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Baylor sees first U.S. birth from uterine transplant recipient
A woman with a transplanted uterus gave birth to a live baby boy in Dallas, the first birth from a transplanted uterus in the United States. It is also the first birth resulting from uterine transplantation to be performed outside of Sweden, where a total of eight births have occurred.
“This really confirms that this is doable, that it can be replicated,” said Giuliano Testa, MD, chief of abdominal transplantation at Baylor University Medical Center, Dallas, during a press conference to discuss the birth.
With time, Dr. Testa said in an interview, he foresees uterine transplantation becoming a realistic alternative for some women. “It’s a great solution for the woman who really wants to carry her own pregnancy.”
“This is the best of academic medicine,” Dr. Testa said of the international collaboration and transparency among investigators working in the nascent field. “The communication is constant; we learn from each other ... I am very excited about what will come in the future.”
In order to protect the privacy of the patient and her family, physicians did not disclose the patient’s name, location, or the exact date of the birth. The patient also did not wish to share the infant’s gestational age at birth or birth weight, or whether the uterus had been removed after the birth. Transplanted uteri are meant to be removed after one or two pregnancies, so the recipient doesn’t have to be on lifelong immunosuppression once the desired pregnancies have been achieved.
However, during the press conference, the surgical team shared that the mother is home and doing well, and the infant is on room air and feeding well. A video of the birth shown at the press conference showed a vernix-covered baby who began crying vigorously even before his feet were delivered during the cesarean delivery.
The transplantation, pregnancy via in vitro fertilization, and subsequent birth were accomplished as part of a 10-patient clinical trial of uterine transplantation at Baylor University Medical Center. Women aged 20-35 years with absolute uterine factor infertility, such as those with congenitally absent uteri, were eligible to participate. Donors must have had one full-term delivery and may be aged 30-65 years; menopause does not render a uterus incapable of carrying a pregnancy. Donors are able to retain their ovaries.
Another study participant at Baylor is late into her pregnancy as well, Dr. Testa said.
The extensive screening process for uterus donation ensures that the team is using “a good organ from a good donor,” said Liza Johannesson, MD, PhD. In an interview, she said that the harvest is now about a 4-5 hour open procedure that takes the uterus, the cervix, and the very superior portion of the vagina, as well as the uterine arteries and veins out to the internal iliac bilaterally. The utero-ovarian veins also are harvested.
To date, the six women who have been donors in the Baylor program have not had serious complications and have returned to their previous level of function, said Dr. Johannesson, who came to Baylor from Sahlgrenska University Hospital’s successful uterine transplantation team in Gothenburg, Sweden.
Internationally, investigators have been working to reduce morbidity for women who donate their uterus. Since the vascular tree of the uterus must also be dissected and preserved during the organ harvesting procedure, operative time is longer than for a simple hysterectomy, and there’s increased risk of urinary dysfunction because of the extensive dissection, Antonio R. Gargiulo, MD, said in an interview.*
Dr. Gargiulo, medical director of the center for robotic surgery at Brigham and Women’s Hospital, Boston, said that the first few uterine harvest procedures took much longer, up to 10 hours. But, he said, the vascular harvest “is well within the capability of the best gynecologic oncology surgeons,” and newer techniques may further reduce the donor morbidity.
Using the utero-ovarian vein as the primary outflow tract is “a promising modification of this operation” that may be the “technical key to making this procedure the least morbid possible,” said Dr. Gargiulo, a reproductive endocrinologist who is involved with the development of a uterine transplantation program at the Brigham and Women’s Hospital.
Dr. Johannesson said that the Baylor team currently dissects the entire uterine vascular tree and reanastomoses what vessels they can. She pointed out that even with the best imaging techniques, it can be difficult to ascertain the best vessels until the surgery’s actually being performed.
All of the surgeons interviewed emphasized that each procedure represents an opportunity for growth in a young field with a steep learning curve. They expect ongoing technical advances, including the use of robotic surgery, to reduce operative time and lessen morbidity.
It’s worth pressing on in this field for the sake of the patients, said Dr. Testa, speaking for his transplant team. “We are all humbled by the depth of the desire of a woman to carry her own pregnancy.”
Dr. Johannesson said that she hopes that today when gynecologists talk to teenage patients who have absolute uterine infertility, they will be offering a message of hope. “When they meet young women, they should tell them that they shouldn’t stop hoping,” she said. “There is hope that they will be able to carry their own pregnancy.”
Dr. Gargiulo has been a paid consultant for Kawasaki Robotics and OmniGuide. Dr. Testa and Dr. Johannesson reported that they had no relevant conflicts of interest.
*Correction, 12/12/17: The reason for the increased risk of urinary dysfunction was misstated.
[email protected]
On Twitter @karioakes
A woman with a transplanted uterus gave birth to a live baby boy in Dallas, the first birth from a transplanted uterus in the United States. It is also the first birth resulting from uterine transplantation to be performed outside of Sweden, where a total of eight births have occurred.
“This really confirms that this is doable, that it can be replicated,” said Giuliano Testa, MD, chief of abdominal transplantation at Baylor University Medical Center, Dallas, during a press conference to discuss the birth.
With time, Dr. Testa said in an interview, he foresees uterine transplantation becoming a realistic alternative for some women. “It’s a great solution for the woman who really wants to carry her own pregnancy.”
“This is the best of academic medicine,” Dr. Testa said of the international collaboration and transparency among investigators working in the nascent field. “The communication is constant; we learn from each other ... I am very excited about what will come in the future.”
In order to protect the privacy of the patient and her family, physicians did not disclose the patient’s name, location, or the exact date of the birth. The patient also did not wish to share the infant’s gestational age at birth or birth weight, or whether the uterus had been removed after the birth. Transplanted uteri are meant to be removed after one or two pregnancies, so the recipient doesn’t have to be on lifelong immunosuppression once the desired pregnancies have been achieved.
However, during the press conference, the surgical team shared that the mother is home and doing well, and the infant is on room air and feeding well. A video of the birth shown at the press conference showed a vernix-covered baby who began crying vigorously even before his feet were delivered during the cesarean delivery.
The transplantation, pregnancy via in vitro fertilization, and subsequent birth were accomplished as part of a 10-patient clinical trial of uterine transplantation at Baylor University Medical Center. Women aged 20-35 years with absolute uterine factor infertility, such as those with congenitally absent uteri, were eligible to participate. Donors must have had one full-term delivery and may be aged 30-65 years; menopause does not render a uterus incapable of carrying a pregnancy. Donors are able to retain their ovaries.
Another study participant at Baylor is late into her pregnancy as well, Dr. Testa said.
The extensive screening process for uterus donation ensures that the team is using “a good organ from a good donor,” said Liza Johannesson, MD, PhD. In an interview, she said that the harvest is now about a 4-5 hour open procedure that takes the uterus, the cervix, and the very superior portion of the vagina, as well as the uterine arteries and veins out to the internal iliac bilaterally. The utero-ovarian veins also are harvested.
To date, the six women who have been donors in the Baylor program have not had serious complications and have returned to their previous level of function, said Dr. Johannesson, who came to Baylor from Sahlgrenska University Hospital’s successful uterine transplantation team in Gothenburg, Sweden.
Internationally, investigators have been working to reduce morbidity for women who donate their uterus. Since the vascular tree of the uterus must also be dissected and preserved during the organ harvesting procedure, operative time is longer than for a simple hysterectomy, and there’s increased risk of urinary dysfunction because of the extensive dissection, Antonio R. Gargiulo, MD, said in an interview.*
Dr. Gargiulo, medical director of the center for robotic surgery at Brigham and Women’s Hospital, Boston, said that the first few uterine harvest procedures took much longer, up to 10 hours. But, he said, the vascular harvest “is well within the capability of the best gynecologic oncology surgeons,” and newer techniques may further reduce the donor morbidity.
Using the utero-ovarian vein as the primary outflow tract is “a promising modification of this operation” that may be the “technical key to making this procedure the least morbid possible,” said Dr. Gargiulo, a reproductive endocrinologist who is involved with the development of a uterine transplantation program at the Brigham and Women’s Hospital.
Dr. Johannesson said that the Baylor team currently dissects the entire uterine vascular tree and reanastomoses what vessels they can. She pointed out that even with the best imaging techniques, it can be difficult to ascertain the best vessels until the surgery’s actually being performed.
All of the surgeons interviewed emphasized that each procedure represents an opportunity for growth in a young field with a steep learning curve. They expect ongoing technical advances, including the use of robotic surgery, to reduce operative time and lessen morbidity.
It’s worth pressing on in this field for the sake of the patients, said Dr. Testa, speaking for his transplant team. “We are all humbled by the depth of the desire of a woman to carry her own pregnancy.”
Dr. Johannesson said that she hopes that today when gynecologists talk to teenage patients who have absolute uterine infertility, they will be offering a message of hope. “When they meet young women, they should tell them that they shouldn’t stop hoping,” she said. “There is hope that they will be able to carry their own pregnancy.”
Dr. Gargiulo has been a paid consultant for Kawasaki Robotics and OmniGuide. Dr. Testa and Dr. Johannesson reported that they had no relevant conflicts of interest.
*Correction, 12/12/17: The reason for the increased risk of urinary dysfunction was misstated.
[email protected]
On Twitter @karioakes
A woman with a transplanted uterus gave birth to a live baby boy in Dallas, the first birth from a transplanted uterus in the United States. It is also the first birth resulting from uterine transplantation to be performed outside of Sweden, where a total of eight births have occurred.
“This really confirms that this is doable, that it can be replicated,” said Giuliano Testa, MD, chief of abdominal transplantation at Baylor University Medical Center, Dallas, during a press conference to discuss the birth.
With time, Dr. Testa said in an interview, he foresees uterine transplantation becoming a realistic alternative for some women. “It’s a great solution for the woman who really wants to carry her own pregnancy.”
“This is the best of academic medicine,” Dr. Testa said of the international collaboration and transparency among investigators working in the nascent field. “The communication is constant; we learn from each other ... I am very excited about what will come in the future.”
In order to protect the privacy of the patient and her family, physicians did not disclose the patient’s name, location, or the exact date of the birth. The patient also did not wish to share the infant’s gestational age at birth or birth weight, or whether the uterus had been removed after the birth. Transplanted uteri are meant to be removed after one or two pregnancies, so the recipient doesn’t have to be on lifelong immunosuppression once the desired pregnancies have been achieved.
However, during the press conference, the surgical team shared that the mother is home and doing well, and the infant is on room air and feeding well. A video of the birth shown at the press conference showed a vernix-covered baby who began crying vigorously even before his feet were delivered during the cesarean delivery.
The transplantation, pregnancy via in vitro fertilization, and subsequent birth were accomplished as part of a 10-patient clinical trial of uterine transplantation at Baylor University Medical Center. Women aged 20-35 years with absolute uterine factor infertility, such as those with congenitally absent uteri, were eligible to participate. Donors must have had one full-term delivery and may be aged 30-65 years; menopause does not render a uterus incapable of carrying a pregnancy. Donors are able to retain their ovaries.
Another study participant at Baylor is late into her pregnancy as well, Dr. Testa said.
The extensive screening process for uterus donation ensures that the team is using “a good organ from a good donor,” said Liza Johannesson, MD, PhD. In an interview, she said that the harvest is now about a 4-5 hour open procedure that takes the uterus, the cervix, and the very superior portion of the vagina, as well as the uterine arteries and veins out to the internal iliac bilaterally. The utero-ovarian veins also are harvested.
To date, the six women who have been donors in the Baylor program have not had serious complications and have returned to their previous level of function, said Dr. Johannesson, who came to Baylor from Sahlgrenska University Hospital’s successful uterine transplantation team in Gothenburg, Sweden.
Internationally, investigators have been working to reduce morbidity for women who donate their uterus. Since the vascular tree of the uterus must also be dissected and preserved during the organ harvesting procedure, operative time is longer than for a simple hysterectomy, and there’s increased risk of urinary dysfunction because of the extensive dissection, Antonio R. Gargiulo, MD, said in an interview.*
Dr. Gargiulo, medical director of the center for robotic surgery at Brigham and Women’s Hospital, Boston, said that the first few uterine harvest procedures took much longer, up to 10 hours. But, he said, the vascular harvest “is well within the capability of the best gynecologic oncology surgeons,” and newer techniques may further reduce the donor morbidity.
Using the utero-ovarian vein as the primary outflow tract is “a promising modification of this operation” that may be the “technical key to making this procedure the least morbid possible,” said Dr. Gargiulo, a reproductive endocrinologist who is involved with the development of a uterine transplantation program at the Brigham and Women’s Hospital.
Dr. Johannesson said that the Baylor team currently dissects the entire uterine vascular tree and reanastomoses what vessels they can. She pointed out that even with the best imaging techniques, it can be difficult to ascertain the best vessels until the surgery’s actually being performed.
All of the surgeons interviewed emphasized that each procedure represents an opportunity for growth in a young field with a steep learning curve. They expect ongoing technical advances, including the use of robotic surgery, to reduce operative time and lessen morbidity.
It’s worth pressing on in this field for the sake of the patients, said Dr. Testa, speaking for his transplant team. “We are all humbled by the depth of the desire of a woman to carry her own pregnancy.”
Dr. Johannesson said that she hopes that today when gynecologists talk to teenage patients who have absolute uterine infertility, they will be offering a message of hope. “When they meet young women, they should tell them that they shouldn’t stop hoping,” she said. “There is hope that they will be able to carry their own pregnancy.”
Dr. Gargiulo has been a paid consultant for Kawasaki Robotics and OmniGuide. Dr. Testa and Dr. Johannesson reported that they had no relevant conflicts of interest.
*Correction, 12/12/17: The reason for the increased risk of urinary dysfunction was misstated.
[email protected]
On Twitter @karioakes
Fecal microbiota transplants by oral capsule noninferior to colonoscopy
Fecal microbiota transplantation (FMT) using oral capsules as the delivery method has been shown to be noninferior to delivery using colonoscopy for the treatment of Clostridium difficile infection, but with a significantly lower price tag.
In an unblended noninferiority trial, published in the Nov. 28 issue of JAMA, 116 adults with at least three documented episodes of C. difficile infection were randomized to either 360 mL of fecal slurry delivered to the cecum via colonoscopy or to 40 capsules of processed fecal microbiota swallowed under direct observation.
