, PulmonX, PneumRx/BTG, and Nuvaira, which provided the funding for this study.

PARIS – In a sham-controlled randomized trial that enrolled patients with moderate to severe chronic obstructive pulmonary disease (COPD), targeted lung denervation (TLD) was not only found safe, which was the primary goal of the study, but effective, according to data presented at the annual congress of the European Respiratory Society.

Ted Bosworth/MDedge News

Within the first year of follow-up, “the positive benefit in those randomized to TLD persisted with a more than 50% reduction in the number of patients hospitalized for respiratory complications,” reported Dirk-Jan Slebos, MD, department of lung diseases and tuberculosis, University of Gröningen, the Netherlands.

In this phase 2 trial, called AIRFLOW-2, 82 patients were randomized to receive TLD, which ablates nerves with radiofrequency energy, or a sham procedure. The study enrolled patients with moderate to severe COPD and forced expiratory volume in 1 second of 30%-60% predicted. All patients were treated with the long-acting muscarinic antagonist (LAMA) tiotropium.

The primary endpoint was a composite of respiratory-related adverse events, such as respiratory failure, worsening bronchitis, or worsening dyspnea. Secondary endpoints included serious adverse events of any kind as well as a variety of measures of efficacy, including changes in quality of life as measured with standardized tools such as the St. George’s Respiratory Questionnaire (SGRQ).

Within 6 months of the procedure, 71% of those randomized to the sham procedure and 32% of those treated with TLD experienced one of the predefined respiratory adverse events (P = .0008). At 1 year, 25% of patients in the sham group versus 12% in the TLD group were hospitalized for an exacerbation (P = .039). In addition to achieving greater improvement in several of the individual symptoms, such as dyspnea, those randomized to TLD also achieved numerical improvements in SGRQ scores (–8.3 vs. –3.8) at 12 months.

Gastrointestinal adverse events were more common in the TLD group (15% vs. 5%). Although the higher rate of GI events, which included nausea, bloating, and abdominal discomfort, did not reach statistical significance, it was attributed to off-target exposure of nerves in the GI system to the radiofrequency energy.

“We are improving our imaging process in order to implement additional measures to avoid these nerves,” said Dr. Slebos, who added that this potential risk can be modified. In this study, all of the GI symptoms resolved.

Dr. Slebos emphasized that the 12-month follow-up permitted the study to “confirm that TLD is safe and technically feasible with no late-onset safety signals.” It has set the stage for AIRFLOW-3, a phase 3 trial that is expected to lead to regulatory approval of the catheter if it shows similar safety and efficacy.

The principle of TLD is to deliver energy to ablate parasympathetic pulmonary nerves. The exact mechanism of benefit has not been proved, but it is believed that inhibiting release of acetylcholine that induces smooth muscle constriction has several beneficial downstream effects, including prevention of hyperinflation and reduced mucus production. AIRFLOW-3, like AIRFLOW-2, will evaluate a proprietary catheter developed for this purpose.

“TLD will not replace pharmaceutical therapy. Rather, it appears to have a synergistic effect,” explained Dr. Slebos, who said the procedure is performed on an outpatient basis. The average procedure time for TLD in AIRFLOW-2 was 42 minutes.

The first human study of TLD, also led by Dr. Slebos, was published in 2015. While several subsequent patient series support efficacy and benefit, Daiana Stolz, MD, Clinic for Respiratory Medicine and Pulmonary Cell Research, University of Basel (Switzerland), called the data from this sham-controlled trial “really exciting and important.” However, she said, the larger AIRFLOW-3 trial is needed “to confirm this is an effective and safe treatment.”
 

Dr. Slebos receives consultancy fees from Aeris Therapeutics, Boston Scientific, Broncus Technologies, CSA Medical. Olympus, Portaero, PulmonX, PneumRx/BTG, and Nuvaira, which provided the funding for this study.

PARIS – In a sham-controlled randomized trial that enrolled patients with moderate to severe chronic obstructive pulmonary disease (COPD), targeted lung denervation (TLD) was not only found safe, which was the primary goal of the study, but effective, according to data presented at the annual congress of the European Respiratory Society.

Ted Bosworth/MDedge News

Within the first year of follow-up, “the positive benefit in those randomized to TLD persisted with a more than 50% reduction in the number of patients hospitalized for respiratory complications,” reported Dirk-Jan Slebos, MD, department of lung diseases and tuberculosis, University of Gröningen, the Netherlands.

In this phase 2 trial, called AIRFLOW-2, 82 patients were randomized to receive TLD, which ablates nerves with radiofrequency energy, or a sham procedure. The study enrolled patients with moderate to severe COPD and forced expiratory volume in 1 second of 30%-60% predicted. All patients were treated with the long-acting muscarinic antagonist (LAMA) tiotropium.

The primary endpoint was a composite of respiratory-related adverse events, such as respiratory failure, worsening bronchitis, or worsening dyspnea. Secondary endpoints included serious adverse events of any kind as well as a variety of measures of efficacy, including changes in quality of life as measured with standardized tools such as the St. George’s Respiratory Questionnaire (SGRQ).

Within 6 months of the procedure, 71% of those randomized to the sham procedure and 32% of those treated with TLD experienced one of the predefined respiratory adverse events (P = .0008). At 1 year, 25% of patients in the sham group versus 12% in the TLD group were hospitalized for an exacerbation (P = .039). In addition to achieving greater improvement in several of the individual symptoms, such as dyspnea, those randomized to TLD also achieved numerical improvements in SGRQ scores (–8.3 vs. –3.8) at 12 months.

Gastrointestinal adverse events were more common in the TLD group (15% vs. 5%). Although the higher rate of GI events, which included nausea, bloating, and abdominal discomfort, did not reach statistical significance, it was attributed to off-target exposure of nerves in the GI system to the radiofrequency energy.

“We are improving our imaging process in order to implement additional measures to avoid these nerves,” said Dr. Slebos, who added that this potential risk can be modified. In this study, all of the GI symptoms resolved.

Dr. Slebos emphasized that the 12-month follow-up permitted the study to “confirm that TLD is safe and technically feasible with no late-onset safety signals.” It has set the stage for AIRFLOW-3, a phase 3 trial that is expected to lead to regulatory approval of the catheter if it shows similar safety and efficacy.

The principle of TLD is to deliver energy to ablate parasympathetic pulmonary nerves. The exact mechanism of benefit has not been proved, but it is believed that inhibiting release of acetylcholine that induces smooth muscle constriction has several beneficial downstream effects, including prevention of hyperinflation and reduced mucus production. AIRFLOW-3, like AIRFLOW-2, will evaluate a proprietary catheter developed for this purpose.

“TLD will not replace pharmaceutical therapy. Rather, it appears to have a synergistic effect,” explained Dr. Slebos, who said the procedure is performed on an outpatient basis. The average procedure time for TLD in AIRFLOW-2 was 42 minutes.

The first human study of TLD, also led by Dr. Slebos, was published in 2015. While several subsequent patient series support efficacy and benefit, Daiana Stolz, MD, Clinic for Respiratory Medicine and Pulmonary Cell Research, University of Basel (Switzerland), called the data from this sham-controlled trial “really exciting and important.” However, she said, the larger AIRFLOW-3 trial is needed “to confirm this is an effective and safe treatment.”
 

Dr. Slebos receives consultancy fees from Aeris Therapeutics, Boston Scientific, Broncus Technologies, CSA Medical. Olympus, Portaero, PulmonX, PneumRx/BTG, and Nuvaira, which provided the funding for this study.

SAN DIEGO – Simply offering an ice pop to children who are receiving care in an ED boosts satisfaction scores and physician ratings by their children’s parents, according to data presented at the annual meeting of the American College of Emergency Physicians.

Patient experience and subsequently patient satisfaction scores “have become an increasingly important component of health care delivery. ... Does [the act of] administering Popsicles actually make us better clinicians?” asked Ryan Finn, MD, of the Mayo Clinic, Rochester, Minn., who presented these data.

Exploring low-cost ways to improve patient experience and, by extension, patient satisfaction led to this study of an ice pop intervention, Dr. Finn explained. The study design was simple. During a 3-month period, all children under the age of 14 years (mean age, 6 years) who visited the ED on an even numbered date were offered an ice pop. On odd numbered dates, no ice pop was given. There were no other differences in care.

Parent perceptions of care were assessed with the proprietary Press Ganey patient satisfaction survey. Although a completed survey was submitted for less than 5% of the more than 4,500 patients treated during the study period, differences between the groups still reached statistical significance.

When parents were asked to rate physicians on concern for their child’s comfort, 74% of the group given ice pops and 58% of the group given no ice pops gave favorable responses (P less than.05). The parents of children in the ice pop group also were significantly more likely to rate physicians favorably for their courtesy (77% vs. 62%; P less than .04) and for their willingness to take the time to listen (84% vs. 57%; P less than .03).

Overall rating of care (64% vs. 61%) and likelihood of recommending the ED to others (66% vs. 59%) did not approach statistical significance, according to Dr. Finn.

There are numerous potential advantages to improving the patient experience and boosting patient satisfaction in the ED, as is the case in other areas of the hospital. Even if medical care is of high quality, patient satisfaction does not necessarily follow. Although this single-center study had limitations, such as the low survey completion rate, the measurable effects of the ice pop intervention encourages this direction of research.

“Further studies should increase sample size, assess age group subsets, and assess return on investment for this and other low-cost interventions with the potential to alter patient perceptions,” Dr. Finn said. Because patient satisfaction can be reasonably expected to favorably affect quality of care assessments, he indicated that this is a reasonable target for quality improvement strategies.

SAN DIEGO – Simply offering an ice pop to children who are receiving care in an ED boosts satisfaction scores and physician ratings by their children’s parents, according to data presented at the annual meeting of the American College of Emergency Physicians.

Patient experience and subsequently patient satisfaction scores “have become an increasingly important component of health care delivery. ... Does [the act of] administering Popsicles actually make us better clinicians?” asked Ryan Finn, MD, of the Mayo Clinic, Rochester, Minn., who presented these data.

Exploring low-cost ways to improve patient experience and, by extension, patient satisfaction led to this study of an ice pop intervention, Dr. Finn explained. The study design was simple. During a 3-month period, all children under the age of 14 years (mean age, 6 years) who visited the ED on an even numbered date were offered an ice pop. On odd numbered dates, no ice pop was given. There were no other differences in care.

Parent perceptions of care were assessed with the proprietary Press Ganey patient satisfaction survey. Although a completed survey was submitted for less than 5% of the more than 4,500 patients treated during the study period, differences between the groups still reached statistical significance.

When parents were asked to rate physicians on concern for their child’s comfort, 74% of the group given ice pops and 58% of the group given no ice pops gave favorable responses (P less than.05). The parents of children in the ice pop group also were significantly more likely to rate physicians favorably for their courtesy (77% vs. 62%; P less than .04) and for their willingness to take the time to listen (84% vs. 57%; P less than .03).

Overall rating of care (64% vs. 61%) and likelihood of recommending the ED to others (66% vs. 59%) did not approach statistical significance, according to Dr. Finn.

There are numerous potential advantages to improving the patient experience and boosting patient satisfaction in the ED, as is the case in other areas of the hospital. Even if medical care is of high quality, patient satisfaction does not necessarily follow. Although this single-center study had limitations, such as the low survey completion rate, the measurable effects of the ice pop intervention encourages this direction of research.

“Further studies should increase sample size, assess age group subsets, and assess return on investment for this and other low-cost interventions with the potential to alter patient perceptions,” Dr. Finn said. Because patient satisfaction can be reasonably expected to favorably affect quality of care assessments, he indicated that this is a reasonable target for quality improvement strategies.

SAN DIEGO – Simply offering an ice pop to children who are receiving care in an ED boosts satisfaction scores and physician ratings by their children’s parents, according to data presented at the annual meeting of the American College of Emergency Physicians.

Patient experience and subsequently patient satisfaction scores “have become an increasingly important component of health care delivery. ... Does [the act of] administering Popsicles actually make us better clinicians?” asked Ryan Finn, MD, of the Mayo Clinic, Rochester, Minn., who presented these data.

Exploring low-cost ways to improve patient experience and, by extension, patient satisfaction led to this study of an ice pop intervention, Dr. Finn explained. The study design was simple. During a 3-month period, all children under the age of 14 years (mean age, 6 years) who visited the ED on an even numbered date were offered an ice pop. On odd numbered dates, no ice pop was given. There were no other differences in care.

Parent perceptions of care were assessed with the proprietary Press Ganey patient satisfaction survey. Although a completed survey was submitted for less than 5% of the more than 4,500 patients treated during the study period, differences between the groups still reached statistical significance.

When parents were asked to rate physicians on concern for their child’s comfort, 74% of the group given ice pops and 58% of the group given no ice pops gave favorable responses (P less than.05). The parents of children in the ice pop group also were significantly more likely to rate physicians favorably for their courtesy (77% vs. 62%; P less than .04) and for their willingness to take the time to listen (84% vs. 57%; P less than .03).

Overall rating of care (64% vs. 61%) and likelihood of recommending the ED to others (66% vs. 59%) did not approach statistical significance, according to Dr. Finn.

There are numerous potential advantages to improving the patient experience and boosting patient satisfaction in the ED, as is the case in other areas of the hospital. Even if medical care is of high quality, patient satisfaction does not necessarily follow. Although this single-center study had limitations, such as the low survey completion rate, the measurable effects of the ice pop intervention encourages this direction of research.

“Further studies should increase sample size, assess age group subsets, and assess return on investment for this and other low-cost interventions with the potential to alter patient perceptions,” Dr. Finn said. Because patient satisfaction can be reasonably expected to favorably affect quality of care assessments, he indicated that this is a reasonable target for quality improvement strategies.

