Timothy F. Kirn

KEYSTONE, COLO. — The time has come to revisit anterior cruciate ligament repair as an alternative to reconstruction for certain patients, said speakers at the annual meeting of the American Orthopaedic Society for Sports Medicine.

“Primary repair has potential advantages over reconstruction in that we can preserve the anatomy better,” said Martha M. Murray, M.D., of the department of orthopedic surgery at Children's Hospital of Boston.

“We can also preserve the physiology and proprioceptive nerves,” she said.

Primary anterior cruciate ligament (ACL) repair went out of favor in the 1990s because reconstruction techniques produced such good results.

However, a classic paper from a pioneer of repair, John A. Feagin Jr., M.D., showed that his early repairs done in West Point cadets mostly failed (a 70% failure rate), said Mark E. Sherman, M.D., an orthopedist who practices in Staten Island, N.Y.

A few surgeons have persisted with trying repairs, however, and technology has improved as well, he said. For example, endoscopy is possible, instrumentation has improved, and MRI is used routinely.

In the pioneering days, Dr. Feagin used a single, absorbable suture in his repairs, Dr. Sherman noted. Today, Dr. Sherman routinely uses two or three sutures.

While there is no definitive evidence supporting primary repair, experience has shown us successes, which in turn suggest one could identify good candidates, he said.

In his experience, the best candidates for ACL repair are skiers with a type I or type IIproximal tear caused by valgus stress, perhaps the most common skiing-related ACL tear, Dr. Sherman said. About 90% of these tears will have a proximal stump of the ligament long enough for the surgeon to use to reattach the ligament, Dr. Sherman said.

In a series of about 150 repair cases, Dr. Sherman said he has a 54% subjective and objective success rate, with various lengths of follow-up. But the series includes patients with football injuries and patients under age 22 years, both of which he has now found do not do well, he noted.

Addressing the conference audience after Dr. Sherman's presentation, Stephen Abelow, M.D., of South Lake Tahoe, Calif., said he has had very good results with just the type of patient Dr. Sherman identified.

He has experience with almost 200 repairs, performed since the early 1980s. In an analysis of those cases, less than 10% went on to reconstruction. Moreover, among the patients who were over age 40 and followed for at least 2 years, less than 5% went on to reconstruction.

“Skiers tend to tear their ACLs very proximally, and those can be repaired,” he said.

Overall, around 60% of ACL tear patients will have a proximal tear with a ligament-bundle stump adequate for the repair procedure, Dr. Murray said.

Dr. Murray said the reason the ACL does not heal itself naturally is probably because of the abundance of plasmin in joint synovial fluid. The plasmin keeps the joint mobile when there is an injury by interfering with clotting and fibrin formation. But fibrin formation is also the first step in tissue repair.

In tendon injuries, for example, fibrin forms a bridge in the gap between the ends of a rupture, a bridge that migrating cells follow to bring the ends back together.

She is attempting to develop a collagen-rich scaffolding that can be placed into a repair as an artificial bridge to stimulate ligament regeneration, and in the laboratory it works well.

This technique could dramatically improve repair results, she said.

KEYSTONE, COLO. — The time has come to revisit anterior cruciate ligament repair as an alternative to reconstruction for certain patients, said speakers at the annual meeting of the American Orthopaedic Society for Sports Medicine.

“Primary repair has potential advantages over reconstruction in that we can preserve the anatomy better,” said Martha M. Murray, M.D., of the department of orthopedic surgery at Children's Hospital of Boston.

“We can also preserve the physiology and proprioceptive nerves,” she said.

Primary anterior cruciate ligament (ACL) repair went out of favor in the 1990s because reconstruction techniques produced such good results.

However, a classic paper from a pioneer of repair, John A. Feagin Jr., M.D., showed that his early repairs done in West Point cadets mostly failed (a 70% failure rate), said Mark E. Sherman, M.D., an orthopedist who practices in Staten Island, N.Y.

A few surgeons have persisted with trying repairs, however, and technology has improved as well, he said. For example, endoscopy is possible, instrumentation has improved, and MRI is used routinely.

In the pioneering days, Dr. Feagin used a single, absorbable suture in his repairs, Dr. Sherman noted. Today, Dr. Sherman routinely uses two or three sutures.

While there is no definitive evidence supporting primary repair, experience has shown us successes, which in turn suggest one could identify good candidates, he said.

In his experience, the best candidates for ACL repair are skiers with a type I or type IIproximal tear caused by valgus stress, perhaps the most common skiing-related ACL tear, Dr. Sherman said. About 90% of these tears will have a proximal stump of the ligament long enough for the surgeon to use to reattach the ligament, Dr. Sherman said.

In a series of about 150 repair cases, Dr. Sherman said he has a 54% subjective and objective success rate, with various lengths of follow-up. But the series includes patients with football injuries and patients under age 22 years, both of which he has now found do not do well, he noted.

Addressing the conference audience after Dr. Sherman's presentation, Stephen Abelow, M.D., of South Lake Tahoe, Calif., said he has had very good results with just the type of patient Dr. Sherman identified.

He has experience with almost 200 repairs, performed since the early 1980s. In an analysis of those cases, less than 10% went on to reconstruction. Moreover, among the patients who were over age 40 and followed for at least 2 years, less than 5% went on to reconstruction.

“Skiers tend to tear their ACLs very proximally, and those can be repaired,” he said.

Overall, around 60% of ACL tear patients will have a proximal tear with a ligament-bundle stump adequate for the repair procedure, Dr. Murray said.

Dr. Murray said the reason the ACL does not heal itself naturally is probably because of the abundance of plasmin in joint synovial fluid. The plasmin keeps the joint mobile when there is an injury by interfering with clotting and fibrin formation. But fibrin formation is also the first step in tissue repair.

In tendon injuries, for example, fibrin forms a bridge in the gap between the ends of a rupture, a bridge that migrating cells follow to bring the ends back together.

She is attempting to develop a collagen-rich scaffolding that can be placed into a repair as an artificial bridge to stimulate ligament regeneration, and in the laboratory it works well.

This technique could dramatically improve repair results, she said.

KEYSTONE, COLO. — The time has come to revisit anterior cruciate ligament repair as an alternative to reconstruction for certain patients, said speakers at the annual meeting of the American Orthopaedic Society for Sports Medicine.

“Primary repair has potential advantages over reconstruction in that we can preserve the anatomy better,” said Martha M. Murray, M.D., of the department of orthopedic surgery at Children's Hospital of Boston.

“We can also preserve the physiology and proprioceptive nerves,” she said.

Primary anterior cruciate ligament (ACL) repair went out of favor in the 1990s because reconstruction techniques produced such good results.

However, a classic paper from a pioneer of repair, John A. Feagin Jr., M.D., showed that his early repairs done in West Point cadets mostly failed (a 70% failure rate), said Mark E. Sherman, M.D., an orthopedist who practices in Staten Island, N.Y.

A few surgeons have persisted with trying repairs, however, and technology has improved as well, he said. For example, endoscopy is possible, instrumentation has improved, and MRI is used routinely.

In the pioneering days, Dr. Feagin used a single, absorbable suture in his repairs, Dr. Sherman noted. Today, Dr. Sherman routinely uses two or three sutures.

While there is no definitive evidence supporting primary repair, experience has shown us successes, which in turn suggest one could identify good candidates, he said.

In his experience, the best candidates for ACL repair are skiers with a type I or type IIproximal tear caused by valgus stress, perhaps the most common skiing-related ACL tear, Dr. Sherman said. About 90% of these tears will have a proximal stump of the ligament long enough for the surgeon to use to reattach the ligament, Dr. Sherman said.

In a series of about 150 repair cases, Dr. Sherman said he has a 54% subjective and objective success rate, with various lengths of follow-up. But the series includes patients with football injuries and patients under age 22 years, both of which he has now found do not do well, he noted.

Addressing the conference audience after Dr. Sherman's presentation, Stephen Abelow, M.D., of South Lake Tahoe, Calif., said he has had very good results with just the type of patient Dr. Sherman identified.

He has experience with almost 200 repairs, performed since the early 1980s. In an analysis of those cases, less than 10% went on to reconstruction. Moreover, among the patients who were over age 40 and followed for at least 2 years, less than 5% went on to reconstruction.

“Skiers tend to tear their ACLs very proximally, and those can be repaired,” he said.

Overall, around 60% of ACL tear patients will have a proximal tear with a ligament-bundle stump adequate for the repair procedure, Dr. Murray said.

Dr. Murray said the reason the ACL does not heal itself naturally is probably because of the abundance of plasmin in joint synovial fluid. The plasmin keeps the joint mobile when there is an injury by interfering with clotting and fibrin formation. But fibrin formation is also the first step in tissue repair.

In tendon injuries, for example, fibrin forms a bridge in the gap between the ends of a rupture, a bridge that migrating cells follow to bring the ends back together.

She is attempting to develop a collagen-rich scaffolding that can be placed into a repair as an artificial bridge to stimulate ligament regeneration, and in the laboratory it works well.

This technique could dramatically improve repair results, she said.

KEYSTONE, COLO. — Growing adolescents can undergo anterior cruciate ligament repair safely, and perhaps should have the surgery to avoid the possibility of later problems, George A. Paletta Jr., M.D., said at the annual meeting of the American Orthopaedic Society for Sports Medicine.

Recommendations for the management of anterior cruciate ligament (ACL) injury in the skeletally immature patient have varied, but Dr. Paletta's thorough investigations, and case series of patients, have convinced him that it is possible to perform a reconstruction without compromising the tibial growth plate and creating a leg length discrepancy, he said.

The natural history of an ACL injury in a skeletally immature patient is that the majority continue to have knee instability and many develop meniscal tears, said Dr. Paletta, chief of sports medicine service at Washington University, St. Louis. In one series of 38 junior high athletes with ACL injuries who did not have ACL surgery and were followed for a minimum of 2 years, 27 developed meniscal tears (Am. J. Sports Med. 1994;22:478–84).

That is to say nothing of what could be happening to these children's knees in the even longer term, Dr. Paletta said.

And keeping the child or adolescent out of hazardous sports is not really the answer because most who reinjure their knees do so not during an organized activity but during recess or some other time when they are just being exuberant.

On the other hand, animal studies have shown that one needs to damage a greater proportion of the physeal plates than is normally damaged during an ACL reconstruction to create growth arrest. And in a series of growing athletes who have undergone reconstruction, 90% or better have reportedly returned to sports.

In his own series of patients, yet to be published, Dr. Paletta performed ACL reconstruction in 29 patients aged 10–13 years by using either an over-the-top technique that spared the physeal area of the femur or a technique that drilled through the physeal areas of the tibia and the femur.

At a minimum of 2 years' follow-up, none of the patients had any radiographic evidence of premature closure of the growth plates, and all but two patients (one from each group) had returned to sports participation at the same level as before their injury.

Though the results from both techniques were similar, pivot-testing suggested the complete transphyseal technique produced somewhat better stability, Dr. Paletta said.

In another series of Dr. Paletta's patients, 49 preadolescents (Tanner stage 0, 1, or 2) with ACL tears were treated with complete transphyseal reconstruction, he said.

Again at a minimum follow-up of 24 months (with an average follow-up of 40 months), none of the patients had a leg length discrepancy greater than 1 cm and none had an angular deformity of more than 5 degrees.

