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Perfluorodecalin-spiked patch improves tattoo removal results
Laser tattoo removal with use of a perfluorodecalin (PFD)-infused patch allowed significantly more passes during a 5-minute treatment session, in a randomized trial of 30 adults.
In the study, published online in Lasers in Surgery and Medicine, an average of 3.7 laser treatment passes (range 2-4) were used when the laser was combined with a PFD-infused patch during a 5-minute session, compared with an average of 1.4 passes (range 1-3) with the laser alone (P less than .0001).
“Laser-assisted tattoo removal is generally regarded as safe and effective, but the procedure is subject to several important limitations,” wrote Brian S. Biesman, MD, and Cara Costner, RN, FNP, who practice in Nashville, Tenn. These limitations include the need to wait for epidermal whitening to dissipate between laser passes, but “one strategy for improving the efficiency of laser-assisted tattoo removal involves the topical use of an optical clearing agent to reduce the epidermal whitening effect,” they explained.
“Topical use of PFD reduces optical scattering at the skin surface, which helps to improve energy delivery to the tattoo ink in deeper layers of the skin and may reduce the potential of epidermal injury and treatment-related AEs,” they added (Lasers Surg Med. 2017 March 20. doi: 10.1002/lsm.22659).
They enrolled 16 women and 14 men seeking tattoo removal in the randomized, split-area study. The mean age of the subjects was 37 years; most were Fitzpatrick skin type II or III. One side of each tattoo was treated with the 755-nm Q-Switched Alexandrite nanosecond laser alone, and the other half was treated with the same laser through the PFD patch.
Patients’ reports of pain based on the Visual Analog Scale were approximately one point lower on the areas treated with the laser and the patch compared with the laser alone. Compared with the laser-only areas, a lower proportion of the areas treated with the patch were affected by edema (36.7% vs. 63.3%) or erythema (33.3% vs. 70%). None of the patients had hypopigmentation or hyperpigmentation. “All AEs [adverse events] were transient and had resolved by the 1-month follow-up visit,” at which time all 30 patients said they preferred to continue their tattoo removal using the PFD patch, the investigators wrote.
The findings were limited by several factors, including the use of a single laser and the predominance of black or dark blue tattoos, as well as the lack of patients with darker skin types. However, “incorporation of the PFD patch into laser tattoo removal procedures may afford multiple benefits to the patient and provider, including increased efficiency, improved patient safety, fewer AEs associated with epidermal injury, and protection of the patient and provider from tissue splatter and laser plume,” the authors concluded.
Dr. Biesman disclosed grant support, honoraria, or consulting fees from Allergan, Cutera, Cytrellis, Evolus Galderma, Intraderm, Merz, ON Light Sciences, Revance, Sienna, Suneva, Syneron-Candela, Valeant, and Zeltiq. The study was sponsored by ON Light Sciences.
Laser tattoo removal with use of a perfluorodecalin (PFD)-infused patch allowed significantly more passes during a 5-minute treatment session, in a randomized trial of 30 adults.
In the study, published online in Lasers in Surgery and Medicine, an average of 3.7 laser treatment passes (range 2-4) were used when the laser was combined with a PFD-infused patch during a 5-minute session, compared with an average of 1.4 passes (range 1-3) with the laser alone (P less than .0001).
“Laser-assisted tattoo removal is generally regarded as safe and effective, but the procedure is subject to several important limitations,” wrote Brian S. Biesman, MD, and Cara Costner, RN, FNP, who practice in Nashville, Tenn. These limitations include the need to wait for epidermal whitening to dissipate between laser passes, but “one strategy for improving the efficiency of laser-assisted tattoo removal involves the topical use of an optical clearing agent to reduce the epidermal whitening effect,” they explained.
“Topical use of PFD reduces optical scattering at the skin surface, which helps to improve energy delivery to the tattoo ink in deeper layers of the skin and may reduce the potential of epidermal injury and treatment-related AEs,” they added (Lasers Surg Med. 2017 March 20. doi: 10.1002/lsm.22659).
They enrolled 16 women and 14 men seeking tattoo removal in the randomized, split-area study. The mean age of the subjects was 37 years; most were Fitzpatrick skin type II or III. One side of each tattoo was treated with the 755-nm Q-Switched Alexandrite nanosecond laser alone, and the other half was treated with the same laser through the PFD patch.
Patients’ reports of pain based on the Visual Analog Scale were approximately one point lower on the areas treated with the laser and the patch compared with the laser alone. Compared with the laser-only areas, a lower proportion of the areas treated with the patch were affected by edema (36.7% vs. 63.3%) or erythema (33.3% vs. 70%). None of the patients had hypopigmentation or hyperpigmentation. “All AEs [adverse events] were transient and had resolved by the 1-month follow-up visit,” at which time all 30 patients said they preferred to continue their tattoo removal using the PFD patch, the investigators wrote.
The findings were limited by several factors, including the use of a single laser and the predominance of black or dark blue tattoos, as well as the lack of patients with darker skin types. However, “incorporation of the PFD patch into laser tattoo removal procedures may afford multiple benefits to the patient and provider, including increased efficiency, improved patient safety, fewer AEs associated with epidermal injury, and protection of the patient and provider from tissue splatter and laser plume,” the authors concluded.
Dr. Biesman disclosed grant support, honoraria, or consulting fees from Allergan, Cutera, Cytrellis, Evolus Galderma, Intraderm, Merz, ON Light Sciences, Revance, Sienna, Suneva, Syneron-Candela, Valeant, and Zeltiq. The study was sponsored by ON Light Sciences.
Laser tattoo removal with use of a perfluorodecalin (PFD)-infused patch allowed significantly more passes during a 5-minute treatment session, in a randomized trial of 30 adults.
In the study, published online in Lasers in Surgery and Medicine, an average of 3.7 laser treatment passes (range 2-4) were used when the laser was combined with a PFD-infused patch during a 5-minute session, compared with an average of 1.4 passes (range 1-3) with the laser alone (P less than .0001).
“Laser-assisted tattoo removal is generally regarded as safe and effective, but the procedure is subject to several important limitations,” wrote Brian S. Biesman, MD, and Cara Costner, RN, FNP, who practice in Nashville, Tenn. These limitations include the need to wait for epidermal whitening to dissipate between laser passes, but “one strategy for improving the efficiency of laser-assisted tattoo removal involves the topical use of an optical clearing agent to reduce the epidermal whitening effect,” they explained.
“Topical use of PFD reduces optical scattering at the skin surface, which helps to improve energy delivery to the tattoo ink in deeper layers of the skin and may reduce the potential of epidermal injury and treatment-related AEs,” they added (Lasers Surg Med. 2017 March 20. doi: 10.1002/lsm.22659).
They enrolled 16 women and 14 men seeking tattoo removal in the randomized, split-area study. The mean age of the subjects was 37 years; most were Fitzpatrick skin type II or III. One side of each tattoo was treated with the 755-nm Q-Switched Alexandrite nanosecond laser alone, and the other half was treated with the same laser through the PFD patch.
Patients’ reports of pain based on the Visual Analog Scale were approximately one point lower on the areas treated with the laser and the patch compared with the laser alone. Compared with the laser-only areas, a lower proportion of the areas treated with the patch were affected by edema (36.7% vs. 63.3%) or erythema (33.3% vs. 70%). None of the patients had hypopigmentation or hyperpigmentation. “All AEs [adverse events] were transient and had resolved by the 1-month follow-up visit,” at which time all 30 patients said they preferred to continue their tattoo removal using the PFD patch, the investigators wrote.
The findings were limited by several factors, including the use of a single laser and the predominance of black or dark blue tattoos, as well as the lack of patients with darker skin types. However, “incorporation of the PFD patch into laser tattoo removal procedures may afford multiple benefits to the patient and provider, including increased efficiency, improved patient safety, fewer AEs associated with epidermal injury, and protection of the patient and provider from tissue splatter and laser plume,” the authors concluded.
Dr. Biesman disclosed grant support, honoraria, or consulting fees from Allergan, Cutera, Cytrellis, Evolus Galderma, Intraderm, Merz, ON Light Sciences, Revance, Sienna, Suneva, Syneron-Candela, Valeant, and Zeltiq. The study was sponsored by ON Light Sciences.
Key clinical point: Addition of a perfluorodecalin-infused patch to a laser treatment protocol allowed significantly more laser passes with no difference in adverse events.
Major finding: More laser treatment passes for tattoo removal were possible when the laser was combined with a perfluorodecalin patch vs. laser alone (an average of 3.7 vs. 1.4 passes in a 5-minute session, a significant difference).
Data source: A prospective, randomized study of 30 adults seeking removal of tattoos.
Disclosures: Dr. Biesman disclosed grant support, honoraria, or consulting fees from Allergan, Cutera, Cytrellis, Evolus Galderma, Intraderm, Merz, ON Light Sciences, Revance, Sienna, Suneva, Syneron-Candela, Valeant, and Zeltiq. The study was sponsored by ON Light Sciences.
Update on the False Claims Act
Question: Which of the following is correct?
A. The False Claims Act dates back to the Civil War era.
B. The FCA covers only patently false statements.
C. Material misrepresentation is insufficient.
D. Negligence constitutes a violation.
E. A qui tam lawsuit under FCA refers to a third party who has suffered personal harm.
Answer: A. The False Claims Act (FCA) is an old law, enacted by Congress in 1863 to impose liability for submitting a payment demand to the federal government when there is actual or constructive knowledge that the claim is false.1 Many states now have their own versions of FCA.
Intent to defraud is not a required element, but knowing or reckless disregard of the truth or material misrepresentation are – whereas negligence is insufficient to constitute a violation.
In the health care field, FCA most commonly involves false claims made to Medicare or Medicaid. Pitfalls include billing for noncovered services such as experimental treatments, double billing, unnecessary services, billing the government as the primary payer when inappropriate, or regularly waiving deductibles and copayments.
Other activities that constitute wrongdoing in this context include knowingly using another patient’s name for purposes of federal drug coverage, billing for no-shows, and misrepresenting the diagnosis to justify services.
The electronic medical record enables easy check-offs as documentation of actual work done, and fraud is implicated if the information is deliberately misleading, as in the example of upcoding.
Importantly, physicians are liable for the actions of their office staff, so it is prudent to oversee and supervise all billing activities. Aggrieved or disgruntled employees or contractors, popularly known as whistle-blowers, can file a qui tam action. They stand to collect a substantial bounty, up to 30% of the proceeds. They do not have to show legal standing and need not sustain any personal injury.
FCA prosecutions are daily affairs, with egregious examples regularly making the news headlines. A few random pickings might give you an idea of the problem:
In 2015, in its largest case of health care fraud, the federal Department of Justice filed criminal charges against 243 individuals across the nation. Some of the violations included billings for intensive psychotherapy sessions for noncommunicative dementia patients, simply moving patients to different locations, and fraudulent prescriptions under Medicare Part D.
In 2016, a pain management clinic used “ill-equipped, desperate doctors in dire need of work” to write faked prescriptions for narcotics. The clinic owner, a doctor, was sentenced to 144 months in prison for running what was described as a “pill-mill zoo.”
Arguably, the most dramatic physician case occurred in 2017 and involved a Florida dermatologist who settled with the government for $18 million for treating patients for skin cancer they did not have. The action came from a qui tam lawsuit filed by another dermatologist.
A major development in the false claims law came with last year’s U.S. Supreme Court decision in Universal Health Services v. Escobar.2
This landmark case dealt with claims made by Arbour Counseling Services to the Massachusetts’ Medicaid program for mental health counseling and prescriptions, a satellite mental health facility of Universal Health Services. It turned out that relatively few Arbour employees were actually licensed to provide mental health counseling or authorized to prescribe medications. A death resulted from a reaction to an unlicensed prescription.
In a unanimous decision, the Supreme Court held that there can be FCA liability when a defendant submitting a claim makes specific representations about the goods or services provided but fails to disclose noncompliance with material statutory, regulatory, or contractual requirements. Technically referred to as “implied false certification,” such material omissions may amount to a misrepresentation and may be deemed fraudulent, even if the requirements were not expressly designated as conditions of payment.
In the words of the court, “Today’s decision holds that the claims at issue may be actionable because they do more than merely demand payment; they fall squarely within the rule that representations that state the truth only so far as it goes, while omitting critical qualifying information, can be actionable misrepresentations.”
The implied false certification, or implied fraud, ruling has widespread implications, as it does not require a patently false statement. A material misrepresentation or omission may suffice.
There is concern that this ruling will open the floodgates of FCA prosecution. However, the federal Ninth Circuit Court of Appeals has recently quashed an attempt to invoke the implied certification claim in an FCA suit against DJO Global and Biomet, brought by a medical device salesman and his private investigator. Their rejected whistle-blower suit alleged that the defendants were providing their spinal bone growth stimulation devices for use on the cervical spine, even though Food and Drug Administration approval was for use only on the lumbar spine.
Another concern is, can an alleged wrong prognosis regarding life expectancy amount to a false claim?
Under Medicare rules, a physician certifying that a patient is eligible for hospice care must attest that the condition is terminal, with death expected within 6 months.
AseraCare, a hospice company, was accused of knowingly submitting false claims to Medicare by certifying patients as eligible for hospice who did not have a life expectancy of 6 months or less. The government claimed that the medical records of the 123 patients at issue did not contain clinical information and other documentation that supported the medical prognosis. Thus, AseraCare’s claims for those patients were false.
The case brought out the conflicting views of physicians: Did the medical records supported AseraCare’s certifications that the patients were eligible? The defendants argued that, when hospice-certifying physicians and government medical experts look at the very same medical records and disagree about eligibility, the opinion of one medical expert alone cannot prove falsity without further evidence of an objective falsehood.
AseraCare won a summary judgment defending against the $200 million lawsuit in the U.S. District Court for the Northern District of Alabama.3 In a memorandum opinion, the court began with Blaise Pascal’s axiom that “Contradiction is not a sign of falsity, nor the lack of contradiction the sign of truth.” Federal prosecutors have appealed to the federal 11th Circuit Court of Appeals, which recently heard oral arguments. Its decision is pending.
In support of the hospice center physicians, the American Medical Association and other organizations have filed an amicus brief asserting that a physician’s opinion may be deemed false only if no reasonable physician could hold that opinion.