The FDA’s MedWatch program safety labeling changes for boxed warnings are compiled quarterly for drugs and therapeutic biologics where important changes have been made to the safety information. These and other label changes are searchable in the Drug Safety Labeling Changes (SLC) database, where data are available to the public in downloadable and searchable formats. Boxed warnings are ordinarily used to highlight either adverse reactions so serious in proportion to the potential benefi t from the drug that it is essential that it be considered in assessing the risks and benefi ts of using the drug; or serious adverse reactions that can be prevented/reduced in frequency or severity by appropriate use of the drug; or FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted. For complete FDA Drug Safety Labeling changes, please visit http://www.accessdata.fda.gov/scripts/cder/safetylabelingchanges.

DESOGEN (DESOGESTREL AND ETHINYL ESTRADIOL TABLETS

• Edited boxed warning, June 2018

WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS

Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs are contraindicated in women who are over 35 years of age, and smoke.

TRIZIVIR (ABACAVIR, LAMIVUDINE, AND ZIDOVUDINE TABLETS)

• Edited boxed warning, April 2018

Lactic Acidosis and Severe Hepatomegaly with Steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including abacavir, lamivudine, and zidovudine (components of TRIZIVIR). Discontinue TRIZIVIR if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur [see Warnings and Precautions (5.4)].

ERBITUX (CETUXIMAB)

• Edited boxed warning, June 2018

WARNING: INFUSION REACTIONS and CARDIOPULMONARY ARREST

Infusion Reactions: ERBITUX can cause serious and fatal infusion reactions [see Warnings and Precautions (5.1), Adverse Reactions (6)]. Immediately interrupt and permanently discontinue ERBITUX for serious infusion reactions [see Dosage and Administration (2.4)].

Cardiopulmonary Arrest: Cardiopulmonary arrest or sudden death occurred in patients with squamous cell carcinoma of the head and neck receiving ERBITUX with radiation therapy or a cetuximab product with platinum-based therapy and fluorouracil. Monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after ERBITUX administration [see Warnings and Precautions (5.2, 5.6)].

AUSTEDO (DEUTETRABENAZINE)

• Edited boxed warning, June 2018

WARNING: DEPRESSION AND SUICIDALITY IN PATIENTS WITH HUNTINGTON’S DISEASE

AUSTEDO can increase the risk of depression …

EXJADE (DEFERASIROX)

• Edited boxed warning, May 2018

Renal Failure: EXJADE can cause acute renal failure and death, particularly in patients with comorbidities and those who are in the advanced stages of their hematologic disorders. Evaluate baseline renal function prior to starting or increasing Exjade dosing in all patients. Exjade is contraindicated in adult and pediatric patients with eGFR less than 40 mL/min/1.73 m2. Measure serum creatinine in duplicate prior to initiation of therapy. Monitor renal function at least monthly. For patients with baseline renal impairment or increased risk of acute renal failure, monitor renal function weekly for the first month, then at least monthly. Reduce the starting dose in patients with pre-existing renal disease. During therapy, increase the frequency of monitoring and modify the dose for patients with an increased risk of renal impairment, including use of concomitant nephrotoxic drugs, and pediatric patients with volume depletion or overchelation.

TUXARIN ER (CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE)

• Edited boxed warning, June 2018

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; MEDICATION ERRORS; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; NEONATAL OPIOID WITHDRAWAL SYNDROME.

Addiction, Abuse, and Misuse: TUXARIN ER exposes patients and other users to the risks of opioid addiction, abuse, and misuse,
which can lead to overdose and death. Reserve TUXARIN ER for use in adult patients for whom the benefits of cough suppression
are expected to outweigh the risks, and in whom an adequate assessment of the etiology of the cough has been made. Assess each
patient’s risk prior to prescribing TUXARIN ER, prescribe TUXARIN ER for the shortest duration that is consistent with individual patient
treatment goals, monitor all patients regularly for the development of addition or abuse, and refill only after reevaluation of the need for continued treatment. [see Warnings and Precautions (5.1)]

Life-Threatening Respiratory Depression: Serious, life-threatening, or fatal respiratory depression may occur with use of TUXARIN ER.
Monitor for respiratory depression, especially during initiation of TUXARIN ER therapy or when used in patients at higher risk [see Warnings and Precautions (5.2)].

Accidental Ingestion: Accidental ingestion of even one dose of TUXARIN ER, especially by children, can result in a fatal overdose of codeine [see Warnings and Precautions (5.2)].

Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children: Life threatening
respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a
CYP2D6 polymorphism. [see Warnings and Precautions (5.3)]. TUXARIN ER is contraindicated in children younger than 12 years of age and
in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications (4)]. Avoid the use of TUXARIN ER in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine. [see Warnings and Precautions (5.1)].

Interactions with Drugs Affecting Cytochrome P450 Isoenzymes: The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with codeine are complex, requiring careful consideration of the effects on the parent drug, codeine, and the active metabolite, morphine. Avoid the use of TUXARIN ER in patients who are taking a CYP3A4 inhibitor, CYP3A4 inducer, or 2D6 inhibitor [see Warnings and Precautions (5.8), Drug Interactions (7.1,7.2, 7.4)]

Risks from Concomitant Use with Benzodiazepines, CNS Depressants: Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Avoid use of TUXARIN ER in patients taking benzodiazepines, other CNS depressants, or alcohol. [see Warning and Precautions (5.9) Drug Interactions (7.5)].

Neonatal Opioid Withdrawal Syndrome: TUXARIN ER is not recommended for use in pregnant women [see Use in Specific Populations
(8.1)]. Prolonged use of TUXARIN ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If TUXARIN ER is used for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.15)].

PROGRAF (TACROLIMUS)

• Edited boxed warning, May 2018

Increased risk for developing serious infections and malignancies with PROGRAF or other immunosuppressants that may lead to hospitalization or death [(see Warnings and Precautions 5.1,5.2)].

SAMSCA (TOLVAPTAN)

• Edited boxed warning, April 2018

Addition of the following:

WARNING: NOT FOR USE FOR AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD)

Because of the risk of hepatoxicity, tolvaptan should not be used for ADPKD outside of the FDA-approved REMS

GLUCOPHAGE/GLUCOPHAGE XR (METFORMIN HYDROCHLORIDE)

• Edited boxed warning, May 2018

PLR conversion; Lactic Acidosis warning is highlighted as boxed warning.

The FDA’s MedWatch program safety labeling changes for boxed warnings are compiled quarterly for drugs and therapeutic biologics where important changes have been made to the safety information. These and other label changes are searchable in the Drug Safety Labeling Changes (SLC) database, where data are available to the public in downloadable and searchable formats. Boxed warnings are ordinarily used to highlight either adverse reactions so serious in proportion to the potential benefi t from the drug that it is essential that it be considered in assessing the risks and benefi ts of using the drug; or serious adverse reactions that can be prevented/reduced in frequency or severity by appropriate use of the drug; or FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted. For complete FDA Drug Safety Labeling changes, please visit http://www.accessdata.fda.gov/scripts/cder/safetylabelingchanges.

DESOGEN (DESOGESTREL AND ETHINYL ESTRADIOL TABLETS

• Edited boxed warning, June 2018

WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS

Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs are contraindicated in women who are over 35 years of age, and smoke.

TRIZIVIR (ABACAVIR, LAMIVUDINE, AND ZIDOVUDINE TABLETS)

• Edited boxed warning, April 2018

Lactic Acidosis and Severe Hepatomegaly with Steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including abacavir, lamivudine, and zidovudine (components of TRIZIVIR). Discontinue TRIZIVIR if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur [see Warnings and Precautions (5.4)].

ERBITUX (CETUXIMAB)

• Edited boxed warning, June 2018

WARNING: INFUSION REACTIONS and CARDIOPULMONARY ARREST

Infusion Reactions: ERBITUX can cause serious and fatal infusion reactions [see Warnings and Precautions (5.1), Adverse Reactions (6)]. Immediately interrupt and permanently discontinue ERBITUX for serious infusion reactions [see Dosage and Administration (2.4)].

Cardiopulmonary Arrest: Cardiopulmonary arrest or sudden death occurred in patients with squamous cell carcinoma of the head and neck receiving ERBITUX with radiation therapy or a cetuximab product with platinum-based therapy and fluorouracil. Monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after ERBITUX administration [see Warnings and Precautions (5.2, 5.6)].

AUSTEDO (DEUTETRABENAZINE)

• Edited boxed warning, June 2018

WARNING: DEPRESSION AND SUICIDALITY IN PATIENTS WITH HUNTINGTON’S DISEASE

AUSTEDO can increase the risk of depression …

EXJADE (DEFERASIROX)

• Edited boxed warning, May 2018

Renal Failure: EXJADE can cause acute renal failure and death, particularly in patients with comorbidities and those who are in the advanced stages of their hematologic disorders. Evaluate baseline renal function prior to starting or increasing Exjade dosing in all patients. Exjade is contraindicated in adult and pediatric patients with eGFR less than 40 mL/min/1.73 m2. Measure serum creatinine in duplicate prior to initiation of therapy. Monitor renal function at least monthly. For patients with baseline renal impairment or increased risk of acute renal failure, monitor renal function weekly for the first month, then at least monthly. Reduce the starting dose in patients with pre-existing renal disease. During therapy, increase the frequency of monitoring and modify the dose for patients with an increased risk of renal impairment, including use of concomitant nephrotoxic drugs, and pediatric patients with volume depletion or overchelation.

TUXARIN ER (CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE)

• Edited boxed warning, June 2018

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; MEDICATION ERRORS; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; NEONATAL OPIOID WITHDRAWAL SYNDROME.

Addiction, Abuse, and Misuse: TUXARIN ER exposes patients and other users to the risks of opioid addiction, abuse, and misuse,
which can lead to overdose and death. Reserve TUXARIN ER for use in adult patients for whom the benefits of cough suppression
are expected to outweigh the risks, and in whom an adequate assessment of the etiology of the cough has been made. Assess each
patient’s risk prior to prescribing TUXARIN ER, prescribe TUXARIN ER for the shortest duration that is consistent with individual patient
treatment goals, monitor all patients regularly for the development of addition or abuse, and refill only after reevaluation of the need for continued treatment. [see Warnings and Precautions (5.1)]

Life-Threatening Respiratory Depression: Serious, life-threatening, or fatal respiratory depression may occur with use of TUXARIN ER.
Monitor for respiratory depression, especially during initiation of TUXARIN ER therapy or when used in patients at higher risk [see Warnings and Precautions (5.2)].

Accidental Ingestion: Accidental ingestion of even one dose of TUXARIN ER, especially by children, can result in a fatal overdose of codeine [see Warnings and Precautions (5.2)].

Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children: Life threatening
respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a
CYP2D6 polymorphism. [see Warnings and Precautions (5.3)]. TUXARIN ER is contraindicated in children younger than 12 years of age and
in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications (4)]. Avoid the use of TUXARIN ER in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine. [see Warnings and Precautions (5.1)].

Interactions with Drugs Affecting Cytochrome P450 Isoenzymes: The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with codeine are complex, requiring careful consideration of the effects on the parent drug, codeine, and the active metabolite, morphine. Avoid the use of TUXARIN ER in patients who are taking a CYP3A4 inhibitor, CYP3A4 inducer, or 2D6 inhibitor [see Warnings and Precautions (5.8), Drug Interactions (7.1,7.2, 7.4)]

Risks from Concomitant Use with Benzodiazepines, CNS Depressants: Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Avoid use of TUXARIN ER in patients taking benzodiazepines, other CNS depressants, or alcohol. [see Warning and Precautions (5.9) Drug Interactions (7.5)].

Neonatal Opioid Withdrawal Syndrome: TUXARIN ER is not recommended for use in pregnant women [see Use in Specific Populations
(8.1)]. Prolonged use of TUXARIN ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If TUXARIN ER is used for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.15)].

PROGRAF (TACROLIMUS)

• Edited boxed warning, May 2018

Increased risk for developing serious infections and malignancies with PROGRAF or other immunosuppressants that may lead to hospitalization or death [(see Warnings and Precautions 5.1,5.2)].

SAMSCA (TOLVAPTAN)

• Edited boxed warning, April 2018

Addition of the following:

WARNING: NOT FOR USE FOR AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD)

Because of the risk of hepatoxicity, tolvaptan should not be used for ADPKD outside of the FDA-approved REMS

GLUCOPHAGE/GLUCOPHAGE XR (METFORMIN HYDROCHLORIDE)

• Edited boxed warning, May 2018

PLR conversion; Lactic Acidosis warning is highlighted as boxed warning.

The FDA’s MedWatch program safety labeling changes for boxed warnings are compiled quarterly for drugs and therapeutic biologics where important changes have been made to the safety information. These and other label changes are searchable in the Drug Safety Labeling Changes (SLC) database, where data are available to the public in downloadable and searchable formats. Boxed warnings are ordinarily used to highlight either adverse reactions so serious in proportion to the potential benefi t from the drug that it is essential that it be considered in assessing the risks and benefi ts of using the drug; or serious adverse reactions that can be prevented/reduced in frequency or severity by appropriate use of the drug; or FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted. For complete FDA Drug Safety Labeling changes, please visit http://www.accessdata.fda.gov/scripts/cder/safetylabelingchanges.

DESOGEN (DESOGESTREL AND ETHINYL ESTRADIOL TABLETS

• Edited boxed warning, June 2018

WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS

Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs are contraindicated in women who are over 35 years of age, and smoke.

TRIZIVIR (ABACAVIR, LAMIVUDINE, AND ZIDOVUDINE TABLETS)

• Edited boxed warning, April 2018

Lactic Acidosis and Severe Hepatomegaly with Steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including abacavir, lamivudine, and zidovudine (components of TRIZIVIR). Discontinue TRIZIVIR if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur [see Warnings and Precautions (5.4)].

