Behind the competition and pageantry of the 2016 Summer Olympics and Paralympics in Rio de Janeiro, researchers at the University of Utah will be busy monitoring a subset of athletes, coaches, and other U.S. Olympic Committee staff for potential Zika virus exposure.

“Of everyone I talk to who’s at risk for Zika virus, their No. 1 question is, what are the risks to my reproductive health?” said the study’s principal investigator Carrie L. Byington, MD, a pediatrician and infectious disease specialist who is codirector of Utah Center for Clinical and Translational Science at the University of Utah in Salt Lake City. “Can I have a healthy baby? How can I protect that opportunity to reproduce? We are dedicated to trying to find some answers.”

In a study funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Dr. Byington and a team of six other clinicians will recruit up to 1,000 athletes, coaches, and other U.S. Olympic Committee (USOC) staff attending the games to complete health surveys and undergo pre- and post-travel periodic antibody testing for Zika virus, a mosquito-borne flavivirus that has emerged in the Americas with local transmission identified in 30 countries and territories as of April 2016, including Brazil. From that group they expect to identify infected individuals. “Hopefully, it’s a very small proportion of the group but we think that we will identify some, because it is going to be impossible to prevent all mosquito exposure, even over the short term,” Dr. Byington said. Those found to harbor Zika virus by antibody testing will be followed for up to 2 years and will be asked to submit self-collected samples of blood, urine, saliva, semen, and vaginal secretions monthly. Affected individuals who wish to conceive after the games will have access to the study personnel, who include four infectious disease specialists, two obstetrician-gynecologists, and a laboratory expert. “We will have monthly testing and direct consultation with them regarding their test results and help them make the best reproductive decisions they can,” Dr. Byington said.

In April 2016, the Centers for Disease Control and Prevention confirmed that fetal infection with Zika virus was the cause of microcephaly and other severe brain anomalies that result in permanent morbidity in surviving infants. According to a description of the current study published by the National Institutes of Health, many questions remain regarding infection with Zika virus, including the duration and potential for sexual or perinatal transmission from body fluids; the short and long-term reproductive outcomes of individuals infected with Zika virus; and the outcomes for infants born to men and women with either symptomatic or asymptomatic Zika virus infection. The researchers consider each study participant as equally susceptible to Zika virus exposure, regardless of his or her sport or role with the USOC. “People will be both indoors and outdoors, and these are indoor-dwelling mosquitoes, so I don’t think we can completely eliminate the risk for any type of traveler,” Dr. Byington said. “We’re very interested in the water venues, but we’re also concerned about standing water outside other venues or hotel rooms.” If a study participant falls ill in Rio de Janeiro with symptoms consistent with Zika virus, USOC medical personnel will send samples of blood, urine, and saliva to the Utah-based research team for confirmatory polymerase chain reaction testing.

The idea for the current study grew out of a pilot trial that Dr. Byington and her associates conducted in 150 individuals affiliated with the USOC who were traveling back and forth to Brazil in preparation for the games during March and April of 2016. It enabled the researchers to develop online web-based tools for consenting, tracking, and returning test results. “It allowed us to do some work with our laboratory facilities for shipping and receiving specimens and processing and running specimens and returning some results,” Dr. Byington said. “That work has been really important. We found that about one-third of our pilot was interested in becoming pregnant very shortly after the games, so that was very important information that we were able to share with the USOC and the NIH. This is a group that is very interested in their reproductive health, which makes an ideal cohort for the study.”

David Turok, MD, an ob.gyn. and member of the research team, planned long ago to attend the Olympic Games in Rio as a spectator with his wife and 14-year-old son. He intends to carry out those plans and described the current study as a unique opportunity to better understand the Zika virus. “The need for data on the topic is pressing,” said Dr. Turok, who directs the family planning fellowship at the University of Utah. “People who are Olympic athletes and coaches are probably more likely to plan their lives. We know from a wealth of epidemiologic data that people who plan their pregnancies have better outcomes. This is something that our society has done a really poor job in communicating: the challenges of parenting and the benefits of planning pregnancy and making the most effective methods of contraception available. This study is an opportunity to better our game. There’s probably no better opportunity for prospective evaluation of a group of people who we know are going to have some exposure [to Zika virus]. The known exposure and the known desired outcome make it a unique opportunity.”

The 2016 Summer Olympics will take place in Rio de Janeiro Aug. 5-21, while the Paralympic Games take place Sept. 7-18. Dr. Byington said that she hopes to be able to share preliminary study results with the public sometime in October.

Behind the competition and pageantry of the 2016 Summer Olympics and Paralympics in Rio de Janeiro, researchers at the University of Utah will be busy monitoring a subset of athletes, coaches, and other U.S. Olympic Committee staff for potential Zika virus exposure.

“Of everyone I talk to who’s at risk for Zika virus, their No. 1 question is, what are the risks to my reproductive health?” said the study’s principal investigator Carrie L. Byington, MD, a pediatrician and infectious disease specialist who is codirector of Utah Center for Clinical and Translational Science at the University of Utah in Salt Lake City. “Can I have a healthy baby? How can I protect that opportunity to reproduce? We are dedicated to trying to find some answers.”

In a study funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Dr. Byington and a team of six other clinicians will recruit up to 1,000 athletes, coaches, and other U.S. Olympic Committee (USOC) staff attending the games to complete health surveys and undergo pre- and post-travel periodic antibody testing for Zika virus, a mosquito-borne flavivirus that has emerged in the Americas with local transmission identified in 30 countries and territories as of April 2016, including Brazil. From that group they expect to identify infected individuals. “Hopefully, it’s a very small proportion of the group but we think that we will identify some, because it is going to be impossible to prevent all mosquito exposure, even over the short term,” Dr. Byington said. Those found to harbor Zika virus by antibody testing will be followed for up to 2 years and will be asked to submit self-collected samples of blood, urine, saliva, semen, and vaginal secretions monthly. Affected individuals who wish to conceive after the games will have access to the study personnel, who include four infectious disease specialists, two obstetrician-gynecologists, and a laboratory expert. “We will have monthly testing and direct consultation with them regarding their test results and help them make the best reproductive decisions they can,” Dr. Byington said.

In April 2016, the Centers for Disease Control and Prevention confirmed that fetal infection with Zika virus was the cause of microcephaly and other severe brain anomalies that result in permanent morbidity in surviving infants. According to a description of the current study published by the National Institutes of Health, many questions remain regarding infection with Zika virus, including the duration and potential for sexual or perinatal transmission from body fluids; the short and long-term reproductive outcomes of individuals infected with Zika virus; and the outcomes for infants born to men and women with either symptomatic or asymptomatic Zika virus infection. The researchers consider each study participant as equally susceptible to Zika virus exposure, regardless of his or her sport or role with the USOC. “People will be both indoors and outdoors, and these are indoor-dwelling mosquitoes, so I don’t think we can completely eliminate the risk for any type of traveler,” Dr. Byington said. “We’re very interested in the water venues, but we’re also concerned about standing water outside other venues or hotel rooms.” If a study participant falls ill in Rio de Janeiro with symptoms consistent with Zika virus, USOC medical personnel will send samples of blood, urine, and saliva to the Utah-based research team for confirmatory polymerase chain reaction testing.

The idea for the current study grew out of a pilot trial that Dr. Byington and her associates conducted in 150 individuals affiliated with the USOC who were traveling back and forth to Brazil in preparation for the games during March and April of 2016. It enabled the researchers to develop online web-based tools for consenting, tracking, and returning test results. “It allowed us to do some work with our laboratory facilities for shipping and receiving specimens and processing and running specimens and returning some results,” Dr. Byington said. “That work has been really important. We found that about one-third of our pilot was interested in becoming pregnant very shortly after the games, so that was very important information that we were able to share with the USOC and the NIH. This is a group that is very interested in their reproductive health, which makes an ideal cohort for the study.”

David Turok, MD, an ob.gyn. and member of the research team, planned long ago to attend the Olympic Games in Rio as a spectator with his wife and 14-year-old son. He intends to carry out those plans and described the current study as a unique opportunity to better understand the Zika virus. “The need for data on the topic is pressing,” said Dr. Turok, who directs the family planning fellowship at the University of Utah. “People who are Olympic athletes and coaches are probably more likely to plan their lives. We know from a wealth of epidemiologic data that people who plan their pregnancies have better outcomes. This is something that our society has done a really poor job in communicating: the challenges of parenting and the benefits of planning pregnancy and making the most effective methods of contraception available. This study is an opportunity to better our game. There’s probably no better opportunity for prospective evaluation of a group of people who we know are going to have some exposure [to Zika virus]. The known exposure and the known desired outcome make it a unique opportunity.”

The 2016 Summer Olympics will take place in Rio de Janeiro Aug. 5-21, while the Paralympic Games take place Sept. 7-18. Dr. Byington said that she hopes to be able to share preliminary study results with the public sometime in October.

Behind the competition and pageantry of the 2016 Summer Olympics and Paralympics in Rio de Janeiro, researchers at the University of Utah will be busy monitoring a subset of athletes, coaches, and other U.S. Olympic Committee staff for potential Zika virus exposure.

“Of everyone I talk to who’s at risk for Zika virus, their No. 1 question is, what are the risks to my reproductive health?” said the study’s principal investigator Carrie L. Byington, MD, a pediatrician and infectious disease specialist who is codirector of Utah Center for Clinical and Translational Science at the University of Utah in Salt Lake City. “Can I have a healthy baby? How can I protect that opportunity to reproduce? We are dedicated to trying to find some answers.”

In a study funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Dr. Byington and a team of six other clinicians will recruit up to 1,000 athletes, coaches, and other U.S. Olympic Committee (USOC) staff attending the games to complete health surveys and undergo pre- and post-travel periodic antibody testing for Zika virus, a mosquito-borne flavivirus that has emerged in the Americas with local transmission identified in 30 countries and territories as of April 2016, including Brazil. From that group they expect to identify infected individuals. “Hopefully, it’s a very small proportion of the group but we think that we will identify some, because it is going to be impossible to prevent all mosquito exposure, even over the short term,” Dr. Byington said. Those found to harbor Zika virus by antibody testing will be followed for up to 2 years and will be asked to submit self-collected samples of blood, urine, saliva, semen, and vaginal secretions monthly. Affected individuals who wish to conceive after the games will have access to the study personnel, who include four infectious disease specialists, two obstetrician-gynecologists, and a laboratory expert. “We will have monthly testing and direct consultation with them regarding their test results and help them make the best reproductive decisions they can,” Dr. Byington said.

In April 2016, the Centers for Disease Control and Prevention confirmed that fetal infection with Zika virus was the cause of microcephaly and other severe brain anomalies that result in permanent morbidity in surviving infants. According to a description of the current study published by the National Institutes of Health, many questions remain regarding infection with Zika virus, including the duration and potential for sexual or perinatal transmission from body fluids; the short and long-term reproductive outcomes of individuals infected with Zika virus; and the outcomes for infants born to men and women with either symptomatic or asymptomatic Zika virus infection. The researchers consider each study participant as equally susceptible to Zika virus exposure, regardless of his or her sport or role with the USOC. “People will be both indoors and outdoors, and these are indoor-dwelling mosquitoes, so I don’t think we can completely eliminate the risk for any type of traveler,” Dr. Byington said. “We’re very interested in the water venues, but we’re also concerned about standing water outside other venues or hotel rooms.” If a study participant falls ill in Rio de Janeiro with symptoms consistent with Zika virus, USOC medical personnel will send samples of blood, urine, and saliva to the Utah-based research team for confirmatory polymerase chain reaction testing.

The idea for the current study grew out of a pilot trial that Dr. Byington and her associates conducted in 150 individuals affiliated with the USOC who were traveling back and forth to Brazil in preparation for the games during March and April of 2016. It enabled the researchers to develop online web-based tools for consenting, tracking, and returning test results. “It allowed us to do some work with our laboratory facilities for shipping and receiving specimens and processing and running specimens and returning some results,” Dr. Byington said. “That work has been really important. We found that about one-third of our pilot was interested in becoming pregnant very shortly after the games, so that was very important information that we were able to share with the USOC and the NIH. This is a group that is very interested in their reproductive health, which makes an ideal cohort for the study.”

David Turok, MD, an ob.gyn. and member of the research team, planned long ago to attend the Olympic Games in Rio as a spectator with his wife and 14-year-old son. He intends to carry out those plans and described the current study as a unique opportunity to better understand the Zika virus. “The need for data on the topic is pressing,” said Dr. Turok, who directs the family planning fellowship at the University of Utah. “People who are Olympic athletes and coaches are probably more likely to plan their lives. We know from a wealth of epidemiologic data that people who plan their pregnancies have better outcomes. This is something that our society has done a really poor job in communicating: the challenges of parenting and the benefits of planning pregnancy and making the most effective methods of contraception available. This study is an opportunity to better our game. There’s probably no better opportunity for prospective evaluation of a group of people who we know are going to have some exposure [to Zika virus]. The known exposure and the known desired outcome make it a unique opportunity.”