Dr. Tan is emeritus professor of medicine and former adjunct professor of law at the University of Hawaii, Honolulu. This article is meant to be educational and does not constitute medical, ethical, or legal advice. Some of the materials have been taken from earlier columns in Internal Medicine News. For additional information, readers may contact the author at siang@hawaii.edu.
References
1. 31 U.S. Code, Section 3729(a)(1)(A).
2. Universal Health Services v. United States ex rel. Escobar, 579 U.S. ____ (2016).
3. U.S. ex rel. Paradies et al. v. AseraCare Inc. et al., Case number 2:12-CV-245-KOB, in the U.S. District Court for the Northern District of Alabama.
Question: Which of the following is correct?
A. The False Claims Act dates back to the Civil War era.
B. The FCA covers only patently false statements.
C. Material misrepresentation is insufficient.
D. Negligence constitutes a violation.
E. A qui tam lawsuit under FCA refers to a third party who has suffered personal harm.
Answer: A. The False Claims Act (FCA) is an old law, enacted by Congress in 1863 to impose liability for submitting a payment demand to the federal government when there is actual or constructive knowledge that the claim is false.1 Many states now have their own versions of FCA.
Intent to defraud is not a required element, but knowing or reckless disregard of the truth or material misrepresentation are – whereas negligence is insufficient to constitute a violation.
In the health care field, FCA most commonly involves false claims made to Medicare or Medicaid. Pitfalls include billing for noncovered services such as experimental treatments, double billing, unnecessary services, billing the government as the primary payer when inappropriate, or regularly waiving deductibles and copayments.
Other activities that constitute wrongdoing in this context include knowingly using another patient’s name for purposes of federal drug coverage, billing for no-shows, and misrepresenting the diagnosis to justify services.
The electronic medical record enables easy check-offs as documentation of actual work done, and fraud is implicated if the information is deliberately misleading, as in the example of upcoding.
Importantly, physicians are liable for the actions of their office staff, so it is prudent to oversee and supervise all billing activities. Aggrieved or disgruntled employees or contractors, popularly known as whistle-blowers, can file a qui tam action. They stand to collect a substantial bounty, up to 30% of the proceeds. They do not have to show legal standing and need not sustain any personal injury.
FCA prosecutions are daily affairs, with egregious examples regularly making the news headlines. A few random pickings might give you an idea of the problem:
In 2015, in its largest case of health care fraud, the federal Department of Justice filed criminal charges against 243 individuals across the nation. Some of the violations included billings for intensive psychotherapy sessions for noncommunicative dementia patients, simply moving patients to different locations, and fraudulent prescriptions under Medicare Part D.
In 2016, a pain management clinic used “ill-equipped, desperate doctors in dire need of work” to write faked prescriptions for narcotics. The clinic owner, a doctor, was sentenced to 144 months in prison for running what was described as a “pill-mill zoo.”
Arguably, the most dramatic physician case occurred in 2017 and involved a Florida dermatologist who settled with the government for $18 million for treating patients for skin cancer they did not have. The action came from a qui tam lawsuit filed by another dermatologist.
A major development in the false claims law came with last year’s U.S. Supreme Court decision in Universal Health Services v. Escobar.2
This landmark case dealt with claims made by Arbour Counseling Services to the Massachusetts’ Medicaid program for mental health counseling and prescriptions, a satellite mental health facility of Universal Health Services. It turned out that relatively few Arbour employees were actually licensed to provide mental health counseling or authorized to prescribe medications. A death resulted from a reaction to an unlicensed prescription.
In a unanimous decision, the Supreme Court held that there can be FCA liability when a defendant submitting a claim makes specific representations about the goods or services provided but fails to disclose noncompliance with material statutory, regulatory, or contractual requirements. Technically referred to as “implied false certification,” such material omissions may amount to a misrepresentation and may be deemed fraudulent, even if the requirements were not expressly designated as conditions of payment.
In the words of the court, “Today’s decision holds that the claims at issue may be actionable because they do more than merely demand payment; they fall squarely within the rule that representations that state the truth only so far as it goes, while omitting critical qualifying information, can be actionable misrepresentations.”
The implied false certification, or implied fraud, ruling has widespread implications, as it does not require a patently false statement. A material misrepresentation or omission may suffice.
There is concern that this ruling will open the floodgates of FCA prosecution. However, the federal Ninth Circuit Court of Appeals has recently quashed an attempt to invoke the implied certification claim in an FCA suit against DJO Global and Biomet, brought by a medical device salesman and his private investigator. Their rejected whistle-blower suit alleged that the defendants were providing their spinal bone growth stimulation devices for use on the cervical spine, even though Food and Drug Administration approval was for use only on the lumbar spine.
Another concern is, can an alleged wrong prognosis regarding life expectancy amount to a false claim?
Under Medicare rules, a physician certifying that a patient is eligible for hospice care must attest that the condition is terminal, with death expected within 6 months.
AseraCare, a hospice company, was accused of knowingly submitting false claims to Medicare by certifying patients as eligible for hospice who did not have a life expectancy of 6 months or less. The government claimed that the medical records of the 123 patients at issue did not contain clinical information and other documentation that supported the medical prognosis. Thus, AseraCare’s claims for those patients were false.
The case brought out the conflicting views of physicians: Did the medical records supported AseraCare’s certifications that the patients were eligible? The defendants argued that, when hospice-certifying physicians and government medical experts look at the very same medical records and disagree about eligibility, the opinion of one medical expert alone cannot prove falsity without further evidence of an objective falsehood.
AseraCare won a summary judgment defending against the $200 million lawsuit in the U.S. District Court for the Northern District of Alabama.3 In a memorandum opinion, the court began with Blaise Pascal’s axiom that “Contradiction is not a sign of falsity, nor the lack of contradiction the sign of truth.” Federal prosecutors have appealed to the federal 11th Circuit Court of Appeals, which recently heard oral arguments. Its decision is pending.
In support of the hospice center physicians, the American Medical Association and other organizations have filed an amicus brief asserting that a physician’s opinion may be deemed false only if no reasonable physician could hold that opinion.
Dr. Tan is emeritus professor of medicine and former adjunct professor of law at the University of Hawaii, Honolulu. This article is meant to be educational and does not constitute medical, ethical, or legal advice. Some of the materials have been taken from earlier columns in Internal Medicine News. For additional information, readers may contact the author at siang@hawaii.edu.
References
1. 31 U.S. Code, Section 3729(a)(1)(A).
2. Universal Health Services v. United States ex rel. Escobar, 579 U.S. ____ (2016).
3. U.S. ex rel. Paradies et al. v. AseraCare Inc. et al., Case number 2:12-CV-245-KOB, in the U.S. District Court for the Northern District of Alabama.
Question: Which of the following is correct?
A. The False Claims Act dates back to the Civil War era.
B. The FCA covers only patently false statements.
C. Material misrepresentation is insufficient.
D. Negligence constitutes a violation.
E. A qui tam lawsuit under FCA refers to a third party who has suffered personal harm.
Answer: A. The False Claims Act (FCA) is an old law, enacted by Congress in 1863 to impose liability for submitting a payment demand to the federal government when there is actual or constructive knowledge that the claim is false.1 Many states now have their own versions of FCA.
Intent to defraud is not a required element, but knowing or reckless disregard of the truth or material misrepresentation are – whereas negligence is insufficient to constitute a violation.
In the health care field, FCA most commonly involves false claims made to Medicare or Medicaid. Pitfalls include billing for noncovered services such as experimental treatments, double billing, unnecessary services, billing the government as the primary payer when inappropriate, or regularly waiving deductibles and copayments.
Other activities that constitute wrongdoing in this context include knowingly using another patient’s name for purposes of federal drug coverage, billing for no-shows, and misrepresenting the diagnosis to justify services.
The electronic medical record enables easy check-offs as documentation of actual work done, and fraud is implicated if the information is deliberately misleading, as in the example of upcoding.
Importantly, physicians are liable for the actions of their office staff, so it is prudent to oversee and supervise all billing activities. Aggrieved or disgruntled employees or contractors, popularly known as whistle-blowers, can file a qui tam action. They stand to collect a substantial bounty, up to 30% of the proceeds. They do not have to show legal standing and need not sustain any personal injury.
FCA prosecutions are daily affairs, with egregious examples regularly making the news headlines. A few random pickings might give you an idea of the problem:
In 2015, in its largest case of health care fraud, the federal Department of Justice filed criminal charges against 243 individuals across the nation. Some of the violations included billings for intensive psychotherapy sessions for noncommunicative dementia patients, simply moving patients to different locations, and fraudulent prescriptions under Medicare Part D.
In 2016, a pain management clinic used “ill-equipped, desperate doctors in dire need of work” to write faked prescriptions for narcotics. The clinic owner, a doctor, was sentenced to 144 months in prison for running what was described as a “pill-mill zoo.”
Arguably, the most dramatic physician case occurred in 2017 and involved a Florida dermatologist who settled with the government for $18 million for treating patients for skin cancer they did not have. The action came from a qui tam lawsuit filed by another dermatologist.
A major development in the false claims law came with last year’s U.S. Supreme Court decision in Universal Health Services v. Escobar.2
This landmark case dealt with claims made by Arbour Counseling Services to the Massachusetts’ Medicaid program for mental health counseling and prescriptions, a satellite mental health facility of Universal Health Services. It turned out that relatively few Arbour employees were actually licensed to provide mental health counseling or authorized to prescribe medications. A death resulted from a reaction to an unlicensed prescription.
In a unanimous decision, the Supreme Court held that there can be FCA liability when a defendant submitting a claim makes specific representations about the goods or services provided but fails to disclose noncompliance with material statutory, regulatory, or contractual requirements. Technically referred to as “implied false certification,” such material omissions may amount to a misrepresentation and may be deemed fraudulent, even if the requirements were not expressly designated as conditions of payment.
In the words of the court, “Today’s decision holds that the claims at issue may be actionable because they do more than merely demand payment; they fall squarely within the rule that representations that state the truth only so far as it goes, while omitting critical qualifying information, can be actionable misrepresentations.”
The implied false certification, or implied fraud, ruling has widespread implications, as it does not require a patently false statement. A material misrepresentation or omission may suffice.
There is concern that this ruling will open the floodgates of FCA prosecution. However, the federal Ninth Circuit Court of Appeals has recently quashed an attempt to invoke the implied certification claim in an FCA suit against DJO Global and Biomet, brought by a medical device salesman and his private investigator. Their rejected whistle-blower suit alleged that the defendants were providing their spinal bone growth stimulation devices for use on the cervical spine, even though Food and Drug Administration approval was for use only on the lumbar spine.
Another concern is, can an alleged wrong prognosis regarding life expectancy amount to a false claim?
Under Medicare rules, a physician certifying that a patient is eligible for hospice care must attest that the condition is terminal, with death expected within 6 months.
AseraCare, a hospice company, was accused of knowingly submitting false claims to Medicare by certifying patients as eligible for hospice who did not have a life expectancy of 6 months or less. The government claimed that the medical records of the 123 patients at issue did not contain clinical information and other documentation that supported the medical prognosis. Thus, AseraCare’s claims for those patients were false.
The case brought out the conflicting views of physicians: Did the medical records supported AseraCare’s certifications that the patients were eligible? The defendants argued that, when hospice-certifying physicians and government medical experts look at the very same medical records and disagree about eligibility, the opinion of one medical expert alone cannot prove falsity without further evidence of an objective falsehood.
AseraCare won a summary judgment defending against the $200 million lawsuit in the U.S. District Court for the Northern District of Alabama.3 In a memorandum opinion, the court began with Blaise Pascal’s axiom that “Contradiction is not a sign of falsity, nor the lack of contradiction the sign of truth.” Federal prosecutors have appealed to the federal 11th Circuit Court of Appeals, which recently heard oral arguments. Its decision is pending.
In support of the hospice center physicians, the American Medical Association and other organizations have filed an amicus brief asserting that a physician’s opinion may be deemed false only if no reasonable physician could hold that opinion.
Dr. Tan is emeritus professor of medicine and former adjunct professor of law at the University of Hawaii, Honolulu. This article is meant to be educational and does not constitute medical, ethical, or legal advice. Some of the materials have been taken from earlier columns in Internal Medicine News. For additional information, readers may contact the author at siang@hawaii.edu.
References
1. 31 U.S. Code, Section 3729(a)(1)(A).
2. Universal Health Services v. United States ex rel. Escobar, 579 U.S. ____ (2016).
3. U.S. ex rel. Paradies et al. v. AseraCare Inc. et al., Case number 2:12-CV-245-KOB, in the U.S. District Court for the Northern District of Alabama.
Oral Contraceptives for Acne Treatment: Prescribing Practices of US Dermatologists
Confirmatory blood typing unnecessary for closed prolapse repairs
SAN ANTONIO – It was safe to skip preoperative blood type and antibody screening before vaginal and robotic apical prolapse surgeries at the University of North Carolina, Chapel Hill, so long as the women didn’t have hemorrhage risk factors.
The rate of blood transfusions was 0.5% for both the 204 women who had vaginal repairs and the 203 women who underwent robotic repairs; the rate of positive antibody tests was 1.6%. Given the 0.4% risk of transfusion reactions in unscreened women, the investigators calculated that the risk of serious transfusion reactions was 1 in 50,000 with closed vaginal prolapse repairs.
“The bottom line for us is that the risk in this situation is very low, even if preop type and screens are not performed, and women hemorrhage. This information provides insight to answer our key clinical question, which was if we should continue to order preop type and screens,” lead investigator Taylor Brueseke, MD, an ob.gyn. fellow at the University of North Carolina, Chapel Hill, said at the annual scientific meeting of the Society of Gynecologic Surgeons.
That question has been on the minds of gynecologic surgeons, and it’s probably never been parsed out before by route of surgery. The American College of Pathologists recommends two blood type and antibody screens from separate venipunctures before surgery. Often, the second, confirmatory test means that women have to come in even earlier on the morning of surgery and deal with another painful blood draw. It also adds a few hundred dollars to the bill.
Every surgeon needs to draw their own line between risks and benefits, Dr. Brueseke said, but it seems reasonable in many cases to skip the second screening for closed repairs. Even if a woman has a transfusion reaction, “it doesn’t mean that the patient is going to die. It’s something that you can deal with,” he said.