Twenty-seven of the patients had reached skeletal maturity by the time of the last examination.

Forty-seven of the 49 patients reported no instability, and 45 of the patients had returned to sports at or above the same level as before their injury. Only one patient had a rerupture, an injury that occurred 6 years after the surgery.

On the basis of his experience, Dr. Paletta said his recommendations for management would be to perform transphyseal hamstring reconstruction for isolated ACL insufficiency for male patients who are Tanner stage 1, 2, or 3, and for premenarcheal females, if there is functional instability.

If there is no functional instability, Dr. Paletta would recommend treating patients conservatively.

For older patients with isolated ACL insufficiency—males Tanner stage 4 or 5, and postmenarcheal females—he would recommend reconstruction.

He would also recommend reconstruction for any patient if there also was meniscus damage.

KEYSTONE, COLO. — Growing adolescents can undergo anterior cruciate ligament repair safely, and perhaps should have the surgery to avoid the possibility of later problems, George A. Paletta Jr., M.D., said at the annual meeting of the American Orthopaedic Society for Sports Medicine.

Recommendations for the management of anterior cruciate ligament (ACL) injury in the skeletally immature patient have varied, but Dr. Paletta's thorough investigations, and case series of patients, have convinced him that it is possible to perform a reconstruction without compromising the tibial growth plate and creating a leg length discrepancy, he said.

The natural history of an ACL injury in a skeletally immature patient is that the majority continue to have knee instability and many develop meniscal tears, said Dr. Paletta, chief of sports medicine service at Washington University, St. Louis. In one series of 38 junior high athletes with ACL injuries who did not have ACL surgery and were followed for a minimum of 2 years, 27 developed meniscal tears (Am. J. Sports Med. 1994;22:478–84).

That is to say nothing of what could be happening to these children's knees in the even longer term, Dr. Paletta said.

And keeping the child or adolescent out of hazardous sports is not really the answer because most who reinjure their knees do so not during an organized activity but during recess or some other time when they are just being exuberant.

On the other hand, animal studies have shown that one needs to damage a greater proportion of the physeal plates than is normally damaged during an ACL reconstruction to create growth arrest. And in a series of growing athletes who have undergone reconstruction, 90% or better have reportedly returned to sports.

In his own series of patients, yet to be published, Dr. Paletta performed ACL reconstruction in 29 patients aged 10–13 years by using either an over-the-top technique that spared the physeal area of the femur or a technique that drilled through the physeal areas of the tibia and the femur.

At a minimum of 2 years' follow-up, none of the patients had any radiographic evidence of premature closure of the growth plates, and all but two patients (one from each group) had returned to sports participation at the same level as before their injury.

Though the results from both techniques were similar, pivot-testing suggested the complete transphyseal technique produced somewhat better stability, Dr. Paletta said.

In another series of Dr. Paletta's patients, 49 preadolescents (Tanner stage 0, 1, or 2) with ACL tears were treated with complete transphyseal reconstruction, he said.

Again at a minimum follow-up of 24 months (with an average follow-up of 40 months), none of the patients had a leg length discrepancy greater than 1 cm and none had an angular deformity of more than 5 degrees.

Twenty-seven of the patients had reached skeletal maturity by the time of the last examination.

Forty-seven of the 49 patients reported no instability, and 45 of the patients had returned to sports at or above the same level as before their injury. Only one patient had a rerupture, an injury that occurred 6 years after the surgery.

On the basis of his experience, Dr. Paletta said his recommendations for management would be to perform transphyseal hamstring reconstruction for isolated ACL insufficiency for male patients who are Tanner stage 1, 2, or 3, and for premenarcheal females, if there is functional instability.

If there is no functional instability, Dr. Paletta would recommend treating patients conservatively.

For older patients with isolated ACL insufficiency—males Tanner stage 4 or 5, and postmenarcheal females—he would recommend reconstruction.

He would also recommend reconstruction for any patient if there also was meniscus damage.

KEYSTONE, COLO. — Growing adolescents can undergo anterior cruciate ligament repair safely, and perhaps should have the surgery to avoid the possibility of later problems, George A. Paletta Jr., M.D., said at the annual meeting of the American Orthopaedic Society for Sports Medicine.

Recommendations for the management of anterior cruciate ligament (ACL) injury in the skeletally immature patient have varied, but Dr. Paletta's thorough investigations, and case series of patients, have convinced him that it is possible to perform a reconstruction without compromising the tibial growth plate and creating a leg length discrepancy, he said.

The natural history of an ACL injury in a skeletally immature patient is that the majority continue to have knee instability and many develop meniscal tears, said Dr. Paletta, chief of sports medicine service at Washington University, St. Louis. In one series of 38 junior high athletes with ACL injuries who did not have ACL surgery and were followed for a minimum of 2 years, 27 developed meniscal tears (Am. J. Sports Med. 1994;22:478–84).

That is to say nothing of what could be happening to these children's knees in the even longer term, Dr. Paletta said.

And keeping the child or adolescent out of hazardous sports is not really the answer because most who reinjure their knees do so not during an organized activity but during recess or some other time when they are just being exuberant.

On the other hand, animal studies have shown that one needs to damage a greater proportion of the physeal plates than is normally damaged during an ACL reconstruction to create growth arrest. And in a series of growing athletes who have undergone reconstruction, 90% or better have reportedly returned to sports.

In his own series of patients, yet to be published, Dr. Paletta performed ACL reconstruction in 29 patients aged 10–13 years by using either an over-the-top technique that spared the physeal area of the femur or a technique that drilled through the physeal areas of the tibia and the femur.

At a minimum of 2 years' follow-up, none of the patients had any radiographic evidence of premature closure of the growth plates, and all but two patients (one from each group) had returned to sports participation at the same level as before their injury.

Though the results from both techniques were similar, pivot-testing suggested the complete transphyseal technique produced somewhat better stability, Dr. Paletta said.

In another series of Dr. Paletta's patients, 49 preadolescents (Tanner stage 0, 1, or 2) with ACL tears were treated with complete transphyseal reconstruction, he said.

Again at a minimum follow-up of 24 months (with an average follow-up of 40 months), none of the patients had a leg length discrepancy greater than 1 cm and none had an angular deformity of more than 5 degrees.

Twenty-seven of the patients had reached skeletal maturity by the time of the last examination.

Forty-seven of the 49 patients reported no instability, and 45 of the patients had returned to sports at or above the same level as before their injury. Only one patient had a rerupture, an injury that occurred 6 years after the surgery.

On the basis of his experience, Dr. Paletta said his recommendations for management would be to perform transphyseal hamstring reconstruction for isolated ACL insufficiency for male patients who are Tanner stage 1, 2, or 3, and for premenarcheal females, if there is functional instability.

If there is no functional instability, Dr. Paletta would recommend treating patients conservatively.

For older patients with isolated ACL insufficiency—males Tanner stage 4 or 5, and postmenarcheal females—he would recommend reconstruction.

He would also recommend reconstruction for any patient if there also was meniscus damage.

NAPLES, FLA. — Retinoids, NSAIDs, and perhaps statins lead the increasingly long list of possible skin cancer chemopreventive agents, James Spencer, M.D., said at the annual meeting of the Florida Society for Dermatology and Dermatologic Surgery.

In a wide-ranging discussion of the highly active field of cancer chemoprevention, Dr. Spencer made the following comments about the more notable, possible agents:

▸ Retinoids. Without a doubt, retinoids have been shown to prevent the development of skin cancer, said Dr. Spencer, the director of Mohs micrographic surgery at the Mt. Sinai Medical Center, New York. But they may never be an agent for the general, average patient.

Oral retinoids have been most thoroughly investigated in studies with solid organ transplant patients, who are extremely prone to the development of skin cancers.

In one study of Australian renal transplant patients followed for 20 years, 70% had developed skin cancers, and in a study that looked specifically at what caused death in heart transplant patients who had survived for 4 years, skin cancer was the cause of death in one-third of them.

Transplant-patient studies have been conducted with both etretinate and acitretin, with acitretin being the more commonly used drug now, at a dose of 30 mg/day. In a blinded trial in which 38 renal transplant patients received either drug or placebo for just 6 months, 11% of the acitretin-treated patients developed new squamous cell carcinomas vs. 47% of the placebo patients, and there was a 41% decline in keratotic skin lesions.

Unfortunately, transplant patients who take a retinoid have retinoid side effects, and it is not clear how low a dose they can be given to minimize those side effects, Dr. Spencer said. One trial of 10 mg/day was not effective.

Moreover, the evidence suggests that retinoids do not kill cancers, but simply halt their development during the drug's course. In one study of patients with xeroderma pigmentosum, isotretinoin significantly reduced the development of skin cancer, and it did so extremely rapidly, with a decrease in the incidence of skin cancer within 2 months of starting the drug. But the study also showed that the beneficial effect went away just as rapidly. Cancerous lesions began to reappear within 3 months of stopping the drug, too soon for it to be likely that the lesions were brand new malignancies that sprang up after the drug was stopped.

▸ Vitamin D. Vitamin D is being touted as having several health benefits, including cancer chemoprevention, and this is calling into question the wisdom of sunscreen use. The issue is being covered in the media, and the concept is being taken seriously enough by endocrinologists and oncologists that a recent paper (Cancer 2002;94:1864–75) actually tried to calculate how many excess deaths occur annually in the United States due to inadequate vitamin D. It estimated 21,000 excess deaths.

The major evidence for vitamin D chemoprevention comes from the epidemiologic observation that colon, breast, and prostate cancer incidences are lower in the lower latitudes and higher in the northern latitudes.

However, in the United States, that pattern is true in the East, but it is not so clearly apparent in the West, Dr. Spencer said.

The amount of vitamin D thought to be necessary to prevent cancer is very high, and some endocrinologists who advocate vitamin D are actually calling for amounts three times above the generally recommended minimum daily requirement. At the same time, it is known that too much vitamin D can have adverse health effects, including causing kidney stones, Dr. Spencer noted.

Because the evidence is so tentative, Dr. Spencer said he would advise patients who were worried about vitamin D not to give up sunscreen and instead take a supplement at a rational dose.

▸ NSAIDs. Ample evidence suggests that nonsteroidal anti-inflammatory drugs can prevent colon cancer, among other malignancies. A case-control study has suggested that they may protect against melanoma (Oncol. Rep. 2001;8:655–7).

Two large trials of NSAID prevention of skin cancer are underway, and they should be completed in the next year or so, Dr. Spencer said.

“This would be so simple, because you have NSAIDs in your medicine cabinet at home right now,” he said.

▸ Statins. Epidemiologic evidence has suggested that statin use is associated with decreased risk of breast, advanced prostate, lung, esophageal, colon, and pancreatic cancers. Laboratory evidence suggests that statins have this effect because they interfere with two oncogenes, Ras and Rho. Those oncogenes are involved in most melanomas.

▸ Vitamins E and C. Trial results of the chemoprevention effect of vitamin E and vitamin C have not been positive. However, a recent trial of both vitamins together reported that the combination provided significant UV protection, increasing the minimal erythema dose by an average of about 50% in just a single week, Dr. Spencer said.

He noted that sunburn does not necessarily equate with skin cancer risk, but it is a surrogate often used.