The 2016 Summer Olympics will take place in Rio de Janeiro Aug. 5-21, while the Paralympic Games take place Sept. 7-18. Dr. Byington said that she hopes to be able to share preliminary study results with the public sometime in October.

Vaginal cuff dehiscence, or separation of the vaginal incision, is a rare postoperative complication unique to hysterectomy. Morbidity related to evisceration of abdominal contents can be profound and prompt intervention is required.

A 10-year observational study of 11,000 patients described a 0.24% cumulative incidence after all modes of hysterectomy.¹ Though data are varied, the mode of hysterectomy does have an impact on the risk of dehiscence.

Laparoscopic (0.64%-1.35%) and robotic (0.46%-1.5%) hysterectomy have a higher incidence than abdominal (0.15%-0.26%) and vaginal (0.08%-0.25%) approaches.² The use of monopolar cautery for colpotomy and different closure techniques may account for these differences.

Cuff cellulitis, early sexual intercourse, cigarette smoking, poor nutrition, obesity, menopausal status, and corticosteroid use are all proposed risk factors that promote infection, pressure at the vaginal cuff, and poor wound healing. Although some are modifiable, the rarity of this complication has made establishing causality and promoting prevention challenging.

Prevention

• Preoperatively. Treating bacterial vaginosis, Trichomonas vaginalis, gonorrhea, and chlamydia can decrease the risk of cuff cellulitis and dehiscence.³

• Intraoperatively. Surgeons should ensure adequate vaginal margins (greater than 1 cm) with full-thickness cuff closures while avoiding excessive electrocautery.⁴ Retrospective data show that transvaginal cuff closure is associated with a decreased risk of dehiscence.⁵ However, given the lack of randomized data and the difficulty controlling for surgeon experience, gynecologists should use the approach that they are most comfortable with. Though the various laparoscopic cuff closure techniques have limited evidence regarding superiority, some experts propose using two-layer cuff closure and barbed sutures.^6-8 Several retrospective studies have found an equivalent or a decreased incidence of cuff dehiscence with barbed sutures, compared with other methods (e.g., 0-Vicryl, Endo Stitch).^9,10

• Postoperatively. Women should avoid intercourse and lifting more than 15 pounds for at least 6-8 weeks as the vaginal cuff gains tensile strength. Vaginal estrogen can promote healing in postmenopausal patients.¹¹

Management

Patients with vaginal cuff dehiscence commonly present within the first several weeks to months after surgery with pelvic pain (60%-100%), vaginal bleeding (30%-60%), vaginal discharge (30%), or vaginal pressure/mass (30%).^1,7 Posthysterectomy patients with these complaints warrant an urgent evaluation. The diagnosis is made during a pelvic exam.

Broad-spectrum antibiotics are necessary because all vaginal cuff separations or dehiscences expose the peritoneal cavity to vaginal flora. Nonsurgical management is reasonable for small separations – less than 25% of the cuff – if there is no evidence of evisceration.

However, surgically closing all recognized cuff dehiscences is reasonable, given the potential for further separation. A vaginal approach is preferred when possible. Women with vaginal cuff dehiscence, stable vital signs, and no evidence of bowel evisceration can be repaired vaginally without an abdominal survey.

In contrast, women with bowel evisceration have a surgical emergency because of the risk of peritonitis and bowel injury. If the eviscerated bowel is not reducible, it should be irrigated and wrapped in a warm moist towel or gauze in preparation for inspection and reduction in the operating room. If the bowel is reducible, the patient can be placed in Trendelenburg’s position. Her vagina should be packed to reduce the risk of re-evisceration as she moves toward operative cuff repair.

If the physician is concerned about bowel injury, inspection via laparoscopy or laparotomy would be reasonable. However, when bowel injury is not suspected, a vaginal technique for dehiscence repair has been described by Matthews et al.:¹²

1. Expose the cuff with a weighted speculum and Breisky-Navratil retractors.

2. Sharply debride the cuff edges back to viable tissue.

3. Dissect adherent bowel or omentum to allow for full-thickness closure.

4. Place full-thickness, interrupted delayed absorbable sutures to reapproximate the cuff edges.

Cuff dehiscence is a rare but potentially morbid complication of hysterectomy. Prevention, recognition, and appropriate management can avoid life-threatening sequelae.

References

1. Obstet Gynecol. 2011 Oct;118(4):794-801.

2. JSLS. 2012 Oct-Dec;16(4):530-6.

3. Am J Obstet Gynecol. 1990 Sep;163(3):1016-21; discussion 1021-3.

4. Obstet Gynecol. 2013 Mar;121(3):654-73.

5. Obstet Gynecol. 2012 Sep;120(3):516-23.

6. J Am Assoc Gynecol Laparosc. 2002 Nov;9(4):474-80.

7. Eur J Obstet Gynecol Reprod Biol. 2006 Mar 1;125(1):134-8.

8. Obstet Gynecol. 2009 Aug;114(2 Pt 1):231-5.

9. J Minim Invasive Gynecol. 2011 Mar-Apr;18(2):218-23.

10. Int J Surg. 2015 Jul;19:27-30.

11. Maturitas. 2006 Feb 20;53(3):282-98.

12. Obstet Gynecol. 2014 Oct;124(4):705-8.

Dr. Pierce is a gynecologic oncology fellow in the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill. Dr. Clarke-Pearson is the chair and the Robert A. Ross Distinguished Professor of Obstetrics and Gynecology and professor in the division of gynecologic oncology at the university. They reported having no relevant financial disclosures.

Vaginal cuff dehiscence, or separation of the vaginal incision, is a rare postoperative complication unique to hysterectomy. Morbidity related to evisceration of abdominal contents can be profound and prompt intervention is required.

A 10-year observational study of 11,000 patients described a 0.24% cumulative incidence after all modes of hysterectomy.¹ Though data are varied, the mode of hysterectomy does have an impact on the risk of dehiscence.

Laparoscopic (0.64%-1.35%) and robotic (0.46%-1.5%) hysterectomy have a higher incidence than abdominal (0.15%-0.26%) and vaginal (0.08%-0.25%) approaches.² The use of monopolar cautery for colpotomy and different closure techniques may account for these differences.

Cuff cellulitis, early sexual intercourse, cigarette smoking, poor nutrition, obesity, menopausal status, and corticosteroid use are all proposed risk factors that promote infection, pressure at the vaginal cuff, and poor wound healing. Although some are modifiable, the rarity of this complication has made establishing causality and promoting prevention challenging.

Prevention

• Preoperatively. Treating bacterial vaginosis, Trichomonas vaginalis, gonorrhea, and chlamydia can decrease the risk of cuff cellulitis and dehiscence.³

• Intraoperatively. Surgeons should ensure adequate vaginal margins (greater than 1 cm) with full-thickness cuff closures while avoiding excessive electrocautery.⁴ Retrospective data show that transvaginal cuff closure is associated with a decreased risk of dehiscence.⁵ However, given the lack of randomized data and the difficulty controlling for surgeon experience, gynecologists should use the approach that they are most comfortable with. Though the various laparoscopic cuff closure techniques have limited evidence regarding superiority, some experts propose using two-layer cuff closure and barbed sutures.^6-8 Several retrospective studies have found an equivalent or a decreased incidence of cuff dehiscence with barbed sutures, compared with other methods (e.g., 0-Vicryl, Endo Stitch).^9,10

• Postoperatively. Women should avoid intercourse and lifting more than 15 pounds for at least 6-8 weeks as the vaginal cuff gains tensile strength. Vaginal estrogen can promote healing in postmenopausal patients.¹¹

Management

Patients with vaginal cuff dehiscence commonly present within the first several weeks to months after surgery with pelvic pain (60%-100%), vaginal bleeding (30%-60%), vaginal discharge (30%), or vaginal pressure/mass (30%).^1,7 Posthysterectomy patients with these complaints warrant an urgent evaluation. The diagnosis is made during a pelvic exam.

Broad-spectrum antibiotics are necessary because all vaginal cuff separations or dehiscences expose the peritoneal cavity to vaginal flora. Nonsurgical management is reasonable for small separations – less than 25% of the cuff – if there is no evidence of evisceration.

However, surgically closing all recognized cuff dehiscences is reasonable, given the potential for further separation. A vaginal approach is preferred when possible. Women with vaginal cuff dehiscence, stable vital signs, and no evidence of bowel evisceration can be repaired vaginally without an abdominal survey.

In contrast, women with bowel evisceration have a surgical emergency because of the risk of peritonitis and bowel injury. If the eviscerated bowel is not reducible, it should be irrigated and wrapped in a warm moist towel or gauze in preparation for inspection and reduction in the operating room. If the bowel is reducible, the patient can be placed in Trendelenburg’s position. Her vagina should be packed to reduce the risk of re-evisceration as she moves toward operative cuff repair.

If the physician is concerned about bowel injury, inspection via laparoscopy or laparotomy would be reasonable. However, when bowel injury is not suspected, a vaginal technique for dehiscence repair has been described by Matthews et al.:¹²

1. Expose the cuff with a weighted speculum and Breisky-Navratil retractors.

2. Sharply debride the cuff edges back to viable tissue.

3. Dissect adherent bowel or omentum to allow for full-thickness closure.

4. Place full-thickness, interrupted delayed absorbable sutures to reapproximate the cuff edges.

Cuff dehiscence is a rare but potentially morbid complication of hysterectomy. Prevention, recognition, and appropriate management can avoid life-threatening sequelae.

References

1. Obstet Gynecol. 2011 Oct;118(4):794-801.

2. JSLS. 2012 Oct-Dec;16(4):530-6.

3. Am J Obstet Gynecol. 1990 Sep;163(3):1016-21; discussion 1021-3.

4. Obstet Gynecol. 2013 Mar;121(3):654-73.

5. Obstet Gynecol. 2012 Sep;120(3):516-23.

6. J Am Assoc Gynecol Laparosc. 2002 Nov;9(4):474-80.

7. Eur J Obstet Gynecol Reprod Biol. 2006 Mar 1;125(1):134-8.

8. Obstet Gynecol. 2009 Aug;114(2 Pt 1):231-5.

9. J Minim Invasive Gynecol. 2011 Mar-Apr;18(2):218-23.

10. Int J Surg. 2015 Jul;19:27-30.

11. Maturitas. 2006 Feb 20;53(3):282-98.

12. Obstet Gynecol. 2014 Oct;124(4):705-8.

Dr. Pierce is a gynecologic oncology fellow in the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill. Dr. Clarke-Pearson is the chair and the Robert A. Ross Distinguished Professor of Obstetrics and Gynecology and professor in the division of gynecologic oncology at the university. They reported having no relevant financial disclosures.

Vaginal cuff dehiscence, or separation of the vaginal incision, is a rare postoperative complication unique to hysterectomy. Morbidity related to evisceration of abdominal contents can be profound and prompt intervention is required.

A 10-year observational study of 11,000 patients described a 0.24% cumulative incidence after all modes of hysterectomy.¹ Though data are varied, the mode of hysterectomy does have an impact on the risk of dehiscence.

Laparoscopic (0.64%-1.35%) and robotic (0.46%-1.5%) hysterectomy have a higher incidence than abdominal (0.15%-0.26%) and vaginal (0.08%-0.25%) approaches.² The use of monopolar cautery for colpotomy and different closure techniques may account for these differences.

Cuff cellulitis, early sexual intercourse, cigarette smoking, poor nutrition, obesity, menopausal status, and corticosteroid use are all proposed risk factors that promote infection, pressure at the vaginal cuff, and poor wound healing. Although some are modifiable, the rarity of this complication has made establishing causality and promoting prevention challenging.

Prevention

• Preoperatively. Treating bacterial vaginosis, Trichomonas vaginalis, gonorrhea, and chlamydia can decrease the risk of cuff cellulitis and dehiscence.³

• Intraoperatively. Surgeons should ensure adequate vaginal margins (greater than 1 cm) with full-thickness cuff closures while avoiding excessive electrocautery.⁴ Retrospective data show that transvaginal cuff closure is associated with a decreased risk of dehiscence.⁵ However, given the lack of randomized data and the difficulty controlling for surgeon experience, gynecologists should use the approach that they are most comfortable with. Though the various laparoscopic cuff closure techniques have limited evidence regarding superiority, some experts propose using two-layer cuff closure and barbed sutures.^6-8 Several retrospective studies have found an equivalent or a decreased incidence of cuff dehiscence with barbed sutures, compared with other methods (e.g., 0-Vicryl, Endo Stitch).^9,10

• Postoperatively. Women should avoid intercourse and lifting more than 15 pounds for at least 6-8 weeks as the vaginal cuff gains tensile strength. Vaginal estrogen can promote healing in postmenopausal patients.¹¹

Management

Patients with vaginal cuff dehiscence commonly present within the first several weeks to months after surgery with pelvic pain (60%-100%), vaginal bleeding (30%-60%), vaginal discharge (30%), or vaginal pressure/mass (30%).^1,7 Posthysterectomy patients with these complaints warrant an urgent evaluation. The diagnosis is made during a pelvic exam.