However, the team reached a different conclusion for women who undergo open abdominal repairs. Among the 201 cases they reviewed, 10.5% had a transfusion, which translated to a transfusion reaction risk of 1 in 2,645 for unscreened women undergoing open apical prolapse surgery. The higher hemorrhage rate was probably due to concomitant Burch procedures and other open incontinence operations.
For abdominal cases, and for women who have had prior transfusions, surgeries, or anticoagulation, “consider type and screen,” Dr. Brueseke said at the meeting.
In a separate study presented at the conference, more than 50,000 pelvic floor disorder surgeries in the National Surgery Quality Improvement Program database further defined the hemorrhage risk.
Investigators at Ohio State University, Columbus, found that the overall incidence of blood transfusions was low at 1.26%, but open abdominal procedures again increased the risk. Other factors associated with an increased risk of blood transfusion included preoperative hematocrit less than 30%, an American Society of Anesthesiologists physical status score of 3 or higher, concomitant hysterectomy, body mass index below 18.5 kg/m2, age less than 30 and over 65 years, and a history of bleeding disorders.
In the UNC study, the median Pelvic Organ Prolapse Quantification was stage III. Patients with bleeding disorders, anticoagulant use, or combined surgery with other services were excluded.
There was no industry funding for the two studies, and the investigators reported having no relevant financial disclosures.
* The meeting sponsor information was updated 6/9/2017.
A lot of people automatically order type and screen for vaginal prolapse repairs, but we really need to rethink that if there aren’t risk factors that warrant it. I defer to the anesthesiologists because they are the ones who usually want this, but most of the time we screen but don’t use the results. There’s room to improve clinical practice here.
Robert Gutman, MD, is a gynecologic surgeon in Washington, D.C., and the program chair for the 2017 Society of Gynecologic Surgeons annual scientific meeting. He wasn’t involved in the studies presented.
A lot of people automatically order type and screen for vaginal prolapse repairs, but we really need to rethink that if there aren’t risk factors that warrant it. I defer to the anesthesiologists because they are the ones who usually want this, but most of the time we screen but don’t use the results. There’s room to improve clinical practice here.
Robert Gutman, MD, is a gynecologic surgeon in Washington, D.C., and the program chair for the 2017 Society of Gynecologic Surgeons annual scientific meeting. He wasn’t involved in the studies presented.
A lot of people automatically order type and screen for vaginal prolapse repairs, but we really need to rethink that if there aren’t risk factors that warrant it. I defer to the anesthesiologists because they are the ones who usually want this, but most of the time we screen but don’t use the results. There’s room to improve clinical practice here.
Robert Gutman, MD, is a gynecologic surgeon in Washington, D.C., and the program chair for the 2017 Society of Gynecologic Surgeons annual scientific meeting. He wasn’t involved in the studies presented.
SAN ANTONIO – It was safe to skip preoperative blood type and antibody screening before vaginal and robotic apical prolapse surgeries at the University of North Carolina, Chapel Hill, so long as the women didn’t have hemorrhage risk factors.
The rate of blood transfusions was 0.5% for both the 204 women who had vaginal repairs and the 203 women who underwent robotic repairs; the rate of positive antibody tests was 1.6%. Given the 0.4% risk of transfusion reactions in unscreened women, the investigators calculated that the risk of serious transfusion reactions was 1 in 50,000 with closed vaginal prolapse repairs.
“The bottom line for us is that the risk in this situation is very low, even if preop type and screens are not performed, and women hemorrhage. This information provides insight to answer our key clinical question, which was if we should continue to order preop type and screens,” lead investigator Taylor Brueseke, MD, an ob.gyn. fellow at the University of North Carolina, Chapel Hill, said at the annual scientific meeting of the Society of Gynecologic Surgeons.
That question has been on the minds of gynecologic surgeons, and it’s probably never been parsed out before by route of surgery. The American College of Pathologists recommends two blood type and antibody screens from separate venipunctures before surgery. Often, the second, confirmatory test means that women have to come in even earlier on the morning of surgery and deal with another painful blood draw. It also adds a few hundred dollars to the bill.
Every surgeon needs to draw their own line between risks and benefits, Dr. Brueseke said, but it seems reasonable in many cases to skip the second screening for closed repairs. Even if a woman has a transfusion reaction, “it doesn’t mean that the patient is going to die. It’s something that you can deal with,” he said.
However, the team reached a different conclusion for women who undergo open abdominal repairs. Among the 201 cases they reviewed, 10.5% had a transfusion, which translated to a transfusion reaction risk of 1 in 2,645 for unscreened women undergoing open apical prolapse surgery. The higher hemorrhage rate was probably due to concomitant Burch procedures and other open incontinence operations.
For abdominal cases, and for women who have had prior transfusions, surgeries, or anticoagulation, “consider type and screen,” Dr. Brueseke said at the meeting.
In a separate study presented at the conference, more than 50,000 pelvic floor disorder surgeries in the National Surgery Quality Improvement Program database further defined the hemorrhage risk.
Investigators at Ohio State University, Columbus, found that the overall incidence of blood transfusions was low at 1.26%, but open abdominal procedures again increased the risk. Other factors associated with an increased risk of blood transfusion included preoperative hematocrit less than 30%, an American Society of Anesthesiologists physical status score of 3 or higher, concomitant hysterectomy, body mass index below 18.5 kg/m2, age less than 30 and over 65 years, and a history of bleeding disorders.
In the UNC study, the median Pelvic Organ Prolapse Quantification was stage III. Patients with bleeding disorders, anticoagulant use, or combined surgery with other services were excluded.
There was no industry funding for the two studies, and the investigators reported having no relevant financial disclosures.
* The meeting sponsor information was updated 6/9/2017.
SAN ANTONIO – It was safe to skip preoperative blood type and antibody screening before vaginal and robotic apical prolapse surgeries at the University of North Carolina, Chapel Hill, so long as the women didn’t have hemorrhage risk factors.
The rate of blood transfusions was 0.5% for both the 204 women who had vaginal repairs and the 203 women who underwent robotic repairs; the rate of positive antibody tests was 1.6%. Given the 0.4% risk of transfusion reactions in unscreened women, the investigators calculated that the risk of serious transfusion reactions was 1 in 50,000 with closed vaginal prolapse repairs.
“The bottom line for us is that the risk in this situation is very low, even if preop type and screens are not performed, and women hemorrhage. This information provides insight to answer our key clinical question, which was if we should continue to order preop type and screens,” lead investigator Taylor Brueseke, MD, an ob.gyn. fellow at the University of North Carolina, Chapel Hill, said at the annual scientific meeting of the Society of Gynecologic Surgeons.
That question has been on the minds of gynecologic surgeons, and it’s probably never been parsed out before by route of surgery. The American College of Pathologists recommends two blood type and antibody screens from separate venipunctures before surgery. Often, the second, confirmatory test means that women have to come in even earlier on the morning of surgery and deal with another painful blood draw. It also adds a few hundred dollars to the bill.
Every surgeon needs to draw their own line between risks and benefits, Dr. Brueseke said, but it seems reasonable in many cases to skip the second screening for closed repairs. Even if a woman has a transfusion reaction, “it doesn’t mean that the patient is going to die. It’s something that you can deal with,” he said.
However, the team reached a different conclusion for women who undergo open abdominal repairs. Among the 201 cases they reviewed, 10.5% had a transfusion, which translated to a transfusion reaction risk of 1 in 2,645 for unscreened women undergoing open apical prolapse surgery. The higher hemorrhage rate was probably due to concomitant Burch procedures and other open incontinence operations.
For abdominal cases, and for women who have had prior transfusions, surgeries, or anticoagulation, “consider type and screen,” Dr. Brueseke said at the meeting.
In a separate study presented at the conference, more than 50,000 pelvic floor disorder surgeries in the National Surgery Quality Improvement Program database further defined the hemorrhage risk.
Investigators at Ohio State University, Columbus, found that the overall incidence of blood transfusions was low at 1.26%, but open abdominal procedures again increased the risk. Other factors associated with an increased risk of blood transfusion included preoperative hematocrit less than 30%, an American Society of Anesthesiologists physical status score of 3 or higher, concomitant hysterectomy, body mass index below 18.5 kg/m2, age less than 30 and over 65 years, and a history of bleeding disorders.
In the UNC study, the median Pelvic Organ Prolapse Quantification was stage III. Patients with bleeding disorders, anticoagulant use, or combined surgery with other services were excluded.
There was no industry funding for the two studies, and the investigators reported having no relevant financial disclosures.
* The meeting sponsor information was updated 6/9/2017.
Key clinical point:
Major finding: Given the 0.4% risk of transfusion reactions in unscreened women, the risk of serious transfusion reactions was 1 in 50,000 women with closed apical prolapse repairs.
Data source: A review of more than 600 cases of apical prolapse surgery at a single center.
Disclosures: There was no industry funding, and the investigators reported having no relevant financial disclosures.
Neoadjuvant chemotherapy induces mutational, molecular shifts in ovarian cancers
NATIONAL HARBOR, MD. – Treatment of high-grade serous ovarian carcinomas with platinum-based neoadjuvant chemotherapy led to significant changes in the expression of genes encoding “canonical” cell cycle and DNA damage pathways, said Rebecca C. Arend, MD.
Analyses of cell-free (plasma) DNA also revealed mutations that matched those in tumor specimens obtained before and after platinum-based neoadjuvant chemotherapy, Dr. Arend reported at the annual meeting of the Society of Gynecologic Oncology. “Understanding the effect of chemotherapy on gene expression profiles may help guide therapy, and plasma cfDNA could provide a noninvasive approach for monitoring tumor mutations,” said Dr. Arend of the University of Alabama at Birmingham.
High-grade serous ovarian carcinoma is genetically heterogeneous, and chemotherapy further alters gene expression profiles and causes molecular derangement, Dr. Arend noted. “Neoadjuvant chemotherapy provides a unique opportunity to evaluate biospecimens before and afterward,” she added.
Both gene expression and mutational profiles have been used to characterize HGSC, but researchers lack solid methods to evaluate tumor heterogeneity and clonal evolution. To begin filling this gap, Dr. Arend and her associates analyzed plasma and tumor specimens from 19 patients with stage 3 or 4 high-grade serous ovarian carcinoma before and after they underwent three to six cycles of neoadjuvant chemotherapy. Biopsies yielded the baseline tumor specimens, and follow-up specimens were obtained during interval debulking.
The investigators used the NanoString PanCancer 770 gene pathway panel, the Ingenuity Pathway Analysis tool, and nSolver Analysis software to assess changes in gene expression. To quantify mutations, they performed longitudinal next-generation sequencing of 50 genes in tumor and plasma specimens with a 50-gene Ion Torrent panel.
After neoadjuvant chemotherapy, the most up-regulated genes included NR4A1 and NR4A3, which regulate cellular proliferation, differentiation, and apoptosis, and SFRP2, which promotes resistance to chemotherapy by modulating Wnt signaling, Dr. Arend said. The most down-regulated genes included E2F1, which helps mediate the cell cycle and the activity of tumor suppressor genes, and BRCA2, the tumor suppressor gene that encodes a DNA repair protein.
Pathway analysis confirmed that the cell cycle pathway was most up-regulated after neoadjuvant chemotherapy, and that the DNA damage repair pathway was the most downregulated, Dr. Arend reported. Within the DNA damage repair pathway, no gene was significantly up-regulated, while RAD51C, BRCA1, BRCA2, and the FA core complex genes were down-regulated.
Next-generation sequencing of baseline plasma cfDNA identified 57 mutations, of which 6 persisted after neoadjuvant chemotherapy. In contrast, of 38 mutations in tumor at baseline, 33 persisted after chemotherapy.
Only 15 of the 38 mutations in tumor also appeared in cfDNA before treatment. At the time of interval debulking, tumor specimens yielded 36 mutations, of which 11 were detected in cfDNA.
At baseline and after treatment, all patients had TP53 mutations either tumor alone, or in both tumor and plasma. Among four patients whose cancer recurred, three had mutations in cfDNA that were previously detected in tumor. Implicated genes included PIK3CA, TP53, KIT, and KDR.
Overall, the study suggests that gene expression profiling of ovarian HGSC tumor tissue taken at interval debulking could someday help guide treatment decisions after neoadjuvant chemotherapy, Dr. Arend said. “To be able to use cfDNA as liquid biopsy, more studies like this one, which match tumor and cfDNA from multiple time points, are needed,” she added.
Dr. Arend cited no funding sources and reported having no conflicts of interest.
NATIONAL HARBOR, MD. – Treatment of high-grade serous ovarian carcinomas with platinum-based neoadjuvant chemotherapy led to significant changes in the expression of genes encoding “canonical” cell cycle and DNA damage pathways, said Rebecca C. Arend, MD.
Analyses of cell-free (plasma) DNA also revealed mutations that matched those in tumor specimens obtained before and after platinum-based neoadjuvant chemotherapy, Dr. Arend reported at the annual meeting of the Society of Gynecologic Oncology. “Understanding the effect of chemotherapy on gene expression profiles may help guide therapy, and plasma cfDNA could provide a noninvasive approach for monitoring tumor mutations,” said Dr. Arend of the University of Alabama at Birmingham.
High-grade serous ovarian carcinoma is genetically heterogeneous, and chemotherapy further alters gene expression profiles and causes molecular derangement, Dr. Arend noted. “Neoadjuvant chemotherapy provides a unique opportunity to evaluate biospecimens before and afterward,” she added.
Both gene expression and mutational profiles have been used to characterize HGSC, but researchers lack solid methods to evaluate tumor heterogeneity and clonal evolution. To begin filling this gap, Dr. Arend and her associates analyzed plasma and tumor specimens from 19 patients with stage 3 or 4 high-grade serous ovarian carcinoma before and after they underwent three to six cycles of neoadjuvant chemotherapy. Biopsies yielded the baseline tumor specimens, and follow-up specimens were obtained during interval debulking.
The investigators used the NanoString PanCancer 770 gene pathway panel, the Ingenuity Pathway Analysis tool, and nSolver Analysis software to assess changes in gene expression. To quantify mutations, they performed longitudinal next-generation sequencing of 50 genes in tumor and plasma specimens with a 50-gene Ion Torrent panel.