ERBITUX (CETUXIMAB)

• Edited boxed warning, June 2018

WARNING: INFUSION REACTIONS and CARDIOPULMONARY ARREST

Infusion Reactions: ERBITUX can cause serious and fatal infusion reactions [see Warnings and Precautions (5.1), Adverse Reactions (6)]. Immediately interrupt and permanently discontinue ERBITUX for serious infusion reactions [see Dosage and Administration (2.4)].

Cardiopulmonary Arrest: Cardiopulmonary arrest or sudden death occurred in patients with squamous cell carcinoma of the head and neck receiving ERBITUX with radiation therapy or a cetuximab product with platinum-based therapy and fluorouracil. Monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after ERBITUX administration [see Warnings and Precautions (5.2, 5.6)].

AUSTEDO (DEUTETRABENAZINE)

• Edited boxed warning, June 2018

WARNING: DEPRESSION AND SUICIDALITY IN PATIENTS WITH HUNTINGTON’S DISEASE

AUSTEDO can increase the risk of depression …

EXJADE (DEFERASIROX)

• Edited boxed warning, May 2018

Renal Failure: EXJADE can cause acute renal failure and death, particularly in patients with comorbidities and those who are in the advanced stages of their hematologic disorders. Evaluate baseline renal function prior to starting or increasing Exjade dosing in all patients. Exjade is contraindicated in adult and pediatric patients with eGFR less than 40 mL/min/1.73 m2. Measure serum creatinine in duplicate prior to initiation of therapy. Monitor renal function at least monthly. For patients with baseline renal impairment or increased risk of acute renal failure, monitor renal function weekly for the first month, then at least monthly. Reduce the starting dose in patients with pre-existing renal disease. During therapy, increase the frequency of monitoring and modify the dose for patients with an increased risk of renal impairment, including use of concomitant nephrotoxic drugs, and pediatric patients with volume depletion or overchelation.

TUXARIN ER (CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE)

• Edited boxed warning, June 2018

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; MEDICATION ERRORS; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; NEONATAL OPIOID WITHDRAWAL SYNDROME.

Addiction, Abuse, and Misuse: TUXARIN ER exposes patients and other users to the risks of opioid addiction, abuse, and misuse,
which can lead to overdose and death. Reserve TUXARIN ER for use in adult patients for whom the benefits of cough suppression
are expected to outweigh the risks, and in whom an adequate assessment of the etiology of the cough has been made. Assess each
patient’s risk prior to prescribing TUXARIN ER, prescribe TUXARIN ER for the shortest duration that is consistent with individual patient
treatment goals, monitor all patients regularly for the development of addition or abuse, and refill only after reevaluation of the need for continued treatment. [see Warnings and Precautions (5.1)]

Life-Threatening Respiratory Depression: Serious, life-threatening, or fatal respiratory depression may occur with use of TUXARIN ER.
Monitor for respiratory depression, especially during initiation of TUXARIN ER therapy or when used in patients at higher risk [see Warnings and Precautions (5.2)].

Accidental Ingestion: Accidental ingestion of even one dose of TUXARIN ER, especially by children, can result in a fatal overdose of codeine [see Warnings and Precautions (5.2)].

Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children: Life threatening
respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a
CYP2D6 polymorphism. [see Warnings and Precautions (5.3)]. TUXARIN ER is contraindicated in children younger than 12 years of age and
in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications (4)]. Avoid the use of TUXARIN ER in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine. [see Warnings and Precautions (5.1)].

Interactions with Drugs Affecting Cytochrome P450 Isoenzymes: The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with codeine are complex, requiring careful consideration of the effects on the parent drug, codeine, and the active metabolite, morphine. Avoid the use of TUXARIN ER in patients who are taking a CYP3A4 inhibitor, CYP3A4 inducer, or 2D6 inhibitor [see Warnings and Precautions (5.8), Drug Interactions (7.1,7.2, 7.4)]

Risks from Concomitant Use with Benzodiazepines, CNS Depressants: Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Avoid use of TUXARIN ER in patients taking benzodiazepines, other CNS depressants, or alcohol. [see Warning and Precautions (5.9) Drug Interactions (7.5)].

Neonatal Opioid Withdrawal Syndrome: TUXARIN ER is not recommended for use in pregnant women [see Use in Specific Populations
(8.1)]. Prolonged use of TUXARIN ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If TUXARIN ER is used for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.15)].

PROGRAF (TACROLIMUS)

• Edited boxed warning, May 2018

Increased risk for developing serious infections and malignancies with PROGRAF or other immunosuppressants that may lead to hospitalization or death [(see Warnings and Precautions 5.1,5.2)].

SAMSCA (TOLVAPTAN)

• Edited boxed warning, April 2018

Addition of the following:

WARNING: NOT FOR USE FOR AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD)

Because of the risk of hepatoxicity, tolvaptan should not be used for ADPKD outside of the FDA-approved REMS

GLUCOPHAGE/GLUCOPHAGE XR (METFORMIN HYDROCHLORIDE)

• Edited boxed warning, May 2018

PLR conversion; Lactic Acidosis warning is highlighted as boxed warning.

Patients with pulmonary arterial hypertension as a consequence of systemic lupus erythematosus can be classified into two different subtypes, one of which shows significantly greater mortality, new research suggests.

Systemic lupus erythematosus–associated pulmonary arterial hypertension (SLE-PAH) has a poor prognosis with 3-year mortality ranging from 45% to 88%, leading the first author of the study Fangfang Sun of the School of Medicine at Shanghai (China) Jiaotong University and coauthors to seek “to further differentiate among SLE-PAH patterns to better understand the disease and optimize its management,

In a letter published online in Annals of the Rheumatic Diseases, the researchers presented data from a retrospective study of a derivation cohort of 108 Chinese patients with SLE-PAH and a validation cohort of 87 patients. Using clinical and laboratory characteristics, the researchers classified the derivation cohort into two clusters, which they labeled as the vasculitic and vasculopathic subtypes.

Patients with the vasculitic subtype of SLE-PAH had higher levels of SLE disease activity and manifestations, such as pericarditis, rash, arthritis, nephritis, and neuropsychiatric lupus, while those with the vasculopathic subtype showed “purer” PAH and lower lupus disease activity.

The researchers found that the vasculitic subtype had around a threefold higher 3-year mortality than did the vasculopathic subtype (34.5%-40.2% vs. 13.0%-18.6%; hazard ratio, 2.84-3.15; P less than .05), even after adjusting for differences in treatments.

Patients who developed PAH less than 2 years after being diagnosed with SLE were significantly more likely to have the vasculitic subtype of SLE-PAH (P less than .0001). A SLE disease activity index score greater than nine was also significantly associated with the vasculitic subtype (P = .001).

The prediction model developed based on these two factors had a sensitivity of 98.5% and a specificity of 74.4% (area under the curve = 0.94; P less than .0001), for a weighted score of two or more, in identifying patients with the vasculitic subtype of SLE-PAH.

Dr. Sun and colleagues suggested that the existence of two distinct clinical subtypes of SLE-PAH points to different underlying pathophysiologic mechanisms; one that is autoimmune mediated and one that involves noninflammatory vascular remodeling. However, the authors stressed that their findings needed confirmation in prospective studies.

“The next key question that remains unanswered is how to balance the utility of immunosuppressants and PAH-targeted drugs in patients with different phenotypes,” they wrote.

Two authors declared research funding from academic and government agencies. No conflicts of interest were declared.

SOURCE: Sun F et al. Ann Rheum Dis. 2018 Sep 19. doi: 10.1136/annrheumdis-2018-214197.

Patients with pulmonary arterial hypertension as a consequence of systemic lupus erythematosus can be classified into two different subtypes, one of which shows significantly greater mortality, new research suggests.

Systemic lupus erythematosus–associated pulmonary arterial hypertension (SLE-PAH) has a poor prognosis with 3-year mortality ranging from 45% to 88%, leading the first author of the study Fangfang Sun of the School of Medicine at Shanghai (China) Jiaotong University and coauthors to seek “to further differentiate among SLE-PAH patterns to better understand the disease and optimize its management,

In a letter published online in Annals of the Rheumatic Diseases, the researchers presented data from a retrospective study of a derivation cohort of 108 Chinese patients with SLE-PAH and a validation cohort of 87 patients. Using clinical and laboratory characteristics, the researchers classified the derivation cohort into two clusters, which they labeled as the vasculitic and vasculopathic subtypes.

Patients with the vasculitic subtype of SLE-PAH had higher levels of SLE disease activity and manifestations, such as pericarditis, rash, arthritis, nephritis, and neuropsychiatric lupus, while those with the vasculopathic subtype showed “purer” PAH and lower lupus disease activity.

The researchers found that the vasculitic subtype had around a threefold higher 3-year mortality than did the vasculopathic subtype (34.5%-40.2% vs. 13.0%-18.6%; hazard ratio, 2.84-3.15; P less than .05), even after adjusting for differences in treatments.

Patients who developed PAH less than 2 years after being diagnosed with SLE were significantly more likely to have the vasculitic subtype of SLE-PAH (P less than .0001). A SLE disease activity index score greater than nine was also significantly associated with the vasculitic subtype (P = .001).

The prediction model developed based on these two factors had a sensitivity of 98.5% and a specificity of 74.4% (area under the curve = 0.94; P less than .0001), for a weighted score of two or more, in identifying patients with the vasculitic subtype of SLE-PAH.

Dr. Sun and colleagues suggested that the existence of two distinct clinical subtypes of SLE-PAH points to different underlying pathophysiologic mechanisms; one that is autoimmune mediated and one that involves noninflammatory vascular remodeling. However, the authors stressed that their findings needed confirmation in prospective studies.

“The next key question that remains unanswered is how to balance the utility of immunosuppressants and PAH-targeted drugs in patients with different phenotypes,” they wrote.

Two authors declared research funding from academic and government agencies. No conflicts of interest were declared.

SOURCE: Sun F et al. Ann Rheum Dis. 2018 Sep 19. doi: 10.1136/annrheumdis-2018-214197.

Patients with pulmonary arterial hypertension as a consequence of systemic lupus erythematosus can be classified into two different subtypes, one of which shows significantly greater mortality, new research suggests.

Systemic lupus erythematosus–associated pulmonary arterial hypertension (SLE-PAH) has a poor prognosis with 3-year mortality ranging from 45% to 88%, leading the first author of the study Fangfang Sun of the School of Medicine at Shanghai (China) Jiaotong University and coauthors to seek “to further differentiate among SLE-PAH patterns to better understand the disease and optimize its management,

In a letter published online in Annals of the Rheumatic Diseases, the researchers presented data from a retrospective study of a derivation cohort of 108 Chinese patients with SLE-PAH and a validation cohort of 87 patients. Using clinical and laboratory characteristics, the researchers classified the derivation cohort into two clusters, which they labeled as the vasculitic and vasculopathic subtypes.

Patients with the vasculitic subtype of SLE-PAH had higher levels of SLE disease activity and manifestations, such as pericarditis, rash, arthritis, nephritis, and neuropsychiatric lupus, while those with the vasculopathic subtype showed “purer” PAH and lower lupus disease activity.

The researchers found that the vasculitic subtype had around a threefold higher 3-year mortality than did the vasculopathic subtype (34.5%-40.2% vs. 13.0%-18.6%; hazard ratio, 2.84-3.15; P less than .05), even after adjusting for differences in treatments.

Patients who developed PAH less than 2 years after being diagnosed with SLE were significantly more likely to have the vasculitic subtype of SLE-PAH (P less than .0001). A SLE disease activity index score greater than nine was also significantly associated with the vasculitic subtype (P = .001).

The prediction model developed based on these two factors had a sensitivity of 98.5% and a specificity of 74.4% (area under the curve = 0.94; P less than .0001), for a weighted score of two or more, in identifying patients with the vasculitic subtype of SLE-PAH.

Dr. Sun and colleagues suggested that the existence of two distinct clinical subtypes of SLE-PAH points to different underlying pathophysiologic mechanisms; one that is autoimmune mediated and one that involves noninflammatory vascular remodeling. However, the authors stressed that their findings needed confirmation in prospective studies.

“The next key question that remains unanswered is how to balance the utility of immunosuppressants and PAH-targeted drugs in patients with different phenotypes,” they wrote.

Two authors declared research funding from academic and government agencies. No conflicts of interest were declared.

SOURCE: Sun F et al. Ann Rheum Dis. 2018 Sep 19. doi: 10.1136/annrheumdis-2018-214197.

SAN DIEGO – Being prepared to manage difficult dislocations is key to maintaining the flow of patient care in any emergency department.

In a video interview at the annual meeting of the American College of Emergency Physicians, Danielle D. Campagne, MD, FACEP, shared her clinical pearls for managing dislocations of the jaw, hip, ankle, and shoulder.

Dr. Campagne is an emergency medicine physician who practices at Community Regional Medical Center in Fresno, Calif. She is also vice chief of emergency medicine at University of California, San Francisco, Fresno. She reported having no financial disclosures.

[email protected]

SAN DIEGO – Being prepared to manage difficult dislocations is key to maintaining the flow of patient care in any emergency department.

In a video interview at the annual meeting of the American College of Emergency Physicians, Danielle D. Campagne, MD, FACEP, shared her clinical pearls for managing dislocations of the jaw, hip, ankle, and shoulder.

Dr. Campagne is an emergency medicine physician who practices at Community Regional Medical Center in Fresno, Calif. She is also vice chief of emergency medicine at University of California, San Francisco, Fresno. She reported having no financial disclosures.

[email protected]

SAN DIEGO – Being prepared to manage difficult dislocations is key to maintaining the flow of patient care in any emergency department.