Broad-spectrum antibiotics are necessary because all vaginal cuff separations or dehiscences expose the peritoneal cavity to vaginal flora. Nonsurgical management is reasonable for small separations – less than 25% of the cuff – if there is no evidence of evisceration.

However, surgically closing all recognized cuff dehiscences is reasonable, given the potential for further separation. A vaginal approach is preferred when possible. Women with vaginal cuff dehiscence, stable vital signs, and no evidence of bowel evisceration can be repaired vaginally without an abdominal survey.

In contrast, women with bowel evisceration have a surgical emergency because of the risk of peritonitis and bowel injury. If the eviscerated bowel is not reducible, it should be irrigated and wrapped in a warm moist towel or gauze in preparation for inspection and reduction in the operating room. If the bowel is reducible, the patient can be placed in Trendelenburg’s position. Her vagina should be packed to reduce the risk of re-evisceration as she moves toward operative cuff repair.

If the physician is concerned about bowel injury, inspection via laparoscopy or laparotomy would be reasonable. However, when bowel injury is not suspected, a vaginal technique for dehiscence repair has been described by Matthews et al.:¹²

1. Expose the cuff with a weighted speculum and Breisky-Navratil retractors.

2. Sharply debride the cuff edges back to viable tissue.

3. Dissect adherent bowel or omentum to allow for full-thickness closure.

4. Place full-thickness, interrupted delayed absorbable sutures to reapproximate the cuff edges.

Cuff dehiscence is a rare but potentially morbid complication of hysterectomy. Prevention, recognition, and appropriate management can avoid life-threatening sequelae.

References

1. Obstet Gynecol. 2011 Oct;118(4):794-801.

2. JSLS. 2012 Oct-Dec;16(4):530-6.

3. Am J Obstet Gynecol. 1990 Sep;163(3):1016-21; discussion 1021-3.

4. Obstet Gynecol. 2013 Mar;121(3):654-73.

5. Obstet Gynecol. 2012 Sep;120(3):516-23.

6. J Am Assoc Gynecol Laparosc. 2002 Nov;9(4):474-80.

7. Eur J Obstet Gynecol Reprod Biol. 2006 Mar 1;125(1):134-8.

8. Obstet Gynecol. 2009 Aug;114(2 Pt 1):231-5.

9. J Minim Invasive Gynecol. 2011 Mar-Apr;18(2):218-23.

10. Int J Surg. 2015 Jul;19:27-30.

11. Maturitas. 2006 Feb 20;53(3):282-98.

12. Obstet Gynecol. 2014 Oct;124(4):705-8.

Dr. Pierce is a gynecologic oncology fellow in the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill. Dr. Clarke-Pearson is the chair and the Robert A. Ross Distinguished Professor of Obstetrics and Gynecology and professor in the division of gynecologic oncology at the university. They reported having no relevant financial disclosures.

CHICAGO - Medicare enrollees are moving in greater numbers than ever to the program's managed care option as a way to save money. But the tradeoff is much less ability to use their preferred doctors and hospitals.

Seniors can choose between traditional fee-for-service Medicare - which is accepted by most healthcare providers - or a Medicare Advantage plan. The latter encompasses health maintenance organizations (HMOs) or preferred provider organizations (PPOs), which control costs by creating healthcare provider networks that enrollees must use.

In theory, prospective Advantage enrollees can review lists of in-network providers before opting into a plan. But a new study by the Kaiser Family Foundation (KFF) finds that provider data often is very difficult to review, can be out of date and frequently contain inaccurate information.

KFF's review also found shortcomings in the quality of providers in some Medicare Advantage provider networks. One out of every five plans did not include a regional academic medical center - institutions which usually offer the highest quality care and top specialists. And only 40 percent of Advantage provider networks included top-quality cancer centers, as indicated by membership in the National Cancer Institute's network.

NCI-designated cancer centers offer cutting-edge treatments and tend to have greater access to clinical trials. They are especially important for patients with rare and advanced cancers, or other complicating conditions, said Gretchen Jacobson, KFF's associate director of the program on Medicare policy and co-author of the study.

The upshot: Medicare Advantage may be just fine if you are healthy, but problems may crop up if your healthcare needs become more complex and you have very specific healthcare provider preferences.

This year, 31 percent of Medicare enrollees are in Advantage plans, up from 11 percent in 2010. That number is expected to hit 41 percent by 2026, according to a forecast by the Congressional Budget Office.

When you sign up for Advantage, your Part B premium goes to the insurance company providing the plan. The largest providers are UnitedHealthcare, Humana Inc and Blue Cross Blue Shield.

One often hears critics claim that healthcare providers are bailing out of traditional Medicare in large numbers - but that is not actually the case. Last year, 14 percent of Medicare enrollees who were seeking a new primary care doctor reported major problems in finding a physician who would treat them, according to survey data from the Medicare Payment Advisory Commission, an independent congressional agency. Among those seeking a new specialist, 6 percent reported major problems. In both cases, that represents 1 percent of the total Medicare population.

ADVANTAGES, PITFALLS

Advantage plans often offer extra benefits, such as health club memberships, vision care and some limited dental care. Cost-sharing is often lower, and many plans provide prescription drug coverage with no extra premium. "It can be very attractive to many seniors who are living on a fixed budget," Jacobson said.

The trade-off is limited provider networks - and the challenges prospective enrollees face in determining who they are allowed to see for healthcare, and who is off-limits. KFF reviewed 409 Advantage plans, including 307 HMOs and 102 PPOs. Researchers found provider directories often were riddled with errors, omissions and outdated information.

"There's no reason in this era of technology why this needs to be as difficult as it is," Jacobson said. "People should be able to simply tell the system who their doctors are, the illnesses they have, and get a recommendation for a plan that will work for them."

KFF also found that Advantage provider network quality differs significantly. For example, Los Angeles has three NCI-designated cancer centers. Most of the Advantage plans there do not include any of them, but one plan includes all three.

A report last year by the U.S. Government Accountability Office found that the Centers for Medicare & Medicaid Services (CMS), which runs Medicare, needs to improve its oversight of Advantage plans to assure that provider networks are robust. The report also criticized CMS for doing too little to assess the accuracy of Advantage plan provider lists.

Even when Advantage enrollees are able to confirm participation by their healthcare providers, there is no guarantee that will continue. Advantage plans are free to add or drop health providers during the course of an enrollment season.

That became an especially hot issue in 2014 when UnitedHealthcare dropped providers who covered thousands of the insurer's patients, including the prominent Yale-New Haven Hospital system.

Democrats in Congress have proposed legislation that would prohibit Advantage plans from dropping providers without cause during the middle of an enrollment year.

Under current rules, plans must provide 30 days' notice to enrollees when providers are dropped. Enrollees who lose access to a provider can make a midyear plan change only under very limited circumstances. "You can do it only if you are receiving ongoing care from a provider that is terminated," Jacobson said. "Otherwise you need to wait until the next open enrollment period."

The annual enrollment period for Advantage and Part D prescription drug plans are held from Oct. 15 to Dec. 7 each year. At that point, a beneficiary could switch to a different Advantage plan, or shift back to traditional Medicare. But a serious diagnosis in January would leave you hamstrung until the following year.

Said Jacobson: "It can be a roll of the dice."

(The opinions expressed here are those of the author, a columnist for Reuters.)

CHICAGO - Medicare enrollees are moving in greater numbers than ever to the program's managed care option as a way to save money. But the tradeoff is much less ability to use their preferred doctors and hospitals.

Seniors can choose between traditional fee-for-service Medicare - which is accepted by most healthcare providers - or a Medicare Advantage plan. The latter encompasses health maintenance organizations (HMOs) or preferred provider organizations (PPOs), which control costs by creating healthcare provider networks that enrollees must use.

In theory, prospective Advantage enrollees can review lists of in-network providers before opting into a plan. But a new study by the Kaiser Family Foundation (KFF) finds that provider data often is very difficult to review, can be out of date and frequently contain inaccurate information.

KFF's review also found shortcomings in the quality of providers in some Medicare Advantage provider networks. One out of every five plans did not include a regional academic medical center - institutions which usually offer the highest quality care and top specialists. And only 40 percent of Advantage provider networks included top-quality cancer centers, as indicated by membership in the National Cancer Institute's network.

NCI-designated cancer centers offer cutting-edge treatments and tend to have greater access to clinical trials. They are especially important for patients with rare and advanced cancers, or other complicating conditions, said Gretchen Jacobson, KFF's associate director of the program on Medicare policy and co-author of the study.

The upshot: Medicare Advantage may be just fine if you are healthy, but problems may crop up if your healthcare needs become more complex and you have very specific healthcare provider preferences.

This year, 31 percent of Medicare enrollees are in Advantage plans, up from 11 percent in 2010. That number is expected to hit 41 percent by 2026, according to a forecast by the Congressional Budget Office.

When you sign up for Advantage, your Part B premium goes to the insurance company providing the plan. The largest providers are UnitedHealthcare, Humana Inc and Blue Cross Blue Shield.

One often hears critics claim that healthcare providers are bailing out of traditional Medicare in large numbers - but that is not actually the case. Last year, 14 percent of Medicare enrollees who were seeking a new primary care doctor reported major problems in finding a physician who would treat them, according to survey data from the Medicare Payment Advisory Commission, an independent congressional agency. Among those seeking a new specialist, 6 percent reported major problems. In both cases, that represents 1 percent of the total Medicare population.

ADVANTAGES, PITFALLS

Advantage plans often offer extra benefits, such as health club memberships, vision care and some limited dental care. Cost-sharing is often lower, and many plans provide prescription drug coverage with no extra premium. "It can be very attractive to many seniors who are living on a fixed budget," Jacobson said.

The trade-off is limited provider networks - and the challenges prospective enrollees face in determining who they are allowed to see for healthcare, and who is off-limits. KFF reviewed 409 Advantage plans, including 307 HMOs and 102 PPOs. Researchers found provider directories often were riddled with errors, omissions and outdated information.

"There's no reason in this era of technology why this needs to be as difficult as it is," Jacobson said. "People should be able to simply tell the system who their doctors are, the illnesses they have, and get a recommendation for a plan that will work for them."

KFF also found that Advantage provider network quality differs significantly. For example, Los Angeles has three NCI-designated cancer centers. Most of the Advantage plans there do not include any of them, but one plan includes all three.

A report last year by the U.S. Government Accountability Office found that the Centers for Medicare & Medicaid Services (CMS), which runs Medicare, needs to improve its oversight of Advantage plans to assure that provider networks are robust. The report also criticized CMS for doing too little to assess the accuracy of Advantage plan provider lists.

Even when Advantage enrollees are able to confirm participation by their healthcare providers, there is no guarantee that will continue. Advantage plans are free to add or drop health providers during the course of an enrollment season.

That became an especially hot issue in 2014 when UnitedHealthcare dropped providers who covered thousands of the insurer's patients, including the prominent Yale-New Haven Hospital system.

Democrats in Congress have proposed legislation that would prohibit Advantage plans from dropping providers without cause during the middle of an enrollment year.

Under current rules, plans must provide 30 days' notice to enrollees when providers are dropped. Enrollees who lose access to a provider can make a midyear plan change only under very limited circumstances. "You can do it only if you are receiving ongoing care from a provider that is terminated," Jacobson said. "Otherwise you need to wait until the next open enrollment period."

The annual enrollment period for Advantage and Part D prescription drug plans are held from Oct. 15 to Dec. 7 each year. At that point, a beneficiary could switch to a different Advantage plan, or shift back to traditional Medicare. But a serious diagnosis in January would leave you hamstrung until the following year.

Said Jacobson: "It can be a roll of the dice."

(The opinions expressed here are those of the author, a columnist for Reuters.)

CHICAGO - Medicare enrollees are moving in greater numbers than ever to the program's managed care option as a way to save money. But the tradeoff is much less ability to use their preferred doctors and hospitals.

Seniors can choose between traditional fee-for-service Medicare - which is accepted by most healthcare providers - or a Medicare Advantage plan. The latter encompasses health maintenance organizations (HMOs) or preferred provider organizations (PPOs), which control costs by creating healthcare provider networks that enrollees must use.

In theory, prospective Advantage enrollees can review lists of in-network providers before opting into a plan. But a new study by the Kaiser Family Foundation (KFF) finds that provider data often is very difficult to review, can be out of date and frequently contain inaccurate information.

KFF's review also found shortcomings in the quality of providers in some Medicare Advantage provider networks. One out of every five plans did not include a regional academic medical center - institutions which usually offer the highest quality care and top specialists. And only 40 percent of Advantage provider networks included top-quality cancer centers, as indicated by membership in the National Cancer Institute's network.

NCI-designated cancer centers offer cutting-edge treatments and tend to have greater access to clinical trials. They are especially important for patients with rare and advanced cancers, or other complicating conditions, said Gretchen Jacobson, KFF's associate director of the program on Medicare policy and co-author of the study.

The upshot: Medicare Advantage may be just fine if you are healthy, but problems may crop up if your healthcare needs become more complex and you have very specific healthcare provider preferences.