After neoadjuvant chemotherapy, the most up-regulated genes included NR4A1 and NR4A3, which regulate cellular proliferation, differentiation, and apoptosis, and SFRP2, which promotes resistance to chemotherapy by modulating Wnt signaling, Dr. Arend said. The most down-regulated genes included E2F1, which helps mediate the cell cycle and the activity of tumor suppressor genes, and BRCA2, the tumor suppressor gene that encodes a DNA repair protein.
Pathway analysis confirmed that the cell cycle pathway was most up-regulated after neoadjuvant chemotherapy, and that the DNA damage repair pathway was the most downregulated, Dr. Arend reported. Within the DNA damage repair pathway, no gene was significantly up-regulated, while RAD51C, BRCA1, BRCA2, and the FA core complex genes were down-regulated.
Next-generation sequencing of baseline plasma cfDNA identified 57 mutations, of which 6 persisted after neoadjuvant chemotherapy. In contrast, of 38 mutations in tumor at baseline, 33 persisted after chemotherapy.
Only 15 of the 38 mutations in tumor also appeared in cfDNA before treatment. At the time of interval debulking, tumor specimens yielded 36 mutations, of which 11 were detected in cfDNA.
At baseline and after treatment, all patients had TP53 mutations either tumor alone, or in both tumor and plasma. Among four patients whose cancer recurred, three had mutations in cfDNA that were previously detected in tumor. Implicated genes included PIK3CA, TP53, KIT, and KDR.
Overall, the study suggests that gene expression profiling of ovarian HGSC tumor tissue taken at interval debulking could someday help guide treatment decisions after neoadjuvant chemotherapy, Dr. Arend said. “To be able to use cfDNA as liquid biopsy, more studies like this one, which match tumor and cfDNA from multiple time points, are needed,” she added.
Dr. Arend cited no funding sources and reported having no conflicts of interest.
NATIONAL HARBOR, MD. – Treatment of high-grade serous ovarian carcinomas with platinum-based neoadjuvant chemotherapy led to significant changes in the expression of genes encoding “canonical” cell cycle and DNA damage pathways, said Rebecca C. Arend, MD.
Analyses of cell-free (plasma) DNA also revealed mutations that matched those in tumor specimens obtained before and after platinum-based neoadjuvant chemotherapy, Dr. Arend reported at the annual meeting of the Society of Gynecologic Oncology. “Understanding the effect of chemotherapy on gene expression profiles may help guide therapy, and plasma cfDNA could provide a noninvasive approach for monitoring tumor mutations,” said Dr. Arend of the University of Alabama at Birmingham.
High-grade serous ovarian carcinoma is genetically heterogeneous, and chemotherapy further alters gene expression profiles and causes molecular derangement, Dr. Arend noted. “Neoadjuvant chemotherapy provides a unique opportunity to evaluate biospecimens before and afterward,” she added.
Both gene expression and mutational profiles have been used to characterize HGSC, but researchers lack solid methods to evaluate tumor heterogeneity and clonal evolution. To begin filling this gap, Dr. Arend and her associates analyzed plasma and tumor specimens from 19 patients with stage 3 or 4 high-grade serous ovarian carcinoma before and after they underwent three to six cycles of neoadjuvant chemotherapy. Biopsies yielded the baseline tumor specimens, and follow-up specimens were obtained during interval debulking.
The investigators used the NanoString PanCancer 770 gene pathway panel, the Ingenuity Pathway Analysis tool, and nSolver Analysis software to assess changes in gene expression. To quantify mutations, they performed longitudinal next-generation sequencing of 50 genes in tumor and plasma specimens with a 50-gene Ion Torrent panel.
After neoadjuvant chemotherapy, the most up-regulated genes included NR4A1 and NR4A3, which regulate cellular proliferation, differentiation, and apoptosis, and SFRP2, which promotes resistance to chemotherapy by modulating Wnt signaling, Dr. Arend said. The most down-regulated genes included E2F1, which helps mediate the cell cycle and the activity of tumor suppressor genes, and BRCA2, the tumor suppressor gene that encodes a DNA repair protein.
Pathway analysis confirmed that the cell cycle pathway was most up-regulated after neoadjuvant chemotherapy, and that the DNA damage repair pathway was the most downregulated, Dr. Arend reported. Within the DNA damage repair pathway, no gene was significantly up-regulated, while RAD51C, BRCA1, BRCA2, and the FA core complex genes were down-regulated.
Next-generation sequencing of baseline plasma cfDNA identified 57 mutations, of which 6 persisted after neoadjuvant chemotherapy. In contrast, of 38 mutations in tumor at baseline, 33 persisted after chemotherapy.
Only 15 of the 38 mutations in tumor also appeared in cfDNA before treatment. At the time of interval debulking, tumor specimens yielded 36 mutations, of which 11 were detected in cfDNA.
At baseline and after treatment, all patients had TP53 mutations either tumor alone, or in both tumor and plasma. Among four patients whose cancer recurred, three had mutations in cfDNA that were previously detected in tumor. Implicated genes included PIK3CA, TP53, KIT, and KDR.
Overall, the study suggests that gene expression profiling of ovarian HGSC tumor tissue taken at interval debulking could someday help guide treatment decisions after neoadjuvant chemotherapy, Dr. Arend said. “To be able to use cfDNA as liquid biopsy, more studies like this one, which match tumor and cfDNA from multiple time points, are needed,” she added.
Dr. Arend cited no funding sources and reported having no conflicts of interest.
Key clinical point. Neoadjuvant chemotherapy was associated with changes in gene expression and associated pathways in high-grade serous ovarian carcinomas. Some mutations in tumors were also present in plasma cell-free DNA.
Major finding: Pathway analysis confirmed that the cell cycle and apoptosis pathway was the most up-regulated after neoadjuvant chemotherapy, while the DNA damage repair pathway was the most down-regulated. Among 38 baseline mutations in tumor specimens, 15 of 38 appeared in plasma cell-free DNA. At interval debulking, tumor specimens yielded 36 mutations, of which 11 were detected in cfDNA.
Data source: Gene expression profiling, pathway analysis, and next-generation sequencing of 19 patients with high-grade serous ovarian carcinomas.
Disclosures: Dr. Arend cited no funding sources and reported having no conflicts of interest.
Uptake of new heart failure drugs slow despite guidelines
SNOWMASS, COLO. – As William T. Abraham, MD, speaks to colleagues around the country about heart failure therapy, he has noticed that the first-in-class drug ivabradine remains below the radar of most physicians.
“I’ve found that this is an agent that very few people know about, even though it’s been FDA [Food and Drug Administration] approved for about 3 years. It’s used fairly extensively in Europe because that’s where the pivotal SHIFT trial was done, but not very much in the United States,” according to Dr. Abraham, professor of medicine, physiology, and cell biology and director of the division of cardiovascular medicine at Ohio State University in Columbus.
That’s likely to change as word spreads about the May 2016 update of the American College of Cardiology/American Heart Association Guideline for the Management of Heart Failure. The update incorporated evidence-based recommendations on the use of two important new heart failure medications: ivabradine (Corlanor), which received a moderate class IIa recommendation, meaning the drug “should be considered,” and sacubitril/valsartan (Entresto), which received the strongest class I recommendation.
In the right patients, these two oral medications improve heart failure morbidity and mortality significantly beyond what’s achievable with what has been the gold standard, guideline-directed medical therapy. Dr. Abraham described how to get started using the two medications at the Annual Cardiovascular Conference at Snowmass.
Ivabradine
Ivabradine is a selective inhibitor of the sinoatrial pacemaker modulating I(f) current. It acts by slowing the sinus rate without reducing myocardial contractility.
“This agent does one thing and one thing alone: It lowers heart rate,” the cardiologist explained.
And that, he added, was sufficient to significantly reduce the risks of death due to heart failure and recurrent hospitalization for worsening heart failure in the pivotal SHIFT trial.
SHIFT included 6,505 patients with moderate to severe heart failure with reduced left ventricular ejection fraction (LVEF) and a resting heart rate above 70 bpm despite background guideline-directed medical therapy. Participants were randomized double blind to ivabradine titrated to a maximum of 7.5 mg twice daily or placebo and followed for a median of about 23 months. The rate of death due to heart failure was 3% with ivabradine and 5% with placebo, for a statistically significant 26% relative risk reduction favoring ivabradine.
But the drug’s main benefit was in reducing recurrent hospitalizations for heart failure, an endpoint of particular interest to health policy officials given that heart failure hospitalizations chew up a substantial proportion of the Medicare budget. Ivabradine reduced first hospitalizations for heart failure during the study period by 25%, second hospitalizations by 34%, and third hospitalizations by 29% (Eur Heart J. 2012 Nov;33[22]:2813-20).
The ACC/AHA guideline update stresses the importance of reserving ivabradine for heart failure patients whose resting heart rate exceeds 70 bpm, despite being on their maximum tolerated dose of a beta-blocker, Dr. Abraham noted.
Ivabradine is contraindicated in the setting of acute decompensated heart failure, severe liver disease, or hypotension, in patients on any of the numerous agents that strongly inhibit the enzyme cytochrome P450 3A4, and in those who have sick sinus syndrome, have sinoatrial block, or are pacemaker dependent.
Sacubitril/valsartan
Sacubitril inhibits neprilysin, an enzyme that blocks the action of endogenous vasoactive peptides including bradykinin, substance P, and natriuretic peptides, all of which counter important maladaptive mechanisms in heart failure. Sacubitril has been combined with the angiotensin receptor blocker valsartan to form the first-in-class angiotensin receptor neprilysin inhibitor, or ARNI, formerly known as LCZ696 and now marketed as Entresto.
In the pivotal double-blind PARADIGM-HF trial, 8,442 patients with heart failure with reduced ejection fraction were randomized to the ARNI at 200 mg b.i.d. or to enalapril at 10 mg b.i.d. on top of background guideline-directed medical therapy. The trial was stopped early because of evidence of overwhelming benefit: a 20% relative risk reduction in cardiovascular death and a 21% decrease in the risk of heart failure hospitalizations in the sacubitril/valsartan group, as well as significant reductions in heart failure symptoms and physical limitations (N Engl J Med. 2014 Sep 11;371[11]:993-1004).
The updated heart failure guidelines strongly recommend that patients with heart failure should be treated with either an ACE inhibitor, an angiotensin receptor blocker, or an ARNI. Further, patients who remain symptomatic on an ACE inhibitor or angiotensin receptor blocker should be switched to an ARNI; that’s a class Ib recommendation based upon the results of PARADIGM-HF.
In getting started using the ARNI, Dr. Abraham said it’s important to understand as background the selective nature of the PARADIGM-HF study design. During the single-blind run-in period of 5-8 weeks, roughly 10% of patients dropped out because they couldn’t tolerate enalapril at 10 mg b.i.d., and a similar percentage dropped out during the ARNI run-in. Thus, patients who couldn’t tolerate a low dose of an ACE inhibitor weren’t in the study. And patients capable of tolerating guideline-recommended full-dose ACE inhibitor therapy were not specifically sought for participation.
“So there are some unanswered questions about the ARNI. If you’re just getting started with this compound in treating your heart failure patients, my own feeling is you should maybe aim for the type of patient that was included in this trial: patients who could tolerate a moderate dose of an ACE inhibitor and had generally good blood pressure. That’s a great way to begin to get experience with this agent in heart failure,” the cardiologist advised.
He reported serving as a consultant to Abbott Vascular, Medtronic, Novartis, and St. Jude Medical.
SNOWMASS, COLO. – As William T. Abraham, MD, speaks to colleagues around the country about heart failure therapy, he has noticed that the first-in-class drug ivabradine remains below the radar of most physicians.
“I’ve found that this is an agent that very few people know about, even though it’s been FDA [Food and Drug Administration] approved for about 3 years. It’s used fairly extensively in Europe because that’s where the pivotal SHIFT trial was done, but not very much in the United States,” according to Dr. Abraham, professor of medicine, physiology, and cell biology and director of the division of cardiovascular medicine at Ohio State University in Columbus.
That’s likely to change as word spreads about the May 2016 update of the American College of Cardiology/American Heart Association Guideline for the Management of Heart Failure. The update incorporated evidence-based recommendations on the use of two important new heart failure medications: ivabradine (Corlanor), which received a moderate class IIa recommendation, meaning the drug “should be considered,” and sacubitril/valsartan (Entresto), which received the strongest class I recommendation.
In the right patients, these two oral medications improve heart failure morbidity and mortality significantly beyond what’s achievable with what has been the gold standard, guideline-directed medical therapy. Dr. Abraham described how to get started using the two medications at the Annual Cardiovascular Conference at Snowmass.
Ivabradine
Ivabradine is a selective inhibitor of the sinoatrial pacemaker modulating I(f) current. It acts by slowing the sinus rate without reducing myocardial contractility.
“This agent does one thing and one thing alone: It lowers heart rate,” the cardiologist explained.
And that, he added, was sufficient to significantly reduce the risks of death due to heart failure and recurrent hospitalization for worsening heart failure in the pivotal SHIFT trial.
SHIFT included 6,505 patients with moderate to severe heart failure with reduced left ventricular ejection fraction (LVEF) and a resting heart rate above 70 bpm despite background guideline-directed medical therapy. Participants were randomized double blind to ivabradine titrated to a maximum of 7.5 mg twice daily or placebo and followed for a median of about 23 months. The rate of death due to heart failure was 3% with ivabradine and 5% with placebo, for a statistically significant 26% relative risk reduction favoring ivabradine.
But the drug’s main benefit was in reducing recurrent hospitalizations for heart failure, an endpoint of particular interest to health policy officials given that heart failure hospitalizations chew up a substantial proportion of the Medicare budget. Ivabradine reduced first hospitalizations for heart failure during the study period by 25%, second hospitalizations by 34%, and third hospitalizations by 29% (Eur Heart J. 2012 Nov;33[22]:2813-20).
The ACC/AHA guideline update stresses the importance of reserving ivabradine for heart failure patients whose resting heart rate exceeds 70 bpm, despite being on their maximum tolerated dose of a beta-blocker, Dr. Abraham noted.
Ivabradine is contraindicated in the setting of acute decompensated heart failure, severe liver disease, or hypotension, in patients on any of the numerous agents that strongly inhibit the enzyme cytochrome P450 3A4, and in those who have sick sinus syndrome, have sinoatrial block, or are pacemaker dependent.