In a video interview at the annual meeting of the American College of Emergency Physicians, Danielle D. Campagne, MD, FACEP, shared her clinical pearls for managing dislocations of the jaw, hip, ankle, and shoulder.

Dr. Campagne is an emergency medicine physician who practices at Community Regional Medical Center in Fresno, Calif. She is also vice chief of emergency medicine at University of California, San Francisco, Fresno. She reported having no financial disclosures.

[email protected]

Cancer geneticists have identified 21 clusters of complex chromosomal rearrangements in breast cancers that contain both known oncogenes and potential new driver loci.

A systematic analysis of chromosomal rearrangements in tissues from 560 patients with breast cancer identified 21 “hotspots,” some of which contain known oncogene chromosomal loci, and others of which contain genes not typically associated with breast cancer, reported Serena Nik-Zainal, PhD, of the University of Cambridge, England, and her colleagues.

“Detailed analysis of rearrangements at these hotspots highlights chromosomal aberrations likely driven by selection, and reveal underlying mutational processes,” they wrote in a study published online in Annals of Oncology.

The investigators sought insight into mutational mechanisms of gene amplifications by examining clustered rearrangements – somatic breakpoints occurring in high densities – in individual patients.

To see whether these rearrangements were associated with breast cancer, they identified the aforementioned chromosomal hotspots where clustered rearrangements were seen in samples from different patients.

They identified 624 cluster rearrangements in the 560 breast cancer genomes, including 17,247 within-chromosome rearrangements, and 6,509 between-chromosome translocations.

Of the 560 samples, 372 had at least one rearrangement cluster, with the frequency of clusters similar between some breast cancer types. For example, there were 0.96 rearrangements clusters per sample from patients with triple negative breast cancers, and 1.00 per sample from women with estrogen receptor–positive tumors.

“To identify loci where clusters of rearrangements recur across multiple independent tumor samples, we pooled all breakpoints in the ‘clustered’ category and sorted them according to position in the reference genome,” the investigators explained.

They used a Piecewise-Constant-Fitting algorithm to identify genome sequences where there were short inter-mutation distances between rearrangement clusters, suggesting the presence of hotspots.

In the 21 hotspots they identified, they found, as expected, common driver amplification regions (e.g., CCND1, ERBB2, ZNF217, chr8:ZNF703/FGFR1, IGF1R, and MYC), but also several hotspots near oncogenes that are not typically associated with breast cancer.

Notably, they saw simultaneous amplification of regions on chromosomes 8 and 11 (chr8:ZNF703/FGFR1 and chr11:CCND1). Amplification of these regions are frequent in estrogen receptor–positive breast cancers. The investigators propose a pathogenic model in which a chromosome 8 to chromosome 11 translocation is an early, critical event leading to breast tumor development.

“Clustered rearrangements are common in breast cancer genomes, and often associated with gene amplifications that drive oncogenesis. Understanding the process of amplicon formation, an example of which we present here for the chr8:ZNF703/FGFR1 and chr11:CCND1 co-amplifications, will be important for our understanding of the origins of a subset of breast cancers,” they concluded.

The study was supported by an award from the Wellcome Trust. Dr. Nik-Zainal and coauthor Dominik Glodzik are inventors on several patent applications. All remaining authors declared no conflicts of interest.
 

SOURCE: Glodzik D et al. Ann Oncol. 2018 Sept 25. doi: 10.1093/annonc/mdy404.

Cancer geneticists have identified 21 clusters of complex chromosomal rearrangements in breast cancers that contain both known oncogenes and potential new driver loci.

A systematic analysis of chromosomal rearrangements in tissues from 560 patients with breast cancer identified 21 “hotspots,” some of which contain known oncogene chromosomal loci, and others of which contain genes not typically associated with breast cancer, reported Serena Nik-Zainal, PhD, of the University of Cambridge, England, and her colleagues.

“Detailed analysis of rearrangements at these hotspots highlights chromosomal aberrations likely driven by selection, and reveal underlying mutational processes,” they wrote in a study published online in Annals of Oncology.

The investigators sought insight into mutational mechanisms of gene amplifications by examining clustered rearrangements – somatic breakpoints occurring in high densities – in individual patients.

To see whether these rearrangements were associated with breast cancer, they identified the aforementioned chromosomal hotspots where clustered rearrangements were seen in samples from different patients.

They identified 624 cluster rearrangements in the 560 breast cancer genomes, including 17,247 within-chromosome rearrangements, and 6,509 between-chromosome translocations.

Of the 560 samples, 372 had at least one rearrangement cluster, with the frequency of clusters similar between some breast cancer types. For example, there were 0.96 rearrangements clusters per sample from patients with triple negative breast cancers, and 1.00 per sample from women with estrogen receptor–positive tumors.

“To identify loci where clusters of rearrangements recur across multiple independent tumor samples, we pooled all breakpoints in the ‘clustered’ category and sorted them according to position in the reference genome,” the investigators explained.

They used a Piecewise-Constant-Fitting algorithm to identify genome sequences where there were short inter-mutation distances between rearrangement clusters, suggesting the presence of hotspots.

In the 21 hotspots they identified, they found, as expected, common driver amplification regions (e.g., CCND1, ERBB2, ZNF217, chr8:ZNF703/FGFR1, IGF1R, and MYC), but also several hotspots near oncogenes that are not typically associated with breast cancer.

Notably, they saw simultaneous amplification of regions on chromosomes 8 and 11 (chr8:ZNF703/FGFR1 and chr11:CCND1). Amplification of these regions are frequent in estrogen receptor–positive breast cancers. The investigators propose a pathogenic model in which a chromosome 8 to chromosome 11 translocation is an early, critical event leading to breast tumor development.

“Clustered rearrangements are common in breast cancer genomes, and often associated with gene amplifications that drive oncogenesis. Understanding the process of amplicon formation, an example of which we present here for the chr8:ZNF703/FGFR1 and chr11:CCND1 co-amplifications, will be important for our understanding of the origins of a subset of breast cancers,” they concluded.

The study was supported by an award from the Wellcome Trust. Dr. Nik-Zainal and coauthor Dominik Glodzik are inventors on several patent applications. All remaining authors declared no conflicts of interest.
 

SOURCE: Glodzik D et al. Ann Oncol. 2018 Sept 25. doi: 10.1093/annonc/mdy404.

Cancer geneticists have identified 21 clusters of complex chromosomal rearrangements in breast cancers that contain both known oncogenes and potential new driver loci.

A systematic analysis of chromosomal rearrangements in tissues from 560 patients with breast cancer identified 21 “hotspots,” some of which contain known oncogene chromosomal loci, and others of which contain genes not typically associated with breast cancer, reported Serena Nik-Zainal, PhD, of the University of Cambridge, England, and her colleagues.

“Detailed analysis of rearrangements at these hotspots highlights chromosomal aberrations likely driven by selection, and reveal underlying mutational processes,” they wrote in a study published online in Annals of Oncology.

The investigators sought insight into mutational mechanisms of gene amplifications by examining clustered rearrangements – somatic breakpoints occurring in high densities – in individual patients.

To see whether these rearrangements were associated with breast cancer, they identified the aforementioned chromosomal hotspots where clustered rearrangements were seen in samples from different patients.

They identified 624 cluster rearrangements in the 560 breast cancer genomes, including 17,247 within-chromosome rearrangements, and 6,509 between-chromosome translocations.

Of the 560 samples, 372 had at least one rearrangement cluster, with the frequency of clusters similar between some breast cancer types. For example, there were 0.96 rearrangements clusters per sample from patients with triple negative breast cancers, and 1.00 per sample from women with estrogen receptor–positive tumors.

“To identify loci where clusters of rearrangements recur across multiple independent tumor samples, we pooled all breakpoints in the ‘clustered’ category and sorted them according to position in the reference genome,” the investigators explained.

They used a Piecewise-Constant-Fitting algorithm to identify genome sequences where there were short inter-mutation distances between rearrangement clusters, suggesting the presence of hotspots.

In the 21 hotspots they identified, they found, as expected, common driver amplification regions (e.g., CCND1, ERBB2, ZNF217, chr8:ZNF703/FGFR1, IGF1R, and MYC), but also several hotspots near oncogenes that are not typically associated with breast cancer.

Notably, they saw simultaneous amplification of regions on chromosomes 8 and 11 (chr8:ZNF703/FGFR1 and chr11:CCND1). Amplification of these regions are frequent in estrogen receptor–positive breast cancers. The investigators propose a pathogenic model in which a chromosome 8 to chromosome 11 translocation is an early, critical event leading to breast tumor development.

“Clustered rearrangements are common in breast cancer genomes, and often associated with gene amplifications that drive oncogenesis. Understanding the process of amplicon formation, an example of which we present here for the chr8:ZNF703/FGFR1 and chr11:CCND1 co-amplifications, will be important for our understanding of the origins of a subset of breast cancers,” they concluded.

The study was supported by an award from the Wellcome Trust. Dr. Nik-Zainal and coauthor Dominik Glodzik are inventors on several patent applications. All remaining authors declared no conflicts of interest.
 

SOURCE: Glodzik D et al. Ann Oncol. 2018 Sept 25. doi: 10.1093/annonc/mdy404.

Sexual harassment and assault may have significant health impacts on women in midlife, including greater risk of hypertension, poor sleep, depression, and anxiety, research suggests.

thodonal/Thinkstock

In the Oct. 3 online edition of JAMA Internal Medicine, a study of 304 women aged 40-60 years showed that 19% reported a history of workplace sexual harassment, 22% reported a history of sexual assault, and 10% reported both. The report was presented simultaneously at the North American Menopause Society annual meeting in San Diego.

The researchers found that those with a history of sexual assault had an almost threefold higher odds of clinically elevated depressive symptoms (OR, 2.86, P = .003), and more than twofold greater odds of anxiety and poor sleep (OR, 2.26, P = .006 and OR, 2.15, P = .007 respectively).

Women who reported experiencing sexual harassment in the workplace – and who were not taking antihypertensive medication – were more than twice as likely to have stage 1 or 2 hypertension, compared with women who had not experienced sexual harassment (OR, 2.36, P = .03). They also had 89% higher odds of poor sleep consistent with clinical insomnia (P = .03).

These associations all persisted even after adjustment for demographic and biomedical factors such as age, ethnicity, body mass index, snoring, and the use of antihypertensive, antidepressant, and anti-anxiety medications.

“Given the high prevalence of sexual harassment and assault, addressing these prevalent and potent social exposures may be critical to promoting health and preventing disease in women,” wrote Rebecca C. Thurston, PhD, of the department of psychiatry at the University of Pittsburgh, and her coauthors.

The study was supported by the National Institutes of Health, National Heart Lung and Blood Institute, and the University of Pittsburgh Clinical and Translational Science Institute. Dr. Thurston declared consultancies for MAS Innovations, Procter & Gamble, and Pfizer, but no other conflicts of interest were declared.

SOURCE: Thurston R et al. JAMA Intern Med. 2018, Oct 3. doi: 10.1001/jamainternmed.2018.4886.

Sexual harassment and assault may have significant health impacts on women in midlife, including greater risk of hypertension, poor sleep, depression, and anxiety, research suggests.

thodonal/Thinkstock

In the Oct. 3 online edition of JAMA Internal Medicine, a study of 304 women aged 40-60 years showed that 19% reported a history of workplace sexual harassment, 22% reported a history of sexual assault, and 10% reported both. The report was presented simultaneously at the North American Menopause Society annual meeting in San Diego.

The researchers found that those with a history of sexual assault had an almost threefold higher odds of clinically elevated depressive symptoms (OR, 2.86, P = .003), and more than twofold greater odds of anxiety and poor sleep (OR, 2.26, P = .006 and OR, 2.15, P = .007 respectively).

Women who reported experiencing sexual harassment in the workplace – and who were not taking antihypertensive medication – were more than twice as likely to have stage 1 or 2 hypertension, compared with women who had not experienced sexual harassment (OR, 2.36, P = .03). They also had 89% higher odds of poor sleep consistent with clinical insomnia (P = .03).

These associations all persisted even after adjustment for demographic and biomedical factors such as age, ethnicity, body mass index, snoring, and the use of antihypertensive, antidepressant, and anti-anxiety medications.

“Given the high prevalence of sexual harassment and assault, addressing these prevalent and potent social exposures may be critical to promoting health and preventing disease in women,” wrote Rebecca C. Thurston, PhD, of the department of psychiatry at the University of Pittsburgh, and her coauthors.

The study was supported by the National Institutes of Health, National Heart Lung and Blood Institute, and the University of Pittsburgh Clinical and Translational Science Institute. Dr. Thurston declared consultancies for MAS Innovations, Procter & Gamble, and Pfizer, but no other conflicts of interest were declared.

SOURCE: Thurston R et al. JAMA Intern Med. 2018, Oct 3. doi: 10.1001/jamainternmed.2018.4886.

Sexual harassment and assault may have significant health impacts on women in midlife, including greater risk of hypertension, poor sleep, depression, and anxiety, research suggests.

thodonal/Thinkstock

In the Oct. 3 online edition of JAMA Internal Medicine, a study of 304 women aged 40-60 years showed that 19% reported a history of workplace sexual harassment, 22% reported a history of sexual assault, and 10% reported both. The report was presented simultaneously at the North American Menopause Society annual meeting in San Diego.

The researchers found that those with a history of sexual assault had an almost threefold higher odds of clinically elevated depressive symptoms (OR, 2.86, P = .003), and more than twofold greater odds of anxiety and poor sleep (OR, 2.26, P = .006 and OR, 2.15, P = .007 respectively).