Dina Kao, MD, of the department of medicine at the University of Alberta, Edmonton, and coauthors commented that the response rate with the capsules was higher than that seen in other studies of fecal microbiota capsules, which they suggested may partly be due to the larger amount of donor stool used in the study: 80-100 g, compared with 17 g and 25 g used in other studies.
“The higher efficacy observed in this study suggests a dose-dependent response to FMT, and a benefit of bowel lavage prior to FMT, because residual vancomycin was detected up to 8 days despite its discontinuation,” they wrote.
Both treatment modalities achieved similar quality of life improvements. Both groups reported major improvements in domains including physical and emotional health, physical and social functioning, and general health, with no significant differences between the two arms of the study.
The cost per treatment in the colonoscopy group was $874 per patient, compared with $308 per patient in the capsule group.
“Although colonoscopy delivery is more invasive, resource intensive, costly, and inconvenient for patients, it has the advantage of identifying alternative diagnoses,” the authors wrote. “Conversely, when FMT is given by oral capsules, it can be administered in an office setting, which could substantially reduce cost and wait time.”
Both groups also showed significantly improved gut microbiota diversity, which approached that of the donor just 1 week after administration of the treatment.
While 30% of patients characterized FMTs as “unpleasant, gross, or disgusting,” 79% of participants said the unpleasantness was the same or less than anticipated, and 97% said they would undergo the same treatment by the same delivery method again if needed.
However, significantly more patients in the capsule group described their experience as “not at all unpleasant,” compared with the colonoscopy group (66% vs. 44%; 95% CI, 3%-40%; P = .01).
There were no colonic perforations seen in the colonoscopy group, and no infectious complications relating to the treatment in either group. One patient in each group died of underlying cardiopulmonary illness that was unrelated to the treatment, and the rate of minor adverse events was 5.4% in the capsule group and 12.5% in the colonoscopy group.
The authors acknowledged that the lack of a placebo group in the study meant they were not able to measure the size of the effect of fecal microbiota transplantation by either route. One earlier trial had also shown a placebo response rate of 45%.
The study was funded by Alberta Health Services and the University of Alberta Hospital Foundation. Four authors declared grants and other funding from the study funder and the pharmaceutical industry.
The AGA Center for Gut Microbiome Research and Education serves as a virtual “home” for AGA activities related to the gut microbiome, including the AGA FMT National Registry, which will assess short- and long-term patient outcomes associated with FMT. Learn more at http://www.gastro.org/about/initiatives/aga-center-for-gut-microbiome-research-education.
Clostridium difficile infection costs the U.S. health care system an estimated $1.5 billion each year, with 450,000 cases reported annually, 20% of which involve a recurrence of the infection. Fecal microbiota transplantation is increasingly being used as a treatment, but more widespread adoption is limited partly by the logistical difficulties of delivery.
This study offers encouraging data on delivery of fecal microbiota transplants via capsule, which may reduce barriers to adoption of this treatment; however, there are still some questions to be answered about the treatment’s efficacy, such as the timing of delivery and the relative importance of stool components.
There are also other approaches that should be considered in future research on C. difficile infection, including the use of vancomycin tapers with and without “chasers” of fidaxomicin/rifaximin, the use of defined microbial communities, and the use of sterile, fecal-derived products, which may even supplant standard fecal microbial transplants in the future.
Krishna Rao, MD, Vincent B. Young, MD, PhD, and Preeti N. Malani, MD, are with the division of infectious diseases in the department of internal medicine at the University of Michigan, Ann Arbor. These comments are taken from an accompanying editorial (JAMA. 2017 Nov 28;381:1979-80. doi: 10.1001/jama.2017.17969). Dr. Young reported consulting fees from Vedanta, Merck, and Finch Therapeutics and grants from MedImmune. No other disclosures were reported.
Clostridium difficile infection costs the U.S. health care system an estimated $1.5 billion each year, with 450,000 cases reported annually, 20% of which involve a recurrence of the infection. Fecal microbiota transplantation is increasingly being used as a treatment, but more widespread adoption is limited partly by the logistical difficulties of delivery.
This study offers encouraging data on delivery of fecal microbiota transplants via capsule, which may reduce barriers to adoption of this treatment; however, there are still some questions to be answered about the treatment’s efficacy, such as the timing of delivery and the relative importance of stool components.
There are also other approaches that should be considered in future research on C. difficile infection, including the use of vancomycin tapers with and without “chasers” of fidaxomicin/rifaximin, the use of defined microbial communities, and the use of sterile, fecal-derived products, which may even supplant standard fecal microbial transplants in the future.
Krishna Rao, MD, Vincent B. Young, MD, PhD, and Preeti N. Malani, MD, are with the division of infectious diseases in the department of internal medicine at the University of Michigan, Ann Arbor. These comments are taken from an accompanying editorial (JAMA. 2017 Nov 28;381:1979-80. doi: 10.1001/jama.2017.17969). Dr. Young reported consulting fees from Vedanta, Merck, and Finch Therapeutics and grants from MedImmune. No other disclosures were reported.
Clostridium difficile infection costs the U.S. health care system an estimated $1.5 billion each year, with 450,000 cases reported annually, 20% of which involve a recurrence of the infection. Fecal microbiota transplantation is increasingly being used as a treatment, but more widespread adoption is limited partly by the logistical difficulties of delivery.
This study offers encouraging data on delivery of fecal microbiota transplants via capsule, which may reduce barriers to adoption of this treatment; however, there are still some questions to be answered about the treatment’s efficacy, such as the timing of delivery and the relative importance of stool components.
There are also other approaches that should be considered in future research on C. difficile infection, including the use of vancomycin tapers with and without “chasers” of fidaxomicin/rifaximin, the use of defined microbial communities, and the use of sterile, fecal-derived products, which may even supplant standard fecal microbial transplants in the future.
Krishna Rao, MD, Vincent B. Young, MD, PhD, and Preeti N. Malani, MD, are with the division of infectious diseases in the department of internal medicine at the University of Michigan, Ann Arbor. These comments are taken from an accompanying editorial (JAMA. 2017 Nov 28;381:1979-80. doi: 10.1001/jama.2017.17969). Dr. Young reported consulting fees from Vedanta, Merck, and Finch Therapeutics and grants from MedImmune. No other disclosures were reported.
Fecal microbiota transplantation (FMT) using oral capsules as the delivery method has been shown to be noninferior to delivery using colonoscopy for the treatment of Clostridium difficile infection, but with a significantly lower price tag.
In an unblended noninferiority trial, published in the Nov. 28 issue of JAMA, 116 adults with at least three documented episodes of C. difficile infection were randomized to either 360 mL of fecal slurry delivered to the cecum via colonoscopy or to 40 capsules of processed fecal microbiota swallowed under direct observation.
Dina Kao, MD, of the department of medicine at the University of Alberta, Edmonton, and coauthors commented that the response rate with the capsules was higher than that seen in other studies of fecal microbiota capsules, which they suggested may partly be due to the larger amount of donor stool used in the study: 80-100 g, compared with 17 g and 25 g used in other studies.
“The higher efficacy observed in this study suggests a dose-dependent response to FMT, and a benefit of bowel lavage prior to FMT, because residual vancomycin was detected up to 8 days despite its discontinuation,” they wrote.
Both treatment modalities achieved similar quality of life improvements. Both groups reported major improvements in domains including physical and emotional health, physical and social functioning, and general health, with no significant differences between the two arms of the study.
The cost per treatment in the colonoscopy group was $874 per patient, compared with $308 per patient in the capsule group.
“Although colonoscopy delivery is more invasive, resource intensive, costly, and inconvenient for patients, it has the advantage of identifying alternative diagnoses,” the authors wrote. “Conversely, when FMT is given by oral capsules, it can be administered in an office setting, which could substantially reduce cost and wait time.”
Both groups also showed significantly improved gut microbiota diversity, which approached that of the donor just 1 week after administration of the treatment.
While 30% of patients characterized FMTs as “unpleasant, gross, or disgusting,” 79% of participants said the unpleasantness was the same or less than anticipated, and 97% said they would undergo the same treatment by the same delivery method again if needed.
However, significantly more patients in the capsule group described their experience as “not at all unpleasant,” compared with the colonoscopy group (66% vs. 44%; 95% CI, 3%-40%; P = .01).
There were no colonic perforations seen in the colonoscopy group, and no infectious complications relating to the treatment in either group. One patient in each group died of underlying cardiopulmonary illness that was unrelated to the treatment, and the rate of minor adverse events was 5.4% in the capsule group and 12.5% in the colonoscopy group.
The authors acknowledged that the lack of a placebo group in the study meant they were not able to measure the size of the effect of fecal microbiota transplantation by either route. One earlier trial had also shown a placebo response rate of 45%.
The study was funded by Alberta Health Services and the University of Alberta Hospital Foundation. Four authors declared grants and other funding from the study funder and the pharmaceutical industry.
The AGA Center for Gut Microbiome Research and Education serves as a virtual “home” for AGA activities related to the gut microbiome, including the AGA FMT National Registry, which will assess short- and long-term patient outcomes associated with FMT. Learn more at http://www.gastro.org/about/initiatives/aga-center-for-gut-microbiome-research-education.
Fecal microbiota transplantation (FMT) using oral capsules as the delivery method has been shown to be noninferior to delivery using colonoscopy for the treatment of Clostridium difficile infection, but with a significantly lower price tag.
In an unblended noninferiority trial, published in the Nov. 28 issue of JAMA, 116 adults with at least three documented episodes of C. difficile infection were randomized to either 360 mL of fecal slurry delivered to the cecum via colonoscopy or to 40 capsules of processed fecal microbiota swallowed under direct observation.
Dina Kao, MD, of the department of medicine at the University of Alberta, Edmonton, and coauthors commented that the response rate with the capsules was higher than that seen in other studies of fecal microbiota capsules, which they suggested may partly be due to the larger amount of donor stool used in the study: 80-100 g, compared with 17 g and 25 g used in other studies.
“The higher efficacy observed in this study suggests a dose-dependent response to FMT, and a benefit of bowel lavage prior to FMT, because residual vancomycin was detected up to 8 days despite its discontinuation,” they wrote.
Both treatment modalities achieved similar quality of life improvements. Both groups reported major improvements in domains including physical and emotional health, physical and social functioning, and general health, with no significant differences between the two arms of the study.
The cost per treatment in the colonoscopy group was $874 per patient, compared with $308 per patient in the capsule group.
“Although colonoscopy delivery is more invasive, resource intensive, costly, and inconvenient for patients, it has the advantage of identifying alternative diagnoses,” the authors wrote. “Conversely, when FMT is given by oral capsules, it can be administered in an office setting, which could substantially reduce cost and wait time.”
Both groups also showed significantly improved gut microbiota diversity, which approached that of the donor just 1 week after administration of the treatment.
While 30% of patients characterized FMTs as “unpleasant, gross, or disgusting,” 79% of participants said the unpleasantness was the same or less than anticipated, and 97% said they would undergo the same treatment by the same delivery method again if needed.
However, significantly more patients in the capsule group described their experience as “not at all unpleasant,” compared with the colonoscopy group (66% vs. 44%; 95% CI, 3%-40%; P = .01).
There were no colonic perforations seen in the colonoscopy group, and no infectious complications relating to the treatment in either group. One patient in each group died of underlying cardiopulmonary illness that was unrelated to the treatment, and the rate of minor adverse events was 5.4% in the capsule group and 12.5% in the colonoscopy group.
The authors acknowledged that the lack of a placebo group in the study meant they were not able to measure the size of the effect of fecal microbiota transplantation by either route. One earlier trial had also shown a placebo response rate of 45%.
The study was funded by Alberta Health Services and the University of Alberta Hospital Foundation. Four authors declared grants and other funding from the study funder and the pharmaceutical industry.
The AGA Center for Gut Microbiome Research and Education serves as a virtual “home” for AGA activities related to the gut microbiome, including the AGA FMT National Registry, which will assess short- and long-term patient outcomes associated with FMT. Learn more at http://www.gastro.org/about/initiatives/aga-center-for-gut-microbiome-research-education.
FROM JAMA
Key clinical point: Delivering fecal microbiota transplants using oral capsules is noninferior to delivery via colonoscopy in the treatment of Clostridium difficile infection.
Major finding: The rates of resolution of recurrent C. difficile infection with fecal microbiota transplants are similar for delivery via oral capsule or via colonoscopy.
Data source: A randomized, unblended noninferiority trial in 116 adults with recurrent C. difficile infection.
Disclosures: The study was funded by Alberta Health Services and the University of Alberta Hospital Foundation. Four authors declared grants and other funding from the study funder and the pharmaceutical industry.
FDA approves first trastuzumab biosimilar
The Food and Drug Administration has approved trastuzumab-dkst (Ogivri) as a biosimilar to trastuzumab (Herceptin) for the treatment of patients with HER2+ breast or metastatic gastric or gastroesophageal junction adenocarcinoma.
This is the first biosimilar approved in the United States for the treatment of breast cancer or gastric cancer and the second biosimilar approved for the treatment of cancer, the FDA said in a statement.
The approval of trastuzumab-dkst is based on structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamic data, clinical immunogenicity data, and other clinical safety and effectiveness data.
Common expected side effects of trastuzumab-dkst for the treatment of HER2+ breast cancer include headache, diarrhea, nausea, chills, fever, infection, congestive heart failure, insomnia, cough, and rash. Common expected side effects for the treatment of HER2+ metastatic gastric cancer include neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia.
The biosimilar label contains a Boxed Warning – as trastuzumab does – about increased risks of cardiomyopathy, infusion reactions, pulmonary toxicity, and fetal toxicity.
The FDA’s Oncologic Drugs Advisory Committee voted unanimously in July to recommend approval of the biosimilar, made by Mylan and Biocon.
To prepare for the entry of biosimilars to the market, AGA is taking the lead in educating health-care professionals and patients about biosimilars. Visit www.gastro.org/biosimilars to learn more.
The Food and Drug Administration has approved trastuzumab-dkst (Ogivri) as a biosimilar to trastuzumab (Herceptin) for the treatment of patients with HER2+ breast or metastatic gastric or gastroesophageal junction adenocarcinoma.
This is the first biosimilar approved in the United States for the treatment of breast cancer or gastric cancer and the second biosimilar approved for the treatment of cancer, the FDA said in a statement.
