Bruce Jancin

PRAGUE – A novel self-occlusive topical anesthetic cream newly approved by the Food and Drug Administration for local analgesia in superficial dermatologic procedures displayed persuasive evidence of efficacy in a phase III study highlighted at the annual congress of the European Academy of Dermatology and Venereology.

The topical anesthetic cream, called Pliaglis, incorporates lidocaine and tetracaine at 70 mg/g each. The FDA approved the product in October 2012 for use in conjunction with filler injections, laser-assisted tattoo removal, pulsed dye laser therapy, and other dermatologic procedures.

At the congress, Y. May Ma, Ph.D., presented the results of a multicenter phase III clinical trial involving 50 patients undergoing laser-assisted hair removal. Investigators applied Pliaglis to half of the skin surface scheduled for treatment and a placebo cream to the other half. Thirty minutes later dermatologists peeled off both materials and got to work.

Participants’ mean pain score for the laser procedure on a 0-100 visual analog scale was 23 for the Pliaglis-pretreated areas compared with 32 for hair removal on the control areas. Eighty percent of patients rated the analgesic effect as adequate on Pliaglis-pretreated skin areas, but only 52% did so for placebo-pretreated areas, reported Dr. Ma of Galderma Laboratories in Sophia Antipolis, France.

Blinded investigators rated 44% of patients as having no pain during laser therapy on areas that had been pretreated with Pliaglis, compared with an investigator-judged 22% pain-free procedure rate on placebo-pretreated areas.

Mild, transient stinging, redness, and erythema were fairly common on Pliaglis-treated skin, but quickly resolved without any intervention, Dr. Ma observed.

This study was funded by Galderma and presented by a full-time Galderma employee.

PRAGUE – A novel self-occlusive topical anesthetic cream newly approved by the Food and Drug Administration for local analgesia in superficial dermatologic procedures displayed persuasive evidence of efficacy in a phase III study highlighted at the annual congress of the European Academy of Dermatology and Venereology.

The topical anesthetic cream, called Pliaglis, incorporates lidocaine and tetracaine at 70 mg/g each. The FDA approved the product in October 2012 for use in conjunction with filler injections, laser-assisted tattoo removal, pulsed dye laser therapy, and other dermatologic procedures.

At the congress, Y. May Ma, Ph.D., presented the results of a multicenter phase III clinical trial involving 50 patients undergoing laser-assisted hair removal. Investigators applied Pliaglis to half of the skin surface scheduled for treatment and a placebo cream to the other half. Thirty minutes later dermatologists peeled off both materials and got to work.

Participants’ mean pain score for the laser procedure on a 0-100 visual analog scale was 23 for the Pliaglis-pretreated areas compared with 32 for hair removal on the control areas. Eighty percent of patients rated the analgesic effect as adequate on Pliaglis-pretreated skin areas, but only 52% did so for placebo-pretreated areas, reported Dr. Ma of Galderma Laboratories in Sophia Antipolis, France.

Blinded investigators rated 44% of patients as having no pain during laser therapy on areas that had been pretreated with Pliaglis, compared with an investigator-judged 22% pain-free procedure rate on placebo-pretreated areas.

Mild, transient stinging, redness, and erythema were fairly common on Pliaglis-treated skin, but quickly resolved without any intervention, Dr. Ma observed.

This study was funded by Galderma and presented by a full-time Galderma employee.

PRAGUE – A novel self-occlusive topical anesthetic cream newly approved by the Food and Drug Administration for local analgesia in superficial dermatologic procedures displayed persuasive evidence of efficacy in a phase III study highlighted at the annual congress of the European Academy of Dermatology and Venereology.

The topical anesthetic cream, called Pliaglis, incorporates lidocaine and tetracaine at 70 mg/g each. The FDA approved the product in October 2012 for use in conjunction with filler injections, laser-assisted tattoo removal, pulsed dye laser therapy, and other dermatologic procedures.

At the congress, Y. May Ma, Ph.D., presented the results of a multicenter phase III clinical trial involving 50 patients undergoing laser-assisted hair removal. Investigators applied Pliaglis to half of the skin surface scheduled for treatment and a placebo cream to the other half. Thirty minutes later dermatologists peeled off both materials and got to work.

Participants’ mean pain score for the laser procedure on a 0-100 visual analog scale was 23 for the Pliaglis-pretreated areas compared with 32 for hair removal on the control areas. Eighty percent of patients rated the analgesic effect as adequate on Pliaglis-pretreated skin areas, but only 52% did so for placebo-pretreated areas, reported Dr. Ma of Galderma Laboratories in Sophia Antipolis, France.

Blinded investigators rated 44% of patients as having no pain during laser therapy on areas that had been pretreated with Pliaglis, compared with an investigator-judged 22% pain-free procedure rate on placebo-pretreated areas.

Mild, transient stinging, redness, and erythema were fairly common on Pliaglis-treated skin, but quickly resolved without any intervention, Dr. Ma observed.

This study was funded by Galderma and presented by a full-time Galderma employee.

PRAGUE – Intensified photodynamic therapy assisted by ablative fractional laser resurfacing is a new and more effective way to treat thick actinic keratoses, according to Dr. Merete Haedersdal.

At 3 months’ follow-up, cure rates were significantly better with fractional CO₂ laser-assisted photodynamic therapy (PDT) than with standard PDT in a randomized trial, she reported at the annual congress of the European Academy of Dermatology and Venereology.

"As a side benefit, the combined therapy gives a nice decrease in photoaging. There is photorejuvenation of the skin," noted Dr. Haedersdal of the University of Copenhagen.

Stand-alone PDT gets good results in thinner AKs, Bowen’s lesions, and basal cell carcinomas, both superficial and nodular. But effectiveness drops off considerably for thicker lesions.

That’s why Dr. Haedersdal and her Copenhagen colleagues, together with researchers at the Wellman Center for Photomedicine at Massachusetts General Hospital, Boston, where she has been a visiting scientist, are developing intensified PDT.

Basically, the dermatologists are using the fractional CO₂ laser at 10,600 nm to drill tiny vertical channels surrounded by areas of unexposed skin. These channels facilitate uptake of the photosensitizing agent, rendering PDT more effective at greater depths. The enhanced uptake of photosensitizer is not merely a hypothesis; it has been documented via a marked increase in fluorescence intensity during illumination, she explained.

Dr. Haedersdal reported on 15 patients with a total of 212 AKs on severely photodamaged skin of the scalp and face. Two symmetrical randomly selected areas were chosen on each patient to receive one fractional CO₂ laser-assisted PDT treatment and one standard PDT treatment. First, however, both treatment areas underwent curettage. Then one site was treated with the UltraPulse laser using the DeepFx handpiece set to 10 mJ per pulse and a single pulse density of 5%. The photosensitizing agent, methyl aminolevulinate cream, was then applied under occlusion for 3 hours at both sites. This was followed by illumination using a red light–emitting diode at 37 J/cm².

At 3 months’ follow-up, the complete response rate of thicker grade II-III AKs was 88% with intensified PDT, compared with 59% with conventional PDT. For thinner grade I lesions, the complete response rates were 100% and 79%, respectively.

Only 3 new lesions arose at the intensified PDT-treated sites within 3 months, compared with 11 new lesions in areas that received standard PDT.

"So there might – in terms of avoiding future treatment procedures – be a benefit in combining the photothermal efficacy of the laser with the photochemical response from the PDT procedure," Dr. Haedersdal noted.

Pain scores were significantly higher during illumination in the intensified PDT areas, with a mean of 6.5 on a 1-10 scale compared with 5.4 on skin sites that got standard PDT. Erythema and crusting were also more intense at intensified PDT sites, and long-term pigmentary changes were more frequent at these sites as well.

"We have to be aware that the clinical reactions that we see from this new procedure are more intense than with conventional PDT. So for now we have to take care that we’re not using it for really large treatment areas because then the patients will have really intense phototoxic reactions," the dermatologist cautioned.

She and her coinvestigators are conducting an ongoing clinical trial combining mild daylight PDT and intensified PDT in organ transplant recipients, who are highly prone to the development of numerous skin cancers.

In pig models, the investigators are able to get the photosensitizing agent to a depth of 1.8 mm with the help of the fractional CO₂ laser. This makes intensified PDT an attractive proposition for the treatment of basal cell carcinomas. Indeed, Dr. Haedersdal and her coinvestigators are now in the middle of a clinical trial of fractional CO₂ laser-assisted PDT in patients with difficult-to-treat basal cell carcinomas.

"It seems very promising so far. We don’t have an evidence base yet, but I believe in it," she said.

The dermatologist reported serving on the advisory boards of Lumenis and Galderma, which are providing financial support for the development of intensified PDT.

PRAGUE – Intensified photodynamic therapy assisted by ablative fractional laser resurfacing is a new and more effective way to treat thick actinic keratoses, according to Dr. Merete Haedersdal.

At 3 months’ follow-up, cure rates were significantly better with fractional CO₂ laser-assisted photodynamic therapy (PDT) than with standard PDT in a randomized trial, she reported at the annual congress of the European Academy of Dermatology and Venereology.

"As a side benefit, the combined therapy gives a nice decrease in photoaging. There is photorejuvenation of the skin," noted Dr. Haedersdal of the University of Copenhagen.

Stand-alone PDT gets good results in thinner AKs, Bowen’s lesions, and basal cell carcinomas, both superficial and nodular. But effectiveness drops off considerably for thicker lesions.

That’s why Dr. Haedersdal and her Copenhagen colleagues, together with researchers at the Wellman Center for Photomedicine at Massachusetts General Hospital, Boston, where she has been a visiting scientist, are developing intensified PDT.

Basically, the dermatologists are using the fractional CO₂ laser at 10,600 nm to drill tiny vertical channels surrounded by areas of unexposed skin. These channels facilitate uptake of the photosensitizing agent, rendering PDT more effective at greater depths. The enhanced uptake of photosensitizer is not merely a hypothesis; it has been documented via a marked increase in fluorescence intensity during illumination, she explained.

Dr. Haedersdal reported on 15 patients with a total of 212 AKs on severely photodamaged skin of the scalp and face. Two symmetrical randomly selected areas were chosen on each patient to receive one fractional CO₂ laser-assisted PDT treatment and one standard PDT treatment. First, however, both treatment areas underwent curettage. Then one site was treated with the UltraPulse laser using the DeepFx handpiece set to 10 mJ per pulse and a single pulse density of 5%. The photosensitizing agent, methyl aminolevulinate cream, was then applied under occlusion for 3 hours at both sites. This was followed by illumination using a red light–emitting diode at 37 J/cm².

