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Bioterrorism, Vaccine-Related Events Still a Threat : Dermatologists should be aware of risk factors for vaccine reactions, one of which is skin disorders.
SCOTTSDALE, ARIZ. Despite the grateful lull that has followed Sept. 11 and the anthrax scare in 2001, bioterrorism remains a very real threat, according to a Food and Drug Administration counterterrorism official.
Dr. Boris Lushniak, the FDA's assistant commissioner for counterterrorism policy and assistant U.S. Surgeon General, hopes that vigilance remains active in medical offices and emergency departments across the United Statesbut frankly, he has his doubts.
"I daresay we are going to be caught off guard," Dr. Lushniak said during the Alfred L. Weiner Lecture at the 50th annual meeting of the Noah Worcester Dermatological Society.
A disturbing number of organisms meet all or some of the criteria for an ideal agent of biological terrorism: easy to obtain and work with; inexpensive to produce; able to be widely disseminated; fairly stable in the environment; capable of producing high morbidity and mortality; transmissible person to person; and difficult to diagnose and treat, which would allow an attack to quickly overwhelm the health care system.
On a positive note, the U.S. government has now stockpiled enough vaccine against smallpox to inoculate every man, woman, and child in the country, Dr. Lushniak reported.
On the other hand, when U.S. public health authorities were notified recently about an individual with suspicious skin lesions on an inbound flight from China, they were unable to find any hospital in a major metropolitan area willing to admit and quarantine the 200 people aboard until danger to the public was ruled out.
Fortunately, in that case, the threat was nullified during 4 hours of frantic planning as the airliner approached U.S. shores, but it stands as a wake-up call about preparedness. "If this is ever to occur, we really have to change the way we do our business," he said.
The potential agents of greatest concernlabeled category A by the Centers for Disease Control and Preventionremain the same as ever: anthrax, smallpox, plague, tularemia, viral hemorrhagic fevers, and botulinum toxin.
"All suspicious or confirmed cases should be reported to health authorities immediately," Dr. Lushniak said.
"We should all have that high level of suspicion. If you're worried, if you think it's part of your differential, you really should give someone a call. It may be a false alarm, may be overreading, but … really what we're looking for is someone to be able to ring that first fire alarm," he said. The timing could be critical.
Anthrax, for example, can be controlled with antibiotics if it is recognized and treated with postexposure prophylaxis before protein-rich toxins are produced by the organism.
"If you can nip it in the spore bud, so to speak, then you really have solved the problem," he said. The disease is heralded by a flulike prodrome, progressing to hypoxia, dyspnea, and, often, mediastinal widening on x-ray.
He reminded dermatologists of the clinical presentation of cutaneous anthrax exposure following a 1- to 12-day incubation period.
The presenting symptom might be tender pruritic macules that evolve into papules, which progress to vesicles and bullae formation in 24-48 hours. Bullae may rupture when they reach 1-2 cm. Eventually, telltale black necrotic ulcers may be seen, with a jet black eschar visible by day 6.
Differential diagnoses for cutaneous anthrax include brown recluse spider bites, ecthyma gangrenosum, tularemia, staph infections, and herpes labialis.
If smallpox is ever used in a bioterrorist attack, the tip-off may be its severe prodrome, which follows a noninfectious incubation period lasting 7-17 days, said Dr. Lushniak.
For 2-4 days, infected patients have very high fevers (101°104°), prostration, myalgias, and malaise as small red macules and papules begin to form and even ulcerate on the tongue and mouth. An exanthem then appears in a centrifugal pattern on the face, arms, hands, legs, and feet. Macules form, then papules. By day 5, tense, often umbilicated vesicles can be seen that look like "BB pellets embedded in the skin," he noted.
By day 6-12, pustules begin to form crusts that remain intact throughout a long period of infection until they separate at about day 28, leaving depressed scars.
Differential diagnoses include varicella, molluscum contagiosum, hand-foot-and-mouth disease, disseminated herpes simplex virus, herpes zoster, pustular drug eruptions, and scabies.
"If this were to come back into the world, the feeling is that at least the prodrome may keep people at home, in bed," he said. Even preventive efforts aimed at a potential bioterrorism attack have health implications that physicians should recognize, Dr. Lushniak said.
He described a 2007 case of household transmission of the live virus through a vaccine involving 1 of the nearly 500,000 Americans inoculated against smallpox either through the military or a civilian volunteer program.
The active-duty father came into contact with his infant son, who had eczema, within a month of the father having received a smallpox vaccination prior to deployment overseas. Although the father's vaccine site was covered during the unplanned visit, the child developed a high fever and a generalized papular, vesicular rash that began on the head and neck. Within days, umbilicated lesions covered more than 50% of the child's body and he required mechanical ventilation.
After a course of antiviral and vasopressor medications, intravenous immunoglobulin, and supportive therapy, the child was discharged from the hospital48 days after admission.
His mother, who had rested her head on the child's chest at one point, also developed a mild vesicular rash on her face.
Cell cultures in the home found evidence of the virus on a booster seat, a toy, and a slipper.
"This ain't real smallpox, people!" Dr. Lushniak said to emphasize the high level of transmission there would be in an actual attack, and the importance of then having a "ring" vaccination strategy aimed at everyone in contact with an exposed subject within 3-4 days.
In the meantime, dermatologists and other physicians should be aware of individuals at high risk for vaccine reactions, including pregnant women, patients with skin disorders characterized by epidermal disruption, immunodeficient patients, those with life-threatening allergies or cardiovascular disease, and their household contacts, he said.
How to Learn More or Deploy
▸ Learn more by going to
▸ Join the civilian volunteer Medical Reserve Corps and participate in disaster response in your community (
▸ Train and deploy with a National Disaster Medical Assistance Team (
www.hhs.gov/aspr/opeo/ndms/teams/dmat.html
▸ Join the active reserve corps of the U.S. Public Health Service (
Source: Dr. Lushniak
SCOTTSDALE, ARIZ. Despite the grateful lull that has followed Sept. 11 and the anthrax scare in 2001, bioterrorism remains a very real threat, according to a Food and Drug Administration counterterrorism official.
Dr. Boris Lushniak, the FDA's assistant commissioner for counterterrorism policy and assistant U.S. Surgeon General, hopes that vigilance remains active in medical offices and emergency departments across the United Statesbut frankly, he has his doubts.
"I daresay we are going to be caught off guard," Dr. Lushniak said during the Alfred L. Weiner Lecture at the 50th annual meeting of the Noah Worcester Dermatological Society.
A disturbing number of organisms meet all or some of the criteria for an ideal agent of biological terrorism: easy to obtain and work with; inexpensive to produce; able to be widely disseminated; fairly stable in the environment; capable of producing high morbidity and mortality; transmissible person to person; and difficult to diagnose and treat, which would allow an attack to quickly overwhelm the health care system.
On a positive note, the U.S. government has now stockpiled enough vaccine against smallpox to inoculate every man, woman, and child in the country, Dr. Lushniak reported.
On the other hand, when U.S. public health authorities were notified recently about an individual with suspicious skin lesions on an inbound flight from China, they were unable to find any hospital in a major metropolitan area willing to admit and quarantine the 200 people aboard until danger to the public was ruled out.
Fortunately, in that case, the threat was nullified during 4 hours of frantic planning as the airliner approached U.S. shores, but it stands as a wake-up call about preparedness. "If this is ever to occur, we really have to change the way we do our business," he said.
The potential agents of greatest concernlabeled category A by the Centers for Disease Control and Preventionremain the same as ever: anthrax, smallpox, plague, tularemia, viral hemorrhagic fevers, and botulinum toxin.
"All suspicious or confirmed cases should be reported to health authorities immediately," Dr. Lushniak said.
"We should all have that high level of suspicion. If you're worried, if you think it's part of your differential, you really should give someone a call. It may be a false alarm, may be overreading, but … really what we're looking for is someone to be able to ring that first fire alarm," he said. The timing could be critical.
Anthrax, for example, can be controlled with antibiotics if it is recognized and treated with postexposure prophylaxis before protein-rich toxins are produced by the organism.
"If you can nip it in the spore bud, so to speak, then you really have solved the problem," he said. The disease is heralded by a flulike prodrome, progressing to hypoxia, dyspnea, and, often, mediastinal widening on x-ray.
He reminded dermatologists of the clinical presentation of cutaneous anthrax exposure following a 1- to 12-day incubation period.
The presenting symptom might be tender pruritic macules that evolve into papules, which progress to vesicles and bullae formation in 24-48 hours. Bullae may rupture when they reach 1-2 cm. Eventually, telltale black necrotic ulcers may be seen, with a jet black eschar visible by day 6.
Differential diagnoses for cutaneous anthrax include brown recluse spider bites, ecthyma gangrenosum, tularemia, staph infections, and herpes labialis.
If smallpox is ever used in a bioterrorist attack, the tip-off may be its severe prodrome, which follows a noninfectious incubation period lasting 7-17 days, said Dr. Lushniak.
For 2-4 days, infected patients have very high fevers (101°104°), prostration, myalgias, and malaise as small red macules and papules begin to form and even ulcerate on the tongue and mouth. An exanthem then appears in a centrifugal pattern on the face, arms, hands, legs, and feet. Macules form, then papules. By day 5, tense, often umbilicated vesicles can be seen that look like "BB pellets embedded in the skin," he noted.
By day 6-12, pustules begin to form crusts that remain intact throughout a long period of infection until they separate at about day 28, leaving depressed scars.
Differential diagnoses include varicella, molluscum contagiosum, hand-foot-and-mouth disease, disseminated herpes simplex virus, herpes zoster, pustular drug eruptions, and scabies.
"If this were to come back into the world, the feeling is that at least the prodrome may keep people at home, in bed," he said. Even preventive efforts aimed at a potential bioterrorism attack have health implications that physicians should recognize, Dr. Lushniak said.
He described a 2007 case of household transmission of the live virus through a vaccine involving 1 of the nearly 500,000 Americans inoculated against smallpox either through the military or a civilian volunteer program.
The active-duty father came into contact with his infant son, who had eczema, within a month of the father having received a smallpox vaccination prior to deployment overseas. Although the father's vaccine site was covered during the unplanned visit, the child developed a high fever and a generalized papular, vesicular rash that began on the head and neck. Within days, umbilicated lesions covered more than 50% of the child's body and he required mechanical ventilation.
After a course of antiviral and vasopressor medications, intravenous immunoglobulin, and supportive therapy, the child was discharged from the hospital48 days after admission.
His mother, who had rested her head on the child's chest at one point, also developed a mild vesicular rash on her face.
Cell cultures in the home found evidence of the virus on a booster seat, a toy, and a slipper.
"This ain't real smallpox, people!" Dr. Lushniak said to emphasize the high level of transmission there would be in an actual attack, and the importance of then having a "ring" vaccination strategy aimed at everyone in contact with an exposed subject within 3-4 days.
In the meantime, dermatologists and other physicians should be aware of individuals at high risk for vaccine reactions, including pregnant women, patients with skin disorders characterized by epidermal disruption, immunodeficient patients, those with life-threatening allergies or cardiovascular disease, and their household contacts, he said.
How to Learn More or Deploy
▸ Learn more by going to
▸ Join the civilian volunteer Medical Reserve Corps and participate in disaster response in your community (
▸ Train and deploy with a National Disaster Medical Assistance Team (
www.hhs.gov/aspr/opeo/ndms/teams/dmat.html
▸ Join the active reserve corps of the U.S. Public Health Service (
Source: Dr. Lushniak
SCOTTSDALE, ARIZ. Despite the grateful lull that has followed Sept. 11 and the anthrax scare in 2001, bioterrorism remains a very real threat, according to a Food and Drug Administration counterterrorism official.
Dr. Boris Lushniak, the FDA's assistant commissioner for counterterrorism policy and assistant U.S. Surgeon General, hopes that vigilance remains active in medical offices and emergency departments across the United Statesbut frankly, he has his doubts.
"I daresay we are going to be caught off guard," Dr. Lushniak said during the Alfred L. Weiner Lecture at the 50th annual meeting of the Noah Worcester Dermatological Society.
A disturbing number of organisms meet all or some of the criteria for an ideal agent of biological terrorism: easy to obtain and work with; inexpensive to produce; able to be widely disseminated; fairly stable in the environment; capable of producing high morbidity and mortality; transmissible person to person; and difficult to diagnose and treat, which would allow an attack to quickly overwhelm the health care system.
On a positive note, the U.S. government has now stockpiled enough vaccine against smallpox to inoculate every man, woman, and child in the country, Dr. Lushniak reported.
On the other hand, when U.S. public health authorities were notified recently about an individual with suspicious skin lesions on an inbound flight from China, they were unable to find any hospital in a major metropolitan area willing to admit and quarantine the 200 people aboard until danger to the public was ruled out.
Fortunately, in that case, the threat was nullified during 4 hours of frantic planning as the airliner approached U.S. shores, but it stands as a wake-up call about preparedness. "If this is ever to occur, we really have to change the way we do our business," he said.
The potential agents of greatest concernlabeled category A by the Centers for Disease Control and Preventionremain the same as ever: anthrax, smallpox, plague, tularemia, viral hemorrhagic fevers, and botulinum toxin.
"All suspicious or confirmed cases should be reported to health authorities immediately," Dr. Lushniak said.
"We should all have that high level of suspicion. If you're worried, if you think it's part of your differential, you really should give someone a call. It may be a false alarm, may be overreading, but … really what we're looking for is someone to be able to ring that first fire alarm," he said. The timing could be critical.
Anthrax, for example, can be controlled with antibiotics if it is recognized and treated with postexposure prophylaxis before protein-rich toxins are produced by the organism.
"If you can nip it in the spore bud, so to speak, then you really have solved the problem," he said. The disease is heralded by a flulike prodrome, progressing to hypoxia, dyspnea, and, often, mediastinal widening on x-ray.
He reminded dermatologists of the clinical presentation of cutaneous anthrax exposure following a 1- to 12-day incubation period.
The presenting symptom might be tender pruritic macules that evolve into papules, which progress to vesicles and bullae formation in 24-48 hours. Bullae may rupture when they reach 1-2 cm. Eventually, telltale black necrotic ulcers may be seen, with a jet black eschar visible by day 6.
Differential diagnoses for cutaneous anthrax include brown recluse spider bites, ecthyma gangrenosum, tularemia, staph infections, and herpes labialis.
If smallpox is ever used in a bioterrorist attack, the tip-off may be its severe prodrome, which follows a noninfectious incubation period lasting 7-17 days, said Dr. Lushniak.
For 2-4 days, infected patients have very high fevers (101°104°), prostration, myalgias, and malaise as small red macules and papules begin to form and even ulcerate on the tongue and mouth. An exanthem then appears in a centrifugal pattern on the face, arms, hands, legs, and feet. Macules form, then papules. By day 5, tense, often umbilicated vesicles can be seen that look like "BB pellets embedded in the skin," he noted.
By day 6-12, pustules begin to form crusts that remain intact throughout a long period of infection until they separate at about day 28, leaving depressed scars.
Differential diagnoses include varicella, molluscum contagiosum, hand-foot-and-mouth disease, disseminated herpes simplex virus, herpes zoster, pustular drug eruptions, and scabies.
"If this were to come back into the world, the feeling is that at least the prodrome may keep people at home, in bed," he said. Even preventive efforts aimed at a potential bioterrorism attack have health implications that physicians should recognize, Dr. Lushniak said.
