User login
Open-capsule PPIs linked to faster ulcer healing after Roux-en-Y
The use of proton pump inhibitors in opened instead of closed capsules was associated with a nearly fourfold shorter median healing time among patients who developed marginal ulcers after Roux-en-Y gastric bypass, in a single-center retrospective cohort study.
In contrast, the specific class of proton pump inhibitor (PPI) did not affect healing times, wrote Allison R. Schulman, MD, and her associates at Brigham and Women’s Hospital, Boston. The report is in the April issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2016.10.015). “Given these results and the high prevalence of marginal ulceration in this patient population, further study in a randomized controlled setting is warranted, and use of open-capsule PPIs should be considered as a low-risk, low-cost alternative,” they added.
Roux-en-Y gastric bypass is one of the most common types of gastric bypass surgeries in the world, and up to 16% of patients develop postsurgical ulcers at the gastrojejunal anastomosis, the investigators noted. Acidity is a prime suspect in these “marginal ulcerations” because bypassing the acid-buffering duodenum exposes the jejunum to acid from the stomach, they added. High-dose PPIs are the main treatment, but there is no consensus on the formulation or dose of therapy. Because Roux-en-Y creates a small gastric pouch and hastens small-bowel transit, closed capsules designed to break down in the stomach “even may make their way to the colon before breakdown occurs,” they wrote.
They reviewed medical charts from patients who developed marginal ulcerations after undergoing Roux-en-Y gastric bypass at their hospital from 2000 through 2015. A total of 115 patients received open-capsule PPIs and 49 received intact capsules. All were followed until their ulcers healed.
For the open-capsule group, median time to healing was 91 days, compared with 342 days for the closed-capsule group (P less than .001). Importantly, capsule type was the only independent predictor of healing time (hazard ratio, 6.0; 95% confidence interval, 3.7 to 9.8; P less than .001) in a Cox regression model that included other known correlates of ulcer healing, including age, smoking status, the use of nonsteroidal anti-inflammatory drugs, Helicobacter pylori infection, the length of the gastric pouch, and the presence of fistulae or foreign bodies such as sutures or staples.
The use of sucralfate also did not affect time to ulcer healing, reflecting “many previous studies showing a lack of definitive benefit to this medication,” the researchers said. The findings have “tremendous implications” for health care utilization, they added. Indeed, patients who received open-capsule PPIs needed significantly fewer endoscopic procedures (median, 1.2 versus 1.8; P = .02) and used fewer health care resources overall ($7,206 versus $11,009; P = .05) compared with those prescribed intact PPI capsules.
This study was limited to patients who developed ulcer symptoms and underwent repeated surveillance endoscopies after surgery, the researchers noted. Selection bias is always a concern with retrospective studies, but insurers always covered both types of therapy and the choice of capsule type was entirely up to providers, all of whom consistently prescribed either open- or closed-capsule PPI therapy, they added.
The investigators did not acknowledge external funding sources. Dr. Schulman and four coinvestigators reported having no competing interests. One coinvestigator disclosed ties to Olympus, Boston Scientific, and Covidien.
Proton pump inhibitors (PPIs) are frequently employed to treat marginal ulcers after Roux-en-Y gastric bypass (RYGB). In a retrospective study, Schulman et al. compared intact vs. “open” PPI capsules. 
They state that “this may be overcome by use of a soluble form of PPI,” but don’t state what is meant by “soluble PPI” or how the open-capsule PPI was delivered. Among the PPIs they reported using to compare intact vs. open capsules was Protonix [pantoprazole] which is not produced as a capsule, and soluble Prevacid [lansoprazole], which is an orally disintegrating tablet that should provide characteristics similar to an “open capsule.”
PPI capsules provide PPI in enteric-coated granules, which are designed to protect the PPI from acid degradation in the stomach of individuals with intact gastrointestinal tracts and allow more of the PPI dose to reach the small intestine where it is absorbed. If capsules really fail to release their enteric-coated granules until very distally in RYGB patients, bypassing this step to allow earlier release of PPI makes intuitive sense; formulations such as suspensions and rapidly disintegrating tablets that deliver enteric-coated granules without capsules are currently available.
However, if this is an issue, administering a suspension of uncoated PPI with bicarbonate potentially might be the most attractive option, given more rapid absorption than PPI delivered as enteric-coated granules.
Loren Laine, MD, AGAF, professor of medicine, digestive diseases, Yale University, New Haven, Conn. He has no conflicts of interest.
Proton pump inhibitors (PPIs) are frequently employed to treat marginal ulcers after Roux-en-Y gastric bypass (RYGB). In a retrospective study, Schulman et al. compared intact vs. “open” PPI capsules.
They state that “this may be overcome by use of a soluble form of PPI,” but don’t state what is meant by “soluble PPI” or how the open-capsule PPI was delivered. Among the PPIs they reported using to compare intact vs. open capsules was Protonix [pantoprazole] which is not produced as a capsule, and soluble Prevacid [lansoprazole], which is an orally disintegrating tablet that should provide characteristics similar to an “open capsule.”
PPI capsules provide PPI in enteric-coated granules, which are designed to protect the PPI from acid degradation in the stomach of individuals with intact gastrointestinal tracts and allow more of the PPI dose to reach the small intestine where it is absorbed. If capsules really fail to release their enteric-coated granules until very distally in RYGB patients, bypassing this step to allow earlier release of PPI makes intuitive sense; formulations such as suspensions and rapidly disintegrating tablets that deliver enteric-coated granules without capsules are currently available.
However, if this is an issue, administering a suspension of uncoated PPI with bicarbonate potentially might be the most attractive option, given more rapid absorption than PPI delivered as enteric-coated granules.
Loren Laine, MD, AGAF, professor of medicine, digestive diseases, Yale University, New Haven, Conn. He has no conflicts of interest.
Proton pump inhibitors (PPIs) are frequently employed to treat marginal ulcers after Roux-en-Y gastric bypass (RYGB). In a retrospective study, Schulman et al. compared intact vs. “open” PPI capsules.
They state that “this may be overcome by use of a soluble form of PPI,” but don’t state what is meant by “soluble PPI” or how the open-capsule PPI was delivered. Among the PPIs they reported using to compare intact vs. open capsules was Protonix [pantoprazole] which is not produced as a capsule, and soluble Prevacid [lansoprazole], which is an orally disintegrating tablet that should provide characteristics similar to an “open capsule.”
PPI capsules provide PPI in enteric-coated granules, which are designed to protect the PPI from acid degradation in the stomach of individuals with intact gastrointestinal tracts and allow more of the PPI dose to reach the small intestine where it is absorbed. If capsules really fail to release their enteric-coated granules until very distally in RYGB patients, bypassing this step to allow earlier release of PPI makes intuitive sense; formulations such as suspensions and rapidly disintegrating tablets that deliver enteric-coated granules without capsules are currently available.
However, if this is an issue, administering a suspension of uncoated PPI with bicarbonate potentially might be the most attractive option, given more rapid absorption than PPI delivered as enteric-coated granules.
Loren Laine, MD, AGAF, professor of medicine, digestive diseases, Yale University, New Haven, Conn. He has no conflicts of interest.
The use of proton pump inhibitors in opened instead of closed capsules was associated with a nearly fourfold shorter median healing time among patients who developed marginal ulcers after Roux-en-Y gastric bypass, in a single-center retrospective cohort study.
In contrast, the specific class of proton pump inhibitor (PPI) did not affect healing times, wrote Allison R. Schulman, MD, and her associates at Brigham and Women’s Hospital, Boston. The report is in the April issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2016.10.015). “Given these results and the high prevalence of marginal ulceration in this patient population, further study in a randomized controlled setting is warranted, and use of open-capsule PPIs should be considered as a low-risk, low-cost alternative,” they added.
Roux-en-Y gastric bypass is one of the most common types of gastric bypass surgeries in the world, and up to 16% of patients develop postsurgical ulcers at the gastrojejunal anastomosis, the investigators noted. Acidity is a prime suspect in these “marginal ulcerations” because bypassing the acid-buffering duodenum exposes the jejunum to acid from the stomach, they added. High-dose PPIs are the main treatment, but there is no consensus on the formulation or dose of therapy. Because Roux-en-Y creates a small gastric pouch and hastens small-bowel transit, closed capsules designed to break down in the stomach “even may make their way to the colon before breakdown occurs,” they wrote.
They reviewed medical charts from patients who developed marginal ulcerations after undergoing Roux-en-Y gastric bypass at their hospital from 2000 through 2015. A total of 115 patients received open-capsule PPIs and 49 received intact capsules. All were followed until their ulcers healed.
For the open-capsule group, median time to healing was 91 days, compared with 342 days for the closed-capsule group (P less than .001). Importantly, capsule type was the only independent predictor of healing time (hazard ratio, 6.0; 95% confidence interval, 3.7 to 9.8; P less than .001) in a Cox regression model that included other known correlates of ulcer healing, including age, smoking status, the use of nonsteroidal anti-inflammatory drugs, Helicobacter pylori infection, the length of the gastric pouch, and the presence of fistulae or foreign bodies such as sutures or staples.
The use of sucralfate also did not affect time to ulcer healing, reflecting “many previous studies showing a lack of definitive benefit to this medication,” the researchers said. The findings have “tremendous implications” for health care utilization, they added. Indeed, patients who received open-capsule PPIs needed significantly fewer endoscopic procedures (median, 1.2 versus 1.8; P = .02) and used fewer health care resources overall ($7,206 versus $11,009; P = .05) compared with those prescribed intact PPI capsules.
This study was limited to patients who developed ulcer symptoms and underwent repeated surveillance endoscopies after surgery, the researchers noted. Selection bias is always a concern with retrospective studies, but insurers always covered both types of therapy and the choice of capsule type was entirely up to providers, all of whom consistently prescribed either open- or closed-capsule PPI therapy, they added.
The investigators did not acknowledge external funding sources. Dr. Schulman and four coinvestigators reported having no competing interests. One coinvestigator disclosed ties to Olympus, Boston Scientific, and Covidien.
The use of proton pump inhibitors in opened instead of closed capsules was associated with a nearly fourfold shorter median healing time among patients who developed marginal ulcers after Roux-en-Y gastric bypass, in a single-center retrospective cohort study.
In contrast, the specific class of proton pump inhibitor (PPI) did not affect healing times, wrote Allison R. Schulman, MD, and her associates at Brigham and Women’s Hospital, Boston. The report is in the April issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2016.10.015). “Given these results and the high prevalence of marginal ulceration in this patient population, further study in a randomized controlled setting is warranted, and use of open-capsule PPIs should be considered as a low-risk, low-cost alternative,” they added.
Roux-en-Y gastric bypass is one of the most common types of gastric bypass surgeries in the world, and up to 16% of patients develop postsurgical ulcers at the gastrojejunal anastomosis, the investigators noted. Acidity is a prime suspect in these “marginal ulcerations” because bypassing the acid-buffering duodenum exposes the jejunum to acid from the stomach, they added. High-dose PPIs are the main treatment, but there is no consensus on the formulation or dose of therapy. Because Roux-en-Y creates a small gastric pouch and hastens small-bowel transit, closed capsules designed to break down in the stomach “even may make their way to the colon before breakdown occurs,” they wrote.
They reviewed medical charts from patients who developed marginal ulcerations after undergoing Roux-en-Y gastric bypass at their hospital from 2000 through 2015. A total of 115 patients received open-capsule PPIs and 49 received intact capsules. All were followed until their ulcers healed.
For the open-capsule group, median time to healing was 91 days, compared with 342 days for the closed-capsule group (P less than .001). Importantly, capsule type was the only independent predictor of healing time (hazard ratio, 6.0; 95% confidence interval, 3.7 to 9.8; P less than .001) in a Cox regression model that included other known correlates of ulcer healing, including age, smoking status, the use of nonsteroidal anti-inflammatory drugs, Helicobacter pylori infection, the length of the gastric pouch, and the presence of fistulae or foreign bodies such as sutures or staples.
The use of sucralfate also did not affect time to ulcer healing, reflecting “many previous studies showing a lack of definitive benefit to this medication,” the researchers said. The findings have “tremendous implications” for health care utilization, they added. Indeed, patients who received open-capsule PPIs needed significantly fewer endoscopic procedures (median, 1.2 versus 1.8; P = .02) and used fewer health care resources overall ($7,206 versus $11,009; P = .05) compared with those prescribed intact PPI capsules.
This study was limited to patients who developed ulcer symptoms and underwent repeated surveillance endoscopies after surgery, the researchers noted. Selection bias is always a concern with retrospective studies, but insurers always covered both types of therapy and the choice of capsule type was entirely up to providers, all of whom consistently prescribed either open- or closed-capsule PPI therapy, they added.
The investigators did not acknowledge external funding sources. Dr. Schulman and four coinvestigators reported having no competing interests. One coinvestigator disclosed ties to Olympus, Boston Scientific, and Covidien.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Key clinical point: The use of proton pump inhibitors in opened instead of closed capsules was associated with a nearly fourfold shorter median healing time among patients who developed ulcers at the gastrojejunal anastomosis after Roux-en-Y gastric bypass.
Major finding: The median time to ulcer healing was 91.0 versus 342.0 days for the open- and closed-capsule groups, respectively (P less than .001).
Data source: A single-center retrospective study of 162 patients.
Disclosures: The investigators did not acknowledge external funding sources. Dr. Schulman and four coinvestigators reported having no competing interests. One coinvestigator disclosed ties to Olympus, Boston Scientific, and Covidien.
Expect tricky journey with BDD patients
LAS VEGAS – When working with patients referred for suspected body dysmorphic disorder, expect the initial groundwork to take more time than for other disorders.
“I think that these patients are among the most severely ill that we see in clinical practice – although body dysmorphic disorder often goes unrecognized, because patients are often very ashamed of their concerns, and they find it hard to talk about them,” Katharine A. Phillips, MD, said at the annual psychopharmacology update held by the Nevada Psychiatric Association.