The approval of trastuzumab-dkst is based on structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamic data, clinical immunogenicity data, and other clinical safety and effectiveness data.
Common expected side effects of trastuzumab-dkst for the treatment of HER2+ breast cancer include headache, diarrhea, nausea, chills, fever, infection, congestive heart failure, insomnia, cough, and rash. Common expected side effects for the treatment of HER2+ metastatic gastric cancer include neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia.
The biosimilar label contains a Boxed Warning – as trastuzumab does – about increased risks of cardiomyopathy, infusion reactions, pulmonary toxicity, and fetal toxicity.
The FDA’s Oncologic Drugs Advisory Committee voted unanimously in July to recommend approval of the biosimilar, made by Mylan and Biocon.
To prepare for the entry of biosimilars to the market, AGA is taking the lead in educating health-care professionals and patients about biosimilars. Visit www.gastro.org/biosimilars to learn more.
The Food and Drug Administration has approved trastuzumab-dkst (Ogivri) as a biosimilar to trastuzumab (Herceptin) for the treatment of patients with HER2+ breast or metastatic gastric or gastroesophageal junction adenocarcinoma.
This is the first biosimilar approved in the United States for the treatment of breast cancer or gastric cancer and the second biosimilar approved for the treatment of cancer, the FDA said in a statement.
The approval of trastuzumab-dkst is based on structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamic data, clinical immunogenicity data, and other clinical safety and effectiveness data.
Common expected side effects of trastuzumab-dkst for the treatment of HER2+ breast cancer include headache, diarrhea, nausea, chills, fever, infection, congestive heart failure, insomnia, cough, and rash. Common expected side effects for the treatment of HER2+ metastatic gastric cancer include neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia.
The biosimilar label contains a Boxed Warning – as trastuzumab does – about increased risks of cardiomyopathy, infusion reactions, pulmonary toxicity, and fetal toxicity.
The FDA’s Oncologic Drugs Advisory Committee voted unanimously in July to recommend approval of the biosimilar, made by Mylan and Biocon.
To prepare for the entry of biosimilars to the market, AGA is taking the lead in educating health-care professionals and patients about biosimilars. Visit www.gastro.org/biosimilars to learn more.
Hippocampal features may predispose children with febrile status epilepticus to poorer memory
WASHINGTON – Children with febrile status epilepticus (FSE) may be at risk for memory impairment when abnormal hippocampal development or acute injury is also present, according to research presented at the annual meeting of the American Epilepsy Society.
This analysis of patients enrolled in the FEBSTAT study presents some of the first prospective data available regarding significant risk factors for cognitive dysfunction in children with FSE.
“Overall, children with FSE have generally intact memory function and generally intact IQ,” said Erica Weiss, PhD, a neurology instructor at the Albert Einstein College of Medicine, New York. “However, children with acute T2 [hyperintensities on MRI] and kids who have hippocampal malrotation [HIMAL] tend to have weaker memory scores.”
The investigators conducted a prospective study of 113 children with FSE using data gathered from five medical centers across the United States between June 2003 and March 2010.
Children included in the study were followed with serial MRIs and electroencephalograms for more than 5 years after their having FSE; during this time, their verbal, visual, and screening memory abilities were tested using the Wide Range Assessment of Memory and Learning, Second Edition, (WRAML2) test.
Patients had an average age of 15.5 months at time of FSE. Of the children in the study, 46% were female, and 46% were non-white.
Overall, mean scores at baseline on the WRAML2 were significantly lower for children with acute hippocampal injury shown on T2 hyperintensities or HIMAL than they were for children with a normal MRI scan. On individual memory functions of the WRAML2, mean scores at baseline for children with acute T2 hyperintensities were lower than they were for those with a normal MRI on the verbal index (79 vs. 102.3), visual index (81 vs. 93.7), and screening memory index (76 vs. 97.7). Children with HIMAL at baseline also had lower scores on those indexes (94.9 for verbal memory, 82.5 for visual memory, and 97 for screening memory) than did children with a normal MRI.
The differences were statistically significant for lower verbal memory and screening memory scores in patients with acute T2 hyperintensities and for lower visual memory scores in patients with HIMAL. The differences trended toward statistical significance for lower visual memory scores in children with acute T2 hyperintensities and for lower verbal memory scores in children with focal FSE seizures.
The researchers found no significant differences in memory task performances when stratifying for age at time of FSE, duration of FSE, or patients’ sex, according to Dr. Weiss.
With this initial connection uncovered, Dr. Weiss and her colleagues are looking to dive deeper into different aspects of hippocampal properties and FSE.
“We’re looking into the relationship between hippocampus size and memory performances, as well as continue to track these studies,” Dr. Weiss said in an interview. “Another factor to consider when you talk about memory is attention, and we have looked into it a bit, but we need more information.”
This study was funded by a grant from the National Institute of Neurological Disorders and Stroke. The presenters reported no relevant financial disclosures.
[email protected]
On Twitter @eaztweets
WASHINGTON – Children with febrile status epilepticus (FSE) may be at risk for memory impairment when abnormal hippocampal development or acute injury is also present, according to research presented at the annual meeting of the American Epilepsy Society.
This analysis of patients enrolled in the FEBSTAT study presents some of the first prospective data available regarding significant risk factors for cognitive dysfunction in children with FSE.
“Overall, children with FSE have generally intact memory function and generally intact IQ,” said Erica Weiss, PhD, a neurology instructor at the Albert Einstein College of Medicine, New York. “However, children with acute T2 [hyperintensities on MRI] and kids who have hippocampal malrotation [HIMAL] tend to have weaker memory scores.”
The investigators conducted a prospective study of 113 children with FSE using data gathered from five medical centers across the United States between June 2003 and March 2010.
Children included in the study were followed with serial MRIs and electroencephalograms for more than 5 years after their having FSE; during this time, their verbal, visual, and screening memory abilities were tested using the Wide Range Assessment of Memory and Learning, Second Edition, (WRAML2) test.
Patients had an average age of 15.5 months at time of FSE. Of the children in the study, 46% were female, and 46% were non-white.
Overall, mean scores at baseline on the WRAML2 were significantly lower for children with acute hippocampal injury shown on T2 hyperintensities or HIMAL than they were for children with a normal MRI scan. On individual memory functions of the WRAML2, mean scores at baseline for children with acute T2 hyperintensities were lower than they were for those with a normal MRI on the verbal index (79 vs. 102.3), visual index (81 vs. 93.7), and screening memory index (76 vs. 97.7). Children with HIMAL at baseline also had lower scores on those indexes (94.9 for verbal memory, 82.5 for visual memory, and 97 for screening memory) than did children with a normal MRI.
The differences were statistically significant for lower verbal memory and screening memory scores in patients with acute T2 hyperintensities and for lower visual memory scores in patients with HIMAL. The differences trended toward statistical significance for lower visual memory scores in children with acute T2 hyperintensities and for lower verbal memory scores in children with focal FSE seizures.
The researchers found no significant differences in memory task performances when stratifying for age at time of FSE, duration of FSE, or patients’ sex, according to Dr. Weiss.
With this initial connection uncovered, Dr. Weiss and her colleagues are looking to dive deeper into different aspects of hippocampal properties and FSE.
“We’re looking into the relationship between hippocampus size and memory performances, as well as continue to track these studies,” Dr. Weiss said in an interview. “Another factor to consider when you talk about memory is attention, and we have looked into it a bit, but we need more information.”
This study was funded by a grant from the National Institute of Neurological Disorders and Stroke. The presenters reported no relevant financial disclosures.
[email protected]
On Twitter @eaztweets
WASHINGTON – Children with febrile status epilepticus (FSE) may be at risk for memory impairment when abnormal hippocampal development or acute injury is also present, according to research presented at the annual meeting of the American Epilepsy Society.
This analysis of patients enrolled in the FEBSTAT study presents some of the first prospective data available regarding significant risk factors for cognitive dysfunction in children with FSE.
“Overall, children with FSE have generally intact memory function and generally intact IQ,” said Erica Weiss, PhD, a neurology instructor at the Albert Einstein College of Medicine, New York. “However, children with acute T2 [hyperintensities on MRI] and kids who have hippocampal malrotation [HIMAL] tend to have weaker memory scores.”
The investigators conducted a prospective study of 113 children with FSE using data gathered from five medical centers across the United States between June 2003 and March 2010.
Children included in the study were followed with serial MRIs and electroencephalograms for more than 5 years after their having FSE; during this time, their verbal, visual, and screening memory abilities were tested using the Wide Range Assessment of Memory and Learning, Second Edition, (WRAML2) test.
Patients had an average age of 15.5 months at time of FSE. Of the children in the study, 46% were female, and 46% were non-white.
Overall, mean scores at baseline on the WRAML2 were significantly lower for children with acute hippocampal injury shown on T2 hyperintensities or HIMAL than they were for children with a normal MRI scan. On individual memory functions of the WRAML2, mean scores at baseline for children with acute T2 hyperintensities were lower than they were for those with a normal MRI on the verbal index (79 vs. 102.3), visual index (81 vs. 93.7), and screening memory index (76 vs. 97.7). Children with HIMAL at baseline also had lower scores on those indexes (94.9 for verbal memory, 82.5 for visual memory, and 97 for screening memory) than did children with a normal MRI.
The differences were statistically significant for lower verbal memory and screening memory scores in patients with acute T2 hyperintensities and for lower visual memory scores in patients with HIMAL. The differences trended toward statistical significance for lower visual memory scores in children with acute T2 hyperintensities and for lower verbal memory scores in children with focal FSE seizures.
The researchers found no significant differences in memory task performances when stratifying for age at time of FSE, duration of FSE, or patients’ sex, according to Dr. Weiss.
With this initial connection uncovered, Dr. Weiss and her colleagues are looking to dive deeper into different aspects of hippocampal properties and FSE.
“We’re looking into the relationship between hippocampus size and memory performances, as well as continue to track these studies,” Dr. Weiss said in an interview. “Another factor to consider when you talk about memory is attention, and we have looked into it a bit, but we need more information.”
This study was funded by a grant from the National Institute of Neurological Disorders and Stroke. The presenters reported no relevant financial disclosures.
[email protected]
On Twitter @eaztweets
AT AES 2017
Key clinical point:
Major finding: On individual memory functions of the Wide Range Assessment of Memory and Learning, Second Edition, test, mean scores at baseline for children with acute T2 hyperintensities or hippocampal malrotation were lower than they were for those with a normal MRI on the verbal index (79 and 94.9, respectively, vs. 102.3), the visual index (81 and 82.5 vs. 93.7), and the screening memory (76 and 97 vs. 97.7) index.
Data source: Prospective study of 113 children, the data for which was gathered from five medical centers across the United States between 2003 and 2010.
Disclosures: The study was funded by a grant from the National Institute of Neurological Disorders and Stroke. The presenters reported no relevant financial disclosures.
Biosimilars and sources show mostly parallel safety profiles
Biosimilars are primarily as safe as their originators, based on data from a review of current European regulatory documents. The findings were published online in the British Journal of Clinical Pharmacology.
“Biosimilars are officially approved as similar products to a biopharmaceutical originator, which often share the same International Nonproprietary Name,” wrote L.R.A. Lepelaars, MD, of Utrecht University, the Netherlands, and colleagues. However, many clinicians remain cautious about using biosimilars, particularly those in the United States, they noted. The European Medicines Agency (EMA) has filed safety data on biosimilars, but comparative effectiveness studies often are lacking, they wrote.
In this study, the researchers compared data on 25 biologic medicinal products (19 biosimilars and 6 originators). The biosimilars were authorized by the EMA between Jan. 1, 2005 and Oct. 30, 2015 (Br. J. Clin. Pharmacol. 2017 Nov 22; doi: 10.1111/bcp.13454).
Overall, the researchers found 55 general safety concerns, including 22 that were deemed highly clinically relevant. Another 21 were defined as medium, while 12 had low levels of clinical relevance.
Infliximab was the only active substance with more than one difference in safety concerns between the biosimilar and originator; three more general safety concerns (all of medium clinical relevance) were noted for infliximab biosimilars compared with the originator (bowel obstruction, hematologic reactions, and lack of efficacy).
For all other active substances included in the study, one difference or no difference was found in the general safety concerns between the biosimilars and originators, and none of the differences was related to immunogenicity
The researchers assessed the safety of biosimilars by comparing them with European Risk Management Plan or Summary of Product Characteristics.
The findings support the value of biosimilars based on comparable safety profiles, the researchers noted. However, “a direct comparison between biosimilars and related originators through formal postmarketing studies (observational or clinical trials) is mandatory for specific safety and effectiveness issues emerging during the products’ life cycle,” they said.
The researchers had no financial conflicts to disclose.
Biosimilars are primarily as safe as their originators, based on data from a review of current European regulatory documents. The findings were published online in the British Journal of Clinical Pharmacology.
“Biosimilars are officially approved as similar products to a biopharmaceutical originator, which often share the same International Nonproprietary Name,” wrote L.R.A. Lepelaars, MD, of Utrecht University, the Netherlands, and colleagues. However, many clinicians remain cautious about using biosimilars, particularly those in the United States, they noted. The European Medicines Agency (EMA) has filed safety data on biosimilars, but comparative effectiveness studies often are lacking, they wrote.
In this study, the researchers compared data on 25 biologic medicinal products (19 biosimilars and 6 originators). The biosimilars were authorized by the EMA between Jan. 1, 2005 and Oct. 30, 2015 (Br. J. Clin. Pharmacol. 2017 Nov 22; doi: 10.1111/bcp.13454).
Overall, the researchers found 55 general safety concerns, including 22 that were deemed highly clinically relevant. Another 21 were defined as medium, while 12 had low levels of clinical relevance.
Infliximab was the only active substance with more than one difference in safety concerns between the biosimilar and originator; three more general safety concerns (all of medium clinical relevance) were noted for infliximab biosimilars compared with the originator (bowel obstruction, hematologic reactions, and lack of efficacy).
For all other active substances included in the study, one difference or no difference was found in the general safety concerns between the biosimilars and originators, and none of the differences was related to immunogenicity
The researchers assessed the safety of biosimilars by comparing them with European Risk Management Plan or Summary of Product Characteristics.