This year, 31 percent of Medicare enrollees are in Advantage plans, up from 11 percent in 2010. That number is expected to hit 41 percent by 2026, according to a forecast by the Congressional Budget Office.

When you sign up for Advantage, your Part B premium goes to the insurance company providing the plan. The largest providers are UnitedHealthcare, Humana Inc and Blue Cross Blue Shield.

One often hears critics claim that healthcare providers are bailing out of traditional Medicare in large numbers - but that is not actually the case. Last year, 14 percent of Medicare enrollees who were seeking a new primary care doctor reported major problems in finding a physician who would treat them, according to survey data from the Medicare Payment Advisory Commission, an independent congressional agency. Among those seeking a new specialist, 6 percent reported major problems. In both cases, that represents 1 percent of the total Medicare population.

ADVANTAGES, PITFALLS

Advantage plans often offer extra benefits, such as health club memberships, vision care and some limited dental care. Cost-sharing is often lower, and many plans provide prescription drug coverage with no extra premium. "It can be very attractive to many seniors who are living on a fixed budget," Jacobson said.

The trade-off is limited provider networks - and the challenges prospective enrollees face in determining who they are allowed to see for healthcare, and who is off-limits. KFF reviewed 409 Advantage plans, including 307 HMOs and 102 PPOs. Researchers found provider directories often were riddled with errors, omissions and outdated information.

"There's no reason in this era of technology why this needs to be as difficult as it is," Jacobson said. "People should be able to simply tell the system who their doctors are, the illnesses they have, and get a recommendation for a plan that will work for them."

KFF also found that Advantage provider network quality differs significantly. For example, Los Angeles has three NCI-designated cancer centers. Most of the Advantage plans there do not include any of them, but one plan includes all three.

A report last year by the U.S. Government Accountability Office found that the Centers for Medicare & Medicaid Services (CMS), which runs Medicare, needs to improve its oversight of Advantage plans to assure that provider networks are robust. The report also criticized CMS for doing too little to assess the accuracy of Advantage plan provider lists.

Even when Advantage enrollees are able to confirm participation by their healthcare providers, there is no guarantee that will continue. Advantage plans are free to add or drop health providers during the course of an enrollment season.

That became an especially hot issue in 2014 when UnitedHealthcare dropped providers who covered thousands of the insurer's patients, including the prominent Yale-New Haven Hospital system.

Democrats in Congress have proposed legislation that would prohibit Advantage plans from dropping providers without cause during the middle of an enrollment year.

Under current rules, plans must provide 30 days' notice to enrollees when providers are dropped. Enrollees who lose access to a provider can make a midyear plan change only under very limited circumstances. "You can do it only if you are receiving ongoing care from a provider that is terminated," Jacobson said. "Otherwise you need to wait until the next open enrollment period."

The annual enrollment period for Advantage and Part D prescription drug plans are held from Oct. 15 to Dec. 7 each year. At that point, a beneficiary could switch to a different Advantage plan, or shift back to traditional Medicare. But a serious diagnosis in January would leave you hamstrung until the following year.

Said Jacobson: "It can be a roll of the dice."

(The opinions expressed here are those of the author, a columnist for Reuters.)

As a treatment for scalp psoriasis, the combination of a topical steroid and topical vitamin D was marginally better than topical steroids alone, but both approaches have a similar safety profile, according to a Cochrane review.

The systematic review included 59 randomized controlled trials of topical treatments for scalp psoriasis, representing a total of 11,561 participants of all ages, most of whom were followed for less than 6 months, according to Justin Schlager, MD, of the Charité – Universitätsmedizin Berlin, and coauthors (Cochrane Database of Systematic Reviews 2016. Issue 2. doi: 10.1002/14651858.CD009687.pub2).

Christine Langer-p?schel/Thinkstock

In the analysis, topical steroid monotherapy was significantly better than topical vitamin D for clearance, as assessed by the Investigator’s Global Assessment of Disease Severity (risk ratio, 1.82; 95% confidence interval, 1.52-2.18). But the combination of a topical steroid and vitamin D showed a small but statistically significant advantage over steroids alone (RR, 1.22; 95% CI, 1.08-1.36) and an even greater advantage over vitamin D alone (RR, 2.28; 95% CI, 1.87-2.78).

Similarly, for treatment response, the combination of a topical steroid and vitamin D showed the greatest benefit in terms of treatment response when compared with steroid monotherapy (RR, 1.15; 95% CI, 1.06-1.25) – an additional benefit the authors observed was small – and when compared with vitamin D alone (RR, 2.31; 95% CI, 1.75-3.04).

But for monotherapy, corticosteroids were more than twice as effective as vitamin D alone for treatment response (RR, 2.09; 95% CI, 1.80-2.41). The analysis also showed that corticosteroids of moderate, high, and very high potency were similarly effective.

Steroids were associated with a significantly lower risk of withdrawal because of adverse events than vitamin D (RR, 0.22; 95% CI, 0.11-0.42). Patients using topical steroids reported adverse events such as a burning sensation or irritation at the site of application, while patients taking vitamin D reported side effects such as pruritus, candidiasis, dermatitis, and erythema, although in both cases these were mostly limited to the application site.

The combination of vitamin D and topical steroid had a lower risk of withdrawals because of adverse events than vitamin D alone, but showed a similar rate to topical steroids alone.

“Given the similar safety profile and only slim benefit of the two-compound combination over the steroid alone, monotherapy with generic topical corticosteroids may be fully acceptable for short-term therapy,” the authors wrote. The authors noted that data on patients’ quality of life was poor across all the studies included in the analysis and called for future trials to address this gap, and more long-term assessments.

“Regardless of the type of psoriasis, up to 79% of people with the condition present with scalp involvement, which has frequently been the first site to show symptoms of the disease,” they pointed out.

Thirty of the 59 studies were either conducted or sponsored by the manufacturer of the study medication, and the authors described the overall quality of the studies as “moderate.” Thirty-three studies were double blind, 14 were single blind, two had “third-party” blinding, six were open-label, and four did not report blinding information.

The study was supported by the Universidade Federal de São Paulo, Brazil; the Universidade Federal do Rio Grande do Norte, Brazil; and the National Institute for Health Research, United Kingdom. Six authors and one clinical referee declared speakers’ fees, research grants, and funding from the pharmaceutical industry. One author had no conflicts of interest to disclose.

As a treatment for scalp psoriasis, the combination of a topical steroid and topical vitamin D was marginally better than topical steroids alone, but both approaches have a similar safety profile, according to a Cochrane review.

The systematic review included 59 randomized controlled trials of topical treatments for scalp psoriasis, representing a total of 11,561 participants of all ages, most of whom were followed for less than 6 months, according to Justin Schlager, MD, of the Charité – Universitätsmedizin Berlin, and coauthors (Cochrane Database of Systematic Reviews 2016. Issue 2. doi: 10.1002/14651858.CD009687.pub2).

Christine Langer-p?schel/Thinkstock

In the analysis, topical steroid monotherapy was significantly better than topical vitamin D for clearance, as assessed by the Investigator’s Global Assessment of Disease Severity (risk ratio, 1.82; 95% confidence interval, 1.52-2.18). But the combination of a topical steroid and vitamin D showed a small but statistically significant advantage over steroids alone (RR, 1.22; 95% CI, 1.08-1.36) and an even greater advantage over vitamin D alone (RR, 2.28; 95% CI, 1.87-2.78).

Similarly, for treatment response, the combination of a topical steroid and vitamin D showed the greatest benefit in terms of treatment response when compared with steroid monotherapy (RR, 1.15; 95% CI, 1.06-1.25) – an additional benefit the authors observed was small – and when compared with vitamin D alone (RR, 2.31; 95% CI, 1.75-3.04).

But for monotherapy, corticosteroids were more than twice as effective as vitamin D alone for treatment response (RR, 2.09; 95% CI, 1.80-2.41). The analysis also showed that corticosteroids of moderate, high, and very high potency were similarly effective.

Steroids were associated with a significantly lower risk of withdrawal because of adverse events than vitamin D (RR, 0.22; 95% CI, 0.11-0.42). Patients using topical steroids reported adverse events such as a burning sensation or irritation at the site of application, while patients taking vitamin D reported side effects such as pruritus, candidiasis, dermatitis, and erythema, although in both cases these were mostly limited to the application site.

The combination of vitamin D and topical steroid had a lower risk of withdrawals because of adverse events than vitamin D alone, but showed a similar rate to topical steroids alone.

“Given the similar safety profile and only slim benefit of the two-compound combination over the steroid alone, monotherapy with generic topical corticosteroids may be fully acceptable for short-term therapy,” the authors wrote. The authors noted that data on patients’ quality of life was poor across all the studies included in the analysis and called for future trials to address this gap, and more long-term assessments.

“Regardless of the type of psoriasis, up to 79% of people with the condition present with scalp involvement, which has frequently been the first site to show symptoms of the disease,” they pointed out.

Thirty of the 59 studies were either conducted or sponsored by the manufacturer of the study medication, and the authors described the overall quality of the studies as “moderate.” Thirty-three studies were double blind, 14 were single blind, two had “third-party” blinding, six were open-label, and four did not report blinding information.

The study was supported by the Universidade Federal de São Paulo, Brazil; the Universidade Federal do Rio Grande do Norte, Brazil; and the National Institute for Health Research, United Kingdom. Six authors and one clinical referee declared speakers’ fees, research grants, and funding from the pharmaceutical industry. One author had no conflicts of interest to disclose.

As a treatment for scalp psoriasis, the combination of a topical steroid and topical vitamin D was marginally better than topical steroids alone, but both approaches have a similar safety profile, according to a Cochrane review.

The systematic review included 59 randomized controlled trials of topical treatments for scalp psoriasis, representing a total of 11,561 participants of all ages, most of whom were followed for less than 6 months, according to Justin Schlager, MD, of the Charité – Universitätsmedizin Berlin, and coauthors (Cochrane Database of Systematic Reviews 2016. Issue 2. doi: 10.1002/14651858.CD009687.pub2).

Christine Langer-p?schel/Thinkstock

In the analysis, topical steroid monotherapy was significantly better than topical vitamin D for clearance, as assessed by the Investigator’s Global Assessment of Disease Severity (risk ratio, 1.82; 95% confidence interval, 1.52-2.18). But the combination of a topical steroid and vitamin D showed a small but statistically significant advantage over steroids alone (RR, 1.22; 95% CI, 1.08-1.36) and an even greater advantage over vitamin D alone (RR, 2.28; 95% CI, 1.87-2.78).

Similarly, for treatment response, the combination of a topical steroid and vitamin D showed the greatest benefit in terms of treatment response when compared with steroid monotherapy (RR, 1.15; 95% CI, 1.06-1.25) – an additional benefit the authors observed was small – and when compared with vitamin D alone (RR, 2.31; 95% CI, 1.75-3.04).

But for monotherapy, corticosteroids were more than twice as effective as vitamin D alone for treatment response (RR, 2.09; 95% CI, 1.80-2.41). The analysis also showed that corticosteroids of moderate, high, and very high potency were similarly effective.

Steroids were associated with a significantly lower risk of withdrawal because of adverse events than vitamin D (RR, 0.22; 95% CI, 0.11-0.42). Patients using topical steroids reported adverse events such as a burning sensation or irritation at the site of application, while patients taking vitamin D reported side effects such as pruritus, candidiasis, dermatitis, and erythema, although in both cases these were mostly limited to the application site.

The combination of vitamin D and topical steroid had a lower risk of withdrawals because of adverse events than vitamin D alone, but showed a similar rate to topical steroids alone.

“Given the similar safety profile and only slim benefit of the two-compound combination over the steroid alone, monotherapy with generic topical corticosteroids may be fully acceptable for short-term therapy,” the authors wrote. The authors noted that data on patients’ quality of life was poor across all the studies included in the analysis and called for future trials to address this gap, and more long-term assessments.

“Regardless of the type of psoriasis, up to 79% of people with the condition present with scalp involvement, which has frequently been the first site to show symptoms of the disease,” they pointed out.

Thirty of the 59 studies were either conducted or sponsored by the manufacturer of the study medication, and the authors described the overall quality of the studies as “moderate.” Thirty-three studies were double blind, 14 were single blind, two had “third-party” blinding, six were open-label, and four did not report blinding information.

The study was supported by the Universidade Federal de São Paulo, Brazil; the Universidade Federal do Rio Grande do Norte, Brazil; and the National Institute for Health Research, United Kingdom. Six authors and one clinical referee declared speakers’ fees, research grants, and funding from the pharmaceutical industry. One author had no conflicts of interest to disclose.

Quality-switched (QS) laser therapy with a ruby laser and topical triple-combination therapy (TCT) were similarly effective in lightening solar lentigines, based on data from a prospective, open label study of 15 adults. The findings were published in Dermatologic Surgery.