▸ Diet. The evidence linking diet to cancer risk is confounding. For example, studies have suggested that a diet high in fat may be associated with an increased cancer risk, but also that saturated fat specifically may be protective.

The soy isoflavone genistein is a potent antioxidant and can block sunburn. However, it probably needs to be used in extremely high concentrations.

“It's a very promising, potential medication, however, in real life I would say buyer beware,” Dr. Spencer said.

▸ Melanin. An Australian company has a patent on an injectable, depot form of melanocyte-stimulating hormone, developed at the University of Arizona, Tucson, that induces a true tan (Melanotan, Epitan Ltd.). The product could prove to be a convenient way to have sun protection, since patients would need a shot only once every few months to have a tan.

However, it could have downsides as well, Dr. Spencer noted. The product could reinforce the idea that tanned skin looks attractive, and that could encourage tanning behavior. Also, it is not known how the hormone might affect existing melanomas.

▸ Polypodium leucotomos. In vitro studies suggest that this extract of a South American fern may be an antioxidant and have antitumor activity.

In one nine-subject study, a single dose significantly increased the minimal erythema dose of the subjects and reduced the levels of histologic markers of malignancy-associated sun damage within a few hours.

“It is not a sunscreen, so the UV light still gets in. For our endocrinology colleagues who are worried about vitamin D, it seems to me this may allow UV-induced, vitamin D production while lowering the UV damage,” Dr. Spencer said.

NAPLES, FLA. — Retinoids, NSAIDs, and perhaps statins lead the increasingly long list of possible skin cancer chemopreventive agents, James Spencer, M.D., said at the annual meeting of the Florida Society for Dermatology and Dermatologic Surgery.

In a wide-ranging discussion of the highly active field of cancer chemoprevention, Dr. Spencer made the following comments about the more notable, possible agents:

▸ Retinoids. Without a doubt, retinoids have been shown to prevent the development of skin cancer, said Dr. Spencer, the director of Mohs micrographic surgery at the Mt. Sinai Medical Center, New York. But they may never be an agent for the general, average patient.

Oral retinoids have been most thoroughly investigated in studies with solid organ transplant patients, who are extremely prone to the development of skin cancers.

In one study of Australian renal transplant patients followed for 20 years, 70% had developed skin cancers, and in a study that looked specifically at what caused death in heart transplant patients who had survived for 4 years, skin cancer was the cause of death in one-third of them.

Transplant-patient studies have been conducted with both etretinate and acitretin, with acitretin being the more commonly used drug now, at a dose of 30 mg/day. In a blinded trial in which 38 renal transplant patients received either drug or placebo for just 6 months, 11% of the acitretin-treated patients developed new squamous cell carcinomas vs. 47% of the placebo patients, and there was a 41% decline in keratotic skin lesions.

Unfortunately, transplant patients who take a retinoid have retinoid side effects, and it is not clear how low a dose they can be given to minimize those side effects, Dr. Spencer said. One trial of 10 mg/day was not effective.

Moreover, the evidence suggests that retinoids do not kill cancers, but simply halt their development during the drug's course. In one study of patients with xeroderma pigmentosum, isotretinoin significantly reduced the development of skin cancer, and it did so extremely rapidly, with a decrease in the incidence of skin cancer within 2 months of starting the drug. But the study also showed that the beneficial effect went away just as rapidly. Cancerous lesions began to reappear within 3 months of stopping the drug, too soon for it to be likely that the lesions were brand new malignancies that sprang up after the drug was stopped.

▸ Vitamin D. Vitamin D is being touted as having several health benefits, including cancer chemoprevention, and this is calling into question the wisdom of sunscreen use. The issue is being covered in the media, and the concept is being taken seriously enough by endocrinologists and oncologists that a recent paper (Cancer 2002;94:1864–75) actually tried to calculate how many excess deaths occur annually in the United States due to inadequate vitamin D. It estimated 21,000 excess deaths.

The major evidence for vitamin D chemoprevention comes from the epidemiologic observation that colon, breast, and prostate cancer incidences are lower in the lower latitudes and higher in the northern latitudes.

However, in the United States, that pattern is true in the East, but it is not so clearly apparent in the West, Dr. Spencer said.

The amount of vitamin D thought to be necessary to prevent cancer is very high, and some endocrinologists who advocate vitamin D are actually calling for amounts three times above the generally recommended minimum daily requirement. At the same time, it is known that too much vitamin D can have adverse health effects, including causing kidney stones, Dr. Spencer noted.

Because the evidence is so tentative, Dr. Spencer said he would advise patients who were worried about vitamin D not to give up sunscreen and instead take a supplement at a rational dose.

▸ NSAIDs. Ample evidence suggests that nonsteroidal anti-inflammatory drugs can prevent colon cancer, among other malignancies. A case-control study has suggested that they may protect against melanoma (Oncol. Rep. 2001;8:655–7).

Two large trials of NSAID prevention of skin cancer are underway, and they should be completed in the next year or so, Dr. Spencer said.

“This would be so simple, because you have NSAIDs in your medicine cabinet at home right now,” he said.

▸ Statins. Epidemiologic evidence has suggested that statin use is associated with decreased risk of breast, advanced prostate, lung, esophageal, colon, and pancreatic cancers. Laboratory evidence suggests that statins have this effect because they interfere with two oncogenes, Ras and Rho. Those oncogenes are involved in most melanomas.

▸ Vitamins E and C. Trial results of the chemoprevention effect of vitamin E and vitamin C have not been positive. However, a recent trial of both vitamins together reported that the combination provided significant UV protection, increasing the minimal erythema dose by an average of about 50% in just a single week, Dr. Spencer said.

He noted that sunburn does not necessarily equate with skin cancer risk, but it is a surrogate often used.

▸ Diet. The evidence linking diet to cancer risk is confounding. For example, studies have suggested that a diet high in fat may be associated with an increased cancer risk, but also that saturated fat specifically may be protective.

The soy isoflavone genistein is a potent antioxidant and can block sunburn. However, it probably needs to be used in extremely high concentrations.

“It's a very promising, potential medication, however, in real life I would say buyer beware,” Dr. Spencer said.

▸ Melanin. An Australian company has a patent on an injectable, depot form of melanocyte-stimulating hormone, developed at the University of Arizona, Tucson, that induces a true tan (Melanotan, Epitan Ltd.). The product could prove to be a convenient way to have sun protection, since patients would need a shot only once every few months to have a tan.

However, it could have downsides as well, Dr. Spencer noted. The product could reinforce the idea that tanned skin looks attractive, and that could encourage tanning behavior. Also, it is not known how the hormone might affect existing melanomas.

▸ Polypodium leucotomos. In vitro studies suggest that this extract of a South American fern may be an antioxidant and have antitumor activity.

In one nine-subject study, a single dose significantly increased the minimal erythema dose of the subjects and reduced the levels of histologic markers of malignancy-associated sun damage within a few hours.

“It is not a sunscreen, so the UV light still gets in. For our endocrinology colleagues who are worried about vitamin D, it seems to me this may allow UV-induced, vitamin D production while lowering the UV damage,” Dr. Spencer said.

NAPLES, FLA. — Retinoids, NSAIDs, and perhaps statins lead the increasingly long list of possible skin cancer chemopreventive agents, James Spencer, M.D., said at the annual meeting of the Florida Society for Dermatology and Dermatologic Surgery.

In a wide-ranging discussion of the highly active field of cancer chemoprevention, Dr. Spencer made the following comments about the more notable, possible agents:

▸ Retinoids. Without a doubt, retinoids have been shown to prevent the development of skin cancer, said Dr. Spencer, the director of Mohs micrographic surgery at the Mt. Sinai Medical Center, New York. But they may never be an agent for the general, average patient.

Oral retinoids have been most thoroughly investigated in studies with solid organ transplant patients, who are extremely prone to the development of skin cancers.

In one study of Australian renal transplant patients followed for 20 years, 70% had developed skin cancers, and in a study that looked specifically at what caused death in heart transplant patients who had survived for 4 years, skin cancer was the cause of death in one-third of them.

Transplant-patient studies have been conducted with both etretinate and acitretin, with acitretin being the more commonly used drug now, at a dose of 30 mg/day. In a blinded trial in which 38 renal transplant patients received either drug or placebo for just 6 months, 11% of the acitretin-treated patients developed new squamous cell carcinomas vs. 47% of the placebo patients, and there was a 41% decline in keratotic skin lesions.

Unfortunately, transplant patients who take a retinoid have retinoid side effects, and it is not clear how low a dose they can be given to minimize those side effects, Dr. Spencer said. One trial of 10 mg/day was not effective.

Moreover, the evidence suggests that retinoids do not kill cancers, but simply halt their development during the drug's course. In one study of patients with xeroderma pigmentosum, isotretinoin significantly reduced the development of skin cancer, and it did so extremely rapidly, with a decrease in the incidence of skin cancer within 2 months of starting the drug. But the study also showed that the beneficial effect went away just as rapidly. Cancerous lesions began to reappear within 3 months of stopping the drug, too soon for it to be likely that the lesions were brand new malignancies that sprang up after the drug was stopped.

▸ Vitamin D. Vitamin D is being touted as having several health benefits, including cancer chemoprevention, and this is calling into question the wisdom of sunscreen use. The issue is being covered in the media, and the concept is being taken seriously enough by endocrinologists and oncologists that a recent paper (Cancer 2002;94:1864–75) actually tried to calculate how many excess deaths occur annually in the United States due to inadequate vitamin D. It estimated 21,000 excess deaths.

The major evidence for vitamin D chemoprevention comes from the epidemiologic observation that colon, breast, and prostate cancer incidences are lower in the lower latitudes and higher in the northern latitudes.

However, in the United States, that pattern is true in the East, but it is not so clearly apparent in the West, Dr. Spencer said.

The amount of vitamin D thought to be necessary to prevent cancer is very high, and some endocrinologists who advocate vitamin D are actually calling for amounts three times above the generally recommended minimum daily requirement. At the same time, it is known that too much vitamin D can have adverse health effects, including causing kidney stones, Dr. Spencer noted.

Because the evidence is so tentative, Dr. Spencer said he would advise patients who were worried about vitamin D not to give up sunscreen and instead take a supplement at a rational dose.

▸ NSAIDs. Ample evidence suggests that nonsteroidal anti-inflammatory drugs can prevent colon cancer, among other malignancies. A case-control study has suggested that they may protect against melanoma (Oncol. Rep. 2001;8:655–7).

Two large trials of NSAID prevention of skin cancer are underway, and they should be completed in the next year or so, Dr. Spencer said.

“This would be so simple, because you have NSAIDs in your medicine cabinet at home right now,” he said.

▸ Statins. Epidemiologic evidence has suggested that statin use is associated with decreased risk of breast, advanced prostate, lung, esophageal, colon, and pancreatic cancers. Laboratory evidence suggests that statins have this effect because they interfere with two oncogenes, Ras and Rho. Those oncogenes are involved in most melanomas.

▸ Vitamins E and C. Trial results of the chemoprevention effect of vitamin E and vitamin C have not been positive. However, a recent trial of both vitamins together reported that the combination provided significant UV protection, increasing the minimal erythema dose by an average of about 50% in just a single week, Dr. Spencer said.

He noted that sunburn does not necessarily equate with skin cancer risk, but it is a surrogate often used.