The findings support the value of biosimilars based on comparable safety profiles, the researchers noted. However, “a direct comparison between biosimilars and related originators through formal postmarketing studies (observational or clinical trials) is mandatory for specific safety and effectiveness issues emerging during the products’ life cycle,” they said.
The researchers had no financial conflicts to disclose.
Biosimilars are primarily as safe as their originators, based on data from a review of current European regulatory documents. The findings were published online in the British Journal of Clinical Pharmacology.
“Biosimilars are officially approved as similar products to a biopharmaceutical originator, which often share the same International Nonproprietary Name,” wrote L.R.A. Lepelaars, MD, of Utrecht University, the Netherlands, and colleagues. However, many clinicians remain cautious about using biosimilars, particularly those in the United States, they noted. The European Medicines Agency (EMA) has filed safety data on biosimilars, but comparative effectiveness studies often are lacking, they wrote.
In this study, the researchers compared data on 25 biologic medicinal products (19 biosimilars and 6 originators). The biosimilars were authorized by the EMA between Jan. 1, 2005 and Oct. 30, 2015 (Br. J. Clin. Pharmacol. 2017 Nov 22; doi: 10.1111/bcp.13454).
Overall, the researchers found 55 general safety concerns, including 22 that were deemed highly clinically relevant. Another 21 were defined as medium, while 12 had low levels of clinical relevance.
Infliximab was the only active substance with more than one difference in safety concerns between the biosimilar and originator; three more general safety concerns (all of medium clinical relevance) were noted for infliximab biosimilars compared with the originator (bowel obstruction, hematologic reactions, and lack of efficacy).
For all other active substances included in the study, one difference or no difference was found in the general safety concerns between the biosimilars and originators, and none of the differences was related to immunogenicity
The researchers assessed the safety of biosimilars by comparing them with European Risk Management Plan or Summary of Product Characteristics.
The findings support the value of biosimilars based on comparable safety profiles, the researchers noted. However, “a direct comparison between biosimilars and related originators through formal postmarketing studies (observational or clinical trials) is mandatory for specific safety and effectiveness issues emerging during the products’ life cycle,” they said.
The researchers had no financial conflicts to disclose.
FROM THE BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
Key clinical point: Most biosimilars show safety profiles comparable to their originators.
Major finding: Infliximab biosimilars demonstrated three more general safety concerns than the originator.
Data source: The data come from a cross-sectional analysis 19 biosimilars and 6 originators.
Disclosures: The researchers had no financial conflicts to disclose.
ASCO platelet transfusion guidelines updated
A lot has happened in oncology since the American Society of Clinical Oncology (ASCO) first issued its guidelines on platelet transfusion for patients with cancer in 2001, noted the authors of the updated recommendations.
“The expense of platelet transfusions, coupled with potential adverse effects such as febrile and allergic reactions, transfusion-related acute lung injury, and bacterial contamination point to the importance of evidence-based transfusion practice,” wrote Charles A Schiffer, MD, of Wayne State Michigan, Detroit, and his colleagues in the updated guidelines.
Many of the original recommendations remain unchanged, but there are updated evidence-based recommendations in five key areas.
For example, regarding platelet transfusion thresholds in the setting of hematologic stem-cell transplantation in adults, the guidelines incorporate evidence from randomized clinical trials showing that among adults who have received autologous hematologic stem-cell transplantation, bleeding rates with decreased use of platelets are similar whether patients are treated prophylactically or at the first sign of bleeding, “and this approach may be used in experienced centers,” wrote Dr. Schiffer and his colleagues (J Clin Oncol. 2017 Nov 28. doi: 10.1200/JCO.2017.76.1734).
The authors caution, however, that the recommendation applies to adults only.
Other updated recommendations include:
• Rhesus D alloimmunization from platelet transfusions to RhD-negative patients can be prevented through either exclusive use of platelet products from RhD-negative donors or immunoprophylaxis. The guidelines note that there is a low rate of RhD alloimmunization in cancer patients in general, but state that prevention may be used in girls and in women of child-bearing age who are being treated with curative intent.
• For patients with acute myeloid leukemia, receiving induction chemotherapy, the use of leukoreduced platelet and red blood cell products can reduce the likelihood that patients will develop alloantibody-mediated refractory reactions to plate transfusions.
“It is therefore appropriate to provide leukoreduced blood products to patients with [acute myeloid leukemia] from the time of diagnosis to ameliorate this important clinical problem,” the investigators wrote.
They noted that leukoreduction to prevent alloimmunization might benefit patients with other leukemia histologies and with other types of cancer who are undergoing chemotherapy, but added that there is a lack of evidence to support this as a recommendation outside of acute myeloid leukemia.
To reduce the risk of bleeding due to thrombocytopenia in patients with solid tumors who are undergoing chemotherapy, the panelists recommend transfusing patients when their platelet levels fall below 10 x 109 per liter. It is appropriate to give platelet transfusions to patients with higher levels when there is active localized bleeding, they stated.
The guideline authors also recommend that when refractoriness to platelet infusions is suspected, clinicians should perform platelet counts from 10 to 60 minutes after the transfusion is completed. A refractoriness determination should be made only after two or more infusions of ABO-compatible units that have been stored for less than 72 hours result in poor increments, they advised.
The guideline development process is supported by ASCO. Dr. Schiffer and six other guideline authors disclosed consulting or advisory roles, research funding, honoraria and/or fees with various pharmaceutical companies or other corporate entities.
A lot has happened in oncology since the American Society of Clinical Oncology (ASCO) first issued its guidelines on platelet transfusion for patients with cancer in 2001, noted the authors of the updated recommendations.
“The expense of platelet transfusions, coupled with potential adverse effects such as febrile and allergic reactions, transfusion-related acute lung injury, and bacterial contamination point to the importance of evidence-based transfusion practice,” wrote Charles A Schiffer, MD, of Wayne State Michigan, Detroit, and his colleagues in the updated guidelines.
Many of the original recommendations remain unchanged, but there are updated evidence-based recommendations in five key areas.
For example, regarding platelet transfusion thresholds in the setting of hematologic stem-cell transplantation in adults, the guidelines incorporate evidence from randomized clinical trials showing that among adults who have received autologous hematologic stem-cell transplantation, bleeding rates with decreased use of platelets are similar whether patients are treated prophylactically or at the first sign of bleeding, “and this approach may be used in experienced centers,” wrote Dr. Schiffer and his colleagues (J Clin Oncol. 2017 Nov 28. doi: 10.1200/JCO.2017.76.1734).
The authors caution, however, that the recommendation applies to adults only.
Other updated recommendations include:
• Rhesus D alloimmunization from platelet transfusions to RhD-negative patients can be prevented through either exclusive use of platelet products from RhD-negative donors or immunoprophylaxis. The guidelines note that there is a low rate of RhD alloimmunization in cancer patients in general, but state that prevention may be used in girls and in women of child-bearing age who are being treated with curative intent.
• For patients with acute myeloid leukemia, receiving induction chemotherapy, the use of leukoreduced platelet and red blood cell products can reduce the likelihood that patients will develop alloantibody-mediated refractory reactions to plate transfusions.
“It is therefore appropriate to provide leukoreduced blood products to patients with [acute myeloid leukemia] from the time of diagnosis to ameliorate this important clinical problem,” the investigators wrote.
They noted that leukoreduction to prevent alloimmunization might benefit patients with other leukemia histologies and with other types of cancer who are undergoing chemotherapy, but added that there is a lack of evidence to support this as a recommendation outside of acute myeloid leukemia.
To reduce the risk of bleeding due to thrombocytopenia in patients with solid tumors who are undergoing chemotherapy, the panelists recommend transfusing patients when their platelet levels fall below 10 x 109 per liter. It is appropriate to give platelet transfusions to patients with higher levels when there is active localized bleeding, they stated.
The guideline authors also recommend that when refractoriness to platelet infusions is suspected, clinicians should perform platelet counts from 10 to 60 minutes after the transfusion is completed. A refractoriness determination should be made only after two or more infusions of ABO-compatible units that have been stored for less than 72 hours result in poor increments, they advised.
The guideline development process is supported by ASCO. Dr. Schiffer and six other guideline authors disclosed consulting or advisory roles, research funding, honoraria and/or fees with various pharmaceutical companies or other corporate entities.
A lot has happened in oncology since the American Society of Clinical Oncology (ASCO) first issued its guidelines on platelet transfusion for patients with cancer in 2001, noted the authors of the updated recommendations.
“The expense of platelet transfusions, coupled with potential adverse effects such as febrile and allergic reactions, transfusion-related acute lung injury, and bacterial contamination point to the importance of evidence-based transfusion practice,” wrote Charles A Schiffer, MD, of Wayne State Michigan, Detroit, and his colleagues in the updated guidelines.
Many of the original recommendations remain unchanged, but there are updated evidence-based recommendations in five key areas.
For example, regarding platelet transfusion thresholds in the setting of hematologic stem-cell transplantation in adults, the guidelines incorporate evidence from randomized clinical trials showing that among adults who have received autologous hematologic stem-cell transplantation, bleeding rates with decreased use of platelets are similar whether patients are treated prophylactically or at the first sign of bleeding, “and this approach may be used in experienced centers,” wrote Dr. Schiffer and his colleagues (J Clin Oncol. 2017 Nov 28. doi: 10.1200/JCO.2017.76.1734).
The authors caution, however, that the recommendation applies to adults only.
Other updated recommendations include:
• Rhesus D alloimmunization from platelet transfusions to RhD-negative patients can be prevented through either exclusive use of platelet products from RhD-negative donors or immunoprophylaxis. The guidelines note that there is a low rate of RhD alloimmunization in cancer patients in general, but state that prevention may be used in girls and in women of child-bearing age who are being treated with curative intent.
• For patients with acute myeloid leukemia, receiving induction chemotherapy, the use of leukoreduced platelet and red blood cell products can reduce the likelihood that patients will develop alloantibody-mediated refractory reactions to plate transfusions.
“It is therefore appropriate to provide leukoreduced blood products to patients with [acute myeloid leukemia] from the time of diagnosis to ameliorate this important clinical problem,” the investigators wrote.
They noted that leukoreduction to prevent alloimmunization might benefit patients with other leukemia histologies and with other types of cancer who are undergoing chemotherapy, but added that there is a lack of evidence to support this as a recommendation outside of acute myeloid leukemia.
To reduce the risk of bleeding due to thrombocytopenia in patients with solid tumors who are undergoing chemotherapy, the panelists recommend transfusing patients when their platelet levels fall below 10 x 109 per liter. It is appropriate to give platelet transfusions to patients with higher levels when there is active localized bleeding, they stated.
The guideline authors also recommend that when refractoriness to platelet infusions is suspected, clinicians should perform platelet counts from 10 to 60 minutes after the transfusion is completed. A refractoriness determination should be made only after two or more infusions of ABO-compatible units that have been stored for less than 72 hours result in poor increments, they advised.
The guideline development process is supported by ASCO. Dr. Schiffer and six other guideline authors disclosed consulting or advisory roles, research funding, honoraria and/or fees with various pharmaceutical companies or other corporate entities.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Myth of the Month: MONA for acute treatment of chest pain?
A 66-year-old man presents with substernal chest pressure and dyspnea that has been present for 45 minutes. He has nausea. Vital signs: blood pressure, 110/60; pulse, 100; oxygen saturation, 92%. Neck: elevated jugular venous pressure. Chest: clear. Cardiac: normal S1 S2, no murmurs. ECG: ST elevation in 2, 3, and aVF leads.
Which of these treatments do you recommend?
A. Morphine, oxygen, nitroglycerin, and aspirin (ASA).
B. Oxygen, morphine, ASA.
C. ASA.
In this patient, I think the correct approach would be to just give aspirin. Nitroglycerin would be problematic, as it appears that this patient might be having a right ventricular infarct, and lowering right-sided filling pressures with nitroglycerin may lead to severe hypotension.
There is controversy over the safety of routine morphine use for patients with chest pain.
Trip J. Meine, MD, and colleagues found that use of morphine either alone or in combination with nitroglycerin for patients presenting with non–ST-elevation acute coronary syndrome (NSTE-ACS) was associated with higher mortality.1 Cian P. McCarthy, MD, and colleagues found the same results, with morphine use associated with larger infarct size, a longer hospital stay, and a trend toward increased mortality in invasively managed NSTE-ACS patients.2 Suzanne de Waha and colleagues found that morphine use in patients with ST-segment elevation MIs had larger infarct size and less reperfusion success, as measured by cardiac MRI.3
Not all recent studies show a detrimental effect of morphine. Etienne Puymirat et al. reviewed in-hospital complications (death, nonfatal re-MI, stroke, stent thrombosis, and bleeding) and 1-year survival according to prehospital morphine use in 2,438 ST-elevation MI (STEMI) patients from the French Registry of Acute ST-elevation and non–ST-elevation Myocardial Infarction (FAST-MI).4 They found no increase in in-hospital complications or 1-year mortality.
The practice of using supplemental oxygen to treat all patients with MI became standard nearly a century ago, after oxygen was found in 1900 to relieve angina, and led to clinical improvement in four MI patients in a 1930 case series.5,6
It was not studied in a controlled trial until 1976, when J.M. Rawles, MD, and colleagues randomized 157 patients with MI to 24 hours of oxygen at 8 L/min or to ambient air. They found no difference in mortality between the groups, but they did find a higher burden of MI in the intervention arm receiving supplemental oxygen, as measured by mean serum aspartate aminotransferase levels.7
The topic was not addressed again in a significant randomized trial until this century. Most notably, two recent studies again demonstrated no benefit of supplemental oxygen in normoxemic patients with MI.
In the AVOID trial in 2015, Dion Stub, MD, PhD, and colleagues randomized 441 patients with STEMI to oxygen at 8 L/min – from diagnosis in an ambulance until after cardiac catheterization – or to ambient air. They found no difference in death at 6 months, but did find an increased rate of in-hospital recurrent MIs, with 0.9% of the control group and 5.5% of the oxygen intervention arm suffering recurrence (P = .006).8 They also showed a larger area of myocardial infarct in the oxygen group, as measured by peak creatine kinase levels and cardiac MRI at 6 months.
Proposed mechanisms of increased myocardial injury from hyperoxia include increased coronary vascular resistance resulting in decreased myocardial perfusion, and increased reperfusion injury from formation of free radicals.9
Where does all this leave us in the treatment of suspected MI?