At 3 months’ follow-up, the complete response rate of thicker grade II-III AKs was 88% with intensified PDT, compared with 59% with conventional PDT. For thinner grade I lesions, the complete response rates were 100% and 79%, respectively.

Only 3 new lesions arose at the intensified PDT-treated sites within 3 months, compared with 11 new lesions in areas that received standard PDT.

"So there might – in terms of avoiding future treatment procedures – be a benefit in combining the photothermal efficacy of the laser with the photochemical response from the PDT procedure," Dr. Haedersdal noted.

Pain scores were significantly higher during illumination in the intensified PDT areas, with a mean of 6.5 on a 1-10 scale compared with 5.4 on skin sites that got standard PDT. Erythema and crusting were also more intense at intensified PDT sites, and long-term pigmentary changes were more frequent at these sites as well.

"We have to be aware that the clinical reactions that we see from this new procedure are more intense than with conventional PDT. So for now we have to take care that we’re not using it for really large treatment areas because then the patients will have really intense phototoxic reactions," the dermatologist cautioned.

She and her coinvestigators are conducting an ongoing clinical trial combining mild daylight PDT and intensified PDT in organ transplant recipients, who are highly prone to the development of numerous skin cancers.

In pig models, the investigators are able to get the photosensitizing agent to a depth of 1.8 mm with the help of the fractional CO₂ laser. This makes intensified PDT an attractive proposition for the treatment of basal cell carcinomas. Indeed, Dr. Haedersdal and her coinvestigators are now in the middle of a clinical trial of fractional CO₂ laser-assisted PDT in patients with difficult-to-treat basal cell carcinomas.

"It seems very promising so far. We don’t have an evidence base yet, but I believe in it," she said.

The dermatologist reported serving on the advisory boards of Lumenis and Galderma, which are providing financial support for the development of intensified PDT.

PRAGUE – Intensified photodynamic therapy assisted by ablative fractional laser resurfacing is a new and more effective way to treat thick actinic keratoses, according to Dr. Merete Haedersdal.

At 3 months’ follow-up, cure rates were significantly better with fractional CO₂ laser-assisted photodynamic therapy (PDT) than with standard PDT in a randomized trial, she reported at the annual congress of the European Academy of Dermatology and Venereology.

"As a side benefit, the combined therapy gives a nice decrease in photoaging. There is photorejuvenation of the skin," noted Dr. Haedersdal of the University of Copenhagen.

Stand-alone PDT gets good results in thinner AKs, Bowen’s lesions, and basal cell carcinomas, both superficial and nodular. But effectiveness drops off considerably for thicker lesions.

That’s why Dr. Haedersdal and her Copenhagen colleagues, together with researchers at the Wellman Center for Photomedicine at Massachusetts General Hospital, Boston, where she has been a visiting scientist, are developing intensified PDT.

Basically, the dermatologists are using the fractional CO₂ laser at 10,600 nm to drill tiny vertical channels surrounded by areas of unexposed skin. These channels facilitate uptake of the photosensitizing agent, rendering PDT more effective at greater depths. The enhanced uptake of photosensitizer is not merely a hypothesis; it has been documented via a marked increase in fluorescence intensity during illumination, she explained.

Dr. Haedersdal reported on 15 patients with a total of 212 AKs on severely photodamaged skin of the scalp and face. Two symmetrical randomly selected areas were chosen on each patient to receive one fractional CO₂ laser-assisted PDT treatment and one standard PDT treatment. First, however, both treatment areas underwent curettage. Then one site was treated with the UltraPulse laser using the DeepFx handpiece set to 10 mJ per pulse and a single pulse density of 5%. The photosensitizing agent, methyl aminolevulinate cream, was then applied under occlusion for 3 hours at both sites. This was followed by illumination using a red light–emitting diode at 37 J/cm².

At 3 months’ follow-up, the complete response rate of thicker grade II-III AKs was 88% with intensified PDT, compared with 59% with conventional PDT. For thinner grade I lesions, the complete response rates were 100% and 79%, respectively.

Only 3 new lesions arose at the intensified PDT-treated sites within 3 months, compared with 11 new lesions in areas that received standard PDT.

"So there might – in terms of avoiding future treatment procedures – be a benefit in combining the photothermal efficacy of the laser with the photochemical response from the PDT procedure," Dr. Haedersdal noted.

Pain scores were significantly higher during illumination in the intensified PDT areas, with a mean of 6.5 on a 1-10 scale compared with 5.4 on skin sites that got standard PDT. Erythema and crusting were also more intense at intensified PDT sites, and long-term pigmentary changes were more frequent at these sites as well.

"We have to be aware that the clinical reactions that we see from this new procedure are more intense than with conventional PDT. So for now we have to take care that we’re not using it for really large treatment areas because then the patients will have really intense phototoxic reactions," the dermatologist cautioned.

She and her coinvestigators are conducting an ongoing clinical trial combining mild daylight PDT and intensified PDT in organ transplant recipients, who are highly prone to the development of numerous skin cancers.

In pig models, the investigators are able to get the photosensitizing agent to a depth of 1.8 mm with the help of the fractional CO₂ laser. This makes intensified PDT an attractive proposition for the treatment of basal cell carcinomas. Indeed, Dr. Haedersdal and her coinvestigators are now in the middle of a clinical trial of fractional CO₂ laser-assisted PDT in patients with difficult-to-treat basal cell carcinomas.

"It seems very promising so far. We don’t have an evidence base yet, but I believe in it," she said.

The dermatologist reported serving on the advisory boards of Lumenis and Galderma, which are providing financial support for the development of intensified PDT.

PRAGUE – Tacrolimus 0.03% ointment has earned first-line, treatment-of-choice status in atopic blepharoconjunctivitis, the most common ocular complication of atopic dermatitis, Dr. Ville Kiiski said at the annual congress of the European Academy of Dermatology and Venereology.

In a 10-year, single-center review of 338 patients on long-term topical therapy for atopic blepharoconjunctivitis with either tacrolimus (Protopic), pimecrolimus 1% cream (Elidel), or topical corticosteroids, tacrolimus displayed the best efficacy and tolerability, according to Dr. Kiiski of Helsinki University Central Hospital.

Tacrolimus ointment was the primary therapy in 297 patients as young as 2 years old. Thirty-three patients were on pimecrolimus, while just eight patients were treated mainly with topical steroids. Most Finnish physicians are reluctant to prescribe topical steroids for long-term use in the eyelid area because of the well-known associated increased risks of cataracts, elevated intraocular pressure, and skin atrophy, the dermatologist noted.

The mean follow-up was 1.5 years for treatment efficacy and 5.8 years for malignancy risk.

The treatment discontinuation rate because of intolerance of side effects was 33% with pimecrolimus and 9.1% for tacrolimus. Twenty-two percent of patients placed on pimecrolimus discontinued the drug because of insufficient efficacy, compared with 1.6% on tacrolimus.

The blepharitis response rate was 90% in tacrolimus-treated patients, 79% with pimecrolimus, and 88% in the handful of patients on topical steroids. The conjunctivitis response rates were 80%, 55%, and 50% with tacrolimus, pimecrolimus, and topical steroids, respectively.

Tacrolimus-treated patients were an adjusted 2.37-fold more likely to experience significant improvement in their blepharitis than patients on pimecrolimus and 2.34-fold more likely to see improvement in their conjunctivitis.

Intraocular pressure dropped over time by a mean of 0.6 mm Hg in patients on either of the topical calcineurin inhibitors. None of the three topical therapies was associated with adverse effects on vision, lens, or cornea, nor were there adverse trends in terms of bacterial infections or malignancies.

Atopic blepharoconjunctivitis occurs when inflammatory disease activity at the eyelid margins traumatizes the ocular surface, aggravating keratitis and conjunctivitis.

The study was free of commercial sponsorship or investigator financial conflicts.

PRAGUE – Tacrolimus 0.03% ointment has earned first-line, treatment-of-choice status in atopic blepharoconjunctivitis, the most common ocular complication of atopic dermatitis, Dr. Ville Kiiski said at the annual congress of the European Academy of Dermatology and Venereology.

In a 10-year, single-center review of 338 patients on long-term topical therapy for atopic blepharoconjunctivitis with either tacrolimus (Protopic), pimecrolimus 1% cream (Elidel), or topical corticosteroids, tacrolimus displayed the best efficacy and tolerability, according to Dr. Kiiski of Helsinki University Central Hospital.

Tacrolimus ointment was the primary therapy in 297 patients as young as 2 years old. Thirty-three patients were on pimecrolimus, while just eight patients were treated mainly with topical steroids. Most Finnish physicians are reluctant to prescribe topical steroids for long-term use in the eyelid area because of the well-known associated increased risks of cataracts, elevated intraocular pressure, and skin atrophy, the dermatologist noted.

The mean follow-up was 1.5 years for treatment efficacy and 5.8 years for malignancy risk.

The treatment discontinuation rate because of intolerance of side effects was 33% with pimecrolimus and 9.1% for tacrolimus. Twenty-two percent of patients placed on pimecrolimus discontinued the drug because of insufficient efficacy, compared with 1.6% on tacrolimus.

The blepharitis response rate was 90% in tacrolimus-treated patients, 79% with pimecrolimus, and 88% in the handful of patients on topical steroids. The conjunctivitis response rates were 80%, 55%, and 50% with tacrolimus, pimecrolimus, and topical steroids, respectively.

Tacrolimus-treated patients were an adjusted 2.37-fold more likely to experience significant improvement in their blepharitis than patients on pimecrolimus and 2.34-fold more likely to see improvement in their conjunctivitis.

Intraocular pressure dropped over time by a mean of 0.6 mm Hg in patients on either of the topical calcineurin inhibitors. None of the three topical therapies was associated with adverse effects on vision, lens, or cornea, nor were there adverse trends in terms of bacterial infections or malignancies.

Atopic blepharoconjunctivitis occurs when inflammatory disease activity at the eyelid margins traumatizes the ocular surface, aggravating keratitis and conjunctivitis.

The study was free of commercial sponsorship or investigator financial conflicts.