Defined in the DSM-5 as preoccupation with one or more perceived defects or flaws in physical appearance that are not observable or that appear slight to others, body dysmorphic disorder (BDD) often causes substantial distress and impairment of day-to-day functioning and is associated with a high rate of suicidality. “When these patients walk into your office, you cannot tell by looking at them what their appearance concern is going to be,” said Dr. Phillips, professor of psychiatry and human behavior at Brown University, Providence, R.I. “Sometimes they point it out to you and you can see that their nostrils are a tiny bit asymmetrical or that they have a little scar on their chin, but it’s not very noticeable. It’s not noticeable until the patient points it out, and even then it’s a slight flaw. But in most cases, the body areas that the patient is preoccupied with look entirely normal.”
BDD affects an estimated 1.7%-2.9% of the general population; about 60% are female. In two-thirds of cases, it onsets during childhood or adolescence. The preoccupations about physical appearance that are associated with the disorder “are very obsessional and distressing,” Dr. Phillips said. “They may think ‘I look ugly. People are laughing at me. I look like a freak.’ They can be focused on any part of their appearance, but most often it’s the face or head. Skin is No. 1, followed by hair and nose.” Complaints may include perceptions of scarring, perceptions of skin color, too much facial hair, or hair that’s too curly or straight. On average, BDD patients report thinking about their perceived flaws for 3-8 hours a day. “Some say it’s all they think about all day long,” said Dr. Phillips, who also directs the Body Dysmorphic Disorder Program at Rhode Island Hospital, in Providence.
“Insight is usually absent or poor, and BDD-related ideas or delusions of reference are common. A majority mistakenly think that other people are taking special notice of them in a negative way because of how they look. If they walk down the street, for example, they may misperceive people as staring at them. If they hear people talking to one another they may think, ‘They must be talking about how ugly my nose is.’ I have patients who have physically assaulted strangers on the street because they’re so certain that they’re being made fun of because of their appearance flaws, which exist in their mind.”
Functional MRI studies of BDD patients demonstrate aberrant visual processing. “They overfocus on tiny details, so the brain is trying to extract detail where there isn’t any,” she explained. “A complementary finding is that they have reduced visual processing of holistic visual stimuli (“seeing the big picture”), compared with healthy controls. One of my patients said to me, ‘When I look at myself I’m just one big pimple without any feet or even any toes.’ They focus in on the body areas they hate and have trouble perceiving the rest of themselves.”
Compulsive repetitive behaviors that are done in response to the appearance preoccupations may include camouflaging (for example, covering perceived hair thinning with a hat), comparing their appearance with that of other people, mirror checking, excessive grooming, questioning others about their appearance or seeking reassurance about the perceived flaws, skin picking, and tanning (often to darken “pale” skin). Functional impairment varies but is usually substantial. For example, in several studies, Dr. Phillips and her associates found that 39% of BDD patients were currently not working because of psychopathology (for most, BDD was their primary diagnosis), about 20% had dropped out of school primarily because of BDD symptoms, 29% had been housebound for at least a week because of their BDD symptoms, 38% had been psychiatrically hospitalized, and the rates of lifetime suicidal ideation ranged from 71% to 81%. “More than one-quarter have attempted suicide,” she said.
About three-quarters seek and two-thirds receive some kind of cosmetic treatment for BDD, most commonly dermatologic treatment and plastic surgery (most often rhinoplasty). “General recommendations are that cosmetic treatment should not be done on these patients,” Dr. Phillips said. A recent practice guideline from the American Academy of Otolaryngology–Head and Neck Surgery recommends that surgeons not operate on a rhinoplasty candidate who screens positive for BDD (Otolaryngol Head Neck Surg. 2017 Feb;156 [2 _suppl]:S1-30).
Serotonin reuptake inhibitors (SRIs) at a high enough dose and for a trial duration of 12-16 weeks are the first-line medications for both nondelusional BDD and delusional BDD. “Most patients with BDD don’t receive adequate first-line pharmacotherapy,” Dr. Phillips said. “Often, high doses of SRIs are needed, sometimes above the [Food and Drug Administration]-approved limits, but I don’t exceed these limits for clomipramine or citalopram.” Recommended SRI doses for BDD are similar to those in the American Psychiatric Association’s practice guideline for obsessive-compulsive disorder. She recommends checking an EKG when patients take a high dose of escitalopram.
In cases of partial or no response to an SRI, consider whether the dose was high enough. “In the vast majority of patients I see for consultation, it wasn’t,” Dr. Phillips said. “Check adherence, and extend the trial if necessary, with 3-4 weeks at the maximum recommended tolerated dose.” In her clinical experience, atypical antipsychotics can sometimes help when added to an SRI, especially in patients who are agitated, aggressive, impulsive, or severely anxious, but antipsychotics are not currently recommended as monotherapy. “In my view, the most pressing need in the BDD field is for research on the efficacy of antipsychotics, especially as SRI augmentation agents,” she said. “We have so little data.” SRI augmentation of buspirone also can prove helpful.
Cognitive-behavioral therapy is the psychosocial treatment of choice for BDD. However, Dr. Phillips cautioned that if BDD patients receive treatment comparable to that of patients with OCD or depression, they probably won’t get better. “It needs to be tailored to BDD symptoms, which are unique in many ways,” she said. “As you would with any patient, express empathy, instill hope, and attend to the therapeutic alliance.”
She recommended using one of the two published evidence-based CBT manuals for BDD: “Cognitive-Behavioral Therapy for Body Dysmorphic Disorder: A Treatment Manual,” by Sabine Wilhelm, PhD, Dr. Phillips, and Gail Steketee, PhD (New York: Guilford Press, 2013) and “Body Dysmorphic Disorder” by David Veale, MD and Fugen Neziroglu, PhD (West Sussex, U.K.: 2010).
Key CBT principles include helping patients cut down on BDD rituals – for example, by spending less time in front of mirrors or discarding their pocket mirrors. Gradual exposure to social situations, combined with behavioral experiments, also is recommended. Other core CBT components include cognitive therapy, perceptual retraining, motivational interviewing, and providing psychoeducation about BDD.
“I explain to patients that people with BDD see themselves differently than others do, which is supported by visual processing studies,” Dr. Phillips said. “They don’t necessarily buy it, but I think it’s worth putting it out there. Instead of trying to convince them that they look fine, focus on their suffering, preoccupation, and the effect of symptoms on their life. They will usually agree that they are suffering a lot, and that may motivate them for treatment.”
These questions that can help you better understand and diagnose the concerns of BDD patients: “Are you very worried about your appearance in any way?” If yes, “Can you tell me about your concern?”
Suggested questions regarding preoccupations about appearance (DSM-5 criteria A) are: “Does this concern preoccupy you? Do you think about it a lot and wish you could think about it less?” To elicit discussion on the topic of repetitive behaviors (DSM-5 criteria B), consider asking, “Is there anything you feel an urge to do over and over again in response to your appearance concerns?” To determine whether the preoccupations cause clinically significant distress or impairment in functioning (DSM-5 criteria C), ask, “How much does this concern upset you? Does it cause you any problems – socially, in relationships, or with school or work?”
Dr. Phillips disclosed that during the past year, she has received honoraria from the Merck Manual and from Royal Pharma as well as royalties from Oxford University Press, International Creative Management, American Psychiatric Publishing, Guilford Press, and UpToDate.
LAS VEGAS – When working with patients referred for suspected body dysmorphic disorder, expect the initial groundwork to take more time than for other disorders.
“I think that these patients are among the most severely ill that we see in clinical practice – although body dysmorphic disorder often goes unrecognized, because patients are often very ashamed of their concerns, and they find it hard to talk about them,” Katharine A. Phillips, MD, said at the annual psychopharmacology update held by the Nevada Psychiatric Association.
Defined in the DSM-5 as preoccupation with one or more perceived defects or flaws in physical appearance that are not observable or that appear slight to others, body dysmorphic disorder (BDD) often causes substantial distress and impairment of day-to-day functioning and is associated with a high rate of suicidality. “When these patients walk into your office, you cannot tell by looking at them what their appearance concern is going to be,” said Dr. Phillips, professor of psychiatry and human behavior at Brown University, Providence, R.I. “Sometimes they point it out to you and you can see that their nostrils are a tiny bit asymmetrical or that they have a little scar on their chin, but it’s not very noticeable. It’s not noticeable until the patient points it out, and even then it’s a slight flaw. But in most cases, the body areas that the patient is preoccupied with look entirely normal.”
BDD affects an estimated 1.7%-2.9% of the general population; about 60% are female. In two-thirds of cases, it onsets during childhood or adolescence. The preoccupations about physical appearance that are associated with the disorder “are very obsessional and distressing,” Dr. Phillips said. “They may think ‘I look ugly. People are laughing at me. I look like a freak.’ They can be focused on any part of their appearance, but most often it’s the face or head. Skin is No. 1, followed by hair and nose.” Complaints may include perceptions of scarring, perceptions of skin color, too much facial hair, or hair that’s too curly or straight. On average, BDD patients report thinking about their perceived flaws for 3-8 hours a day. “Some say it’s all they think about all day long,” said Dr. Phillips, who also directs the Body Dysmorphic Disorder Program at Rhode Island Hospital, in Providence.
“Insight is usually absent or poor, and BDD-related ideas or delusions of reference are common. A majority mistakenly think that other people are taking special notice of them in a negative way because of how they look. If they walk down the street, for example, they may misperceive people as staring at them. If they hear people talking to one another they may think, ‘They must be talking about how ugly my nose is.’ I have patients who have physically assaulted strangers on the street because they’re so certain that they’re being made fun of because of their appearance flaws, which exist in their mind.”
Functional MRI studies of BDD patients demonstrate aberrant visual processing. “They overfocus on tiny details, so the brain is trying to extract detail where there isn’t any,” she explained. “A complementary finding is that they have reduced visual processing of holistic visual stimuli (“seeing the big picture”), compared with healthy controls. One of my patients said to me, ‘When I look at myself I’m just one big pimple without any feet or even any toes.’ They focus in on the body areas they hate and have trouble perceiving the rest of themselves.”
Compulsive repetitive behaviors that are done in response to the appearance preoccupations may include camouflaging (for example, covering perceived hair thinning with a hat), comparing their appearance with that of other people, mirror checking, excessive grooming, questioning others about their appearance or seeking reassurance about the perceived flaws, skin picking, and tanning (often to darken “pale” skin). Functional impairment varies but is usually substantial. For example, in several studies, Dr. Phillips and her associates found that 39% of BDD patients were currently not working because of psychopathology (for most, BDD was their primary diagnosis), about 20% had dropped out of school primarily because of BDD symptoms, 29% had been housebound for at least a week because of their BDD symptoms, 38% had been psychiatrically hospitalized, and the rates of lifetime suicidal ideation ranged from 71% to 81%. “More than one-quarter have attempted suicide,” she said.
About three-quarters seek and two-thirds receive some kind of cosmetic treatment for BDD, most commonly dermatologic treatment and plastic surgery (most often rhinoplasty). “General recommendations are that cosmetic treatment should not be done on these patients,” Dr. Phillips said. A recent practice guideline from the American Academy of Otolaryngology–Head and Neck Surgery recommends that surgeons not operate on a rhinoplasty candidate who screens positive for BDD (Otolaryngol Head Neck Surg. 2017 Feb;156 [2 _suppl]:S1-30).
Serotonin reuptake inhibitors (SRIs) at a high enough dose and for a trial duration of 12-16 weeks are the first-line medications for both nondelusional BDD and delusional BDD. “Most patients with BDD don’t receive adequate first-line pharmacotherapy,” Dr. Phillips said. “Often, high doses of SRIs are needed, sometimes above the [Food and Drug Administration]-approved limits, but I don’t exceed these limits for clomipramine or citalopram.” Recommended SRI doses for BDD are similar to those in the American Psychiatric Association’s practice guideline for obsessive-compulsive disorder. She recommends checking an EKG when patients take a high dose of escitalopram.
In cases of partial or no response to an SRI, consider whether the dose was high enough. “In the vast majority of patients I see for consultation, it wasn’t,” Dr. Phillips said. “Check adherence, and extend the trial if necessary, with 3-4 weeks at the maximum recommended tolerated dose.” In her clinical experience, atypical antipsychotics can sometimes help when added to an SRI, especially in patients who are agitated, aggressive, impulsive, or severely anxious, but antipsychotics are not currently recommended as monotherapy. “In my view, the most pressing need in the BDD field is for research on the efficacy of antipsychotics, especially as SRI augmentation agents,” she said. “We have so little data.” SRI augmentation of buspirone also can prove helpful.
Cognitive-behavioral therapy is the psychosocial treatment of choice for BDD. However, Dr. Phillips cautioned that if BDD patients receive treatment comparable to that of patients with OCD or depression, they probably won’t get better. “It needs to be tailored to BDD symptoms, which are unique in many ways,” she said. “As you would with any patient, express empathy, instill hope, and attend to the therapeutic alliance.”
She recommended using one of the two published evidence-based CBT manuals for BDD: “Cognitive-Behavioral Therapy for Body Dysmorphic Disorder: A Treatment Manual,” by Sabine Wilhelm, PhD, Dr. Phillips, and Gail Steketee, PhD (New York: Guilford Press, 2013) and “Body Dysmorphic Disorder” by David Veale, MD and Fugen Neziroglu, PhD (West Sussex, U.K.: 2010).
Key CBT principles include helping patients cut down on BDD rituals – for example, by spending less time in front of mirrors or discarding their pocket mirrors. Gradual exposure to social situations, combined with behavioral experiments, also is recommended. Other core CBT components include cognitive therapy, perceptual retraining, motivational interviewing, and providing psychoeducation about BDD.
“I explain to patients that people with BDD see themselves differently than others do, which is supported by visual processing studies,” Dr. Phillips said. “They don’t necessarily buy it, but I think it’s worth putting it out there. Instead of trying to convince them that they look fine, focus on their suffering, preoccupation, and the effect of symptoms on their life. They will usually agree that they are suffering a lot, and that may motivate them for treatment.”
These questions that can help you better understand and diagnose the concerns of BDD patients: “Are you very worried about your appearance in any way?” If yes, “Can you tell me about your concern?”
Suggested questions regarding preoccupations about appearance (DSM-5 criteria A) are: “Does this concern preoccupy you? Do you think about it a lot and wish you could think about it less?” To elicit discussion on the topic of repetitive behaviors (DSM-5 criteria B), consider asking, “Is there anything you feel an urge to do over and over again in response to your appearance concerns?” To determine whether the preoccupations cause clinically significant distress or impairment in functioning (DSM-5 criteria C), ask, “How much does this concern upset you? Does it cause you any problems – socially, in relationships, or with school or work?”