Morphine should only be used when the patient has pain, and is probably best reserved for severe pain, as the safety of its use is not clear. While hypoxemia is a common consequence of MI – and may correlate with worse outcomes – treatment with supplemental oxygen in the absence of hypoxemia is not supported by current evidence, and may carry risk of harm. Nitroglycerin should be avoided in patients with right ventricular infarcts, and in patients who present with hypotension.
Dr. Tubbesing is a senior resident in medicine at the University of Washington, Seattle. Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].
References
1. Am Heart J. 2005 Jun;149(6):1043-9.
2. J Interv Cardiol. 2017 Nov 22. doi: 10.1111/joic.12464.
3. Clin Res Cardiol. 2015 Sep;104(9):727-34.
4. Eur Heart J. 2016 Apr 1;37(13):1063-71.
5. BMJ. 1900 Dec 1;2(2083):1568.
6. JAMA. 1930 May 3;94(18):1363-5.
7. Br Med J. 1976 May 8;1(6018):1121-3.
8. Circulation. 2015 Jun 16;131(24):2143-50.
9. Cochrane Database Syst Rev. 2016 Dec 19;12:CD007160.
10. N Engl J Med. 2017 Sep 28;377(13):1240-9.
A 66-year-old man presents with substernal chest pressure and dyspnea that has been present for 45 minutes. He has nausea. Vital signs: blood pressure, 110/60; pulse, 100; oxygen saturation, 92%. Neck: elevated jugular venous pressure. Chest: clear. Cardiac: normal S1 S2, no murmurs. ECG: ST elevation in 2, 3, and aVF leads.
Which of these treatments do you recommend?
A. Morphine, oxygen, nitroglycerin, and aspirin (ASA).
B. Oxygen, morphine, ASA.
C. ASA.
In this patient, I think the correct approach would be to just give aspirin. Nitroglycerin would be problematic, as it appears that this patient might be having a right ventricular infarct, and lowering right-sided filling pressures with nitroglycerin may lead to severe hypotension.
There is controversy over the safety of routine morphine use for patients with chest pain.
Trip J. Meine, MD, and colleagues found that use of morphine either alone or in combination with nitroglycerin for patients presenting with non–ST-elevation acute coronary syndrome (NSTE-ACS) was associated with higher mortality.1 Cian P. McCarthy, MD, and colleagues found the same results, with morphine use associated with larger infarct size, a longer hospital stay, and a trend toward increased mortality in invasively managed NSTE-ACS patients.2 Suzanne de Waha and colleagues found that morphine use in patients with ST-segment elevation MIs had larger infarct size and less reperfusion success, as measured by cardiac MRI.3
Not all recent studies show a detrimental effect of morphine. Etienne Puymirat et al. reviewed in-hospital complications (death, nonfatal re-MI, stroke, stent thrombosis, and bleeding) and 1-year survival according to prehospital morphine use in 2,438 ST-elevation MI (STEMI) patients from the French Registry of Acute ST-elevation and non–ST-elevation Myocardial Infarction (FAST-MI).4 They found no increase in in-hospital complications or 1-year mortality.
The practice of using supplemental oxygen to treat all patients with MI became standard nearly a century ago, after oxygen was found in 1900 to relieve angina, and led to clinical improvement in four MI patients in a 1930 case series.5,6
It was not studied in a controlled trial until 1976, when J.M. Rawles, MD, and colleagues randomized 157 patients with MI to 24 hours of oxygen at 8 L/min or to ambient air. They found no difference in mortality between the groups, but they did find a higher burden of MI in the intervention arm receiving supplemental oxygen, as measured by mean serum aspartate aminotransferase levels.7
The topic was not addressed again in a significant randomized trial until this century. Most notably, two recent studies again demonstrated no benefit of supplemental oxygen in normoxemic patients with MI.
In the AVOID trial in 2015, Dion Stub, MD, PhD, and colleagues randomized 441 patients with STEMI to oxygen at 8 L/min – from diagnosis in an ambulance until after cardiac catheterization – or to ambient air. They found no difference in death at 6 months, but did find an increased rate of in-hospital recurrent MIs, with 0.9% of the control group and 5.5% of the oxygen intervention arm suffering recurrence (P = .006).8 They also showed a larger area of myocardial infarct in the oxygen group, as measured by peak creatine kinase levels and cardiac MRI at 6 months.
Proposed mechanisms of increased myocardial injury from hyperoxia include increased coronary vascular resistance resulting in decreased myocardial perfusion, and increased reperfusion injury from formation of free radicals.9
Where does all this leave us in the treatment of suspected MI?
Morphine should only be used when the patient has pain, and is probably best reserved for severe pain, as the safety of its use is not clear. While hypoxemia is a common consequence of MI – and may correlate with worse outcomes – treatment with supplemental oxygen in the absence of hypoxemia is not supported by current evidence, and may carry risk of harm. Nitroglycerin should be avoided in patients with right ventricular infarcts, and in patients who present with hypotension.
Dr. Tubbesing is a senior resident in medicine at the University of Washington, Seattle. Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].
References
1. Am Heart J. 2005 Jun;149(6):1043-9.
2. J Interv Cardiol. 2017 Nov 22. doi: 10.1111/joic.12464.
3. Clin Res Cardiol. 2015 Sep;104(9):727-34.
4. Eur Heart J. 2016 Apr 1;37(13):1063-71.
5. BMJ. 1900 Dec 1;2(2083):1568.
6. JAMA. 1930 May 3;94(18):1363-5.
7. Br Med J. 1976 May 8;1(6018):1121-3.
8. Circulation. 2015 Jun 16;131(24):2143-50.
9. Cochrane Database Syst Rev. 2016 Dec 19;12:CD007160.
10. N Engl J Med. 2017 Sep 28;377(13):1240-9.
A 66-year-old man presents with substernal chest pressure and dyspnea that has been present for 45 minutes. He has nausea. Vital signs: blood pressure, 110/60; pulse, 100; oxygen saturation, 92%. Neck: elevated jugular venous pressure. Chest: clear. Cardiac: normal S1 S2, no murmurs. ECG: ST elevation in 2, 3, and aVF leads.
Which of these treatments do you recommend?
A. Morphine, oxygen, nitroglycerin, and aspirin (ASA).
B. Oxygen, morphine, ASA.
C. ASA.
In this patient, I think the correct approach would be to just give aspirin. Nitroglycerin would be problematic, as it appears that this patient might be having a right ventricular infarct, and lowering right-sided filling pressures with nitroglycerin may lead to severe hypotension.
There is controversy over the safety of routine morphine use for patients with chest pain.
Trip J. Meine, MD, and colleagues found that use of morphine either alone or in combination with nitroglycerin for patients presenting with non–ST-elevation acute coronary syndrome (NSTE-ACS) was associated with higher mortality.1 Cian P. McCarthy, MD, and colleagues found the same results, with morphine use associated with larger infarct size, a longer hospital stay, and a trend toward increased mortality in invasively managed NSTE-ACS patients.2 Suzanne de Waha and colleagues found that morphine use in patients with ST-segment elevation MIs had larger infarct size and less reperfusion success, as measured by cardiac MRI.3
Not all recent studies show a detrimental effect of morphine. Etienne Puymirat et al. reviewed in-hospital complications (death, nonfatal re-MI, stroke, stent thrombosis, and bleeding) and 1-year survival according to prehospital morphine use in 2,438 ST-elevation MI (STEMI) patients from the French Registry of Acute ST-elevation and non–ST-elevation Myocardial Infarction (FAST-MI).4 They found no increase in in-hospital complications or 1-year mortality.
The practice of using supplemental oxygen to treat all patients with MI became standard nearly a century ago, after oxygen was found in 1900 to relieve angina, and led to clinical improvement in four MI patients in a 1930 case series.5,6
It was not studied in a controlled trial until 1976, when J.M. Rawles, MD, and colleagues randomized 157 patients with MI to 24 hours of oxygen at 8 L/min or to ambient air. They found no difference in mortality between the groups, but they did find a higher burden of MI in the intervention arm receiving supplemental oxygen, as measured by mean serum aspartate aminotransferase levels.7
The topic was not addressed again in a significant randomized trial until this century. Most notably, two recent studies again demonstrated no benefit of supplemental oxygen in normoxemic patients with MI.
In the AVOID trial in 2015, Dion Stub, MD, PhD, and colleagues randomized 441 patients with STEMI to oxygen at 8 L/min – from diagnosis in an ambulance until after cardiac catheterization – or to ambient air. They found no difference in death at 6 months, but did find an increased rate of in-hospital recurrent MIs, with 0.9% of the control group and 5.5% of the oxygen intervention arm suffering recurrence (P = .006).8 They also showed a larger area of myocardial infarct in the oxygen group, as measured by peak creatine kinase levels and cardiac MRI at 6 months.
Proposed mechanisms of increased myocardial injury from hyperoxia include increased coronary vascular resistance resulting in decreased myocardial perfusion, and increased reperfusion injury from formation of free radicals.9
Where does all this leave us in the treatment of suspected MI?
Morphine should only be used when the patient has pain, and is probably best reserved for severe pain, as the safety of its use is not clear. While hypoxemia is a common consequence of MI – and may correlate with worse outcomes – treatment with supplemental oxygen in the absence of hypoxemia is not supported by current evidence, and may carry risk of harm. Nitroglycerin should be avoided in patients with right ventricular infarcts, and in patients who present with hypotension.
Dr. Tubbesing is a senior resident in medicine at the University of Washington, Seattle. Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].
References
1. Am Heart J. 2005 Jun;149(6):1043-9.
2. J Interv Cardiol. 2017 Nov 22. doi: 10.1111/joic.12464.
3. Clin Res Cardiol. 2015 Sep;104(9):727-34.
4. Eur Heart J. 2016 Apr 1;37(13):1063-71.
5. BMJ. 1900 Dec 1;2(2083):1568.
6. JAMA. 1930 May 3;94(18):1363-5.
7. Br Med J. 1976 May 8;1(6018):1121-3.
8. Circulation. 2015 Jun 16;131(24):2143-50.
9. Cochrane Database Syst Rev. 2016 Dec 19;12:CD007160.
10. N Engl J Med. 2017 Sep 28;377(13):1240-9.
Genital Ulcers and Swelling in an Adolescent Girl
The Diagnosis: Epstein-Barr Virus
Physical examination revealed bilateral 1-cm ulcerated lesions on the labia minora with vulvar edema (Figure). She had a palpable liver edge but no splenomegaly, oral ulcers or lesions, conjunctivitis or scleral icterus, or cervical or inguinal lymphadenopathy. A detailed genitourinary examination was performed under anesthesia, but the hymen was not commented on. Inflammatory markers were elevated with a C-reactive protein level of 16.4 mg/L (reference range, 0.08-3.1 mg/mL), erythrocyte sedimentation rate of39 mm/h (reference range, 0-20 mm/h), white blood cell count of 7.1×109/L (reference range, 4.5-11.0×109/L) with 57% neutrophils and 30% lymphocytes, an alanine aminotransferase level of 41 U/L (reference range, 10-40 U/L), and an aspartate aminotransferase level of 126 U/L (reference range, 10-30 U/L).
Bacterial and fungal cultures of vulvar tissue were negative as well as blood and urine cultures. Serological tests for herpes simplex virus (HSV), syphilis, and cytomegalovirus were negative, and urine testing for gonorrhea and chlamydia were negative. Serologies for Epstein-Barr virus (EBV) all were strongly positive with an EBV viral capsid antigen (VCA) IgM greater than 160 U/mL, early antigen IgG of 68 U/mL, and EBV VCA IgG of 456 U/mL. Two years after the initial presentation, repeat EBV serologies were obtained, showing a strongly positive EBV VCA IgG (>8.0 antibody index; reference range, 0-0.8), and a negative EBV VCA IgM.
Infectious etiologies of genital ulcers in a sexually active female include HSV, syphilis, lymphogranuloma venereum, and chancroid. Herpes simplex virus often is the assumed etiology of genital ulcers, especially in sexually active patients, and misdiagnosis in the setting of negative HSV testing may be high. Less common infectious causes such as mumps and cytomegalovirus also have been reported.1,2 Lichen planus and lichen sclerosus are noninfectious inflammatory causes, both of which may involve and be limited to the genitals. Autoimmune disorders include Crohn disease and Behçet disease, and vulvar ulcers with an eschar, consistent with aphthous major or complex apotheosis, has been used to describe patients with severe recurrent oral and genital ulcerations without other systemic manifestations of Behçet disease.3
Genital ulcers are an uncommon manifestation of EBV infection. The formation of genital ulcers in EBV infection has been hypothesized to be due to immune complex formation during the acute phase that becomes activated in the vasculature, leading to microthrombosis and eventually necrosis of the tissue.4 The mode of transmission for EBV-related acute genital ulcers has been postulated to be hematogenous spread in lymphocytes or EBV shedding in the urine with subsequent transfer to the genital mucosa.5
Epstein-Barr virus-related acute genital ulcers are self-limiting. The average healing time for the ulcers is 14 to 18 days.6,7 Antivirals are ineffective in treating this condition; however, supportive treatment with systemic glucocorticoids for associated swelling and pain medications could be considered. Our patient was treated symptomatically. Two weeks after debridement, granulation tissue was noted at the site and her pain and discomfort had resolved. This case illustrates an uncommon manifestation of EBV in a sexually inactive adolescent and is a reminder for the dermatologist of the diverse spectrum of illness caused by this common virus.
- Chanal J, Carlotti A, Laude H, et al. Lipschütz genital ulceration associated with mumps. Dermatology. 2010;221:292-295.
- Martin JM, Godoy R, Calduch L, et al. Lipschütz acute vulval ulcers associated with primary cytomegalovirus infection. Pediatr Dermatol. 2008;25:113-115.
- Huppert JS, Gerber MA, Deitch HR, et al. Vulvar ulcers in young females: a manifestation of aphthosis. J Pediatr Adolesc Gynecol. 2006;19:195-204.
- Sárdy M, Wollenberg A, Niedermeier A, et al. Genital ulcers associated with Epstein-Barr virus infection (ulcus vulvae acutum). Acta Derm Venereol. 2011;91:55-59.
- Di Lernia V, Mansouri Y. Epstein-Barr virus and skin manifestations in childhood. Int J Dermatol. 2013;52:1177-1184.