Sacubitril/valsartan
Sacubitril inhibits neprilysin, an enzyme that blocks the action of endogenous vasoactive peptides including bradykinin, substance P, and natriuretic peptides, all of which counter important maladaptive mechanisms in heart failure. Sacubitril has been combined with the angiotensin receptor blocker valsartan to form the first-in-class angiotensin receptor neprilysin inhibitor, or ARNI, formerly known as LCZ696 and now marketed as Entresto.
In the pivotal double-blind PARADIGM-HF trial, 8,442 patients with heart failure with reduced ejection fraction were randomized to the ARNI at 200 mg b.i.d. or to enalapril at 10 mg b.i.d. on top of background guideline-directed medical therapy. The trial was stopped early because of evidence of overwhelming benefit: a 20% relative risk reduction in cardiovascular death and a 21% decrease in the risk of heart failure hospitalizations in the sacubitril/valsartan group, as well as significant reductions in heart failure symptoms and physical limitations (N Engl J Med. 2014 Sep 11;371[11]:993-1004).
The updated heart failure guidelines strongly recommend that patients with heart failure should be treated with either an ACE inhibitor, an angiotensin receptor blocker, or an ARNI. Further, patients who remain symptomatic on an ACE inhibitor or angiotensin receptor blocker should be switched to an ARNI; that’s a class Ib recommendation based upon the results of PARADIGM-HF.
In getting started using the ARNI, Dr. Abraham said it’s important to understand as background the selective nature of the PARADIGM-HF study design. During the single-blind run-in period of 5-8 weeks, roughly 10% of patients dropped out because they couldn’t tolerate enalapril at 10 mg b.i.d., and a similar percentage dropped out during the ARNI run-in. Thus, patients who couldn’t tolerate a low dose of an ACE inhibitor weren’t in the study. And patients capable of tolerating guideline-recommended full-dose ACE inhibitor therapy were not specifically sought for participation.
“So there are some unanswered questions about the ARNI. If you’re just getting started with this compound in treating your heart failure patients, my own feeling is you should maybe aim for the type of patient that was included in this trial: patients who could tolerate a moderate dose of an ACE inhibitor and had generally good blood pressure. That’s a great way to begin to get experience with this agent in heart failure,” the cardiologist advised.
He reported serving as a consultant to Abbott Vascular, Medtronic, Novartis, and St. Jude Medical.
SNOWMASS, COLO. – As William T. Abraham, MD, speaks to colleagues around the country about heart failure therapy, he has noticed that the first-in-class drug ivabradine remains below the radar of most physicians.
“I’ve found that this is an agent that very few people know about, even though it’s been FDA [Food and Drug Administration] approved for about 3 years. It’s used fairly extensively in Europe because that’s where the pivotal SHIFT trial was done, but not very much in the United States,” according to Dr. Abraham, professor of medicine, physiology, and cell biology and director of the division of cardiovascular medicine at Ohio State University in Columbus.
That’s likely to change as word spreads about the May 2016 update of the American College of Cardiology/American Heart Association Guideline for the Management of Heart Failure. The update incorporated evidence-based recommendations on the use of two important new heart failure medications: ivabradine (Corlanor), which received a moderate class IIa recommendation, meaning the drug “should be considered,” and sacubitril/valsartan (Entresto), which received the strongest class I recommendation.
In the right patients, these two oral medications improve heart failure morbidity and mortality significantly beyond what’s achievable with what has been the gold standard, guideline-directed medical therapy. Dr. Abraham described how to get started using the two medications at the Annual Cardiovascular Conference at Snowmass.
Ivabradine
Ivabradine is a selective inhibitor of the sinoatrial pacemaker modulating I(f) current. It acts by slowing the sinus rate without reducing myocardial contractility.
“This agent does one thing and one thing alone: It lowers heart rate,” the cardiologist explained.
And that, he added, was sufficient to significantly reduce the risks of death due to heart failure and recurrent hospitalization for worsening heart failure in the pivotal SHIFT trial.
SHIFT included 6,505 patients with moderate to severe heart failure with reduced left ventricular ejection fraction (LVEF) and a resting heart rate above 70 bpm despite background guideline-directed medical therapy. Participants were randomized double blind to ivabradine titrated to a maximum of 7.5 mg twice daily or placebo and followed for a median of about 23 months. The rate of death due to heart failure was 3% with ivabradine and 5% with placebo, for a statistically significant 26% relative risk reduction favoring ivabradine.
But the drug’s main benefit was in reducing recurrent hospitalizations for heart failure, an endpoint of particular interest to health policy officials given that heart failure hospitalizations chew up a substantial proportion of the Medicare budget. Ivabradine reduced first hospitalizations for heart failure during the study period by 25%, second hospitalizations by 34%, and third hospitalizations by 29% (Eur Heart J. 2012 Nov;33[22]:2813-20).
The ACC/AHA guideline update stresses the importance of reserving ivabradine for heart failure patients whose resting heart rate exceeds 70 bpm, despite being on their maximum tolerated dose of a beta-blocker, Dr. Abraham noted.
Ivabradine is contraindicated in the setting of acute decompensated heart failure, severe liver disease, or hypotension, in patients on any of the numerous agents that strongly inhibit the enzyme cytochrome P450 3A4, and in those who have sick sinus syndrome, have sinoatrial block, or are pacemaker dependent.
Sacubitril/valsartan
Sacubitril inhibits neprilysin, an enzyme that blocks the action of endogenous vasoactive peptides including bradykinin, substance P, and natriuretic peptides, all of which counter important maladaptive mechanisms in heart failure. Sacubitril has been combined with the angiotensin receptor blocker valsartan to form the first-in-class angiotensin receptor neprilysin inhibitor, or ARNI, formerly known as LCZ696 and now marketed as Entresto.
In the pivotal double-blind PARADIGM-HF trial, 8,442 patients with heart failure with reduced ejection fraction were randomized to the ARNI at 200 mg b.i.d. or to enalapril at 10 mg b.i.d. on top of background guideline-directed medical therapy. The trial was stopped early because of evidence of overwhelming benefit: a 20% relative risk reduction in cardiovascular death and a 21% decrease in the risk of heart failure hospitalizations in the sacubitril/valsartan group, as well as significant reductions in heart failure symptoms and physical limitations (N Engl J Med. 2014 Sep 11;371[11]:993-1004).
The updated heart failure guidelines strongly recommend that patients with heart failure should be treated with either an ACE inhibitor, an angiotensin receptor blocker, or an ARNI. Further, patients who remain symptomatic on an ACE inhibitor or angiotensin receptor blocker should be switched to an ARNI; that’s a class Ib recommendation based upon the results of PARADIGM-HF.
In getting started using the ARNI, Dr. Abraham said it’s important to understand as background the selective nature of the PARADIGM-HF study design. During the single-blind run-in period of 5-8 weeks, roughly 10% of patients dropped out because they couldn’t tolerate enalapril at 10 mg b.i.d., and a similar percentage dropped out during the ARNI run-in. Thus, patients who couldn’t tolerate a low dose of an ACE inhibitor weren’t in the study. And patients capable of tolerating guideline-recommended full-dose ACE inhibitor therapy were not specifically sought for participation.
“So there are some unanswered questions about the ARNI. If you’re just getting started with this compound in treating your heart failure patients, my own feeling is you should maybe aim for the type of patient that was included in this trial: patients who could tolerate a moderate dose of an ACE inhibitor and had generally good blood pressure. That’s a great way to begin to get experience with this agent in heart failure,” the cardiologist advised.
He reported serving as a consultant to Abbott Vascular, Medtronic, Novartis, and St. Jude Medical.
EXPERT ANALYSIS FROM THE CARDIOVASCULAR CONFERENCE AT SNOWMASS
Boston - Rich History, Lively Cultural Scene
There is history around every corner in Boston. This vibrant city is rich with art, music, and dance institutions, theatre and cultural attractions, distinguished dining and nightlife venues, world-class shopping and championship sports teams that attract millions of visitors each year.
The city’s downtown neighborhoods, each with its own personality, offer endless unique experiences, and Boston’s proximity to other must-see sites all around New England make it one of the country’s most diverse and exciting locales.Each of the city’s neighborhoods has a remarkably different style and tone. From the Back Bay’s cosmopolitan streets and ornate Victorian townhouses to the aromas spilling into the narrow and jumbled 17th-century streets of Boston’s North End to the spirited and funky neighborhood squares of Cambridge – all within easy distance from one another.Boston is “America’s Walking City.” Even though it is one of the largest cities in the country, its accessibility is unparalleled. And while sightseeing on foot is easy, Boston also has an excellent public transportation system to help you get around.
Boston is also known as the mecca of medicine. Boston is home to some of the most prestigious hospitals and medical schools, physicians, and medical scientists in the world. Thoralf M. Sundt, III, MD, and the AATS Centennial Committee have organized an engaging social program for the AATS Centennial.
Tour 1: ITALIAN GASTRONOMY NORTH END MARKET TOUR
Sunday, April 30, 2017
10:30 a.m.– 1:15 p.m.
Cost: $95 per person
Tour 2: A VISIT TO THE ISABELLA STEWART GARDNER MUSEUM
Monday, May 1, 2017
12:15 p.m. – 2:45 p.m.
Cost: $85 per person
Enjoy the Gardners’ compilation of tapestries, exquisite antique furniture, and famous collections while hearing wonderful anecdotes about Mrs. Gardner’s sophisticated and eclectic life and the famous heist. A docent will be available to guidevisitors.
Tour 3: BEACON HILL CIRCLE “BEHIND THE BRAHMIN DOORS”
Tuesday, May 2, 2017
9:15 a.m. – 11:45 a.m.
Cost: $110 per person
*Preregistration for social events and tours are required. Tours require a minimum number of participants. All tours will depart from the Hynes Convention Center.
For additional visit information and things to do in Boston, go to https://www.bostonusa.com/things-to-do.
There is history around every corner in Boston. This vibrant city is rich with art, music, and dance institutions, theatre and cultural attractions, distinguished dining and nightlife venues, world-class shopping and championship sports teams that attract millions of visitors each year.
The city’s downtown neighborhoods, each with its own personality, offer endless unique experiences, and Boston’s proximity to other must-see sites all around New England make it one of the country’s most diverse and exciting locales.Each of the city’s neighborhoods has a remarkably different style and tone. From the Back Bay’s cosmopolitan streets and ornate Victorian townhouses to the aromas spilling into the narrow and jumbled 17th-century streets of Boston’s North End to the spirited and funky neighborhood squares of Cambridge – all within easy distance from one another.Boston is “America’s Walking City.” Even though it is one of the largest cities in the country, its accessibility is unparalleled. And while sightseeing on foot is easy, Boston also has an excellent public transportation system to help you get around.
Boston is also known as the mecca of medicine. Boston is home to some of the most prestigious hospitals and medical schools, physicians, and medical scientists in the world. Thoralf M. Sundt, III, MD, and the AATS Centennial Committee have organized an engaging social program for the AATS Centennial.
Tour 1: ITALIAN GASTRONOMY NORTH END MARKET TOUR
Sunday, April 30, 2017
10:30 a.m.– 1:15 p.m.
Cost: $95 per person
Tour 2: A VISIT TO THE ISABELLA STEWART GARDNER MUSEUM
Monday, May 1, 2017
12:15 p.m. – 2:45 p.m.
Cost: $85 per person
Enjoy the Gardners’ compilation of tapestries, exquisite antique furniture, and famous collections while hearing wonderful anecdotes about Mrs. Gardner’s sophisticated and eclectic life and the famous heist. A docent will be available to guidevisitors.
Tour 3: BEACON HILL CIRCLE “BEHIND THE BRAHMIN DOORS”
Tuesday, May 2, 2017
9:15 a.m. – 11:45 a.m.
Cost: $110 per person
*Preregistration for social events and tours are required. Tours require a minimum number of participants. All tours will depart from the Hynes Convention Center.
For additional visit information and things to do in Boston, go to https://www.bostonusa.com/things-to-do.
There is history around every corner in Boston. This vibrant city is rich with art, music, and dance institutions, theatre and cultural attractions, distinguished dining and nightlife venues, world-class shopping and championship sports teams that attract millions of visitors each year.
The city’s downtown neighborhoods, each with its own personality, offer endless unique experiences, and Boston’s proximity to other must-see sites all around New England make it one of the country’s most diverse and exciting locales.Each of the city’s neighborhoods has a remarkably different style and tone. From the Back Bay’s cosmopolitan streets and ornate Victorian townhouses to the aromas spilling into the narrow and jumbled 17th-century streets of Boston’s North End to the spirited and funky neighborhood squares of Cambridge – all within easy distance from one another.Boston is “America’s Walking City.” Even though it is one of the largest cities in the country, its accessibility is unparalleled. And while sightseeing on foot is easy, Boston also has an excellent public transportation system to help you get around.
Boston is also known as the mecca of medicine. Boston is home to some of the most prestigious hospitals and medical schools, physicians, and medical scientists in the world. Thoralf M. Sundt, III, MD, and the AATS Centennial Committee have organized an engaging social program for the AATS Centennial.
Tour 1: ITALIAN GASTRONOMY NORTH END MARKET TOUR
Sunday, April 30, 2017
10:30 a.m.– 1:15 p.m.
Cost: $95 per person
Tour 2: A VISIT TO THE ISABELLA STEWART GARDNER MUSEUM
Monday, May 1, 2017
12:15 p.m. – 2:45 p.m.
Cost: $85 per person
Enjoy the Gardners’ compilation of tapestries, exquisite antique furniture, and famous collections while hearing wonderful anecdotes about Mrs. Gardner’s sophisticated and eclectic life and the famous heist. A docent will be available to guidevisitors.
Tour 3: BEACON HILL CIRCLE “BEHIND THE BRAHMIN DOORS”
Tuesday, May 2, 2017
9:15 a.m. – 11:45 a.m.
Cost: $110 per person
*Preregistration for social events and tours are required. Tours require a minimum number of participants. All tours will depart from the Hynes Convention Center.
For additional visit information and things to do in Boston, go to https://www.bostonusa.com/things-to-do.
Off-the-shelf T cells an option for post-HCT viral infections
ORLANDO – Infusions of banked multivirus-specific T lymphocytes were associated with complete or partial responses in 93% of 42 patients who had undergone hematopoietic cell transplants and had drug-refractory viral illnesses. Further, these patients experienced minimal new or reactivated graft-versus-host disease (GVHD).