Dr. Phillips disclosed that during the past year, she has received honoraria from the Merck Manual and from Royal Pharma as well as royalties from Oxford University Press, International Creative Management, American Psychiatric Publishing, Guilford Press, and UpToDate.
LAS VEGAS – When working with patients referred for suspected body dysmorphic disorder, expect the initial groundwork to take more time than for other disorders.
“I think that these patients are among the most severely ill that we see in clinical practice – although body dysmorphic disorder often goes unrecognized, because patients are often very ashamed of their concerns, and they find it hard to talk about them,” Katharine A. Phillips, MD, said at the annual psychopharmacology update held by the Nevada Psychiatric Association.
Defined in the DSM-5 as preoccupation with one or more perceived defects or flaws in physical appearance that are not observable or that appear slight to others, body dysmorphic disorder (BDD) often causes substantial distress and impairment of day-to-day functioning and is associated with a high rate of suicidality. “When these patients walk into your office, you cannot tell by looking at them what their appearance concern is going to be,” said Dr. Phillips, professor of psychiatry and human behavior at Brown University, Providence, R.I. “Sometimes they point it out to you and you can see that their nostrils are a tiny bit asymmetrical or that they have a little scar on their chin, but it’s not very noticeable. It’s not noticeable until the patient points it out, and even then it’s a slight flaw. But in most cases, the body areas that the patient is preoccupied with look entirely normal.”
BDD affects an estimated 1.7%-2.9% of the general population; about 60% are female. In two-thirds of cases, it onsets during childhood or adolescence. The preoccupations about physical appearance that are associated with the disorder “are very obsessional and distressing,” Dr. Phillips said. “They may think ‘I look ugly. People are laughing at me. I look like a freak.’ They can be focused on any part of their appearance, but most often it’s the face or head. Skin is No. 1, followed by hair and nose.” Complaints may include perceptions of scarring, perceptions of skin color, too much facial hair, or hair that’s too curly or straight. On average, BDD patients report thinking about their perceived flaws for 3-8 hours a day. “Some say it’s all they think about all day long,” said Dr. Phillips, who also directs the Body Dysmorphic Disorder Program at Rhode Island Hospital, in Providence.
“Insight is usually absent or poor, and BDD-related ideas or delusions of reference are common. A majority mistakenly think that other people are taking special notice of them in a negative way because of how they look. If they walk down the street, for example, they may misperceive people as staring at them. If they hear people talking to one another they may think, ‘They must be talking about how ugly my nose is.’ I have patients who have physically assaulted strangers on the street because they’re so certain that they’re being made fun of because of their appearance flaws, which exist in their mind.”
Functional MRI studies of BDD patients demonstrate aberrant visual processing. “They overfocus on tiny details, so the brain is trying to extract detail where there isn’t any,” she explained. “A complementary finding is that they have reduced visual processing of holistic visual stimuli (“seeing the big picture”), compared with healthy controls. One of my patients said to me, ‘When I look at myself I’m just one big pimple without any feet or even any toes.’ They focus in on the body areas they hate and have trouble perceiving the rest of themselves.”
Compulsive repetitive behaviors that are done in response to the appearance preoccupations may include camouflaging (for example, covering perceived hair thinning with a hat), comparing their appearance with that of other people, mirror checking, excessive grooming, questioning others about their appearance or seeking reassurance about the perceived flaws, skin picking, and tanning (often to darken “pale” skin). Functional impairment varies but is usually substantial. For example, in several studies, Dr. Phillips and her associates found that 39% of BDD patients were currently not working because of psychopathology (for most, BDD was their primary diagnosis), about 20% had dropped out of school primarily because of BDD symptoms, 29% had been housebound for at least a week because of their BDD symptoms, 38% had been psychiatrically hospitalized, and the rates of lifetime suicidal ideation ranged from 71% to 81%. “More than one-quarter have attempted suicide,” she said.
About three-quarters seek and two-thirds receive some kind of cosmetic treatment for BDD, most commonly dermatologic treatment and plastic surgery (most often rhinoplasty). “General recommendations are that cosmetic treatment should not be done on these patients,” Dr. Phillips said. A recent practice guideline from the American Academy of Otolaryngology–Head and Neck Surgery recommends that surgeons not operate on a rhinoplasty candidate who screens positive for BDD (Otolaryngol Head Neck Surg. 2017 Feb;156 [2 _suppl]:S1-30).
Serotonin reuptake inhibitors (SRIs) at a high enough dose and for a trial duration of 12-16 weeks are the first-line medications for both nondelusional BDD and delusional BDD. “Most patients with BDD don’t receive adequate first-line pharmacotherapy,” Dr. Phillips said. “Often, high doses of SRIs are needed, sometimes above the [Food and Drug Administration]-approved limits, but I don’t exceed these limits for clomipramine or citalopram.” Recommended SRI doses for BDD are similar to those in the American Psychiatric Association’s practice guideline for obsessive-compulsive disorder. She recommends checking an EKG when patients take a high dose of escitalopram.
In cases of partial or no response to an SRI, consider whether the dose was high enough. “In the vast majority of patients I see for consultation, it wasn’t,” Dr. Phillips said. “Check adherence, and extend the trial if necessary, with 3-4 weeks at the maximum recommended tolerated dose.” In her clinical experience, atypical antipsychotics can sometimes help when added to an SRI, especially in patients who are agitated, aggressive, impulsive, or severely anxious, but antipsychotics are not currently recommended as monotherapy. “In my view, the most pressing need in the BDD field is for research on the efficacy of antipsychotics, especially as SRI augmentation agents,” she said. “We have so little data.” SRI augmentation of buspirone also can prove helpful.
Cognitive-behavioral therapy is the psychosocial treatment of choice for BDD. However, Dr. Phillips cautioned that if BDD patients receive treatment comparable to that of patients with OCD or depression, they probably won’t get better. “It needs to be tailored to BDD symptoms, which are unique in many ways,” she said. “As you would with any patient, express empathy, instill hope, and attend to the therapeutic alliance.”
She recommended using one of the two published evidence-based CBT manuals for BDD: “Cognitive-Behavioral Therapy for Body Dysmorphic Disorder: A Treatment Manual,” by Sabine Wilhelm, PhD, Dr. Phillips, and Gail Steketee, PhD (New York: Guilford Press, 2013) and “Body Dysmorphic Disorder” by David Veale, MD and Fugen Neziroglu, PhD (West Sussex, U.K.: 2010).
Key CBT principles include helping patients cut down on BDD rituals – for example, by spending less time in front of mirrors or discarding their pocket mirrors. Gradual exposure to social situations, combined with behavioral experiments, also is recommended. Other core CBT components include cognitive therapy, perceptual retraining, motivational interviewing, and providing psychoeducation about BDD.
“I explain to patients that people with BDD see themselves differently than others do, which is supported by visual processing studies,” Dr. Phillips said. “They don’t necessarily buy it, but I think it’s worth putting it out there. Instead of trying to convince them that they look fine, focus on their suffering, preoccupation, and the effect of symptoms on their life. They will usually agree that they are suffering a lot, and that may motivate them for treatment.”
These questions that can help you better understand and diagnose the concerns of BDD patients: “Are you very worried about your appearance in any way?” If yes, “Can you tell me about your concern?”
Suggested questions regarding preoccupations about appearance (DSM-5 criteria A) are: “Does this concern preoccupy you? Do you think about it a lot and wish you could think about it less?” To elicit discussion on the topic of repetitive behaviors (DSM-5 criteria B), consider asking, “Is there anything you feel an urge to do over and over again in response to your appearance concerns?” To determine whether the preoccupations cause clinically significant distress or impairment in functioning (DSM-5 criteria C), ask, “How much does this concern upset you? Does it cause you any problems – socially, in relationships, or with school or work?”
Dr. Phillips disclosed that during the past year, she has received honoraria from the Merck Manual and from Royal Pharma as well as royalties from Oxford University Press, International Creative Management, American Psychiatric Publishing, Guilford Press, and UpToDate.
EXPERT ANALYSIS AT THE NPA PSYCHOPHARMACOLOGY UPDATE
Point/Counterpoint: Is endograft PAA repair durable?
Endovascular repair is durable
Endovascular repair of popliteal artery aneurysms is vastly superior to all other previous techniques of popliteal aneurysm repair. Half of all popliteal artery aneurysms are bilateral, and 40% are associated with abdominal aortic aneurysm; 1%-2% of patients with abdominal aortic aneurysm have a popliteal aneurysm (ANZ J Surg. 2006 Oct;76[10]:912-5). Less than 0.01% of hospitalized patients have popliteal artery aneurysms, and men are 20 times more prone to them than women are.
Traditional treatment involves either bypass with interval ligation or a direct posterior approach with an interposition graft, but surgery is not without its problems. I think of the retired anesthesiologist who came to me with a popliteal artery aneurysm (PAA) that his primary care doctor diagnosed. “I’m not having any damn femoral popliteal bypass operation,” he told me. “Every single one of those patients dies.”
Endograft repair is a technique that is reaching its prime, as a growing number of reports have shown – although none of these studies has large numbers because the volume just isn’t available. One recent paper compared 52 open and 23 endovascular PAA repairs (Ann Vasc Surg. 2016 Jan;30:253-7) and found both had similarly high rates of reintervention – 50% at 4 years. But it is noteworthy that the endovascular results improved with time.
A University of Pittsburgh study of 186 open and endovascular repairs found that patients with acute presentations of embolization or aneurysm thrombosis did better with open surgery. In addition, while open repair had superior patency initially after surgery, midterm secondary patency and amputation rates of open and endovascular repair were similar (J Vasc Surg. 2016 Jan;63[1]:70-6).
A Netherlands study of 72 PAA treated with endografting showed that 84% had primary patency at 1 year, and 74% had assisted primary patency at 3 years (Eur J Vasc Endovasc Surg. 2016 Jul;52[1]:99-104). Among these patients, 13 had late occlusions, 7 were converted to bypass, and 2 required thrombolysis; but none required limb amputation.
A meta-analysis of 540 patients found no statistically significant difference in outcomes between endovascular and open repair for PAA (Eur J Vasc Endovasc Surg. 2015 Sep;50(3):351-9). Another systematic review and meta-analysis of 14 studies and 514 patients also found no difference in pooled primary and secondary patency at 5 years (J Endovasc Ther. 2015 Jun;22[3]:330-7).
There certainly are contradictory studies, such as one by Dr. Alik Farber’s group in Boston that showed open repair is superior to endovascular surgery (J Vasc Surg. 2015 Mar;61[3]:663-9); but retrospective database mining certainly has its limitations. Their retrospective study queried the Vascular Quality Initiative database and found that 95% of patients who had open elective popliteal aneurysm repair were free from major adverse limb events, vs. 80% for endovascular treatments.
The best outcomes of open repair happen with autologous vein, but there is precious little of that around now. Emergency patients would probably do better with open surgery, but in elective repair there is no clear differential data.
So, if that’s the case, I’m going to take the small incision.
Peter Rossi, MD, FACS, is an associate professor of surgery and radiology, and the clinical director of vascular surgery, at the Medical College of Wisconsin, Milwaukee. He is also on staff at Clement J. Zablocki Veterans Affairs Medical Center in Milwaukee. Dr. Rossi had no financial relationships to disclose.
Endovascular repair may not be durable
Debating the durability of elective endovascular repair of popliteal artery aneurysm raises a question: Who determines durability anyway?
Is it the patients who only want the Band-Aid and no incision? I don’t think so. Is it the interventionalist who only does endovascular repairs? I don’t think so. I’m sure it’s not the insurance companies, who only worry about cost containment, either.
So, who should determine durability of endovascular popliteal artery aneurysm (PAA) repair?
So, the question is, do we have such data?
There are multiple reports looking at how well open repair works. It has been done for decades. In 2008, a Veterans Affairs study of 583 open PAA repairs reported low death rates and excellent rates of limb salvage at 2 years, even in high-risk patients (J Vasc Surg. 2008 Oct;48[4]:845-51). Open surgical repair has excellent documented durability, and that is not the question at hand.
Endovascular repair has some presumed advantages. It’s less invasive and involves less postoperative pain and a quicker recovery. But it is not without problems – graft thrombosis and occlusion, endoleaks, distal limb ischemia, and stent fractures among them.
Surgery, to be clear, is not perfect, either. One of my patients who years ago presented with an occluded PAA underwent open bypass repair – but then went on later to have a pseudoaneurysm of the proximal anastomosis. I repaired this with an endograft, and he has done quite well. So, we all do endograft repairs, walk out, chest bump the Gore rep, and send the patient home that day.
Is it durable, though?
Most of the data on endovascular repair are from single-center studies dating back to 2003. There’s only one prospective trial comparing endovascular vs. open repair (J Vasc Surg. 2005 Aug;42[2]:185-93), but it was a single-center trial with a severe power limitation, because it involved only 30 patients. It found endovascular repair was comparable to open surgery. Also, I suspect a great deal of selection bias is involved in studies of endovascular repair.
A number of studies have found endovascular repair is not inferior to surgical repair. For example, a study by Dr. Audra Duncan, at Mayo Clinic, and her colleagues found that primary and secondary patency rates of elective and emergent stenting were excellent – but the study results only extended out to 2 years (J Vasc Surg. 2013 May;57[5]:1299-305). I don’t think we could hang our hat on that.
A Swedish study that compared open and endovascular surgery in 592 patients reported that endovascular repair has “significantly inferior results compared with open repair,” particularly in those who present with acute ischemia (Eur J Vasc Endovasc Surg. 2015 Sep;50[3]:342-50). A close look at the data shows that primary patency rates were 89% for open repair and 67.4% for stent graft.
Referencing the systematic review and meta-analysis that Dr. Rossi cited, the primary patency of endovascular repair was only 69% and the secondary patency rate was 77% at 5 years (J Endovasc Ther. 2015 Jun;22[3]:330-7). As physicians, I submit that we can do better.
A Netherlands study investigated stent fractures, finding that 17% (13 out of 78 cases) had circumferential fractures (J Vasc Surg. 2010 Jun;51[6]:1413-8). This study only included circumferential stent fractures and excluded localized strut fractures. I think these studies show that endovascular repair is not always durable.