- Halvorsen JA, Brevig T, Aas T, et al. Genital ulcers as initial manifestation of Epstein-Barr virus infection: two new cases and a review of the literature. Acta Derm Venereol. 2006;86:439-442.
- Jerdan K, Aronson I, Hernandez C, et al. Genital ulcers associated with Epstein-Barr virus. Cutis. 2013;91:273-276.
The Diagnosis: Epstein-Barr Virus
Physical examination revealed bilateral 1-cm ulcerated lesions on the labia minora with vulvar edema (Figure). She had a palpable liver edge but no splenomegaly, oral ulcers or lesions, conjunctivitis or scleral icterus, or cervical or inguinal lymphadenopathy. A detailed genitourinary examination was performed under anesthesia, but the hymen was not commented on. Inflammatory markers were elevated with a C-reactive protein level of 16.4 mg/L (reference range, 0.08-3.1 mg/mL), erythrocyte sedimentation rate of39 mm/h (reference range, 0-20 mm/h), white blood cell count of 7.1×109/L (reference range, 4.5-11.0×109/L) with 57% neutrophils and 30% lymphocytes, an alanine aminotransferase level of 41 U/L (reference range, 10-40 U/L), and an aspartate aminotransferase level of 126 U/L (reference range, 10-30 U/L).
Bacterial and fungal cultures of vulvar tissue were negative as well as blood and urine cultures. Serological tests for herpes simplex virus (HSV), syphilis, and cytomegalovirus were negative, and urine testing for gonorrhea and chlamydia were negative. Serologies for Epstein-Barr virus (EBV) all were strongly positive with an EBV viral capsid antigen (VCA) IgM greater than 160 U/mL, early antigen IgG of 68 U/mL, and EBV VCA IgG of 456 U/mL. Two years after the initial presentation, repeat EBV serologies were obtained, showing a strongly positive EBV VCA IgG (>8.0 antibody index; reference range, 0-0.8), and a negative EBV VCA IgM.
Infectious etiologies of genital ulcers in a sexually active female include HSV, syphilis, lymphogranuloma venereum, and chancroid. Herpes simplex virus often is the assumed etiology of genital ulcers, especially in sexually active patients, and misdiagnosis in the setting of negative HSV testing may be high. Less common infectious causes such as mumps and cytomegalovirus also have been reported.1,2 Lichen planus and lichen sclerosus are noninfectious inflammatory causes, both of which may involve and be limited to the genitals. Autoimmune disorders include Crohn disease and Behçet disease, and vulvar ulcers with an eschar, consistent with aphthous major or complex apotheosis, has been used to describe patients with severe recurrent oral and genital ulcerations without other systemic manifestations of Behçet disease.3
Genital ulcers are an uncommon manifestation of EBV infection. The formation of genital ulcers in EBV infection has been hypothesized to be due to immune complex formation during the acute phase that becomes activated in the vasculature, leading to microthrombosis and eventually necrosis of the tissue.4 The mode of transmission for EBV-related acute genital ulcers has been postulated to be hematogenous spread in lymphocytes or EBV shedding in the urine with subsequent transfer to the genital mucosa.5
Epstein-Barr virus-related acute genital ulcers are self-limiting. The average healing time for the ulcers is 14 to 18 days.6,7 Antivirals are ineffective in treating this condition; however, supportive treatment with systemic glucocorticoids for associated swelling and pain medications could be considered. Our patient was treated symptomatically. Two weeks after debridement, granulation tissue was noted at the site and her pain and discomfort had resolved. This case illustrates an uncommon manifestation of EBV in a sexually inactive adolescent and is a reminder for the dermatologist of the diverse spectrum of illness caused by this common virus.
The Diagnosis: Epstein-Barr Virus
Physical examination revealed bilateral 1-cm ulcerated lesions on the labia minora with vulvar edema (Figure). She had a palpable liver edge but no splenomegaly, oral ulcers or lesions, conjunctivitis or scleral icterus, or cervical or inguinal lymphadenopathy. A detailed genitourinary examination was performed under anesthesia, but the hymen was not commented on. Inflammatory markers were elevated with a C-reactive protein level of 16.4 mg/L (reference range, 0.08-3.1 mg/mL), erythrocyte sedimentation rate of39 mm/h (reference range, 0-20 mm/h), white blood cell count of 7.1×109/L (reference range, 4.5-11.0×109/L) with 57% neutrophils and 30% lymphocytes, an alanine aminotransferase level of 41 U/L (reference range, 10-40 U/L), and an aspartate aminotransferase level of 126 U/L (reference range, 10-30 U/L).
Bacterial and fungal cultures of vulvar tissue were negative as well as blood and urine cultures. Serological tests for herpes simplex virus (HSV), syphilis, and cytomegalovirus were negative, and urine testing for gonorrhea and chlamydia were negative. Serologies for Epstein-Barr virus (EBV) all were strongly positive with an EBV viral capsid antigen (VCA) IgM greater than 160 U/mL, early antigen IgG of 68 U/mL, and EBV VCA IgG of 456 U/mL. Two years after the initial presentation, repeat EBV serologies were obtained, showing a strongly positive EBV VCA IgG (>8.0 antibody index; reference range, 0-0.8), and a negative EBV VCA IgM.
Infectious etiologies of genital ulcers in a sexually active female include HSV, syphilis, lymphogranuloma venereum, and chancroid. Herpes simplex virus often is the assumed etiology of genital ulcers, especially in sexually active patients, and misdiagnosis in the setting of negative HSV testing may be high. Less common infectious causes such as mumps and cytomegalovirus also have been reported.1,2 Lichen planus and lichen sclerosus are noninfectious inflammatory causes, both of which may involve and be limited to the genitals. Autoimmune disorders include Crohn disease and Behçet disease, and vulvar ulcers with an eschar, consistent with aphthous major or complex apotheosis, has been used to describe patients with severe recurrent oral and genital ulcerations without other systemic manifestations of Behçet disease.3
Genital ulcers are an uncommon manifestation of EBV infection. The formation of genital ulcers in EBV infection has been hypothesized to be due to immune complex formation during the acute phase that becomes activated in the vasculature, leading to microthrombosis and eventually necrosis of the tissue.4 The mode of transmission for EBV-related acute genital ulcers has been postulated to be hematogenous spread in lymphocytes or EBV shedding in the urine with subsequent transfer to the genital mucosa.5
Epstein-Barr virus-related acute genital ulcers are self-limiting. The average healing time for the ulcers is 14 to 18 days.6,7 Antivirals are ineffective in treating this condition; however, supportive treatment with systemic glucocorticoids for associated swelling and pain medications could be considered. Our patient was treated symptomatically. Two weeks after debridement, granulation tissue was noted at the site and her pain and discomfort had resolved. This case illustrates an uncommon manifestation of EBV in a sexually inactive adolescent and is a reminder for the dermatologist of the diverse spectrum of illness caused by this common virus.
- Chanal J, Carlotti A, Laude H, et al. Lipschütz genital ulceration associated with mumps. Dermatology. 2010;221:292-295.
- Martin JM, Godoy R, Calduch L, et al. Lipschütz acute vulval ulcers associated with primary cytomegalovirus infection. Pediatr Dermatol. 2008;25:113-115.
- Huppert JS, Gerber MA, Deitch HR, et al. Vulvar ulcers in young females: a manifestation of aphthosis. J Pediatr Adolesc Gynecol. 2006;19:195-204.
- Sárdy M, Wollenberg A, Niedermeier A, et al. Genital ulcers associated with Epstein-Barr virus infection (ulcus vulvae acutum). Acta Derm Venereol. 2011;91:55-59.
- Di Lernia V, Mansouri Y. Epstein-Barr virus and skin manifestations in childhood. Int J Dermatol. 2013;52:1177-1184.
- Halvorsen JA, Brevig T, Aas T, et al. Genital ulcers as initial manifestation of Epstein-Barr virus infection: two new cases and a review of the literature. Acta Derm Venereol. 2006;86:439-442.
- Jerdan K, Aronson I, Hernandez C, et al. Genital ulcers associated with Epstein-Barr virus. Cutis. 2013;91:273-276.
- Chanal J, Carlotti A, Laude H, et al. Lipschütz genital ulceration associated with mumps. Dermatology. 2010;221:292-295.
- Martin JM, Godoy R, Calduch L, et al. Lipschütz acute vulval ulcers associated with primary cytomegalovirus infection. Pediatr Dermatol. 2008;25:113-115.
- Huppert JS, Gerber MA, Deitch HR, et al. Vulvar ulcers in young females: a manifestation of aphthosis. J Pediatr Adolesc Gynecol. 2006;19:195-204.
- Sárdy M, Wollenberg A, Niedermeier A, et al. Genital ulcers associated with Epstein-Barr virus infection (ulcus vulvae acutum). Acta Derm Venereol. 2011;91:55-59.
- Di Lernia V, Mansouri Y. Epstein-Barr virus and skin manifestations in childhood. Int J Dermatol. 2013;52:1177-1184.
- Halvorsen JA, Brevig T, Aas T, et al. Genital ulcers as initial manifestation of Epstein-Barr virus infection: two new cases and a review of the literature. Acta Derm Venereol. 2006;86:439-442.
- Jerdan K, Aronson I, Hernandez C, et al. Genital ulcers associated with Epstein-Barr virus. Cutis. 2013;91:273-276.
A 14-year-old previously healthy, postmenarcheal adolescent girl with a family history of thyroid disease and rheumatoid arthritis presented with vulvar pain and swelling. Vulvar pruritus was noted 6 days prior, which worsened and became associated with vulvar swelling, yellow vaginal discharge, difficulty walking, and a fever (temperature, 39.3.2 °C). Her condition did not improve after a course of cephalexin and trimethoprim-sulfamethoxazole. She denied being sexually active or exposing foreign objects or chemicals to the vaginal area.
Helping patients process sexual harassment
Years ago, after the revelation of sexual predations of male members of the U.S. Navy upon their female underlings, the Navy announced a “zero tolerance” policy. I, then the chair of the American Psychiatric Association Committee on Women, was invited to address a meeting of top Naval officers. They seemed dismayed when I told them that zero tolerance was just the beginning. Declarations that certain behaviors are unacceptable are facile, flimsy, and ultimately disingenuous substitutes for the infinitely more difficult task of monitoring and policing forbidden behaviors and protecting potential and actual victims.
The United States, I pointed out, has a zero tolerance policy on murder but still has to maintain a large force of police officers, detectives, judges, and prison guards to enforce that policy. The Navy had to have a similar approach to sexual assaults. Judging from the recent reports of female members of the military, that hasn’t happened.
Clarity in the law
Unwanted physical intrusion by one adult on another is against the law in the United States. Then why do we need laws specifically banning rape? In addition to the fact that rape, unlike any other assault, can result in conception, sexual assault is recognized as a particularly and uniquely evil and damaging invasion and degradation.
Although there are cultural differences about responsibility for rape, and whether marriage obviates a woman’s right to refuse sexual contact, there is little or no dispute about the need to recognize rape as a distinct, degrading, and particularly heinous attack. It is, therefore, no surprise that people who are raped feel soiled, shamed, and degraded. Those feelings are exacerbated by centuries of shifting responsibility for sexual assault, whether forced intercourse or other unwanted sexual behavior, from the perpetrator onto the victim.
The shifting of blame has been rejected in theory, but it very much persists in actuality. Who among us does not wonder how the victim was dressed or why (s)he was on that street, at that party, in that man’s room? Other forms of harassment echo the motivations of rape – to demonstrate the unanswerable power to degrade – and result in similar psychological responses.
The recent media revelations have lumped physical assault together with unwanted touching, sexual acts undergone as a result of psychological coercion, unwanted exposure to perpetrators’ genitalia and masturbation, and offensive sexual requests and comments. All of those acts are wrong, but they are not equivalent. An elderly man in a wheelchair grabbing an adult woman’s buttocks is not in the same category as an adult man sexually assaulting an underage girl.
What is the genesis of all this misbehavior? It’s not just about sex; it’s about sex and power. For many men, bragging about sexual conquests and making derogatory remarks about women’s physical appearance demonstrate machismo – define maleness.
It is not surprising that such comments are called “locker room talk”; sports are macho displays as well. Physically violating sexual boundaries is just the talk put into action. And macho works. Last November, more than 40% of female voters in the United States voted for the candidate who reportedly cheated on at least one of his three wives, bragged about unwanted sexual assault, and has been credibly accused of many other illegal and/or inappropriate behaviors.
Where does it end?
What is going to be the result of all this hullabaloo? The list of convincingly accused perpetrators grows by the day. Sexism and sexual misbehavior are endemic in every sphere of human endeavor, up to and including, of course, the clergy, who are meant to be models and protectors of virtue. The scope of recent revelations may be unusual, but revelations about one sector or another have happened every few years: the military, clergy, Wall Street, Silicon Valley, academia. What would happen if all the sexual misbehavior were to be revealed, and the perpetrators removed from their leadership and management positions? Would we have a film industry, a financial industry, a legislature? I saw a headline somewhere: “He’s always indispensable; you never are.” The argument, or myth, of indispensability is a powerful protection for powerful individuals. The powerful are too powerful to tolerate mass expulsions. Already, Congress has resorted to the time-honored and demonstrably useless response: training. Others among the accused report that they are undergoing treatment of sex addiction, a diagnosis our profession has wisely discarded, and for which there was no effective treatment.
Sex, while not addictive, does have a role in sexual misbehavior. Through the ages, women’s reproductive hormones have been a focus of social and medical attention, as the source of unpleasant behaviors, and, in fact, psychopathology: premenstrual dysphoric disorder, postpartum depression. Little or no attention has been paid to the problematic psychosocial effects of male reproductive hormones. In addition to the offensive behaviors currently in the headlines, there is the behavior of adolescent males. Isn’t reckless driving related to the pubertal influx of testosterone (Neurosci Biobehav Rev. 2006;30[3]:319-45)? This gender discrepancy deserves scientific and social attention.
What can psychiatrists do to help women (and men) who are affected by sexual misbehavior? This is a difficult problem. What would help most victims, of any injustice, most would be to confront those responsible, and see them removed from positions of power and otherwise punished. However, the recent reports of seemingly swift and severe responses are misleading. The responsible journalists who have reported these cases have, in most cases, devoted months to finding victimized women, persuading them to go public, and corroborating their accounts. The perpetrators, even when complaints have been made, have gone unpunished, and often been promoted, for years or even decades. Women who complain often are subject to employer retaliation.