Viral infections cause nearly 40% of deaths after alternative donor hematopoietic cell transfer (HCT), Ifigeneia Tzannou, MD, said at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society of Blood and Marrow Transplantation. Banked, “off-the-shelf” donor virus-resistant T cells can be an alternative to antiviral drugs, which are far from universally effective and may have serious side effects.
“Traditionally, we have generated T cells for infusion from the stem cell donor” by isolating and then stimulating and expanding the peripheral blood mononuclear cells for about 10 days ex vivo, said Dr. Tzannou. At that point, the clonal multivirus-resistant T cells can then be transferred to the recipient.
Donor-derived T cells have been used to prevent and treat Epstein-Barr virus (EBV), cytomegalovirus (CMV), adenovirus (AdV), BK virus (BKV), and human herpes virus 6 (HHV6) infections. The approach has been safe, reconstituting antiviral immunity and clearing disease effectively, with a 94% response rate reported in one recent study. However, said Dr. Tzannou, donor-derived virus-specific T cells (VSTs) have their limitations. Donors are increasingly younger and cord blood is being used more commonly, so there are growing numbers of donors who are seronegative for pathogenic viruses. In addition, the 10 days of production time and the additional week or 10 days required for release means that donor-derived VSTs can’t be urgently used.
The concept of banked third party VST therapy came about to address those limitations, said Dr. Tzannou of Baylor College of Medicine, Houston.
In a banked VST scenario, donor T cells with specific multiviral immunity are human leukocyte antigen (HLA) typed, expanded, and cryopreserved. A post-HCT patient with drug-refractory viral illness can receive T cells that are partially matched at HLA –A, HLA-B, or HLA-DR. Dr. Tzannou said that her group has now generated a bank of 59 VST lines to use in clinical testing of the third party approach.
In the study, Dr. Tzannou and her colleagues included both pediatric and adult post-allo-HCT patients with refractory EBV, CMV, AdV, BKV, and/or HHV6 infections. All had either failed a 14-day trial of antiviral therapy or could not tolerate antivirals. Patients could not be on more than 0.5 mg/kg per day of prednisone; they had to have an absolute neutrophil count above 500 per microliter and hemoglobin greater than 8 g/dL. Patients were excluded if they had acute GVHD of grade 2 or higher. There had to be a compatible VST line available that matched both the patient’s illness and HLA typing.
Patients initially received 20,000,000 VST cells per square meter of body surface area. If the investigators saw a partial response, patients could receive additional VST doses every 2 weeks.
Of the 42 patients infused, 23 received one infusion and 19 required two or more infusions. Seven study participants had two viral infections; 18 had CMV, 2 had EBV, 9 had AdV, 17 had BKV, and 3 had HHV6.
Dr. Tzannou and her colleagues tracked the virus-specific T cells and viral load for particular viruses. Virus-specific peripheral T cell counts also rose measurably and viral load plummeted within 2 weeks of VST infusions for most patients.
Overall, 93% of patients met the primary outcome measure of achieving complete or partial response; a partial response was defined as a 50% or better decrease in the viral load and/or clinical improvement.
All of the 17 BKV patients treated to date had tissue disease; 15 had hemorrhagic cystitis and 2 had nephritis. All responded to VSTs, and all of those with hemorrhagic cystitis had symptomatic improvement or resolution.
Overall, the safety profile for VST was good, said Dr. Tzannou. Four patients developed grade 1 acute cutaneous GVHD within 45 days of infusion; one of these developed de novo, but resolved with topical steroids. Another patient had a flare of gastrointestinal GVHD when immunosuppresion was being tapered. One more patient had a transient fever post infusion that resolved spontaneously, said Dr. Tzannou.
Next steps include a multicenter registration study, said Dr. Tzannou, who reports being a consultant for ViraCyte, which helped fund the study.
koakes@frontlinemedcom.com
On Twitter @karioakes
ORLANDO – Infusions of banked multivirus-specific T lymphocytes were associated with complete or partial responses in 93% of 42 patients who had undergone hematopoietic cell transplants and had drug-refractory viral illnesses. Further, these patients experienced minimal new or reactivated graft-versus-host disease (GVHD).
Viral infections cause nearly 40% of deaths after alternative donor hematopoietic cell transfer (HCT), Ifigeneia Tzannou, MD, said at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society of Blood and Marrow Transplantation. Banked, “off-the-shelf” donor virus-resistant T cells can be an alternative to antiviral drugs, which are far from universally effective and may have serious side effects.
“Traditionally, we have generated T cells for infusion from the stem cell donor” by isolating and then stimulating and expanding the peripheral blood mononuclear cells for about 10 days ex vivo, said Dr. Tzannou. At that point, the clonal multivirus-resistant T cells can then be transferred to the recipient.
Donor-derived T cells have been used to prevent and treat Epstein-Barr virus (EBV), cytomegalovirus (CMV), adenovirus (AdV), BK virus (BKV), and human herpes virus 6 (HHV6) infections. The approach has been safe, reconstituting antiviral immunity and clearing disease effectively, with a 94% response rate reported in one recent study. However, said Dr. Tzannou, donor-derived virus-specific T cells (VSTs) have their limitations. Donors are increasingly younger and cord blood is being used more commonly, so there are growing numbers of donors who are seronegative for pathogenic viruses. In addition, the 10 days of production time and the additional week or 10 days required for release means that donor-derived VSTs can’t be urgently used.
The concept of banked third party VST therapy came about to address those limitations, said Dr. Tzannou of Baylor College of Medicine, Houston.
In a banked VST scenario, donor T cells with specific multiviral immunity are human leukocyte antigen (HLA) typed, expanded, and cryopreserved. A post-HCT patient with drug-refractory viral illness can receive T cells that are partially matched at HLA –A, HLA-B, or HLA-DR. Dr. Tzannou said that her group has now generated a bank of 59 VST lines to use in clinical testing of the third party approach.
In the study, Dr. Tzannou and her colleagues included both pediatric and adult post-allo-HCT patients with refractory EBV, CMV, AdV, BKV, and/or HHV6 infections. All had either failed a 14-day trial of antiviral therapy or could not tolerate antivirals. Patients could not be on more than 0.5 mg/kg per day of prednisone; they had to have an absolute neutrophil count above 500 per microliter and hemoglobin greater than 8 g/dL. Patients were excluded if they had acute GVHD of grade 2 or higher. There had to be a compatible VST line available that matched both the patient’s illness and HLA typing.
Patients initially received 20,000,000 VST cells per square meter of body surface area. If the investigators saw a partial response, patients could receive additional VST doses every 2 weeks.
Of the 42 patients infused, 23 received one infusion and 19 required two or more infusions. Seven study participants had two viral infections; 18 had CMV, 2 had EBV, 9 had AdV, 17 had BKV, and 3 had HHV6.
Dr. Tzannou and her colleagues tracked the virus-specific T cells and viral load for particular viruses. Virus-specific peripheral T cell counts also rose measurably and viral load plummeted within 2 weeks of VST infusions for most patients.
Overall, 93% of patients met the primary outcome measure of achieving complete or partial response; a partial response was defined as a 50% or better decrease in the viral load and/or clinical improvement.
All of the 17 BKV patients treated to date had tissue disease; 15 had hemorrhagic cystitis and 2 had nephritis. All responded to VSTs, and all of those with hemorrhagic cystitis had symptomatic improvement or resolution.
Overall, the safety profile for VST was good, said Dr. Tzannou. Four patients developed grade 1 acute cutaneous GVHD within 45 days of infusion; one of these developed de novo, but resolved with topical steroids. Another patient had a flare of gastrointestinal GVHD when immunosuppresion was being tapered. One more patient had a transient fever post infusion that resolved spontaneously, said Dr. Tzannou.
Next steps include a multicenter registration study, said Dr. Tzannou, who reports being a consultant for ViraCyte, which helped fund the study.
koakes@frontlinemedcom.com
On Twitter @karioakes
ORLANDO – Infusions of banked multivirus-specific T lymphocytes were associated with complete or partial responses in 93% of 42 patients who had undergone hematopoietic cell transplants and had drug-refractory viral illnesses. Further, these patients experienced minimal new or reactivated graft-versus-host disease (GVHD).
Viral infections cause nearly 40% of deaths after alternative donor hematopoietic cell transfer (HCT), Ifigeneia Tzannou, MD, said at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society of Blood and Marrow Transplantation. Banked, “off-the-shelf” donor virus-resistant T cells can be an alternative to antiviral drugs, which are far from universally effective and may have serious side effects.
“Traditionally, we have generated T cells for infusion from the stem cell donor” by isolating and then stimulating and expanding the peripheral blood mononuclear cells for about 10 days ex vivo, said Dr. Tzannou. At that point, the clonal multivirus-resistant T cells can then be transferred to the recipient.
Donor-derived T cells have been used to prevent and treat Epstein-Barr virus (EBV), cytomegalovirus (CMV), adenovirus (AdV), BK virus (BKV), and human herpes virus 6 (HHV6) infections. The approach has been safe, reconstituting antiviral immunity and clearing disease effectively, with a 94% response rate reported in one recent study. However, said Dr. Tzannou, donor-derived virus-specific T cells (VSTs) have their limitations. Donors are increasingly younger and cord blood is being used more commonly, so there are growing numbers of donors who are seronegative for pathogenic viruses. In addition, the 10 days of production time and the additional week or 10 days required for release means that donor-derived VSTs can’t be urgently used.
The concept of banked third party VST therapy came about to address those limitations, said Dr. Tzannou of Baylor College of Medicine, Houston.
In a banked VST scenario, donor T cells with specific multiviral immunity are human leukocyte antigen (HLA) typed, expanded, and cryopreserved. A post-HCT patient with drug-refractory viral illness can receive T cells that are partially matched at HLA –A, HLA-B, or HLA-DR. Dr. Tzannou said that her group has now generated a bank of 59 VST lines to use in clinical testing of the third party approach.
In the study, Dr. Tzannou and her colleagues included both pediatric and adult post-allo-HCT patients with refractory EBV, CMV, AdV, BKV, and/or HHV6 infections. All had either failed a 14-day trial of antiviral therapy or could not tolerate antivirals. Patients could not be on more than 0.5 mg/kg per day of prednisone; they had to have an absolute neutrophil count above 500 per microliter and hemoglobin greater than 8 g/dL. Patients were excluded if they had acute GVHD of grade 2 or higher. There had to be a compatible VST line available that matched both the patient’s illness and HLA typing.
Patients initially received 20,000,000 VST cells per square meter of body surface area. If the investigators saw a partial response, patients could receive additional VST doses every 2 weeks.
Of the 42 patients infused, 23 received one infusion and 19 required two or more infusions. Seven study participants had two viral infections; 18 had CMV, 2 had EBV, 9 had AdV, 17 had BKV, and 3 had HHV6.
Dr. Tzannou and her colleagues tracked the virus-specific T cells and viral load for particular viruses. Virus-specific peripheral T cell counts also rose measurably and viral load plummeted within 2 weeks of VST infusions for most patients.
Overall, 93% of patients met the primary outcome measure of achieving complete or partial response; a partial response was defined as a 50% or better decrease in the viral load and/or clinical improvement.
All of the 17 BKV patients treated to date had tissue disease; 15 had hemorrhagic cystitis and 2 had nephritis. All responded to VSTs, and all of those with hemorrhagic cystitis had symptomatic improvement or resolution.
Overall, the safety profile for VST was good, said Dr. Tzannou. Four patients developed grade 1 acute cutaneous GVHD within 45 days of infusion; one of these developed de novo, but resolved with topical steroids. Another patient had a flare of gastrointestinal GVHD when immunosuppresion was being tapered. One more patient had a transient fever post infusion that resolved spontaneously, said Dr. Tzannou.
Next steps include a multicenter registration study, said Dr. Tzannou, who reports being a consultant for ViraCyte, which helped fund the study.
koakes@frontlinemedcom.com
On Twitter @karioakes
AT THE 2017 BMT TANDEM MEETINGS
Key clinical point:
Major finding: With banked multivirus-specific T cells, viral illnesses either improved or resolved in 93% of 42 patients.
Data source: Clinical trial of 42 postallogeneic hematopoietic cell transfer patients who had any of five viral illnesses and had either failed a 14-day trial of antiviral therapy or could not tolerate antivirals.
Disclosures: Dr. Tzannou is a consultant for Incyte, which partially funded the trial and is developing third-party VSTs.
Pruritic Rash on the Buttock
Cutaneous Larva Migrans
Cutaneous larva migrans (CLM) is caused by the larval migration of animal hookworms. Ancylostoma braziliense, Ancylostoma ceylanicum, and Ancylostoma caninum are the species most commonly associated with the disease. The hookworm is endemic to tropical and subtropical climates in areas such as Africa, Southeast Asia, South America, and the southeastern United States.1 Although cats and dogs are most commonly affected, humans can be infected if they are exposed to sand or soil containing hookworm larvae, often due to contamination from animal feces.2 Cutaneous larva migrans is characterized by pruritic erythematous papules and linear or serpiginous, reddish brown, elevated tracks most commonly appearing on the feet, buttocks, thighs, and lower legs; however, lesions can appear anywhere. In human hosts, the larvae travel in the epidermis and are unable to invade the dermis; it is speculated that they lack the collagenase enzymes required to penetrate the basement membrane before invading the dermis.2
On histopathology, there typically are small cavities in the epidermis corresponding to the track of the larvae.3 There often is a spongiotic dermatitis with a mixed inflammatory infiltrate following the larvae with scattered eosinophils. The migrating larvae may be up to 1 mm in size and have bilateral double alae, or winglike projections, on the side of the body (Figure 1).4 The larvae are difficult to find on histopathology because they often travel beyond the areas that demonstrate clinical findings. The diagnosis of CLM is mostly clinical, but if a biopsy is performed, the specimen should be taken ahead of the track.
Disseminated strongyloidiasis is caused by Strongyloides stercoralis. When filariform larvae migrate out of the intestinal tract into the skin, they can cause an urticarial rash and serpiginous patterns on the skin that can move 5 to 15 cm per hour, a clinical condition known as larva currens. In immunocompromised individuals, there can be hyperinfection with diffuse petechial thumbprint purpura seen clinically, which characteristically radiate from the periumbilical area.1 On pathology, there may be numerous larvae found between the dermal collagen bundles, measuring 9 to 15 µm in diameter. Rarely, they also can be found in small blood vessels.3 They often are accompanied by extravasated red blood cells in the tissues (Figure 2).