I want to remind you that we are vascular surgeons, so it is appropriate for us to embrace surgical bypass and its known durability, especially when the durability of endovascular repair is still not known.
Patrick Muck, MD, is chief of vascular surgery and director of vascular residency and fellowship at Good Samaritan Hospital, Cincinnati. He is also on staff at Bethesda North Hospital, Cincinnati, and is affiliated with TriHealth Heart Institute in southwestern Ohio. Dr. Muck had no financial relationships to disclose.
Endovascular repair is durable
Endovascular repair of popliteal artery aneurysms is vastly superior to all other previous techniques of popliteal aneurysm repair. Half of all popliteal artery aneurysms are bilateral, and 40% are associated with abdominal aortic aneurysm; 1%-2% of patients with abdominal aortic aneurysm have a popliteal aneurysm (ANZ J Surg. 2006 Oct;76[10]:912-5). Less than 0.01% of hospitalized patients have popliteal artery aneurysms, and men are 20 times more prone to them than women are.
Traditional treatment involves either bypass with interval ligation or a direct posterior approach with an interposition graft, but surgery is not without its problems. I think of the retired anesthesiologist who came to me with a popliteal artery aneurysm (PAA) that his primary care doctor diagnosed. “I’m not having any damn femoral popliteal bypass operation,” he told me. “Every single one of those patients dies.”
Endograft repair is a technique that is reaching its prime, as a growing number of reports have shown – although none of these studies has large numbers because the volume just isn’t available. One recent paper compared 52 open and 23 endovascular PAA repairs (Ann Vasc Surg. 2016 Jan;30:253-7) and found both had similarly high rates of reintervention – 50% at 4 years. But it is noteworthy that the endovascular results improved with time.
A University of Pittsburgh study of 186 open and endovascular repairs found that patients with acute presentations of embolization or aneurysm thrombosis did better with open surgery. In addition, while open repair had superior patency initially after surgery, midterm secondary patency and amputation rates of open and endovascular repair were similar (J Vasc Surg. 2016 Jan;63[1]:70-6).
A Netherlands study of 72 PAA treated with endografting showed that 84% had primary patency at 1 year, and 74% had assisted primary patency at 3 years (Eur J Vasc Endovasc Surg. 2016 Jul;52[1]:99-104). Among these patients, 13 had late occlusions, 7 were converted to bypass, and 2 required thrombolysis; but none required limb amputation.
A meta-analysis of 540 patients found no statistically significant difference in outcomes between endovascular and open repair for PAA (Eur J Vasc Endovasc Surg. 2015 Sep;50(3):351-9). Another systematic review and meta-analysis of 14 studies and 514 patients also found no difference in pooled primary and secondary patency at 5 years (J Endovasc Ther. 2015 Jun;22[3]:330-7).
There certainly are contradictory studies, such as one by Dr. Alik Farber’s group in Boston that showed open repair is superior to endovascular surgery (J Vasc Surg. 2015 Mar;61[3]:663-9); but retrospective database mining certainly has its limitations. Their retrospective study queried the Vascular Quality Initiative database and found that 95% of patients who had open elective popliteal aneurysm repair were free from major adverse limb events, vs. 80% for endovascular treatments.
The best outcomes of open repair happen with autologous vein, but there is precious little of that around now. Emergency patients would probably do better with open surgery, but in elective repair there is no clear differential data.
So, if that’s the case, I’m going to take the small incision.
Peter Rossi, MD, FACS, is an associate professor of surgery and radiology, and the clinical director of vascular surgery, at the Medical College of Wisconsin, Milwaukee. He is also on staff at Clement J. Zablocki Veterans Affairs Medical Center in Milwaukee. Dr. Rossi had no financial relationships to disclose.
Endovascular repair may not be durable
Debating the durability of elective endovascular repair of popliteal artery aneurysm raises a question: Who determines durability anyway?
Is it the patients who only want the Band-Aid and no incision? I don’t think so. Is it the interventionalist who only does endovascular repairs? I don’t think so. I’m sure it’s not the insurance companies, who only worry about cost containment, either.
So, who should determine durability of endovascular popliteal artery aneurysm (PAA) repair?
So, the question is, do we have such data?
There are multiple reports looking at how well open repair works. It has been done for decades. In 2008, a Veterans Affairs study of 583 open PAA repairs reported low death rates and excellent rates of limb salvage at 2 years, even in high-risk patients (J Vasc Surg. 2008 Oct;48[4]:845-51). Open surgical repair has excellent documented durability, and that is not the question at hand.
Endovascular repair has some presumed advantages. It’s less invasive and involves less postoperative pain and a quicker recovery. But it is not without problems – graft thrombosis and occlusion, endoleaks, distal limb ischemia, and stent fractures among them.
Surgery, to be clear, is not perfect, either. One of my patients who years ago presented with an occluded PAA underwent open bypass repair – but then went on later to have a pseudoaneurysm of the proximal anastomosis. I repaired this with an endograft, and he has done quite well. So, we all do endograft repairs, walk out, chest bump the Gore rep, and send the patient home that day.
Is it durable, though?
Most of the data on endovascular repair are from single-center studies dating back to 2003. There’s only one prospective trial comparing endovascular vs. open repair (J Vasc Surg. 2005 Aug;42[2]:185-93), but it was a single-center trial with a severe power limitation, because it involved only 30 patients. It found endovascular repair was comparable to open surgery. Also, I suspect a great deal of selection bias is involved in studies of endovascular repair.
A number of studies have found endovascular repair is not inferior to surgical repair. For example, a study by Dr. Audra Duncan, at Mayo Clinic, and her colleagues found that primary and secondary patency rates of elective and emergent stenting were excellent – but the study results only extended out to 2 years (J Vasc Surg. 2013 May;57[5]:1299-305). I don’t think we could hang our hat on that.
A Swedish study that compared open and endovascular surgery in 592 patients reported that endovascular repair has “significantly inferior results compared with open repair,” particularly in those who present with acute ischemia (Eur J Vasc Endovasc Surg. 2015 Sep;50[3]:342-50). A close look at the data shows that primary patency rates were 89% for open repair and 67.4% for stent graft.
Referencing the systematic review and meta-analysis that Dr. Rossi cited, the primary patency of endovascular repair was only 69% and the secondary patency rate was 77% at 5 years (J Endovasc Ther. 2015 Jun;22[3]:330-7). As physicians, I submit that we can do better.
A Netherlands study investigated stent fractures, finding that 17% (13 out of 78 cases) had circumferential fractures (J Vasc Surg. 2010 Jun;51[6]:1413-8). This study only included circumferential stent fractures and excluded localized strut fractures. I think these studies show that endovascular repair is not always durable.
I want to remind you that we are vascular surgeons, so it is appropriate for us to embrace surgical bypass and its known durability, especially when the durability of endovascular repair is still not known.
Patrick Muck, MD, is chief of vascular surgery and director of vascular residency and fellowship at Good Samaritan Hospital, Cincinnati. He is also on staff at Bethesda North Hospital, Cincinnati, and is affiliated with TriHealth Heart Institute in southwestern Ohio. Dr. Muck had no financial relationships to disclose.
Endovascular repair is durable
Endovascular repair of popliteal artery aneurysms is vastly superior to all other previous techniques of popliteal aneurysm repair. Half of all popliteal artery aneurysms are bilateral, and 40% are associated with abdominal aortic aneurysm; 1%-2% of patients with abdominal aortic aneurysm have a popliteal aneurysm (ANZ J Surg. 2006 Oct;76[10]:912-5). Less than 0.01% of hospitalized patients have popliteal artery aneurysms, and men are 20 times more prone to them than women are.
Traditional treatment involves either bypass with interval ligation or a direct posterior approach with an interposition graft, but surgery is not without its problems. I think of the retired anesthesiologist who came to me with a popliteal artery aneurysm (PAA) that his primary care doctor diagnosed. “I’m not having any damn femoral popliteal bypass operation,” he told me. “Every single one of those patients dies.”
Endograft repair is a technique that is reaching its prime, as a growing number of reports have shown – although none of these studies has large numbers because the volume just isn’t available. One recent paper compared 52 open and 23 endovascular PAA repairs (Ann Vasc Surg. 2016 Jan;30:253-7) and found both had similarly high rates of reintervention – 50% at 4 years. But it is noteworthy that the endovascular results improved with time.
A University of Pittsburgh study of 186 open and endovascular repairs found that patients with acute presentations of embolization or aneurysm thrombosis did better with open surgery. In addition, while open repair had superior patency initially after surgery, midterm secondary patency and amputation rates of open and endovascular repair were similar (J Vasc Surg. 2016 Jan;63[1]:70-6).
A Netherlands study of 72 PAA treated with endografting showed that 84% had primary patency at 1 year, and 74% had assisted primary patency at 3 years (Eur J Vasc Endovasc Surg. 2016 Jul;52[1]:99-104). Among these patients, 13 had late occlusions, 7 were converted to bypass, and 2 required thrombolysis; but none required limb amputation.
A meta-analysis of 540 patients found no statistically significant difference in outcomes between endovascular and open repair for PAA (Eur J Vasc Endovasc Surg. 2015 Sep;50(3):351-9). Another systematic review and meta-analysis of 14 studies and 514 patients also found no difference in pooled primary and secondary patency at 5 years (J Endovasc Ther. 2015 Jun;22[3]:330-7).
There certainly are contradictory studies, such as one by Dr. Alik Farber’s group in Boston that showed open repair is superior to endovascular surgery (J Vasc Surg. 2015 Mar;61[3]:663-9); but retrospective database mining certainly has its limitations. Their retrospective study queried the Vascular Quality Initiative database and found that 95% of patients who had open elective popliteal aneurysm repair were free from major adverse limb events, vs. 80% for endovascular treatments.
The best outcomes of open repair happen with autologous vein, but there is precious little of that around now. Emergency patients would probably do better with open surgery, but in elective repair there is no clear differential data.
So, if that’s the case, I’m going to take the small incision.
Peter Rossi, MD, FACS, is an associate professor of surgery and radiology, and the clinical director of vascular surgery, at the Medical College of Wisconsin, Milwaukee. He is also on staff at Clement J. Zablocki Veterans Affairs Medical Center in Milwaukee. Dr. Rossi had no financial relationships to disclose.
Endovascular repair may not be durable
Debating the durability of elective endovascular repair of popliteal artery aneurysm raises a question: Who determines durability anyway?
Is it the patients who only want the Band-Aid and no incision? I don’t think so. Is it the interventionalist who only does endovascular repairs? I don’t think so. I’m sure it’s not the insurance companies, who only worry about cost containment, either.
So, who should determine durability of endovascular popliteal artery aneurysm (PAA) repair?
So, the question is, do we have such data?
There are multiple reports looking at how well open repair works. It has been done for decades. In 2008, a Veterans Affairs study of 583 open PAA repairs reported low death rates and excellent rates of limb salvage at 2 years, even in high-risk patients (J Vasc Surg. 2008 Oct;48[4]:845-51). Open surgical repair has excellent documented durability, and that is not the question at hand.
Endovascular repair has some presumed advantages. It’s less invasive and involves less postoperative pain and a quicker recovery. But it is not without problems – graft thrombosis and occlusion, endoleaks, distal limb ischemia, and stent fractures among them.
Surgery, to be clear, is not perfect, either. One of my patients who years ago presented with an occluded PAA underwent open bypass repair – but then went on later to have a pseudoaneurysm of the proximal anastomosis. I repaired this with an endograft, and he has done quite well. So, we all do endograft repairs, walk out, chest bump the Gore rep, and send the patient home that day.
Is it durable, though?
Most of the data on endovascular repair are from single-center studies dating back to 2003. There’s only one prospective trial comparing endovascular vs. open repair (J Vasc Surg. 2005 Aug;42[2]:185-93), but it was a single-center trial with a severe power limitation, because it involved only 30 patients. It found endovascular repair was comparable to open surgery. Also, I suspect a great deal of selection bias is involved in studies of endovascular repair.
A number of studies have found endovascular repair is not inferior to surgical repair. For example, a study by Dr. Audra Duncan, at Mayo Clinic, and her colleagues found that primary and secondary patency rates of elective and emergent stenting were excellent – but the study results only extended out to 2 years (J Vasc Surg. 2013 May;57[5]:1299-305). I don’t think we could hang our hat on that.
A Swedish study that compared open and endovascular surgery in 592 patients reported that endovascular repair has “significantly inferior results compared with open repair,” particularly in those who present with acute ischemia (Eur J Vasc Endovasc Surg. 2015 Sep;50[3]:342-50). A close look at the data shows that primary patency rates were 89% for open repair and 67.4% for stent graft.
Referencing the systematic review and meta-analysis that Dr. Rossi cited, the primary patency of endovascular repair was only 69% and the secondary patency rate was 77% at 5 years (J Endovasc Ther. 2015 Jun;22[3]:330-7). As physicians, I submit that we can do better.
A Netherlands study investigated stent fractures, finding that 17% (13 out of 78 cases) had circumferential fractures (J Vasc Surg. 2010 Jun;51[6]:1413-8). This study only included circumferential stent fractures and excluded localized strut fractures. I think these studies show that endovascular repair is not always durable.
I want to remind you that we are vascular surgeons, so it is appropriate for us to embrace surgical bypass and its known durability, especially when the durability of endovascular repair is still not known.
Patrick Muck, MD, is chief of vascular surgery and director of vascular residency and fellowship at Good Samaritan Hospital, Cincinnati. He is also on staff at Bethesda North Hospital, Cincinnati, and is affiliated with TriHealth Heart Institute in southwestern Ohio. Dr. Muck had no financial relationships to disclose.
AT MIDWESTERN VASCULAR 2016
Adding rituximab to reduced intensity conditioning boosts PFS
ORLANDO – Rituximab conferred a significant progression-free survival benefit in reduced intensity conditioning regimens for patients with B-cell non-Hodgkin lymphoma who underwent allogeneic hematopoietic cell transplantation, based on data from the Center for International Blood & Marrow Transplant Research.
Further, higher cumulative rituximab doses appeared to confer a benefit in overall survival.