PRAGUE – Tacrolimus 0.03% ointment has earned first-line, treatment-of-choice status in atopic blepharoconjunctivitis, the most common ocular complication of atopic dermatitis, Dr. Ville Kiiski said at the annual congress of the European Academy of Dermatology and Venereology.

In a 10-year, single-center review of 338 patients on long-term topical therapy for atopic blepharoconjunctivitis with either tacrolimus (Protopic), pimecrolimus 1% cream (Elidel), or topical corticosteroids, tacrolimus displayed the best efficacy and tolerability, according to Dr. Kiiski of Helsinki University Central Hospital.

Tacrolimus ointment was the primary therapy in 297 patients as young as 2 years old. Thirty-three patients were on pimecrolimus, while just eight patients were treated mainly with topical steroids. Most Finnish physicians are reluctant to prescribe topical steroids for long-term use in the eyelid area because of the well-known associated increased risks of cataracts, elevated intraocular pressure, and skin atrophy, the dermatologist noted.

The mean follow-up was 1.5 years for treatment efficacy and 5.8 years for malignancy risk.

The treatment discontinuation rate because of intolerance of side effects was 33% with pimecrolimus and 9.1% for tacrolimus. Twenty-two percent of patients placed on pimecrolimus discontinued the drug because of insufficient efficacy, compared with 1.6% on tacrolimus.

The blepharitis response rate was 90% in tacrolimus-treated patients, 79% with pimecrolimus, and 88% in the handful of patients on topical steroids. The conjunctivitis response rates were 80%, 55%, and 50% with tacrolimus, pimecrolimus, and topical steroids, respectively.

Tacrolimus-treated patients were an adjusted 2.37-fold more likely to experience significant improvement in their blepharitis than patients on pimecrolimus and 2.34-fold more likely to see improvement in their conjunctivitis.

Intraocular pressure dropped over time by a mean of 0.6 mm Hg in patients on either of the topical calcineurin inhibitors. None of the three topical therapies was associated with adverse effects on vision, lens, or cornea, nor were there adverse trends in terms of bacterial infections or malignancies.

Atopic blepharoconjunctivitis occurs when inflammatory disease activity at the eyelid margins traumatizes the ocular surface, aggravating keratitis and conjunctivitis.

The study was free of commercial sponsorship or investigator financial conflicts.

PRAGUE – It has been a big year for dermatologic laser therapy.

Among the major advances in the field seen during 2012 has been introduction of novel techniques for remodeling mature burn scars and removing tattoos, as well as welcome, albeit preliminary, data supporting laser therapy of onychomycosis, and – finally – some long-overdue first persuasive evidence of the effectiveness of a home-use, light-based device for unwanted hair removal, Dr. Merete Haedersdal said in a keynote year-in-review laser lecture at the annual congress of the European Academy of Dermatology and Venereology.

• Tattoos. Based upon the concept of selective photothermolysis coupled with recognition that tattoo pigment particles are really tiny – a mere 40-300 nm in size – dermatologists at SkinCare Physicians in Chestnut Hill (Mass.) treated 12 patients using a novel picosecond 755-nm alexandrite laser.

After an average of 4.2 treatment sessions spaced roughly 6 weeks apart, all 12 patients showed greater than 75% clearance upon blinded physician assessment. All 12 declared themselves either satisfied or extremely satisfied with their results (Arch. Dermatol. 2012;17:1-4).

This picosecond alexandrite laser delivers pulses 100 times shorter than the familiar nanosecond lasers. It’s not yet commercially available, but is expected to be quite soon, according to Dr. Haedersdal of the University of Copenhagen.

Meanwhile, Greek dermatologists have pioneered a laser technique for tattoo removal that entails four treatment passes separated by 20-minute intervals, all delivered in a single lengthy session. The underlying concept is that the downtime between passes allows the treated skin to relax and shed treatment-induced air bubbles. In an 18-patient study, the clinical results were demonstrably better with the four-pass technique than with conventional single-treatment sessions (J. Am. Acad. Dermatol. 2012;66:271-7).

Dr. Haedersdal said that she’s heard some colleagues who’ve tried the four-pass-in-a-session technique say they’re not convinced it really does work better than the standard approach. She has tweaked the technique somewhat to good effect in her own practice: She starts out removing a tattoo using the standard single-treatment-per-session method and sticks with it until there is no further improvement. Then she switches to the four-pass-per-session technique.

"I would say it works very nicely when we add it on," the dermatologist commented.

• Home-use hair-removal device effectiveness. The home-device market has been on fire in the United States for more than 5 years and in Europe for the last couple. It is a field that’s been long on claims and short on evidence of meaningful efficacy and safety – until 2012. Just in September, Dr. Ronald G. Wheeland, professor of dermatology and chief of dermatologic surgery at the University of Missouri, Columbia, published a case-controlled study that Dr. Haedersdal considers most welcome.

Thirteen patients underwent eight hair removal treatment sessions at monthly intervals using an 810-nm home-use diode laser marketed as the Tria Hair Removal Laser. Untreated areas of unwanted hair growth served as controls. At 1 year of follow-up after completing the eighth and final treatment, the mean hair count reduction was 44%, 49%, and 65%, respectively, in areas treated at fluences of 7, 12, and 20 J/cm² compared with controls (Lasers Surg. Med. 2012;44:550-7).

In addition, Dr. Haedersdal coauthored a systematic literature review of the two approved diode laser devices and nine intense pulsed light devices marketed for home use for hair removal. The cumulative supporting evidence isn’t super strong: six prospective uncontrolled studies and one controlled study (J. Eur. Acad. Dermatol. Venereol. 2012;26:545-53).

"Clearly, there is something to this home therapy based on the Wheeland study and our systematic review. We really need some randomized comparative trials, though," she said.

• Home-device safety. This is an area of such great concern that she and her colleagues in the European Society for Laser Dermatology recently published hair-removal home-device safety guidelines (J. Eur. Acad. Dermatol. Venereol. 2012;26: 799-811).

"People just aren’t being trained in the safe use of these devices," she cautioned.

The risks associated with improper use include ocular injury, skin burns, and paradoxical hair growth, as is the case with devices used in physicians’ offices.

The paradoxical hair growth risk in untreated areas close by treated skin is an issue that has been largely beneath dermatologists’ radar prior to the European guidelines. The reported risk with professional devices used by dermatologists is 0.6%-10%. With home devices, who knows?

"It’s a real matter of concern these days. When you lower the fluences, the incidence of paradoxical hair growth may be even higher. There’s nothing in the literature yet, but I’m sure there will be in the next few years," Dr. Haedersdal said.

Patients at increased risk for paradoxical hair regrowth are women with darker skin types, typically with polycystic ovarian syndrome, who are undergoing facial treatment. The mechanism of paradoxical hair regrowth is unknown. Two leading possibilities are light-driven triggering of inflammatory mediators or stimulation of the hair cycle secondary to subtherapeutic thermal injury, she continued.

• Burn scars. A solid body of evidence has accrued regarding the efficacy and safety of both ablative and nonablative fractional lasers to remodel mature burn scars.

Particularly noteworthy was a recent prospective, single-arm, blinded-evaluator study in which a 1,550-nm nonablative fractional erbium laser was employed to treat burn scars in 10 patients. Ninety percent of patients showed improved skin texture and 80% demonstrated improvement in dyschromia, something that hasn’t previously been reported with laser therapy (Lasers Surg. Med. 2012;44:441-6).

The 13 published studies of nonablative fractional laser therapy for burn scars show 26%-50% improvement. That’s slightly less than the 26%-83% improvement reported in the 13 studies of ablative fractional lasers. On the other hand, nonablative fractional laser therapy entails fewer side effects: 1-3 days of erythema and a postinflammatory hyperpigmentation rate of up to 13%, compared with 3-14 days of erythema with ablative fractional laser therapy and a postinflammatory hyperpigmentation rate of up to 92%. As yet, though, there have been no head-to-head comparative studies of the two types of devices.

• Onychomycosis. This is a brand-new area for laser therapy. A recent review noted that, while the Food and Drug Administration has approved four YAG lasers for treatment of onychomycosis, the regulatory standards for device approval don’t require persuasive evidence of efficacy, unlike for drugs (J. Am. Podiatr. Med. Assoc. 2012;102:428-30). Although it’s a promising technology, the authors stated that there are as yet no data showing how laser therapy stacks up against existing standard treatments for onychomycosis in terms of efficacy.

Nevertheless, Dr. Haedersdal noted, attention-getting cure rates were seen in a recent Chinese study involving 154 laser-treated nails in 33 patients. The week-24 complete cure rate, both mycologic and clinical, was 51% after eight weekly treatments and 53% after four weekly treatments (Chin. Med. J. 2012;125:3288-91).

Dr. Haedersdal reported serving on the scientific advisory boards for Galderma, LEO Pharma, and Procter & Gamble.

PRAGUE – It has been a big year for dermatologic laser therapy.

Among the major advances in the field seen during 2012 has been introduction of novel techniques for remodeling mature burn scars and removing tattoos, as well as welcome, albeit preliminary, data supporting laser therapy of onychomycosis, and – finally – some long-overdue first persuasive evidence of the effectiveness of a home-use, light-based device for unwanted hair removal, Dr. Merete Haedersdal said in a keynote year-in-review laser lecture at the annual congress of the European Academy of Dermatology and Venereology.

• Tattoos. Based upon the concept of selective photothermolysis coupled with recognition that tattoo pigment particles are really tiny – a mere 40-300 nm in size – dermatologists at SkinCare Physicians in Chestnut Hill (Mass.) treated 12 patients using a novel picosecond 755-nm alexandrite laser.

After an average of 4.2 treatment sessions spaced roughly 6 weeks apart, all 12 patients showed greater than 75% clearance upon blinded physician assessment. All 12 declared themselves either satisfied or extremely satisfied with their results (Arch. Dermatol. 2012;17:1-4).

This picosecond alexandrite laser delivers pulses 100 times shorter than the familiar nanosecond lasers. It’s not yet commercially available, but is expected to be quite soon, according to Dr. Haedersdal of the University of Copenhagen.

Meanwhile, Greek dermatologists have pioneered a laser technique for tattoo removal that entails four treatment passes separated by 20-minute intervals, all delivered in a single lengthy session. The underlying concept is that the downtime between passes allows the treated skin to relax and shed treatment-induced air bubbles. In an 18-patient study, the clinical results were demonstrably better with the four-pass technique than with conventional single-treatment sessions (J. Am. Acad. Dermatol. 2012;66:271-7).