Women who reported experiencing sexual harassment in the workplace – and who were not taking antihypertensive medication – were more than twice as likely to have stage 1 or 2 hypertension, compared with women who had not experienced sexual harassment (OR, 2.36, P = .03). They also had 89% higher odds of poor sleep consistent with clinical insomnia (P = .03).

These associations all persisted even after adjustment for demographic and biomedical factors such as age, ethnicity, body mass index, snoring, and the use of antihypertensive, antidepressant, and anti-anxiety medications.

“Given the high prevalence of sexual harassment and assault, addressing these prevalent and potent social exposures may be critical to promoting health and preventing disease in women,” wrote Rebecca C. Thurston, PhD, of the department of psychiatry at the University of Pittsburgh, and her coauthors.

The study was supported by the National Institutes of Health, National Heart Lung and Blood Institute, and the University of Pittsburgh Clinical and Translational Science Institute. Dr. Thurston declared consultancies for MAS Innovations, Procter & Gamble, and Pfizer, but no other conflicts of interest were declared.

SOURCE: Thurston R et al. JAMA Intern Med. 2018, Oct 3. doi: 10.1001/jamainternmed.2018.4886.

TORONTO – Adding the programmed death-ligand 1 (PD-L1) inhibitor atezolizumab to standard first-line chemotherapy and maintenance therapy in patients with advanced nonsquamous non–small-cell lung cancer significantly improved progression-free survival (PFS), in the randomized, open-label IMpower132 trial.

At a minimum follow-up of 11.7 months (median, 14.8 months), investigator-assessed median PFS in 292 patients enrolled in the atezolizumab arm of the global study was 7.6 months, compared with 5.2 months – a 40% reduction in risk of disease progression – in 286 patients who received only first-line carboplatin plus pemetrexed and pemetrexed maintenance therapy (hazard ratio, 0.60), Vassiliki A Papadimitrakopoulou, MD, reported at the World Conference on Lung Cancer.

“The landmark PFS at 12-months showed almost a doubling for the investigational arm [at] 33.7% vs. 17%,” said Dr. Papadimitrakopoulou, professor of medicine and chief of the section of thoracic medical oncology at MD Anderson Cancer Center in Houston. “PFS benefit was seen across all key subgroups, [and was] especially pronounced for female patients (HR, 0.51), Asian patients (HR, 0.42), never-smokers (HR, 0.49), and patients who didn’t have liver metastases (HR, 0.56).”

PFS was also looked at – as an exploratory endpoint – by PD-L1 status in biomarker-evaluable patients, and “again, benefit was seen across all PD-L1-defined subgroups with a consistent trend for most benefit among the highest expressers,” she noted.

Median PFS was 10.8 months in 25 atezolizumab-treated patients with high PD-L1 expression, vs. 6.5 months in 20 control group patients with high PD-L1 expression; 6.2 vs. 5.7 months in 63 and 73 patients with low-PD-L1 expression in the groups, respectively; and 8.5 vs. 4.9 months in 88 and 75 PD-L1-negative patients in the groups, respectively, she reported at the conference, which was sponsored by the International Association for the Study of Lung Cancer.

Interim analyses also showed a numerically superior improvement in median and 12-month overall survival in the atezolizumab vs. control group (median, 18.1 vs. 13.6 months; HR, 0.813; P = .0797; 12-month, 59.6% vs. 55.4%), she said, adding that overall survival will be looked at again at the final analysis of the data, which is anticipated some time in the first half of 2019.

Study participants were chemotherapy-naive patients with measurable stage IV nonsquamous NSCLC and Eastern Cooperative Oncology Group Performance Status 0-1. Those with tumors known to harbor epidermal growth factor receptor or anaplastic lymphoma kinase driver mutations were excluded, as were those with untreated central nervous system metastases, autoimmune disease, and prior exposure to immunotherapy.

All patients received four or six cycles of carboplatin at a dose of area under the curve 6 mg/mL/min or cisplatin at a dose of 75 mg/m² plus 500 mg/m² of pemetrexed every 3 weeks, and those in the experimental arm also received 1,200 mg of atezolizumab every 3 weeks. Maintenance therapy included pemetrexed alone in the control arm, and atezolizumab plus pemetrexed in the experimental arm.

Treatment was well tolerated, and no new safety signals emerged, Dr. Papadimitrakopoulou said, noting that adverse events were similar in the groups, but more common in the atezolizumab-treated patients. Grade 3-4 treatment-related adverse events occurred in 54% of patients receiving atezolizumab vs. 39% of those in the control group, and serious adverse events occurred in 33% vs. 16%.

“The findings from IMpower132 indicate that the addition of atezolizumab to a backbone of carboplatin and pemetrexed chemotherapy provides better clinical efficacy than carboplatin and pemetrexed alone,” Dr. Papadimitrakopoulou said in a press statement. “By inhibiting the interaction of PD-L1 with its receptors PD-1 and B7.1, atezolizumab restores tumor-specific T-cell immunity, offering a valuable treatment option that prolongs survival for patients with stage IV nonsquamous NSCLC.”

IMpower132 is sponsored by F. Hoffmann–La Roche Ltd. Dr. Papadimitrakopoulou has received research support from, and/or is an advisory board member for numerous companies including F. Hoffmann–La Roche.

SOURCE: Papadimitrakopoulou V et al. WCLC 2018 Abstract OA05.07.

TORONTO – Adding the programmed death-ligand 1 (PD-L1) inhibitor atezolizumab to standard first-line chemotherapy and maintenance therapy in patients with advanced nonsquamous non–small-cell lung cancer significantly improved progression-free survival (PFS), in the randomized, open-label IMpower132 trial.

At a minimum follow-up of 11.7 months (median, 14.8 months), investigator-assessed median PFS in 292 patients enrolled in the atezolizumab arm of the global study was 7.6 months, compared with 5.2 months – a 40% reduction in risk of disease progression – in 286 patients who received only first-line carboplatin plus pemetrexed and pemetrexed maintenance therapy (hazard ratio, 0.60), Vassiliki A Papadimitrakopoulou, MD, reported at the World Conference on Lung Cancer.

“The landmark PFS at 12-months showed almost a doubling for the investigational arm [at] 33.7% vs. 17%,” said Dr. Papadimitrakopoulou, professor of medicine and chief of the section of thoracic medical oncology at MD Anderson Cancer Center in Houston. “PFS benefit was seen across all key subgroups, [and was] especially pronounced for female patients (HR, 0.51), Asian patients (HR, 0.42), never-smokers (HR, 0.49), and patients who didn’t have liver metastases (HR, 0.56).”

PFS was also looked at – as an exploratory endpoint – by PD-L1 status in biomarker-evaluable patients, and “again, benefit was seen across all PD-L1-defined subgroups with a consistent trend for most benefit among the highest expressers,” she noted.

Median PFS was 10.8 months in 25 atezolizumab-treated patients with high PD-L1 expression, vs. 6.5 months in 20 control group patients with high PD-L1 expression; 6.2 vs. 5.7 months in 63 and 73 patients with low-PD-L1 expression in the groups, respectively; and 8.5 vs. 4.9 months in 88 and 75 PD-L1-negative patients in the groups, respectively, she reported at the conference, which was sponsored by the International Association for the Study of Lung Cancer.

Interim analyses also showed a numerically superior improvement in median and 12-month overall survival in the atezolizumab vs. control group (median, 18.1 vs. 13.6 months; HR, 0.813; P = .0797; 12-month, 59.6% vs. 55.4%), she said, adding that overall survival will be looked at again at the final analysis of the data, which is anticipated some time in the first half of 2019.

Study participants were chemotherapy-naive patients with measurable stage IV nonsquamous NSCLC and Eastern Cooperative Oncology Group Performance Status 0-1. Those with tumors known to harbor epidermal growth factor receptor or anaplastic lymphoma kinase driver mutations were excluded, as were those with untreated central nervous system metastases, autoimmune disease, and prior exposure to immunotherapy.

All patients received four or six cycles of carboplatin at a dose of area under the curve 6 mg/mL/min or cisplatin at a dose of 75 mg/m² plus 500 mg/m² of pemetrexed every 3 weeks, and those in the experimental arm also received 1,200 mg of atezolizumab every 3 weeks. Maintenance therapy included pemetrexed alone in the control arm, and atezolizumab plus pemetrexed in the experimental arm.

Treatment was well tolerated, and no new safety signals emerged, Dr. Papadimitrakopoulou said, noting that adverse events were similar in the groups, but more common in the atezolizumab-treated patients. Grade 3-4 treatment-related adverse events occurred in 54% of patients receiving atezolizumab vs. 39% of those in the control group, and serious adverse events occurred in 33% vs. 16%.

“The findings from IMpower132 indicate that the addition of atezolizumab to a backbone of carboplatin and pemetrexed chemotherapy provides better clinical efficacy than carboplatin and pemetrexed alone,” Dr. Papadimitrakopoulou said in a press statement. “By inhibiting the interaction of PD-L1 with its receptors PD-1 and B7.1, atezolizumab restores tumor-specific T-cell immunity, offering a valuable treatment option that prolongs survival for patients with stage IV nonsquamous NSCLC.”

IMpower132 is sponsored by F. Hoffmann–La Roche Ltd. Dr. Papadimitrakopoulou has received research support from, and/or is an advisory board member for numerous companies including F. Hoffmann–La Roche.

SOURCE: Papadimitrakopoulou V et al. WCLC 2018 Abstract OA05.07.

TORONTO – Adding the programmed death-ligand 1 (PD-L1) inhibitor atezolizumab to standard first-line chemotherapy and maintenance therapy in patients with advanced nonsquamous non–small-cell lung cancer significantly improved progression-free survival (PFS), in the randomized, open-label IMpower132 trial.

At a minimum follow-up of 11.7 months (median, 14.8 months), investigator-assessed median PFS in 292 patients enrolled in the atezolizumab arm of the global study was 7.6 months, compared with 5.2 months – a 40% reduction in risk of disease progression – in 286 patients who received only first-line carboplatin plus pemetrexed and pemetrexed maintenance therapy (hazard ratio, 0.60), Vassiliki A Papadimitrakopoulou, MD, reported at the World Conference on Lung Cancer.

“The landmark PFS at 12-months showed almost a doubling for the investigational arm [at] 33.7% vs. 17%,” said Dr. Papadimitrakopoulou, professor of medicine and chief of the section of thoracic medical oncology at MD Anderson Cancer Center in Houston. “PFS benefit was seen across all key subgroups, [and was] especially pronounced for female patients (HR, 0.51), Asian patients (HR, 0.42), never-smokers (HR, 0.49), and patients who didn’t have liver metastases (HR, 0.56).”

PFS was also looked at – as an exploratory endpoint – by PD-L1 status in biomarker-evaluable patients, and “again, benefit was seen across all PD-L1-defined subgroups with a consistent trend for most benefit among the highest expressers,” she noted.

Median PFS was 10.8 months in 25 atezolizumab-treated patients with high PD-L1 expression, vs. 6.5 months in 20 control group patients with high PD-L1 expression; 6.2 vs. 5.7 months in 63 and 73 patients with low-PD-L1 expression in the groups, respectively; and 8.5 vs. 4.9 months in 88 and 75 PD-L1-negative patients in the groups, respectively, she reported at the conference, which was sponsored by the International Association for the Study of Lung Cancer.

Interim analyses also showed a numerically superior improvement in median and 12-month overall survival in the atezolizumab vs. control group (median, 18.1 vs. 13.6 months; HR, 0.813; P = .0797; 12-month, 59.6% vs. 55.4%), she said, adding that overall survival will be looked at again at the final analysis of the data, which is anticipated some time in the first half of 2019.

Study participants were chemotherapy-naive patients with measurable stage IV nonsquamous NSCLC and Eastern Cooperative Oncology Group Performance Status 0-1. Those with tumors known to harbor epidermal growth factor receptor or anaplastic lymphoma kinase driver mutations were excluded, as were those with untreated central nervous system metastases, autoimmune disease, and prior exposure to immunotherapy.

All patients received four or six cycles of carboplatin at a dose of area under the curve 6 mg/mL/min or cisplatin at a dose of 75 mg/m² plus 500 mg/m² of pemetrexed every 3 weeks, and those in the experimental arm also received 1,200 mg of atezolizumab every 3 weeks. Maintenance therapy included pemetrexed alone in the control arm, and atezolizumab plus pemetrexed in the experimental arm.

Treatment was well tolerated, and no new safety signals emerged, Dr. Papadimitrakopoulou said, noting that adverse events were similar in the groups, but more common in the atezolizumab-treated patients. Grade 3-4 treatment-related adverse events occurred in 54% of patients receiving atezolizumab vs. 39% of those in the control group, and serious adverse events occurred in 33% vs. 16%.

“The findings from IMpower132 indicate that the addition of atezolizumab to a backbone of carboplatin and pemetrexed chemotherapy provides better clinical efficacy than carboplatin and pemetrexed alone,” Dr. Papadimitrakopoulou said in a press statement. “By inhibiting the interaction of PD-L1 with its receptors PD-1 and B7.1, atezolizumab restores tumor-specific T-cell immunity, offering a valuable treatment option that prolongs survival for patients with stage IV nonsquamous NSCLC.”

IMpower132 is sponsored by F. Hoffmann–La Roche Ltd. Dr. Papadimitrakopoulou has received research support from, and/or is an advisory board member for numerous companies including F. Hoffmann–La Roche.

SOURCE: Papadimitrakopoulou V et al. WCLC 2018 Abstract OA05.07.

Placenta accreta spectrum (PAS) describes abnormal invasion of placental tissue into or through the myometrium, comprising 3 distinct conditions: placenta accreta, placenta increta, and placenta percreta. This complication is relatively new to obstetrics, first described in 1937.¹

The overall incidence of PAS has been increasing over several decades, in parallel to an increasing rate of cesarean delivery (CD), with an incidence from 1982 through 2002 of 1 in 533 pregnancies, representing a 5-fold increase since the 1980s.² PAS is associated with significant morbidity and mortality, including fetal growth restriction, preterm delivery, placental abruption antenatally, and hemorrhage during delivery or postpartum.