The QS ruby laser (QSRL) delivered longer-lasting skin-lightening results in less time, but the topical therapy is less expensive and has a lower risk of adverse events, wrote Dr. Laurence Imhof of the department of dermatology, University Hospital Zürich, and colleagues (Dermatol Surg. 2016;42:853-57. doi: 10.1097/DSS.0000000000000793). “Although therapy [for solar lentigines] is not medically indicated, there is a rising treatment demand for aesthetic reasons. Therefore, the treatment should be very safe and affordable,” they wrote.

The researchers compared the safety and efficacy of treating solar lentigines with a 694-nm QSRL and TCT (hydroquinone 5%, tretinoin 0.03%, and dexamethasone 0.03%). The patients included 14 women and 1 man with evenly distributed solar lentigines on the backs of both hands. Each patient was treated with 1-2 QSRL sessions on the back of the right hand and 7 weeks of once-daily application of TCT on the back of the left hand. The average age of the patients was 61 years; 13 were Fitzpatrick Skin Types II and III. Adverse events were mild and transient with both treatments, although the QSRL caused significantly more crusting and hyperpigmentation than the TCT.

Both treatments significantly reduced pigment at the end of treatment (day 56) and 12 weeks’ post treatment (140 days), compared with baseline. Treatment areas were evaluated at days 28, 56, and 140 by the treating physician, the patient, and a blinded physician (based on photos).The 6-point grading scale rated the degree of lightening/percentage of clearing, ranging from worse (less than 0%) to excellent (76%-100%).

At 56 days, the mean macroscopic improvement with QSRL laser was rated 3.5 by the treating physician and patient and 3 by a blinded physician; the mean macroscopic improvement with TCT was rated 2.4 by the treating physician, 2.2 by the patient, and 1.7 by the blinded physician. At 140 days, the mean macroscopic improvements with the laser were rated 2.9 by the treating physician, 2.7 by the patient, and 2.8 by the blinded physician, compared with 1.2, 1.1, and 0.7, respectively, with TCT.

The results were limited by the small size, short follow-up period, and open-label design, the researchers noted. However, the study is the first known to compare a laser and a topical treatment for the management of solar lentigines, and the findings suggest that both therapies can be recommended for the aesthetic treatment of solar lentigines, they said.

The TCT cream used in the study was provided by Louis Widmer SA, which provided a grant to the University of Zürich. The researchers had no financial conflicts to disclose.

Quality-switched (QS) laser therapy with a ruby laser and topical triple-combination therapy (TCT) were similarly effective in lightening solar lentigines, based on data from a prospective, open label study of 15 adults. The findings were published in Dermatologic Surgery.

The QS ruby laser (QSRL) delivered longer-lasting skin-lightening results in less time, but the topical therapy is less expensive and has a lower risk of adverse events, wrote Dr. Laurence Imhof of the department of dermatology, University Hospital Zürich, and colleagues (Dermatol Surg. 2016;42:853-57. doi: 10.1097/DSS.0000000000000793). “Although therapy [for solar lentigines] is not medically indicated, there is a rising treatment demand for aesthetic reasons. Therefore, the treatment should be very safe and affordable,” they wrote.

The researchers compared the safety and efficacy of treating solar lentigines with a 694-nm QSRL and TCT (hydroquinone 5%, tretinoin 0.03%, and dexamethasone 0.03%). The patients included 14 women and 1 man with evenly distributed solar lentigines on the backs of both hands. Each patient was treated with 1-2 QSRL sessions on the back of the right hand and 7 weeks of once-daily application of TCT on the back of the left hand. The average age of the patients was 61 years; 13 were Fitzpatrick Skin Types II and III. Adverse events were mild and transient with both treatments, although the QSRL caused significantly more crusting and hyperpigmentation than the TCT.

Both treatments significantly reduced pigment at the end of treatment (day 56) and 12 weeks’ post treatment (140 days), compared with baseline. Treatment areas were evaluated at days 28, 56, and 140 by the treating physician, the patient, and a blinded physician (based on photos).The 6-point grading scale rated the degree of lightening/percentage of clearing, ranging from worse (less than 0%) to excellent (76%-100%).

At 56 days, the mean macroscopic improvement with QSRL laser was rated 3.5 by the treating physician and patient and 3 by a blinded physician; the mean macroscopic improvement with TCT was rated 2.4 by the treating physician, 2.2 by the patient, and 1.7 by the blinded physician. At 140 days, the mean macroscopic improvements with the laser were rated 2.9 by the treating physician, 2.7 by the patient, and 2.8 by the blinded physician, compared with 1.2, 1.1, and 0.7, respectively, with TCT.

The results were limited by the small size, short follow-up period, and open-label design, the researchers noted. However, the study is the first known to compare a laser and a topical treatment for the management of solar lentigines, and the findings suggest that both therapies can be recommended for the aesthetic treatment of solar lentigines, they said.

The TCT cream used in the study was provided by Louis Widmer SA, which provided a grant to the University of Zürich. The researchers had no financial conflicts to disclose.

Quality-switched (QS) laser therapy with a ruby laser and topical triple-combination therapy (TCT) were similarly effective in lightening solar lentigines, based on data from a prospective, open label study of 15 adults. The findings were published in Dermatologic Surgery.

The QS ruby laser (QSRL) delivered longer-lasting skin-lightening results in less time, but the topical therapy is less expensive and has a lower risk of adverse events, wrote Dr. Laurence Imhof of the department of dermatology, University Hospital Zürich, and colleagues (Dermatol Surg. 2016;42:853-57. doi: 10.1097/DSS.0000000000000793). “Although therapy [for solar lentigines] is not medically indicated, there is a rising treatment demand for aesthetic reasons. Therefore, the treatment should be very safe and affordable,” they wrote.

The researchers compared the safety and efficacy of treating solar lentigines with a 694-nm QSRL and TCT (hydroquinone 5%, tretinoin 0.03%, and dexamethasone 0.03%). The patients included 14 women and 1 man with evenly distributed solar lentigines on the backs of both hands. Each patient was treated with 1-2 QSRL sessions on the back of the right hand and 7 weeks of once-daily application of TCT on the back of the left hand. The average age of the patients was 61 years; 13 were Fitzpatrick Skin Types II and III. Adverse events were mild and transient with both treatments, although the QSRL caused significantly more crusting and hyperpigmentation than the TCT.

Both treatments significantly reduced pigment at the end of treatment (day 56) and 12 weeks’ post treatment (140 days), compared with baseline. Treatment areas were evaluated at days 28, 56, and 140 by the treating physician, the patient, and a blinded physician (based on photos).The 6-point grading scale rated the degree of lightening/percentage of clearing, ranging from worse (less than 0%) to excellent (76%-100%).

At 56 days, the mean macroscopic improvement with QSRL laser was rated 3.5 by the treating physician and patient and 3 by a blinded physician; the mean macroscopic improvement with TCT was rated 2.4 by the treating physician, 2.2 by the patient, and 1.7 by the blinded physician. At 140 days, the mean macroscopic improvements with the laser were rated 2.9 by the treating physician, 2.7 by the patient, and 2.8 by the blinded physician, compared with 1.2, 1.1, and 0.7, respectively, with TCT.

The results were limited by the small size, short follow-up period, and open-label design, the researchers noted. However, the study is the first known to compare a laser and a topical treatment for the management of solar lentigines, and the findings suggest that both therapies can be recommended for the aesthetic treatment of solar lentigines, they said.

The TCT cream used in the study was provided by Louis Widmer SA, which provided a grant to the University of Zürich. The researchers had no financial conflicts to disclose.

This July, medical students, residents, and fellows in almost every medical and surgical specialty will join nurses at all levels of training, undergraduate and graduate pharmacists, dentists, and allied health students to train at a VA hospital. The VA Office of Academic Affiliations (OAA), which coordinates this massive educational effort, reported that in 2015, the last year for which data are available, 123,552 health care trainees were enrolled in VA programs.¹ That’s in addition to the hundreds of health care professionals trained in the 4 branches of the armed services, including students at the Uniformed Services University of the Health Sciences and those receiving a health care education through the PHS. Federal institutions are easily the largest contributors to health care education in the nation and very likely in the world.

This mission to educate the U.S. health care workforce is not new. This year marks the 70th anniversary of the collaboration between the VA and academic affiliates across the country to ensure a highly qualified cadre of health care professionals care, not only for veterans, but also for the public. Hence, the OAA motto: To educate for VA and for the nation.

When allopathic and osteopathic medical schools are combined, there are partnerships between the VA and 90% of U.S. medical schools. More than 70% of all U.S. practicing physicians trained at a VA facility at some time.² Currently, the VA has more than 40 different health care professional training programs under its auspices.

This educational mission is a core VA function that is enshrined in law as are VA’s other 3 core charges. According to the statute, the VA secretary shall “to the extent feasible without interfering with the medical care and treatment of veterans, develop and carry out a program of education and training of health personnel.” The primary clinical care, education, and research functions of the VA are inseparable, and none can be carried out without an adequate number of qualified staff.

Government reports and the media have identified the shortage of VA health care professionals as a major contributor to the wait times crisis of the past several years.³ Section 301 of the Veterans Access, Choice, and Accountability Act of 2014 actually requires the VA Office of Inspector General (OIG) to conduct assessments of the staffing shortages in the department. Reports from the OIG have identified 5 critical need occupations: medical officer, nurse, psychologist, physician assistant, and physical therapist.⁴

From my perspective as a medical officer, I am certain that the reason I went straight to the VA after my residency in psychiatry and have never left is my overwhelmingly positive experience as a medical student and resident. The VA had many of the best teachers in my training programs. The patients were—and still are nearly 20 years later—among the most respectful and appreciative of any I have treated.

Many VA patients considered us, even as trainees, their doctors and often asked us when we were residents whether they could “keep us,” although they knew that as former members of the military, most of us would rotate out of their lives. Yet they also knew that because of the strength of the training programs, a new young doctor would come to take care of them. Even now when the occasional angry patient says, “all you doctors care about is money,” I am proud to say that I could probably make more money in the private sector, but I choose to work at the VA.

Many of my fine colleagues in medicine, nursing, psychology, and allied health also remained at the VA after their training, inspired to provide public health to those who served and were underserved. Those who entered military medicine or the PHS had similar ideals borne of the role models who taught them in those federal institutions. One of the often unappreciated negative consequences of the VA scandal is that it may discouarge students in the health care professions from rotating through or seriously considering careers in the VA.

The VA and the military often do not receive the recognition they deserve as academic medical institutions. Some of the most renowned and accomplished faculty of prestigious medical universities also work at VA facilities. The ability to simultaneously teach gifted students, conduct cutting-edge research, and practice high-quality medicine all in a public health setting are what attracted me and many other idealistic health care professionals to the VA.

The VA, however, has taken active steps to restore its reputation as one of the best places to learn and work. Three outstanding initiatives deserve special attention. The first being a series of visits to medical schools that Carolyn M. Clancy, MD, made when she was the interim under secretary for health. Fortunately for me, she spoke at the academic affiliate of my VAMC (the University of New Mexico School of Medicine), where she talked about the excitement and rewards of VA clinical care and research.⁵

The VA Nursing Academic Partnerships (VANAP) is another initiative to promote VA as an educator and employer of health professionals. Comprised of 18 competitively selected nursing schools in the nation and the VA, VANAP’s objective is “increasing recruitment and retention of VA nurses as a result of enhanced roles in nursing education.” The New Mexico VA Health Care System, the hospital I practice at, had the honor of being awarded one of these partnerships, and I have been encouraged to see many student nurses choose the training track at the VA and express interest in employment.

According to a nurse at the Oregon Health & Science University VA partnership, “One thing I learned that I did not expect was about the wars the clients had served in. I gained a greater respect for our men and women in the service past and present…I have now an understanding of not only the physical, but also the mental and emotional effects war has on an individual.”⁶ It is important to realize that even if physicians and nurses in training do not ultimately enter the VA workforce, they still leave their educational experience with a more empathic understanding of the health care needs of veterans.

The salience of the third endeavor, however, has not been widely recognized. In March, Secretary Robert McDonald spoke at a meeting of the Association of American Medical Colleges Council of Deans. His speech traced the history of academic collaboration with the VA; acknowledged the bureaucratic, information technology, and other challenges faced by the VA and its academic affiliates; and reaffirmed the VA’s commitment to academic partnerships. He recognized the significant and lasting contributions the relationship with academic medical centers has had on the care of veterans and the community for decades. His remarks concluded with a vision of the potential the partnership has to transform health education and the delivery of care in the years to come. But perhaps the most hopeful remarks in the speech came not from Secretary McDonald but from the comments of medical students who had rotated at the San Diego VAMC, which he shared:

“The emphasis on teaching was fantastic, and far superior to most other rotations.”

“The vets were a wonderful patient population who really allowed us a great opportunity to learn.”

“The VA is the best place for medical students to work.”⁷ 

This July, medical students, residents, and fellows in almost every medical and surgical specialty will join nurses at all levels of training, undergraduate and graduate pharmacists, dentists, and allied health students to train at a VA hospital. The VA Office of Academic Affiliations (OAA), which coordinates this massive educational effort, reported that in 2015, the last year for which data are available, 123,552 health care trainees were enrolled in VA programs.¹ That’s in addition to the hundreds of health care professionals trained in the 4 branches of the armed services, including students at the Uniformed Services University of the Health Sciences and those receiving a health care education through the PHS. Federal institutions are easily the largest contributors to health care education in the nation and very likely in the world.