Dr. Haedersdal said that she’s heard some colleagues who’ve tried the four-pass-in-a-session technique say they’re not convinced it really does work better than the standard approach. She has tweaked the technique somewhat to good effect in her own practice: She starts out removing a tattoo using the standard single-treatment-per-session method and sticks with it until there is no further improvement. Then she switches to the four-pass-per-session technique.

"I would say it works very nicely when we add it on," the dermatologist commented.

• Home-use hair-removal device effectiveness. The home-device market has been on fire in the United States for more than 5 years and in Europe for the last couple. It is a field that’s been long on claims and short on evidence of meaningful efficacy and safety – until 2012. Just in September, Dr. Ronald G. Wheeland, professor of dermatology and chief of dermatologic surgery at the University of Missouri, Columbia, published a case-controlled study that Dr. Haedersdal considers most welcome.

Thirteen patients underwent eight hair removal treatment sessions at monthly intervals using an 810-nm home-use diode laser marketed as the Tria Hair Removal Laser. Untreated areas of unwanted hair growth served as controls. At 1 year of follow-up after completing the eighth and final treatment, the mean hair count reduction was 44%, 49%, and 65%, respectively, in areas treated at fluences of 7, 12, and 20 J/cm² compared with controls (Lasers Surg. Med. 2012;44:550-7).

In addition, Dr. Haedersdal coauthored a systematic literature review of the two approved diode laser devices and nine intense pulsed light devices marketed for home use for hair removal. The cumulative supporting evidence isn’t super strong: six prospective uncontrolled studies and one controlled study (J. Eur. Acad. Dermatol. Venereol. 2012;26:545-53).

"Clearly, there is something to this home therapy based on the Wheeland study and our systematic review. We really need some randomized comparative trials, though," she said.

• Home-device safety. This is an area of such great concern that she and her colleagues in the European Society for Laser Dermatology recently published hair-removal home-device safety guidelines (J. Eur. Acad. Dermatol. Venereol. 2012;26: 799-811).

"People just aren’t being trained in the safe use of these devices," she cautioned.

The risks associated with improper use include ocular injury, skin burns, and paradoxical hair growth, as is the case with devices used in physicians’ offices.

The paradoxical hair growth risk in untreated areas close by treated skin is an issue that has been largely beneath dermatologists’ radar prior to the European guidelines. The reported risk with professional devices used by dermatologists is 0.6%-10%. With home devices, who knows?

"It’s a real matter of concern these days. When you lower the fluences, the incidence of paradoxical hair growth may be even higher. There’s nothing in the literature yet, but I’m sure there will be in the next few years," Dr. Haedersdal said.

Patients at increased risk for paradoxical hair regrowth are women with darker skin types, typically with polycystic ovarian syndrome, who are undergoing facial treatment. The mechanism of paradoxical hair regrowth is unknown. Two leading possibilities are light-driven triggering of inflammatory mediators or stimulation of the hair cycle secondary to subtherapeutic thermal injury, she continued.

• Burn scars. A solid body of evidence has accrued regarding the efficacy and safety of both ablative and nonablative fractional lasers to remodel mature burn scars.

Particularly noteworthy was a recent prospective, single-arm, blinded-evaluator study in which a 1,550-nm nonablative fractional erbium laser was employed to treat burn scars in 10 patients. Ninety percent of patients showed improved skin texture and 80% demonstrated improvement in dyschromia, something that hasn’t previously been reported with laser therapy (Lasers Surg. Med. 2012;44:441-6).

The 13 published studies of nonablative fractional laser therapy for burn scars show 26%-50% improvement. That’s slightly less than the 26%-83% improvement reported in the 13 studies of ablative fractional lasers. On the other hand, nonablative fractional laser therapy entails fewer side effects: 1-3 days of erythema and a postinflammatory hyperpigmentation rate of up to 13%, compared with 3-14 days of erythema with ablative fractional laser therapy and a postinflammatory hyperpigmentation rate of up to 92%. As yet, though, there have been no head-to-head comparative studies of the two types of devices.

• Onychomycosis. This is a brand-new area for laser therapy. A recent review noted that, while the Food and Drug Administration has approved four YAG lasers for treatment of onychomycosis, the regulatory standards for device approval don’t require persuasive evidence of efficacy, unlike for drugs (J. Am. Podiatr. Med. Assoc. 2012;102:428-30). Although it’s a promising technology, the authors stated that there are as yet no data showing how laser therapy stacks up against existing standard treatments for onychomycosis in terms of efficacy.

Nevertheless, Dr. Haedersdal noted, attention-getting cure rates were seen in a recent Chinese study involving 154 laser-treated nails in 33 patients. The week-24 complete cure rate, both mycologic and clinical, was 51% after eight weekly treatments and 53% after four weekly treatments (Chin. Med. J. 2012;125:3288-91).

Dr. Haedersdal reported serving on the scientific advisory boards for Galderma, LEO Pharma, and Procter & Gamble.

PRAGUE – It has been a big year for dermatologic laser therapy.

Among the major advances in the field seen during 2012 has been introduction of novel techniques for remodeling mature burn scars and removing tattoos, as well as welcome, albeit preliminary, data supporting laser therapy of onychomycosis, and – finally – some long-overdue first persuasive evidence of the effectiveness of a home-use, light-based device for unwanted hair removal, Dr. Merete Haedersdal said in a keynote year-in-review laser lecture at the annual congress of the European Academy of Dermatology and Venereology.

• Tattoos. Based upon the concept of selective photothermolysis coupled with recognition that tattoo pigment particles are really tiny – a mere 40-300 nm in size – dermatologists at SkinCare Physicians in Chestnut Hill (Mass.) treated 12 patients using a novel picosecond 755-nm alexandrite laser.

After an average of 4.2 treatment sessions spaced roughly 6 weeks apart, all 12 patients showed greater than 75% clearance upon blinded physician assessment. All 12 declared themselves either satisfied or extremely satisfied with their results (Arch. Dermatol. 2012;17:1-4).

This picosecond alexandrite laser delivers pulses 100 times shorter than the familiar nanosecond lasers. It’s not yet commercially available, but is expected to be quite soon, according to Dr. Haedersdal of the University of Copenhagen.

Meanwhile, Greek dermatologists have pioneered a laser technique for tattoo removal that entails four treatment passes separated by 20-minute intervals, all delivered in a single lengthy session. The underlying concept is that the downtime between passes allows the treated skin to relax and shed treatment-induced air bubbles. In an 18-patient study, the clinical results were demonstrably better with the four-pass technique than with conventional single-treatment sessions (J. Am. Acad. Dermatol. 2012;66:271-7).

Dr. Haedersdal said that she’s heard some colleagues who’ve tried the four-pass-in-a-session technique say they’re not convinced it really does work better than the standard approach. She has tweaked the technique somewhat to good effect in her own practice: She starts out removing a tattoo using the standard single-treatment-per-session method and sticks with it until there is no further improvement. Then she switches to the four-pass-per-session technique.

"I would say it works very nicely when we add it on," the dermatologist commented.

• Home-use hair-removal device effectiveness. The home-device market has been on fire in the United States for more than 5 years and in Europe for the last couple. It is a field that’s been long on claims and short on evidence of meaningful efficacy and safety – until 2012. Just in September, Dr. Ronald G. Wheeland, professor of dermatology and chief of dermatologic surgery at the University of Missouri, Columbia, published a case-controlled study that Dr. Haedersdal considers most welcome.

Thirteen patients underwent eight hair removal treatment sessions at monthly intervals using an 810-nm home-use diode laser marketed as the Tria Hair Removal Laser. Untreated areas of unwanted hair growth served as controls. At 1 year of follow-up after completing the eighth and final treatment, the mean hair count reduction was 44%, 49%, and 65%, respectively, in areas treated at fluences of 7, 12, and 20 J/cm² compared with controls (Lasers Surg. Med. 2012;44:550-7).

In addition, Dr. Haedersdal coauthored a systematic literature review of the two approved diode laser devices and nine intense pulsed light devices marketed for home use for hair removal. The cumulative supporting evidence isn’t super strong: six prospective uncontrolled studies and one controlled study (J. Eur. Acad. Dermatol. Venereol. 2012;26:545-53).

"Clearly, there is something to this home therapy based on the Wheeland study and our systematic review. We really need some randomized comparative trials, though," she said.

• Home-device safety. This is an area of such great concern that she and her colleagues in the European Society for Laser Dermatology recently published hair-removal home-device safety guidelines (J. Eur. Acad. Dermatol. Venereol. 2012;26: 799-811).

"People just aren’t being trained in the safe use of these devices," she cautioned.

The risks associated with improper use include ocular injury, skin burns, and paradoxical hair growth, as is the case with devices used in physicians’ offices.

The paradoxical hair growth risk in untreated areas close by treated skin is an issue that has been largely beneath dermatologists’ radar prior to the European guidelines. The reported risk with professional devices used by dermatologists is 0.6%-10%. With home devices, who knows?

"It’s a real matter of concern these days. When you lower the fluences, the incidence of paradoxical hair growth may be even higher. There’s nothing in the literature yet, but I’m sure there will be in the next few years," Dr. Haedersdal said.

Patients at increased risk for paradoxical hair regrowth are women with darker skin types, typically with polycystic ovarian syndrome, who are undergoing facial treatment. The mechanism of paradoxical hair regrowth is unknown. Two leading possibilities are light-driven triggering of inflammatory mediators or stimulation of the hair cycle secondary to subtherapeutic thermal injury, she continued.

• Burn scars. A solid body of evidence has accrued regarding the efficacy and safety of both ablative and nonablative fractional lasers to remodel mature burn scars.

Particularly noteworthy was a recent prospective, single-arm, blinded-evaluator study in which a 1,550-nm nonablative fractional erbium laser was employed to treat burn scars in 10 patients. Ninety percent of patients showed improved skin texture and 80% demonstrated improvement in dyschromia, something that hasn’t previously been reported with laser therapy (Lasers Surg. Med. 2012;44:441-6).

The 13 published studies of nonablative fractional laser therapy for burn scars show 26%-50% improvement. That’s slightly less than the 26%-83% improvement reported in the 13 studies of ablative fractional lasers. On the other hand, nonablative fractional laser therapy entails fewer side effects: 1-3 days of erythema and a postinflammatory hyperpigmentation rate of up to 13%, compared with 3-14 days of erythema with ablative fractional laser therapy and a postinflammatory hyperpigmentation rate of up to 92%. As yet, though, there have been no head-to-head comparative studies of the two types of devices.