Prenatal diagnosis of PAS and planned delivery at an experienced center are associated with significant reduction in maternal and fetal morbidity.³ In an era of advanced imaging modalities, prenatal detection of PAS regrettably remains variable and largely subjective: As many as 20% to 50% of cases of PAS escape prenatal diagnosis.^3,4

In this article, we review the sonographic markers of PAS, including diagnostic accuracy, and propose a standardized approach to prenatal diagnosis. Throughout our discussion, we describe protocols for detection of PAS practiced at our Maternal-Fetal Medicine Program in the Department of Obstetrics and Gynecology, Eastern Virginia Medical School (also see “US evaluation of PAS risk: The authors’ recommended approach”).

Numerous risk factors

There are many risk factors for PAS, including prior uterine surgery or instrumentation, such as CD, uterine curettage, myomectomy, pelvic radiation, and endometrial ablation. Other risk factors include smoking, in vitro fertilization, advanced maternal age, multiparity, and a brief interval between prior CD and subsequent pregnancy.⁵ Of major significance is the increased risk of PAS in the presence of placenta previa with prior CD.⁶ Knowledge of clinical risk factors by the interpreting physician appears to be associated with improved detection of PAS on ultrasonography (US).⁴

Ultrasonographic markers of PAS

First-trimester markers

Sonographic markers of PAS in the first trimester include:

• a gestational sac implanted in the lower uterine segment or in a CD scar
• multiple hypoechoic spaces within the placenta (lacunae).⁷

Lower uterine-segment implantation has been defined by Ballas and colleagues as 1) a gestational sac implanted in the lower one-third of the uterus between 8 and 10 weeks’ gestation or 2) a gestational sac occupying primarily the lower uterine segment from 10 weeks’ gestation onward (FIGURE 1).⁸ Our experience is that it is difficult to accurately assess lower uterine-segment implantation beyond 13 weeks of gestation because the sac typically expands to fill the upper uterine cavity.

Continue to: Color Doppler US...

Color Doppler US can help differentiate lower uterine-segment implantation from a gestational sac of a failed pregnancy in the process of expulsion by demonstrating loss of circumferential blood flow in the failed pregnancy. Furthermore, applying pressure to the anterior surface of the uterus will result in downward movement of the gestational sac of a failed pregnancy.⁹

Not all gestational sacs that implant in the lower uterine segment lead to PAS: Subsequent normal pregnancies have been reported in this circumstance. In such cases, a normal thick myometrium is noted anterior to the gestational sac.⁷ A patient with lower uterine-segment implantation without evidence of anterior myometrial thinning remains at risk for third-trimester placenta previa.⁷

Cesarean scar pregnancy carries significant risk of PAS. In these cases, the gestational sac is typically implanted within the scar, resulting in a thin anterior myometrium and significantly increased vascularity of the placental–myometrial and bladder–uterine wall interfaces (FIGURE 2).⁹ Differentiating cesarean scar pregnancy from a lower uterine-segment implantation is easier to perform before the eighth week of gestation but becomes more difficult as pregnancy advances. Although it might be useful to distinguish between true cesarean scar pregnancy and lower uterine-segment implantation adjacent to or involving the scar, both carry considerable risk of PAS and excessive hemorrhage, and the approach to treating both conditions is quite similar.

Lacunae, with or without documented blood flow on color Doppler US, are the third marker of PAS in the first trimester.⁸ Although some retrospective series and case reports describe the finding of lacunae in the first trimester of patients with diagnosed PAS, more recent literature suggests that these spaces are seen infrequently and at a similar frequency in women with and without PAS at delivery.⁷

Second- and third-trimester markers

Multiple diagnostic sonographic markers of PAS have been described in the second and third trimesters.

Placental location is a significant risk factor for PAS. Placenta previa in the setting of prior CD carries the highest risk of PAS—as high as 61% in women with both placenta previa and a history of 3 CDs.¹⁰ An anterior placenta appears to be a stronger risk factor for PAS than a posterior placenta in women with prior CD; the location of the placenta should therefore be evaluated in all women in the second trimester.

Continue to: Lacunae

Lacunae. The finding of multiple hypoechoic vascular spaces within the placental parenchyma has been associated with PAS (FIGURES 3 and 4). The pathogenesis of this finding is probably related to alterations in placental tissue resulting from long-term exposure to pulsatile blood flow.¹¹

Finberg and colleagues introduced a grading system for placental lacunae in 1992 that is still used:

• Grade 0: no lacunae seen
• Grade 1: 1 to 3 lacunae seen
• Grade 2: 4 to 6 lacunae seen
• Grade 3: multiple lacunae seen throughout the placenta.¹²

The sensitivity and specificity of lacunae as an independent marker for PAS have been reported to be 77% and 95%, respectively.¹³ Despite these findings, several studies report a range of sensitivity (73% to 100%) and negative predictive value (88% to 100%).¹⁴ Even in Finberg’s original work, 27% of cases of confirmed PAS had Grade 0 or Grade 1 placental lacunae and 11% of cases of placenta previa, without PAS, demonstrated Grade 2 lacunae.¹² There is agreement, however, that, the more lacunae, the higher the risk of PAS.

Continue to: Other US markers for PAS

Retroplacental–myometrial interface

Loss of the normal hypoechoic (clear) retroplacental zone, also referred to as loss of the clear space between placenta and uterus, is another marker of PAS (FIGURE 5). This finding corresponds to pathologic loss of the decidua basalis as trophoblastic tissue invades directly through the myometrium.¹⁵ This sonographic finding has been reported to have a detection rate of approximately 93%, with sensitivity of 52% and specificity of 57%, for PAS; the false-positive rate, however, has been in the range of 21% or higher. This marker should not be used alone because it is angle-dependent and can be found (as an absent clear zone) in normal anterior placentas.¹⁶

The strength of this US marker is in its negative predictive value, which ranges from 96% to 100%. The presence of a hypoechoic retroplacental clear space that extends the length of the placenta makes PAS unlikely.¹⁷ Of note, the clear zone may appear falsely absent as a result of increased pressure from the US probe.

Retroplacental myometrial thickness

Retroplacental myometrial thickness is difficult to assess because the lower uterine-segment myometrium thins in normal pregnancy as term approaches. This measurement also can be influenced by direct pressure of the US probe and fullness of the maternal bladder.¹⁸ In patients who have had a CD but who do not have PAS, the median myometrial thickness of the lower uterine segment in the third trimester is 2.4 mm.¹⁹

Thinning of the myometrium in the upper uterine segment always should be of concern. Studies of this marker have reported sensitivity of US ranging from 22% to 100% and specificity from 72% to 100%.^9,20 Given such variability, it is important to standardize the gestational age and sonographic approach for this marker.

Continue to: Uterovesical interface

Studies also have reported that abnormalities of the uterovesical interface are predictive of PAS. The uterovesical interface is best evaluated in a sagittal plane containing the lower uterine segment and a partially full bladder in gray-scale and color Doppler US.¹⁵ The normal uterovesical interface appears as a smooth line, without irregularities or increased vascularity on sagittal imaging.

Abnormalities include focal interruption of the hyperechoic bladder wall, bulging of the bladder wall, and increased vascularity, such as varicosities (FIGURES 5, 6, and 7).¹⁵ These findings may be seen as early as the first trimester but are more commonly noted in the second and third trimesters.⁷ The authors of a recent meta-analysis concluded that irregularity of the uterovesical interface is the most specific marker for invasive placentation (99.75% confidence interval; range, 99.5% to 99.9%).¹³

Other US markers and modalities

Three-dimensional US. Studies have evaluated the role of 3-dimensional (3D) US for predicting PAS. Application of 3D US in vascular mode has shown promise because it allows for semiquantitative assessment of placental vasculature.²² Using 3D US to screen for PAS presents drawbacks, however: The technology is not well-standardized and requires significant operator expertise for volume acquisition and manipulation. Prospective studies are needed before 3D US can be applied routinely to screen for and diagnose PAS.

Color Doppler US. As an adjunct to gray-scale US, color Doppler US can be used for making a diagnosis of PAS. Color Doppler US helps differentiate a normal subplacental venous complex with nonpulsatile, low-velocity venous blood flow waveforms from markedly dilated peripheral subplacental vascular channels with pulsatile venous-type flow, which suggests PAS. These vascular channels are often located directly over the cervix. In addition, the observation of bridging vessels linking the placenta and bladder with high diastolic arterial blood flow also suggests invasion.²¹ In a meta-analysis, overall sensitivity of color Doppler US for the diagnosis of PAS was 91%, with specificity of 87%.¹³

The value of utilizing multiple markers

The accuracy of US diagnosis of PAS is likely improved by using more than 1 sonographic marker. Pilloni and colleagues,²⁰ in a prospective analysis, found that 81% of cases of confirmed PAS had ≥2 markers and 51% of cases had ≥3 markers.

Several scoring systems have been proposed for making the diagnosis of PAS using combinations of sonographic markers, placental location, and clinical history.^19,24,25 In 2016, Tovbin and colleagues,²⁵ in a prospective study, evaluated a scoring system that included:

• number of previous CDs
• number of, maximum dimension of, and presence of blood flow in lacunae
• loss of uteroplacental clear zone
• placental location
• hypervascularity of the uterovesical or uteroplacental interface.

Tovbin assigned 1 or 2 points to each criterion. Each sonographic marker was found to be significantly associated with PAS when compared to a high-risk control group. A score of ≥8 was considered “at high risk” and predicted 69% of PAS cases.

Regrettably, no combination of US markers reliably predicts the depth of invasion of the placenta.²⁶

Continue to: A standardized approach is needed

To decrease variability and improve the US diagnosis of PAS, it is important to define and standardize the diagnosis of each sonographic marker for PAS.⁴ In 2016, the European Working Group on Abnormally Invasive Placenta (EW-AIP) proposed a set of US markers that always should be reported when performing an US examination for suspected abnormal placentation (TABLE).²³ Despite this effort by the EW-AIP, ambiguity remains over sonographic definitions of several PAS markers. For example, what determines a placental lacuna on US? And what constitutes an abnormal uterovesical interface? There is a need for a more objective definition of US markers of PAS and a standardized approach to the US examination in at-risk pregnancies.

The Society for Maternal-Fetal Medicine is coordinating a multi-society task force to address the need to define and standardize the US diagnosis of PAS.

Observations on other PAS diagnostic modalities

Magnetic resonance imaging

Adjunctive role. Magnetic resonance imaging (MRI) is often used as an adjunctive diagnostic modality in cases of suspected PAS. Several markers for PAS have been described on MRI, including¹⁵:

• intraplacental T2-weighted dark bands
• abnormal intraplacental vascularity
• heterogeneous intraplacental signal intensity
• focal interruption of the myometrium by the placenta
• uterine bulging.

Based on a recent meta-analysis, overall sensitivity of MRI for detecting PAS is 86% to 95%, with specificity of 80% to 95%. Although this is comparable to the sensitivity and specificity of US,²⁷ studies of MRI in PAS are smaller and more prone to bias than in studies of US, because MRI typically is used only in patients at highest risk for PAS. Few studies comparing US to MRI for PAS have been performed; all are small and lack statistical power.

Complementary role. MRI can be complementary to US in cases in which the placenta is posterior or located laterally²⁸ but, importantly, rarely changes decisions about surgical management when used in conjunction with US to assess patients for the diagnosis of PAS. (An exception might lie in the ability of MRI to assess the degree or depth of invasion of the placenta and discerning placenta percreta from placenta accreta.¹⁵)

Enhancement with contrast. Addition of gadolinium-based contrast might improve the ability of MRI to make a diagnosis of PAS, but gadolinium crosses the placenta barrier. Although fetal effects of gadolinium have not been observed, American College of Radiology guidelines recommend avoiding this contrast agent during pregnancy unless absolutely essential.²⁹

Specific indications. MRI without contrast should be considered 1) when US is inconclusive and 2) to further evaluate a posterior placenta suspicious for invasion, to define the precise topography of extrauterine placental invasion. The additional information offered by MRI might alter surgical planning.¹⁵

Biomarkers

Multiple serum biomarkers have been proposed to predict PAS in high-risk women. PAS might be associated with increased levels of first-trimester pregnancy-associated plasma protein A, second-trimester maternal serum alpha fetoprotein, and human chorionic gonadotropin, but studies of the utility of these biomarkers have yielded contradictory results.^30,31 Biomarkers are of interest and have significant clinical applicability, but none of the ones identified to date have high sensitivity or specificity for predicting PAS prenatally. Research is ongoing to identify markers of PAS that have sufficient predictive power.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Placenta accreta spectrum (PAS) describes abnormal invasion of placental tissue into or through the myometrium, comprising 3 distinct conditions: placenta accreta, placenta increta, and placenta percreta. This complication is relatively new to obstetrics, first described in 1937.¹

The overall incidence of PAS has been increasing over several decades, in parallel to an increasing rate of cesarean delivery (CD), with an incidence from 1982 through 2002 of 1 in 533 pregnancies, representing a 5-fold increase since the 1980s.² PAS is associated with significant morbidity and mortality, including fetal growth restriction, preterm delivery, placental abruption antenatally, and hemorrhage during delivery or postpartum.