Myiasis represents the largest pathogen in the differential diagnosis for CLM. In myiasis, fly larvae will infest human tissue, usually by forming a small cavity in the dermis or subcutaneous tissue. The larvae are visible to the human eye and can be up to several centimeters in length. In the skin, the histology of myiasis usually is accompanied by a heavy mixed inflammatory cell infiltrate with many eosinophils. Fragments of the larvae are seen encased by a thick chitinous cuticle with widely spaced spines or pigmented setae (Figure 3) on the surface of the cuticle.5 Layers of striated muscle and internal organs may be seen beneath the cuticle.3
Onchocerciasis, or river blindness, is a parasitic disease caused by Onchocerca volvulus that is most often seen in sub-Saharan Africa. It may cause the skin finding of an onchocercoma, a subcutaneous nodule made up of Onchocerca nematodes. However, when the filaria disseminate, it may cause onchocerciasis with cutaneous findings of an eczematous dermatitis with itching and lichenification.1 In onchocercal dermatitis, microfilariae may be found in the dermis and there may be a mild dermal chronic inflammatory infiltrate with eosinophils.3 These microfilariae are smaller than Strongyloides larvae (Figure 4).
Sarcoptes scabiei are mites that are pathologically found limited to the stratum corneum. There often is a spongiotic dermatitis as the mite travels with an accompanying mixed cell inflammatory infiltrate with many eosinophils. One or more mites may be seen with or without eggs and excreta or scybala (Figure 5). Pink pigtails may be seen connected to the stratum corneum, representing egg fragments or casings left behind after the mite hatches.3 The female mite measures up to 0.4 mm in length.3
- Lupi O, Downing C, Lee M, et al. Mucocutaneous manifestations of helminth infections. J Am Acad Dermatol. 2015;73:929-944.
- James WD, Berger T, Elston D. Andrews' Diseases of the Skin: Clinical Dermatology. 12th ed. Philadelphia, PA: Elsevier; 2016.
- Patterson J. Weedon's Skin Pathology. 4th ed. London, England: Churchill Livingstone Elsevier; 2016.
- Milner D. Diagnostic Pathology: Infectious Diseases. Philadelphia, PA: Elsevier; 2015.
- Ferringer T, Peckham S, Ko CJ, et al. Dermatopathology. 2nd ed. Philadelphia, PA: Elsevier Saunders; 2013.
Cutaneous Larva Migrans
Cutaneous larva migrans (CLM) is caused by the larval migration of animal hookworms. Ancylostoma braziliense, Ancylostoma ceylanicum, and Ancylostoma caninum are the species most commonly associated with the disease. The hookworm is endemic to tropical and subtropical climates in areas such as Africa, Southeast Asia, South America, and the southeastern United States.1 Although cats and dogs are most commonly affected, humans can be infected if they are exposed to sand or soil containing hookworm larvae, often due to contamination from animal feces.2 Cutaneous larva migrans is characterized by pruritic erythematous papules and linear or serpiginous, reddish brown, elevated tracks most commonly appearing on the feet, buttocks, thighs, and lower legs; however, lesions can appear anywhere. In human hosts, the larvae travel in the epidermis and are unable to invade the dermis; it is speculated that they lack the collagenase enzymes required to penetrate the basement membrane before invading the dermis.2
On histopathology, there typically are small cavities in the epidermis corresponding to the track of the larvae.3 There often is a spongiotic dermatitis with a mixed inflammatory infiltrate following the larvae with scattered eosinophils. The migrating larvae may be up to 1 mm in size and have bilateral double alae, or winglike projections, on the side of the body (Figure 1).4 The larvae are difficult to find on histopathology because they often travel beyond the areas that demonstrate clinical findings. The diagnosis of CLM is mostly clinical, but if a biopsy is performed, the specimen should be taken ahead of the track.
Disseminated strongyloidiasis is caused by Strongyloides stercoralis. When filariform larvae migrate out of the intestinal tract into the skin, they can cause an urticarial rash and serpiginous patterns on the skin that can move 5 to 15 cm per hour, a clinical condition known as larva currens. In immunocompromised individuals, there can be hyperinfection with diffuse petechial thumbprint purpura seen clinically, which characteristically radiate from the periumbilical area.1 On pathology, there may be numerous larvae found between the dermal collagen bundles, measuring 9 to 15 µm in diameter. Rarely, they also can be found in small blood vessels.3 They often are accompanied by extravasated red blood cells in the tissues (Figure 2).
Myiasis represents the largest pathogen in the differential diagnosis for CLM. In myiasis, fly larvae will infest human tissue, usually by forming a small cavity in the dermis or subcutaneous tissue. The larvae are visible to the human eye and can be up to several centimeters in length. In the skin, the histology of myiasis usually is accompanied by a heavy mixed inflammatory cell infiltrate with many eosinophils. Fragments of the larvae are seen encased by a thick chitinous cuticle with widely spaced spines or pigmented setae (Figure 3) on the surface of the cuticle.5 Layers of striated muscle and internal organs may be seen beneath the cuticle.3
Onchocerciasis, or river blindness, is a parasitic disease caused by Onchocerca volvulus that is most often seen in sub-Saharan Africa. It may cause the skin finding of an onchocercoma, a subcutaneous nodule made up of Onchocerca nematodes. However, when the filaria disseminate, it may cause onchocerciasis with cutaneous findings of an eczematous dermatitis with itching and lichenification.1 In onchocercal dermatitis, microfilariae may be found in the dermis and there may be a mild dermal chronic inflammatory infiltrate with eosinophils.3 These microfilariae are smaller than Strongyloides larvae (Figure 4).
Sarcoptes scabiei are mites that are pathologically found limited to the stratum corneum. There often is a spongiotic dermatitis as the mite travels with an accompanying mixed cell inflammatory infiltrate with many eosinophils. One or more mites may be seen with or without eggs and excreta or scybala (Figure 5). Pink pigtails may be seen connected to the stratum corneum, representing egg fragments or casings left behind after the mite hatches.3 The female mite measures up to 0.4 mm in length.3
Cutaneous Larva Migrans
Cutaneous larva migrans (CLM) is caused by the larval migration of animal hookworms. Ancylostoma braziliense, Ancylostoma ceylanicum, and Ancylostoma caninum are the species most commonly associated with the disease. The hookworm is endemic to tropical and subtropical climates in areas such as Africa, Southeast Asia, South America, and the southeastern United States.1 Although cats and dogs are most commonly affected, humans can be infected if they are exposed to sand or soil containing hookworm larvae, often due to contamination from animal feces.2 Cutaneous larva migrans is characterized by pruritic erythematous papules and linear or serpiginous, reddish brown, elevated tracks most commonly appearing on the feet, buttocks, thighs, and lower legs; however, lesions can appear anywhere. In human hosts, the larvae travel in the epidermis and are unable to invade the dermis; it is speculated that they lack the collagenase enzymes required to penetrate the basement membrane before invading the dermis.2
On histopathology, there typically are small cavities in the epidermis corresponding to the track of the larvae.3 There often is a spongiotic dermatitis with a mixed inflammatory infiltrate following the larvae with scattered eosinophils. The migrating larvae may be up to 1 mm in size and have bilateral double alae, or winglike projections, on the side of the body (Figure 1).4 The larvae are difficult to find on histopathology because they often travel beyond the areas that demonstrate clinical findings. The diagnosis of CLM is mostly clinical, but if a biopsy is performed, the specimen should be taken ahead of the track.
Disseminated strongyloidiasis is caused by Strongyloides stercoralis. When filariform larvae migrate out of the intestinal tract into the skin, they can cause an urticarial rash and serpiginous patterns on the skin that can move 5 to 15 cm per hour, a clinical condition known as larva currens. In immunocompromised individuals, there can be hyperinfection with diffuse petechial thumbprint purpura seen clinically, which characteristically radiate from the periumbilical area.1 On pathology, there may be numerous larvae found between the dermal collagen bundles, measuring 9 to 15 µm in diameter. Rarely, they also can be found in small blood vessels.3 They often are accompanied by extravasated red blood cells in the tissues (Figure 2).
Myiasis represents the largest pathogen in the differential diagnosis for CLM. In myiasis, fly larvae will infest human tissue, usually by forming a small cavity in the dermis or subcutaneous tissue. The larvae are visible to the human eye and can be up to several centimeters in length. In the skin, the histology of myiasis usually is accompanied by a heavy mixed inflammatory cell infiltrate with many eosinophils. Fragments of the larvae are seen encased by a thick chitinous cuticle with widely spaced spines or pigmented setae (Figure 3) on the surface of the cuticle.5 Layers of striated muscle and internal organs may be seen beneath the cuticle.3
Onchocerciasis, or river blindness, is a parasitic disease caused by Onchocerca volvulus that is most often seen in sub-Saharan Africa. It may cause the skin finding of an onchocercoma, a subcutaneous nodule made up of Onchocerca nematodes. However, when the filaria disseminate, it may cause onchocerciasis with cutaneous findings of an eczematous dermatitis with itching and lichenification.1 In onchocercal dermatitis, microfilariae may be found in the dermis and there may be a mild dermal chronic inflammatory infiltrate with eosinophils.3 These microfilariae are smaller than Strongyloides larvae (Figure 4).
Sarcoptes scabiei are mites that are pathologically found limited to the stratum corneum. There often is a spongiotic dermatitis as the mite travels with an accompanying mixed cell inflammatory infiltrate with many eosinophils. One or more mites may be seen with or without eggs and excreta or scybala (Figure 5). Pink pigtails may be seen connected to the stratum corneum, representing egg fragments or casings left behind after the mite hatches.3 The female mite measures up to 0.4 mm in length.3
- Lupi O, Downing C, Lee M, et al. Mucocutaneous manifestations of helminth infections. J Am Acad Dermatol. 2015;73:929-944.
- James WD, Berger T, Elston D. Andrews' Diseases of the Skin: Clinical Dermatology. 12th ed. Philadelphia, PA: Elsevier; 2016.
- Patterson J. Weedon's Skin Pathology. 4th ed. London, England: Churchill Livingstone Elsevier; 2016.
- Milner D. Diagnostic Pathology: Infectious Diseases. Philadelphia, PA: Elsevier; 2015.
- Ferringer T, Peckham S, Ko CJ, et al. Dermatopathology. 2nd ed. Philadelphia, PA: Elsevier Saunders; 2013.
- Lupi O, Downing C, Lee M, et al. Mucocutaneous manifestations of helminth infections. J Am Acad Dermatol. 2015;73:929-944.
- James WD, Berger T, Elston D. Andrews' Diseases of the Skin: Clinical Dermatology. 12th ed. Philadelphia, PA: Elsevier; 2016.
- Patterson J. Weedon's Skin Pathology. 4th ed. London, England: Churchill Livingstone Elsevier; 2016.
- Milner D. Diagnostic Pathology: Infectious Diseases. Philadelphia, PA: Elsevier; 2015.
- Ferringer T, Peckham S, Ko CJ, et al. Dermatopathology. 2nd ed. Philadelphia, PA: Elsevier Saunders; 2013.
An 18-year-old man presented with a several-week history of an expanding pruritic serpiginous and linear eruption on the buttock. The patient recently had spent some time vacationing at the beach in the southeastern United States. Physical examination revealed erythematous linear papules and serpiginous raised tracks on the buttock. A biopsy of the lesion was performed.
Large Hyperpigmented Plaques on the Trunk of a Newborn
The Diagnosis: Cutaneous Mastocytoma
Physical examination revealed a 58×51-mm hyperpigmented plaque with central pink coloration and scale on the right side of the back as well as a 39×33-mm pink plaque with a hyperpigmented border on the left side of the flank (Figure 1). At follow-up 2 weeks later, the patient's parents reported that blisters formed within both of the plaques. The blisters ruptured a few hours after forming and drained clear fluid with scant blood. Both plaques contained erosions from the ruptured bullae but remained the same size with no surrounding erythema or warmth. A 4-mm punch biopsy was performed of intact skin from the back lesion (Figure 2A). Histologic examination revealed a cellular infiltrate of monotonous bland cells that completely filled the dermis without epidermal involvement, along with occasional intermixed eosinophils. The morphology of these infiltrating cells was compatible with mast cells confirmed by strongly positive Leder staining (Figure 2B).
Mastocytosis encompasses a rare group of disorders characterized by abnormal mast cell accumulation or mast cell mediator release in various tissues. These disorders can be classified as either systemic mastocytosis with mast cell infiltration into bone marrow or other extracutaneous organs, or cutaneous mastocytosis with disease limited to the skin.1 Mutations involving activation of the c-Kit receptor in stimulating mast cell growth and development have been implicated in both systemic and cutaneous forms of the disease.2,3
Cutaneous mastocytosis is most often diagnosed in childhood and typically is characterized by spontaneous regression before puberty in a majority of cases.1,4 Under the World Health Organization classification system, cutaneous mastocytosis can be further subdivided into 3 disorders (listed in order of most to least common): urticaria pigmentosa (also known as maculopapular cutaneous mastocytosis) with typical, plaque, and nodular forms; cutaneous mastocytoma (as seen in this patient); and diffuse cutaneous mastocytosis.5 Compared to the widespread distribution of small macules and papules in urticaria pigmentosa, the cutaneous mastocytoma subtype presents with 1 to 6 brown to orange-yellow plaques or nodules measuring more than 1 cm in diameter. Cutaneous mastocytoma typically presents in infancy and is located most commonly on the trunk and extremities, though it may be found on the face or scalp. The plaques of mastocytoma often have well-defined margins, and these lesions may become bullous or demonstrate Darier sign of urtication and erythema on physical stimulation. Patients most commonly experience pruritus from mast cell degranulation and rarely exhibit systemic symptoms of mast cell mediator release; however, generalized flushing, hypotension, headaches, and gastrointestinal symptoms may occur, particularly if the lesion is vigorously rubbed.6,7 Conditions in the differential include aplasia cutis congenita, connective tissue nevus, epidermal nevus, and epidermolysis bullosa. They should not elicit a blister if rubbed, except for epidermolysis bullosa, which can easily be differentiated based on histology.