He described a 2007 case of household transmission of the live virus through a vaccine involving 1 of the nearly 500,000 Americans inoculated against smallpox either through the military or a civilian volunteer program.
The active-duty father came into contact with his infant son, who had eczema, within a month of the father having received a smallpox vaccination prior to deployment overseas. Although the father's vaccine site was covered during the unplanned visit, the child developed a high fever and a generalized papular, vesicular rash that began on the head and neck. Within days, umbilicated lesions covered more than 50% of the child's body and he required mechanical ventilation.
After a course of antiviral and vasopressor medications, intravenous immunoglobulin, and supportive therapy, the child was discharged from the hospital48 days after admission.
His mother, who had rested her head on the child's chest at one point, also developed a mild vesicular rash on her face.
Cell cultures in the home found evidence of the virus on a booster seat, a toy, and a slipper.
"This ain't real smallpox, people!" Dr. Lushniak said to emphasize the high level of transmission there would be in an actual attack, and the importance of then having a "ring" vaccination strategy aimed at everyone in contact with an exposed subject within 3-4 days.
In the meantime, dermatologists and other physicians should be aware of individuals at high risk for vaccine reactions, including pregnant women, patients with skin disorders characterized by epidermal disruption, immunodeficient patients, those with life-threatening allergies or cardiovascular disease, and their household contacts, he said.
How to Learn More or Deploy
▸ Learn more by going to
▸ Join the civilian volunteer Medical Reserve Corps and participate in disaster response in your community (
▸ Train and deploy with a National Disaster Medical Assistance Team (
www.hhs.gov/aspr/opeo/ndms/teams/dmat.html
▸ Join the active reserve corps of the U.S. Public Health Service (
Source: Dr. Lushniak
Autoimmune Testing Helps Guide Urticaria Tx
SCOTTSDALE, ARIZ. Autoimmune testing may not be perfectly sensitive, but it can help to guide therapeutic decisions regarding patients with severe, recalcitrant chronic idiopathic urticaria.
By simple definition, chronic idiopathic urticaria is characterized by the appearance of transitory, pruritic wheals that occur on a daily basis for a period of at least 6 weeks, "but in reality, we know that many of our patients have disease lasting months to years," Dr. Diane R. Baker said at the annual meeting of the Noah Worcester Dermatological Society.
"It can be very resistant to treatment and has an impact on quality of life that is similar to what we see in our severe atopic dermatitis patients," said Dr. Baker, a dermatologist in private practice in Portland, Ore., and former president of the American Academy of Dermatology.
Research conducted in the past 10-15 years has ushered in a new era of understanding about the etiology of chronic idiopathic urticaria. It is now known that approximately 40% of patients demonstrate autoimmune dysfunction.
These patients often have other autoimmune diseases and demonstrate a reduced histamine release from the basophils.
Dr. Baker advised using this new information to one's advantage in clinical practice by inquiring about a chronic urticaria patient's personal or family history of autoimmune disease, conducting autologous serum skin testing (ASST), and/or ordering a functional anti-Fc(ϵ) RI autoimmune test.
ASST is performed by injecting 0.05 cc autologous serum, 0.9% saline, and 10 mcg histamine into three separate sites on the volar forearm. A positive result, read at 15 and 30 minutes, comprises a skin reaction at the serum site that is 1.5-mm greater than any reaction at the saline control site and more than 50% larger than the histamine response.
The reaction in a patient with autologous chronic idiopathic urticaria is "across-the-room positive," she said.
Results of this test sometimes correlate well with ex vivo autoantibody testing for functional (histamine-releasing) anti-Fc(ϵ) RI. This test is performed at an external laboratory by combining at least 1 cc of the patient's serum with positive and negative controls and donor basophils. The supernate is assayed for histamine, with a positive result defined as a histamine release from the patient's serum that is greater than the mean plus two standard deviations of the control, Dr. Baker explained.
These autoantibodies are usually not detectable in normal, healthy controls, and although they can be identified in patients with other skin diseases in a nonfunctional form, functional anti-Fc(ϵ) RI antibodies appear to be specific to patients with chronic idiopathic urticaria.
One source for autoimmune testing is the IBT Reference Laboratory in Lenexa, Kan., noted Dr. Baker, who said she had no financial interest in the company nor any other company mentioned in her talk.
The functional anti-Fc(ϵ) RI autoantibody test and the AAST are an imperfect measures, however, because negative test results do not necessarily rule out autoimmunity as a basis for urticaria, she said.
The tests may draw an incomplete picture of abnormalities in patients with autoimmune chronic idiopathic dysfunction. For example, results do not correlate with basophilic dysfunction, which improves considerably when patients go into remission, whether or not they have a positive autoantibody test.
Nonetheless, the two-pronged approach to identifying autoimmunity may have clinical relevance as important preliminary information, Dr. Baker said.
"I think a positive ASST or demonstration of the presence of functional antibodies helps support your decision about whether to put a patient on something more than an antihistamine, [such as] an immunomodulatory treatment," she said.
In her experience, patients with positive results in either test seem to have more severe and resistant disease that requires higher than usual doses of antihistamines, often in conjunction with systemic corticosteroids or immunomodulatory agents such as methotrexate or cyclosporine.
Case reports generally guide this immunomodulatory therapy, although in one randomized, double-blind study cyclosporine added to an antihistamine produced marked improvement in two-thirds of 99 patients (J. Am. Acad. Dermatol. 2006;55:705-9).
SCOTTSDALE, ARIZ. Autoimmune testing may not be perfectly sensitive, but it can help to guide therapeutic decisions regarding patients with severe, recalcitrant chronic idiopathic urticaria.
By simple definition, chronic idiopathic urticaria is characterized by the appearance of transitory, pruritic wheals that occur on a daily basis for a period of at least 6 weeks, "but in reality, we know that many of our patients have disease lasting months to years," Dr. Diane R. Baker said at the annual meeting of the Noah Worcester Dermatological Society.
"It can be very resistant to treatment and has an impact on quality of life that is similar to what we see in our severe atopic dermatitis patients," said Dr. Baker, a dermatologist in private practice in Portland, Ore., and former president of the American Academy of Dermatology.
Research conducted in the past 10-15 years has ushered in a new era of understanding about the etiology of chronic idiopathic urticaria. It is now known that approximately 40% of patients demonstrate autoimmune dysfunction.
These patients often have other autoimmune diseases and demonstrate a reduced histamine release from the basophils.
Dr. Baker advised using this new information to one's advantage in clinical practice by inquiring about a chronic urticaria patient's personal or family history of autoimmune disease, conducting autologous serum skin testing (ASST), and/or ordering a functional anti-Fc(ϵ) RI autoimmune test.
ASST is performed by injecting 0.05 cc autologous serum, 0.9% saline, and 10 mcg histamine into three separate sites on the volar forearm. A positive result, read at 15 and 30 minutes, comprises a skin reaction at the serum site that is 1.5-mm greater than any reaction at the saline control site and more than 50% larger than the histamine response.
The reaction in a patient with autologous chronic idiopathic urticaria is "across-the-room positive," she said.
Results of this test sometimes correlate well with ex vivo autoantibody testing for functional (histamine-releasing) anti-Fc(ϵ) RI. This test is performed at an external laboratory by combining at least 1 cc of the patient's serum with positive and negative controls and donor basophils. The supernate is assayed for histamine, with a positive result defined as a histamine release from the patient's serum that is greater than the mean plus two standard deviations of the control, Dr. Baker explained.
These autoantibodies are usually not detectable in normal, healthy controls, and although they can be identified in patients with other skin diseases in a nonfunctional form, functional anti-Fc(ϵ) RI antibodies appear to be specific to patients with chronic idiopathic urticaria.
One source for autoimmune testing is the IBT Reference Laboratory in Lenexa, Kan., noted Dr. Baker, who said she had no financial interest in the company nor any other company mentioned in her talk.
The functional anti-Fc(ϵ) RI autoantibody test and the AAST are an imperfect measures, however, because negative test results do not necessarily rule out autoimmunity as a basis for urticaria, she said.
The tests may draw an incomplete picture of abnormalities in patients with autoimmune chronic idiopathic dysfunction. For example, results do not correlate with basophilic dysfunction, which improves considerably when patients go into remission, whether or not they have a positive autoantibody test.
Nonetheless, the two-pronged approach to identifying autoimmunity may have clinical relevance as important preliminary information, Dr. Baker said.
"I think a positive ASST or demonstration of the presence of functional antibodies helps support your decision about whether to put a patient on something more than an antihistamine, [such as] an immunomodulatory treatment," she said.
In her experience, patients with positive results in either test seem to have more severe and resistant disease that requires higher than usual doses of antihistamines, often in conjunction with systemic corticosteroids or immunomodulatory agents such as methotrexate or cyclosporine.
Case reports generally guide this immunomodulatory therapy, although in one randomized, double-blind study cyclosporine added to an antihistamine produced marked improvement in two-thirds of 99 patients (J. Am. Acad. Dermatol. 2006;55:705-9).
SCOTTSDALE, ARIZ. Autoimmune testing may not be perfectly sensitive, but it can help to guide therapeutic decisions regarding patients with severe, recalcitrant chronic idiopathic urticaria.
By simple definition, chronic idiopathic urticaria is characterized by the appearance of transitory, pruritic wheals that occur on a daily basis for a period of at least 6 weeks, "but in reality, we know that many of our patients have disease lasting months to years," Dr. Diane R. Baker said at the annual meeting of the Noah Worcester Dermatological Society.
"It can be very resistant to treatment and has an impact on quality of life that is similar to what we see in our severe atopic dermatitis patients," said Dr. Baker, a dermatologist in private practice in Portland, Ore., and former president of the American Academy of Dermatology.
Research conducted in the past 10-15 years has ushered in a new era of understanding about the etiology of chronic idiopathic urticaria. It is now known that approximately 40% of patients demonstrate autoimmune dysfunction.
These patients often have other autoimmune diseases and demonstrate a reduced histamine release from the basophils.
Dr. Baker advised using this new information to one's advantage in clinical practice by inquiring about a chronic urticaria patient's personal or family history of autoimmune disease, conducting autologous serum skin testing (ASST), and/or ordering a functional anti-Fc(ϵ) RI autoimmune test.
ASST is performed by injecting 0.05 cc autologous serum, 0.9% saline, and 10 mcg histamine into three separate sites on the volar forearm. A positive result, read at 15 and 30 minutes, comprises a skin reaction at the serum site that is 1.5-mm greater than any reaction at the saline control site and more than 50% larger than the histamine response.
The reaction in a patient with autologous chronic idiopathic urticaria is "across-the-room positive," she said.
Results of this test sometimes correlate well with ex vivo autoantibody testing for functional (histamine-releasing) anti-Fc(ϵ) RI. This test is performed at an external laboratory by combining at least 1 cc of the patient's serum with positive and negative controls and donor basophils. The supernate is assayed for histamine, with a positive result defined as a histamine release from the patient's serum that is greater than the mean plus two standard deviations of the control, Dr. Baker explained.
These autoantibodies are usually not detectable in normal, healthy controls, and although they can be identified in patients with other skin diseases in a nonfunctional form, functional anti-Fc(ϵ) RI antibodies appear to be specific to patients with chronic idiopathic urticaria.
One source for autoimmune testing is the IBT Reference Laboratory in Lenexa, Kan., noted Dr. Baker, who said she had no financial interest in the company nor any other company mentioned in her talk.
The functional anti-Fc(ϵ) RI autoantibody test and the AAST are an imperfect measures, however, because negative test results do not necessarily rule out autoimmunity as a basis for urticaria, she said.
The tests may draw an incomplete picture of abnormalities in patients with autoimmune chronic idiopathic dysfunction. For example, results do not correlate with basophilic dysfunction, which improves considerably when patients go into remission, whether or not they have a positive autoantibody test.
Nonetheless, the two-pronged approach to identifying autoimmunity may have clinical relevance as important preliminary information, Dr. Baker said.
"I think a positive ASST or demonstration of the presence of functional antibodies helps support your decision about whether to put a patient on something more than an antihistamine, [such as] an immunomodulatory treatment," she said.
In her experience, patients with positive results in either test seem to have more severe and resistant disease that requires higher than usual doses of antihistamines, often in conjunction with systemic corticosteroids or immunomodulatory agents such as methotrexate or cyclosporine.
Case reports generally guide this immunomodulatory therapy, although in one randomized, double-blind study cyclosporine added to an antihistamine produced marked improvement in two-thirds of 99 patients (J. Am. Acad. Dermatol. 2006;55:705-9).
Bleomycin as Second Line Therapy Clears Cancerous Lesions
SCOTTSDALE, ARIZ. If there was an award given for "oldies but goodies" in the dermatologic armamentarium, Dr. Haines Ely would surely nominate bleomycin, a medication he has long relied upon for difficult squamous and Merkel cell lesions.
"My love affair with bleomycin began when I was a senior medical student," he recalled at the annual meeting of the Noah Worcester Dermatological Society.
The experience exposed him to two near-miraculous responses to intralesional bleomycin: the first, in a patient who refused a penectomy for advanced squamous cell carcinoma (SCC) of the penis.
And the second, in a patient with multiple fast-growing metastatic skin lesions from SCC of the lung that had left the patient "screaming in agony" on the hospital ward where Dr. Ely was moonlighting as a phlebotomist.
"By morning, those tumors had resolved. He was sitting up and eating breakfast," said Dr. Ely, a dermatologist in private practice in Grass Valley, Calif.
Through the years, Dr. Ely's reliance on bleomycin in tough cases has been reconfirmed.
The drug has a profound antiviral effect, demonstrated by the drug's effectiveness for treating Kaposi's sarcoma patients in the early days of HIV therapy.
It has also been useful for treating aggressive acantholytic SCC patients who refused surgery or were poor surgical candidates, he said. But perhaps its greatest utility is in treating patients with Merkel cell carcinoma (MCC), which has recently been linked to a previously unknown polyomavirus that may prove susceptible to bleomycin (Science 2008;319:1096-100).
"The treatment of choice is still surgery," he emphasized, but patients are often unable to undergo surgery because of their advanced age, comorbidities, and immunocompromised state. In several cases he presented, radiation therapy proved unsuccessful or resulted in profound complications.
One such case involved an 84-year-old woman residing in a nursing home who was seen for a "cyst" on her cheek that proved to be a 6-cm MCC. "I called several plastic surgeons in town, but nobody would touch it," he said.
Radiation was followed by "tremendous regrowth," prompting Dr. Ely to inject bleomycin directly into the tumor base in two treatments, 1 week apart.
The tumor resolved. "She lived 5 years with no recurrences," he said.
For tumors that strongly resemble MCC, "I don't even fool around," said Dr. Ely, noting that he injects 3 IU of bleomycin with lidocaine prior to biopsying the site. In one such case sent for referral following prebiopsy intralesional bleomycin, no evidence could be found of MCC by the time of excision.
Dr. Ely said his experience has led him to add to the recently described acronym AEIOU associated with features of MCC: asymptomatic/lack of tenderness, expanding rapidly, immune suppression, older than age 50, and UV-exposed site in a fair-skinned person (J. Am. Acad. Dermatol. 2008;58:375-81).
His own acronym, AEIOU-VB, includes "viral associated" and "bleomycin sensitive."
He cautioned that patients must have adequate renal function for bleomycin to be considered, and some patients may have transient side effects such as chills and fever following intralesional injections of the medication. The most serious, albeit rare, complication of bleomycin is pulmonary fibrosis, more commonly seen in elderly patients and those receiving high doses of the chemotherapy.