This mission to educate the U.S. health care workforce is not new. This year marks the 70th anniversary of the collaboration between the VA and academic affiliates across the country to ensure a highly qualified cadre of health care professionals care, not only for veterans, but also for the public. Hence, the OAA motto: To educate for VA and for the nation.

When allopathic and osteopathic medical schools are combined, there are partnerships between the VA and 90% of U.S. medical schools. More than 70% of all U.S. practicing physicians trained at a VA facility at some time.² Currently, the VA has more than 40 different health care professional training programs under its auspices.

This educational mission is a core VA function that is enshrined in law as are VA’s other 3 core charges. According to the statute, the VA secretary shall “to the extent feasible without interfering with the medical care and treatment of veterans, develop and carry out a program of education and training of health personnel.” The primary clinical care, education, and research functions of the VA are inseparable, and none can be carried out without an adequate number of qualified staff.

Government reports and the media have identified the shortage of VA health care professionals as a major contributor to the wait times crisis of the past several years.³ Section 301 of the Veterans Access, Choice, and Accountability Act of 2014 actually requires the VA Office of Inspector General (OIG) to conduct assessments of the staffing shortages in the department. Reports from the OIG have identified 5 critical need occupations: medical officer, nurse, psychologist, physician assistant, and physical therapist.⁴

From my perspective as a medical officer, I am certain that the reason I went straight to the VA after my residency in psychiatry and have never left is my overwhelmingly positive experience as a medical student and resident. The VA had many of the best teachers in my training programs. The patients were—and still are nearly 20 years later—among the most respectful and appreciative of any I have treated.

Many VA patients considered us, even as trainees, their doctors and often asked us when we were residents whether they could “keep us,” although they knew that as former members of the military, most of us would rotate out of their lives. Yet they also knew that because of the strength of the training programs, a new young doctor would come to take care of them. Even now when the occasional angry patient says, “all you doctors care about is money,” I am proud to say that I could probably make more money in the private sector, but I choose to work at the VA.

Many of my fine colleagues in medicine, nursing, psychology, and allied health also remained at the VA after their training, inspired to provide public health to those who served and were underserved. Those who entered military medicine or the PHS had similar ideals borne of the role models who taught them in those federal institutions. One of the often unappreciated negative consequences of the VA scandal is that it may discouarge students in the health care professions from rotating through or seriously considering careers in the VA.

The VA and the military often do not receive the recognition they deserve as academic medical institutions. Some of the most renowned and accomplished faculty of prestigious medical universities also work at VA facilities. The ability to simultaneously teach gifted students, conduct cutting-edge research, and practice high-quality medicine all in a public health setting are what attracted me and many other idealistic health care professionals to the VA.

The VA, however, has taken active steps to restore its reputation as one of the best places to learn and work. Three outstanding initiatives deserve special attention. The first being a series of visits to medical schools that Carolyn M. Clancy, MD, made when she was the interim under secretary for health. Fortunately for me, she spoke at the academic affiliate of my VAMC (the University of New Mexico School of Medicine), where she talked about the excitement and rewards of VA clinical care and research.⁵

The VA Nursing Academic Partnerships (VANAP) is another initiative to promote VA as an educator and employer of health professionals. Comprised of 18 competitively selected nursing schools in the nation and the VA, VANAP’s objective is “increasing recruitment and retention of VA nurses as a result of enhanced roles in nursing education.” The New Mexico VA Health Care System, the hospital I practice at, had the honor of being awarded one of these partnerships, and I have been encouraged to see many student nurses choose the training track at the VA and express interest in employment.

According to a nurse at the Oregon Health & Science University VA partnership, “One thing I learned that I did not expect was about the wars the clients had served in. I gained a greater respect for our men and women in the service past and present…I have now an understanding of not only the physical, but also the mental and emotional effects war has on an individual.”⁶ It is important to realize that even if physicians and nurses in training do not ultimately enter the VA workforce, they still leave their educational experience with a more empathic understanding of the health care needs of veterans.

The salience of the third endeavor, however, has not been widely recognized. In March, Secretary Robert McDonald spoke at a meeting of the Association of American Medical Colleges Council of Deans. His speech traced the history of academic collaboration with the VA; acknowledged the bureaucratic, information technology, and other challenges faced by the VA and its academic affiliates; and reaffirmed the VA’s commitment to academic partnerships. He recognized the significant and lasting contributions the relationship with academic medical centers has had on the care of veterans and the community for decades. His remarks concluded with a vision of the potential the partnership has to transform health education and the delivery of care in the years to come. But perhaps the most hopeful remarks in the speech came not from Secretary McDonald but from the comments of medical students who had rotated at the San Diego VAMC, which he shared:

“The emphasis on teaching was fantastic, and far superior to most other rotations.”

“The vets were a wonderful patient population who really allowed us a great opportunity to learn.”

“The VA is the best place for medical students to work.”⁷ 

This July, medical students, residents, and fellows in almost every medical and surgical specialty will join nurses at all levels of training, undergraduate and graduate pharmacists, dentists, and allied health students to train at a VA hospital. The VA Office of Academic Affiliations (OAA), which coordinates this massive educational effort, reported that in 2015, the last year for which data are available, 123,552 health care trainees were enrolled in VA programs.¹ That’s in addition to the hundreds of health care professionals trained in the 4 branches of the armed services, including students at the Uniformed Services University of the Health Sciences and those receiving a health care education through the PHS. Federal institutions are easily the largest contributors to health care education in the nation and very likely in the world.

This mission to educate the U.S. health care workforce is not new. This year marks the 70th anniversary of the collaboration between the VA and academic affiliates across the country to ensure a highly qualified cadre of health care professionals care, not only for veterans, but also for the public. Hence, the OAA motto: To educate for VA and for the nation.

When allopathic and osteopathic medical schools are combined, there are partnerships between the VA and 90% of U.S. medical schools. More than 70% of all U.S. practicing physicians trained at a VA facility at some time.² Currently, the VA has more than 40 different health care professional training programs under its auspices.

This educational mission is a core VA function that is enshrined in law as are VA’s other 3 core charges. According to the statute, the VA secretary shall “to the extent feasible without interfering with the medical care and treatment of veterans, develop and carry out a program of education and training of health personnel.” The primary clinical care, education, and research functions of the VA are inseparable, and none can be carried out without an adequate number of qualified staff.

Government reports and the media have identified the shortage of VA health care professionals as a major contributor to the wait times crisis of the past several years.³ Section 301 of the Veterans Access, Choice, and Accountability Act of 2014 actually requires the VA Office of Inspector General (OIG) to conduct assessments of the staffing shortages in the department. Reports from the OIG have identified 5 critical need occupations: medical officer, nurse, psychologist, physician assistant, and physical therapist.⁴

From my perspective as a medical officer, I am certain that the reason I went straight to the VA after my residency in psychiatry and have never left is my overwhelmingly positive experience as a medical student and resident. The VA had many of the best teachers in my training programs. The patients were—and still are nearly 20 years later—among the most respectful and appreciative of any I have treated.

Many VA patients considered us, even as trainees, their doctors and often asked us when we were residents whether they could “keep us,” although they knew that as former members of the military, most of us would rotate out of their lives. Yet they also knew that because of the strength of the training programs, a new young doctor would come to take care of them. Even now when the occasional angry patient says, “all you doctors care about is money,” I am proud to say that I could probably make more money in the private sector, but I choose to work at the VA.

Many of my fine colleagues in medicine, nursing, psychology, and allied health also remained at the VA after their training, inspired to provide public health to those who served and were underserved. Those who entered military medicine or the PHS had similar ideals borne of the role models who taught them in those federal institutions. One of the often unappreciated negative consequences of the VA scandal is that it may discouarge students in the health care professions from rotating through or seriously considering careers in the VA.

The VA and the military often do not receive the recognition they deserve as academic medical institutions. Some of the most renowned and accomplished faculty of prestigious medical universities also work at VA facilities. The ability to simultaneously teach gifted students, conduct cutting-edge research, and practice high-quality medicine all in a public health setting are what attracted me and many other idealistic health care professionals to the VA.

The VA, however, has taken active steps to restore its reputation as one of the best places to learn and work. Three outstanding initiatives deserve special attention. The first being a series of visits to medical schools that Carolyn M. Clancy, MD, made when she was the interim under secretary for health. Fortunately for me, she spoke at the academic affiliate of my VAMC (the University of New Mexico School of Medicine), where she talked about the excitement and rewards of VA clinical care and research.⁵

The VA Nursing Academic Partnerships (VANAP) is another initiative to promote VA as an educator and employer of health professionals. Comprised of 18 competitively selected nursing schools in the nation and the VA, VANAP’s objective is “increasing recruitment and retention of VA nurses as a result of enhanced roles in nursing education.” The New Mexico VA Health Care System, the hospital I practice at, had the honor of being awarded one of these partnerships, and I have been encouraged to see many student nurses choose the training track at the VA and express interest in employment.

According to a nurse at the Oregon Health & Science University VA partnership, “One thing I learned that I did not expect was about the wars the clients had served in. I gained a greater respect for our men and women in the service past and present…I have now an understanding of not only the physical, but also the mental and emotional effects war has on an individual.”⁶ It is important to realize that even if physicians and nurses in training do not ultimately enter the VA workforce, they still leave their educational experience with a more empathic understanding of the health care needs of veterans.

The salience of the third endeavor, however, has not been widely recognized. In March, Secretary Robert McDonald spoke at a meeting of the Association of American Medical Colleges Council of Deans. His speech traced the history of academic collaboration with the VA; acknowledged the bureaucratic, information technology, and other challenges faced by the VA and its academic affiliates; and reaffirmed the VA’s commitment to academic partnerships. He recognized the significant and lasting contributions the relationship with academic medical centers has had on the care of veterans and the community for decades. His remarks concluded with a vision of the potential the partnership has to transform health education and the delivery of care in the years to come. But perhaps the most hopeful remarks in the speech came not from Secretary McDonald but from the comments of medical students who had rotated at the San Diego VAMC, which he shared:

“The emphasis on teaching was fantastic, and far superior to most other rotations.”

“The vets were a wonderful patient population who really allowed us a great opportunity to learn.”

“The VA is the best place for medical students to work.”⁷ 

T cells

Image from NIAID

The US Food and Drug Administration (FDA) has removed the clinical hold on the phase 2 ROCKET trial, a study of the chimeric antigen receptor (CAR) T-cell therapy JCAR015 in adults with relapsed or refractory B-cell acute lymphoblastic leukemia.

The trial will continue with a revised protocol, under which patients will receive only cyclophosphamide as conditioning.

The ROCKET trial was placed on hold after 3 patients died of cerebral edema.

Juno Therapeutics, the company developing JCAR015, believes the deaths were likely a result of adding fludarabine to the conditioning regimen.

Patients initially received conditioning with cyclophosphamide alone, but investigators decided to add fludarabine in hopes of increasing efficacy. Adding fludarabine to conditioning had been shown to increase the efficacy of 2 other CAR T-cell therapies, JCAR014 and JCAR017, in phase 1/2 trials.

However, in the ROCKET trial, the addition of fludarabine was associated with an increase in the incidence of severe neurotoxicity and the 3 deaths from cerebral edema.

Although other factors may have contributed to the deaths, Juno said fludarabine was the most likely culprit. So the company asked the FDA if it could continue the ROCKET trial using conditioning with cyclophosphamide alone.

In response, the FDA requested that Juno submit a revised patient informed consent form, revised investigator brochure, revised trial protocol, and a copy of a presentation the company made to the FDA.

The FDA said it would review these documents within 30 days of receiving them, but the review only took a few days. The agency agreed to lift the clinical hold and allow the trial to proceed with the revised protocol.

ROCKET is not the first trial of JCAR015 to be placed on clinical hold. The phase 1 trial of the therapy was placed on hold in 2014, after 2 patients died of cytokine release syndrome.

That hold was lifted following changes to enrollment criteria and dosing. Results from this trial were presented at ASCO 2015 and ASCO 2016.

T cells

Image from NIAID

The US Food and Drug Administration (FDA) has removed the clinical hold on the phase 2 ROCKET trial, a study of the chimeric antigen receptor (CAR) T-cell therapy JCAR015 in adults with relapsed or refractory B-cell acute lymphoblastic leukemia.

The trial will continue with a revised protocol, under which patients will receive only cyclophosphamide as conditioning.

The ROCKET trial was placed on hold after 3 patients died of cerebral edema.

Juno Therapeutics, the company developing JCAR015, believes the deaths were likely a result of adding fludarabine to the conditioning regimen.

Patients initially received conditioning with cyclophosphamide alone, but investigators decided to add fludarabine in hopes of increasing efficacy. Adding fludarabine to conditioning had been shown to increase the efficacy of 2 other CAR T-cell therapies, JCAR014 and JCAR017, in phase 1/2 trials.