▸ Diet. The evidence linking diet to cancer risk is confounding. For example, studies have suggested that a diet high in fat may be associated with an increased cancer risk, but also that saturated fat specifically may be protective.

The soy isoflavone genistein is a potent antioxidant and can block sunburn. However, it probably needs to be used in extremely high concentrations.

“It's a very promising, potential medication, however, in real life I would say buyer beware,” Dr. Spencer said.

▸ Melanin. An Australian company has a patent on an injectable, depot form of melanocyte-stimulating hormone, developed at the University of Arizona, Tucson, that induces a true tan (Melanotan, Epitan Ltd.). The product could prove to be a convenient way to have sun protection, since patients would need a shot only once every few months to have a tan.

However, it could have downsides as well, Dr. Spencer noted. The product could reinforce the idea that tanned skin looks attractive, and that could encourage tanning behavior. Also, it is not known how the hormone might affect existing melanomas.

▸ Polypodium leucotomos. In vitro studies suggest that this extract of a South American fern may be an antioxidant and have antitumor activity.

In one nine-subject study, a single dose significantly increased the minimal erythema dose of the subjects and reduced the levels of histologic markers of malignancy-associated sun damage within a few hours.

“It is not a sunscreen, so the UV light still gets in. For our endocrinology colleagues who are worried about vitamin D, it seems to me this may allow UV-induced, vitamin D production while lowering the UV damage,” Dr. Spencer said.

NAPLES, FLA. — Patients with genital herpes often believe they can't transmit the infection while they are asymptomatic, and the majority of transmissions probably stem from this ignorance, Stephen K. Tyring, M.D., said at the annual meeting of the Florida Society of Dermatology and Dermatologic Surgery.

Many patients may be incredulous when you tell them this, because they have been told they must have a lesion or symptoms to transmit the virus. With such patients, you can point out that 80% of the population is herpes simplex virus type-1 seropositive, but almost nobody ever kisses someone when they have a fever blister on their mouth, said Dr. Tyring, a dermatologist and infectious disease specialist who is medical director of the Center for Clinical Studies at the University of Texas Health Sciences Center, Houston.

The prevalence of herpes simplex type-2 (HSV-2) increased by 30% during the last 2 decades, he noted. It is now estimated that 45 million people in the United States, or 15% of the population, are seropositive for HSV-2. An estimated 80% of transmissions occur when the carrier is asymptomatic, Dr. Tyring said.

Women are at greater risk of acquiring the virus, he said. The overall rate of transmission from an infected partner to an uninfected partner is about 10% per year. But the annual rate rises if the infected partner is the male; the female partner has a 20% chance of becoming infected, and a 30% chance if she is seronegative for HSV-1. If the female is the infected partner, the male has a less than 10% chance of infection.

Condoms protect against transmission but are not foolproof, and they probably benefit women more than men. When men develop herpes lesions or have viral shedding, they tend to do so on the distal genitalia, which the condom covers. Women, however, shed virus into secretions that can get on the base of the penis or even the scrotum.

In a seminal study published last year, in which almost 1,500 infected individuals with seronegative partners were randomly assigned to 500 mg of valacyclovir or placebo once daily, Dr. Tyring and colleagues reported that the rate of transmission was reduced by 50% over an 8-month period (N. Engl. J. Med. 2004;350:11–20).

“The study used valacyclovir, but you can substitute famciclovir or acyclovir and probably get the same result,” Dr. Tyring said.

“The bad news is, we don't have a cure,” he added. “This is just one more tool in the armamentarium.”

The new genital herpes vaccine has been shown to be highly effective, but, unexpectedly, only in women. A major new trial is underway to better understand why this might be and, specifically, the mucosal immunity women appear to develop.

Genital herpes increases the risk of HIV transmission two- to fivefold, Dr. Tyring said. This increased risk occurs because there is a reduced epithelial barrier in a person with herpes, but also because the individual with herpes has infiltrates of CD-4-positive cells where the lesions occur. Studies have shown that one can use acyclovir, valacyclovir, or famciclovir to keep herpes in check in the HIV-infected individual—which not only addresses the herpes but sometimes improves the response to HIV therapy as well, Dr. Tyring said.

For HIV patients with resistant herpes, the Centers for Disease Control and Prevention recommends using a topical formulation of cidofovir.

Genital areas that are not completely covered by a condom remain susceptible to herpes simplex type-2 infection. ©W.B. Saunders 2002, Dermatologic Clinics. Volume 20. Number 2

NAPLES, FLA. — Patients with genital herpes often believe they can't transmit the infection while they are asymptomatic, and the majority of transmissions probably stem from this ignorance, Stephen K. Tyring, M.D., said at the annual meeting of the Florida Society of Dermatology and Dermatologic Surgery.

Many patients may be incredulous when you tell them this, because they have been told they must have a lesion or symptoms to transmit the virus. With such patients, you can point out that 80% of the population is herpes simplex virus type-1 seropositive, but almost nobody ever kisses someone when they have a fever blister on their mouth, said Dr. Tyring, a dermatologist and infectious disease specialist who is medical director of the Center for Clinical Studies at the University of Texas Health Sciences Center, Houston.

The prevalence of herpes simplex type-2 (HSV-2) increased by 30% during the last 2 decades, he noted. It is now estimated that 45 million people in the United States, or 15% of the population, are seropositive for HSV-2. An estimated 80% of transmissions occur when the carrier is asymptomatic, Dr. Tyring said.

Women are at greater risk of acquiring the virus, he said. The overall rate of transmission from an infected partner to an uninfected partner is about 10% per year. But the annual rate rises if the infected partner is the male; the female partner has a 20% chance of becoming infected, and a 30% chance if she is seronegative for HSV-1. If the female is the infected partner, the male has a less than 10% chance of infection.

Condoms protect against transmission but are not foolproof, and they probably benefit women more than men. When men develop herpes lesions or have viral shedding, they tend to do so on the distal genitalia, which the condom covers. Women, however, shed virus into secretions that can get on the base of the penis or even the scrotum.

In a seminal study published last year, in which almost 1,500 infected individuals with seronegative partners were randomly assigned to 500 mg of valacyclovir or placebo once daily, Dr. Tyring and colleagues reported that the rate of transmission was reduced by 50% over an 8-month period (N. Engl. J. Med. 2004;350:11–20).

“The study used valacyclovir, but you can substitute famciclovir or acyclovir and probably get the same result,” Dr. Tyring said.

“The bad news is, we don't have a cure,” he added. “This is just one more tool in the armamentarium.”

The new genital herpes vaccine has been shown to be highly effective, but, unexpectedly, only in women. A major new trial is underway to better understand why this might be and, specifically, the mucosal immunity women appear to develop.

Genital herpes increases the risk of HIV transmission two- to fivefold, Dr. Tyring said. This increased risk occurs because there is a reduced epithelial barrier in a person with herpes, but also because the individual with herpes has infiltrates of CD-4-positive cells where the lesions occur. Studies have shown that one can use acyclovir, valacyclovir, or famciclovir to keep herpes in check in the HIV-infected individual—which not only addresses the herpes but sometimes improves the response to HIV therapy as well, Dr. Tyring said.

For HIV patients with resistant herpes, the Centers for Disease Control and Prevention recommends using a topical formulation of cidofovir.

Genital areas that are not completely covered by a condom remain susceptible to herpes simplex type-2 infection. ©W.B. Saunders 2002, Dermatologic Clinics. Volume 20. Number 2

NAPLES, FLA. — Patients with genital herpes often believe they can't transmit the infection while they are asymptomatic, and the majority of transmissions probably stem from this ignorance, Stephen K. Tyring, M.D., said at the annual meeting of the Florida Society of Dermatology and Dermatologic Surgery.

Many patients may be incredulous when you tell them this, because they have been told they must have a lesion or symptoms to transmit the virus. With such patients, you can point out that 80% of the population is herpes simplex virus type-1 seropositive, but almost nobody ever kisses someone when they have a fever blister on their mouth, said Dr. Tyring, a dermatologist and infectious disease specialist who is medical director of the Center for Clinical Studies at the University of Texas Health Sciences Center, Houston.

The prevalence of herpes simplex type-2 (HSV-2) increased by 30% during the last 2 decades, he noted. It is now estimated that 45 million people in the United States, or 15% of the population, are seropositive for HSV-2. An estimated 80% of transmissions occur when the carrier is asymptomatic, Dr. Tyring said.

Women are at greater risk of acquiring the virus, he said. The overall rate of transmission from an infected partner to an uninfected partner is about 10% per year. But the annual rate rises if the infected partner is the male; the female partner has a 20% chance of becoming infected, and a 30% chance if she is seronegative for HSV-1. If the female is the infected partner, the male has a less than 10% chance of infection.

Condoms protect against transmission but are not foolproof, and they probably benefit women more than men. When men develop herpes lesions or have viral shedding, they tend to do so on the distal genitalia, which the condom covers. Women, however, shed virus into secretions that can get on the base of the penis or even the scrotum.

In a seminal study published last year, in which almost 1,500 infected individuals with seronegative partners were randomly assigned to 500 mg of valacyclovir or placebo once daily, Dr. Tyring and colleagues reported that the rate of transmission was reduced by 50% over an 8-month period (N. Engl. J. Med. 2004;350:11–20).

“The study used valacyclovir, but you can substitute famciclovir or acyclovir and probably get the same result,” Dr. Tyring said.

“The bad news is, we don't have a cure,” he added. “This is just one more tool in the armamentarium.”

The new genital herpes vaccine has been shown to be highly effective, but, unexpectedly, only in women. A major new trial is underway to better understand why this might be and, specifically, the mucosal immunity women appear to develop.

Genital herpes increases the risk of HIV transmission two- to fivefold, Dr. Tyring said. This increased risk occurs because there is a reduced epithelial barrier in a person with herpes, but also because the individual with herpes has infiltrates of CD-4-positive cells where the lesions occur. Studies have shown that one can use acyclovir, valacyclovir, or famciclovir to keep herpes in check in the HIV-infected individual—which not only addresses the herpes but sometimes improves the response to HIV therapy as well, Dr. Tyring said.

For HIV patients with resistant herpes, the Centers for Disease Control and Prevention recommends using a topical formulation of cidofovir.

Genital areas that are not completely covered by a condom remain susceptible to herpes simplex type-2 infection. ©W.B. Saunders 2002, Dermatologic Clinics. Volume 20. Number 2

NAPLES, FLA. — Botulinum toxin may be a good treatment for primary focal hyperhidrosis, but for patients with hand or foot hyperhidrosis you should try iontophoresis first, Lewis P. Stolman, M.D., said at the annual meeting of the Florida Society of Dermatology and Dermatologic Surgery.

What you do not want to do for hyperhidrosis is refer patients for sympathectomy, he added, except as a very last resort.

The majority of patients who undergo sympathectomy for focal hyperhidrosis develop compensatory, and often severe, hyperhidrosis that can be more dispiriting and debilitating than their original condition, said Dr. Stolman of New Jersey Medical School, Newark.

"I don't think we as dermatologists should be referring patients for sympathectomy quite as quickly as we do," Dr. Stolman said.

Compensatory hyperhidrosis is an acknowledged consequence of sympathectomy, and in reported case series the incidence has ranged as high as 67%. In a recent review of reports, the incidence of compensatory hyperhidrosis in 22,000 patients was 52%.