Dr. Ely reported having no conflicts of interest.
'My love affair with bleomycin began when Iwas a senior medical student.' DR. ELY
SCOTTSDALE, ARIZ. If there was an award given for "oldies but goodies" in the dermatologic armamentarium, Dr. Haines Ely would surely nominate bleomycin, a medication he has long relied upon for difficult squamous and Merkel cell lesions.
"My love affair with bleomycin began when I was a senior medical student," he recalled at the annual meeting of the Noah Worcester Dermatological Society.
The experience exposed him to two near-miraculous responses to intralesional bleomycin: the first, in a patient who refused a penectomy for advanced squamous cell carcinoma (SCC) of the penis.
And the second, in a patient with multiple fast-growing metastatic skin lesions from SCC of the lung that had left the patient "screaming in agony" on the hospital ward where Dr. Ely was moonlighting as a phlebotomist.
"By morning, those tumors had resolved. He was sitting up and eating breakfast," said Dr. Ely, a dermatologist in private practice in Grass Valley, Calif.
Through the years, Dr. Ely's reliance on bleomycin in tough cases has been reconfirmed.
The drug has a profound antiviral effect, demonstrated by the drug's effectiveness for treating Kaposi's sarcoma patients in the early days of HIV therapy.
It has also been useful for treating aggressive acantholytic SCC patients who refused surgery or were poor surgical candidates, he said. But perhaps its greatest utility is in treating patients with Merkel cell carcinoma (MCC), which has recently been linked to a previously unknown polyomavirus that may prove susceptible to bleomycin (Science 2008;319:1096-100).
"The treatment of choice is still surgery," he emphasized, but patients are often unable to undergo surgery because of their advanced age, comorbidities, and immunocompromised state. In several cases he presented, radiation therapy proved unsuccessful or resulted in profound complications.
One such case involved an 84-year-old woman residing in a nursing home who was seen for a "cyst" on her cheek that proved to be a 6-cm MCC. "I called several plastic surgeons in town, but nobody would touch it," he said.
Radiation was followed by "tremendous regrowth," prompting Dr. Ely to inject bleomycin directly into the tumor base in two treatments, 1 week apart.
The tumor resolved. "She lived 5 years with no recurrences," he said.
For tumors that strongly resemble MCC, "I don't even fool around," said Dr. Ely, noting that he injects 3 IU of bleomycin with lidocaine prior to biopsying the site. In one such case sent for referral following prebiopsy intralesional bleomycin, no evidence could be found of MCC by the time of excision.
Dr. Ely said his experience has led him to add to the recently described acronym AEIOU associated with features of MCC: asymptomatic/lack of tenderness, expanding rapidly, immune suppression, older than age 50, and UV-exposed site in a fair-skinned person (J. Am. Acad. Dermatol. 2008;58:375-81).
His own acronym, AEIOU-VB, includes "viral associated" and "bleomycin sensitive."
He cautioned that patients must have adequate renal function for bleomycin to be considered, and some patients may have transient side effects such as chills and fever following intralesional injections of the medication. The most serious, albeit rare, complication of bleomycin is pulmonary fibrosis, more commonly seen in elderly patients and those receiving high doses of the chemotherapy.
Dr. Ely reported having no conflicts of interest.
'My love affair with bleomycin began when Iwas a senior medical student.' DR. ELY
SCOTTSDALE, ARIZ. If there was an award given for "oldies but goodies" in the dermatologic armamentarium, Dr. Haines Ely would surely nominate bleomycin, a medication he has long relied upon for difficult squamous and Merkel cell lesions.
"My love affair with bleomycin began when I was a senior medical student," he recalled at the annual meeting of the Noah Worcester Dermatological Society.
The experience exposed him to two near-miraculous responses to intralesional bleomycin: the first, in a patient who refused a penectomy for advanced squamous cell carcinoma (SCC) of the penis.
And the second, in a patient with multiple fast-growing metastatic skin lesions from SCC of the lung that had left the patient "screaming in agony" on the hospital ward where Dr. Ely was moonlighting as a phlebotomist.
"By morning, those tumors had resolved. He was sitting up and eating breakfast," said Dr. Ely, a dermatologist in private practice in Grass Valley, Calif.
Through the years, Dr. Ely's reliance on bleomycin in tough cases has been reconfirmed.
The drug has a profound antiviral effect, demonstrated by the drug's effectiveness for treating Kaposi's sarcoma patients in the early days of HIV therapy.
It has also been useful for treating aggressive acantholytic SCC patients who refused surgery or were poor surgical candidates, he said. But perhaps its greatest utility is in treating patients with Merkel cell carcinoma (MCC), which has recently been linked to a previously unknown polyomavirus that may prove susceptible to bleomycin (Science 2008;319:1096-100).
"The treatment of choice is still surgery," he emphasized, but patients are often unable to undergo surgery because of their advanced age, comorbidities, and immunocompromised state. In several cases he presented, radiation therapy proved unsuccessful or resulted in profound complications.
One such case involved an 84-year-old woman residing in a nursing home who was seen for a "cyst" on her cheek that proved to be a 6-cm MCC. "I called several plastic surgeons in town, but nobody would touch it," he said.
Radiation was followed by "tremendous regrowth," prompting Dr. Ely to inject bleomycin directly into the tumor base in two treatments, 1 week apart.
The tumor resolved. "She lived 5 years with no recurrences," he said.
For tumors that strongly resemble MCC, "I don't even fool around," said Dr. Ely, noting that he injects 3 IU of bleomycin with lidocaine prior to biopsying the site. In one such case sent for referral following prebiopsy intralesional bleomycin, no evidence could be found of MCC by the time of excision.
Dr. Ely said his experience has led him to add to the recently described acronym AEIOU associated with features of MCC: asymptomatic/lack of tenderness, expanding rapidly, immune suppression, older than age 50, and UV-exposed site in a fair-skinned person (J. Am. Acad. Dermatol. 2008;58:375-81).
His own acronym, AEIOU-VB, includes "viral associated" and "bleomycin sensitive."
He cautioned that patients must have adequate renal function for bleomycin to be considered, and some patients may have transient side effects such as chills and fever following intralesional injections of the medication. The most serious, albeit rare, complication of bleomycin is pulmonary fibrosis, more commonly seen in elderly patients and those receiving high doses of the chemotherapy.
Dr. Ely reported having no conflicts of interest.
'My love affair with bleomycin began when Iwas a senior medical student.' DR. ELY
Aggressive Skin Cancers: On Rise and Easily Missed
SCOTTSDALE, ARIZ. There are four aggressive skin cancers that are increasing in incidence and can be easily overlooked, warned Dr. Marc D. Brown during the Harold O. Perry lecture at the annual meeting of the Noah Worcester Dermatological Society.
Lentigo Maligna
Once cavalierly called a "Hutchinson's freckle" because it can resemble a dab of shoe polish, patients may not even notice the subtle appearance and growth of a lentigo maligna. Even dermatologists may overlook the amelanotic variety of this in situ tumor, said Dr. Brown, director of the division of dermatologic surgery, oncology, and Mohs surgery at the University of Rochester (N.Y.).
"It's very, very difficult to make the diagnosis," Dr. Brown said. "I've missed it several times."
Lentigo maligna lesions are slow to develop and evolve almost imperceptibly. They may lie camouflaged in contiguous solar lentigos or pigmented actinic keratoses, as was the case in nearly half of 147 lesions described in a recent study (J. Am. Acad. Dermatol. 2005;52:85962).
However, it is not a disease to be trivialized, according to Dr. Brown.
"It's my feeling that if you give it a long enough period of time, it will become an invasive tumor," he said.
Two decades ago, when he began performing Mohs surgery, Dr. Brown almost exclusively encountered lentigo malignas on elderly patients. Now he's making it a practice to hunt for them on much younger patients. "It's not at all unusual for me to see patients … in their 40s or 50s with their first lentigo maligna," he said.
Finding a surefire treatment approach to lentigo malignas remains challenging.
Increasing evidence suggests that the lesions often extend far beyond the 5-mm clinical margins that once were considered adequate for melanoma in situ lesions. Frozen section proponents have reported low recurrence rates, but, Dr. Brown advised, "you really have to have an excellent lab and be very good at this."
He said he prefers a "modified Mohs," or "slow Mohs" approach that involves sending sequential sections to a histopathologic laboratory over several days after a "very meticulous" collection of tissue around the peripheral margin. In 210 cases performed in such a manner, he reported a recurrence rate of less than 2%.
For elderly patients and difficult anatomic sites, radiation therapy or daily use of imiquimod has been proposed. Dr. Brown cautioned that the use of the immune response modifier should be considered experimental, because only 67 cases in which it has been used are described in the literature, and 8 of those involved treatment failures.
Atypical Fibroxanthoma
Also increasing in incidence is this tumor, which is believed to be secondary to UV exposure, said Dr. Brown.
Unlike lentigo maligna, atypical fibroxanthoma (AFX) seems to be confined to an older population.
"It usually appears relatively nonspecifically," he said. "Most of the time when I submit a specimen to the pathologist, I don't say, 'Rule out AFX.' It's usually squamous cell versus basal cell cancer [in my mind]."
In general, these tumors are small, superficial, and well managed by excision with a 1-cm margin or Mohs surgery, said Dr. Brown. He was a coinvestigator in a study that found a 100% cure rate in 20 such tumors (J. Dermatol. Surg. Oncol. 1989;15:128792).
"If it sounds too good to be true, it's too good to be true," he said, noting that he has now had 6 cases of metastatic AFX in his practice, and 25 have been reported in the literature.
In his experience with metastatic cases, the original lesion was small (average, 1.5 cm) and metastasis occurred early (on average, 9 months after diagnosis). The most common metastatic site was the regional lymph nodes.
Fortunately, there is a clue to potential aggressive behavior in such tumors, he said. The immunostain LN-2 (CD74) often "lights up" in more aggressive AFX tumors, including five of the six of his cases. When he sees a worrisome clinical AFX tumor and LN-2 is strongly positive, he refers patients for adjunctive radiation therapy.
Merkel Cell Carcinoma
Unknown until 1972 and then considered exceedingly rare, Merkel cell carcinoma appears to be on the rise. More than 1,000 cases have been reported in patients aged 775 years (although most patients are older than 65 years).
Up to 15% of cases are seen in immunocompromised patients, a number that is driven by long-term survivors of HIV, chronic lymphocytic leukemia, and organ transplantation. "I'm seeing a lot of these," said Dr. Brown. Sometimes dome shaped and distinctly red or violaceous, they may present more subtly.
In one case, the small scalp lesion was barely pink, ill defined, and bound down to the adjacent skin. "No way I thought this was a Merkel cell," he admitted.
When the diagnosis is confirmed by its blue cell clusters in sheets or a trabecular pattern in the dermis, with frequent mitosis and cell necrosis, dermatologists should take heed. "This is probably one of the worst cutaneous tumors that we, as dermatologists, can see. It's right up there with a bad angiosarcoma," he said.
Local recurrences are seen in 25%-33% of cases, regional spread in 25%, and distant metastasis in 33% of cases50% by some reportswith a 3-year overall survival of 31%.
Treatment is controversial, noted Dr. Brown. Wide local excision down to the fascia or Mohs surgery with sentinel lymph node biopsy is recommended, guiding the need for total lymph node dissection, postoperative radiation therapy, and perhaps adjuvant chemotherapy. A negative sentinel lymph node carries a fairly reassuring prognosis.
He added that an immunostain for anti-CK20 antibody may detect micrometastases in patients who appear to be tumor free on routine histology, according to a small study (J. Am. Acad. Dermatol. 2002;46:6616).
SCC in Organ Transplant Patients
The growing population of long-term survivors of organ transplantation has a 65-fold increased risk of squamous cell carcinoma.
Their cancers may be multiple, fast growing, and atypical in appearance, Dr. Brown said.
In one such case, a liver transplant patient he had seen 3 weeks previously presented with a 3-cm SCC at the base of his thumb. He had a positive lymph node in his axilla and developed metastatic disease in his lung within 3 months.
"We're all going to be seeing more and more of these patients," Dr. Brown predicted.
The keys to management of these challenging patients are education first, then vigilance. Many transplant centers fail to warn patients that they may be at elevated risk for skin cancers and that they should be examined frequently.
When a lesion appears, have a low threshold for suspicion, he said. "It is very difficult sometimes to determine which is the bad [lesion] and which is not."
High-risk SCCs are those that are large, multiple, deeply invasive, painful or tender, rapidly growing, recurrent, and on high-risk sites: the scalp, ear, lip, neck, and face. Warning signs histologically include poor cell differentiation and perineural invasion.
"How do you manage these? Aggressively," he emphasized.
Employ whichever tools work: surgery, cryotherapy, 5-fluorouracil, photodynamic therapy, or topical imiquimod. Systemic retinoids, perhaps in conjunction with a reduction in immunosuppressive therapy, may be appropriate for patients with recurrent, aggressive, or metastatic SCCs, he added.
Dr. Brown disclosed that he is a consultant to Graceway Pharmaceuticals LLC and Novartis. His presentation, however, was not sponsored by any company.
Long-term survivors of organ transplantation have a 65-fold increased risk of squamous cell carcinoma. DR. BROWN
SCOTTSDALE, ARIZ. There are four aggressive skin cancers that are increasing in incidence and can be easily overlooked, warned Dr. Marc D. Brown during the Harold O. Perry lecture at the annual meeting of the Noah Worcester Dermatological Society.
Lentigo Maligna
Once cavalierly called a "Hutchinson's freckle" because it can resemble a dab of shoe polish, patients may not even notice the subtle appearance and growth of a lentigo maligna. Even dermatologists may overlook the amelanotic variety of this in situ tumor, said Dr. Brown, director of the division of dermatologic surgery, oncology, and Mohs surgery at the University of Rochester (N.Y.).
"It's very, very difficult to make the diagnosis," Dr. Brown said. "I've missed it several times."
Lentigo maligna lesions are slow to develop and evolve almost imperceptibly. They may lie camouflaged in contiguous solar lentigos or pigmented actinic keratoses, as was the case in nearly half of 147 lesions described in a recent study (J. Am. Acad. Dermatol. 2005;52:85962).
However, it is not a disease to be trivialized, according to Dr. Brown.
"It's my feeling that if you give it a long enough period of time, it will become an invasive tumor," he said.
Two decades ago, when he began performing Mohs surgery, Dr. Brown almost exclusively encountered lentigo malignas on elderly patients. Now he's making it a practice to hunt for them on much younger patients. "It's not at all unusual for me to see patients … in their 40s or 50s with their first lentigo maligna," he said.
Finding a surefire treatment approach to lentigo malignas remains challenging.
Increasing evidence suggests that the lesions often extend far beyond the 5-mm clinical margins that once were considered adequate for melanoma in situ lesions. Frozen section proponents have reported low recurrence rates, but, Dr. Brown advised, "you really have to have an excellent lab and be very good at this."
He said he prefers a "modified Mohs," or "slow Mohs" approach that involves sending sequential sections to a histopathologic laboratory over several days after a "very meticulous" collection of tissue around the peripheral margin. In 210 cases performed in such a manner, he reported a recurrence rate of less than 2%.
For elderly patients and difficult anatomic sites, radiation therapy or daily use of imiquimod has been proposed. Dr. Brown cautioned that the use of the immune response modifier should be considered experimental, because only 67 cases in which it has been used are described in the literature, and 8 of those involved treatment failures.
Atypical Fibroxanthoma
Also increasing in incidence is this tumor, which is believed to be secondary to UV exposure, said Dr. Brown.