• Onychomycosis. This is a brand-new area for laser therapy. A recent review noted that, while the Food and Drug Administration has approved four YAG lasers for treatment of onychomycosis, the regulatory standards for device approval don’t require persuasive evidence of efficacy, unlike for drugs (J. Am. Podiatr. Med. Assoc. 2012;102:428-30). Although it’s a promising technology, the authors stated that there are as yet no data showing how laser therapy stacks up against existing standard treatments for onychomycosis in terms of efficacy.

Nevertheless, Dr. Haedersdal noted, attention-getting cure rates were seen in a recent Chinese study involving 154 laser-treated nails in 33 patients. The week-24 complete cure rate, both mycologic and clinical, was 51% after eight weekly treatments and 53% after four weekly treatments (Chin. Med. J. 2012;125:3288-91).

Dr. Haedersdal reported serving on the scientific advisory boards for Galderma, LEO Pharma, and Procter & Gamble.

PRAGUE – Add Merkel cell carcinoma to the seemingly ever-growing list of malignancies linked to vitamin D deficiency.

A multicenter French study involving 89 patients with histologically confirmed Merkel cell carcinoma indicates that individuals with this rare and often aggressive neuroendocrine skin malignancy have an increased prevalence of vitamin D deficiency. Moreover, the vitamin D–deficient subgroup had a greater mean tumor size at diagnosis and sharply worse outcomes, Dr. Mahtab Samimi reported at the annual congress of the European Academy of Dermatology and Venereology.

© Kaspri/Fotolia.com

Fifty-eight of the 89 (65%) Merkel cell carcinoma patients were vitamin D deficient as defined by a serum level below 50 nmol/L. During follow-up, 33 patients developed nodal and/or distant metastases and 19 died of Merkel cell carcinoma. The 4-year Merkel cell carcinoma–free survival rate was 40% in the vitamin D deficient group and more than 90% in patients with normal-range vitamin D. The metastasis-free survival rate at 4 years was 20% in vitamin D–deficient patients and 70% in those without serum vitamin D deficiency.

In a multivariate regression analysis, low vitamin D was independently associated with an adjusted 2.89-fold increased risk of developing nodal and/or distant metastases and a 5.28-fold increased risk for death from their malignancy, reported Dr. Samimi of Francois Rabelais University in Tours, France.

The multivariate analysis was adjusted for age, gender, immune status, tumor location, time of year of the serum vitamin D measurement, and Merkel cell polyomavirus DNA levels.

It’s biologically plausible that a patient’s vitamin D status influences Merkel cell carcinoma behavior, according to Dr. Samimi. She and her coworkers analyzed 19 primary tumor specimens and 9 nodal metastases and found every single one strongly expressed the vitamin D receptor.

"The active metabolites of vitamin D bind to the vitamin D receptor, which is able to regulate genes involved in cell cycle control and others that have anti-inflammatory effects," the dermatologist explained.

Other investigators have shown that melanoma, too, is affected by a patient’s vitamin D status. Vitamin D deficiency is associated with thicker melanomas at diagnosis and reduced survival, she noted.

Dr. Samimi stressed that the newly shown association that she and her coworkers have found between vitamin D deficiency and worse-prognosis Merkel cell carcinoma must be considered hypothesis-generating rather than proof of causality. Serum vitamin D wasn’t measured until an average of 3 months after cancer diagnosis.

Asked by the audience if she screens her patients with Merkel cell carcinoma or melanoma for vitamin D deficiency, Dr. Samimi replied affirmatively. And if they’re deficient, as is so often the case, she puts them on vitamin D supplementation.

"The protective role of doing this in terms of cancer prognosis is not proven, but at the very least the supplementation has beneficial effects on skeletal and muscle health, so it’s a good thing," she said.

In a separate study, Dr. Nicolas Kluger of the University of Helsinki presented national Finnish data showing a predisposition of Merkel cell carcinoma for the left side of affected patients.

The comprehensive Finnish Cancer Registry is thought to have captured all 177 Finns diagnosed with Merkel cell carcinoma in a recent 20-year period. Fifty-six percent of the tumors were on the left, 37% on the right, and 7% occurred on the midline.

Tumors located on the trunk were equally likely to be left or right sided, but tumors on the head and neck were 3.2-fold more likely to be on the left side. Merkel cell carcinomas arising on the forearm or hand were fourfold more likely to occur on the left than the right side. On the leg and foot, the left-sided excess was 2.4-fold. Tumors located on the face were 1.5-fold more likely to occur on the left side.

These Finnish data confirm an earlier U.S. study involving a much larger patient population: 2,384 individuals with Merkel cell carcinoma included the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) database, Dr. Kluger noted. In the U.S. study, 52.7% of the cancers occurred on the left side. On the arm it was 55%, while on the face it was 52%, but there was no difference in lateral distribution of the tumors on the legs (J. Am. Acad. Dermatol. 2011;65:35-9).

The same large U.S. study also showed an excess of left-sidedness in the distribution of melanomas among 82,587 affected patients in the SEER registry.

Since ultraviolet light exposure figures in the pathogenesis of both of these serious skin cancers, one leading theory regarding the explanation for the left-sided predominance of Merkel cell carcinoma and melanoma involves increased driver-side UV exposure while operating motor vehicles. Dr. Kluger finds this explanation unlikely. Although steering wheels are placed on the left side of vehicles in Finland, as in the United States, left-side predominance of these skin cancers also has been reported in countries such as Scotland, where drivers stick to the left side of the road and the steering wheel is on the right, he noted.

In Finland, there was a significant excess of Merkel cell carcinomas on the left side in nearly every year of the 20-year study. That means if the skewed lateral distribution of the tumors is due to some as-yet-unidentified environmental factor, it’s a factor that hasn’t changed in 20 years, Dr. Kluger observed.

"For now it’s an interesting curiosity," he commented.

Both Dr. Kluger and Dr. Samimi reported having no financial conflicts.

PRAGUE – Add Merkel cell carcinoma to the seemingly ever-growing list of malignancies linked to vitamin D deficiency.

A multicenter French study involving 89 patients with histologically confirmed Merkel cell carcinoma indicates that individuals with this rare and often aggressive neuroendocrine skin malignancy have an increased prevalence of vitamin D deficiency. Moreover, the vitamin D–deficient subgroup had a greater mean tumor size at diagnosis and sharply worse outcomes, Dr. Mahtab Samimi reported at the annual congress of the European Academy of Dermatology and Venereology.

© Kaspri/Fotolia.com

Fifty-eight of the 89 (65%) Merkel cell carcinoma patients were vitamin D deficient as defined by a serum level below 50 nmol/L. During follow-up, 33 patients developed nodal and/or distant metastases and 19 died of Merkel cell carcinoma. The 4-year Merkel cell carcinoma–free survival rate was 40% in the vitamin D deficient group and more than 90% in patients with normal-range vitamin D. The metastasis-free survival rate at 4 years was 20% in vitamin D–deficient patients and 70% in those without serum vitamin D deficiency.

In a multivariate regression analysis, low vitamin D was independently associated with an adjusted 2.89-fold increased risk of developing nodal and/or distant metastases and a 5.28-fold increased risk for death from their malignancy, reported Dr. Samimi of Francois Rabelais University in Tours, France.

The multivariate analysis was adjusted for age, gender, immune status, tumor location, time of year of the serum vitamin D measurement, and Merkel cell polyomavirus DNA levels.

It’s biologically plausible that a patient’s vitamin D status influences Merkel cell carcinoma behavior, according to Dr. Samimi. She and her coworkers analyzed 19 primary tumor specimens and 9 nodal metastases and found every single one strongly expressed the vitamin D receptor.

"The active metabolites of vitamin D bind to the vitamin D receptor, which is able to regulate genes involved in cell cycle control and others that have anti-inflammatory effects," the dermatologist explained.

Other investigators have shown that melanoma, too, is affected by a patient’s vitamin D status. Vitamin D deficiency is associated with thicker melanomas at diagnosis and reduced survival, she noted.

Dr. Samimi stressed that the newly shown association that she and her coworkers have found between vitamin D deficiency and worse-prognosis Merkel cell carcinoma must be considered hypothesis-generating rather than proof of causality. Serum vitamin D wasn’t measured until an average of 3 months after cancer diagnosis.

Asked by the audience if she screens her patients with Merkel cell carcinoma or melanoma for vitamin D deficiency, Dr. Samimi replied affirmatively. And if they’re deficient, as is so often the case, she puts them on vitamin D supplementation.

"The protective role of doing this in terms of cancer prognosis is not proven, but at the very least the supplementation has beneficial effects on skeletal and muscle health, so it’s a good thing," she said.

In a separate study, Dr. Nicolas Kluger of the University of Helsinki presented national Finnish data showing a predisposition of Merkel cell carcinoma for the left side of affected patients.

The comprehensive Finnish Cancer Registry is thought to have captured all 177 Finns diagnosed with Merkel cell carcinoma in a recent 20-year period. Fifty-six percent of the tumors were on the left, 37% on the right, and 7% occurred on the midline.

Tumors located on the trunk were equally likely to be left or right sided, but tumors on the head and neck were 3.2-fold more likely to be on the left side. Merkel cell carcinomas arising on the forearm or hand were fourfold more likely to occur on the left than the right side. On the leg and foot, the left-sided excess was 2.4-fold. Tumors located on the face were 1.5-fold more likely to occur on the left side.

These Finnish data confirm an earlier U.S. study involving a much larger patient population: 2,384 individuals with Merkel cell carcinoma included the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) database, Dr. Kluger noted. In the U.S. study, 52.7% of the cancers occurred on the left side. On the arm it was 55%, while on the face it was 52%, but there was no difference in lateral distribution of the tumors on the legs (J. Am. Acad. Dermatol. 2011;65:35-9).

The same large U.S. study also showed an excess of left-sidedness in the distribution of melanomas among 82,587 affected patients in the SEER registry.

Since ultraviolet light exposure figures in the pathogenesis of both of these serious skin cancers, one leading theory regarding the explanation for the left-sided predominance of Merkel cell carcinoma and melanoma involves increased driver-side UV exposure while operating motor vehicles. Dr. Kluger finds this explanation unlikely. Although steering wheels are placed on the left side of vehicles in Finland, as in the United States, left-side predominance of these skin cancers also has been reported in countries such as Scotland, where drivers stick to the left side of the road and the steering wheel is on the right, he noted.