For some patients, the compensatory hyperhidrosis is minor and localized to a limited area, and can be managed with botulinum toxin treatment. But it can also be much more severe, Dr. Stolman said.

Iontophoresis has a number of advantages over botulinum toxin, and may be equally effective, Dr. Stolman said. He was one of the early researchers in the use of iontophoresis for this condition but receives no money or grants from any manufacturer of iontophoresis equipment.

Botulinum toxin treatment has been reported to have an efficacy rate of 75%–95% for axillary hyperhidrosis. In his experience, 85%–90% of patients treated with iontophoresis for palmar or plantar hyperhidrosis have satisfactory improvement, and another 5% are improved when Robinul (glycopyrrolate) is added to the trays of water used for the technique, Dr. Stolman said.

Iontophoresis is probably less expensive than botulinum toxin. A 50-U botulinum toxin treatment costs at least $250, and about half of patients will require two treatments to achieve good control. Medicare reimburses an iontophoresis treatment at $24.69, and most patients need four to six treatments to achieve good control. Patients can also purchase their own equipment.

Two devices exist on the market. One costs $150, the battery-operated Drionic device, and the other costs $650, the Fischer MD-1a galvanic unit, which transforms alternating current to direct current. Though the devices are simple equipment, Dr. Stolman said he much prefers the more expensive device.

"The Drionic device in my opinion has given iontophoresis a bad rap because it is rarely effective," he said. "It is not the equal of the Fischer galvanic device in its efficacy, even though the literature may indicate that it is."

Moreover, unlike botulinum toxin, there is no chance of loss of any fine motor control with iontophoresis, Dr. Stolman added.

Most patients can treat themselves at home. The patient attaches the device's cathode to one tray of water and the anode to another tray, submerges their entire palms, one hand in each tray, and turns up the current to 15–18 mA for 10 minutes. Once patients have achieved control of their hyperhidrosis with four to six treatments, they repeat it whenever necessary, Dr. Stolman said. For some individuals that is every few weeks, and for others it is every week.

The sole drawback to iontophoresis is that it does not work well for axillary hyperhidrosis because it is difficult to attach the electrodes to the axillas, and many patients develop irritation.

The mechanism of action of iontophoresis is unclear, Dr. Stolman said. It may cause occlusion of the distal end of the sweat ducts by thickening the stratum corneum. It has been shown that when the stratum corneum in treated areas is stripped off with adhesive tape, the effect is reversed. Biopsy has shown no change in sweat gland structure.

An exciting recent development in the use of iontophoresis, Dr. Stolman said, is that it has now been shown that botulinum toxin can be added to the water trays, and is delivered effectively by the technique.

"Maybe we will find a way to get prolonged suppression of palmar hyperhidrosis for many months, as we do for the axillas, without painful injection," Dr. Stolman said.

NAPLES, FLA. — Botulinum toxin may be a good treatment for primary focal hyperhidrosis, but for patients with hand or foot hyperhidrosis you should try iontophoresis first, Lewis P. Stolman, M.D., said at the annual meeting of the Florida Society of Dermatology and Dermatologic Surgery.

What you do not want to do for hyperhidrosis is refer patients for sympathectomy, he added, except as a very last resort.

The majority of patients who undergo sympathectomy for focal hyperhidrosis develop compensatory, and often severe, hyperhidrosis that can be more dispiriting and debilitating than their original condition, said Dr. Stolman of New Jersey Medical School, Newark.

"I don't think we as dermatologists should be referring patients for sympathectomy quite as quickly as we do," Dr. Stolman said.

Compensatory hyperhidrosis is an acknowledged consequence of sympathectomy, and in reported case series the incidence has ranged as high as 67%. In a recent review of reports, the incidence of compensatory hyperhidrosis in 22,000 patients was 52%.

For some patients, the compensatory hyperhidrosis is minor and localized to a limited area, and can be managed with botulinum toxin treatment. But it can also be much more severe, Dr. Stolman said.

Iontophoresis has a number of advantages over botulinum toxin, and may be equally effective, Dr. Stolman said. He was one of the early researchers in the use of iontophoresis for this condition but receives no money or grants from any manufacturer of iontophoresis equipment.

Botulinum toxin treatment has been reported to have an efficacy rate of 75%–95% for axillary hyperhidrosis. In his experience, 85%–90% of patients treated with iontophoresis for palmar or plantar hyperhidrosis have satisfactory improvement, and another 5% are improved when Robinul (glycopyrrolate) is added to the trays of water used for the technique, Dr. Stolman said.

Iontophoresis is probably less expensive than botulinum toxin. A 50-U botulinum toxin treatment costs at least $250, and about half of patients will require two treatments to achieve good control. Medicare reimburses an iontophoresis treatment at $24.69, and most patients need four to six treatments to achieve good control. Patients can also purchase their own equipment.

Two devices exist on the market. One costs $150, the battery-operated Drionic device, and the other costs $650, the Fischer MD-1a galvanic unit, which transforms alternating current to direct current. Though the devices are simple equipment, Dr. Stolman said he much prefers the more expensive device.

"The Drionic device in my opinion has given iontophoresis a bad rap because it is rarely effective," he said. "It is not the equal of the Fischer galvanic device in its efficacy, even though the literature may indicate that it is."

Moreover, unlike botulinum toxin, there is no chance of loss of any fine motor control with iontophoresis, Dr. Stolman added.

Most patients can treat themselves at home. The patient attaches the device's cathode to one tray of water and the anode to another tray, submerges their entire palms, one hand in each tray, and turns up the current to 15–18 mA for 10 minutes. Once patients have achieved control of their hyperhidrosis with four to six treatments, they repeat it whenever necessary, Dr. Stolman said. For some individuals that is every few weeks, and for others it is every week.

The sole drawback to iontophoresis is that it does not work well for axillary hyperhidrosis because it is difficult to attach the electrodes to the axillas, and many patients develop irritation.

The mechanism of action of iontophoresis is unclear, Dr. Stolman said. It may cause occlusion of the distal end of the sweat ducts by thickening the stratum corneum. It has been shown that when the stratum corneum in treated areas is stripped off with adhesive tape, the effect is reversed. Biopsy has shown no change in sweat gland structure.

An exciting recent development in the use of iontophoresis, Dr. Stolman said, is that it has now been shown that botulinum toxin can be added to the water trays, and is delivered effectively by the technique.

"Maybe we will find a way to get prolonged suppression of palmar hyperhidrosis for many months, as we do for the axillas, without painful injection," Dr. Stolman said.

NAPLES, FLA. — Botulinum toxin may be a good treatment for primary focal hyperhidrosis, but for patients with hand or foot hyperhidrosis you should try iontophoresis first, Lewis P. Stolman, M.D., said at the annual meeting of the Florida Society of Dermatology and Dermatologic Surgery.

What you do not want to do for hyperhidrosis is refer patients for sympathectomy, he added, except as a very last resort.

The majority of patients who undergo sympathectomy for focal hyperhidrosis develop compensatory, and often severe, hyperhidrosis that can be more dispiriting and debilitating than their original condition, said Dr. Stolman of New Jersey Medical School, Newark.

"I don't think we as dermatologists should be referring patients for sympathectomy quite as quickly as we do," Dr. Stolman said.

Compensatory hyperhidrosis is an acknowledged consequence of sympathectomy, and in reported case series the incidence has ranged as high as 67%. In a recent review of reports, the incidence of compensatory hyperhidrosis in 22,000 patients was 52%.

For some patients, the compensatory hyperhidrosis is minor and localized to a limited area, and can be managed with botulinum toxin treatment. But it can also be much more severe, Dr. Stolman said.

Iontophoresis has a number of advantages over botulinum toxin, and may be equally effective, Dr. Stolman said. He was one of the early researchers in the use of iontophoresis for this condition but receives no money or grants from any manufacturer of iontophoresis equipment.

Botulinum toxin treatment has been reported to have an efficacy rate of 75%–95% for axillary hyperhidrosis. In his experience, 85%–90% of patients treated with iontophoresis for palmar or plantar hyperhidrosis have satisfactory improvement, and another 5% are improved when Robinul (glycopyrrolate) is added to the trays of water used for the technique, Dr. Stolman said.

Iontophoresis is probably less expensive than botulinum toxin. A 50-U botulinum toxin treatment costs at least $250, and about half of patients will require two treatments to achieve good control. Medicare reimburses an iontophoresis treatment at $24.69, and most patients need four to six treatments to achieve good control. Patients can also purchase their own equipment.

Two devices exist on the market. One costs $150, the battery-operated Drionic device, and the other costs $650, the Fischer MD-1a galvanic unit, which transforms alternating current to direct current. Though the devices are simple equipment, Dr. Stolman said he much prefers the more expensive device.

"The Drionic device in my opinion has given iontophoresis a bad rap because it is rarely effective," he said. "It is not the equal of the Fischer galvanic device in its efficacy, even though the literature may indicate that it is."

Moreover, unlike botulinum toxin, there is no chance of loss of any fine motor control with iontophoresis, Dr. Stolman added.

Most patients can treat themselves at home. The patient attaches the device's cathode to one tray of water and the anode to another tray, submerges their entire palms, one hand in each tray, and turns up the current to 15–18 mA for 10 minutes. Once patients have achieved control of their hyperhidrosis with four to six treatments, they repeat it whenever necessary, Dr. Stolman said. For some individuals that is every few weeks, and for others it is every week.

The sole drawback to iontophoresis is that it does not work well for axillary hyperhidrosis because it is difficult to attach the electrodes to the axillas, and many patients develop irritation.

The mechanism of action of iontophoresis is unclear, Dr. Stolman said. It may cause occlusion of the distal end of the sweat ducts by thickening the stratum corneum. It has been shown that when the stratum corneum in treated areas is stripped off with adhesive tape, the effect is reversed. Biopsy has shown no change in sweat gland structure.

An exciting recent development in the use of iontophoresis, Dr. Stolman said, is that it has now been shown that botulinum toxin can be added to the water trays, and is delivered effectively by the technique.

"Maybe we will find a way to get prolonged suppression of palmar hyperhidrosis for many months, as we do for the axillas, without painful injection," Dr. Stolman said.

In a move that caught many in the medical community by surprise, the Food and Drug Administration last month announced a comprehensive—and mandatory—risk management program for the teratogenic acne drug isotretinoin that demands complete compliance by year's end.

The program, called iPLEDGE, will require registration and ongoing compliance by all physicians and patients by Dec. 31, 2005. The iPLEDGE initiative replaces Roche's voluntary SMART program for Accutane and similar programs for the four generic versions of isotretinoin.

The FDA informed physicians in November 2004 that SMART would be replaced. “This is a system that has long been coming, and some would say is long overdue,” said Sandra Kweder, M.D., deputy director of the FDA's Office of New Drugs.

The program's implementation will be incremental, starting with the Oct. 31, 2005, deadline for registration of wholesalers and pharmacies to obtain isotretinoin from a manufacturer. Prescribing physicians and their patients will then have two more months to be registered and in full compliance. Under the program, wholesalers of Accutane or the four currently approved generic equivalents will distribute isotretinoin only to pharmacies that have registered with the safety program and continue to demonstrate ongoing compliance.