Unlike lentigo maligna, atypical fibroxanthoma (AFX) seems to be confined to an older population.
"It usually appears relatively nonspecifically," he said. "Most of the time when I submit a specimen to the pathologist, I don't say, 'Rule out AFX.' It's usually squamous cell versus basal cell cancer [in my mind]."
In general, these tumors are small, superficial, and well managed by excision with a 1-cm margin or Mohs surgery, said Dr. Brown. He was a coinvestigator in a study that found a 100% cure rate in 20 such tumors (J. Dermatol. Surg. Oncol. 1989;15:128792).
"If it sounds too good to be true, it's too good to be true," he said, noting that he has now had 6 cases of metastatic AFX in his practice, and 25 have been reported in the literature.
In his experience with metastatic cases, the original lesion was small (average, 1.5 cm) and metastasis occurred early (on average, 9 months after diagnosis). The most common metastatic site was the regional lymph nodes.
Fortunately, there is a clue to potential aggressive behavior in such tumors, he said. The immunostain LN-2 (CD74) often "lights up" in more aggressive AFX tumors, including five of the six of his cases. When he sees a worrisome clinical AFX tumor and LN-2 is strongly positive, he refers patients for adjunctive radiation therapy.
Merkel Cell Carcinoma
Unknown until 1972 and then considered exceedingly rare, Merkel cell carcinoma appears to be on the rise. More than 1,000 cases have been reported in patients aged 775 years (although most patients are older than 65 years).
Up to 15% of cases are seen in immunocompromised patients, a number that is driven by long-term survivors of HIV, chronic lymphocytic leukemia, and organ transplantation. "I'm seeing a lot of these," said Dr. Brown. Sometimes dome shaped and distinctly red or violaceous, they may present more subtly.
In one case, the small scalp lesion was barely pink, ill defined, and bound down to the adjacent skin. "No way I thought this was a Merkel cell," he admitted.
When the diagnosis is confirmed by its blue cell clusters in sheets or a trabecular pattern in the dermis, with frequent mitosis and cell necrosis, dermatologists should take heed. "This is probably one of the worst cutaneous tumors that we, as dermatologists, can see. It's right up there with a bad angiosarcoma," he said.
Local recurrences are seen in 25%-33% of cases, regional spread in 25%, and distant metastasis in 33% of cases50% by some reportswith a 3-year overall survival of 31%.
Treatment is controversial, noted Dr. Brown. Wide local excision down to the fascia or Mohs surgery with sentinel lymph node biopsy is recommended, guiding the need for total lymph node dissection, postoperative radiation therapy, and perhaps adjuvant chemotherapy. A negative sentinel lymph node carries a fairly reassuring prognosis.
He added that an immunostain for anti-CK20 antibody may detect micrometastases in patients who appear to be tumor free on routine histology, according to a small study (J. Am. Acad. Dermatol. 2002;46:6616).
SCC in Organ Transplant Patients
The growing population of long-term survivors of organ transplantation has a 65-fold increased risk of squamous cell carcinoma.
Their cancers may be multiple, fast growing, and atypical in appearance, Dr. Brown said.
In one such case, a liver transplant patient he had seen 3 weeks previously presented with a 3-cm SCC at the base of his thumb. He had a positive lymph node in his axilla and developed metastatic disease in his lung within 3 months.
"We're all going to be seeing more and more of these patients," Dr. Brown predicted.
The keys to management of these challenging patients are education first, then vigilance. Many transplant centers fail to warn patients that they may be at elevated risk for skin cancers and that they should be examined frequently.
When a lesion appears, have a low threshold for suspicion, he said. "It is very difficult sometimes to determine which is the bad [lesion] and which is not."
High-risk SCCs are those that are large, multiple, deeply invasive, painful or tender, rapidly growing, recurrent, and on high-risk sites: the scalp, ear, lip, neck, and face. Warning signs histologically include poor cell differentiation and perineural invasion.
"How do you manage these? Aggressively," he emphasized.
Employ whichever tools work: surgery, cryotherapy, 5-fluorouracil, photodynamic therapy, or topical imiquimod. Systemic retinoids, perhaps in conjunction with a reduction in immunosuppressive therapy, may be appropriate for patients with recurrent, aggressive, or metastatic SCCs, he added.
Dr. Brown disclosed that he is a consultant to Graceway Pharmaceuticals LLC and Novartis. His presentation, however, was not sponsored by any company.
Long-term survivors of organ transplantation have a 65-fold increased risk of squamous cell carcinoma. DR. BROWN
SCOTTSDALE, ARIZ. There are four aggressive skin cancers that are increasing in incidence and can be easily overlooked, warned Dr. Marc D. Brown during the Harold O. Perry lecture at the annual meeting of the Noah Worcester Dermatological Society.
Lentigo Maligna
Once cavalierly called a "Hutchinson's freckle" because it can resemble a dab of shoe polish, patients may not even notice the subtle appearance and growth of a lentigo maligna. Even dermatologists may overlook the amelanotic variety of this in situ tumor, said Dr. Brown, director of the division of dermatologic surgery, oncology, and Mohs surgery at the University of Rochester (N.Y.).
"It's very, very difficult to make the diagnosis," Dr. Brown said. "I've missed it several times."
Lentigo maligna lesions are slow to develop and evolve almost imperceptibly. They may lie camouflaged in contiguous solar lentigos or pigmented actinic keratoses, as was the case in nearly half of 147 lesions described in a recent study (J. Am. Acad. Dermatol. 2005;52:85962).
However, it is not a disease to be trivialized, according to Dr. Brown.
"It's my feeling that if you give it a long enough period of time, it will become an invasive tumor," he said.
Two decades ago, when he began performing Mohs surgery, Dr. Brown almost exclusively encountered lentigo malignas on elderly patients. Now he's making it a practice to hunt for them on much younger patients. "It's not at all unusual for me to see patients … in their 40s or 50s with their first lentigo maligna," he said.
Finding a surefire treatment approach to lentigo malignas remains challenging.
Increasing evidence suggests that the lesions often extend far beyond the 5-mm clinical margins that once were considered adequate for melanoma in situ lesions. Frozen section proponents have reported low recurrence rates, but, Dr. Brown advised, "you really have to have an excellent lab and be very good at this."
He said he prefers a "modified Mohs," or "slow Mohs" approach that involves sending sequential sections to a histopathologic laboratory over several days after a "very meticulous" collection of tissue around the peripheral margin. In 210 cases performed in such a manner, he reported a recurrence rate of less than 2%.
For elderly patients and difficult anatomic sites, radiation therapy or daily use of imiquimod has been proposed. Dr. Brown cautioned that the use of the immune response modifier should be considered experimental, because only 67 cases in which it has been used are described in the literature, and 8 of those involved treatment failures.
Atypical Fibroxanthoma
Also increasing in incidence is this tumor, which is believed to be secondary to UV exposure, said Dr. Brown.
Unlike lentigo maligna, atypical fibroxanthoma (AFX) seems to be confined to an older population.
"It usually appears relatively nonspecifically," he said. "Most of the time when I submit a specimen to the pathologist, I don't say, 'Rule out AFX.' It's usually squamous cell versus basal cell cancer [in my mind]."
In general, these tumors are small, superficial, and well managed by excision with a 1-cm margin or Mohs surgery, said Dr. Brown. He was a coinvestigator in a study that found a 100% cure rate in 20 such tumors (J. Dermatol. Surg. Oncol. 1989;15:128792).
"If it sounds too good to be true, it's too good to be true," he said, noting that he has now had 6 cases of metastatic AFX in his practice, and 25 have been reported in the literature.
In his experience with metastatic cases, the original lesion was small (average, 1.5 cm) and metastasis occurred early (on average, 9 months after diagnosis). The most common metastatic site was the regional lymph nodes.
Fortunately, there is a clue to potential aggressive behavior in such tumors, he said. The immunostain LN-2 (CD74) often "lights up" in more aggressive AFX tumors, including five of the six of his cases. When he sees a worrisome clinical AFX tumor and LN-2 is strongly positive, he refers patients for adjunctive radiation therapy.
Merkel Cell Carcinoma
Unknown until 1972 and then considered exceedingly rare, Merkel cell carcinoma appears to be on the rise. More than 1,000 cases have been reported in patients aged 775 years (although most patients are older than 65 years).
Up to 15% of cases are seen in immunocompromised patients, a number that is driven by long-term survivors of HIV, chronic lymphocytic leukemia, and organ transplantation. "I'm seeing a lot of these," said Dr. Brown. Sometimes dome shaped and distinctly red or violaceous, they may present more subtly.
In one case, the small scalp lesion was barely pink, ill defined, and bound down to the adjacent skin. "No way I thought this was a Merkel cell," he admitted.
When the diagnosis is confirmed by its blue cell clusters in sheets or a trabecular pattern in the dermis, with frequent mitosis and cell necrosis, dermatologists should take heed. "This is probably one of the worst cutaneous tumors that we, as dermatologists, can see. It's right up there with a bad angiosarcoma," he said.
Local recurrences are seen in 25%-33% of cases, regional spread in 25%, and distant metastasis in 33% of cases50% by some reportswith a 3-year overall survival of 31%.
Treatment is controversial, noted Dr. Brown. Wide local excision down to the fascia or Mohs surgery with sentinel lymph node biopsy is recommended, guiding the need for total lymph node dissection, postoperative radiation therapy, and perhaps adjuvant chemotherapy. A negative sentinel lymph node carries a fairly reassuring prognosis.
He added that an immunostain for anti-CK20 antibody may detect micrometastases in patients who appear to be tumor free on routine histology, according to a small study (J. Am. Acad. Dermatol. 2002;46:6616).
SCC in Organ Transplant Patients
The growing population of long-term survivors of organ transplantation has a 65-fold increased risk of squamous cell carcinoma.
Their cancers may be multiple, fast growing, and atypical in appearance, Dr. Brown said.
In one such case, a liver transplant patient he had seen 3 weeks previously presented with a 3-cm SCC at the base of his thumb. He had a positive lymph node in his axilla and developed metastatic disease in his lung within 3 months.
"We're all going to be seeing more and more of these patients," Dr. Brown predicted.
The keys to management of these challenging patients are education first, then vigilance. Many transplant centers fail to warn patients that they may be at elevated risk for skin cancers and that they should be examined frequently.
When a lesion appears, have a low threshold for suspicion, he said. "It is very difficult sometimes to determine which is the bad [lesion] and which is not."
High-risk SCCs are those that are large, multiple, deeply invasive, painful or tender, rapidly growing, recurrent, and on high-risk sites: the scalp, ear, lip, neck, and face. Warning signs histologically include poor cell differentiation and perineural invasion.
"How do you manage these? Aggressively," he emphasized.
Employ whichever tools work: surgery, cryotherapy, 5-fluorouracil, photodynamic therapy, or topical imiquimod. Systemic retinoids, perhaps in conjunction with a reduction in immunosuppressive therapy, may be appropriate for patients with recurrent, aggressive, or metastatic SCCs, he added.
Dr. Brown disclosed that he is a consultant to Graceway Pharmaceuticals LLC and Novartis. His presentation, however, was not sponsored by any company.
Long-term survivors of organ transplantation have a 65-fold increased risk of squamous cell carcinoma. DR. BROWN
Old Drug Combo Prevents Colorectal Adenomas
SAN DIEGO — Small doses of two historic drugs administered in tandem profoundly reduced the development of colorectal adenomas in patients with prior adenoma formation, heralding a “mid-game home run” in secondary chemoprevention investigators reported at the annual meeting of the American Association for Cancer Research.
Dr. Frank L. Meyskens Jr., professor of medicine and biological chemistry at the University of California, Irvine, presented “late-breaking” results from a phase III trial of difluoromethylornithine (DFMO), a synthetic inhibitor of ornithine decarboxylase, and sulindac (Clinoril), a nonsteroidal, anti-inflammatory drug (NSAID), in 375 patients.
Patients were recruited following resection of at least one adenoma (greater than or equal to 3 mm) discovered on colonoscopy—a history placing them at significant risk of recurrence. (Subjects were excluded if they had a history of familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, or inflammatory bowel disease.)
Oral doses of DFMO (500 mg) and sulindac (150 mg) daily were given to 191 randomized patients, while 184 were assigned to placebo. Low-dose aspirin were used by approximately 40% of patients in each group.
At 3 years' follow-up, total adenomas detected by colonoscopy were reduced by 70%, advanced adenomas by 92%, and multiple adenomas by 95% in treated patients versus those on placebo. Specifically, an adenoma was found in 42 of 97 patients who received placebo and completed the trial (43%), compared with 12 of 107 on the DFMO/sulindac combination (11%).
Advanced adenomas—large, intramucosal or invasive adenomas containing histologic features associated with conversion to colorectal cancer—were seen in nine (9.3%) patients in the placebo group and one patient receiving combination chemoprevention. More than one adenoma was found in 15 patients receiving placebo versus just 1 patient in the chemoprevention arm.
“These are absolutely stunning findings,” Dr. Scott M. Lippman told meeting attendees in a formal discussion of the phase III results. “I would consider this a mid-game home run.”
The research culminates a “long quest” by Dr. Meyskens and coinvestigator Dr. Eugene W. Gerner of the University of Arizona, Tucson, to fight the development of cancer by targeting ornithine decarboxylase, a key polyamine pathway that acts as an instigator of growth.
DFMO, long abandoned as chemotherapy because of inefficacy and hearing-related toxicity, was known to prevent many forms of cancer in preclinical and in vitro models. The researchers conducted novel “de-escalation” dose-finding trials, determining in the mid-1990s that a 500-mg dose (one-fiftieth of the therapeutic dose and one-quarter of the ototoxic dose) could reduce the polyamine content of colonic flat mucosa.
The decision was made to combine the drug (approved for African sleeping sickness and, more recently, as a topical depilatory) with sulindac, an NSAID in use for a half-century, to maximize each drug's efficacy at the smallest possible doses.
Sulindac has shown clinical activity against familial adenomatous polyposis (FAP) in vitro and in five preclinical animal models, explained Dr. Meyskens. It has multiple mechanisms of action and was used in the trial at a 150-mg dose daily, half the dose used in the treatment of arthritis.
Adverse events were carefully monitored in the study, with particular attention given to cardiovascular and otologic side effects previously associated with NSAIDs and DFMO.
At least 1 serious adverse event requiring hospitalization was seen in 31 patients receiving placebo and 42 in the DFMO/sulindac group. No significant difference was seen in the number of patients experiencing a serious adverse event (grade III or greater).
Serious cardiovascular side effects occurred in 16 of the patients receiving active treatment versus 9 in the placebo arm. This difference, while not statistically significant, may indicate a “worrisome trend” and deserves further study, according to Dr. Lippman of the M.D. Anderson Cancer Center in Houston, a formal discussant of the study.
No hearing loss was perceived in patients receiving DFMO and sulindac, although a 1-2 dB difference was found in precise hearing tests. This difference is “a sound equivalent to rubbing your two fingers together,” perceptible only to “a very alert 17-year-old,” or a similar individual, Dr. Meyskens said.
The hearing loss was reversible with discontinuation of the drug.
The DFMO/sulindac drug combination has shown “very promising” results in early studies of prostate cancer and is being studied as a topical agent in skin cancers.
Future research may investigate its chemopreventive potential in patients with “cured” low-stage colorectal cancer, and a larger group of patients with prior advanced adenomas detected at colonoscopy. However, because DFMO has gone off patent, creative solutions are being sought to finance future studies of the drug combination's potential as a chemopreventive agent, Dr. Meyskens said.