So a treating psychiatrist is left with less-than-satisfactory recommendations and responses. The most important intervention is to identify and counter the patient’s inaccurate and damaging assumptions: that she was responsible, that she should and could have refused to tolerate the misbehavior, that she has been left tainted, impure. Some social groups and families will have reinforced the latter feeling. The remainder of the psychiatric intervention will be focused on the patient’s particular symptoms – of posttraumatic stress, anxiety, or depression – and the relationship between her symptoms, history, and psychodynamics. Group therapy or other support by women who have faced similar abuse may be helpful. I’m afraid that we will continue to have many such patients to treat.
Dr. Stotland, past president of the American Psychiatric Association, is professor of psychiatry, and obstetrics and gynecology, at Rush Medical College, Chicago. She has written numerous articles and books, including “Cutting Edge Medicine: What Psychiatrists Need to Know” (American Psychiatric Association Publishing, 2002).
Years ago, after the revelation of sexual predations of male members of the U.S. Navy upon their female underlings, the Navy announced a “zero tolerance” policy. I, then the chair of the American Psychiatric Association Committee on Women, was invited to address a meeting of top Naval officers. They seemed dismayed when I told them that zero tolerance was just the beginning. Declarations that certain behaviors are unacceptable are facile, flimsy, and ultimately disingenuous substitutes for the infinitely more difficult task of monitoring and policing forbidden behaviors and protecting potential and actual victims.
The United States, I pointed out, has a zero tolerance policy on murder but still has to maintain a large force of police officers, detectives, judges, and prison guards to enforce that policy. The Navy had to have a similar approach to sexual assaults. Judging from the recent reports of female members of the military, that hasn’t happened.
Clarity in the law
Unwanted physical intrusion by one adult on another is against the law in the United States. Then why do we need laws specifically banning rape? In addition to the fact that rape, unlike any other assault, can result in conception, sexual assault is recognized as a particularly and uniquely evil and damaging invasion and degradation.
Although there are cultural differences about responsibility for rape, and whether marriage obviates a woman’s right to refuse sexual contact, there is little or no dispute about the need to recognize rape as a distinct, degrading, and particularly heinous attack. It is, therefore, no surprise that people who are raped feel soiled, shamed, and degraded. Those feelings are exacerbated by centuries of shifting responsibility for sexual assault, whether forced intercourse or other unwanted sexual behavior, from the perpetrator onto the victim.
The shifting of blame has been rejected in theory, but it very much persists in actuality. Who among us does not wonder how the victim was dressed or why (s)he was on that street, at that party, in that man’s room? Other forms of harassment echo the motivations of rape – to demonstrate the unanswerable power to degrade – and result in similar psychological responses.
The recent media revelations have lumped physical assault together with unwanted touching, sexual acts undergone as a result of psychological coercion, unwanted exposure to perpetrators’ genitalia and masturbation, and offensive sexual requests and comments. All of those acts are wrong, but they are not equivalent. An elderly man in a wheelchair grabbing an adult woman’s buttocks is not in the same category as an adult man sexually assaulting an underage girl.
What is the genesis of all this misbehavior? It’s not just about sex; it’s about sex and power. For many men, bragging about sexual conquests and making derogatory remarks about women’s physical appearance demonstrate machismo – define maleness.
It is not surprising that such comments are called “locker room talk”; sports are macho displays as well. Physically violating sexual boundaries is just the talk put into action. And macho works. Last November, more than 40% of female voters in the United States voted for the candidate who reportedly cheated on at least one of his three wives, bragged about unwanted sexual assault, and has been credibly accused of many other illegal and/or inappropriate behaviors.
Where does it end?
What is going to be the result of all this hullabaloo? The list of convincingly accused perpetrators grows by the day. Sexism and sexual misbehavior are endemic in every sphere of human endeavor, up to and including, of course, the clergy, who are meant to be models and protectors of virtue. The scope of recent revelations may be unusual, but revelations about one sector or another have happened every few years: the military, clergy, Wall Street, Silicon Valley, academia. What would happen if all the sexual misbehavior were to be revealed, and the perpetrators removed from their leadership and management positions? Would we have a film industry, a financial industry, a legislature? I saw a headline somewhere: “He’s always indispensable; you never are.” The argument, or myth, of indispensability is a powerful protection for powerful individuals. The powerful are too powerful to tolerate mass expulsions. Already, Congress has resorted to the time-honored and demonstrably useless response: training. Others among the accused report that they are undergoing treatment of sex addiction, a diagnosis our profession has wisely discarded, and for which there was no effective treatment.
Sex, while not addictive, does have a role in sexual misbehavior. Through the ages, women’s reproductive hormones have been a focus of social and medical attention, as the source of unpleasant behaviors, and, in fact, psychopathology: premenstrual dysphoric disorder, postpartum depression. Little or no attention has been paid to the problematic psychosocial effects of male reproductive hormones. In addition to the offensive behaviors currently in the headlines, there is the behavior of adolescent males. Isn’t reckless driving related to the pubertal influx of testosterone (Neurosci Biobehav Rev. 2006;30[3]:319-45)? This gender discrepancy deserves scientific and social attention.
What can psychiatrists do to help women (and men) who are affected by sexual misbehavior? This is a difficult problem. What would help most victims, of any injustice, most would be to confront those responsible, and see them removed from positions of power and otherwise punished. However, the recent reports of seemingly swift and severe responses are misleading. The responsible journalists who have reported these cases have, in most cases, devoted months to finding victimized women, persuading them to go public, and corroborating their accounts. The perpetrators, even when complaints have been made, have gone unpunished, and often been promoted, for years or even decades. Women who complain often are subject to employer retaliation.
So a treating psychiatrist is left with less-than-satisfactory recommendations and responses. The most important intervention is to identify and counter the patient’s inaccurate and damaging assumptions: that she was responsible, that she should and could have refused to tolerate the misbehavior, that she has been left tainted, impure. Some social groups and families will have reinforced the latter feeling. The remainder of the psychiatric intervention will be focused on the patient’s particular symptoms – of posttraumatic stress, anxiety, or depression – and the relationship between her symptoms, history, and psychodynamics. Group therapy or other support by women who have faced similar abuse may be helpful. I’m afraid that we will continue to have many such patients to treat.
Dr. Stotland, past president of the American Psychiatric Association, is professor of psychiatry, and obstetrics and gynecology, at Rush Medical College, Chicago. She has written numerous articles and books, including “Cutting Edge Medicine: What Psychiatrists Need to Know” (American Psychiatric Association Publishing, 2002).
Years ago, after the revelation of sexual predations of male members of the U.S. Navy upon their female underlings, the Navy announced a “zero tolerance” policy. I, then the chair of the American Psychiatric Association Committee on Women, was invited to address a meeting of top Naval officers. They seemed dismayed when I told them that zero tolerance was just the beginning. Declarations that certain behaviors are unacceptable are facile, flimsy, and ultimately disingenuous substitutes for the infinitely more difficult task of monitoring and policing forbidden behaviors and protecting potential and actual victims.
The United States, I pointed out, has a zero tolerance policy on murder but still has to maintain a large force of police officers, detectives, judges, and prison guards to enforce that policy. The Navy had to have a similar approach to sexual assaults. Judging from the recent reports of female members of the military, that hasn’t happened.
Clarity in the law
Unwanted physical intrusion by one adult on another is against the law in the United States. Then why do we need laws specifically banning rape? In addition to the fact that rape, unlike any other assault, can result in conception, sexual assault is recognized as a particularly and uniquely evil and damaging invasion and degradation.
Although there are cultural differences about responsibility for rape, and whether marriage obviates a woman’s right to refuse sexual contact, there is little or no dispute about the need to recognize rape as a distinct, degrading, and particularly heinous attack. It is, therefore, no surprise that people who are raped feel soiled, shamed, and degraded. Those feelings are exacerbated by centuries of shifting responsibility for sexual assault, whether forced intercourse or other unwanted sexual behavior, from the perpetrator onto the victim.
The shifting of blame has been rejected in theory, but it very much persists in actuality. Who among us does not wonder how the victim was dressed or why (s)he was on that street, at that party, in that man’s room? Other forms of harassment echo the motivations of rape – to demonstrate the unanswerable power to degrade – and result in similar psychological responses.
The recent media revelations have lumped physical assault together with unwanted touching, sexual acts undergone as a result of psychological coercion, unwanted exposure to perpetrators’ genitalia and masturbation, and offensive sexual requests and comments. All of those acts are wrong, but they are not equivalent. An elderly man in a wheelchair grabbing an adult woman’s buttocks is not in the same category as an adult man sexually assaulting an underage girl.
What is the genesis of all this misbehavior? It’s not just about sex; it’s about sex and power. For many men, bragging about sexual conquests and making derogatory remarks about women’s physical appearance demonstrate machismo – define maleness.
It is not surprising that such comments are called “locker room talk”; sports are macho displays as well. Physically violating sexual boundaries is just the talk put into action. And macho works. Last November, more than 40% of female voters in the United States voted for the candidate who reportedly cheated on at least one of his three wives, bragged about unwanted sexual assault, and has been credibly accused of many other illegal and/or inappropriate behaviors.
Where does it end?
What is going to be the result of all this hullabaloo? The list of convincingly accused perpetrators grows by the day. Sexism and sexual misbehavior are endemic in every sphere of human endeavor, up to and including, of course, the clergy, who are meant to be models and protectors of virtue. The scope of recent revelations may be unusual, but revelations about one sector or another have happened every few years: the military, clergy, Wall Street, Silicon Valley, academia. What would happen if all the sexual misbehavior were to be revealed, and the perpetrators removed from their leadership and management positions? Would we have a film industry, a financial industry, a legislature? I saw a headline somewhere: “He’s always indispensable; you never are.” The argument, or myth, of indispensability is a powerful protection for powerful individuals. The powerful are too powerful to tolerate mass expulsions. Already, Congress has resorted to the time-honored and demonstrably useless response: training. Others among the accused report that they are undergoing treatment of sex addiction, a diagnosis our profession has wisely discarded, and for which there was no effective treatment.
Sex, while not addictive, does have a role in sexual misbehavior. Through the ages, women’s reproductive hormones have been a focus of social and medical attention, as the source of unpleasant behaviors, and, in fact, psychopathology: premenstrual dysphoric disorder, postpartum depression. Little or no attention has been paid to the problematic psychosocial effects of male reproductive hormones. In addition to the offensive behaviors currently in the headlines, there is the behavior of adolescent males. Isn’t reckless driving related to the pubertal influx of testosterone (Neurosci Biobehav Rev. 2006;30[3]:319-45)? This gender discrepancy deserves scientific and social attention.
What can psychiatrists do to help women (and men) who are affected by sexual misbehavior? This is a difficult problem. What would help most victims, of any injustice, most would be to confront those responsible, and see them removed from positions of power and otherwise punished. However, the recent reports of seemingly swift and severe responses are misleading. The responsible journalists who have reported these cases have, in most cases, devoted months to finding victimized women, persuading them to go public, and corroborating their accounts. The perpetrators, even when complaints have been made, have gone unpunished, and often been promoted, for years or even decades. Women who complain often are subject to employer retaliation.
So a treating psychiatrist is left with less-than-satisfactory recommendations and responses. The most important intervention is to identify and counter the patient’s inaccurate and damaging assumptions: that she was responsible, that she should and could have refused to tolerate the misbehavior, that she has been left tainted, impure. Some social groups and families will have reinforced the latter feeling. The remainder of the psychiatric intervention will be focused on the patient’s particular symptoms – of posttraumatic stress, anxiety, or depression – and the relationship between her symptoms, history, and psychodynamics. Group therapy or other support by women who have faced similar abuse may be helpful. I’m afraid that we will continue to have many such patients to treat.
Dr. Stotland, past president of the American Psychiatric Association, is professor of psychiatry, and obstetrics and gynecology, at Rush Medical College, Chicago. She has written numerous articles and books, including “Cutting Edge Medicine: What Psychiatrists Need to Know” (American Psychiatric Association Publishing, 2002).
Retinal changes may reflect brain changes in preclinical Alzheimer’s
BOSTON – Changes in the retina seem to mirror changes that begin to reshape the brain in preclinical Alzheimer’s disease.
Manifested as a reduction in volume in the retinal nerve fiber layer, these changes appear to track the aggregation of beta amyloid brain plaques well before cognitive problems arise – and can be easily measured with a piece of equipment already in many optometry offices, Peter J. Snyder, PhD, said at the Clinical Trials in Alzheimer’s Disease conference.
“If we are lucky enough to live past age 45, then it’s a given that we’re all going to develop some presbyopia. So we all have to go to the optometrist sometime, and that may become a point of entry for broad screening and to track changes over time, to keep an eye on at-risk patients, and to refer those with retinal changes that fit the preclinical AD profile to specialty care for more comprehensive diagnostic evaluations.”
The retina begins to form in the third week of embryologic life, arising from the neural tube cells that also form the brain and spinal cord. It makes sense then that very early neuronal changes in Alzheimer’s disease could be occurring in the retina as well, said Dr. Snyder, professor of neurology and surgery (ophthalmology) at Rhode Island Hospital and Brown University, Providence.
“The retina is really a protrusion of the brain, and it is part and parcel of the central nervous system. In terms of the neuronal structure, the retina develops in layers with very specific cell types that are neurochemically and physiologically the same as the nervous tissue in the brain. That’s why it is, potentially, literally a window that could let us see what’s happening in the brain in early Alzheimer’s disease.”
Other researchers have explored amyloid in the lens and retina as a possible early Alzheimer’s identification tool. But Dr. Snyder’s study is the first to demonstrate a longitudinal association between neuronal changes in the eye and amyloid burden in the brain among clinically normal subjects.
For 27 months, he followed 56 people who had normal cognition but were beginning to experience subjective memory complaints. All subjects had at least one parent with Alzheimer’s disease. Everyone underwent an amyloid PET scan at baseline. Of the cohort, 15 had PET imaging evidence of abnormal beta-amyloid protein aggregation in the neocortex. This group was deemed to have preclinical Alzheimer’s disease, while the remainder served as a control group.