Those pharmacies will dispense prescriptions only when the prescribing physician has registered the individual patient being treated and certified that the patient has been informed of the teratogenicity risks and has had two negative pregnancy tests (a screening test and a confirmatory test) performed by a laboratory or in the physician's office. Patient registration will be done over the Internet or by phone.

Patients must also register themselves and sign a consent form agreeing to use two forms of birth control while on the drug. Patients will be required to have repeat pregnancy testing every month while they are on the drug and another 1 month after they stop. Prescriptions will need to be filled within 7 days of pregnancy testing.

The package insert and the patient informed consent form have been updated and now contain a new warning that there have been suicides reported in patients taking isotretinoin. Both inform patients about what signs to watch for and tell them to contact their health care provider if they recognize any of those signs.

The new program replaces the old, required program for Accutane known as SMART (System to Manage Accutane Related Teratogenicity) and the other similar programs for the generic products. Under SMART, physicians who wanted to prescribe Accutane needed to complete an education program to obtain the yellow stickers that needed to be attached to the paper prescriptions for pharmacies to fill the prescriptions. When attaching a sticker, the physician was also required to register the patient and to certify that the patient had undergone pregnancy testing and that the results were negative.

FDA determined that the SMART program needed to be replaced with a more stringent program because data from the first 2 years of the program, which went into effect in 2002, showed that it had not significantly reduced the rate of pregnancies occurring in patients on isotretinoin, which was its aim. Some also claimed that not all physicians were being fully compliant with the pregnancy testing requirement of the program.

Moreover, too few patients were signing up with the voluntary patient registry that was a part of the program.

Physicians can access the iPLEDGE program on the Internet by going to www.ipledgeprogram.com

In a move that caught many in the medical community by surprise, the Food and Drug Administration last month announced a comprehensive—and mandatory—risk management program for the teratogenic acne drug isotretinoin that demands complete compliance by year's end.

The program, called iPLEDGE, will require registration and ongoing compliance by all physicians and patients by Dec. 31, 2005. The iPLEDGE initiative replaces Roche's voluntary SMART program for Accutane and similar programs for the four generic versions of isotretinoin.

The FDA informed physicians in November 2004 that SMART would be replaced. “This is a system that has long been coming, and some would say is long overdue,” said Sandra Kweder, M.D., deputy director of the FDA's Office of New Drugs.

The program's implementation will be incremental, starting with the Oct. 31, 2005, deadline for registration of wholesalers and pharmacies to obtain isotretinoin from a manufacturer. Prescribing physicians and their patients will then have two more months to be registered and in full compliance. Under the program, wholesalers of Accutane or the four currently approved generic equivalents will distribute isotretinoin only to pharmacies that have registered with the safety program and continue to demonstrate ongoing compliance.

Those pharmacies will dispense prescriptions only when the prescribing physician has registered the individual patient being treated and certified that the patient has been informed of the teratogenicity risks and has had two negative pregnancy tests (a screening test and a confirmatory test) performed by a laboratory or in the physician's office. Patient registration will be done over the Internet or by phone.

Patients must also register themselves and sign a consent form agreeing to use two forms of birth control while on the drug. Patients will be required to have repeat pregnancy testing every month while they are on the drug and another 1 month after they stop. Prescriptions will need to be filled within 7 days of pregnancy testing.

The package insert and the patient informed consent form have been updated and now contain a new warning that there have been suicides reported in patients taking isotretinoin. Both inform patients about what signs to watch for and tell them to contact their health care provider if they recognize any of those signs.

The new program replaces the old, required program for Accutane known as SMART (System to Manage Accutane Related Teratogenicity) and the other similar programs for the generic products. Under SMART, physicians who wanted to prescribe Accutane needed to complete an education program to obtain the yellow stickers that needed to be attached to the paper prescriptions for pharmacies to fill the prescriptions. When attaching a sticker, the physician was also required to register the patient and to certify that the patient had undergone pregnancy testing and that the results were negative.

FDA determined that the SMART program needed to be replaced with a more stringent program because data from the first 2 years of the program, which went into effect in 2002, showed that it had not significantly reduced the rate of pregnancies occurring in patients on isotretinoin, which was its aim. Some also claimed that not all physicians were being fully compliant with the pregnancy testing requirement of the program.

Moreover, too few patients were signing up with the voluntary patient registry that was a part of the program.

Physicians can access the iPLEDGE program on the Internet by going to www.ipledgeprogram.com

In a move that caught many in the medical community by surprise, the Food and Drug Administration last month announced a comprehensive—and mandatory—risk management program for the teratogenic acne drug isotretinoin that demands complete compliance by year's end.

The program, called iPLEDGE, will require registration and ongoing compliance by all physicians and patients by Dec. 31, 2005. The iPLEDGE initiative replaces Roche's voluntary SMART program for Accutane and similar programs for the four generic versions of isotretinoin.

The FDA informed physicians in November 2004 that SMART would be replaced. “This is a system that has long been coming, and some would say is long overdue,” said Sandra Kweder, M.D., deputy director of the FDA's Office of New Drugs.

The program's implementation will be incremental, starting with the Oct. 31, 2005, deadline for registration of wholesalers and pharmacies to obtain isotretinoin from a manufacturer. Prescribing physicians and their patients will then have two more months to be registered and in full compliance. Under the program, wholesalers of Accutane or the four currently approved generic equivalents will distribute isotretinoin only to pharmacies that have registered with the safety program and continue to demonstrate ongoing compliance.

Those pharmacies will dispense prescriptions only when the prescribing physician has registered the individual patient being treated and certified that the patient has been informed of the teratogenicity risks and has had two negative pregnancy tests (a screening test and a confirmatory test) performed by a laboratory or in the physician's office. Patient registration will be done over the Internet or by phone.

Patients must also register themselves and sign a consent form agreeing to use two forms of birth control while on the drug. Patients will be required to have repeat pregnancy testing every month while they are on the drug and another 1 month after they stop. Prescriptions will need to be filled within 7 days of pregnancy testing.

The package insert and the patient informed consent form have been updated and now contain a new warning that there have been suicides reported in patients taking isotretinoin. Both inform patients about what signs to watch for and tell them to contact their health care provider if they recognize any of those signs.

The new program replaces the old, required program for Accutane known as SMART (System to Manage Accutane Related Teratogenicity) and the other similar programs for the generic products. Under SMART, physicians who wanted to prescribe Accutane needed to complete an education program to obtain the yellow stickers that needed to be attached to the paper prescriptions for pharmacies to fill the prescriptions. When attaching a sticker, the physician was also required to register the patient and to certify that the patient had undergone pregnancy testing and that the results were negative.

FDA determined that the SMART program needed to be replaced with a more stringent program because data from the first 2 years of the program, which went into effect in 2002, showed that it had not significantly reduced the rate of pregnancies occurring in patients on isotretinoin, which was its aim. Some also claimed that not all physicians were being fully compliant with the pregnancy testing requirement of the program.

Moreover, too few patients were signing up with the voluntary patient registry that was a part of the program.

Physicians can access the iPLEDGE program on the Internet by going to www.ipledgeprogram.com

LOS ANGELES — Oral contraceptive pills do not cause mood swings or depression in most adolescents. On the contrary, overall, it appears that oral contraceptives increase positive mood and decrease negative mood, Mary A. Ott, M.D., said at the annual meeting of the Society for Adolescent Medicine.

“Our pill users in our study felt better,” said Dr. Ott of Indiana University, Indianapolis. “This is different from the adult data.”

Data from studies of adults on whether oral contraception impacts mood negatively have been conflicting, and results of prospective studies have varied from those of retrospective studies. Overall, however, there has been a suggestion in adults that oral contraception can increase depression or exacerbate mood lability, and it is well known that mood changes are a common reason women stop using the pill, Dr. Ott said in a poster presentation.

In her study of 226 adolescent females, oral contraception decreased reports of negative mood by 27% over time and increased positive mood by 32% over time, relative to reports from subjects not on oral contraception.

The 226 enrolled subjects were asked to keep daily mood diaries for two 12-week periods, twice each year, over 2 years. Participants were asked to rate the level of three negative moods they might have experienced during the day (irritable, angry, unhappy) and the level of three positive moods (cheerful, happy, friendly), each on a five-point scale reflecting a range from “not at all” to “all day.”

A diary in which the participant reported being on oral contraception both at the start and end of the period was considered an oral contraception diary. Diary periods during which the participant either started or stopped oral contraception were excluded, but some were on oral contraception for an entire diary period at one time, but not at another.

When mean scores were graphed, negative mood scores in the nonusers stayed relatively stable over time. Scores for the users were lower initially, but by the end of the study scores among users had improved 27% relative to the nonusers.

Positive mood increased for both groups over time, but increased 32% more for the oral contraception users.

LOS ANGELES — Oral contraceptive pills do not cause mood swings or depression in most adolescents. On the contrary, overall, it appears that oral contraceptives increase positive mood and decrease negative mood, Mary A. Ott, M.D., said at the annual meeting of the Society for Adolescent Medicine.

“Our pill users in our study felt better,” said Dr. Ott of Indiana University, Indianapolis. “This is different from the adult data.”

Data from studies of adults on whether oral contraception impacts mood negatively have been conflicting, and results of prospective studies have varied from those of retrospective studies. Overall, however, there has been a suggestion in adults that oral contraception can increase depression or exacerbate mood lability, and it is well known that mood changes are a common reason women stop using the pill, Dr. Ott said in a poster presentation.

In her study of 226 adolescent females, oral contraception decreased reports of negative mood by 27% over time and increased positive mood by 32% over time, relative to reports from subjects not on oral contraception.

The 226 enrolled subjects were asked to keep daily mood diaries for two 12-week periods, twice each year, over 2 years. Participants were asked to rate the level of three negative moods they might have experienced during the day (irritable, angry, unhappy) and the level of three positive moods (cheerful, happy, friendly), each on a five-point scale reflecting a range from “not at all” to “all day.”

A diary in which the participant reported being on oral contraception both at the start and end of the period was considered an oral contraception diary. Diary periods during which the participant either started or stopped oral contraception were excluded, but some were on oral contraception for an entire diary period at one time, but not at another.

When mean scores were graphed, negative mood scores in the nonusers stayed relatively stable over time. Scores for the users were lower initially, but by the end of the study scores among users had improved 27% relative to the nonusers.

Positive mood increased for both groups over time, but increased 32% more for the oral contraception users.

LOS ANGELES — Oral contraceptive pills do not cause mood swings or depression in most adolescents. On the contrary, overall, it appears that oral contraceptives increase positive mood and decrease negative mood, Mary A. Ott, M.D., said at the annual meeting of the Society for Adolescent Medicine.

“Our pill users in our study felt better,” said Dr. Ott of Indiana University, Indianapolis. “This is different from the adult data.”

Data from studies of adults on whether oral contraception impacts mood negatively have been conflicting, and results of prospective studies have varied from those of retrospective studies. Overall, however, there has been a suggestion in adults that oral contraception can increase depression or exacerbate mood lability, and it is well known that mood changes are a common reason women stop using the pill, Dr. Ott said in a poster presentation.

In her study of 226 adolescent females, oral contraception decreased reports of negative mood by 27% over time and increased positive mood by 32% over time, relative to reports from subjects not on oral contraception.