Rituximab is frequently a component of reduced intensity conditioning (RIC) regimens in allogeneic hematopoietic cell transplantation (HCT), but there has been a “paucity of comparative data” for rituximab-containing (R-RIC) versus non–R-RIC conditioning regimens for allogeneic transplant patients, Narendranath Epperla, MD, of the Medical College of Wisconsin, Milwaukee, said during the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society of Blood and Marrow Transplantation.
Using data from the Center for International Blood & Marrow Transplant Research, Dr. Epperla and his colleagues identified 1,022 patients who received rituximab and 379 patients who did not with diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and marginal zone lymphoma. The patients received their first RIC or non-myeloablative allogeneic HCT between 2008 and 2014. The donors were matched, and either related or 8x8 allele-matched unrelated; the graft source could be bone marrow or peripheral blood. Graft versus host disease (GVHD) suppression was calcineurin inhibitor based.
Patients who had received myeloablative conditioning, or who had received radioimmunotherapy or alemtuzumab were excluded, as were those who received alternative donor allografts.
Dr. Epperla and his colleagues factored in patient and disease characteristics, as well as differences in transplant regimen, in determining the adjusted cumulative incidence of relapse or progression, as well as the incidence of nonrelapse mortality.
In the multivariable analysis, overall survival did not differ between the R-RIC and the non–R-RIC cohorts (relative risk [RR] of all-cause mortality, R-RIC = 0.83, 95% CI 0.67-1.03, P = .09).
Based on the cumulative dose of rituximab that patients had received, though, “we noted that patients who got higher doses of rituximab had lower risk of nonrelapse mortality,” Dr. Epperla said. “Higher cumulative doses of rituximab seem to confer overall survival benefit.” This was true even though the higher rituximab doses had no significant effect on the risk of therapy failure, nonrelapse mortality, or the risk of progression/relapse.
When the cumulative rituximab dose was 2,000 to 3,375 mg/m2, the hazard ratio for all-cause mortality fell to 0.43 compared to a cumulative rituximab dose of less than 1,000 mg/m2 (95% confidence interval [CI] 0.21-0.90, P = .02).
Among the R-RIC group, there was a nonsignificant trend toward reduced risk of progression or relapse (relative risk of progression/relapse, R-RIC = 0.79, 95% CI 0.63-1.01, P = .055). However, the R-RIC group fared significantly better in terms of progression-free survival (RR of PFS, R-RIC = 0.76, 95% CI 0.62-0.92, P = .006).
After transplant, patients in the R-RIC group were no more likely than those in the non–R-RIC group to experience chronic GVHD (RR of GVHD, R-RIC = 1.15, 95% CI 0.96-1.39, P = .13). There was no difference in the adjusted curves of nonrelapse mortality between the groups (RR of nonrelapse mortality, R-RIC = 0.90, 95% CI 0.67-1.22, P = .51).
Also, there were no fatal cytopenias in the R-RIC arm, although the literature warrants some concern for increased risk of infection with rituximab, Dr. Epperla said.
At baseline, there were no significant differences in demographic characteristics between the nonrituximab and rituximab arms of the study population. More than 90% of patients were white, and 65% were male; the median age was 57 years (range, 18-74).
Patients had been diagnosed about 3 years before receiving HCT; about 60% of patients had a baseline Karnofsky performance score greater than 90, and the HCT comorbidity index was 2. About 86% of patients were chemosensitive, and patients in both study arms had received a median of three prior lines of therapy.
There were some differences in conditioning regimens between the two groups. “There were a significantly higher number of patients in the nonrituximab group who received fludarabine/busulfan, while there were a significantly high number in the rituximab group who received a fludarabine/cyclophosphamide-based conditioning regimen,” Dr. Epperla said. Follicular lymphomas were more common in the R-RIC arm, while diffuse large B-cell lymphomas were seen more in the non–R-RIC arm.
Given the survival benefit and similar rates of chronic GVHD seen in the retrospective analysis, a prospective, randomized head-to-head trial of R-RIC versus non–R-RIC is warranted, Dr. Epperla concluded.
During the postpresentation discussion, Dr. Epperla acknowledged the variability of the lymphomas in the study, but that there was no significant statistical effect of specific histologies on the findings in a subgroup analysis. Dr. Epperla added that the chemosensitivity status at transplant was checked to account for patient exposure to rituximab before RIC, and that there was no effect of prior rituximab exposure on the outcomes examined.
Dr. Epperla reported no conflicts of interest.
[email protected]
On Twitter @karioakes
ORLANDO – Rituximab conferred a significant progression-free survival benefit in reduced intensity conditioning regimens for patients with B-cell non-Hodgkin lymphoma who underwent allogeneic hematopoietic cell transplantation, based on data from the Center for International Blood & Marrow Transplant Research.
Further, higher cumulative rituximab doses appeared to confer a benefit in overall survival.
Rituximab is frequently a component of reduced intensity conditioning (RIC) regimens in allogeneic hematopoietic cell transplantation (HCT), but there has been a “paucity of comparative data” for rituximab-containing (R-RIC) versus non–R-RIC conditioning regimens for allogeneic transplant patients, Narendranath Epperla, MD, of the Medical College of Wisconsin, Milwaukee, said during the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society of Blood and Marrow Transplantation.
Using data from the Center for International Blood & Marrow Transplant Research, Dr. Epperla and his colleagues identified 1,022 patients who received rituximab and 379 patients who did not with diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and marginal zone lymphoma. The patients received their first RIC or non-myeloablative allogeneic HCT between 2008 and 2014. The donors were matched, and either related or 8x8 allele-matched unrelated; the graft source could be bone marrow or peripheral blood. Graft versus host disease (GVHD) suppression was calcineurin inhibitor based.
Patients who had received myeloablative conditioning, or who had received radioimmunotherapy or alemtuzumab were excluded, as were those who received alternative donor allografts.
Dr. Epperla and his colleagues factored in patient and disease characteristics, as well as differences in transplant regimen, in determining the adjusted cumulative incidence of relapse or progression, as well as the incidence of nonrelapse mortality.
In the multivariable analysis, overall survival did not differ between the R-RIC and the non–R-RIC cohorts (relative risk [RR] of all-cause mortality, R-RIC = 0.83, 95% CI 0.67-1.03, P = .09).
Based on the cumulative dose of rituximab that patients had received, though, “we noted that patients who got higher doses of rituximab had lower risk of nonrelapse mortality,” Dr. Epperla said. “Higher cumulative doses of rituximab seem to confer overall survival benefit.” This was true even though the higher rituximab doses had no significant effect on the risk of therapy failure, nonrelapse mortality, or the risk of progression/relapse.
When the cumulative rituximab dose was 2,000 to 3,375 mg/m2, the hazard ratio for all-cause mortality fell to 0.43 compared to a cumulative rituximab dose of less than 1,000 mg/m2 (95% confidence interval [CI] 0.21-0.90, P = .02).
Among the R-RIC group, there was a nonsignificant trend toward reduced risk of progression or relapse (relative risk of progression/relapse, R-RIC = 0.79, 95% CI 0.63-1.01, P = .055). However, the R-RIC group fared significantly better in terms of progression-free survival (RR of PFS, R-RIC = 0.76, 95% CI 0.62-0.92, P = .006).
After transplant, patients in the R-RIC group were no more likely than those in the non–R-RIC group to experience chronic GVHD (RR of GVHD, R-RIC = 1.15, 95% CI 0.96-1.39, P = .13). There was no difference in the adjusted curves of nonrelapse mortality between the groups (RR of nonrelapse mortality, R-RIC = 0.90, 95% CI 0.67-1.22, P = .51).
Also, there were no fatal cytopenias in the R-RIC arm, although the literature warrants some concern for increased risk of infection with rituximab, Dr. Epperla said.
At baseline, there were no significant differences in demographic characteristics between the nonrituximab and rituximab arms of the study population. More than 90% of patients were white, and 65% were male; the median age was 57 years (range, 18-74).
Patients had been diagnosed about 3 years before receiving HCT; about 60% of patients had a baseline Karnofsky performance score greater than 90, and the HCT comorbidity index was 2. About 86% of patients were chemosensitive, and patients in both study arms had received a median of three prior lines of therapy.
There were some differences in conditioning regimens between the two groups. “There were a significantly higher number of patients in the nonrituximab group who received fludarabine/busulfan, while there were a significantly high number in the rituximab group who received a fludarabine/cyclophosphamide-based conditioning regimen,” Dr. Epperla said. Follicular lymphomas were more common in the R-RIC arm, while diffuse large B-cell lymphomas were seen more in the non–R-RIC arm.
Given the survival benefit and similar rates of chronic GVHD seen in the retrospective analysis, a prospective, randomized head-to-head trial of R-RIC versus non–R-RIC is warranted, Dr. Epperla concluded.
During the postpresentation discussion, Dr. Epperla acknowledged the variability of the lymphomas in the study, but that there was no significant statistical effect of specific histologies on the findings in a subgroup analysis. Dr. Epperla added that the chemosensitivity status at transplant was checked to account for patient exposure to rituximab before RIC, and that there was no effect of prior rituximab exposure on the outcomes examined.
Dr. Epperla reported no conflicts of interest.
[email protected]
On Twitter @karioakes
ORLANDO – Rituximab conferred a significant progression-free survival benefit in reduced intensity conditioning regimens for patients with B-cell non-Hodgkin lymphoma who underwent allogeneic hematopoietic cell transplantation, based on data from the Center for International Blood & Marrow Transplant Research.
Further, higher cumulative rituximab doses appeared to confer a benefit in overall survival.
Rituximab is frequently a component of reduced intensity conditioning (RIC) regimens in allogeneic hematopoietic cell transplantation (HCT), but there has been a “paucity of comparative data” for rituximab-containing (R-RIC) versus non–R-RIC conditioning regimens for allogeneic transplant patients, Narendranath Epperla, MD, of the Medical College of Wisconsin, Milwaukee, said during the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society of Blood and Marrow Transplantation.
Using data from the Center for International Blood & Marrow Transplant Research, Dr. Epperla and his colleagues identified 1,022 patients who received rituximab and 379 patients who did not with diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and marginal zone lymphoma. The patients received their first RIC or non-myeloablative allogeneic HCT between 2008 and 2014. The donors were matched, and either related or 8x8 allele-matched unrelated; the graft source could be bone marrow or peripheral blood. Graft versus host disease (GVHD) suppression was calcineurin inhibitor based.
Patients who had received myeloablative conditioning, or who had received radioimmunotherapy or alemtuzumab were excluded, as were those who received alternative donor allografts.
Dr. Epperla and his colleagues factored in patient and disease characteristics, as well as differences in transplant regimen, in determining the adjusted cumulative incidence of relapse or progression, as well as the incidence of nonrelapse mortality.
In the multivariable analysis, overall survival did not differ between the R-RIC and the non–R-RIC cohorts (relative risk [RR] of all-cause mortality, R-RIC = 0.83, 95% CI 0.67-1.03, P = .09).
Based on the cumulative dose of rituximab that patients had received, though, “we noted that patients who got higher doses of rituximab had lower risk of nonrelapse mortality,” Dr. Epperla said. “Higher cumulative doses of rituximab seem to confer overall survival benefit.” This was true even though the higher rituximab doses had no significant effect on the risk of therapy failure, nonrelapse mortality, or the risk of progression/relapse.
When the cumulative rituximab dose was 2,000 to 3,375 mg/m2, the hazard ratio for all-cause mortality fell to 0.43 compared to a cumulative rituximab dose of less than 1,000 mg/m2 (95% confidence interval [CI] 0.21-0.90, P = .02).
Among the R-RIC group, there was a nonsignificant trend toward reduced risk of progression or relapse (relative risk of progression/relapse, R-RIC = 0.79, 95% CI 0.63-1.01, P = .055). However, the R-RIC group fared significantly better in terms of progression-free survival (RR of PFS, R-RIC = 0.76, 95% CI 0.62-0.92, P = .006).
After transplant, patients in the R-RIC group were no more likely than those in the non–R-RIC group to experience chronic GVHD (RR of GVHD, R-RIC = 1.15, 95% CI 0.96-1.39, P = .13). There was no difference in the adjusted curves of nonrelapse mortality between the groups (RR of nonrelapse mortality, R-RIC = 0.90, 95% CI 0.67-1.22, P = .51).
Also, there were no fatal cytopenias in the R-RIC arm, although the literature warrants some concern for increased risk of infection with rituximab, Dr. Epperla said.
At baseline, there were no significant differences in demographic characteristics between the nonrituximab and rituximab arms of the study population. More than 90% of patients were white, and 65% were male; the median age was 57 years (range, 18-74).
Patients had been diagnosed about 3 years before receiving HCT; about 60% of patients had a baseline Karnofsky performance score greater than 90, and the HCT comorbidity index was 2. About 86% of patients were chemosensitive, and patients in both study arms had received a median of three prior lines of therapy.
There were some differences in conditioning regimens between the two groups. “There were a significantly higher number of patients in the nonrituximab group who received fludarabine/busulfan, while there were a significantly high number in the rituximab group who received a fludarabine/cyclophosphamide-based conditioning regimen,” Dr. Epperla said. Follicular lymphomas were more common in the R-RIC arm, while diffuse large B-cell lymphomas were seen more in the non–R-RIC arm.
Given the survival benefit and similar rates of chronic GVHD seen in the retrospective analysis, a prospective, randomized head-to-head trial of R-RIC versus non–R-RIC is warranted, Dr. Epperla concluded.
During the postpresentation discussion, Dr. Epperla acknowledged the variability of the lymphomas in the study, but that there was no significant statistical effect of specific histologies on the findings in a subgroup analysis. Dr. Epperla added that the chemosensitivity status at transplant was checked to account for patient exposure to rituximab before RIC, and that there was no effect of prior rituximab exposure on the outcomes examined.
Dr. Epperla reported no conflicts of interest.
[email protected]
On Twitter @karioakes
Key clinical point:
Major finding: Patients with rituximab-containing RIC regimens had better progression-free survival (PFS; relative risk of PFS, non–R-RIC=1, R-RIC=076, 95% CI 0.62-092, P = .006).
Data source: Retrospective review of 1,022 allogeneic HCT B-cell non-Hodgkin lymphoma patients who received rituximab and 379 who did not.
Disclosures: The data were obtained from the Center for International Blood & Marrow Transplant Research. Dr. Epperla reported no disclosures.