However, in the ROCKET trial, the addition of fludarabine was associated with an increase in the incidence of severe neurotoxicity and the 3 deaths from cerebral edema.

Although other factors may have contributed to the deaths, Juno said fludarabine was the most likely culprit. So the company asked the FDA if it could continue the ROCKET trial using conditioning with cyclophosphamide alone.

In response, the FDA requested that Juno submit a revised patient informed consent form, revised investigator brochure, revised trial protocol, and a copy of a presentation the company made to the FDA.

The FDA said it would review these documents within 30 days of receiving them, but the review only took a few days. The agency agreed to lift the clinical hold and allow the trial to proceed with the revised protocol.

ROCKET is not the first trial of JCAR015 to be placed on clinical hold. The phase 1 trial of the therapy was placed on hold in 2014, after 2 patients died of cytokine release syndrome.

That hold was lifted following changes to enrollment criteria and dosing. Results from this trial were presented at ASCO 2015 and ASCO 2016.

T cells

Image from NIAID

The US Food and Drug Administration (FDA) has removed the clinical hold on the phase 2 ROCKET trial, a study of the chimeric antigen receptor (CAR) T-cell therapy JCAR015 in adults with relapsed or refractory B-cell acute lymphoblastic leukemia.

The trial will continue with a revised protocol, under which patients will receive only cyclophosphamide as conditioning.

The ROCKET trial was placed on hold after 3 patients died of cerebral edema.

Juno Therapeutics, the company developing JCAR015, believes the deaths were likely a result of adding fludarabine to the conditioning regimen.

Patients initially received conditioning with cyclophosphamide alone, but investigators decided to add fludarabine in hopes of increasing efficacy. Adding fludarabine to conditioning had been shown to increase the efficacy of 2 other CAR T-cell therapies, JCAR014 and JCAR017, in phase 1/2 trials.

However, in the ROCKET trial, the addition of fludarabine was associated with an increase in the incidence of severe neurotoxicity and the 3 deaths from cerebral edema.

Although other factors may have contributed to the deaths, Juno said fludarabine was the most likely culprit. So the company asked the FDA if it could continue the ROCKET trial using conditioning with cyclophosphamide alone.

In response, the FDA requested that Juno submit a revised patient informed consent form, revised investigator brochure, revised trial protocol, and a copy of a presentation the company made to the FDA.

The FDA said it would review these documents within 30 days of receiving them, but the review only took a few days. The agency agreed to lift the clinical hold and allow the trial to proceed with the revised protocol.

ROCKET is not the first trial of JCAR015 to be placed on clinical hold. The phase 1 trial of the therapy was placed on hold in 2014, after 2 patients died of cytokine release syndrome.

That hold was lifted following changes to enrollment criteria and dosing. Results from this trial were presented at ASCO 2015 and ASCO 2016.

Lab mouse

New research suggests the cell of origin controls the aggressiveness and outcome of acute myeloid leukemia (AML) driven by MLL-AF9.

Using a mouse model, investigators found that MLL-AF9 expression in long-term hematopoietic stem cells (HSCs) causes invasive, chemoresistant AML that expresses genes related to epithelial-mesenchymal transition (EMT).

The researchers also found these genes were associated with poor survival in humans with AML.

“The prognosis thus depends on the particular hematopoietic stem or precursor cells in which the genetic alteration occurs and what genes are expressed,” said Antoine Peters, PhD, of Friedrich Miescher Institute for Biomedical Research in Basel, Switzerland.

Dr Peters and his colleagues related these findings in Cancer Cell.

The investigators compared the results of MLL-AF9 expression in long-term HSCs and granulocyte-macrophage progenitors (GMPs) in vitro. They found that colonies derived from long-term HSCs exhibited a greater capacity to migrate and expressed genes known to be involved in cell migration and tissue invasion.

With in vivo experiments, the researchers found that long-term HSCs were more potent in inducing AML than GMPs. Twenty percent of long-term HSC-derived AMLs proved especially aggressive, exhibiting extensive tissue infiltration, resistance to chemotherapy, and the expression of EMT genes such as EVI1, ERG, and ZEB1.

The investigators then tested the function of EMT-related transcription factors in leukemic cell migration and invasion. And they found that knocking down ZEB1 significantly reduced leukemic blast invasion.

Next, the researchers classified mouse and human leukemias according to EVI1/Evi1 and ERG/Erg expression and compared transcriptional profiles between species.

This revealed 111 genes that were more highly expressed in EVI1^highERG^high AML and Evi1^highErg^high iMLL-AF9 long-term-HSC-early AML. These genes were dubbed ‘‘cluster I.’’

The investigators also identified 40 genes that were more highly expressed in EVI1^lowERG^low AML samples and in iMLL-AF9 GMP-derived AML. These were called ‘‘cluster II.’’

Finally, the team evaluated how the 2 gene clusters related to overall survival in patients with 11q23+ AML.

Patients with high expression of cluster I genes tended to have poor survival rates, while patients with high levels of cluster II genes had variable survival rates and a propensity for poor outcomes if they had co-expression of a “substantial fraction” of cluster I genes.

The researchers noted that many cluster I genes are implicated in cell migration, invasion, EMT, and inflammation.

“The expression of genes such as EVI1, ERG, or ZEB1 now allows us to classify patients into different groups according to prognosis and, if necessary, to adapt treatment,” said Jürg Schwaller, MD, of University Children’s Hospital and University of Basel in Switzerland.

“Our findings should also enable us to develop new, more personalized therapies for these patients.”

Lab mouse

New research suggests the cell of origin controls the aggressiveness and outcome of acute myeloid leukemia (AML) driven by MLL-AF9.

Using a mouse model, investigators found that MLL-AF9 expression in long-term hematopoietic stem cells (HSCs) causes invasive, chemoresistant AML that expresses genes related to epithelial-mesenchymal transition (EMT).

The researchers also found these genes were associated with poor survival in humans with AML.

“The prognosis thus depends on the particular hematopoietic stem or precursor cells in which the genetic alteration occurs and what genes are expressed,” said Antoine Peters, PhD, of Friedrich Miescher Institute for Biomedical Research in Basel, Switzerland.

Dr Peters and his colleagues related these findings in Cancer Cell.

The investigators compared the results of MLL-AF9 expression in long-term HSCs and granulocyte-macrophage progenitors (GMPs) in vitro. They found that colonies derived from long-term HSCs exhibited a greater capacity to migrate and expressed genes known to be involved in cell migration and tissue invasion.

With in vivo experiments, the researchers found that long-term HSCs were more potent in inducing AML than GMPs. Twenty percent of long-term HSC-derived AMLs proved especially aggressive, exhibiting extensive tissue infiltration, resistance to chemotherapy, and the expression of EMT genes such as EVI1, ERG, and ZEB1.

The investigators then tested the function of EMT-related transcription factors in leukemic cell migration and invasion. And they found that knocking down ZEB1 significantly reduced leukemic blast invasion.

Next, the researchers classified mouse and human leukemias according to EVI1/Evi1 and ERG/Erg expression and compared transcriptional profiles between species.

This revealed 111 genes that were more highly expressed in EVI1^highERG^high AML and Evi1^highErg^high iMLL-AF9 long-term-HSC-early AML. These genes were dubbed ‘‘cluster I.’’

The investigators also identified 40 genes that were more highly expressed in EVI1^lowERG^low AML samples and in iMLL-AF9 GMP-derived AML. These were called ‘‘cluster II.’’

Finally, the team evaluated how the 2 gene clusters related to overall survival in patients with 11q23+ AML.

Patients with high expression of cluster I genes tended to have poor survival rates, while patients with high levels of cluster II genes had variable survival rates and a propensity for poor outcomes if they had co-expression of a “substantial fraction” of cluster I genes.

The researchers noted that many cluster I genes are implicated in cell migration, invasion, EMT, and inflammation.

“The expression of genes such as EVI1, ERG, or ZEB1 now allows us to classify patients into different groups according to prognosis and, if necessary, to adapt treatment,” said Jürg Schwaller, MD, of University Children’s Hospital and University of Basel in Switzerland.

“Our findings should also enable us to develop new, more personalized therapies for these patients.”

Lab mouse

New research suggests the cell of origin controls the aggressiveness and outcome of acute myeloid leukemia (AML) driven by MLL-AF9.

Using a mouse model, investigators found that MLL-AF9 expression in long-term hematopoietic stem cells (HSCs) causes invasive, chemoresistant AML that expresses genes related to epithelial-mesenchymal transition (EMT).

The researchers also found these genes were associated with poor survival in humans with AML.

“The prognosis thus depends on the particular hematopoietic stem or precursor cells in which the genetic alteration occurs and what genes are expressed,” said Antoine Peters, PhD, of Friedrich Miescher Institute for Biomedical Research in Basel, Switzerland.

Dr Peters and his colleagues related these findings in Cancer Cell.

The investigators compared the results of MLL-AF9 expression in long-term HSCs and granulocyte-macrophage progenitors (GMPs) in vitro. They found that colonies derived from long-term HSCs exhibited a greater capacity to migrate and expressed genes known to be involved in cell migration and tissue invasion.

With in vivo experiments, the researchers found that long-term HSCs were more potent in inducing AML than GMPs. Twenty percent of long-term HSC-derived AMLs proved especially aggressive, exhibiting extensive tissue infiltration, resistance to chemotherapy, and the expression of EMT genes such as EVI1, ERG, and ZEB1.

The investigators then tested the function of EMT-related transcription factors in leukemic cell migration and invasion. And they found that knocking down ZEB1 significantly reduced leukemic blast invasion.

Next, the researchers classified mouse and human leukemias according to EVI1/Evi1 and ERG/Erg expression and compared transcriptional profiles between species.

This revealed 111 genes that were more highly expressed in EVI1^highERG^high AML and Evi1^highErg^high iMLL-AF9 long-term-HSC-early AML. These genes were dubbed ‘‘cluster I.’’

The investigators also identified 40 genes that were more highly expressed in EVI1^lowERG^low AML samples and in iMLL-AF9 GMP-derived AML. These were called ‘‘cluster II.’’

Finally, the team evaluated how the 2 gene clusters related to overall survival in patients with 11q23+ AML.

Patients with high expression of cluster I genes tended to have poor survival rates, while patients with high levels of cluster II genes had variable survival rates and a propensity for poor outcomes if they had co-expression of a “substantial fraction” of cluster I genes.

The researchers noted that many cluster I genes are implicated in cell migration, invasion, EMT, and inflammation.

“The expression of genes such as EVI1, ERG, or ZEB1 now allows us to classify patients into different groups according to prognosis and, if necessary, to adapt treatment,” said Jürg Schwaller, MD, of University Children’s Hospital and University of Basel in Switzerland.

“Our findings should also enable us to develop new, more personalized therapies for these patients.”

Kids in Kenya

Photo by Gabrielle Tenenbaum

Progress in reducing the malaria burden in Africa may have had the paradoxical effect of increasing malaria transmission among older children in recent years, according to research published in PLOS Medicine.

Researchers analyzed data on children admitted to a hospital in Kenya over a 25-year period and found that malaria transmission decreased from 1998 to 2009 but began to rise after that, and older children accounted for most of this increase.

The researchers believe this may be a result of a decrease in acquired immunity among the older children.

Philip Bejon, PhD, of the University of Oxford in the UK, and his colleagues conducted this study. The team analyzed malaria screening data from pediatric emergency admissions to Kilifi County Hospital between 1990 and 2014 and linked it to data on residence and insecticide-treated bednet (ITN) use.

During the period studied, 69,104 children, ages 3 months to 13 years, had malaria screening data available.

The proportion of hospital admissions found positive for malaria decreased from a high of 56% in 1998 to a low of 7% in 2009, but then rose again to 24% in 2014.

The researchers said they were unable to determine the cause of the decline in malaria infections between 1998 and 2009, which pre-dated the dramatic scale-up in ITN distribution and use in the area.

However, they noted that the subsequent increases in malaria infections coincided with a shift in burden from younger to older children, and children who lived in areas with high usage of ITNs were less likely to present with malaria than children who lived in areas with low usage of ITNs.

The researchers said the upswing in malaria transmission among older children following a period of low malaria transmission may be due to decreased acquired immunity because these children were less likely to have been exposed to malaria early in life.

The team also noted that varying levels of access to care and ITN use may have introduced bias in this study, and these data were taken from a single geographic setting. However, they still believe the findings suggest malaria elimination will require continued—and increasing—vigilance.

Kids in Kenya

Photo by Gabrielle Tenenbaum

Progress in reducing the malaria burden in Africa may have had the paradoxical effect of increasing malaria transmission among older children in recent years, according to research published in PLOS Medicine.

Researchers analyzed data on children admitted to a hospital in Kenya over a 25-year period and found that malaria transmission decreased from 1998 to 2009 but began to rise after that, and older children accounted for most of this increase.

The researchers believe this may be a result of a decrease in acquired immunity among the older children.