In Finland, there was a significant excess of Merkel cell carcinomas on the left side in nearly every year of the 20-year study. That means if the skewed lateral distribution of the tumors is due to some as-yet-unidentified environmental factor, it’s a factor that hasn’t changed in 20 years, Dr. Kluger observed.

"For now it’s an interesting curiosity," he commented.

Both Dr. Kluger and Dr. Samimi reported having no financial conflicts.

PRAGUE – Add Merkel cell carcinoma to the seemingly ever-growing list of malignancies linked to vitamin D deficiency.

A multicenter French study involving 89 patients with histologically confirmed Merkel cell carcinoma indicates that individuals with this rare and often aggressive neuroendocrine skin malignancy have an increased prevalence of vitamin D deficiency. Moreover, the vitamin D–deficient subgroup had a greater mean tumor size at diagnosis and sharply worse outcomes, Dr. Mahtab Samimi reported at the annual congress of the European Academy of Dermatology and Venereology.

© Kaspri/Fotolia.com

Fifty-eight of the 89 (65%) Merkel cell carcinoma patients were vitamin D deficient as defined by a serum level below 50 nmol/L. During follow-up, 33 patients developed nodal and/or distant metastases and 19 died of Merkel cell carcinoma. The 4-year Merkel cell carcinoma–free survival rate was 40% in the vitamin D deficient group and more than 90% in patients with normal-range vitamin D. The metastasis-free survival rate at 4 years was 20% in vitamin D–deficient patients and 70% in those without serum vitamin D deficiency.

In a multivariate regression analysis, low vitamin D was independently associated with an adjusted 2.89-fold increased risk of developing nodal and/or distant metastases and a 5.28-fold increased risk for death from their malignancy, reported Dr. Samimi of Francois Rabelais University in Tours, France.

The multivariate analysis was adjusted for age, gender, immune status, tumor location, time of year of the serum vitamin D measurement, and Merkel cell polyomavirus DNA levels.

It’s biologically plausible that a patient’s vitamin D status influences Merkel cell carcinoma behavior, according to Dr. Samimi. She and her coworkers analyzed 19 primary tumor specimens and 9 nodal metastases and found every single one strongly expressed the vitamin D receptor.

"The active metabolites of vitamin D bind to the vitamin D receptor, which is able to regulate genes involved in cell cycle control and others that have anti-inflammatory effects," the dermatologist explained.

Other investigators have shown that melanoma, too, is affected by a patient’s vitamin D status. Vitamin D deficiency is associated with thicker melanomas at diagnosis and reduced survival, she noted.

Dr. Samimi stressed that the newly shown association that she and her coworkers have found between vitamin D deficiency and worse-prognosis Merkel cell carcinoma must be considered hypothesis-generating rather than proof of causality. Serum vitamin D wasn’t measured until an average of 3 months after cancer diagnosis.

Asked by the audience if she screens her patients with Merkel cell carcinoma or melanoma for vitamin D deficiency, Dr. Samimi replied affirmatively. And if they’re deficient, as is so often the case, she puts them on vitamin D supplementation.

"The protective role of doing this in terms of cancer prognosis is not proven, but at the very least the supplementation has beneficial effects on skeletal and muscle health, so it’s a good thing," she said.

In a separate study, Dr. Nicolas Kluger of the University of Helsinki presented national Finnish data showing a predisposition of Merkel cell carcinoma for the left side of affected patients.

The comprehensive Finnish Cancer Registry is thought to have captured all 177 Finns diagnosed with Merkel cell carcinoma in a recent 20-year period. Fifty-six percent of the tumors were on the left, 37% on the right, and 7% occurred on the midline.

Tumors located on the trunk were equally likely to be left or right sided, but tumors on the head and neck were 3.2-fold more likely to be on the left side. Merkel cell carcinomas arising on the forearm or hand were fourfold more likely to occur on the left than the right side. On the leg and foot, the left-sided excess was 2.4-fold. Tumors located on the face were 1.5-fold more likely to occur on the left side.

These Finnish data confirm an earlier U.S. study involving a much larger patient population: 2,384 individuals with Merkel cell carcinoma included the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) database, Dr. Kluger noted. In the U.S. study, 52.7% of the cancers occurred on the left side. On the arm it was 55%, while on the face it was 52%, but there was no difference in lateral distribution of the tumors on the legs (J. Am. Acad. Dermatol. 2011;65:35-9).

The same large U.S. study also showed an excess of left-sidedness in the distribution of melanomas among 82,587 affected patients in the SEER registry.

Since ultraviolet light exposure figures in the pathogenesis of both of these serious skin cancers, one leading theory regarding the explanation for the left-sided predominance of Merkel cell carcinoma and melanoma involves increased driver-side UV exposure while operating motor vehicles. Dr. Kluger finds this explanation unlikely. Although steering wheels are placed on the left side of vehicles in Finland, as in the United States, left-side predominance of these skin cancers also has been reported in countries such as Scotland, where drivers stick to the left side of the road and the steering wheel is on the right, he noted.

In Finland, there was a significant excess of Merkel cell carcinomas on the left side in nearly every year of the 20-year study. That means if the skewed lateral distribution of the tumors is due to some as-yet-unidentified environmental factor, it’s a factor that hasn’t changed in 20 years, Dr. Kluger observed.

"For now it’s an interesting curiosity," he commented.

Both Dr. Kluger and Dr. Samimi reported having no financial conflicts.

LONDON – More than two-thirds of patients with medically refractory chronic cluster headache responded to on-demand, self-administered sphenopalatine ganglion stimulation with acute pain relief, less frequent attacks, or both.

The prophylactic effect – a reduction in cluster attack frequency, but in most cases without acute pain relief – came as a surprise to investigators in the prospective, controlled, multinational Pathway CH-1 study, Dr. Jean Schoenen admitted at the European Headache and Migraine Trust International Congress.

"This was the largest, most rigorous study to date of an implantable medical device for headache treatment. The study was not designed to look at attack frequency; it was designed to look at acute response. Yet, we have this preventive effect that I think now has to be confirmed in another well-designed trial," said Dr. Schoenen, coordinator of the headache research unit at the University of Liege (Belgium).

For more than 100 years, the sphenopalatine ganglion (SPG) has been thought to be a key mediator of the cranial autonomic symptoms and unilateral periorbital pain that define cluster headaches. In the Pathway CH-1 study, Dr. Schoenen and coinvestigators evaluated the efficacy and safety of a miniature electrical neurostimulator implanted in the pterygopalatine fossa near the SPG. The neurostimulator is activated by a hand-held remote controller the patients hold up to their face for on-demand therapy.

A neurosurgeon implants the SPG neurostimulator via a minimally invasive procedure using a transoral, gingival buccal technique that leaves no externally visible scars.

Dr. Schoenen reported on 28 chronic cluster headache patients who were dissatisfied with their current treatment and opted to participate in the trial. They underwent neurostimulator implantation, followed by a minimum 3-week postsurgical stabilization period during which the device remained switched off. During the subsequent controlled experimental phase, they each self-treated a minimum of 30 attacks over a 3- to 8-week period. Once the device was fired up, it couldn’t be employed again for 90 minutes. The remote controller was programmed to randomly deliver full stimulation, subthreshold stimulation, or sham treatment.

Overall, 7of the 28 patients, or 25%, were categorized as acute responders, meaning that full stimulation achieved marked pain relief within 15 minutes with no acute medication in more than half of treated attacks. Another 10 patients (36%) were "frequency responders" who experienced at least a 50% reduction in cluster attack frequency, compared with baseline with no change in preventive medications and with nonacute pain relief. Two patients (7%) were both acute and frequency responders. A total of 32% were nonresponders.

Frequency responders didn’t start experiencing fewer cluster attacks until after the weeks of postsurgical stabilization ended and neurostimulation began. This makes it highly unlikely that the prophylactic effect was somehow due to the surgery itself, according to the neurologist.

Significant pain relief was documented 15 minutes after full stimulation in 67% of treated attacks, half of which involved pain freedom. In contrast, significant pain relief occurred in only 7% of attacks that were addressed with subthreshold stimulation or sham treatment.

Sixty-four percent of subjects showed clinically meaningful and statistically significant reductions in headache disability as indicated by improved scores on the Headache Impact Test-6. Quality of life improved in 75%, as reflected by their scores on the Short Form-36 physical and/or mental component summary scores, Dr. Schoenen continued.

Acute medications were used within 90 minutes of 31% of cluster attacks treated with full stimulation, compared with 78% of those addressed using subthreshold stimulation and 77% that got sham therapy.

Far and away, the most common adverse event involved mild-to-moderate sensory disturbances in the maxillary division of the trigeminal nerve, experienced by 81% of subjects. These symptoms resolved within 3 months. Two patients experienced infections. Two others required device explantation due to lead migration.

The ongoing Pathway CH-1 study will continue on an open-label basis for 1 year post-implantation.

The device, known as the ATI Neurostimulation System, is MRI compatible. It has been approved for marketing by the European regulatory authorities. The manufacturer, Autonomic Technologies of Redwood City, Calif., will also seek Food and Drug Administration approval.

In addition, the company has launched the multicenter, controlled European Pathway M-1 trial in which SPG neurostimulation is being evaluated for the treatment of disabling migraine.

Dr. Rigmor H. Jensen, president of the European Headache Federation, commented that an invasive device such as this will likely be reserved for those few cluster headache patients who are completely refractory to all medications. That’s probably 1%-3% of the cluster headache population, estimated Dr. Jensen, research professor of neurology at the University of Copenhagen.

Dr. Schoenen is a consultant to Autonomic Technologies, which is funding the Pathway CH-1 study.

LONDON – More than two-thirds of patients with medically refractory chronic cluster headache responded to on-demand, self-administered sphenopalatine ganglion stimulation with acute pain relief, less frequent attacks, or both.

The prophylactic effect – a reduction in cluster attack frequency, but in most cases without acute pain relief – came as a surprise to investigators in the prospective, controlled, multinational Pathway CH-1 study, Dr. Jean Schoenen admitted at the European Headache and Migraine Trust International Congress.