Hemorrhagic stroke increases risk of depression and subsequent dementia
HOUSTON – Hemorrhagic stroke sharply increases the risk of new-onset depression which, in turn, is associated with a 30% increased risk of dementia within 5 years.
New-onset depression developed in 40% of intracerebral hemorrhage survivors in a large prospective study, Alessandro Biffi, MD, said at the International Stroke Conference sponsored by the American Heart Association. By the end of 5 years, 80% of these patients had developed some form of dementia.
“This is of great importance from a research and clinical standpoint, as it may represent a marker of ongoing cognitive deterioration,” said Dr. Biffi of Massachusetts General Hospital, Boston.
A number of studies have found that survivors of intracerebral hemorrhage (ICH) face a significantly increased risk of mood disorders and cognitive decline. “There is probably a link between mood disorders and cognition after ICH, as is the case for a number of other neurological conditions,” Dr. Biffi said. “Cerebrovascular small-vessel disease is likely to be involved in the underlying pathogenesis for these disorders, as it is also a risk factor for late-life depression in the general population. Therefore, depression and dementia after ICH may share some etiological connections.”
He and his colleagues enrolled 695 patients who had experienced an ICH and followed them for a mean of 5 years. None of the subjects had ever been diagnosed with a mood disorder or cognitive decline. The subjects were interviewed by telephone every 6 months.
At baseline, investigators collected CT and MRI imaging data, epidemiologic exposure data, and apolipoprotein E4 genotype. The outcomes were new-onset depression and incident dementia.
At baseline, subjects were a mean of 74 years old. About 70% had hypertension and 15% had heart disease. Less than 1% of the cohort was positive for the APOE e4 gene. Imaging-confirmed white matter disease was present in 65%.
Over the follow-up period, new-onset depression developed in 278 (40%). The temporal incidence of this was consistent, at about 7% per year.
Two baseline characteristics were significantly associated with new-onset depression. These included having more than a single copy of the APOE e4 allele (hazard ratio, 1.7) and the presence of white matter disease (HR, 1.82), Dr. Biffi reported.
Having had at least 10 years of school was protective against depression (HR, 0.75), as was functional independence (HR, 0.52).
By the end of the follow-up period, dementia had developed in 80% of those with depression (220). In 81% of cases, depression preceded dementia, with an average time lag of 1.5 years, he noted.
In a multivariate analysis, several factors were significantly associated with incident dementia. Higher education reduced the risk by 40% (HR, 0.60). Factors that increased the risk of dementia were black race (HR, 1.48), carrying the APOE e4 gene (HR, 2.12), presence of white matter disease (HR, 1.7), and poststroke new-onset depression (HR, 1.29).
The study shows only association, Dr. Biffi cautioned. “No causal relationship can be inferred by this study. We also can’t capture the severity of the mood symptoms, and we are unable to examine the relationship between cognition and apathy, which is another highly relevant neuropsychiatric manifestation of small-vessel disease.”
He had no financial disclosures.
[email protected]
On Twitter @alz_gal
HOUSTON – Hemorrhagic stroke sharply increases the risk of new-onset depression which, in turn, is associated with a 30% increased risk of dementia within 5 years.
New-onset depression developed in 40% of intracerebral hemorrhage survivors in a large prospective study, Alessandro Biffi, MD, said at the International Stroke Conference sponsored by the American Heart Association. By the end of 5 years, 80% of these patients had developed some form of dementia.
“This is of great importance from a research and clinical standpoint, as it may represent a marker of ongoing cognitive deterioration,” said Dr. Biffi of Massachusetts General Hospital, Boston.
A number of studies have found that survivors of intracerebral hemorrhage (ICH) face a significantly increased risk of mood disorders and cognitive decline. “There is probably a link between mood disorders and cognition after ICH, as is the case for a number of other neurological conditions,” Dr. Biffi said. “Cerebrovascular small-vessel disease is likely to be involved in the underlying pathogenesis for these disorders, as it is also a risk factor for late-life depression in the general population. Therefore, depression and dementia after ICH may share some etiological connections.”
He and his colleagues enrolled 695 patients who had experienced an ICH and followed them for a mean of 5 years. None of the subjects had ever been diagnosed with a mood disorder or cognitive decline. The subjects were interviewed by telephone every 6 months.
At baseline, investigators collected CT and MRI imaging data, epidemiologic exposure data, and apolipoprotein E4 genotype. The outcomes were new-onset depression and incident dementia.
At baseline, subjects were a mean of 74 years old. About 70% had hypertension and 15% had heart disease. Less than 1% of the cohort was positive for the APOE e4 gene. Imaging-confirmed white matter disease was present in 65%.
Over the follow-up period, new-onset depression developed in 278 (40%). The temporal incidence of this was consistent, at about 7% per year.
Two baseline characteristics were significantly associated with new-onset depression. These included having more than a single copy of the APOE e4 allele (hazard ratio, 1.7) and the presence of white matter disease (HR, 1.82), Dr. Biffi reported.
Having had at least 10 years of school was protective against depression (HR, 0.75), as was functional independence (HR, 0.52).
By the end of the follow-up period, dementia had developed in 80% of those with depression (220). In 81% of cases, depression preceded dementia, with an average time lag of 1.5 years, he noted.
In a multivariate analysis, several factors were significantly associated with incident dementia. Higher education reduced the risk by 40% (HR, 0.60). Factors that increased the risk of dementia were black race (HR, 1.48), carrying the APOE e4 gene (HR, 2.12), presence of white matter disease (HR, 1.7), and poststroke new-onset depression (HR, 1.29).
The study shows only association, Dr. Biffi cautioned. “No causal relationship can be inferred by this study. We also can’t capture the severity of the mood symptoms, and we are unable to examine the relationship between cognition and apathy, which is another highly relevant neuropsychiatric manifestation of small-vessel disease.”
He had no financial disclosures.
[email protected]
On Twitter @alz_gal
HOUSTON – Hemorrhagic stroke sharply increases the risk of new-onset depression which, in turn, is associated with a 30% increased risk of dementia within 5 years.
New-onset depression developed in 40% of intracerebral hemorrhage survivors in a large prospective study, Alessandro Biffi, MD, said at the International Stroke Conference sponsored by the American Heart Association. By the end of 5 years, 80% of these patients had developed some form of dementia.
“This is of great importance from a research and clinical standpoint, as it may represent a marker of ongoing cognitive deterioration,” said Dr. Biffi of Massachusetts General Hospital, Boston.
A number of studies have found that survivors of intracerebral hemorrhage (ICH) face a significantly increased risk of mood disorders and cognitive decline. “There is probably a link between mood disorders and cognition after ICH, as is the case for a number of other neurological conditions,” Dr. Biffi said. “Cerebrovascular small-vessel disease is likely to be involved in the underlying pathogenesis for these disorders, as it is also a risk factor for late-life depression in the general population. Therefore, depression and dementia after ICH may share some etiological connections.”
He and his colleagues enrolled 695 patients who had experienced an ICH and followed them for a mean of 5 years. None of the subjects had ever been diagnosed with a mood disorder or cognitive decline. The subjects were interviewed by telephone every 6 months.
At baseline, investigators collected CT and MRI imaging data, epidemiologic exposure data, and apolipoprotein E4 genotype. The outcomes were new-onset depression and incident dementia.
At baseline, subjects were a mean of 74 years old. About 70% had hypertension and 15% had heart disease. Less than 1% of the cohort was positive for the APOE e4 gene. Imaging-confirmed white matter disease was present in 65%.
Over the follow-up period, new-onset depression developed in 278 (40%). The temporal incidence of this was consistent, at about 7% per year.
Two baseline characteristics were significantly associated with new-onset depression. These included having more than a single copy of the APOE e4 allele (hazard ratio, 1.7) and the presence of white matter disease (HR, 1.82), Dr. Biffi reported.
Having had at least 10 years of school was protective against depression (HR, 0.75), as was functional independence (HR, 0.52).
By the end of the follow-up period, dementia had developed in 80% of those with depression (220). In 81% of cases, depression preceded dementia, with an average time lag of 1.5 years, he noted.
In a multivariate analysis, several factors were significantly associated with incident dementia. Higher education reduced the risk by 40% (HR, 0.60). Factors that increased the risk of dementia were black race (HR, 1.48), carrying the APOE e4 gene (HR, 2.12), presence of white matter disease (HR, 1.7), and poststroke new-onset depression (HR, 1.29).
The study shows only association, Dr. Biffi cautioned. “No causal relationship can be inferred by this study. We also can’t capture the severity of the mood symptoms, and we are unable to examine the relationship between cognition and apathy, which is another highly relevant neuropsychiatric manifestation of small-vessel disease.”
He had no financial disclosures.
[email protected]
On Twitter @alz_gal
AT THE INTERNATIONAL STROKE CONFERENCE
Key clinical point:
Major finding: Depression developed in 40% of survivors, with dementia developing in 80% of that group.
Data source: The prospective longitudinal study involved 695 patients.
Disclosures: Dr. Biffi had no financial disclosures.
Scalp papules in a teenage boy
The patient was given a diagnosis of acne keloidalis nuchae (AKN), a chronic folliculitis that is characterized by smooth, dome-shaped papules on the posterior scalp and neck that become confluent and form firm papules and hairless, keloid-like plaques. Seen almost exclusively in young, postpubescent African American males, the condition is often asymptomatic, although some patients complain of itching at the affected area.
The cause of AKN may be associated with an acute pseudofolliculitis secondary to close-shaved curly hair reentering the skin; this leads to a foreign body reaction to hair protein and subsequent fibrosis. AKN is diagnosed based on the appearance and location of the papules, as well as the patient’s history.
Treatment of AKN is often difficult, but early treatment decreases the potential of developing larger lesions and long-term disfigurement. Topical steroid therapy is indicated for mild to moderate AKN. Application of tretinoin 0.01% gel once or twice daily for several months has an anti-inflammatory effect and alters keratinocyte differentiation, which may discharge ingrown hairs. Topical and systemic antibiotics minimize infection associated with pseudofolliculitis and have anti-inflammatory effects. Intralesional steroid injections (triamcinolone acetonide 2.5-5 mg/cc) with 0.1 cc injected into each lesion every 2 to 3 weeks for 3 to 6 injections can reduce inflammation and pruritus and reduce the thickness of keloidal scars. (For a how-to video that illustrates intralesional injections, go to http://www.mdedge.com/jfponline/article/88050/dermatology/intralesional-injections.)
Surgical management is generally reserved for large lesions that do not respond to medical management. The use of CO2 laser ablation can be considered for advanced cases.
Patients with AKN can prevent further irritation of the affected area by not wearing anything on their head that rubs on the involved area. Patients should also refrain from shaving the posterior scalp and neck to prevent the pseudofolliculitis that may be causing this condition. Electric barber trimmers that leave a short stubble (but do not cleanly shave the skin) are OK.
In this case, the patient’s papules flattened and became asymptomatic over several months of treatment with tretinoin 0.01% gel, doxycycline 100 mg/d, and a series of biweekly intralesional steroid injections. A flat-scarred patch remained.
Adapted from: Rafferty E, Brodell R. Occipital scalp papules in a teenage boy. J Fam Pract. 2014;63:739-740.
The patient was given a diagnosis of acne keloidalis nuchae (AKN), a chronic folliculitis that is characterized by smooth, dome-shaped papules on the posterior scalp and neck that become confluent and form firm papules and hairless, keloid-like plaques. Seen almost exclusively in young, postpubescent African American males, the condition is often asymptomatic, although some patients complain of itching at the affected area.
The cause of AKN may be associated with an acute pseudofolliculitis secondary to close-shaved curly hair reentering the skin; this leads to a foreign body reaction to hair protein and subsequent fibrosis. AKN is diagnosed based on the appearance and location of the papules, as well as the patient’s history.
Treatment of AKN is often difficult, but early treatment decreases the potential of developing larger lesions and long-term disfigurement. Topical steroid therapy is indicated for mild to moderate AKN. Application of tretinoin 0.01% gel once or twice daily for several months has an anti-inflammatory effect and alters keratinocyte differentiation, which may discharge ingrown hairs. Topical and systemic antibiotics minimize infection associated with pseudofolliculitis and have anti-inflammatory effects. Intralesional steroid injections (triamcinolone acetonide 2.5-5 mg/cc) with 0.1 cc injected into each lesion every 2 to 3 weeks for 3 to 6 injections can reduce inflammation and pruritus and reduce the thickness of keloidal scars. (For a how-to video that illustrates intralesional injections, go to http://www.mdedge.com/jfponline/article/88050/dermatology/intralesional-injections.)
Surgical management is generally reserved for large lesions that do not respond to medical management. The use of CO2 laser ablation can be considered for advanced cases.
Patients with AKN can prevent further irritation of the affected area by not wearing anything on their head that rubs on the involved area. Patients should also refrain from shaving the posterior scalp and neck to prevent the pseudofolliculitis that may be causing this condition. Electric barber trimmers that leave a short stubble (but do not cleanly shave the skin) are OK.
In this case, the patient’s papules flattened and became asymptomatic over several months of treatment with tretinoin 0.01% gel, doxycycline 100 mg/d, and a series of biweekly intralesional steroid injections. A flat-scarred patch remained.
Adapted from: Rafferty E, Brodell R. Occipital scalp papules in a teenage boy. J Fam Pract. 2014;63:739-740.
The patient was given a diagnosis of acne keloidalis nuchae (AKN), a chronic folliculitis that is characterized by smooth, dome-shaped papules on the posterior scalp and neck that become confluent and form firm papules and hairless, keloid-like plaques. Seen almost exclusively in young, postpubescent African American males, the condition is often asymptomatic, although some patients complain of itching at the affected area.
The cause of AKN may be associated with an acute pseudofolliculitis secondary to close-shaved curly hair reentering the skin; this leads to a foreign body reaction to hair protein and subsequent fibrosis. AKN is diagnosed based on the appearance and location of the papules, as well as the patient’s history.