The study was published online simultaneously with the presentation at AACR (Cancer Prev. Res. 2008 April [Epub doi: 10.1158/1940-6207.CAPR-08-0042]).
SAN DIEGO — Small doses of two historic drugs administered in tandem profoundly reduced the development of colorectal adenomas in patients with prior adenoma formation, heralding a “mid-game home run” in secondary chemoprevention investigators reported at the annual meeting of the American Association for Cancer Research.
Dr. Frank L. Meyskens Jr., professor of medicine and biological chemistry at the University of California, Irvine, presented “late-breaking” results from a phase III trial of difluoromethylornithine (DFMO), a synthetic inhibitor of ornithine decarboxylase, and sulindac (Clinoril), a nonsteroidal, anti-inflammatory drug (NSAID), in 375 patients.
Patients were recruited following resection of at least one adenoma (greater than or equal to 3 mm) discovered on colonoscopy—a history placing them at significant risk of recurrence. (Subjects were excluded if they had a history of familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, or inflammatory bowel disease.)
Oral doses of DFMO (500 mg) and sulindac (150 mg) daily were given to 191 randomized patients, while 184 were assigned to placebo. Low-dose aspirin were used by approximately 40% of patients in each group.
At 3 years' follow-up, total adenomas detected by colonoscopy were reduced by 70%, advanced adenomas by 92%, and multiple adenomas by 95% in treated patients versus those on placebo. Specifically, an adenoma was found in 42 of 97 patients who received placebo and completed the trial (43%), compared with 12 of 107 on the DFMO/sulindac combination (11%).
Advanced adenomas—large, intramucosal or invasive adenomas containing histologic features associated with conversion to colorectal cancer—were seen in nine (9.3%) patients in the placebo group and one patient receiving combination chemoprevention. More than one adenoma was found in 15 patients receiving placebo versus just 1 patient in the chemoprevention arm.
“These are absolutely stunning findings,” Dr. Scott M. Lippman told meeting attendees in a formal discussion of the phase III results. “I would consider this a mid-game home run.”
The research culminates a “long quest” by Dr. Meyskens and coinvestigator Dr. Eugene W. Gerner of the University of Arizona, Tucson, to fight the development of cancer by targeting ornithine decarboxylase, a key polyamine pathway that acts as an instigator of growth.
DFMO, long abandoned as chemotherapy because of inefficacy and hearing-related toxicity, was known to prevent many forms of cancer in preclinical and in vitro models. The researchers conducted novel “de-escalation” dose-finding trials, determining in the mid-1990s that a 500-mg dose (one-fiftieth of the therapeutic dose and one-quarter of the ototoxic dose) could reduce the polyamine content of colonic flat mucosa.
The decision was made to combine the drug (approved for African sleeping sickness and, more recently, as a topical depilatory) with sulindac, an NSAID in use for a half-century, to maximize each drug's efficacy at the smallest possible doses.
Sulindac has shown clinical activity against familial adenomatous polyposis (FAP) in vitro and in five preclinical animal models, explained Dr. Meyskens. It has multiple mechanisms of action and was used in the trial at a 150-mg dose daily, half the dose used in the treatment of arthritis.
Adverse events were carefully monitored in the study, with particular attention given to cardiovascular and otologic side effects previously associated with NSAIDs and DFMO.
At least 1 serious adverse event requiring hospitalization was seen in 31 patients receiving placebo and 42 in the DFMO/sulindac group. No significant difference was seen in the number of patients experiencing a serious adverse event (grade III or greater).
Serious cardiovascular side effects occurred in 16 of the patients receiving active treatment versus 9 in the placebo arm. This difference, while not statistically significant, may indicate a “worrisome trend” and deserves further study, according to Dr. Lippman of the M.D. Anderson Cancer Center in Houston, a formal discussant of the study.
No hearing loss was perceived in patients receiving DFMO and sulindac, although a 1-2 dB difference was found in precise hearing tests. This difference is “a sound equivalent to rubbing your two fingers together,” perceptible only to “a very alert 17-year-old,” or a similar individual, Dr. Meyskens said.
The hearing loss was reversible with discontinuation of the drug.
The DFMO/sulindac drug combination has shown “very promising” results in early studies of prostate cancer and is being studied as a topical agent in skin cancers.
Future research may investigate its chemopreventive potential in patients with “cured” low-stage colorectal cancer, and a larger group of patients with prior advanced adenomas detected at colonoscopy. However, because DFMO has gone off patent, creative solutions are being sought to finance future studies of the drug combination's potential as a chemopreventive agent, Dr. Meyskens said.
The study was published online simultaneously with the presentation at AACR (Cancer Prev. Res. 2008 April [Epub doi: 10.1158/1940-6207.CAPR-08-0042]).
SAN DIEGO — Small doses of two historic drugs administered in tandem profoundly reduced the development of colorectal adenomas in patients with prior adenoma formation, heralding a “mid-game home run” in secondary chemoprevention investigators reported at the annual meeting of the American Association for Cancer Research.
Dr. Frank L. Meyskens Jr., professor of medicine and biological chemistry at the University of California, Irvine, presented “late-breaking” results from a phase III trial of difluoromethylornithine (DFMO), a synthetic inhibitor of ornithine decarboxylase, and sulindac (Clinoril), a nonsteroidal, anti-inflammatory drug (NSAID), in 375 patients.
Patients were recruited following resection of at least one adenoma (greater than or equal to 3 mm) discovered on colonoscopy—a history placing them at significant risk of recurrence. (Subjects were excluded if they had a history of familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, or inflammatory bowel disease.)
Oral doses of DFMO (500 mg) and sulindac (150 mg) daily were given to 191 randomized patients, while 184 were assigned to placebo. Low-dose aspirin were used by approximately 40% of patients in each group.
At 3 years' follow-up, total adenomas detected by colonoscopy were reduced by 70%, advanced adenomas by 92%, and multiple adenomas by 95% in treated patients versus those on placebo. Specifically, an adenoma was found in 42 of 97 patients who received placebo and completed the trial (43%), compared with 12 of 107 on the DFMO/sulindac combination (11%).
Advanced adenomas—large, intramucosal or invasive adenomas containing histologic features associated with conversion to colorectal cancer—were seen in nine (9.3%) patients in the placebo group and one patient receiving combination chemoprevention. More than one adenoma was found in 15 patients receiving placebo versus just 1 patient in the chemoprevention arm.
“These are absolutely stunning findings,” Dr. Scott M. Lippman told meeting attendees in a formal discussion of the phase III results. “I would consider this a mid-game home run.”
The research culminates a “long quest” by Dr. Meyskens and coinvestigator Dr. Eugene W. Gerner of the University of Arizona, Tucson, to fight the development of cancer by targeting ornithine decarboxylase, a key polyamine pathway that acts as an instigator of growth.
DFMO, long abandoned as chemotherapy because of inefficacy and hearing-related toxicity, was known to prevent many forms of cancer in preclinical and in vitro models. The researchers conducted novel “de-escalation” dose-finding trials, determining in the mid-1990s that a 500-mg dose (one-fiftieth of the therapeutic dose and one-quarter of the ototoxic dose) could reduce the polyamine content of colonic flat mucosa.
The decision was made to combine the drug (approved for African sleeping sickness and, more recently, as a topical depilatory) with sulindac, an NSAID in use for a half-century, to maximize each drug's efficacy at the smallest possible doses.
Sulindac has shown clinical activity against familial adenomatous polyposis (FAP) in vitro and in five preclinical animal models, explained Dr. Meyskens. It has multiple mechanisms of action and was used in the trial at a 150-mg dose daily, half the dose used in the treatment of arthritis.
Adverse events were carefully monitored in the study, with particular attention given to cardiovascular and otologic side effects previously associated with NSAIDs and DFMO.
At least 1 serious adverse event requiring hospitalization was seen in 31 patients receiving placebo and 42 in the DFMO/sulindac group. No significant difference was seen in the number of patients experiencing a serious adverse event (grade III or greater).
Serious cardiovascular side effects occurred in 16 of the patients receiving active treatment versus 9 in the placebo arm. This difference, while not statistically significant, may indicate a “worrisome trend” and deserves further study, according to Dr. Lippman of the M.D. Anderson Cancer Center in Houston, a formal discussant of the study.
No hearing loss was perceived in patients receiving DFMO and sulindac, although a 1-2 dB difference was found in precise hearing tests. This difference is “a sound equivalent to rubbing your two fingers together,” perceptible only to “a very alert 17-year-old,” or a similar individual, Dr. Meyskens said.
The hearing loss was reversible with discontinuation of the drug.
The DFMO/sulindac drug combination has shown “very promising” results in early studies of prostate cancer and is being studied as a topical agent in skin cancers.
Future research may investigate its chemopreventive potential in patients with “cured” low-stage colorectal cancer, and a larger group of patients with prior advanced adenomas detected at colonoscopy. However, because DFMO has gone off patent, creative solutions are being sought to finance future studies of the drug combination's potential as a chemopreventive agent, Dr. Meyskens said.
The study was published online simultaneously with the presentation at AACR (Cancer Prev. Res. 2008 April [Epub doi: 10.1158/1940-6207.CAPR-08-0042]).
Four Skin Cancers Warrant Vigilance as Incidence Rates Rise
SCOTTSDALE, ARIZ. — There are four aggressive skin cancers that are increasing in incidence and can be easily overlooked, warned Dr. Marc D. Brown at the annual meeting of the Noah Worcester Dermatological Society.
Lentigo Maligna
The appearance and growth of this tumor, once cavalierly called a “Hutchinson's freckle” because it resembles a dab of shoe polish, might not be noticed by patients. Even dermatologists may overlook the amelanotic variety of this in situ tumor, said Dr. Brown, director of the division of dermatologic surgery, oncology, and Mohs surgery at the University of Rochester (N.Y.).
The lesions are slow to develop and may lie camouflaged in contiguous solar lentigos or pigmented actinic keratoses, but “if you give it a long enough period of time, it will become an invasive tumor.” Dr. Brown said that 2 decades ago, he encountered lentigo malignas almost exclusively on elderly patients. Now “it's not at all unusual for me to see patients … in their 40s or 50s with their first lentigo maligna.”
Finding a surefire treatment approach to lentigo malignas remains challenging. Increasing evidence suggests the lesions often extend far beyond the 5-mm clinical margins that once were considered adequate for melanoma in situ lesions. Frozen section proponents have reported low recurrence rates, but “you really have to have an excellent lab and be very good at this.”
He said he prefers a “modified Mohs” or “slow Mohs” approach that involves sending sequential sections to a histopathologic laboratory over several days after a “very meticulous” collection of tissue around the peripheral margin. In 210 cases performed in such a manner, he reported a recurrence rate of less than 2%.
SCC in Organ Transplant Patients
The growing population of long-term survivors of organ transplantation has a 65-fold increased risk of squamous cell carcinoma. Their cancers may be multiple, fast growing, and atypical in appearance.
In one such case, a liver transplant patient he had seen 3 weeks previously presented with a 3-cm SCC at the base of his thumb. He had a positive lymph node in his axilla and developed metastatic disease in his lung within 3 months.
“We're going to be seeing more and more of these patients,” he said. The keys to management are education and vigilance. Many transplant centers fail to warn patients they should be examined frequently. When a lesion appears, have a low threshold for suspicion, he said. “It is very difficult sometimes to determine which is the bad [lesion] and which is not.”
High-risk SCCs are those that are large, multiple, deeply invasive, painful or tender, rapidly growing, recurrent, and on high-risk sites such as the scalp, ear, lip, neck, and face. Dr. Brown disclosed that he is a consultant to Graceway Pharmaceuticals LLC and Novartis. His talk, however, was not sponsored by any company.
Atypical Fibroxanthoma
This tumor is believed to be secondary to UV exposure, but unlike lentigo maligna, atypical fibroxanthoma (AFX) seems to be confined to an older population.
“It usually appears relatively nonspecifically,” he said. In general, these tumors are small, superficial, and well managed by excision with a 1-cm margin or Mohs surgery, said Dr. Brown, who was a coinvestigator in a study that found a 100% cure rate in 20 such tumors (J. Dermatol. Surg. Oncol. 1989;15:1287-92).
“If it sounds too good to be true, it's too good to be true,” he said, noting that he has now had 6 cases of metastatic AFX in his practice, and 25 have been reported in the literature.
In his experience with metastatic cases, the original lesion was small (average, 1.5 cm) and metastasis occurred early (on average, 9 months after diagnosis). The most common metastatic site was the regional lymph nodes.
Fortunately, there is a clue to potential aggressive behavior in such tumors: The immunostain LN-2 (CD74) often “lights up” in more aggressive AFX tumors, including five of the six of his cases. When he sees a worrisome clinical AFX tumor and LN-2 is strongly positive, he refers patients for adjunctive radiation therapy.
Merkel Cell Carcinoma
Merkel cell carcinoma was unknown until 1972 and then considered exceedingly rare. More than 1,000 cases have been reported in patients aged 7-75 years (although most patients are older than 65 years). Up to 15% of cases are seen in immunocompromised patients.
“I'm seeing a lot of these,” said Dr. Brown. Sometimes dome shaped and distinctly red or violaceous, they may present more subtly.
In one case, the small scalp lesion was barely pink, ill defined, and bound down to the adjacent skin. “No way I thought this was a Merkel cell,” he admitted.
“This is probably one of the worst cutaneous tumors that we, as dermatologists, can see. It's right up there with a bad angiosarcoma,” he said.
Local recurrences are seen in 25%-33% of cases, regional spread in 25%, and distant metastasis in 33% of cases—50% by some reports—with a 3-year overall survival of 31%.
Treatment is controversial, noted Dr. Brown.
Wide local excision down to the fascia or Mohs surgery with sentinel lymph node biopsy is recommended, guiding the need for total lymph node dissection, postoperative radiation therapy, and perhaps even adjuvant chemotherapy, he said, adding that a negative sentinel lymph node carries a fairly reassuring prognosis.
'It's not at all unusual for me to see patients … in their 40s or 50s with their first lentigo maligna.' DR. BROWN
SCOTTSDALE, ARIZ. — There are four aggressive skin cancers that are increasing in incidence and can be easily overlooked, warned Dr. Marc D. Brown at the annual meeting of the Noah Worcester Dermatological Society.
Lentigo Maligna
The appearance and growth of this tumor, once cavalierly called a “Hutchinson's freckle” because it resembles a dab of shoe polish, might not be noticed by patients. Even dermatologists may overlook the amelanotic variety of this in situ tumor, said Dr. Brown, director of the division of dermatologic surgery, oncology, and Mohs surgery at the University of Rochester (N.Y.).
The lesions are slow to develop and may lie camouflaged in contiguous solar lentigos or pigmented actinic keratoses, but “if you give it a long enough period of time, it will become an invasive tumor.” Dr. Brown said that 2 decades ago, he encountered lentigo malignas almost exclusively on elderly patients. Now “it's not at all unusual for me to see patients … in their 40s or 50s with their first lentigo maligna.”
Finding a surefire treatment approach to lentigo malignas remains challenging. Increasing evidence suggests the lesions often extend far beyond the 5-mm clinical margins that once were considered adequate for melanoma in situ lesions. Frozen section proponents have reported low recurrence rates, but “you really have to have an excellent lab and be very good at this.”