Prenatal diagnosis of PAS and planned delivery at an experienced center are associated with significant reduction in maternal and fetal morbidity.³ In an era of advanced imaging modalities, prenatal detection of PAS regrettably remains variable and largely subjective: As many as 20% to 50% of cases of PAS escape prenatal diagnosis.^3,4

In this article, we review the sonographic markers of PAS, including diagnostic accuracy, and propose a standardized approach to prenatal diagnosis. Throughout our discussion, we describe protocols for detection of PAS practiced at our Maternal-Fetal Medicine Program in the Department of Obstetrics and Gynecology, Eastern Virginia Medical School (also see “US evaluation of PAS risk: The authors’ recommended approach”).

Numerous risk factors

There are many risk factors for PAS, including prior uterine surgery or instrumentation, such as CD, uterine curettage, myomectomy, pelvic radiation, and endometrial ablation. Other risk factors include smoking, in vitro fertilization, advanced maternal age, multiparity, and a brief interval between prior CD and subsequent pregnancy.⁵ Of major significance is the increased risk of PAS in the presence of placenta previa with prior CD.⁶ Knowledge of clinical risk factors by the interpreting physician appears to be associated with improved detection of PAS on ultrasonography (US).⁴

Ultrasonographic markers of PAS

First-trimester markers

Sonographic markers of PAS in the first trimester include:

• a gestational sac implanted in the lower uterine segment or in a CD scar
• multiple hypoechoic spaces within the placenta (lacunae).⁷

Lower uterine-segment implantation has been defined by Ballas and colleagues as 1) a gestational sac implanted in the lower one-third of the uterus between 8 and 10 weeks’ gestation or 2) a gestational sac occupying primarily the lower uterine segment from 10 weeks’ gestation onward (FIGURE 1).⁸ Our experience is that it is difficult to accurately assess lower uterine-segment implantation beyond 13 weeks of gestation because the sac typically expands to fill the upper uterine cavity.

Continue to: Color Doppler US...

Color Doppler US can help differentiate lower uterine-segment implantation from a gestational sac of a failed pregnancy in the process of expulsion by demonstrating loss of circumferential blood flow in the failed pregnancy. Furthermore, applying pressure to the anterior surface of the uterus will result in downward movement of the gestational sac of a failed pregnancy.⁹

Not all gestational sacs that implant in the lower uterine segment lead to PAS: Subsequent normal pregnancies have been reported in this circumstance. In such cases, a normal thick myometrium is noted anterior to the gestational sac.⁷ A patient with lower uterine-segment implantation without evidence of anterior myometrial thinning remains at risk for third-trimester placenta previa.⁷

Cesarean scar pregnancy carries significant risk of PAS. In these cases, the gestational sac is typically implanted within the scar, resulting in a thin anterior myometrium and significantly increased vascularity of the placental–myometrial and bladder–uterine wall interfaces (FIGURE 2).⁹ Differentiating cesarean scar pregnancy from a lower uterine-segment implantation is easier to perform before the eighth week of gestation but becomes more difficult as pregnancy advances. Although it might be useful to distinguish between true cesarean scar pregnancy and lower uterine-segment implantation adjacent to or involving the scar, both carry considerable risk of PAS and excessive hemorrhage, and the approach to treating both conditions is quite similar.

Lacunae, with or without documented blood flow on color Doppler US, are the third marker of PAS in the first trimester.⁸ Although some retrospective series and case reports describe the finding of lacunae in the first trimester of patients with diagnosed PAS, more recent literature suggests that these spaces are seen infrequently and at a similar frequency in women with and without PAS at delivery.⁷

Second- and third-trimester markers

Multiple diagnostic sonographic markers of PAS have been described in the second and third trimesters.

Placental location is a significant risk factor for PAS. Placenta previa in the setting of prior CD carries the highest risk of PAS—as high as 61% in women with both placenta previa and a history of 3 CDs.¹⁰ An anterior placenta appears to be a stronger risk factor for PAS than a posterior placenta in women with prior CD; the location of the placenta should therefore be evaluated in all women in the second trimester.

Continue to: Lacunae

Lacunae. The finding of multiple hypoechoic vascular spaces within the placental parenchyma has been associated with PAS (FIGURES 3 and 4). The pathogenesis of this finding is probably related to alterations in placental tissue resulting from long-term exposure to pulsatile blood flow.¹¹

Finberg and colleagues introduced a grading system for placental lacunae in 1992 that is still used:

• Grade 0: no lacunae seen
• Grade 1: 1 to 3 lacunae seen
• Grade 2: 4 to 6 lacunae seen
• Grade 3: multiple lacunae seen throughout the placenta.¹²

The sensitivity and specificity of lacunae as an independent marker for PAS have been reported to be 77% and 95%, respectively.¹³ Despite these findings, several studies report a range of sensitivity (73% to 100%) and negative predictive value (88% to 100%).¹⁴ Even in Finberg’s original work, 27% of cases of confirmed PAS had Grade 0 or Grade 1 placental lacunae and 11% of cases of placenta previa, without PAS, demonstrated Grade 2 lacunae.¹² There is agreement, however, that, the more lacunae, the higher the risk of PAS.

Continue to: Other US markers for PAS

Retroplacental–myometrial interface

Loss of the normal hypoechoic (clear) retroplacental zone, also referred to as loss of the clear space between placenta and uterus, is another marker of PAS (FIGURE 5). This finding corresponds to pathologic loss of the decidua basalis as trophoblastic tissue invades directly through the myometrium.¹⁵ This sonographic finding has been reported to have a detection rate of approximately 93%, with sensitivity of 52% and specificity of 57%, for PAS; the false-positive rate, however, has been in the range of 21% or higher. This marker should not be used alone because it is angle-dependent and can be found (as an absent clear zone) in normal anterior placentas.¹⁶

The strength of this US marker is in its negative predictive value, which ranges from 96% to 100%. The presence of a hypoechoic retroplacental clear space that extends the length of the placenta makes PAS unlikely.¹⁷ Of note, the clear zone may appear falsely absent as a result of increased pressure from the US probe.

Retroplacental myometrial thickness

Retroplacental myometrial thickness is difficult to assess because the lower uterine-segment myometrium thins in normal pregnancy as term approaches. This measurement also can be influenced by direct pressure of the US probe and fullness of the maternal bladder.¹⁸ In patients who have had a CD but who do not have PAS, the median myometrial thickness of the lower uterine segment in the third trimester is 2.4 mm.¹⁹

Thinning of the myometrium in the upper uterine segment always should be of concern. Studies of this marker have reported sensitivity of US ranging from 22% to 100% and specificity from 72% to 100%.^9,20 Given such variability, it is important to standardize the gestational age and sonographic approach for this marker.

Continue to: Uterovesical interface

Studies also have reported that abnormalities of the uterovesical interface are predictive of PAS. The uterovesical interface is best evaluated in a sagittal plane containing the lower uterine segment and a partially full bladder in gray-scale and color Doppler US.¹⁵ The normal uterovesical interface appears as a smooth line, without irregularities or increased vascularity on sagittal imaging.

Abnormalities include focal interruption of the hyperechoic bladder wall, bulging of the bladder wall, and increased vascularity, such as varicosities (FIGURES 5, 6, and 7).¹⁵ These findings may be seen as early as the first trimester but are more commonly noted in the second and third trimesters.⁷ The authors of a recent meta-analysis concluded that irregularity of the uterovesical interface is the most specific marker for invasive placentation (99.75% confidence interval; range, 99.5% to 99.9%).¹³

Other US markers and modalities

Three-dimensional US. Studies have evaluated the role of 3-dimensional (3D) US for predicting PAS. Application of 3D US in vascular mode has shown promise because it allows for semiquantitative assessment of placental vasculature.²² Using 3D US to screen for PAS presents drawbacks, however: The technology is not well-standardized and requires significant operator expertise for volume acquisition and manipulation. Prospective studies are needed before 3D US can be applied routinely to screen for and diagnose PAS.

Color Doppler US. As an adjunct to gray-scale US, color Doppler US can be used for making a diagnosis of PAS. Color Doppler US helps differentiate a normal subplacental venous complex with nonpulsatile, low-velocity venous blood flow waveforms from markedly dilated peripheral subplacental vascular channels with pulsatile venous-type flow, which suggests PAS. These vascular channels are often located directly over the cervix. In addition, the observation of bridging vessels linking the placenta and bladder with high diastolic arterial blood flow also suggests invasion.²¹ In a meta-analysis, overall sensitivity of color Doppler US for the diagnosis of PAS was 91%, with specificity of 87%.¹³

The value of utilizing multiple markers

The accuracy of US diagnosis of PAS is likely improved by using more than 1 sonographic marker. Pilloni and colleagues,²⁰ in a prospective analysis, found that 81% of cases of confirmed PAS had ≥2 markers and 51% of cases had ≥3 markers.

Several scoring systems have been proposed for making the diagnosis of PAS using combinations of sonographic markers, placental location, and clinical history.^19,24,25 In 2016, Tovbin and colleagues,²⁵ in a prospective study, evaluated a scoring system that included:

• number of previous CDs
• number of, maximum dimension of, and presence of blood flow in lacunae
• loss of uteroplacental clear zone
• placental location
• hypervascularity of the uterovesical or uteroplacental interface.

Tovbin assigned 1 or 2 points to each criterion. Each sonographic marker was found to be significantly associated with PAS when compared to a high-risk control group. A score of ≥8 was considered “at high risk” and predicted 69% of PAS cases.

Regrettably, no combination of US markers reliably predicts the depth of invasion of the placenta.²⁶

Continue to: A standardized approach is needed

To decrease variability and improve the US diagnosis of PAS, it is important to define and standardize the diagnosis of each sonographic marker for PAS.⁴ In 2016, the European Working Group on Abnormally Invasive Placenta (EW-AIP) proposed a set of US markers that always should be reported when performing an US examination for suspected abnormal placentation (TABLE).²³ Despite this effort by the EW-AIP, ambiguity remains over sonographic definitions of several PAS markers. For example, what determines a placental lacuna on US? And what constitutes an abnormal uterovesical interface? There is a need for a more objective definition of US markers of PAS and a standardized approach to the US examination in at-risk pregnancies.

The Society for Maternal-Fetal Medicine is coordinating a multi-society task force to address the need to define and standardize the US diagnosis of PAS.

Observations on other PAS diagnostic modalities

Magnetic resonance imaging

Adjunctive role. Magnetic resonance imaging (MRI) is often used as an adjunctive diagnostic modality in cases of suspected PAS. Several markers for PAS have been described on MRI, including¹⁵:

• intraplacental T2-weighted dark bands
• abnormal intraplacental vascularity
• heterogeneous intraplacental signal intensity
• focal interruption of the myometrium by the placenta
• uterine bulging.

Based on a recent meta-analysis, overall sensitivity of MRI for detecting PAS is 86% to 95%, with specificity of 80% to 95%. Although this is comparable to the sensitivity and specificity of US,²⁷ studies of MRI in PAS are smaller and more prone to bias than in studies of US, because MRI typically is used only in patients at highest risk for PAS. Few studies comparing US to MRI for PAS have been performed; all are small and lack statistical power.

Complementary role. MRI can be complementary to US in cases in which the placenta is posterior or located laterally²⁸ but, importantly, rarely changes decisions about surgical management when used in conjunction with US to assess patients for the diagnosis of PAS. (An exception might lie in the ability of MRI to assess the degree or depth of invasion of the placenta and discerning placenta percreta from placenta accreta.¹⁵)

Enhancement with contrast. Addition of gadolinium-based contrast might improve the ability of MRI to make a diagnosis of PAS, but gadolinium crosses the placenta barrier. Although fetal effects of gadolinium have not been observed, American College of Radiology guidelines recommend avoiding this contrast agent during pregnancy unless absolutely essential.²⁹

Specific indications. MRI without contrast should be considered 1) when US is inconclusive and 2) to further evaluate a posterior placenta suspicious for invasion, to define the precise topography of extrauterine placental invasion. The additional information offered by MRI might alter surgical planning.¹⁵

Biomarkers

Multiple serum biomarkers have been proposed to predict PAS in high-risk women. PAS might be associated with increased levels of first-trimester pregnancy-associated plasma protein A, second-trimester maternal serum alpha fetoprotein, and human chorionic gonadotropin, but studies of the utility of these biomarkers have yielded contradictory results.^30,31 Biomarkers are of interest and have significant clinical applicability, but none of the ones identified to date have high sensitivity or specificity for predicting PAS prenatally. Research is ongoing to identify markers of PAS that have sufficient predictive power.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Placenta accreta spectrum (PAS) describes abnormal invasion of placental tissue into or through the myometrium, comprising 3 distinct conditions: placenta accreta, placenta increta, and placenta percreta. This complication is relatively new to obstetrics, first described in 1937.¹

The overall incidence of PAS has been increasing over several decades, in parallel to an increasing rate of cesarean delivery (CD), with an incidence from 1982 through 2002 of 1 in 533 pregnancies, representing a 5-fold increase since the 1980s.² PAS is associated with significant morbidity and mortality, including fetal growth restriction, preterm delivery, placental abruption antenatally, and hemorrhage during delivery or postpartum.

Prenatal diagnosis of PAS and planned delivery at an experienced center are associated with significant reduction in maternal and fetal morbidity.³ In an era of advanced imaging modalities, prenatal detection of PAS regrettably remains variable and largely subjective: As many as 20% to 50% of cases of PAS escape prenatal diagnosis.^3,4

In this article, we review the sonographic markers of PAS, including diagnostic accuracy, and propose a standardized approach to prenatal diagnosis. Throughout our discussion, we describe protocols for detection of PAS practiced at our Maternal-Fetal Medicine Program in the Department of Obstetrics and Gynecology, Eastern Virginia Medical School (also see “US evaluation of PAS risk: The authors’ recommended approach”).