"This was the largest, most rigorous study to date of an implantable medical device for headache treatment. The study was not designed to look at attack frequency; it was designed to look at acute response. Yet, we have this preventive effect that I think now has to be confirmed in another well-designed trial," said Dr. Schoenen, coordinator of the headache research unit at the University of Liege (Belgium).

For more than 100 years, the sphenopalatine ganglion (SPG) has been thought to be a key mediator of the cranial autonomic symptoms and unilateral periorbital pain that define cluster headaches. In the Pathway CH-1 study, Dr. Schoenen and coinvestigators evaluated the efficacy and safety of a miniature electrical neurostimulator implanted in the pterygopalatine fossa near the SPG. The neurostimulator is activated by a hand-held remote controller the patients hold up to their face for on-demand therapy.

A neurosurgeon implants the SPG neurostimulator via a minimally invasive procedure using a transoral, gingival buccal technique that leaves no externally visible scars.

Dr. Schoenen reported on 28 chronic cluster headache patients who were dissatisfied with their current treatment and opted to participate in the trial. They underwent neurostimulator implantation, followed by a minimum 3-week postsurgical stabilization period during which the device remained switched off. During the subsequent controlled experimental phase, they each self-treated a minimum of 30 attacks over a 3- to 8-week period. Once the device was fired up, it couldn’t be employed again for 90 minutes. The remote controller was programmed to randomly deliver full stimulation, subthreshold stimulation, or sham treatment.

Overall, 7of the 28 patients, or 25%, were categorized as acute responders, meaning that full stimulation achieved marked pain relief within 15 minutes with no acute medication in more than half of treated attacks. Another 10 patients (36%) were "frequency responders" who experienced at least a 50% reduction in cluster attack frequency, compared with baseline with no change in preventive medications and with nonacute pain relief. Two patients (7%) were both acute and frequency responders. A total of 32% were nonresponders.

Frequency responders didn’t start experiencing fewer cluster attacks until after the weeks of postsurgical stabilization ended and neurostimulation began. This makes it highly unlikely that the prophylactic effect was somehow due to the surgery itself, according to the neurologist.

Significant pain relief was documented 15 minutes after full stimulation in 67% of treated attacks, half of which involved pain freedom. In contrast, significant pain relief occurred in only 7% of attacks that were addressed with subthreshold stimulation or sham treatment.

Sixty-four percent of subjects showed clinically meaningful and statistically significant reductions in headache disability as indicated by improved scores on the Headache Impact Test-6. Quality of life improved in 75%, as reflected by their scores on the Short Form-36 physical and/or mental component summary scores, Dr. Schoenen continued.

Acute medications were used within 90 minutes of 31% of cluster attacks treated with full stimulation, compared with 78% of those addressed using subthreshold stimulation and 77% that got sham therapy.

Far and away, the most common adverse event involved mild-to-moderate sensory disturbances in the maxillary division of the trigeminal nerve, experienced by 81% of subjects. These symptoms resolved within 3 months. Two patients experienced infections. Two others required device explantation due to lead migration.

The ongoing Pathway CH-1 study will continue on an open-label basis for 1 year post-implantation.

The device, known as the ATI Neurostimulation System, is MRI compatible. It has been approved for marketing by the European regulatory authorities. The manufacturer, Autonomic Technologies of Redwood City, Calif., will also seek Food and Drug Administration approval.

In addition, the company has launched the multicenter, controlled European Pathway M-1 trial in which SPG neurostimulation is being evaluated for the treatment of disabling migraine.

Dr. Rigmor H. Jensen, president of the European Headache Federation, commented that an invasive device such as this will likely be reserved for those few cluster headache patients who are completely refractory to all medications. That’s probably 1%-3% of the cluster headache population, estimated Dr. Jensen, research professor of neurology at the University of Copenhagen.

Dr. Schoenen is a consultant to Autonomic Technologies, which is funding the Pathway CH-1 study.

LONDON – More than two-thirds of patients with medically refractory chronic cluster headache responded to on-demand, self-administered sphenopalatine ganglion stimulation with acute pain relief, less frequent attacks, or both.

The prophylactic effect – a reduction in cluster attack frequency, but in most cases without acute pain relief – came as a surprise to investigators in the prospective, controlled, multinational Pathway CH-1 study, Dr. Jean Schoenen admitted at the European Headache and Migraine Trust International Congress.

"This was the largest, most rigorous study to date of an implantable medical device for headache treatment. The study was not designed to look at attack frequency; it was designed to look at acute response. Yet, we have this preventive effect that I think now has to be confirmed in another well-designed trial," said Dr. Schoenen, coordinator of the headache research unit at the University of Liege (Belgium).

For more than 100 years, the sphenopalatine ganglion (SPG) has been thought to be a key mediator of the cranial autonomic symptoms and unilateral periorbital pain that define cluster headaches. In the Pathway CH-1 study, Dr. Schoenen and coinvestigators evaluated the efficacy and safety of a miniature electrical neurostimulator implanted in the pterygopalatine fossa near the SPG. The neurostimulator is activated by a hand-held remote controller the patients hold up to their face for on-demand therapy.

A neurosurgeon implants the SPG neurostimulator via a minimally invasive procedure using a transoral, gingival buccal technique that leaves no externally visible scars.

Dr. Schoenen reported on 28 chronic cluster headache patients who were dissatisfied with their current treatment and opted to participate in the trial. They underwent neurostimulator implantation, followed by a minimum 3-week postsurgical stabilization period during which the device remained switched off. During the subsequent controlled experimental phase, they each self-treated a minimum of 30 attacks over a 3- to 8-week period. Once the device was fired up, it couldn’t be employed again for 90 minutes. The remote controller was programmed to randomly deliver full stimulation, subthreshold stimulation, or sham treatment.

Overall, 7of the 28 patients, or 25%, were categorized as acute responders, meaning that full stimulation achieved marked pain relief within 15 minutes with no acute medication in more than half of treated attacks. Another 10 patients (36%) were "frequency responders" who experienced at least a 50% reduction in cluster attack frequency, compared with baseline with no change in preventive medications and with nonacute pain relief. Two patients (7%) were both acute and frequency responders. A total of 32% were nonresponders.

Frequency responders didn’t start experiencing fewer cluster attacks until after the weeks of postsurgical stabilization ended and neurostimulation began. This makes it highly unlikely that the prophylactic effect was somehow due to the surgery itself, according to the neurologist.

Significant pain relief was documented 15 minutes after full stimulation in 67% of treated attacks, half of which involved pain freedom. In contrast, significant pain relief occurred in only 7% of attacks that were addressed with subthreshold stimulation or sham treatment.

Sixty-four percent of subjects showed clinically meaningful and statistically significant reductions in headache disability as indicated by improved scores on the Headache Impact Test-6. Quality of life improved in 75%, as reflected by their scores on the Short Form-36 physical and/or mental component summary scores, Dr. Schoenen continued.

Acute medications were used within 90 minutes of 31% of cluster attacks treated with full stimulation, compared with 78% of those addressed using subthreshold stimulation and 77% that got sham therapy.

Far and away, the most common adverse event involved mild-to-moderate sensory disturbances in the maxillary division of the trigeminal nerve, experienced by 81% of subjects. These symptoms resolved within 3 months. Two patients experienced infections. Two others required device explantation due to lead migration.

The ongoing Pathway CH-1 study will continue on an open-label basis for 1 year post-implantation.

The device, known as the ATI Neurostimulation System, is MRI compatible. It has been approved for marketing by the European regulatory authorities. The manufacturer, Autonomic Technologies of Redwood City, Calif., will also seek Food and Drug Administration approval.

In addition, the company has launched the multicenter, controlled European Pathway M-1 trial in which SPG neurostimulation is being evaluated for the treatment of disabling migraine.

Dr. Rigmor H. Jensen, president of the European Headache Federation, commented that an invasive device such as this will likely be reserved for those few cluster headache patients who are completely refractory to all medications. That’s probably 1%-3% of the cluster headache population, estimated Dr. Jensen, research professor of neurology at the University of Copenhagen.

Dr. Schoenen is a consultant to Autonomic Technologies, which is funding the Pathway CH-1 study.

LOS ANGELES – Patients with diabetes who had revascularization for multivessel coronary artery disease fared significantly better with coronary artery bypass grafting than with percutaneous coronary intervention using drug-eluting stents in the landmark FREEDOM trial.

FREEDOM (Future Revascularization Evaluation in Patients With Diabetes Mellitus: Optimal Management of Multivessel Disease) was an international randomized trial involving 1,900 subjects who were considered candidates for both CABG and PCI. The primary outcome – a composite of 5-year all-cause mortality and nonfatal MI or stroke – occurred in 26.6% of the PCI group, compared with 18.7% of the CABG group. That’s a 7.9% absolute reduction and 30% lower relative risk. The CABG advantage held up regardless of SYNTAX score, a measure of disease extent.

Bruce Jancin/IMNG Medical Media

"The results are clear. I think this is going to change practice," FREEDOM chair Dr. Valentin Fuster predicted in presenting the study’s main findings at the conference.

Participants in the CABG group had a 5-year mortality of 10.9%, compared with 16.3% in the PCI group. Their nonfatal MI rate was less than half of that in the PCI group: 6.0% vs. 13.9%.

The CABG group’s 5.2% nonfatal stroke rate was significantly higher than the 2.4% rate in the PCI group. However, the excess of strokes in the CABG group was confined to the first 30 days post procedure; after that, stroke rates in the two groups didn’t differ significantly. Only 13% of strokes were hemorrhagic. The majority of strokes occurred more than 1 year post procedure, according to Dr. Fuster, professor of medicine and director of the cardiovascular institute at Mount Sinai Medical Center, New York.

The repeat revascularization rate after 1 year of follow-up was 13% in the PCI group and 5% in CABG-treated patients. At 5 years, repeat revascularization had occurred in 30% of the PCI group, compared with 13% in the CABG group.

Thirteen percent of FREEDOM participants had two-vessel disease, and the rest had triple-vessel disease. Outcomes in both groups were superior with CABG.

The CABG and PCI groups didn’t differ significantly in 30-day rates of major bleeding or acute renal failure.

Seventeen years ago, the National Heart, Lung, and Blood Institute issued a clinical alert recommending CABG over PCI for patients with diabetes on the strength of the results of BARI, the Bypass Angioplasty Revascularization Investigation (N. Engl. J. Med. 1996;335:217-25) Yet, PCI has since become increasingly popular in diabetes patients.