He said he prefers a “modified Mohs” or “slow Mohs” approach that involves sending sequential sections to a histopathologic laboratory over several days after a “very meticulous” collection of tissue around the peripheral margin. In 210 cases performed in such a manner, he reported a recurrence rate of less than 2%.
SCC in Organ Transplant Patients
The growing population of long-term survivors of organ transplantation has a 65-fold increased risk of squamous cell carcinoma. Their cancers may be multiple, fast growing, and atypical in appearance.
In one such case, a liver transplant patient he had seen 3 weeks previously presented with a 3-cm SCC at the base of his thumb. He had a positive lymph node in his axilla and developed metastatic disease in his lung within 3 months.
“We're going to be seeing more and more of these patients,” he said. The keys to management are education and vigilance. Many transplant centers fail to warn patients they should be examined frequently. When a lesion appears, have a low threshold for suspicion, he said. “It is very difficult sometimes to determine which is the bad [lesion] and which is not.”
High-risk SCCs are those that are large, multiple, deeply invasive, painful or tender, rapidly growing, recurrent, and on high-risk sites such as the scalp, ear, lip, neck, and face. Dr. Brown disclosed that he is a consultant to Graceway Pharmaceuticals LLC and Novartis. His talk, however, was not sponsored by any company.
Atypical Fibroxanthoma
This tumor is believed to be secondary to UV exposure, but unlike lentigo maligna, atypical fibroxanthoma (AFX) seems to be confined to an older population.
“It usually appears relatively nonspecifically,” he said. In general, these tumors are small, superficial, and well managed by excision with a 1-cm margin or Mohs surgery, said Dr. Brown, who was a coinvestigator in a study that found a 100% cure rate in 20 such tumors (J. Dermatol. Surg. Oncol. 1989;15:1287-92).
“If it sounds too good to be true, it's too good to be true,” he said, noting that he has now had 6 cases of metastatic AFX in his practice, and 25 have been reported in the literature.
In his experience with metastatic cases, the original lesion was small (average, 1.5 cm) and metastasis occurred early (on average, 9 months after diagnosis). The most common metastatic site was the regional lymph nodes.
Fortunately, there is a clue to potential aggressive behavior in such tumors: The immunostain LN-2 (CD74) often “lights up” in more aggressive AFX tumors, including five of the six of his cases. When he sees a worrisome clinical AFX tumor and LN-2 is strongly positive, he refers patients for adjunctive radiation therapy.
Merkel Cell Carcinoma
Merkel cell carcinoma was unknown until 1972 and then considered exceedingly rare. More than 1,000 cases have been reported in patients aged 7-75 years (although most patients are older than 65 years). Up to 15% of cases are seen in immunocompromised patients.
“I'm seeing a lot of these,” said Dr. Brown. Sometimes dome shaped and distinctly red or violaceous, they may present more subtly.
In one case, the small scalp lesion was barely pink, ill defined, and bound down to the adjacent skin. “No way I thought this was a Merkel cell,” he admitted.
“This is probably one of the worst cutaneous tumors that we, as dermatologists, can see. It's right up there with a bad angiosarcoma,” he said.
Local recurrences are seen in 25%-33% of cases, regional spread in 25%, and distant metastasis in 33% of cases—50% by some reports—with a 3-year overall survival of 31%.
Treatment is controversial, noted Dr. Brown.
Wide local excision down to the fascia or Mohs surgery with sentinel lymph node biopsy is recommended, guiding the need for total lymph node dissection, postoperative radiation therapy, and perhaps even adjuvant chemotherapy, he said, adding that a negative sentinel lymph node carries a fairly reassuring prognosis.
'It's not at all unusual for me to see patients … in their 40s or 50s with their first lentigo maligna.' DR. BROWN
SCOTTSDALE, ARIZ. — There are four aggressive skin cancers that are increasing in incidence and can be easily overlooked, warned Dr. Marc D. Brown at the annual meeting of the Noah Worcester Dermatological Society.
Lentigo Maligna
The appearance and growth of this tumor, once cavalierly called a “Hutchinson's freckle” because it resembles a dab of shoe polish, might not be noticed by patients. Even dermatologists may overlook the amelanotic variety of this in situ tumor, said Dr. Brown, director of the division of dermatologic surgery, oncology, and Mohs surgery at the University of Rochester (N.Y.).
The lesions are slow to develop and may lie camouflaged in contiguous solar lentigos or pigmented actinic keratoses, but “if you give it a long enough period of time, it will become an invasive tumor.” Dr. Brown said that 2 decades ago, he encountered lentigo malignas almost exclusively on elderly patients. Now “it's not at all unusual for me to see patients … in their 40s or 50s with their first lentigo maligna.”
Finding a surefire treatment approach to lentigo malignas remains challenging. Increasing evidence suggests the lesions often extend far beyond the 5-mm clinical margins that once were considered adequate for melanoma in situ lesions. Frozen section proponents have reported low recurrence rates, but “you really have to have an excellent lab and be very good at this.”
He said he prefers a “modified Mohs” or “slow Mohs” approach that involves sending sequential sections to a histopathologic laboratory over several days after a “very meticulous” collection of tissue around the peripheral margin. In 210 cases performed in such a manner, he reported a recurrence rate of less than 2%.
SCC in Organ Transplant Patients
The growing population of long-term survivors of organ transplantation has a 65-fold increased risk of squamous cell carcinoma. Their cancers may be multiple, fast growing, and atypical in appearance.
In one such case, a liver transplant patient he had seen 3 weeks previously presented with a 3-cm SCC at the base of his thumb. He had a positive lymph node in his axilla and developed metastatic disease in his lung within 3 months.
“We're going to be seeing more and more of these patients,” he said. The keys to management are education and vigilance. Many transplant centers fail to warn patients they should be examined frequently. When a lesion appears, have a low threshold for suspicion, he said. “It is very difficult sometimes to determine which is the bad [lesion] and which is not.”
High-risk SCCs are those that are large, multiple, deeply invasive, painful or tender, rapidly growing, recurrent, and on high-risk sites such as the scalp, ear, lip, neck, and face. Dr. Brown disclosed that he is a consultant to Graceway Pharmaceuticals LLC and Novartis. His talk, however, was not sponsored by any company.
Atypical Fibroxanthoma
This tumor is believed to be secondary to UV exposure, but unlike lentigo maligna, atypical fibroxanthoma (AFX) seems to be confined to an older population.
“It usually appears relatively nonspecifically,” he said. In general, these tumors are small, superficial, and well managed by excision with a 1-cm margin or Mohs surgery, said Dr. Brown, who was a coinvestigator in a study that found a 100% cure rate in 20 such tumors (J. Dermatol. Surg. Oncol. 1989;15:1287-92).
“If it sounds too good to be true, it's too good to be true,” he said, noting that he has now had 6 cases of metastatic AFX in his practice, and 25 have been reported in the literature.
In his experience with metastatic cases, the original lesion was small (average, 1.5 cm) and metastasis occurred early (on average, 9 months after diagnosis). The most common metastatic site was the regional lymph nodes.
Fortunately, there is a clue to potential aggressive behavior in such tumors: The immunostain LN-2 (CD74) often “lights up” in more aggressive AFX tumors, including five of the six of his cases. When he sees a worrisome clinical AFX tumor and LN-2 is strongly positive, he refers patients for adjunctive radiation therapy.
Merkel Cell Carcinoma
Merkel cell carcinoma was unknown until 1972 and then considered exceedingly rare. More than 1,000 cases have been reported in patients aged 7-75 years (although most patients are older than 65 years). Up to 15% of cases are seen in immunocompromised patients.
“I'm seeing a lot of these,” said Dr. Brown. Sometimes dome shaped and distinctly red or violaceous, they may present more subtly.
In one case, the small scalp lesion was barely pink, ill defined, and bound down to the adjacent skin. “No way I thought this was a Merkel cell,” he admitted.
“This is probably one of the worst cutaneous tumors that we, as dermatologists, can see. It's right up there with a bad angiosarcoma,” he said.
Local recurrences are seen in 25%-33% of cases, regional spread in 25%, and distant metastasis in 33% of cases—50% by some reports—with a 3-year overall survival of 31%.
Treatment is controversial, noted Dr. Brown.
Wide local excision down to the fascia or Mohs surgery with sentinel lymph node biopsy is recommended, guiding the need for total lymph node dissection, postoperative radiation therapy, and perhaps even adjuvant chemotherapy, he said, adding that a negative sentinel lymph node carries a fairly reassuring prognosis.
'It's not at all unusual for me to see patients … in their 40s or 50s with their first lentigo maligna.' DR. BROWN
Hailey-Hailey Disease Goes Undiagnosed for Years
SCOTTSDALE, ARIZ. — An accurate diagnosis of Hailey-Hailey disease was delayed an average of 8 years after onset of the painful disorder, while dermatologists and nondermatologists treated what they presumed to be dermatitis, psoriasis, or a rash, according to a 40-year retrospective study.
“In three patients, believe it or not, the disease actually preceded the diagnosis by more than 30 years,” Dr. Kenneth J. Tomecki, vice chair of dermatology at the Cleveland Clinic, said at the annual meeting of the Noah Worcester Dermatological Society.
Often remembered for the “dilapidated brick wall” appearance of its histology, Hailey-Hailey disease is a rare but important genetic dermatosis, he said.
Intrigued by the disorder since residency, Dr. Tomecki decided to conduct a review of every histologically confirmed case seen at the Cleveland Clinic from 1965 to 2005.
The 28 cases that emerged showed a female predominance (20:8) and an average age of onset of 35 years, although one patient recalled an onset of disease at 10 years old.
In 20 cases, patients reported a family history of the disease. One patient “recalled, in tree fashion,” 10 family members who also had confirmed Hailey-Hailey disease or its signs and symptoms.
Characteristic moist, macerated plaques were present in the patients.
The disease had caused cutaneous symptoms in 24 patients, who described burning, pain, and tenderness exacerbated by friction, heat and humidity, sunlight, and even massage.
The axillae, groin, and perineum were the most common sites of involvement, followed by the neck, inframammary region, and vulva.
In 25 of the 28 patients, more than one area of the body was involved.
The diagnosis is established by the histology, which Dr. Tomecki described as “suprabasilar bullae with acantholysis against a background clinical appearance of moist, macerated plaques.”
All of the patients in Dr. Tomecki's review had received topical therapies: corticosteroids, antifungals, and emollients.
Systemic corticosteroids resulted in improvement in 8 of 12 patients who received them. Tetracycline, likely used for its anti-inflammatory actions, was effective in half of the eight patients to whom it was prescribed. Dapsone, which Dr. Tomecki believed might prove efficacious, only improved 6 of the 10 patients in which it was tried.
“Interestingly enough, in the hands of the surgeons, CO2 laser vaporization actually had a good result in all eight of the patients who underwent this therapy,” he said.
A literature search revealed a similar potpourri of treatments, with similarly uneven results, reported Dr. Tomecki.
He characterized systemic therapies, including oral antibiotics, dapsone, and systemic corticosteroids as “unpredictable, and really not something to lean on.”
First described by dermatologist brothers William Howard Hailey and Hugh Edward Hailey in 1939, Hailey-Hailey disease is a rare autosomal dominant disorder caused by a mutation in chromosome 3q.
“The key abnormality is that the adhesion between epidermal cells is shot,” explained Dr. Tomecki. “They no longer have the glue to hold them together.”
The adhesion between keratinocytes then deteriorates, affecting the desmosomal/keratin filament complex and triggering acantholysis and clinical vesicular changes, blisters, and plaques.
Beyond the discomfort, most patients also suffer from malodorous secondary effects of the lesions, with social and psychological consequences. Despite these challenges, the long-term outlook for most patients is very good, he said.
'In three patients, believe it or not, the disease actually preceded the diagnosis by more than 30 years.' DR. TOMECKI
Adhesion between epidermal cells is shot, causing moist, macerated plaques. Courtesy Dr. Kenneth J. Tomecki
SCOTTSDALE, ARIZ. — An accurate diagnosis of Hailey-Hailey disease was delayed an average of 8 years after onset of the painful disorder, while dermatologists and nondermatologists treated what they presumed to be dermatitis, psoriasis, or a rash, according to a 40-year retrospective study.
“In three patients, believe it or not, the disease actually preceded the diagnosis by more than 30 years,” Dr. Kenneth J. Tomecki, vice chair of dermatology at the Cleveland Clinic, said at the annual meeting of the Noah Worcester Dermatological Society.
Often remembered for the “dilapidated brick wall” appearance of its histology, Hailey-Hailey disease is a rare but important genetic dermatosis, he said.
Intrigued by the disorder since residency, Dr. Tomecki decided to conduct a review of every histologically confirmed case seen at the Cleveland Clinic from 1965 to 2005.
The 28 cases that emerged showed a female predominance (20:8) and an average age of onset of 35 years, although one patient recalled an onset of disease at 10 years old.
In 20 cases, patients reported a family history of the disease. One patient “recalled, in tree fashion,” 10 family members who also had confirmed Hailey-Hailey disease or its signs and symptoms.
Characteristic moist, macerated plaques were present in the patients.
The disease had caused cutaneous symptoms in 24 patients, who described burning, pain, and tenderness exacerbated by friction, heat and humidity, sunlight, and even massage.
The axillae, groin, and perineum were the most common sites of involvement, followed by the neck, inframammary region, and vulva.
In 25 of the 28 patients, more than one area of the body was involved.
The diagnosis is established by the histology, which Dr. Tomecki described as “suprabasilar bullae with acantholysis against a background clinical appearance of moist, macerated plaques.”
All of the patients in Dr. Tomecki's review had received topical therapies: corticosteroids, antifungals, and emollients.
Systemic corticosteroids resulted in improvement in 8 of 12 patients who received them. Tetracycline, likely used for its anti-inflammatory actions, was effective in half of the eight patients to whom it was prescribed. Dapsone, which Dr. Tomecki believed might prove efficacious, only improved 6 of the 10 patients in which it was tried.
“Interestingly enough, in the hands of the surgeons, CO2 laser vaporization actually had a good result in all eight of the patients who underwent this therapy,” he said.
A literature search revealed a similar potpourri of treatments, with similarly uneven results, reported Dr. Tomecki.
He characterized systemic therapies, including oral antibiotics, dapsone, and systemic corticosteroids as “unpredictable, and really not something to lean on.”
First described by dermatologist brothers William Howard Hailey and Hugh Edward Hailey in 1939, Hailey-Hailey disease is a rare autosomal dominant disorder caused by a mutation in chromosome 3q.
“The key abnormality is that the adhesion between epidermal cells is shot,” explained Dr. Tomecki. “They no longer have the glue to hold them together.”
The adhesion between keratinocytes then deteriorates, affecting the desmosomal/keratin filament complex and triggering acantholysis and clinical vesicular changes, blisters, and plaques.
Beyond the discomfort, most patients also suffer from malodorous secondary effects of the lesions, with social and psychological consequences. Despite these challenges, the long-term outlook for most patients is very good, he said.
'In three patients, believe it or not, the disease actually preceded the diagnosis by more than 30 years.' DR. TOMECKI
Adhesion between epidermal cells is shot, causing moist, macerated plaques. Courtesy Dr. Kenneth J. Tomecki
SCOTTSDALE, ARIZ. — An accurate diagnosis of Hailey-Hailey disease was delayed an average of 8 years after onset of the painful disorder, while dermatologists and nondermatologists treated what they presumed to be dermatitis, psoriasis, or a rash, according to a 40-year retrospective study.