Philip Bejon, PhD, of the University of Oxford in the UK, and his colleagues conducted this study. The team analyzed malaria screening data from pediatric emergency admissions to Kilifi County Hospital between 1990 and 2014 and linked it to data on residence and insecticide-treated bednet (ITN) use.

During the period studied, 69,104 children, ages 3 months to 13 years, had malaria screening data available.

The proportion of hospital admissions found positive for malaria decreased from a high of 56% in 1998 to a low of 7% in 2009, but then rose again to 24% in 2014.

The researchers said they were unable to determine the cause of the decline in malaria infections between 1998 and 2009, which pre-dated the dramatic scale-up in ITN distribution and use in the area.

However, they noted that the subsequent increases in malaria infections coincided with a shift in burden from younger to older children, and children who lived in areas with high usage of ITNs were less likely to present with malaria than children who lived in areas with low usage of ITNs.

The researchers said the upswing in malaria transmission among older children following a period of low malaria transmission may be due to decreased acquired immunity because these children were less likely to have been exposed to malaria early in life.

The team also noted that varying levels of access to care and ITN use may have introduced bias in this study, and these data were taken from a single geographic setting. However, they still believe the findings suggest malaria elimination will require continued—and increasing—vigilance.

Kids in Kenya

Photo by Gabrielle Tenenbaum

Progress in reducing the malaria burden in Africa may have had the paradoxical effect of increasing malaria transmission among older children in recent years, according to research published in PLOS Medicine.

Researchers analyzed data on children admitted to a hospital in Kenya over a 25-year period and found that malaria transmission decreased from 1998 to 2009 but began to rise after that, and older children accounted for most of this increase.

The researchers believe this may be a result of a decrease in acquired immunity among the older children.

Philip Bejon, PhD, of the University of Oxford in the UK, and his colleagues conducted this study. The team analyzed malaria screening data from pediatric emergency admissions to Kilifi County Hospital between 1990 and 2014 and linked it to data on residence and insecticide-treated bednet (ITN) use.

During the period studied, 69,104 children, ages 3 months to 13 years, had malaria screening data available.

The proportion of hospital admissions found positive for malaria decreased from a high of 56% in 1998 to a low of 7% in 2009, but then rose again to 24% in 2014.

The researchers said they were unable to determine the cause of the decline in malaria infections between 1998 and 2009, which pre-dated the dramatic scale-up in ITN distribution and use in the area.

However, they noted that the subsequent increases in malaria infections coincided with a shift in burden from younger to older children, and children who lived in areas with high usage of ITNs were less likely to present with malaria than children who lived in areas with low usage of ITNs.

The researchers said the upswing in malaria transmission among older children following a period of low malaria transmission may be due to decreased acquired immunity because these children were less likely to have been exposed to malaria early in life.

The team also noted that varying levels of access to care and ITN use may have introduced bias in this study, and these data were taken from a single geographic setting. However, they still believe the findings suggest malaria elimination will require continued—and increasing—vigilance.

Vials of ipilimumab

Photo from Business Wire

Results of a phase 1 study suggest that repeated doses of the immunotherapy drug ipilimumab is a feasible treatment option for patients with hematologic diseases who relapse after allogeneic hematopoietic stem cell transplant (HSCT).

Seven of the 28 patients studied responded to the treatment, but immune-mediated toxic effects and graft-vs-host disease (GVHD) occurred as well.

These results were published in NEJM.

Ipilimumab, which is already approved to treat unresectable or metastatic melanoma, works by blocking the immune checkpoint CTLA-4. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation.

“We believe [,in the case of relapse after HSCT,] the donor immune cells are present but can’t recognize the tumor cells because of inhibitory signals that disguise them,” said study author Matthew Davids, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.

“By blocking the checkpoint, you allow the donor cells to see the cancer cells.”

Dr Davids and his colleagues tested this theory in 28 patients who had relapsed after allogeneic HSCT. The patients had acute myeloid leukemia (AML, n=12), Hodgkin lymphoma (n=7), non-Hodgkin lymphoma (n=4), myelodysplastic syndromes (MDS, n=2), multiple myeloma (n=1), myeloproliferative neoplasm (n=1), or acute lymphoblastic leukemia (n=1).

Patients had received a median of 3 prior treatment regimens, excluding HSCT (range, 1 to 14), and 20 patients (71%) had received treatment for relapse after transplant. Eight patients (29%) previously had grade 1/2 acute GVHD, and 16 (57%) previously had chronic GVHD.

The median time from transplant to initial treatment with ipilimumab was 675 days (range, 198 to 1830), and the median time from relapse to initial treatment with ipilimumab was 97 days (range, 0 to

1415).

Patients received induction therapy with ipilimumab at a dose of 3 mg/kg or 10 mg/kg every 3 weeks for a total of 4 doses. Those who had a clinical benefit received additional doses every 12 weeks for up to 60 weeks.

Safety

Five patients discontinued ipilimumab due to dose-limiting toxic effects. Four of these patients had GVHD, and 1 had severe immune-related adverse events.

Dose-limiting GVHD presented as chronic GVHD of the liver in 3 patients and acute GVHD of the gut in 1 patient.

Immune-related adverse events included death (n=1), pneumonitis (2 grade 2 events, 1 grade 4 event), colitis (1 grade 3 event), immune thrombocytopenia (1 grade 2 event), and diarrhea (1 grade 2 event).

Efficacy

There were no responses in patients who received ipilimumab at 3 mg/kg. Among the 22 patients who received ipilimumab at 10 mg/kg, 5 had a complete response, and 2 had a partial response.

Six other patients did not qualify as having responses but had a decrease in their tumor burden. Altogether, ipilimumab reduced tumor burden in 59% of patients.

The complete responses occurred in 4 patients with extramedullary AML and 1 patient with MDS developing into AML. Two of the AML patients remained in complete response at 12 and 15 months, and the patient with MDS remained in complete response at 16 months.

At a median follow-up of 15 months (range, 8 to 27), the median duration of response had not been reached. Responses were associated with in situ infiltration of cytotoxic CD8+ T cells, decreased activation of regulatory T cells, and expansion of subpopulations of effector T cells.

The 1-year overall survival rate was 49%.

The investigators said these encouraging results have set the stage for larger trials of checkpoint blockade in this patient population. Further research is planned to determine whether immunotherapy drugs could be given to high-risk patients to prevent relapse.

Vials of ipilimumab

Photo from Business Wire

Results of a phase 1 study suggest that repeated doses of the immunotherapy drug ipilimumab is a feasible treatment option for patients with hematologic diseases who relapse after allogeneic hematopoietic stem cell transplant (HSCT).

Seven of the 28 patients studied responded to the treatment, but immune-mediated toxic effects and graft-vs-host disease (GVHD) occurred as well.

These results were published in NEJM.

Ipilimumab, which is already approved to treat unresectable or metastatic melanoma, works by blocking the immune checkpoint CTLA-4. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation.

“We believe [,in the case of relapse after HSCT,] the donor immune cells are present but can’t recognize the tumor cells because of inhibitory signals that disguise them,” said study author Matthew Davids, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.

“By blocking the checkpoint, you allow the donor cells to see the cancer cells.”

Dr Davids and his colleagues tested this theory in 28 patients who had relapsed after allogeneic HSCT. The patients had acute myeloid leukemia (AML, n=12), Hodgkin lymphoma (n=7), non-Hodgkin lymphoma (n=4), myelodysplastic syndromes (MDS, n=2), multiple myeloma (n=1), myeloproliferative neoplasm (n=1), or acute lymphoblastic leukemia (n=1).

Patients had received a median of 3 prior treatment regimens, excluding HSCT (range, 1 to 14), and 20 patients (71%) had received treatment for relapse after transplant. Eight patients (29%) previously had grade 1/2 acute GVHD, and 16 (57%) previously had chronic GVHD.

The median time from transplant to initial treatment with ipilimumab was 675 days (range, 198 to 1830), and the median time from relapse to initial treatment with ipilimumab was 97 days (range, 0 to

1415).

Patients received induction therapy with ipilimumab at a dose of 3 mg/kg or 10 mg/kg every 3 weeks for a total of 4 doses. Those who had a clinical benefit received additional doses every 12 weeks for up to 60 weeks.

Safety

Five patients discontinued ipilimumab due to dose-limiting toxic effects. Four of these patients had GVHD, and 1 had severe immune-related adverse events.

Dose-limiting GVHD presented as chronic GVHD of the liver in 3 patients and acute GVHD of the gut in 1 patient.

Immune-related adverse events included death (n=1), pneumonitis (2 grade 2 events, 1 grade 4 event), colitis (1 grade 3 event), immune thrombocytopenia (1 grade 2 event), and diarrhea (1 grade 2 event).

Efficacy

There were no responses in patients who received ipilimumab at 3 mg/kg. Among the 22 patients who received ipilimumab at 10 mg/kg, 5 had a complete response, and 2 had a partial response.

Six other patients did not qualify as having responses but had a decrease in their tumor burden. Altogether, ipilimumab reduced tumor burden in 59% of patients.

The complete responses occurred in 4 patients with extramedullary AML and 1 patient with MDS developing into AML. Two of the AML patients remained in complete response at 12 and 15 months, and the patient with MDS remained in complete response at 16 months.

At a median follow-up of 15 months (range, 8 to 27), the median duration of response had not been reached. Responses were associated with in situ infiltration of cytotoxic CD8+ T cells, decreased activation of regulatory T cells, and expansion of subpopulations of effector T cells.

The 1-year overall survival rate was 49%.

The investigators said these encouraging results have set the stage for larger trials of checkpoint blockade in this patient population. Further research is planned to determine whether immunotherapy drugs could be given to high-risk patients to prevent relapse.

Vials of ipilimumab

Photo from Business Wire

Results of a phase 1 study suggest that repeated doses of the immunotherapy drug ipilimumab is a feasible treatment option for patients with hematologic diseases who relapse after allogeneic hematopoietic stem cell transplant (HSCT).

Seven of the 28 patients studied responded to the treatment, but immune-mediated toxic effects and graft-vs-host disease (GVHD) occurred as well.

These results were published in NEJM.

Ipilimumab, which is already approved to treat unresectable or metastatic melanoma, works by blocking the immune checkpoint CTLA-4. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation.

“We believe [,in the case of relapse after HSCT,] the donor immune cells are present but can’t recognize the tumor cells because of inhibitory signals that disguise them,” said study author Matthew Davids, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.

“By blocking the checkpoint, you allow the donor cells to see the cancer cells.”

Dr Davids and his colleagues tested this theory in 28 patients who had relapsed after allogeneic HSCT. The patients had acute myeloid leukemia (AML, n=12), Hodgkin lymphoma (n=7), non-Hodgkin lymphoma (n=4), myelodysplastic syndromes (MDS, n=2), multiple myeloma (n=1), myeloproliferative neoplasm (n=1), or acute lymphoblastic leukemia (n=1).

Patients had received a median of 3 prior treatment regimens, excluding HSCT (range, 1 to 14), and 20 patients (71%) had received treatment for relapse after transplant. Eight patients (29%) previously had grade 1/2 acute GVHD, and 16 (57%) previously had chronic GVHD.

The median time from transplant to initial treatment with ipilimumab was 675 days (range, 198 to 1830), and the median time from relapse to initial treatment with ipilimumab was 97 days (range, 0 to

1415).

Patients received induction therapy with ipilimumab at a dose of 3 mg/kg or 10 mg/kg every 3 weeks for a total of 4 doses. Those who had a clinical benefit received additional doses every 12 weeks for up to 60 weeks.

Safety

Five patients discontinued ipilimumab due to dose-limiting toxic effects. Four of these patients had GVHD, and 1 had severe immune-related adverse events.

Dose-limiting GVHD presented as chronic GVHD of the liver in 3 patients and acute GVHD of the gut in 1 patient.

Immune-related adverse events included death (n=1), pneumonitis (2 grade 2 events, 1 grade 4 event), colitis (1 grade 3 event), immune thrombocytopenia (1 grade 2 event), and diarrhea (1 grade 2 event).

Efficacy

There were no responses in patients who received ipilimumab at 3 mg/kg. Among the 22 patients who received ipilimumab at 10 mg/kg, 5 had a complete response, and 2 had a partial response.

Six other patients did not qualify as having responses but had a decrease in their tumor burden. Altogether, ipilimumab reduced tumor burden in 59% of patients.

The complete responses occurred in 4 patients with extramedullary AML and 1 patient with MDS developing into AML. Two of the AML patients remained in complete response at 12 and 15 months, and the patient with MDS remained in complete response at 16 months.

At a median follow-up of 15 months (range, 8 to 27), the median duration of response had not been reached. Responses were associated with in situ infiltration of cytotoxic CD8+ T cells, decreased activation of regulatory T cells, and expansion of subpopulations of effector T cells.

The 1-year overall survival rate was 49%.

The investigators said these encouraging results have set the stage for larger trials of checkpoint blockade in this patient population. Further research is planned to determine whether immunotherapy drugs could be given to high-risk patients to prevent relapse.