Treatment of AKN is often difficult, but early treatment decreases the potential of developing larger lesions and long-term disfigurement. Topical steroid therapy is indicated for mild to moderate AKN. Application of tretinoin 0.01% gel once or twice daily for several months has an anti-inflammatory effect and alters keratinocyte differentiation, which may discharge ingrown hairs. Topical and systemic antibiotics minimize infection associated with pseudofolliculitis and have anti-inflammatory effects. Intralesional steroid injections (triamcinolone acetonide 2.5-5 mg/cc) with 0.1 cc injected into each lesion every 2 to 3 weeks for 3 to 6 injections can reduce inflammation and pruritus and reduce the thickness of keloidal scars. (For a how-to video that illustrates intralesional injections, go to http://www.mdedge.com/jfponline/article/88050/dermatology/intralesional-injections.)
Surgical management is generally reserved for large lesions that do not respond to medical management. The use of CO2 laser ablation can be considered for advanced cases.
Patients with AKN can prevent further irritation of the affected area by not wearing anything on their head that rubs on the involved area. Patients should also refrain from shaving the posterior scalp and neck to prevent the pseudofolliculitis that may be causing this condition. Electric barber trimmers that leave a short stubble (but do not cleanly shave the skin) are OK.
In this case, the patient’s papules flattened and became asymptomatic over several months of treatment with tretinoin 0.01% gel, doxycycline 100 mg/d, and a series of biweekly intralesional steroid injections. A flat-scarred patch remained.
Adapted from: Rafferty E, Brodell R. Occipital scalp papules in a teenage boy. J Fam Pract. 2014;63:739-740.
Potential therapeutic strategy for BL, DLBCL
Preclinical research has revealed a potential strategy for treating Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL).
Investigators discovered that miR-28 inhibits the growth of B-cell lymphomas, but this microRNA is often lost in these lymphomas.
Re-expressing miR-28 in mouse models of BL and DLBCL inhibited tumor growth, which supports the potential of synthetic miR-28 analogs for the treatment of these lymphomas.
In fact, the investigators believe their work could lead to the development of the first miRNA analog therapy for the treatment of B-cell lymphoma and provide the basis for clinical trials.
Almudena Ramiro, PhD, of Centro Nacional de Investigaciones Cardiovasculares in Madrid, Spain, and her colleagues described the work in Blood.
The team characterized the function of miR-28 in the biology of mature B lymphocytes and in the development of lymphomas associated with this cell type.
The investigators found that miR-28 regulates the terminal differentiation of B lymphocytes, a fundamental process in the biology of these cells that generates memory B lymphocytes and highly specific plasma cells.
But the team found that miR-28 expression is lost in several germinal center-derived lymphoma subtypes, including BL, DLBCL, follicular lymphoma, and chronic lymphocytic leukemia.
In vitro experiments showed that miR-28 expression dampens B-cell receptor signaling and diminishes the proliferation and survival of primary B cells and lymphoma cells.
And in vivo experiments showed that re-establishing miR-28 expression slows tumor growth in DLBCL and BL.
The investigators re-expressed miR-28 in xenograft models of BL and DLBCL via the use of viral vectors or synthetic molecules and found that both methods blocked tumor growth. The same effect was observed in mice with established BL tumors.
Dr Ramiro and her colleagues said these results reveal the therapeutic potential of miR-28 and provide ample justification for the initiation of clinical trials of miR-28-based therapies to treat B-cell lymphomas. 
Preclinical research has revealed a potential strategy for treating Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL).
Investigators discovered that miR-28 inhibits the growth of B-cell lymphomas, but this microRNA is often lost in these lymphomas.
Re-expressing miR-28 in mouse models of BL and DLBCL inhibited tumor growth, which supports the potential of synthetic miR-28 analogs for the treatment of these lymphomas.
In fact, the investigators believe their work could lead to the development of the first miRNA analog therapy for the treatment of B-cell lymphoma and provide the basis for clinical trials.
Almudena Ramiro, PhD, of Centro Nacional de Investigaciones Cardiovasculares in Madrid, Spain, and her colleagues described the work in Blood.
The team characterized the function of miR-28 in the biology of mature B lymphocytes and in the development of lymphomas associated with this cell type.
The investigators found that miR-28 regulates the terminal differentiation of B lymphocytes, a fundamental process in the biology of these cells that generates memory B lymphocytes and highly specific plasma cells.
But the team found that miR-28 expression is lost in several germinal center-derived lymphoma subtypes, including BL, DLBCL, follicular lymphoma, and chronic lymphocytic leukemia.
In vitro experiments showed that miR-28 expression dampens B-cell receptor signaling and diminishes the proliferation and survival of primary B cells and lymphoma cells.
And in vivo experiments showed that re-establishing miR-28 expression slows tumor growth in DLBCL and BL.
The investigators re-expressed miR-28 in xenograft models of BL and DLBCL via the use of viral vectors or synthetic molecules and found that both methods blocked tumor growth. The same effect was observed in mice with established BL tumors.
Dr Ramiro and her colleagues said these results reveal the therapeutic potential of miR-28 and provide ample justification for the initiation of clinical trials of miR-28-based therapies to treat B-cell lymphomas.
Preclinical research has revealed a potential strategy for treating Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL).
Investigators discovered that miR-28 inhibits the growth of B-cell lymphomas, but this microRNA is often lost in these lymphomas.
Re-expressing miR-28 in mouse models of BL and DLBCL inhibited tumor growth, which supports the potential of synthetic miR-28 analogs for the treatment of these lymphomas.
In fact, the investigators believe their work could lead to the development of the first miRNA analog therapy for the treatment of B-cell lymphoma and provide the basis for clinical trials.
Almudena Ramiro, PhD, of Centro Nacional de Investigaciones Cardiovasculares in Madrid, Spain, and her colleagues described the work in Blood.
The team characterized the function of miR-28 in the biology of mature B lymphocytes and in the development of lymphomas associated with this cell type.
The investigators found that miR-28 regulates the terminal differentiation of B lymphocytes, a fundamental process in the biology of these cells that generates memory B lymphocytes and highly specific plasma cells.
But the team found that miR-28 expression is lost in several germinal center-derived lymphoma subtypes, including BL, DLBCL, follicular lymphoma, and chronic lymphocytic leukemia.
In vitro experiments showed that miR-28 expression dampens B-cell receptor signaling and diminishes the proliferation and survival of primary B cells and lymphoma cells.
And in vivo experiments showed that re-establishing miR-28 expression slows tumor growth in DLBCL and BL.
The investigators re-expressed miR-28 in xenograft models of BL and DLBCL via the use of viral vectors or synthetic molecules and found that both methods blocked tumor growth. The same effect was observed in mice with established BL tumors.
Dr Ramiro and her colleagues said these results reveal the therapeutic potential of miR-28 and provide ample justification for the initiation of clinical trials of miR-28-based therapies to treat B-cell lymphomas.
Drug granted priority review for relapsed/refractory AML
The US Food and Drug Administration (FDA) has granted priority review for the new drug application (NDA) for enasidenib (AG-221), an inhibitor of mutant IDH2.
The drug is under review for the treatment of patients with relapsed or refractory acute myeloid leukemia (AML) with an IDH2 mutation.
The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10-month period.
The NDA for enasidenib has been given a Prescription Drug User Fee Act action date of August 30, 2017.
Enasidenib is being developed by Celgene Corporation and Agios Pharmaceuticals.
Phase 1/2 trial
The NDA submission for enasidenib is based on results from AG221-C-001, a single-arm, phase 1/2 study of the drug in patients with advanced hematologic malignancies with an IDH2 mutation.
Early data from the relapsed or refractory AML patients in this study were presented at the 2015 ASH Annual Meeting. (The presentation included updated data that differ from the data in the abstract.)
The trial included a dose-escalation phase and 5 expansion cohorts. The first 4 expansion cohorts had completed enrollment as of the presentation.
- Arm 1: 25 patients with IDH2-mutant-positive relapsed or refractory AML age ≥60 years, or any patient with AML regardless of age who relapsed after a bone marrow transplant (BMT)
- Arm 2: 25 patients with IDH2-mutant-positive relapsed or refractory AML age <60 years, excluding patients with AML who relapsed after a BMT
- Arm 3: 25 patients with IDH2-mutant-positive untreated AML age ≥60 years who decline standard of care chemotherapy
- Arm 4: 25 patients with IDH2-mutant-positive advanced hematologic malignancies not eligible for arms 1 to 3
- Arm 5: The phase 2 portion of the trial included 125 patients with IDH2-mutant-positive AML who were in second or later relapse, refractory to second-line induction or reinduction treatment, or relapsed after allogeneic transplant.
The data reported at ASH were from patients receiving enasidenib administered from 50-mg to 650-mg total daily doses in the dose-escalation arm and 100 mg once daily in the first 4 expansion arms, as of September 1, 2015.
The median age of these patients was 69 (range, 19-100). Patients with relapsed or refractory AML received a median of 2 prior lines of therapy (range, 1-6).
Safety data
A safety analysis was conducted for all 231 treated patients. As of the ASH presentation, a maximum tolerated dose of enasidenib had not been reached.
The majority of adverse events were mild to moderate, with the most common being nausea, diarrhea, fatigue, and febrile neutropenia.
Twenty-three percent of patients had treatment-related serious adverse events—notably, differentiation syndrome (4%), leukocytosis (4%), and nausea (2%).
Drug-related grade 5 serious adverse events include atrial flutter (n=1), cardiac tamponade (n=1), pericardial effusion (n=1), and respiratory failure (n=1).
Efficacy Data
Seventy-nine of the 209 response-evaluable patients achieved investigator-assessed objective responses, for an overall response rate of 38%.
There were 37 (18%) complete remissions (CR), 3 CRs with incomplete platelet recovery (CRp), 14 marrow CRs (mCR), 3 CRs with incomplete hematologic recovery (CRi), and 22 partial remissions (PR).
Of the 159 patients with relapsed or refractory AML, 59 (37%) achieved an objective response, including 29 (18%) CRs, 1 CRp, 9 mCRs, 3 CRis, and 17 PRs.
Of the 24 patients with AML who declined standard of care chemotherapy, 10 achieved an objective response, including 4 CRs, 1 CRp, 1 mCR, and 4 PRs.
The median duration of response was 6.9 months in patients with relapsed or refractory AML.
Responding relapsed/refractory AML patients were on study treatment for up to 18 months. The median duration of treatment was 6.8 months (range, 1.8 to 18 months).
The US Food and Drug Administration (FDA) has granted priority review for the new drug application (NDA) for enasidenib (AG-221), an inhibitor of mutant IDH2.
The drug is under review for the treatment of patients with relapsed or refractory acute myeloid leukemia (AML) with an IDH2 mutation.
The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10-month period.
The NDA for enasidenib has been given a Prescription Drug User Fee Act action date of August 30, 2017.
Enasidenib is being developed by Celgene Corporation and Agios Pharmaceuticals.
Phase 1/2 trial
The NDA submission for enasidenib is based on results from AG221-C-001, a single-arm, phase 1/2 study of the drug in patients with advanced hematologic malignancies with an IDH2 mutation.
Early data from the relapsed or refractory AML patients in this study were presented at the 2015 ASH Annual Meeting. (The presentation included updated data that differ from the data in the abstract.)
The trial included a dose-escalation phase and 5 expansion cohorts. The first 4 expansion cohorts had completed enrollment as of the presentation.
- Arm 1: 25 patients with IDH2-mutant-positive relapsed or refractory AML age ≥60 years, or any patient with AML regardless of age who relapsed after a bone marrow transplant (BMT)
- Arm 2: 25 patients with IDH2-mutant-positive relapsed or refractory AML age <60 years, excluding patients with AML who relapsed after a BMT
- Arm 3: 25 patients with IDH2-mutant-positive untreated AML age ≥60 years who decline standard of care chemotherapy
- Arm 4: 25 patients with IDH2-mutant-positive advanced hematologic malignancies not eligible for arms 1 to 3
- Arm 5: The phase 2 portion of the trial included 125 patients with IDH2-mutant-positive AML who were in second or later relapse, refractory to second-line induction or reinduction treatment, or relapsed after allogeneic transplant.
The data reported at ASH were from patients receiving enasidenib administered from 50-mg to 650-mg total daily doses in the dose-escalation arm and 100 mg once daily in the first 4 expansion arms, as of September 1, 2015.
The median age of these patients was 69 (range, 19-100). Patients with relapsed or refractory AML received a median of 2 prior lines of therapy (range, 1-6).
Safety data
A safety analysis was conducted for all 231 treated patients. As of the ASH presentation, a maximum tolerated dose of enasidenib had not been reached.
The majority of adverse events were mild to moderate, with the most common being nausea, diarrhea, fatigue, and febrile neutropenia.
Twenty-three percent of patients had treatment-related serious adverse events—notably, differentiation syndrome (4%), leukocytosis (4%), and nausea (2%).
Drug-related grade 5 serious adverse events include atrial flutter (n=1), cardiac tamponade (n=1), pericardial effusion (n=1), and respiratory failure (n=1).
Efficacy Data
Seventy-nine of the 209 response-evaluable patients achieved investigator-assessed objective responses, for an overall response rate of 38%.
There were 37 (18%) complete remissions (CR), 3 CRs with incomplete platelet recovery (CRp), 14 marrow CRs (mCR), 3 CRs with incomplete hematologic recovery (CRi), and 22 partial remissions (PR).
Of the 159 patients with relapsed or refractory AML, 59 (37%) achieved an objective response, including 29 (18%) CRs, 1 CRp, 9 mCRs, 3 CRis, and 17 PRs.
Of the 24 patients with AML who declined standard of care chemotherapy, 10 achieved an objective response, including 4 CRs, 1 CRp, 1 mCR, and 4 PRs.
The median duration of response was 6.9 months in patients with relapsed or refractory AML.
Responding relapsed/refractory AML patients were on study treatment for up to 18 months. The median duration of treatment was 6.8 months (range, 1.8 to 18 months).
The US Food and Drug Administration (FDA) has granted priority review for the new drug application (NDA) for enasidenib (AG-221), an inhibitor of mutant IDH2.
The drug is under review for the treatment of patients with relapsed or refractory acute myeloid leukemia (AML) with an IDH2 mutation.
The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10-month period.
The NDA for enasidenib has been given a Prescription Drug User Fee Act action date of August 30, 2017.
Enasidenib is being developed by Celgene Corporation and Agios Pharmaceuticals.
Phase 1/2 trial
The NDA submission for enasidenib is based on results from AG221-C-001, a single-arm, phase 1/2 study of the drug in patients with advanced hematologic malignancies with an IDH2 mutation.