The 226 enrolled subjects were asked to keep daily mood diaries for two 12-week periods, twice each year, over 2 years. Participants were asked to rate the level of three negative moods they might have experienced during the day (irritable, angry, unhappy) and the level of three positive moods (cheerful, happy, friendly), each on a five-point scale reflecting a range from “not at all” to “all day.”

A diary in which the participant reported being on oral contraception both at the start and end of the period was considered an oral contraception diary. Diary periods during which the participant either started or stopped oral contraception were excluded, but some were on oral contraception for an entire diary period at one time, but not at another.

When mean scores were graphed, negative mood scores in the nonusers stayed relatively stable over time. Scores for the users were lower initially, but by the end of the study scores among users had improved 27% relative to the nonusers.

Positive mood increased for both groups over time, but increased 32% more for the oral contraception users.

NAPLES, FLA. — Patients with genital herpes often believe they can't transmit the infection while they are asymptomatic, and the majority of transmissions are probably borne of this ignorance, Stephen K. Tyring, M.D., said at the annual meeting of the Florida Society of Dermatology and Dermatologic Surgery.

Many patients may be incredulous when you tell them this, because they have been told they must have a lesion or symptoms to transmit the virus.

With such patients, you can point out that 80% of the population is herpes simplex virus type-1 seropositive, but almost nobody ever kisses someone when they have a fever blister on their mouth, said Dr. Tyring, a dermatologist and infectious disease specialist who is medical director of the Center for Clinical Studies at the University of Texas Health Sciences Center, Houston.

The prevalence of herpes simplex type-2 (HSV-2) increased by 30% during the last 2 decades, Dr. Tyring noted. It is now estimated that 45 million people in the United States, or 15% of the population, are seropositive for HSV-2.

An estimated 80% of transmissions occur when the carrier is asymptomatic, Dr. Tyring said.

Women are at greater risk of acquiring the virus, he said. The overall rate of transmission from an infected partner to an uninfected partner is about 10% per year. But the annual rate rises if the infected partner is the male; the female partner has a 20% chance of becoming infected, and a 30% chance if she is seronegative for HSV-1. If the female is the infected partner, the male has a less than 10% chance of infection.

Condoms protect against transmission but are not foolproof, and they probably benefit women more than men. When men develop herpes lesions or have viral shedding, they tend to do so on the distal genitalia, which the condom covers. Women, however, shed virus into secretions that can get on the base of the penis or even the scrotum.

In a seminal study published last year, in which almost 1,500 infected individuals with seronegative partners were randomly assigned to 500 mg of valacyclovir or placebo once daily, Dr. Tyring and colleagues reported that the rate of transmission was reduced by 50% over an 8-month period (N. Engl. J. Med. 2004;350:11–20).

“The study used valacyclovir, but you can substitute famciclovir or acyclovir and probably get the same result,” Dr. Tyring said. “The bad news is, we don't have a cure. This is just one more tool in the armamentarium.”

The new genital herpes vaccine has been shown to be highly effective, but, unexpectedly, only in women. A major new trial is underway to better understand why this might be, and, specifically, the mucosal immunity women appear to develop.

Genital herpes increases the risk of HIV transmission two- to fivefold, Dr. Tyring said. This increased risk occurs because there is a reduced epithelial barrier in a person with herpes, but also because the individual with herpes has infiltrates of CD-4-positive cells where the lesions occur.

Studies have shown that one can use acyclovir, valacyclovir, or famciclovir to keep herpes in check in the HIV-infected individual—which not only addresses the herpes but sometimes improves the response to HIV therapy as well, Dr. Tyring said.

For HIV patients with resistant herpes, the Centers for Disease Control and Prevention recommends using a topical formulation of cidofovir.

NAPLES, FLA. — Patients with genital herpes often believe they can't transmit the infection while they are asymptomatic, and the majority of transmissions are probably borne of this ignorance, Stephen K. Tyring, M.D., said at the annual meeting of the Florida Society of Dermatology and Dermatologic Surgery.

Many patients may be incredulous when you tell them this, because they have been told they must have a lesion or symptoms to transmit the virus.

With such patients, you can point out that 80% of the population is herpes simplex virus type-1 seropositive, but almost nobody ever kisses someone when they have a fever blister on their mouth, said Dr. Tyring, a dermatologist and infectious disease specialist who is medical director of the Center for Clinical Studies at the University of Texas Health Sciences Center, Houston.

The prevalence of herpes simplex type-2 (HSV-2) increased by 30% during the last 2 decades, Dr. Tyring noted. It is now estimated that 45 million people in the United States, or 15% of the population, are seropositive for HSV-2.

An estimated 80% of transmissions occur when the carrier is asymptomatic, Dr. Tyring said.

Women are at greater risk of acquiring the virus, he said. The overall rate of transmission from an infected partner to an uninfected partner is about 10% per year. But the annual rate rises if the infected partner is the male; the female partner has a 20% chance of becoming infected, and a 30% chance if she is seronegative for HSV-1. If the female is the infected partner, the male has a less than 10% chance of infection.

Condoms protect against transmission but are not foolproof, and they probably benefit women more than men. When men develop herpes lesions or have viral shedding, they tend to do so on the distal genitalia, which the condom covers. Women, however, shed virus into secretions that can get on the base of the penis or even the scrotum.

In a seminal study published last year, in which almost 1,500 infected individuals with seronegative partners were randomly assigned to 500 mg of valacyclovir or placebo once daily, Dr. Tyring and colleagues reported that the rate of transmission was reduced by 50% over an 8-month period (N. Engl. J. Med. 2004;350:11–20).

“The study used valacyclovir, but you can substitute famciclovir or acyclovir and probably get the same result,” Dr. Tyring said. “The bad news is, we don't have a cure. This is just one more tool in the armamentarium.”

The new genital herpes vaccine has been shown to be highly effective, but, unexpectedly, only in women. A major new trial is underway to better understand why this might be, and, specifically, the mucosal immunity women appear to develop.

Genital herpes increases the risk of HIV transmission two- to fivefold, Dr. Tyring said. This increased risk occurs because there is a reduced epithelial barrier in a person with herpes, but also because the individual with herpes has infiltrates of CD-4-positive cells where the lesions occur.

Studies have shown that one can use acyclovir, valacyclovir, or famciclovir to keep herpes in check in the HIV-infected individual—which not only addresses the herpes but sometimes improves the response to HIV therapy as well, Dr. Tyring said.

For HIV patients with resistant herpes, the Centers for Disease Control and Prevention recommends using a topical formulation of cidofovir.

NAPLES, FLA. — Patients with genital herpes often believe they can't transmit the infection while they are asymptomatic, and the majority of transmissions are probably borne of this ignorance, Stephen K. Tyring, M.D., said at the annual meeting of the Florida Society of Dermatology and Dermatologic Surgery.

Many patients may be incredulous when you tell them this, because they have been told they must have a lesion or symptoms to transmit the virus.

With such patients, you can point out that 80% of the population is herpes simplex virus type-1 seropositive, but almost nobody ever kisses someone when they have a fever blister on their mouth, said Dr. Tyring, a dermatologist and infectious disease specialist who is medical director of the Center for Clinical Studies at the University of Texas Health Sciences Center, Houston.

The prevalence of herpes simplex type-2 (HSV-2) increased by 30% during the last 2 decades, Dr. Tyring noted. It is now estimated that 45 million people in the United States, or 15% of the population, are seropositive for HSV-2.

An estimated 80% of transmissions occur when the carrier is asymptomatic, Dr. Tyring said.

Women are at greater risk of acquiring the virus, he said. The overall rate of transmission from an infected partner to an uninfected partner is about 10% per year. But the annual rate rises if the infected partner is the male; the female partner has a 20% chance of becoming infected, and a 30% chance if she is seronegative for HSV-1. If the female is the infected partner, the male has a less than 10% chance of infection.

Condoms protect against transmission but are not foolproof, and they probably benefit women more than men. When men develop herpes lesions or have viral shedding, they tend to do so on the distal genitalia, which the condom covers. Women, however, shed virus into secretions that can get on the base of the penis or even the scrotum.

In a seminal study published last year, in which almost 1,500 infected individuals with seronegative partners were randomly assigned to 500 mg of valacyclovir or placebo once daily, Dr. Tyring and colleagues reported that the rate of transmission was reduced by 50% over an 8-month period (N. Engl. J. Med. 2004;350:11–20).

“The study used valacyclovir, but you can substitute famciclovir or acyclovir and probably get the same result,” Dr. Tyring said. “The bad news is, we don't have a cure. This is just one more tool in the armamentarium.”

The new genital herpes vaccine has been shown to be highly effective, but, unexpectedly, only in women. A major new trial is underway to better understand why this might be, and, specifically, the mucosal immunity women appear to develop.

Genital herpes increases the risk of HIV transmission two- to fivefold, Dr. Tyring said. This increased risk occurs because there is a reduced epithelial barrier in a person with herpes, but also because the individual with herpes has infiltrates of CD-4-positive cells where the lesions occur.

Studies have shown that one can use acyclovir, valacyclovir, or famciclovir to keep herpes in check in the HIV-infected individual—which not only addresses the herpes but sometimes improves the response to HIV therapy as well, Dr. Tyring said.

For HIV patients with resistant herpes, the Centers for Disease Control and Prevention recommends using a topical formulation of cidofovir.

INDIAN WELLS, CALIF. — Even educated women of high socioeconomic status do not appear to get enough calcium, Andrea Stein, M.D., said at the annual meeting of the Pacific Coast Reproductive Society.

In a survey of 180 middle-aged patients seen in her gynecology practice, in a wealthy area of the Los Angeles region, more than 50% apparently consume less than 1,000–1,500 mg of calcium per day, Dr. Stein said. Overall, 86% of the patients had a college degree, and 36% had an advanced degree. All were 45 years old or older.

Of the 99 patients taking no medications, 75% took a calcium supplement once a day or less, and 48% had a milk product once a day or less. Of the 60 on hormone therapy, 68% took a calcium supplement once a day or less, and 43% had a milk product once or less a day.

For the 21 patients taking a bisphosphonate, raloxifene, or calcitonin, the percentages were 48% and 33%.

A single calcium supplement or a single serving will not provide the recommended amount of calcium for a woman aged 50 years or older, which is 1,200–1,500 mg/day, noted Dr. Stein, whose practice is in Santa Monica, Calif. Supplements contain 500–600 mg elemental calcium per tablet, because that is the maximum an individual can absorb at one time. A single serving of skim milk, yogurt, or cheese contains 300 mg or less of calcium.

The findings suggest women of high socioeconomic status are somewhat better at getting adequate calcium than those of low socioeconomic status, but only marginally so, Dr. Stein said. According to data, 80% of low-income women do not get adequate daily calcium.

INDIAN WELLS, CALIF. — Even educated women of high socioeconomic status do not appear to get enough calcium, Andrea Stein, M.D., said at the annual meeting of the Pacific Coast Reproductive Society.

In a survey of 180 middle-aged patients seen in her gynecology practice, in a wealthy area of the Los Angeles region, more than 50% apparently consume less than 1,000–1,500 mg of calcium per day, Dr. Stein said. Overall, 86% of the patients had a college degree, and 36% had an advanced degree. All were 45 years old or older.