Dr. Snyder imaged each subject’s retinas twice – once at baseline and once at 27 months, when everyone underwent a second amyloid PET scan as well. He examined the retina with spectral domain optical coherence tomography, a relatively new method of imaging the retina.
These scanners are becoming increasingly more common in optometry practices, Dr. Snyder said. “Graduate optometrists tell me they would not want to be in a practice without one.” The scanners are typically used to detect retinal and ocular changes associated with diabetes, macular degeneration, glaucoma and multiple sclerosis.
Dr. Snyder used the scanner to examine the optic nerve head and macula at both baseline and 27 months in his cohort. He was looking for volumetric changes in several of the retinal layers: the peripapillary retinal nerve fiber layer (pRNFL), macular RNFL (mRNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), outer nuclear layer (ONL), outer plexiform layer (OPL), and inner nuclear layer (INL). He also computed changes in total retinal volume.
Even at baseline, he found a significant difference between the groups. Among the amyloid-positive subjects, the inner plexiform layer was slightly larger in volume. “This seems a bit counterintuitive, but I think it suggests that there may be some inflammatory processes going on in this early stage and that we are catching that inflammation.”
Dr. Snyder noted that this finding has recently been replicated by an independent research group in Perth, Australia – with a much larger sample of participants – and will be reported at international conferences this coming year.
At 27 months, both the total retinal volume and the macular retinal nerve fiber layer volume were significantly lower in the preclinical AD group than in the control group. There was also a volume reduction in the peripapillary retinal nerve fiber layer, although the between-group difference was not statistically significant.
In a multivariate linear regression model that controlled for age and total amyloid burden, the mean volume change in the macular retinal nerve fiber layer accounted for about 10% of the variation in PET binding to brain amyloid by 27 months. Volume reductions in all the other layers appeared to be associated only with age, representing normal age-related changes in the eye.
Dr. Snyder said this volume loss in the retinal nerve fiber layer probably represents early demyelination and/or degeneration of the axons coursing from the cell bodies in the ganglion cell layer, which project to the optic nerve head.
“This finding in the retina appears analogous, and possibly directly related to, a similar loss of white matter that is readily observable in the early stages of Alzheimer’s disease. At the same time, patients are beginning to experience both cholinergic changes in the basal forebrain and the abnormal aggregation of fibrillar beta-amyloid plaques. I don’t know to what extent these changes are mechanistically dependent on each other, but they appear to also be happening, in the earliest stages of the disease course, in the retina.”
There is a lot of work left to be done before retinal scanning could be employed as a risk-assessment tool, however. With every new biomarker – and especially with imaging – the ability to measure change occurs far in advance of an understanding of what those changes mean, and how to judge them accurately.
“Every time we have a major advance in imaging, the technical engineering breakthroughs precede our detailed understanding of what we’re looking at and what to measure. This is where we are right now with retinal imaging. Biologically, it makes sense to be looking at this as a marker of risk in those who are clinically healthy, and maybe later as a marker of disease progression. But there is a lot of work to be done here yet.”
Dr. Snyder’s project was funded in part by a research award from Pfizer, with PET imaging supported in part by a grant from Avid Radiopharmaceuticals. He has no financial ties to the company, or other financial interest related to the study.
[email protected]
On Twitter @Alz_Gal
BOSTON – Changes in the retina seem to mirror changes that begin to reshape the brain in preclinical Alzheimer’s disease.
Manifested as a reduction in volume in the retinal nerve fiber layer, these changes appear to track the aggregation of beta amyloid brain plaques well before cognitive problems arise – and can be easily measured with a piece of equipment already in many optometry offices, Peter J. Snyder, PhD, said at the Clinical Trials in Alzheimer’s Disease conference.
“If we are lucky enough to live past age 45, then it’s a given that we’re all going to develop some presbyopia. So we all have to go to the optometrist sometime, and that may become a point of entry for broad screening and to track changes over time, to keep an eye on at-risk patients, and to refer those with retinal changes that fit the preclinical AD profile to specialty care for more comprehensive diagnostic evaluations.”
The retina begins to form in the third week of embryologic life, arising from the neural tube cells that also form the brain and spinal cord. It makes sense then that very early neuronal changes in Alzheimer’s disease could be occurring in the retina as well, said Dr. Snyder, professor of neurology and surgery (ophthalmology) at Rhode Island Hospital and Brown University, Providence.
“The retina is really a protrusion of the brain, and it is part and parcel of the central nervous system. In terms of the neuronal structure, the retina develops in layers with very specific cell types that are neurochemically and physiologically the same as the nervous tissue in the brain. That’s why it is, potentially, literally a window that could let us see what’s happening in the brain in early Alzheimer’s disease.”
Other researchers have explored amyloid in the lens and retina as a possible early Alzheimer’s identification tool. But Dr. Snyder’s study is the first to demonstrate a longitudinal association between neuronal changes in the eye and amyloid burden in the brain among clinically normal subjects.
For 27 months, he followed 56 people who had normal cognition but were beginning to experience subjective memory complaints. All subjects had at least one parent with Alzheimer’s disease. Everyone underwent an amyloid PET scan at baseline. Of the cohort, 15 had PET imaging evidence of abnormal beta-amyloid protein aggregation in the neocortex. This group was deemed to have preclinical Alzheimer’s disease, while the remainder served as a control group.
Dr. Snyder imaged each subject’s retinas twice – once at baseline and once at 27 months, when everyone underwent a second amyloid PET scan as well. He examined the retina with spectral domain optical coherence tomography, a relatively new method of imaging the retina.
These scanners are becoming increasingly more common in optometry practices, Dr. Snyder said. “Graduate optometrists tell me they would not want to be in a practice without one.” The scanners are typically used to detect retinal and ocular changes associated with diabetes, macular degeneration, glaucoma and multiple sclerosis.
Dr. Snyder used the scanner to examine the optic nerve head and macula at both baseline and 27 months in his cohort. He was looking for volumetric changes in several of the retinal layers: the peripapillary retinal nerve fiber layer (pRNFL), macular RNFL (mRNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), outer nuclear layer (ONL), outer plexiform layer (OPL), and inner nuclear layer (INL). He also computed changes in total retinal volume.
Even at baseline, he found a significant difference between the groups. Among the amyloid-positive subjects, the inner plexiform layer was slightly larger in volume. “This seems a bit counterintuitive, but I think it suggests that there may be some inflammatory processes going on in this early stage and that we are catching that inflammation.”
Dr. Snyder noted that this finding has recently been replicated by an independent research group in Perth, Australia – with a much larger sample of participants – and will be reported at international conferences this coming year.
At 27 months, both the total retinal volume and the macular retinal nerve fiber layer volume were significantly lower in the preclinical AD group than in the control group. There was also a volume reduction in the peripapillary retinal nerve fiber layer, although the between-group difference was not statistically significant.
In a multivariate linear regression model that controlled for age and total amyloid burden, the mean volume change in the macular retinal nerve fiber layer accounted for about 10% of the variation in PET binding to brain amyloid by 27 months. Volume reductions in all the other layers appeared to be associated only with age, representing normal age-related changes in the eye.
Dr. Snyder said this volume loss in the retinal nerve fiber layer probably represents early demyelination and/or degeneration of the axons coursing from the cell bodies in the ganglion cell layer, which project to the optic nerve head.
“This finding in the retina appears analogous, and possibly directly related to, a similar loss of white matter that is readily observable in the early stages of Alzheimer’s disease. At the same time, patients are beginning to experience both cholinergic changes in the basal forebrain and the abnormal aggregation of fibrillar beta-amyloid plaques. I don’t know to what extent these changes are mechanistically dependent on each other, but they appear to also be happening, in the earliest stages of the disease course, in the retina.”
There is a lot of work left to be done before retinal scanning could be employed as a risk-assessment tool, however. With every new biomarker – and especially with imaging – the ability to measure change occurs far in advance of an understanding of what those changes mean, and how to judge them accurately.
“Every time we have a major advance in imaging, the technical engineering breakthroughs precede our detailed understanding of what we’re looking at and what to measure. This is where we are right now with retinal imaging. Biologically, it makes sense to be looking at this as a marker of risk in those who are clinically healthy, and maybe later as a marker of disease progression. But there is a lot of work to be done here yet.”
Dr. Snyder’s project was funded in part by a research award from Pfizer, with PET imaging supported in part by a grant from Avid Radiopharmaceuticals. He has no financial ties to the company, or other financial interest related to the study.
[email protected]
On Twitter @Alz_Gal
BOSTON – Changes in the retina seem to mirror changes that begin to reshape the brain in preclinical Alzheimer’s disease.
Manifested as a reduction in volume in the retinal nerve fiber layer, these changes appear to track the aggregation of beta amyloid brain plaques well before cognitive problems arise – and can be easily measured with a piece of equipment already in many optometry offices, Peter J. Snyder, PhD, said at the Clinical Trials in Alzheimer’s Disease conference.
“If we are lucky enough to live past age 45, then it’s a given that we’re all going to develop some presbyopia. So we all have to go to the optometrist sometime, and that may become a point of entry for broad screening and to track changes over time, to keep an eye on at-risk patients, and to refer those with retinal changes that fit the preclinical AD profile to specialty care for more comprehensive diagnostic evaluations.”
The retina begins to form in the third week of embryologic life, arising from the neural tube cells that also form the brain and spinal cord. It makes sense then that very early neuronal changes in Alzheimer’s disease could be occurring in the retina as well, said Dr. Snyder, professor of neurology and surgery (ophthalmology) at Rhode Island Hospital and Brown University, Providence.
“The retina is really a protrusion of the brain, and it is part and parcel of the central nervous system. In terms of the neuronal structure, the retina develops in layers with very specific cell types that are neurochemically and physiologically the same as the nervous tissue in the brain. That’s why it is, potentially, literally a window that could let us see what’s happening in the brain in early Alzheimer’s disease.”
Other researchers have explored amyloid in the lens and retina as a possible early Alzheimer’s identification tool. But Dr. Snyder’s study is the first to demonstrate a longitudinal association between neuronal changes in the eye and amyloid burden in the brain among clinically normal subjects.
For 27 months, he followed 56 people who had normal cognition but were beginning to experience subjective memory complaints. All subjects had at least one parent with Alzheimer’s disease. Everyone underwent an amyloid PET scan at baseline. Of the cohort, 15 had PET imaging evidence of abnormal beta-amyloid protein aggregation in the neocortex. This group was deemed to have preclinical Alzheimer’s disease, while the remainder served as a control group.
Dr. Snyder imaged each subject’s retinas twice – once at baseline and once at 27 months, when everyone underwent a second amyloid PET scan as well. He examined the retina with spectral domain optical coherence tomography, a relatively new method of imaging the retina.
These scanners are becoming increasingly more common in optometry practices, Dr. Snyder said. “Graduate optometrists tell me they would not want to be in a practice without one.” The scanners are typically used to detect retinal and ocular changes associated with diabetes, macular degeneration, glaucoma and multiple sclerosis.
Dr. Snyder used the scanner to examine the optic nerve head and macula at both baseline and 27 months in his cohort. He was looking for volumetric changes in several of the retinal layers: the peripapillary retinal nerve fiber layer (pRNFL), macular RNFL (mRNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), outer nuclear layer (ONL), outer plexiform layer (OPL), and inner nuclear layer (INL). He also computed changes in total retinal volume.
Even at baseline, he found a significant difference between the groups. Among the amyloid-positive subjects, the inner plexiform layer was slightly larger in volume. “This seems a bit counterintuitive, but I think it suggests that there may be some inflammatory processes going on in this early stage and that we are catching that inflammation.”
Dr. Snyder noted that this finding has recently been replicated by an independent research group in Perth, Australia – with a much larger sample of participants – and will be reported at international conferences this coming year.
At 27 months, both the total retinal volume and the macular retinal nerve fiber layer volume were significantly lower in the preclinical AD group than in the control group. There was also a volume reduction in the peripapillary retinal nerve fiber layer, although the between-group difference was not statistically significant.
In a multivariate linear regression model that controlled for age and total amyloid burden, the mean volume change in the macular retinal nerve fiber layer accounted for about 10% of the variation in PET binding to brain amyloid by 27 months. Volume reductions in all the other layers appeared to be associated only with age, representing normal age-related changes in the eye.
Dr. Snyder said this volume loss in the retinal nerve fiber layer probably represents early demyelination and/or degeneration of the axons coursing from the cell bodies in the ganglion cell layer, which project to the optic nerve head.
“This finding in the retina appears analogous, and possibly directly related to, a similar loss of white matter that is readily observable in the early stages of Alzheimer’s disease. At the same time, patients are beginning to experience both cholinergic changes in the basal forebrain and the abnormal aggregation of fibrillar beta-amyloid plaques. I don’t know to what extent these changes are mechanistically dependent on each other, but they appear to also be happening, in the earliest stages of the disease course, in the retina.”
There is a lot of work left to be done before retinal scanning could be employed as a risk-assessment tool, however. With every new biomarker – and especially with imaging – the ability to measure change occurs far in advance of an understanding of what those changes mean, and how to judge them accurately.
“Every time we have a major advance in imaging, the technical engineering breakthroughs precede our detailed understanding of what we’re looking at and what to measure. This is where we are right now with retinal imaging. Biologically, it makes sense to be looking at this as a marker of risk in those who are clinically healthy, and maybe later as a marker of disease progression. But there is a lot of work to be done here yet.”
Dr. Snyder’s project was funded in part by a research award from Pfizer, with PET imaging supported in part by a grant from Avid Radiopharmaceuticals. He has no financial ties to the company, or other financial interest related to the study.
[email protected]
On Twitter @Alz_Gal
AT CTAD
Key clinical point: Retinal scans might eventually be an easy, noninvasive, and inexpensive way to tag people who may be at elevated risk for Alzheimer’s disease.
Major finding: At 27 months, both the total retinal volume and the macular retinal nerve fiber layer volume were significantly lower in 15 patients in the preclinical AD group than in the 41 patients in the control group.
Data source: A follow-up study of 56 people who had at least one parent with Alzheimer’s disease and were beginning to experience subjective memory complaints.
Disclosures: Dr. Snyder’s project was funded in part by a research award from Pfizer, with PET imaging supported in part by a grant from Avid Radiopharmaceuticals. He has no financial ties to the company, or other financial interest related to the study.