“In three patients, believe it or not, the disease actually preceded the diagnosis by more than 30 years,” Dr. Kenneth J. Tomecki, vice chair of dermatology at the Cleveland Clinic, said at the annual meeting of the Noah Worcester Dermatological Society.
Often remembered for the “dilapidated brick wall” appearance of its histology, Hailey-Hailey disease is a rare but important genetic dermatosis, he said.
Intrigued by the disorder since residency, Dr. Tomecki decided to conduct a review of every histologically confirmed case seen at the Cleveland Clinic from 1965 to 2005.
The 28 cases that emerged showed a female predominance (20:8) and an average age of onset of 35 years, although one patient recalled an onset of disease at 10 years old.
In 20 cases, patients reported a family history of the disease. One patient “recalled, in tree fashion,” 10 family members who also had confirmed Hailey-Hailey disease or its signs and symptoms.
Characteristic moist, macerated plaques were present in the patients.
The disease had caused cutaneous symptoms in 24 patients, who described burning, pain, and tenderness exacerbated by friction, heat and humidity, sunlight, and even massage.
The axillae, groin, and perineum were the most common sites of involvement, followed by the neck, inframammary region, and vulva.
In 25 of the 28 patients, more than one area of the body was involved.
The diagnosis is established by the histology, which Dr. Tomecki described as “suprabasilar bullae with acantholysis against a background clinical appearance of moist, macerated plaques.”
All of the patients in Dr. Tomecki's review had received topical therapies: corticosteroids, antifungals, and emollients.
Systemic corticosteroids resulted in improvement in 8 of 12 patients who received them. Tetracycline, likely used for its anti-inflammatory actions, was effective in half of the eight patients to whom it was prescribed. Dapsone, which Dr. Tomecki believed might prove efficacious, only improved 6 of the 10 patients in which it was tried.
“Interestingly enough, in the hands of the surgeons, CO2 laser vaporization actually had a good result in all eight of the patients who underwent this therapy,” he said.
A literature search revealed a similar potpourri of treatments, with similarly uneven results, reported Dr. Tomecki.
He characterized systemic therapies, including oral antibiotics, dapsone, and systemic corticosteroids as “unpredictable, and really not something to lean on.”
First described by dermatologist brothers William Howard Hailey and Hugh Edward Hailey in 1939, Hailey-Hailey disease is a rare autosomal dominant disorder caused by a mutation in chromosome 3q.
“The key abnormality is that the adhesion between epidermal cells is shot,” explained Dr. Tomecki. “They no longer have the glue to hold them together.”
The adhesion between keratinocytes then deteriorates, affecting the desmosomal/keratin filament complex and triggering acantholysis and clinical vesicular changes, blisters, and plaques.
Beyond the discomfort, most patients also suffer from malodorous secondary effects of the lesions, with social and psychological consequences. Despite these challenges, the long-term outlook for most patients is very good, he said.
'In three patients, believe it or not, the disease actually preceded the diagnosis by more than 30 years.' DR. TOMECKI
Adhesion between epidermal cells is shot, causing moist, macerated plaques. Courtesy Dr. Kenneth J. Tomecki
Old Drug Combo Prevents Colorectal Adenomas
SAN DIEGO — Small doses of two historic drugs administered in tandem profoundly reduced the development of colorectal adenomas in patients with prior adenoma formation, heralding a “mid-game home run” in secondary chemoprevention, investigators reported at the annual meeting of the American Association for Cancer Research.
Dr. Frank L. Meyskens Jr., professor of medicine and biological chemistry at the University of California, Irvine, presented late-breaking results from a phase III trial of difluoromethylornithine (DFMO), a synthetic inhibitor of ornithine decarboxylase, and sulindac (Clinoril), an NSAID, in 375 patients.
Patients were recruited following resection of at least one adenoma (3 mm or larger) discovered on colonoscopy—a history placing them at significant risk of recurrence.
Oral doses of DFMO (500 mg) and sulindac (150 mg) daily were given to 191 randomized patients, while 184 were assigned to placebo. Low-dose aspirin was used by approximately 40% of patients in each group.
At 3 years' follow-up, total adenomas detected by colonoscopy were reduced by 70%, advanced adenomas by 92%, and multiple adenomas by 95% in treated patients, compared with those on placebo.
Specifically, an adenoma was found in 42 of 97 patients who received placebo and completed the trial (43%), compared with 12 of 107 on the DFMO/sulindac combination (11%). Advanced adenomas—large, intramucosal or invasive adenomas with histologic features linked with conversion to colorectal cancer—were seen in nine (9.3%) patients in the placebo group and one patient receiving combination chemoprevention. More than one adenoma was found in 15 patients receiving placebo and 1 patient in the chemoprevention arm.
“These are absolutely stunning findings,” Dr. Scott M. Lippman told meeting attendees in a formal discussion of the phase III results. “I would consider this a mid-game home run.”
The research culminates a “long quest” by Dr. Meyskens and coinvestigator Dr. Eugene W. Gerner of the University of Arizona, Tucson, to fight the development of cancer by targeting ornithine decarboxylase, a key polyamine pathway that acts as an instigator of growth.
DFMO, long abandoned as chemotherapy because of inefficacy and hearing-related toxicity, was known to prevent many forms of cancer in preclinical and in vitro models. The researchers conducted novel “de-escalation” dose-finding trials, determining in the mid-1990s that a 500-mg dose (one-fiftieth of the therapeutic dose and one-quarter of the ototoxic dose) could reduce the polyamine content of colonic flat mucosa.
The decision was made to combine the drug (approved for African sleeping sickness and, more recently, as a topical depilatory) with sulindac, an NSAID in use for a half-century, to maximize each drug's efficacy at the smallest possible doses.
Sulindac has multiple mechanisms of action and was used in the trial at a 150-mg dose daily, half the dose used in the treatment of arthritis.
Adverse events were carefully monitored, with particular attention given to cardiovascular and otologic side effects previously associated with NSAIDs and DFMO.
At least one serious adverse event requiring hospitalization was seen in 31 patients receiving placebo and 42 patients in the DFMO/sulindac group. No significant difference was seen in the number of patients experiencing a serious adverse event.
Serious cardiovascular side effects occurred in 16 patients receiving active treatment versus 9 in the placebo arm. This difference, while not statistically significant, may indicate a “worrisome trend” and deserves more study, according to Dr. Lippman of the M.D. Anderson Cancer Center, Houston, a formal discussant of the study.
No hearing loss was perceived in patients receiving DFMO and sulindac, although a 1- to 2-dB difference was found in precise hearing tests. This difference is “a sound equivalent to rubbing your two fingers together,” Dr. Meyskens said. The hearing loss was reversible with discontinuation of the drug.
The DFMO/sulindac drug combination also has shown “very promising” results in early studies of prostate cancer and is being studied as a topical agent in skin cancers.
Future research may investigate its chemopreventive potential in patients with “cured” low-stage colorectal cancer, and a larger group of patients with prior advanced adenomas detected at colonoscopy.
However, because DFMO has gone off patent, creative solutions are being sought to finance future studies of the drug combination's potential as a chemopreventive agent, Dr. Meyskens said.
The study was published online simultaneously with the presentation at AACR (Cancer Prev. Res. 2008 April [Epub doi: 10.1158/1940-6207.CAPR-08-0042]).
SAN DIEGO — Small doses of two historic drugs administered in tandem profoundly reduced the development of colorectal adenomas in patients with prior adenoma formation, heralding a “mid-game home run” in secondary chemoprevention, investigators reported at the annual meeting of the American Association for Cancer Research.
Dr. Frank L. Meyskens Jr., professor of medicine and biological chemistry at the University of California, Irvine, presented late-breaking results from a phase III trial of difluoromethylornithine (DFMO), a synthetic inhibitor of ornithine decarboxylase, and sulindac (Clinoril), an NSAID, in 375 patients.
Patients were recruited following resection of at least one adenoma (3 mm or larger) discovered on colonoscopy—a history placing them at significant risk of recurrence.
Oral doses of DFMO (500 mg) and sulindac (150 mg) daily were given to 191 randomized patients, while 184 were assigned to placebo. Low-dose aspirin was used by approximately 40% of patients in each group.
At 3 years' follow-up, total adenomas detected by colonoscopy were reduced by 70%, advanced adenomas by 92%, and multiple adenomas by 95% in treated patients, compared with those on placebo.
Specifically, an adenoma was found in 42 of 97 patients who received placebo and completed the trial (43%), compared with 12 of 107 on the DFMO/sulindac combination (11%). Advanced adenomas—large, intramucosal or invasive adenomas with histologic features linked with conversion to colorectal cancer—were seen in nine (9.3%) patients in the placebo group and one patient receiving combination chemoprevention. More than one adenoma was found in 15 patients receiving placebo and 1 patient in the chemoprevention arm.
“These are absolutely stunning findings,” Dr. Scott M. Lippman told meeting attendees in a formal discussion of the phase III results. “I would consider this a mid-game home run.”
The research culminates a “long quest” by Dr. Meyskens and coinvestigator Dr. Eugene W. Gerner of the University of Arizona, Tucson, to fight the development of cancer by targeting ornithine decarboxylase, a key polyamine pathway that acts as an instigator of growth.
DFMO, long abandoned as chemotherapy because of inefficacy and hearing-related toxicity, was known to prevent many forms of cancer in preclinical and in vitro models. The researchers conducted novel “de-escalation” dose-finding trials, determining in the mid-1990s that a 500-mg dose (one-fiftieth of the therapeutic dose and one-quarter of the ototoxic dose) could reduce the polyamine content of colonic flat mucosa.
The decision was made to combine the drug (approved for African sleeping sickness and, more recently, as a topical depilatory) with sulindac, an NSAID in use for a half-century, to maximize each drug's efficacy at the smallest possible doses.
Sulindac has multiple mechanisms of action and was used in the trial at a 150-mg dose daily, half the dose used in the treatment of arthritis.
Adverse events were carefully monitored, with particular attention given to cardiovascular and otologic side effects previously associated with NSAIDs and DFMO.
At least one serious adverse event requiring hospitalization was seen in 31 patients receiving placebo and 42 patients in the DFMO/sulindac group. No significant difference was seen in the number of patients experiencing a serious adverse event.
Serious cardiovascular side effects occurred in 16 patients receiving active treatment versus 9 in the placebo arm. This difference, while not statistically significant, may indicate a “worrisome trend” and deserves more study, according to Dr. Lippman of the M.D. Anderson Cancer Center, Houston, a formal discussant of the study.
No hearing loss was perceived in patients receiving DFMO and sulindac, although a 1- to 2-dB difference was found in precise hearing tests. This difference is “a sound equivalent to rubbing your two fingers together,” Dr. Meyskens said. The hearing loss was reversible with discontinuation of the drug.
The DFMO/sulindac drug combination also has shown “very promising” results in early studies of prostate cancer and is being studied as a topical agent in skin cancers.
Future research may investigate its chemopreventive potential in patients with “cured” low-stage colorectal cancer, and a larger group of patients with prior advanced adenomas detected at colonoscopy.
However, because DFMO has gone off patent, creative solutions are being sought to finance future studies of the drug combination's potential as a chemopreventive agent, Dr. Meyskens said.
The study was published online simultaneously with the presentation at AACR (Cancer Prev. Res. 2008 April [Epub doi: 10.1158/1940-6207.CAPR-08-0042]).
SAN DIEGO — Small doses of two historic drugs administered in tandem profoundly reduced the development of colorectal adenomas in patients with prior adenoma formation, heralding a “mid-game home run” in secondary chemoprevention, investigators reported at the annual meeting of the American Association for Cancer Research.
Dr. Frank L. Meyskens Jr., professor of medicine and biological chemistry at the University of California, Irvine, presented late-breaking results from a phase III trial of difluoromethylornithine (DFMO), a synthetic inhibitor of ornithine decarboxylase, and sulindac (Clinoril), an NSAID, in 375 patients.
Patients were recruited following resection of at least one adenoma (3 mm or larger) discovered on colonoscopy—a history placing them at significant risk of recurrence.
Oral doses of DFMO (500 mg) and sulindac (150 mg) daily were given to 191 randomized patients, while 184 were assigned to placebo. Low-dose aspirin was used by approximately 40% of patients in each group.
At 3 years' follow-up, total adenomas detected by colonoscopy were reduced by 70%, advanced adenomas by 92%, and multiple adenomas by 95% in treated patients, compared with those on placebo.
Specifically, an adenoma was found in 42 of 97 patients who received placebo and completed the trial (43%), compared with 12 of 107 on the DFMO/sulindac combination (11%). Advanced adenomas—large, intramucosal or invasive adenomas with histologic features linked with conversion to colorectal cancer—were seen in nine (9.3%) patients in the placebo group and one patient receiving combination chemoprevention. More than one adenoma was found in 15 patients receiving placebo and 1 patient in the chemoprevention arm.
“These are absolutely stunning findings,” Dr. Scott M. Lippman told meeting attendees in a formal discussion of the phase III results. “I would consider this a mid-game home run.”
The research culminates a “long quest” by Dr. Meyskens and coinvestigator Dr. Eugene W. Gerner of the University of Arizona, Tucson, to fight the development of cancer by targeting ornithine decarboxylase, a key polyamine pathway that acts as an instigator of growth.
DFMO, long abandoned as chemotherapy because of inefficacy and hearing-related toxicity, was known to prevent many forms of cancer in preclinical and in vitro models. The researchers conducted novel “de-escalation” dose-finding trials, determining in the mid-1990s that a 500-mg dose (one-fiftieth of the therapeutic dose and one-quarter of the ototoxic dose) could reduce the polyamine content of colonic flat mucosa.
The decision was made to combine the drug (approved for African sleeping sickness and, more recently, as a topical depilatory) with sulindac, an NSAID in use for a half-century, to maximize each drug's efficacy at the smallest possible doses.
Sulindac has multiple mechanisms of action and was used in the trial at a 150-mg dose daily, half the dose used in the treatment of arthritis.
Adverse events were carefully monitored, with particular attention given to cardiovascular and otologic side effects previously associated with NSAIDs and DFMO.
At least one serious adverse event requiring hospitalization was seen in 31 patients receiving placebo and 42 patients in the DFMO/sulindac group. No significant difference was seen in the number of patients experiencing a serious adverse event.
Serious cardiovascular side effects occurred in 16 patients receiving active treatment versus 9 in the placebo arm. This difference, while not statistically significant, may indicate a “worrisome trend” and deserves more study, according to Dr. Lippman of the M.D. Anderson Cancer Center, Houston, a formal discussant of the study.
No hearing loss was perceived in patients receiving DFMO and sulindac, although a 1- to 2-dB difference was found in precise hearing tests. This difference is “a sound equivalent to rubbing your two fingers together,” Dr. Meyskens said. The hearing loss was reversible with discontinuation of the drug.
The DFMO/sulindac drug combination also has shown “very promising” results in early studies of prostate cancer and is being studied as a topical agent in skin cancers.
Future research may investigate its chemopreventive potential in patients with “cured” low-stage colorectal cancer, and a larger group of patients with prior advanced adenomas detected at colonoscopy.
However, because DFMO has gone off patent, creative solutions are being sought to finance future studies of the drug combination's potential as a chemopreventive agent, Dr. Meyskens said.
The study was published online simultaneously with the presentation at AACR (Cancer Prev. Res. 2008 April [Epub doi: 10.1158/1940-6207.CAPR-08-0042]).
Are Wi-Fi, Latte, and E-Mail Physician Marketing Tools of the Future?