The workup for cutaneous mastocytosis in the pediatric population may include a biopsy of lesional skin, though in many cases the characteristic cutaneous manifestations are sufficient to make a diagnosis. Histologically, biopsy results often reveal abundant diffuse dermal infiltration of mast cells, which are characterized by their large pink granular cytoplasm and round dense central nuclei. In pediatric patients, mast cells typically are restricted to the dermis, and there is a low risk for hematologic abnormalities, thereby precluding the need for bone marrow examination in the absence of organomegaly or notable peripheral blood abnormalities such as severe cytopenia.5,6
Management of cutaneous mastocytosis consists of avoidance of mast cell degranulation triggers and symptomatic treatment of histamine release. Triggers include certain medications (eg, narcotic analgesics, aspirin, nonsteroidal anti-inflammatory drugs, iodinated contrast agents, antibiotics, muscle relaxants), mechanical irritation, insect stings, spicy foods, stress, or extreme temperature changes.8 Symptomatic treatment can be achieved through topical corticosteroid or oral antihistamine use. Along with decreasing pruritus, topical corticosteroids also may be helpful in decreasing time to spontaneous resolution and healing.7 The patient in this case was treated with desonide ointment 0.05% daily to both lesions as well as mupirocin ointment 2% as needed for erosions. These treatments helped reduce the patient's symptoms, but her lesions persisted over a follow-up period of 4 months.
- Valent P, Sperr WR, Schwartz LB, et al. Diagnosis and classification of mast cell proliferative disorders: delineation from immunologic diseases and non-mast cell hematopoietic neoplasms. J Allergy Clin Immunol. 2004;114:3-11.
- Bibi S, Langenfeld F, Jeanningros S, et al. Molecular defects in mastocytosis: KIT and beyond KIT. Immunol Allergy Clin North Am. 2014;34:239-262.
- Yavuz AS, Lipsky PE, Yavuz S, et al. Evidence for the involvement of a hematopoietic progenitor cell in systemic mastocytosis from single-cell analysis of mutations in the c-kit gene. Blood. 2002;100:661-665.
- Méni C, Bruneau J, Georgin-Lavialle S, et al. Paediatric mastocytosis: a systematic review of 1747 cases. Br J Dermatol. 2015;172:642-651.
- Valent P, Horny HP, Escribano L, et al. Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leuk Res. 2001;25:603-625.
- Wolff K, Komar M, Petzelbauer P. Clinical and histopathological aspects of cutaneous mastocytosis. Leuk Res. 2001;25:519-528.
- Patrizi A, Tabanelli M, Neri I, et al. Topical corticosteroids versus "wait and see" in the management of solitary mastocytoma in pediatric patients: a long-term follow-up. Dermatol Ther. 2015;28:57-61.
- Bonadonna P, Lombardo C. Drug allergy in mastocytosis. Immunol Allergy Clin North Am. 2014;34:397-405.
The Diagnosis: Cutaneous Mastocytoma
Physical examination revealed a 58×51-mm hyperpigmented plaque with central pink coloration and scale on the right side of the back as well as a 39×33-mm pink plaque with a hyperpigmented border on the left side of the flank (Figure 1). At follow-up 2 weeks later, the patient's parents reported that blisters formed within both of the plaques. The blisters ruptured a few hours after forming and drained clear fluid with scant blood. Both plaques contained erosions from the ruptured bullae but remained the same size with no surrounding erythema or warmth. A 4-mm punch biopsy was performed of intact skin from the back lesion (Figure 2A). Histologic examination revealed a cellular infiltrate of monotonous bland cells that completely filled the dermis without epidermal involvement, along with occasional intermixed eosinophils. The morphology of these infiltrating cells was compatible with mast cells confirmed by strongly positive Leder staining (Figure 2B).
Mastocytosis encompasses a rare group of disorders characterized by abnormal mast cell accumulation or mast cell mediator release in various tissues. These disorders can be classified as either systemic mastocytosis with mast cell infiltration into bone marrow or other extracutaneous organs, or cutaneous mastocytosis with disease limited to the skin.1 Mutations involving activation of the c-Kit receptor in stimulating mast cell growth and development have been implicated in both systemic and cutaneous forms of the disease.2,3
Cutaneous mastocytosis is most often diagnosed in childhood and typically is characterized by spontaneous regression before puberty in a majority of cases.1,4 Under the World Health Organization classification system, cutaneous mastocytosis can be further subdivided into 3 disorders (listed in order of most to least common): urticaria pigmentosa (also known as maculopapular cutaneous mastocytosis) with typical, plaque, and nodular forms; cutaneous mastocytoma (as seen in this patient); and diffuse cutaneous mastocytosis.5 Compared to the widespread distribution of small macules and papules in urticaria pigmentosa, the cutaneous mastocytoma subtype presents with 1 to 6 brown to orange-yellow plaques or nodules measuring more than 1 cm in diameter. Cutaneous mastocytoma typically presents in infancy and is located most commonly on the trunk and extremities, though it may be found on the face or scalp. The plaques of mastocytoma often have well-defined margins, and these lesions may become bullous or demonstrate Darier sign of urtication and erythema on physical stimulation. Patients most commonly experience pruritus from mast cell degranulation and rarely exhibit systemic symptoms of mast cell mediator release; however, generalized flushing, hypotension, headaches, and gastrointestinal symptoms may occur, particularly if the lesion is vigorously rubbed.6,7 Conditions in the differential include aplasia cutis congenita, connective tissue nevus, epidermal nevus, and epidermolysis bullosa. They should not elicit a blister if rubbed, except for epidermolysis bullosa, which can easily be differentiated based on histology.
The workup for cutaneous mastocytosis in the pediatric population may include a biopsy of lesional skin, though in many cases the characteristic cutaneous manifestations are sufficient to make a diagnosis. Histologically, biopsy results often reveal abundant diffuse dermal infiltration of mast cells, which are characterized by their large pink granular cytoplasm and round dense central nuclei. In pediatric patients, mast cells typically are restricted to the dermis, and there is a low risk for hematologic abnormalities, thereby precluding the need for bone marrow examination in the absence of organomegaly or notable peripheral blood abnormalities such as severe cytopenia.5,6
Management of cutaneous mastocytosis consists of avoidance of mast cell degranulation triggers and symptomatic treatment of histamine release. Triggers include certain medications (eg, narcotic analgesics, aspirin, nonsteroidal anti-inflammatory drugs, iodinated contrast agents, antibiotics, muscle relaxants), mechanical irritation, insect stings, spicy foods, stress, or extreme temperature changes.8 Symptomatic treatment can be achieved through topical corticosteroid or oral antihistamine use. Along with decreasing pruritus, topical corticosteroids also may be helpful in decreasing time to spontaneous resolution and healing.7 The patient in this case was treated with desonide ointment 0.05% daily to both lesions as well as mupirocin ointment 2% as needed for erosions. These treatments helped reduce the patient's symptoms, but her lesions persisted over a follow-up period of 4 months.
The Diagnosis: Cutaneous Mastocytoma
Physical examination revealed a 58×51-mm hyperpigmented plaque with central pink coloration and scale on the right side of the back as well as a 39×33-mm pink plaque with a hyperpigmented border on the left side of the flank (Figure 1). At follow-up 2 weeks later, the patient's parents reported that blisters formed within both of the plaques. The blisters ruptured a few hours after forming and drained clear fluid with scant blood. Both plaques contained erosions from the ruptured bullae but remained the same size with no surrounding erythema or warmth. A 4-mm punch biopsy was performed of intact skin from the back lesion (Figure 2A). Histologic examination revealed a cellular infiltrate of monotonous bland cells that completely filled the dermis without epidermal involvement, along with occasional intermixed eosinophils. The morphology of these infiltrating cells was compatible with mast cells confirmed by strongly positive Leder staining (Figure 2B).
Mastocytosis encompasses a rare group of disorders characterized by abnormal mast cell accumulation or mast cell mediator release in various tissues. These disorders can be classified as either systemic mastocytosis with mast cell infiltration into bone marrow or other extracutaneous organs, or cutaneous mastocytosis with disease limited to the skin.1 Mutations involving activation of the c-Kit receptor in stimulating mast cell growth and development have been implicated in both systemic and cutaneous forms of the disease.2,3
Cutaneous mastocytosis is most often diagnosed in childhood and typically is characterized by spontaneous regression before puberty in a majority of cases.1,4 Under the World Health Organization classification system, cutaneous mastocytosis can be further subdivided into 3 disorders (listed in order of most to least common): urticaria pigmentosa (also known as maculopapular cutaneous mastocytosis) with typical, plaque, and nodular forms; cutaneous mastocytoma (as seen in this patient); and diffuse cutaneous mastocytosis.5 Compared to the widespread distribution of small macules and papules in urticaria pigmentosa, the cutaneous mastocytoma subtype presents with 1 to 6 brown to orange-yellow plaques or nodules measuring more than 1 cm in diameter. Cutaneous mastocytoma typically presents in infancy and is located most commonly on the trunk and extremities, though it may be found on the face or scalp. The plaques of mastocytoma often have well-defined margins, and these lesions may become bullous or demonstrate Darier sign of urtication and erythema on physical stimulation. Patients most commonly experience pruritus from mast cell degranulation and rarely exhibit systemic symptoms of mast cell mediator release; however, generalized flushing, hypotension, headaches, and gastrointestinal symptoms may occur, particularly if the lesion is vigorously rubbed.6,7 Conditions in the differential include aplasia cutis congenita, connective tissue nevus, epidermal nevus, and epidermolysis bullosa. They should not elicit a blister if rubbed, except for epidermolysis bullosa, which can easily be differentiated based on histology.
The workup for cutaneous mastocytosis in the pediatric population may include a biopsy of lesional skin, though in many cases the characteristic cutaneous manifestations are sufficient to make a diagnosis. Histologically, biopsy results often reveal abundant diffuse dermal infiltration of mast cells, which are characterized by their large pink granular cytoplasm and round dense central nuclei. In pediatric patients, mast cells typically are restricted to the dermis, and there is a low risk for hematologic abnormalities, thereby precluding the need for bone marrow examination in the absence of organomegaly or notable peripheral blood abnormalities such as severe cytopenia.5,6
Management of cutaneous mastocytosis consists of avoidance of mast cell degranulation triggers and symptomatic treatment of histamine release. Triggers include certain medications (eg, narcotic analgesics, aspirin, nonsteroidal anti-inflammatory drugs, iodinated contrast agents, antibiotics, muscle relaxants), mechanical irritation, insect stings, spicy foods, stress, or extreme temperature changes.8 Symptomatic treatment can be achieved through topical corticosteroid or oral antihistamine use. Along with decreasing pruritus, topical corticosteroids also may be helpful in decreasing time to spontaneous resolution and healing.7 The patient in this case was treated with desonide ointment 0.05% daily to both lesions as well as mupirocin ointment 2% as needed for erosions. These treatments helped reduce the patient's symptoms, but her lesions persisted over a follow-up period of 4 months.
- Valent P, Sperr WR, Schwartz LB, et al. Diagnosis and classification of mast cell proliferative disorders: delineation from immunologic diseases and non-mast cell hematopoietic neoplasms. J Allergy Clin Immunol. 2004;114:3-11.
- Bibi S, Langenfeld F, Jeanningros S, et al. Molecular defects in mastocytosis: KIT and beyond KIT. Immunol Allergy Clin North Am. 2014;34:239-262.
- Yavuz AS, Lipsky PE, Yavuz S, et al. Evidence for the involvement of a hematopoietic progenitor cell in systemic mastocytosis from single-cell analysis of mutations in the c-kit gene. Blood. 2002;100:661-665.
- Méni C, Bruneau J, Georgin-Lavialle S, et al. Paediatric mastocytosis: a systematic review of 1747 cases. Br J Dermatol. 2015;172:642-651.
- Valent P, Horny HP, Escribano L, et al. Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leuk Res. 2001;25:603-625.
- Wolff K, Komar M, Petzelbauer P. Clinical and histopathological aspects of cutaneous mastocytosis. Leuk Res. 2001;25:519-528.
- Patrizi A, Tabanelli M, Neri I, et al. Topical corticosteroids versus "wait and see" in the management of solitary mastocytoma in pediatric patients: a long-term follow-up. Dermatol Ther. 2015;28:57-61.
- Bonadonna P, Lombardo C. Drug allergy in mastocytosis. Immunol Allergy Clin North Am. 2014;34:397-405.
- Valent P, Sperr WR, Schwartz LB, et al. Diagnosis and classification of mast cell proliferative disorders: delineation from immunologic diseases and non-mast cell hematopoietic neoplasms. J Allergy Clin Immunol. 2004;114:3-11.
- Bibi S, Langenfeld F, Jeanningros S, et al. Molecular defects in mastocytosis: KIT and beyond KIT. Immunol Allergy Clin North Am. 2014;34:239-262.
- Yavuz AS, Lipsky PE, Yavuz S, et al. Evidence for the involvement of a hematopoietic progenitor cell in systemic mastocytosis from single-cell analysis of mutations in the c-kit gene. Blood. 2002;100:661-665.
- Méni C, Bruneau J, Georgin-Lavialle S, et al. Paediatric mastocytosis: a systematic review of 1747 cases. Br J Dermatol. 2015;172:642-651.
- Valent P, Horny HP, Escribano L, et al. Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leuk Res. 2001;25:603-625.
- Wolff K, Komar M, Petzelbauer P. Clinical and histopathological aspects of cutaneous mastocytosis. Leuk Res. 2001;25:519-528.
- Patrizi A, Tabanelli M, Neri I, et al. Topical corticosteroids versus "wait and see" in the management of solitary mastocytoma in pediatric patients: a long-term follow-up. Dermatol Ther. 2015;28:57-61.
- Bonadonna P, Lombardo C. Drug allergy in mastocytosis. Immunol Allergy Clin North Am. 2014;34:397-405.
A 4-day-old girl with no notable medical history presented with 2 pink lesions on the right side of the back and left side of the flank. Both lesions were present at birth and had not changed in size, shape, or color in the first 4 days of life. She had no constitutional symptoms. The child was a full-term newborn, and her mother experienced no pregnancy or delivery complications. She had no family history of similar skin findings.