Numerous risk factors

There are many risk factors for PAS, including prior uterine surgery or instrumentation, such as CD, uterine curettage, myomectomy, pelvic radiation, and endometrial ablation. Other risk factors include smoking, in vitro fertilization, advanced maternal age, multiparity, and a brief interval between prior CD and subsequent pregnancy.⁵ Of major significance is the increased risk of PAS in the presence of placenta previa with prior CD.⁶ Knowledge of clinical risk factors by the interpreting physician appears to be associated with improved detection of PAS on ultrasonography (US).⁴

Ultrasonographic markers of PAS

First-trimester markers

Sonographic markers of PAS in the first trimester include:

• a gestational sac implanted in the lower uterine segment or in a CD scar
• multiple hypoechoic spaces within the placenta (lacunae).⁷

Lower uterine-segment implantation has been defined by Ballas and colleagues as 1) a gestational sac implanted in the lower one-third of the uterus between 8 and 10 weeks’ gestation or 2) a gestational sac occupying primarily the lower uterine segment from 10 weeks’ gestation onward (FIGURE 1).⁸ Our experience is that it is difficult to accurately assess lower uterine-segment implantation beyond 13 weeks of gestation because the sac typically expands to fill the upper uterine cavity.

Continue to: Color Doppler US...

Color Doppler US can help differentiate lower uterine-segment implantation from a gestational sac of a failed pregnancy in the process of expulsion by demonstrating loss of circumferential blood flow in the failed pregnancy. Furthermore, applying pressure to the anterior surface of the uterus will result in downward movement of the gestational sac of a failed pregnancy.⁹

Not all gestational sacs that implant in the lower uterine segment lead to PAS: Subsequent normal pregnancies have been reported in this circumstance. In such cases, a normal thick myometrium is noted anterior to the gestational sac.⁷ A patient with lower uterine-segment implantation without evidence of anterior myometrial thinning remains at risk for third-trimester placenta previa.⁷

Cesarean scar pregnancy carries significant risk of PAS. In these cases, the gestational sac is typically implanted within the scar, resulting in a thin anterior myometrium and significantly increased vascularity of the placental–myometrial and bladder–uterine wall interfaces (FIGURE 2).⁹ Differentiating cesarean scar pregnancy from a lower uterine-segment implantation is easier to perform before the eighth week of gestation but becomes more difficult as pregnancy advances. Although it might be useful to distinguish between true cesarean scar pregnancy and lower uterine-segment implantation adjacent to or involving the scar, both carry considerable risk of PAS and excessive hemorrhage, and the approach to treating both conditions is quite similar.

Lacunae, with or without documented blood flow on color Doppler US, are the third marker of PAS in the first trimester.⁸ Although some retrospective series and case reports describe the finding of lacunae in the first trimester of patients with diagnosed PAS, more recent literature suggests that these spaces are seen infrequently and at a similar frequency in women with and without PAS at delivery.⁷

Second- and third-trimester markers

Multiple diagnostic sonographic markers of PAS have been described in the second and third trimesters.

Placental location is a significant risk factor for PAS. Placenta previa in the setting of prior CD carries the highest risk of PAS—as high as 61% in women with both placenta previa and a history of 3 CDs.¹⁰ An anterior placenta appears to be a stronger risk factor for PAS than a posterior placenta in women with prior CD; the location of the placenta should therefore be evaluated in all women in the second trimester.

Continue to: Lacunae

Lacunae. The finding of multiple hypoechoic vascular spaces within the placental parenchyma has been associated with PAS (FIGURES 3 and 4). The pathogenesis of this finding is probably related to alterations in placental tissue resulting from long-term exposure to pulsatile blood flow.¹¹

Finberg and colleagues introduced a grading system for placental lacunae in 1992 that is still used:

• Grade 0: no lacunae seen
• Grade 1: 1 to 3 lacunae seen
• Grade 2: 4 to 6 lacunae seen
• Grade 3: multiple lacunae seen throughout the placenta.¹²

The sensitivity and specificity of lacunae as an independent marker for PAS have been reported to be 77% and 95%, respectively.¹³ Despite these findings, several studies report a range of sensitivity (73% to 100%) and negative predictive value (88% to 100%).¹⁴ Even in Finberg’s original work, 27% of cases of confirmed PAS had Grade 0 or Grade 1 placental lacunae and 11% of cases of placenta previa, without PAS, demonstrated Grade 2 lacunae.¹² There is agreement, however, that, the more lacunae, the higher the risk of PAS.

Continue to: Other US markers for PAS

Retroplacental–myometrial interface

Loss of the normal hypoechoic (clear) retroplacental zone, also referred to as loss of the clear space between placenta and uterus, is another marker of PAS (FIGURE 5). This finding corresponds to pathologic loss of the decidua basalis as trophoblastic tissue invades directly through the myometrium.¹⁵ This sonographic finding has been reported to have a detection rate of approximately 93%, with sensitivity of 52% and specificity of 57%, for PAS; the false-positive rate, however, has been in the range of 21% or higher. This marker should not be used alone because it is angle-dependent and can be found (as an absent clear zone) in normal anterior placentas.¹⁶

The strength of this US marker is in its negative predictive value, which ranges from 96% to 100%. The presence of a hypoechoic retroplacental clear space that extends the length of the placenta makes PAS unlikely.¹⁷ Of note, the clear zone may appear falsely absent as a result of increased pressure from the US probe.

Retroplacental myometrial thickness

Retroplacental myometrial thickness is difficult to assess because the lower uterine-segment myometrium thins in normal pregnancy as term approaches. This measurement also can be influenced by direct pressure of the US probe and fullness of the maternal bladder.¹⁸ In patients who have had a CD but who do not have PAS, the median myometrial thickness of the lower uterine segment in the third trimester is 2.4 mm.¹⁹

Thinning of the myometrium in the upper uterine segment always should be of concern. Studies of this marker have reported sensitivity of US ranging from 22% to 100% and specificity from 72% to 100%.^9,20 Given such variability, it is important to standardize the gestational age and sonographic approach for this marker.

Continue to: Uterovesical interface

Studies also have reported that abnormalities of the uterovesical interface are predictive of PAS. The uterovesical interface is best evaluated in a sagittal plane containing the lower uterine segment and a partially full bladder in gray-scale and color Doppler US.¹⁵ The normal uterovesical interface appears as a smooth line, without irregularities or increased vascularity on sagittal imaging.

Abnormalities include focal interruption of the hyperechoic bladder wall, bulging of the bladder wall, and increased vascularity, such as varicosities (FIGURES 5, 6, and 7).¹⁵ These findings may be seen as early as the first trimester but are more commonly noted in the second and third trimesters.⁷ The authors of a recent meta-analysis concluded that irregularity of the uterovesical interface is the most specific marker for invasive placentation (99.75% confidence interval; range, 99.5% to 99.9%).¹³

Other US markers and modalities

Three-dimensional US. Studies have evaluated the role of 3-dimensional (3D) US for predicting PAS. Application of 3D US in vascular mode has shown promise because it allows for semiquantitative assessment of placental vasculature.²² Using 3D US to screen for PAS presents drawbacks, however: The technology is not well-standardized and requires significant operator expertise for volume acquisition and manipulation. Prospective studies are needed before 3D US can be applied routinely to screen for and diagnose PAS.

Color Doppler US. As an adjunct to gray-scale US, color Doppler US can be used for making a diagnosis of PAS. Color Doppler US helps differentiate a normal subplacental venous complex with nonpulsatile, low-velocity venous blood flow waveforms from markedly dilated peripheral subplacental vascular channels with pulsatile venous-type flow, which suggests PAS. These vascular channels are often located directly over the cervix. In addition, the observation of bridging vessels linking the placenta and bladder with high diastolic arterial blood flow also suggests invasion.²¹ In a meta-analysis, overall sensitivity of color Doppler US for the diagnosis of PAS was 91%, with specificity of 87%.¹³

The value of utilizing multiple markers

The accuracy of US diagnosis of PAS is likely improved by using more than 1 sonographic marker. Pilloni and colleagues,²⁰ in a prospective analysis, found that 81% of cases of confirmed PAS had ≥2 markers and 51% of cases had ≥3 markers.

Several scoring systems have been proposed for making the diagnosis of PAS using combinations of sonographic markers, placental location, and clinical history.^19,24,25 In 2016, Tovbin and colleagues,²⁵ in a prospective study, evaluated a scoring system that included:

• number of previous CDs
• number of, maximum dimension of, and presence of blood flow in lacunae
• loss of uteroplacental clear zone
• placental location
• hypervascularity of the uterovesical or uteroplacental interface.

Tovbin assigned 1 or 2 points to each criterion. Each sonographic marker was found to be significantly associated with PAS when compared to a high-risk control group. A score of ≥8 was considered “at high risk” and predicted 69% of PAS cases.

Regrettably, no combination of US markers reliably predicts the depth of invasion of the placenta.²⁶

Continue to: A standardized approach is needed

To decrease variability and improve the US diagnosis of PAS, it is important to define and standardize the diagnosis of each sonographic marker for PAS.⁴ In 2016, the European Working Group on Abnormally Invasive Placenta (EW-AIP) proposed a set of US markers that always should be reported when performing an US examination for suspected abnormal placentation (TABLE).²³ Despite this effort by the EW-AIP, ambiguity remains over sonographic definitions of several PAS markers. For example, what determines a placental lacuna on US? And what constitutes an abnormal uterovesical interface? There is a need for a more objective definition of US markers of PAS and a standardized approach to the US examination in at-risk pregnancies.

The Society for Maternal-Fetal Medicine is coordinating a multi-society task force to address the need to define and standardize the US diagnosis of PAS.

Observations on other PAS diagnostic modalities

Magnetic resonance imaging

Adjunctive role. Magnetic resonance imaging (MRI) is often used as an adjunctive diagnostic modality in cases of suspected PAS. Several markers for PAS have been described on MRI, including¹⁵:

• intraplacental T2-weighted dark bands
• abnormal intraplacental vascularity
• heterogeneous intraplacental signal intensity
• focal interruption of the myometrium by the placenta
• uterine bulging.

Based on a recent meta-analysis, overall sensitivity of MRI for detecting PAS is 86% to 95%, with specificity of 80% to 95%. Although this is comparable to the sensitivity and specificity of US,²⁷ studies of MRI in PAS are smaller and more prone to bias than in studies of US, because MRI typically is used only in patients at highest risk for PAS. Few studies comparing US to MRI for PAS have been performed; all are small and lack statistical power.

Complementary role. MRI can be complementary to US in cases in which the placenta is posterior or located laterally²⁸ but, importantly, rarely changes decisions about surgical management when used in conjunction with US to assess patients for the diagnosis of PAS. (An exception might lie in the ability of MRI to assess the degree or depth of invasion of the placenta and discerning placenta percreta from placenta accreta.¹⁵)

Enhancement with contrast. Addition of gadolinium-based contrast might improve the ability of MRI to make a diagnosis of PAS, but gadolinium crosses the placenta barrier. Although fetal effects of gadolinium have not been observed, American College of Radiology guidelines recommend avoiding this contrast agent during pregnancy unless absolutely essential.²⁹

Specific indications. MRI without contrast should be considered 1) when US is inconclusive and 2) to further evaluate a posterior placenta suspicious for invasion, to define the precise topography of extrauterine placental invasion. The additional information offered by MRI might alter surgical planning.¹⁵

Biomarkers

Multiple serum biomarkers have been proposed to predict PAS in high-risk women. PAS might be associated with increased levels of first-trimester pregnancy-associated plasma protein A, second-trimester maternal serum alpha fetoprotein, and human chorionic gonadotropin, but studies of the utility of these biomarkers have yielded contradictory results.^30,31 Biomarkers are of interest and have significant clinical applicability, but none of the ones identified to date have high sensitivity or specificity for predicting PAS prenatally. Research is ongoing to identify markers of PAS that have sufficient predictive power.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

SAN DIEGO – Acute promyelocytic leukemia is one of five “can’t miss” oncologic emergencies, Megan Boysen Osborn, MD, MHPE, told a standing-room-only crowd at the annual meeting of the American College of Emergency Physicians.

In our exclusive video interview, Dr. Osborn, vice chair of education and the residency program director in the department of emergency medicine at the University of California, Irvine, offered tips on how to recognize acute promyelocytic leukemia, leukostasis, neutropenic fever, tumor lysis syndrome, and disseminated intravascular coagulation.

“All patients with suspected leukemias should be admitted,” she said. “Time is of the essence.”

Dr. Osborn reported having no financial disclosures related to her presentation.

[email protected]

SAN DIEGO – Acute promyelocytic leukemia is one of five “can’t miss” oncologic emergencies, Megan Boysen Osborn, MD, MHPE, told a standing-room-only crowd at the annual meeting of the American College of Emergency Physicians.

In our exclusive video interview, Dr. Osborn, vice chair of education and the residency program director in the department of emergency medicine at the University of California, Irvine, offered tips on how to recognize acute promyelocytic leukemia, leukostasis, neutropenic fever, tumor lysis syndrome, and disseminated intravascular coagulation.

“All patients with suspected leukemias should be admitted,” she said. “Time is of the essence.”

Dr. Osborn reported having no financial disclosures related to her presentation.

[email protected]

SAN DIEGO – Acute promyelocytic leukemia is one of five “can’t miss” oncologic emergencies, Megan Boysen Osborn, MD, MHPE, told a standing-room-only crowd at the annual meeting of the American College of Emergency Physicians.

In our exclusive video interview, Dr. Osborn, vice chair of education and the residency program director in the department of emergency medicine at the University of California, Irvine, offered tips on how to recognize acute promyelocytic leukemia, leukostasis, neutropenic fever, tumor lysis syndrome, and disseminated intravascular coagulation.

“All patients with suspected leukemias should be admitted,” she said. “Time is of the essence.”

Dr. Osborn reported having no financial disclosures related to her presentation.

[email protected]