Early data from the relapsed or refractory AML patients in this study were presented at the 2015 ASH Annual Meeting. (The presentation included updated data that differ from the data in the abstract.)
The trial included a dose-escalation phase and 5 expansion cohorts. The first 4 expansion cohorts had completed enrollment as of the presentation.
- Arm 1: 25 patients with IDH2-mutant-positive relapsed or refractory AML age ≥60 years, or any patient with AML regardless of age who relapsed after a bone marrow transplant (BMT)
- Arm 2: 25 patients with IDH2-mutant-positive relapsed or refractory AML age <60 years, excluding patients with AML who relapsed after a BMT
- Arm 3: 25 patients with IDH2-mutant-positive untreated AML age ≥60 years who decline standard of care chemotherapy
- Arm 4: 25 patients with IDH2-mutant-positive advanced hematologic malignancies not eligible for arms 1 to 3
- Arm 5: The phase 2 portion of the trial included 125 patients with IDH2-mutant-positive AML who were in second or later relapse, refractory to second-line induction or reinduction treatment, or relapsed after allogeneic transplant.
The data reported at ASH were from patients receiving enasidenib administered from 50-mg to 650-mg total daily doses in the dose-escalation arm and 100 mg once daily in the first 4 expansion arms, as of September 1, 2015.
The median age of these patients was 69 (range, 19-100). Patients with relapsed or refractory AML received a median of 2 prior lines of therapy (range, 1-6).
Safety data
A safety analysis was conducted for all 231 treated patients. As of the ASH presentation, a maximum tolerated dose of enasidenib had not been reached.
The majority of adverse events were mild to moderate, with the most common being nausea, diarrhea, fatigue, and febrile neutropenia.
Twenty-three percent of patients had treatment-related serious adverse events—notably, differentiation syndrome (4%), leukocytosis (4%), and nausea (2%).
Drug-related grade 5 serious adverse events include atrial flutter (n=1), cardiac tamponade (n=1), pericardial effusion (n=1), and respiratory failure (n=1).
Efficacy Data
Seventy-nine of the 209 response-evaluable patients achieved investigator-assessed objective responses, for an overall response rate of 38%.
There were 37 (18%) complete remissions (CR), 3 CRs with incomplete platelet recovery (CRp), 14 marrow CRs (mCR), 3 CRs with incomplete hematologic recovery (CRi), and 22 partial remissions (PR).
Of the 159 patients with relapsed or refractory AML, 59 (37%) achieved an objective response, including 29 (18%) CRs, 1 CRp, 9 mCRs, 3 CRis, and 17 PRs.
Of the 24 patients with AML who declined standard of care chemotherapy, 10 achieved an objective response, including 4 CRs, 1 CRp, 1 mCR, and 4 PRs.
The median duration of response was 6.9 months in patients with relapsed or refractory AML.
Responding relapsed/refractory AML patients were on study treatment for up to 18 months. The median duration of treatment was 6.8 months (range, 1.8 to 18 months).
Hospital floors pose infection risk, team says
Hospital room floors may be an overlooked source of infection, according to a study published in the American Journal of Infection Control.
Researchers surveyed 5 hospitals and found that floors in patient rooms were often contaminated with pathogens.
Certain objects, such as personal items and medical devices and supplies, were in contact with the floor, and touching these objects resulted in the transfer of pathogens to bare and gloved hands.
Abhishek Deshpande, MD, PhD, of Case Western Reserve University School of Medicine in Cleveland, Ohio, and his colleagues conducted this research.
The team cultured 318 floor sites from 159 patient rooms (2 sites per room) in 5 hospitals in the Cleveland area. The rooms included both Clostridium difficile infection (CDI) isolation rooms and non-CDI rooms.
The researchers also cultured hands (gloved and bare) as well as other “high-touch” surfaces such as clothing and medical devices/supplies.
The team found that floors in patient rooms were often contaminated with Methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and C difficile.
C difficile was recovered in 55% of CDI rooms and 47% of non-CDI rooms. MRSA was recovered in 32% of CDI rooms and 8% of non-CDI rooms. VRE was recovered in 30% of CDI rooms and 13% of non-CDI rooms.
The researchers said the frequency of contamination was similar for each of the 5 hospitals and from room and bathroom floor sites.
Of the 100 occupied rooms surveyed, 41% had one or more high-touch objects that were in contact with the floor. These included personal items (eg, clothing, canes, and cellular phone chargers), medical devices and supplies (eg, pulse oximeter, call button, heating pad, urinal, blood pressure cuff, wash basin, and heel protector), and bed linens or towels.
The findings indicate that handling such items resulted in the transfer of pathogens. All 3 pathogens were recovered from bare or gloved hand cultures—MRSA in 6 (18%), VRE in 2 (6%), and C difficile in 1 (3%).
The researchers said these results suggest hospital floors could be an underappreciated source for dissemination of pathogens and are an important area for additional research.
“Understanding gaps in infection prevention is critically important for institutions seeking to improve the quality of care offered to patients,” said Linda Greene, RN, current president of the Association for Professionals in Infection Control and Epidemiology.
“Even though most facilities believe they are taking the proper precautions, this study points out the importance of ensuring cleanliness of the hospital environment and the need for education of both staff and patients on this issue.”
Hospital room floors may be an overlooked source of infection, according to a study published in the American Journal of Infection Control.
Researchers surveyed 5 hospitals and found that floors in patient rooms were often contaminated with pathogens.
Certain objects, such as personal items and medical devices and supplies, were in contact with the floor, and touching these objects resulted in the transfer of pathogens to bare and gloved hands.
Abhishek Deshpande, MD, PhD, of Case Western Reserve University School of Medicine in Cleveland, Ohio, and his colleagues conducted this research.
The team cultured 318 floor sites from 159 patient rooms (2 sites per room) in 5 hospitals in the Cleveland area. The rooms included both Clostridium difficile infection (CDI) isolation rooms and non-CDI rooms.
The researchers also cultured hands (gloved and bare) as well as other “high-touch” surfaces such as clothing and medical devices/supplies.
The team found that floors in patient rooms were often contaminated with Methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and C difficile.
C difficile was recovered in 55% of CDI rooms and 47% of non-CDI rooms. MRSA was recovered in 32% of CDI rooms and 8% of non-CDI rooms. VRE was recovered in 30% of CDI rooms and 13% of non-CDI rooms.
The researchers said the frequency of contamination was similar for each of the 5 hospitals and from room and bathroom floor sites.
Of the 100 occupied rooms surveyed, 41% had one or more high-touch objects that were in contact with the floor. These included personal items (eg, clothing, canes, and cellular phone chargers), medical devices and supplies (eg, pulse oximeter, call button, heating pad, urinal, blood pressure cuff, wash basin, and heel protector), and bed linens or towels.
The findings indicate that handling such items resulted in the transfer of pathogens. All 3 pathogens were recovered from bare or gloved hand cultures—MRSA in 6 (18%), VRE in 2 (6%), and C difficile in 1 (3%).
The researchers said these results suggest hospital floors could be an underappreciated source for dissemination of pathogens and are an important area for additional research.
“Understanding gaps in infection prevention is critically important for institutions seeking to improve the quality of care offered to patients,” said Linda Greene, RN, current president of the Association for Professionals in Infection Control and Epidemiology.
“Even though most facilities believe they are taking the proper precautions, this study points out the importance of ensuring cleanliness of the hospital environment and the need for education of both staff and patients on this issue.”
Hospital room floors may be an overlooked source of infection, according to a study published in the American Journal of Infection Control.
Researchers surveyed 5 hospitals and found that floors in patient rooms were often contaminated with pathogens.
Certain objects, such as personal items and medical devices and supplies, were in contact with the floor, and touching these objects resulted in the transfer of pathogens to bare and gloved hands.
Abhishek Deshpande, MD, PhD, of Case Western Reserve University School of Medicine in Cleveland, Ohio, and his colleagues conducted this research.
The team cultured 318 floor sites from 159 patient rooms (2 sites per room) in 5 hospitals in the Cleveland area. The rooms included both Clostridium difficile infection (CDI) isolation rooms and non-CDI rooms.
The researchers also cultured hands (gloved and bare) as well as other “high-touch” surfaces such as clothing and medical devices/supplies.
The team found that floors in patient rooms were often contaminated with Methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and C difficile.
C difficile was recovered in 55% of CDI rooms and 47% of non-CDI rooms. MRSA was recovered in 32% of CDI rooms and 8% of non-CDI rooms. VRE was recovered in 30% of CDI rooms and 13% of non-CDI rooms.
The researchers said the frequency of contamination was similar for each of the 5 hospitals and from room and bathroom floor sites.
Of the 100 occupied rooms surveyed, 41% had one or more high-touch objects that were in contact with the floor. These included personal items (eg, clothing, canes, and cellular phone chargers), medical devices and supplies (eg, pulse oximeter, call button, heating pad, urinal, blood pressure cuff, wash basin, and heel protector), and bed linens or towels.
The findings indicate that handling such items resulted in the transfer of pathogens. All 3 pathogens were recovered from bare or gloved hand cultures—MRSA in 6 (18%), VRE in 2 (6%), and C difficile in 1 (3%).
The researchers said these results suggest hospital floors could be an underappreciated source for dissemination of pathogens and are an important area for additional research.
“Understanding gaps in infection prevention is critically important for institutions seeking to improve the quality of care offered to patients,” said Linda Greene, RN, current president of the Association for Professionals in Infection Control and Epidemiology.
“Even though most facilities believe they are taking the proper precautions, this study points out the importance of ensuring cleanliness of the hospital environment and the need for education of both staff and patients on this issue.”
Seeing Redness and Ear-itation
ANSWER
The correct diagnosis is relapsing polychondritis (RP; choice “a”). The lack of surface changes in the affected skin rules out contact dermatitis, while the lack of a positive response to antibiotics and absence of an entrance wound eliminate the possibility of an infectious etiology.
DISCUSSION
There are no tests to confirm the diagnosis of RP. It is a rare autoimmune condition that usually manifests in the later decades of life and equally affects men and women.
RP’s ability to appear in cartilage anywhere in the body and in a variety of forms makes timely diagnosis almost impossible. But this case illustrates some diagnostically useful signs to watch for.
The unexplained erythema in the ear, which very obviously spared the cartilage-free lobe, prompted a biopsy of the cartilage; this showed changes consistent with RP. A subsequent review of the patient’s ophthalmology records indicated a chronic episcleritis, most likely due to inflammation of eyelid cartilage.
Further testing was performed to rule out other explanations, such as gout, or autoimmune diseases, such as lupus. Results were negative.
The patient was then referred to a pulmonologist, who found no respiratory involvement, and a rheumatologist, for further evaluation (including blood work) to rule out other conditions and end-organ (eg, renal) involvement.
On follow-up, the patient was responding well to prednisone prescribed by her rheumatologist. Given her limited disease, her prognosis is fairly good.
ANSWER
The correct diagnosis is relapsing polychondritis (RP; choice “a”). The lack of surface changes in the affected skin rules out contact dermatitis, while the lack of a positive response to antibiotics and absence of an entrance wound eliminate the possibility of an infectious etiology.
DISCUSSION
There are no tests to confirm the diagnosis of RP. It is a rare autoimmune condition that usually manifests in the later decades of life and equally affects men and women.
RP’s ability to appear in cartilage anywhere in the body and in a variety of forms makes timely diagnosis almost impossible. But this case illustrates some diagnostically useful signs to watch for.
The unexplained erythema in the ear, which very obviously spared the cartilage-free lobe, prompted a biopsy of the cartilage; this showed changes consistent with RP. A subsequent review of the patient’s ophthalmology records indicated a chronic episcleritis, most likely due to inflammation of eyelid cartilage.
Further testing was performed to rule out other explanations, such as gout, or autoimmune diseases, such as lupus. Results were negative.
The patient was then referred to a pulmonologist, who found no respiratory involvement, and a rheumatologist, for further evaluation (including blood work) to rule out other conditions and end-organ (eg, renal) involvement.
On follow-up, the patient was responding well to prednisone prescribed by her rheumatologist. Given her limited disease, her prognosis is fairly good.
ANSWER
The correct diagnosis is relapsing polychondritis (RP; choice “a”). The lack of surface changes in the affected skin rules out contact dermatitis, while the lack of a positive response to antibiotics and absence of an entrance wound eliminate the possibility of an infectious etiology.
DISCUSSION
There are no tests to confirm the diagnosis of RP. It is a rare autoimmune condition that usually manifests in the later decades of life and equally affects men and women.
RP’s ability to appear in cartilage anywhere in the body and in a variety of forms makes timely diagnosis almost impossible. But this case illustrates some diagnostically useful signs to watch for.
The unexplained erythema in the ear, which very obviously spared the cartilage-free lobe, prompted a biopsy of the cartilage; this showed changes consistent with RP. A subsequent review of the patient’s ophthalmology records indicated a chronic episcleritis, most likely due to inflammation of eyelid cartilage.
Further testing was performed to rule out other explanations, such as gout, or autoimmune diseases, such as lupus. Results were negative.
The patient was then referred to a pulmonologist, who found no respiratory involvement, and a rheumatologist, for further evaluation (including blood work) to rule out other conditions and end-organ (eg, renal) involvement.
On follow-up, the patient was responding well to prednisone prescribed by her rheumatologist. Given her limited disease, her prognosis is fairly good.
Several months ago, family members pointed out that this 60-year-old woman’s left ear was red. She consulted her primary care provider, who prescribed antibiotics. But when these failed to clear the problem, she was referred to dermatology.
Today, the patient complains of some discomfort in the ear but denies actual pain; she is, for example, able to sleep despite the problem. She reports that the redness manifested slowly but has spread over time to encompass most of her ear.
Uniformly distributed, bright red erythema on the left ear spares only the lobe. No wound or epidermal component (eg, scaling or blistering) is noted. However, there is increased warmth and tenderness on palpation of the erythematous portion. No nodes can be felt in the vicinity, nor are any abnormalities observed in the other ear.
The patient denies other skin problems, joint pain, and breathing difficulty. But she does have an ongoing history of irritation in both eyes. She has been seeing an ophthalmologist for months without relief. On examination, both eyes appear injected, with slightly swollen eyelids. Inspection and palpation of the nose reveal no abnormalities.