Of the 99 patients taking no medications, 75% took a calcium supplement once a day or less, and 48% had a milk product once a day or less. Of the 60 on hormone therapy, 68% took a calcium supplement once a day or less, and 43% had a milk product once or less a day.

For the 21 patients taking a bisphosphonate, raloxifene, or calcitonin, the percentages were 48% and 33%.

A single calcium supplement or a single serving will not provide the recommended amount of calcium for a woman aged 50 years or older, which is 1,200–1,500 mg/day, noted Dr. Stein, whose practice is in Santa Monica, Calif. Supplements contain 500–600 mg elemental calcium per tablet, because that is the maximum an individual can absorb at one time. A single serving of skim milk, yogurt, or cheese contains 300 mg or less of calcium.

The findings suggest women of high socioeconomic status are somewhat better at getting adequate calcium than those of low socioeconomic status, but only marginally so, Dr. Stein said. According to data, 80% of low-income women do not get adequate daily calcium.

INDIAN WELLS, CALIF. — Even educated women of high socioeconomic status do not appear to get enough calcium, Andrea Stein, M.D., said at the annual meeting of the Pacific Coast Reproductive Society.

In a survey of 180 middle-aged patients seen in her gynecology practice, in a wealthy area of the Los Angeles region, more than 50% apparently consume less than 1,000–1,500 mg of calcium per day, Dr. Stein said. Overall, 86% of the patients had a college degree, and 36% had an advanced degree. All were 45 years old or older.

Of the 99 patients taking no medications, 75% took a calcium supplement once a day or less, and 48% had a milk product once a day or less. Of the 60 on hormone therapy, 68% took a calcium supplement once a day or less, and 43% had a milk product once or less a day.

For the 21 patients taking a bisphosphonate, raloxifene, or calcitonin, the percentages were 48% and 33%.

A single calcium supplement or a single serving will not provide the recommended amount of calcium for a woman aged 50 years or older, which is 1,200–1,500 mg/day, noted Dr. Stein, whose practice is in Santa Monica, Calif. Supplements contain 500–600 mg elemental calcium per tablet, because that is the maximum an individual can absorb at one time. A single serving of skim milk, yogurt, or cheese contains 300 mg or less of calcium.

The findings suggest women of high socioeconomic status are somewhat better at getting adequate calcium than those of low socioeconomic status, but only marginally so, Dr. Stein said. According to data, 80% of low-income women do not get adequate daily calcium.

SAN FRANCISCO — Pharmacogenomics has already entered the practice of medicine, with several recent developments that went largely unnoticed, Richard M. Weinshilboum, M.D., said at the annual meeting of the American College of Physicians.

New guidelines on pharmacogenomics from the Food and Drug Administration that were first drafted in 2003 were finalized and published in March, noted Dr. Weinshilboum, professor of medicine and pharmacology at the Mayo Clinic, Rochester, Minn.

The guidelines state that when a company with an investigational new drug has pharmacogenomic information on the drug, it should be submitted with the rest of the approval data. Currently, the submission of these data is considered voluntary.

On the one hand, industry is embracing pharmacogenomics because it can provide essential information in the initial studies of an investigational drug about whether it is worth the effort to continue pursuing expensive development. But on the other hand, industry is being “dragged” unwillingly into pharmacogenomics by the FDA because information on patients who may not respond to a drug or who may have side effects could spell the end of blockbuster drugs, Dr. Weinshilboum said.

The guidelines identify two pharmacogenomic biomarkers that the FDA will consider valid biomarkers. They are cytochrome P450 2D6 and thiopurine S-methyltransferase (TPMT). Information on other markers that identify possible genetic variation of response to a new drug should be submitted also, but the information needs to include background data on the biomarker.

TPMT is an enzyme known to be involved specifically in the metabolism of mercaptopurine, which is commonly used for childhood acute lymphoblastic leukemia, and the immunosuppressant azathioprine (Imuran). It has been shown that individuals have wide variation in TPMT activity. There are three important mutations in the TPMT gene, and individuals with low TPMT activity build up high drug levels leading to myelosuppression that is sometimes severe.

Cytochrome P450 2D6 is one of the isoforms of the cytochrome P450 enzyme family. It has been shown that individuals can have more than one copy of the gene for cytochrome P450 2D6, and that persons with more copies are high metabolizers of the affected drugs. At least 41 different drugs are known to be metabolized through cytochrome P450 2D6; an important one is codeine, which cytochrome P450 2D6 transforms to morphine.

Dentists already know about cytochrome P450 2D6, because just this year Roche Diagnostics received approval for its AmpliChip CYP450 test, a microarray test for clinical use. Patients are coming in armed with information from the Internet, demanding to have their cytochrome P450 2D6 status checked to see if they are among those who do not respond to codeine, he said.

Pharmacogenomics also has recently been an issue in the approval of the new “smart” cancer drug gefitinib (Iressa), which is used for non-small cell lung cancer. The drug was given accelerated approval in 2003, based on preliminary data on a response in some end-stage patients. But a new, placebo-controlled trial of the drug was recently halted because gefitinib failed to show any survival benefit.

The study may have failed to show a benefit because the investigators did not obtain genetic profiles of the patients. It now appears that gefitinib can produce a marked response, but only in those patients with a particular mutation of the epidermal growth factor receptor gene—about 10% of all patients, he said.

AstraZeneca, manufacturer of Iressa, has recently announced that it will begin cancer biomarker studies of the drug.

SAN FRANCISCO — Pharmacogenomics has already entered the practice of medicine, with several recent developments that went largely unnoticed, Richard M. Weinshilboum, M.D., said at the annual meeting of the American College of Physicians.

New guidelines on pharmacogenomics from the Food and Drug Administration that were first drafted in 2003 were finalized and published in March, noted Dr. Weinshilboum, professor of medicine and pharmacology at the Mayo Clinic, Rochester, Minn.

The guidelines state that when a company with an investigational new drug has pharmacogenomic information on the drug, it should be submitted with the rest of the approval data. Currently, the submission of these data is considered voluntary.

On the one hand, industry is embracing pharmacogenomics because it can provide essential information in the initial studies of an investigational drug about whether it is worth the effort to continue pursuing expensive development. But on the other hand, industry is being “dragged” unwillingly into pharmacogenomics by the FDA because information on patients who may not respond to a drug or who may have side effects could spell the end of blockbuster drugs, Dr. Weinshilboum said.

The guidelines identify two pharmacogenomic biomarkers that the FDA will consider valid biomarkers. They are cytochrome P450 2D6 and thiopurine S-methyltransferase (TPMT). Information on other markers that identify possible genetic variation of response to a new drug should be submitted also, but the information needs to include background data on the biomarker.

TPMT is an enzyme known to be involved specifically in the metabolism of mercaptopurine, which is commonly used for childhood acute lymphoblastic leukemia, and the immunosuppressant azathioprine (Imuran). It has been shown that individuals have wide variation in TPMT activity. There are three important mutations in the TPMT gene, and individuals with low TPMT activity build up high drug levels leading to myelosuppression that is sometimes severe.

Cytochrome P450 2D6 is one of the isoforms of the cytochrome P450 enzyme family. It has been shown that individuals can have more than one copy of the gene for cytochrome P450 2D6, and that persons with more copies are high metabolizers of the affected drugs. At least 41 different drugs are known to be metabolized through cytochrome P450 2D6; an important one is codeine, which cytochrome P450 2D6 transforms to morphine.

Dentists already know about cytochrome P450 2D6, because just this year Roche Diagnostics received approval for its AmpliChip CYP450 test, a microarray test for clinical use. Patients are coming in armed with information from the Internet, demanding to have their cytochrome P450 2D6 status checked to see if they are among those who do not respond to codeine, he said.

Pharmacogenomics also has recently been an issue in the approval of the new “smart” cancer drug gefitinib (Iressa), which is used for non-small cell lung cancer. The drug was given accelerated approval in 2003, based on preliminary data on a response in some end-stage patients. But a new, placebo-controlled trial of the drug was recently halted because gefitinib failed to show any survival benefit.

The study may have failed to show a benefit because the investigators did not obtain genetic profiles of the patients. It now appears that gefitinib can produce a marked response, but only in those patients with a particular mutation of the epidermal growth factor receptor gene—about 10% of all patients, he said.

AstraZeneca, manufacturer of Iressa, has recently announced that it will begin cancer biomarker studies of the drug.

SAN FRANCISCO — Pharmacogenomics has already entered the practice of medicine, with several recent developments that went largely unnoticed, Richard M. Weinshilboum, M.D., said at the annual meeting of the American College of Physicians.

New guidelines on pharmacogenomics from the Food and Drug Administration that were first drafted in 2003 were finalized and published in March, noted Dr. Weinshilboum, professor of medicine and pharmacology at the Mayo Clinic, Rochester, Minn.

The guidelines state that when a company with an investigational new drug has pharmacogenomic information on the drug, it should be submitted with the rest of the approval data. Currently, the submission of these data is considered voluntary.

On the one hand, industry is embracing pharmacogenomics because it can provide essential information in the initial studies of an investigational drug about whether it is worth the effort to continue pursuing expensive development. But on the other hand, industry is being “dragged” unwillingly into pharmacogenomics by the FDA because information on patients who may not respond to a drug or who may have side effects could spell the end of blockbuster drugs, Dr. Weinshilboum said.

The guidelines identify two pharmacogenomic biomarkers that the FDA will consider valid biomarkers. They are cytochrome P450 2D6 and thiopurine S-methyltransferase (TPMT). Information on other markers that identify possible genetic variation of response to a new drug should be submitted also, but the information needs to include background data on the biomarker.

TPMT is an enzyme known to be involved specifically in the metabolism of mercaptopurine, which is commonly used for childhood acute lymphoblastic leukemia, and the immunosuppressant azathioprine (Imuran). It has been shown that individuals have wide variation in TPMT activity. There are three important mutations in the TPMT gene, and individuals with low TPMT activity build up high drug levels leading to myelosuppression that is sometimes severe.

Cytochrome P450 2D6 is one of the isoforms of the cytochrome P450 enzyme family. It has been shown that individuals can have more than one copy of the gene for cytochrome P450 2D6, and that persons with more copies are high metabolizers of the affected drugs. At least 41 different drugs are known to be metabolized through cytochrome P450 2D6; an important one is codeine, which cytochrome P450 2D6 transforms to morphine.

Dentists already know about cytochrome P450 2D6, because just this year Roche Diagnostics received approval for its AmpliChip CYP450 test, a microarray test for clinical use. Patients are coming in armed with information from the Internet, demanding to have their cytochrome P450 2D6 status checked to see if they are among those who do not respond to codeine, he said.

Pharmacogenomics also has recently been an issue in the approval of the new “smart” cancer drug gefitinib (Iressa), which is used for non-small cell lung cancer. The drug was given accelerated approval in 2003, based on preliminary data on a response in some end-stage patients. But a new, placebo-controlled trial of the drug was recently halted because gefitinib failed to show any survival benefit.

The study may have failed to show a benefit because the investigators did not obtain genetic profiles of the patients. It now appears that gefitinib can produce a marked response, but only in those patients with a particular mutation of the epidermal growth factor receptor gene—about 10% of all patients, he said.

AstraZeneca, manufacturer of Iressa, has recently announced that it will begin cancer biomarker studies of the drug.