LONG BEACH, CALIF. As baby boomers bulge the ranks of the nation's elderly population, physicians are going to have to adapt to meet their expectations, Dr. Alfredo Czerwinski said at a conference on leadership and management in geriatrics.
Coming from a world in which they can get a latte in 20 seconds, lunch in less than a minute, and an oil change in 45 minutes (or it's free), they're not going to like hearing that they won't be able to see a doctor for 3 days or 3 weeks, said Dr. Czerwinski, chief medical officer for Lawson & Associates, a consulting firm in Sacramento, Calif. Same-day scheduling and cohesive, integrated care of chronic conditions will become necessities he predicted at the meeting, presented by SCAN Health Plan.
Dr. Czerwinski reflected on how times have changed since Marcus Welby, M.D., made house calls and saw one grateful patient per episode. These days, patients' trust and confidence in their physicians, which are considered "the traditional hallmarks of care, are at an all-time low."
Research shows that patients will switch doctors if it will save them $10 per month on their insurance plans. To meet the demand of tomorrow's medical consumers, physicians would do well to develop clinical acumen and surgical skills. But they'll be more likely to achieve business success if they think like business people, according to Dr. Czerwinski. Physicians need to look around at what baby boomers enjoy and expect from other businesses:
▸ If they have to wait, cappuccino and free wireless access would be nice.
▸ They're used to booking appointments on the Web.
▸ They appreciate valet parking, and as they lose their ability to drive, they're going to be more likely to choose the physician who subscribes to a transportation service.
▸ They want immediate access to their physicians and expect e-mail contact.
LONG BEACH, CALIF. As baby boomers bulge the ranks of the nation's elderly population, physicians are going to have to adapt to meet their expectations, Dr. Alfredo Czerwinski said at a conference on leadership and management in geriatrics.
Coming from a world in which they can get a latte in 20 seconds, lunch in less than a minute, and an oil change in 45 minutes (or it's free), they're not going to like hearing that they won't be able to see a doctor for 3 days or 3 weeks, said Dr. Czerwinski, chief medical officer for Lawson & Associates, a consulting firm in Sacramento, Calif. Same-day scheduling and cohesive, integrated care of chronic conditions will become necessities he predicted at the meeting, presented by SCAN Health Plan.
Dr. Czerwinski reflected on how times have changed since Marcus Welby, M.D., made house calls and saw one grateful patient per episode. These days, patients' trust and confidence in their physicians, which are considered "the traditional hallmarks of care, are at an all-time low."
Research shows that patients will switch doctors if it will save them $10 per month on their insurance plans. To meet the demand of tomorrow's medical consumers, physicians would do well to develop clinical acumen and surgical skills. But they'll be more likely to achieve business success if they think like business people, according to Dr. Czerwinski. Physicians need to look around at what baby boomers enjoy and expect from other businesses:
▸ If they have to wait, cappuccino and free wireless access would be nice.
▸ They're used to booking appointments on the Web.
▸ They appreciate valet parking, and as they lose their ability to drive, they're going to be more likely to choose the physician who subscribes to a transportation service.
▸ They want immediate access to their physicians and expect e-mail contact.
LONG BEACH, CALIF. As baby boomers bulge the ranks of the nation's elderly population, physicians are going to have to adapt to meet their expectations, Dr. Alfredo Czerwinski said at a conference on leadership and management in geriatrics.
Coming from a world in which they can get a latte in 20 seconds, lunch in less than a minute, and an oil change in 45 minutes (or it's free), they're not going to like hearing that they won't be able to see a doctor for 3 days or 3 weeks, said Dr. Czerwinski, chief medical officer for Lawson & Associates, a consulting firm in Sacramento, Calif. Same-day scheduling and cohesive, integrated care of chronic conditions will become necessities he predicted at the meeting, presented by SCAN Health Plan.
Dr. Czerwinski reflected on how times have changed since Marcus Welby, M.D., made house calls and saw one grateful patient per episode. These days, patients' trust and confidence in their physicians, which are considered "the traditional hallmarks of care, are at an all-time low."
Research shows that patients will switch doctors if it will save them $10 per month on their insurance plans. To meet the demand of tomorrow's medical consumers, physicians would do well to develop clinical acumen and surgical skills. But they'll be more likely to achieve business success if they think like business people, according to Dr. Czerwinski. Physicians need to look around at what baby boomers enjoy and expect from other businesses:
▸ If they have to wait, cappuccino and free wireless access would be nice.
▸ They're used to booking appointments on the Web.
▸ They appreciate valet parking, and as they lose their ability to drive, they're going to be more likely to choose the physician who subscribes to a transportation service.
▸ They want immediate access to their physicians and expect e-mail contact.
BCC Responds to Hedgehog Signal Suppression
SAN DIEGO A custom-designed inhibitor of a mutation in the Hedgehog signaling pathway stimulated antitumor activity in eight of nine patients with locally advanced, multifocal, or metastatic basal cell carcinoma in phase I interim trial results presented at the annual meeting of the American Association for Cancer Research.
Patients in the small, ongoing trial experienced healing of their lesions, diminishment of pain and fatigue, and improvement in dyspnea while taking the study drug GDC-0449 for periods ranging from 120 to 438 days.
"These responses were pretty dramatic, [beginning] within 23 weeks of starting the drug," said Dr. Daniel D. Von Hoff, senior investigator and director of translational research for the Translational Genomics Research Institute in Scottsdale, Ariz.
Basal cell carcinoma is the most common malignancy in humans, diagnosed in approximately 1 million U.S. patients per year. While it typically grows slowly and can be managed by local excision or ionizing radiation, it may infiltrate surrounding tissue. In rare cases (less than 0.1%), it becomes metastatic, most commonly to the lung, liver, and/or bone.
The first three patients enrolled in the study received daily doses of 150 mg, 270 mg, and 540 mg, respectively, of GDC-0449, a synthetic, revved-up version of the naturally occurring Hedgehog pathway antagonist cyclopamine. When antitumor activity was confirmed, six more patients were enrolled, all receiving the 150-mg/day dose.
The average patient was aged 61 years (range 4285 years). Eight were men.
All had undergone surgery (some as many as 20 operations) for their basal cell carcinoma. Four had received radiation, and three were given chemotherapy. Five patients had metastatic disease, two had locally advanced disease of the ear, and two had multifocal disease.
Among four of the patients with metastatic disease, two had a confirmed partial response, one had stable disease, and one progressed while on the study drug and died of his disease. It is too early to assess the response of one recently enrolled patient with metastatic disease, according to Dr. Von Hoff.
In four patients with clinically evaluable locally advanced or multifocal disease, two had a complete response and two had stable disease, meaning that their skin lesions were not advancing.
Metabolic responses to chemotherapy were demonstrated in all five patients who had undergone positron emission tomography evaluations at the time of the presentation, Dr. Van Hoff reported during a late-breaking session.
"Toxicities were relatively mild," he said; they included dysgeusia, an alteration in taste sensations; mild alopecia; mild weight loss; and hyponatremia.
The drug's development represented what Dr. Von Hoff called, "the essence of translational medicine." Molecular biologists first discovered that aberrance in the Hedgehog signaling pathway triggered when patched (PTCH) or smoothened (SMO) gene mutations caused an acceleration of cell growth that proved instrumental in the development of either sporadic or hereditary basal cell carcinoma.
Nature then played a role, he noted.
Serendipitously, it was discovered that cyclopamine, a naturally occurring inhibitor of the SMO mutation, could be found in pregnant ewes that ate corn lilies in the western United States and subsequently gave birth to cyclopslike lambs with oversize heads and a single, central eye.
Genentech Inc., in conjunction with the Curis Inc., developed a synthetic version of cyclopamine 100 times more potent than the version found in corn lilies, naming the agent GDC-0449.
Patients, including Subject #1 in the phase I study, "knew the drug was coming and hung on." Although metastatic basal cell carcinoma is very rare, its prognosis is poor, with a mean survival of approximately 5 months, said Dr. Von Hoff.
Formal discussant Dr. Ervin Epstein of the Children's Hospital Oakland (Calif.) Research Institute noted that many unanswered questions remain about GDC-0449, but he said that, as a "card-carrying dermatologist," he is "full of optimism … that help is on the way."
Dr. Von Hoff receives research grant support from Genentech, developer of GDC-0449. Dr. Epstein is a consultant for Genentech and owns stock in Curis.
SAN DIEGO A custom-designed inhibitor of a mutation in the Hedgehog signaling pathway stimulated antitumor activity in eight of nine patients with locally advanced, multifocal, or metastatic basal cell carcinoma in phase I interim trial results presented at the annual meeting of the American Association for Cancer Research.
Patients in the small, ongoing trial experienced healing of their lesions, diminishment of pain and fatigue, and improvement in dyspnea while taking the study drug GDC-0449 for periods ranging from 120 to 438 days.
"These responses were pretty dramatic, [beginning] within 23 weeks of starting the drug," said Dr. Daniel D. Von Hoff, senior investigator and director of translational research for the Translational Genomics Research Institute in Scottsdale, Ariz.
Basal cell carcinoma is the most common malignancy in humans, diagnosed in approximately 1 million U.S. patients per year. While it typically grows slowly and can be managed by local excision or ionizing radiation, it may infiltrate surrounding tissue. In rare cases (less than 0.1%), it becomes metastatic, most commonly to the lung, liver, and/or bone.
The first three patients enrolled in the study received daily doses of 150 mg, 270 mg, and 540 mg, respectively, of GDC-0449, a synthetic, revved-up version of the naturally occurring Hedgehog pathway antagonist cyclopamine. When antitumor activity was confirmed, six more patients were enrolled, all receiving the 150-mg/day dose.
The average patient was aged 61 years (range 4285 years). Eight were men.
All had undergone surgery (some as many as 20 operations) for their basal cell carcinoma. Four had received radiation, and three were given chemotherapy. Five patients had metastatic disease, two had locally advanced disease of the ear, and two had multifocal disease.
Among four of the patients with metastatic disease, two had a confirmed partial response, one had stable disease, and one progressed while on the study drug and died of his disease. It is too early to assess the response of one recently enrolled patient with metastatic disease, according to Dr. Von Hoff.
In four patients with clinically evaluable locally advanced or multifocal disease, two had a complete response and two had stable disease, meaning that their skin lesions were not advancing.
Metabolic responses to chemotherapy were demonstrated in all five patients who had undergone positron emission tomography evaluations at the time of the presentation, Dr. Van Hoff reported during a late-breaking session.
"Toxicities were relatively mild," he said; they included dysgeusia, an alteration in taste sensations; mild alopecia; mild weight loss; and hyponatremia.
The drug's development represented what Dr. Von Hoff called, "the essence of translational medicine." Molecular biologists first discovered that aberrance in the Hedgehog signaling pathway triggered when patched (PTCH) or smoothened (SMO) gene mutations caused an acceleration of cell growth that proved instrumental in the development of either sporadic or hereditary basal cell carcinoma.
Nature then played a role, he noted.
Serendipitously, it was discovered that cyclopamine, a naturally occurring inhibitor of the SMO mutation, could be found in pregnant ewes that ate corn lilies in the western United States and subsequently gave birth to cyclopslike lambs with oversize heads and a single, central eye.
Genentech Inc., in conjunction with the Curis Inc., developed a synthetic version of cyclopamine 100 times more potent than the version found in corn lilies, naming the agent GDC-0449.
Patients, including Subject #1 in the phase I study, "knew the drug was coming and hung on." Although metastatic basal cell carcinoma is very rare, its prognosis is poor, with a mean survival of approximately 5 months, said Dr. Von Hoff.
Formal discussant Dr. Ervin Epstein of the Children's Hospital Oakland (Calif.) Research Institute noted that many unanswered questions remain about GDC-0449, but he said that, as a "card-carrying dermatologist," he is "full of optimism … that help is on the way."
Dr. Von Hoff receives research grant support from Genentech, developer of GDC-0449. Dr. Epstein is a consultant for Genentech and owns stock in Curis.
SAN DIEGO A custom-designed inhibitor of a mutation in the Hedgehog signaling pathway stimulated antitumor activity in eight of nine patients with locally advanced, multifocal, or metastatic basal cell carcinoma in phase I interim trial results presented at the annual meeting of the American Association for Cancer Research.
Patients in the small, ongoing trial experienced healing of their lesions, diminishment of pain and fatigue, and improvement in dyspnea while taking the study drug GDC-0449 for periods ranging from 120 to 438 days.
"These responses were pretty dramatic, [beginning] within 23 weeks of starting the drug," said Dr. Daniel D. Von Hoff, senior investigator and director of translational research for the Translational Genomics Research Institute in Scottsdale, Ariz.
Basal cell carcinoma is the most common malignancy in humans, diagnosed in approximately 1 million U.S. patients per year. While it typically grows slowly and can be managed by local excision or ionizing radiation, it may infiltrate surrounding tissue. In rare cases (less than 0.1%), it becomes metastatic, most commonly to the lung, liver, and/or bone.
The first three patients enrolled in the study received daily doses of 150 mg, 270 mg, and 540 mg, respectively, of GDC-0449, a synthetic, revved-up version of the naturally occurring Hedgehog pathway antagonist cyclopamine. When antitumor activity was confirmed, six more patients were enrolled, all receiving the 150-mg/day dose.
The average patient was aged 61 years (range 4285 years). Eight were men.
All had undergone surgery (some as many as 20 operations) for their basal cell carcinoma. Four had received radiation, and three were given chemotherapy. Five patients had metastatic disease, two had locally advanced disease of the ear, and two had multifocal disease.
Among four of the patients with metastatic disease, two had a confirmed partial response, one had stable disease, and one progressed while on the study drug and died of his disease. It is too early to assess the response of one recently enrolled patient with metastatic disease, according to Dr. Von Hoff.
In four patients with clinically evaluable locally advanced or multifocal disease, two had a complete response and two had stable disease, meaning that their skin lesions were not advancing.
Metabolic responses to chemotherapy were demonstrated in all five patients who had undergone positron emission tomography evaluations at the time of the presentation, Dr. Van Hoff reported during a late-breaking session.
"Toxicities were relatively mild," he said; they included dysgeusia, an alteration in taste sensations; mild alopecia; mild weight loss; and hyponatremia.
The drug's development represented what Dr. Von Hoff called, "the essence of translational medicine." Molecular biologists first discovered that aberrance in the Hedgehog signaling pathway triggered when patched (PTCH) or smoothened (SMO) gene mutations caused an acceleration of cell growth that proved instrumental in the development of either sporadic or hereditary basal cell carcinoma.
Nature then played a role, he noted.
Serendipitously, it was discovered that cyclopamine, a naturally occurring inhibitor of the SMO mutation, could be found in pregnant ewes that ate corn lilies in the western United States and subsequently gave birth to cyclopslike lambs with oversize heads and a single, central eye.
Genentech Inc., in conjunction with the Curis Inc., developed a synthetic version of cyclopamine 100 times more potent than the version found in corn lilies, naming the agent GDC-0449.
Patients, including Subject #1 in the phase I study, "knew the drug was coming and hung on." Although metastatic basal cell carcinoma is very rare, its prognosis is poor, with a mean survival of approximately 5 months, said Dr. Von Hoff.
Formal discussant Dr. Ervin Epstein of the Children's Hospital Oakland (Calif.) Research Institute noted that many unanswered questions remain about GDC-0449, but he said that, as a "card-carrying dermatologist," he is "full of optimism … that help is on the way."
Dr. Von Hoff receives research grant support from Genentech, developer of GDC-0449. Dr. Epstein is a consultant for Genentech and owns stock in Curis.