Many interventional cardiologists have dismissed the results of BARI and other smaller studies favoring CABG as irrelevant in the contemporary era of much-improved PCI techniques and drug-eluting stents, even though the current joint AHA/American College of Cardiology/Society for Coronary Angiography and Interventions guidelines state as a class IIa recommendation that "it is reasonable" to choose CABG with left internal mammary artery grafting over PCI in diabetic patients with multivessel disease.

FREEDOM discussant and interventional cardiologist Dr. David O. Williams said that this new study should put an end to the controversy. He predicted the guidelines will be revised to raise CABG from a class IIa recommendation to class I.

"The study is very convincing, and I think the guidelines will eventually come down very strongly on this. And so will payers, by the way – and that’s another group that can exert influence," observed Dr. Williams of Brigham and Women’s Hospital, Boston.

Another discussant, Dr. Alice K. Jacobs, also an interventional cardiologist, said she was impressed by the FREEDOM finding that CABG was superior in all patient subgroups, even in patients with normal left ventricular function.

"Certainly it has been the case that if you had reduced left ventricular function, the needle would swing toward CABG, but now even with normal left ventricular function, patients fare better. That needs to be recognized," said Dr. Jacobs, professor of medicine at Boston University.

"With a diabetic patient who is a candidate for either procedure, one would have to think long and hard about performing PCI at this point," she added.

Interventional cardiologist Dr. Gilles Montalescot of Pitie-Salpétrière University Hospital, Paris, found the demonstrated mortality benefit for CABG in FREEDOM compelling.

"This signal cannot be ignored. There has been some reluctance on the part of interventional cardiologists to send patients who have diabetes to the [operating room] for CABG. We should use these FREEDOM data to convince our colleagues that the way to go is to send our patients for surgery, whatever their SYNTAX score. But I think often the patients, too, have been reluctant to go to the OR," he said.

Dr. Fuster agreed, adding that a key implication of FREEDOM is that when a diabetic patient is scheduled for coronary angiography, a conversation about the study findings needs to occur before the trip to the catheterization laboratory. That way the patient understands in advance that if multivessel disease is found, strong consideration needs to be given to CABG.

Courtesy of Dr. Gilles Montalescot

"To me the crux of the trial is to tell the patient early," Dr. Fuster said.

Persons with diabetes comprise roughly 25% of the nearly 1 million patients who undergo multivessel coronary revascularization each year in the United States.

Simultaneous with Dr. Fuster’s presentation at the AHA meeting, the FREEDOM results were published online in the New England Journal of Medicine (doi:10.1056/NEJMoa1211585).

The FREEDOM trial was funded by the National Heart, Lung, and Blood Institute. Dr. Fuster said he had no relevant financial conflicts. The discussants have received research grants from medical device manufacturers.

LOS ANGELES – Patients with diabetes who had revascularization for multivessel coronary artery disease fared significantly better with coronary artery bypass grafting than with percutaneous coronary intervention using drug-eluting stents in the landmark FREEDOM trial.

FREEDOM (Future Revascularization Evaluation in Patients With Diabetes Mellitus: Optimal Management of Multivessel Disease) was an international randomized trial involving 1,900 subjects who were considered candidates for both CABG and PCI. The primary outcome – a composite of 5-year all-cause mortality and nonfatal MI or stroke – occurred in 26.6% of the PCI group, compared with 18.7% of the CABG group. That’s a 7.9% absolute reduction and 30% lower relative risk. The CABG advantage held up regardless of SYNTAX score, a measure of disease extent.

Bruce Jancin/IMNG Medical Media

"The results are clear. I think this is going to change practice," FREEDOM chair Dr. Valentin Fuster predicted in presenting the study’s main findings at the conference.

Participants in the CABG group had a 5-year mortality of 10.9%, compared with 16.3% in the PCI group. Their nonfatal MI rate was less than half of that in the PCI group: 6.0% vs. 13.9%.

The CABG group’s 5.2% nonfatal stroke rate was significantly higher than the 2.4% rate in the PCI group. However, the excess of strokes in the CABG group was confined to the first 30 days post procedure; after that, stroke rates in the two groups didn’t differ significantly. Only 13% of strokes were hemorrhagic. The majority of strokes occurred more than 1 year post procedure, according to Dr. Fuster, professor of medicine and director of the cardiovascular institute at Mount Sinai Medical Center, New York.

The repeat revascularization rate after 1 year of follow-up was 13% in the PCI group and 5% in CABG-treated patients. At 5 years, repeat revascularization had occurred in 30% of the PCI group, compared with 13% in the CABG group.

Thirteen percent of FREEDOM participants had two-vessel disease, and the rest had triple-vessel disease. Outcomes in both groups were superior with CABG.

The CABG and PCI groups didn’t differ significantly in 30-day rates of major bleeding or acute renal failure.

Seventeen years ago, the National Heart, Lung, and Blood Institute issued a clinical alert recommending CABG over PCI for patients with diabetes on the strength of the results of BARI, the Bypass Angioplasty Revascularization Investigation (N. Engl. J. Med. 1996;335:217-25) Yet, PCI has since become increasingly popular in diabetes patients.

Many interventional cardiologists have dismissed the results of BARI and other smaller studies favoring CABG as irrelevant in the contemporary era of much-improved PCI techniques and drug-eluting stents, even though the current joint AHA/American College of Cardiology/Society for Coronary Angiography and Interventions guidelines state as a class IIa recommendation that "it is reasonable" to choose CABG with left internal mammary artery grafting over PCI in diabetic patients with multivessel disease.

FREEDOM discussant and interventional cardiologist Dr. David O. Williams said that this new study should put an end to the controversy. He predicted the guidelines will be revised to raise CABG from a class IIa recommendation to class I.

"The study is very convincing, and I think the guidelines will eventually come down very strongly on this. And so will payers, by the way – and that’s another group that can exert influence," observed Dr. Williams of Brigham and Women’s Hospital, Boston.

Another discussant, Dr. Alice K. Jacobs, also an interventional cardiologist, said she was impressed by the FREEDOM finding that CABG was superior in all patient subgroups, even in patients with normal left ventricular function.

"Certainly it has been the case that if you had reduced left ventricular function, the needle would swing toward CABG, but now even with normal left ventricular function, patients fare better. That needs to be recognized," said Dr. Jacobs, professor of medicine at Boston University.

"With a diabetic patient who is a candidate for either procedure, one would have to think long and hard about performing PCI at this point," she added.

Interventional cardiologist Dr. Gilles Montalescot of Pitie-Salpétrière University Hospital, Paris, found the demonstrated mortality benefit for CABG in FREEDOM compelling.

"This signal cannot be ignored. There has been some reluctance on the part of interventional cardiologists to send patients who have diabetes to the [operating room] for CABG. We should use these FREEDOM data to convince our colleagues that the way to go is to send our patients for surgery, whatever their SYNTAX score. But I think often the patients, too, have been reluctant to go to the OR," he said.

Dr. Fuster agreed, adding that a key implication of FREEDOM is that when a diabetic patient is scheduled for coronary angiography, a conversation about the study findings needs to occur before the trip to the catheterization laboratory. That way the patient understands in advance that if multivessel disease is found, strong consideration needs to be given to CABG.

Courtesy of Dr. Gilles Montalescot

"To me the crux of the trial is to tell the patient early," Dr. Fuster said.

Persons with diabetes comprise roughly 25% of the nearly 1 million patients who undergo multivessel coronary revascularization each year in the United States.

Simultaneous with Dr. Fuster’s presentation at the AHA meeting, the FREEDOM results were published online in the New England Journal of Medicine (doi:10.1056/NEJMoa1211585).

The FREEDOM trial was funded by the National Heart, Lung, and Blood Institute. Dr. Fuster said he had no relevant financial conflicts. The discussants have received research grants from medical device manufacturers.

LOS ANGELES – Patients with diabetes who had revascularization for multivessel coronary artery disease fared significantly better with coronary artery bypass grafting than with percutaneous coronary intervention using drug-eluting stents in the landmark FREEDOM trial.

FREEDOM (Future Revascularization Evaluation in Patients With Diabetes Mellitus: Optimal Management of Multivessel Disease) was an international randomized trial involving 1,900 subjects who were considered candidates for both CABG and PCI. The primary outcome – a composite of 5-year all-cause mortality and nonfatal MI or stroke – occurred in 26.6% of the PCI group, compared with 18.7% of the CABG group. That’s a 7.9% absolute reduction and 30% lower relative risk. The CABG advantage held up regardless of SYNTAX score, a measure of disease extent.

Bruce Jancin/IMNG Medical Media

"The results are clear. I think this is going to change practice," FREEDOM chair Dr. Valentin Fuster predicted in presenting the study’s main findings at the conference.

Participants in the CABG group had a 5-year mortality of 10.9%, compared with 16.3% in the PCI group. Their nonfatal MI rate was less than half of that in the PCI group: 6.0% vs. 13.9%.

The CABG group’s 5.2% nonfatal stroke rate was significantly higher than the 2.4% rate in the PCI group. However, the excess of strokes in the CABG group was confined to the first 30 days post procedure; after that, stroke rates in the two groups didn’t differ significantly. Only 13% of strokes were hemorrhagic. The majority of strokes occurred more than 1 year post procedure, according to Dr. Fuster, professor of medicine and director of the cardiovascular institute at Mount Sinai Medical Center, New York.

The repeat revascularization rate after 1 year of follow-up was 13% in the PCI group and 5% in CABG-treated patients. At 5 years, repeat revascularization had occurred in 30% of the PCI group, compared with 13% in the CABG group.

Thirteen percent of FREEDOM participants had two-vessel disease, and the rest had triple-vessel disease. Outcomes in both groups were superior with CABG.

The CABG and PCI groups didn’t differ significantly in 30-day rates of major bleeding or acute renal failure.

Seventeen years ago, the National Heart, Lung, and Blood Institute issued a clinical alert recommending CABG over PCI for patients with diabetes on the strength of the results of BARI, the Bypass Angioplasty Revascularization Investigation (N. Engl. J. Med. 1996;335:217-25) Yet, PCI has since become increasingly popular in diabetes patients.

Many interventional cardiologists have dismissed the results of BARI and other smaller studies favoring CABG as irrelevant in the contemporary era of much-improved PCI techniques and drug-eluting stents, even though the current joint AHA/American College of Cardiology/Society for Coronary Angiography and Interventions guidelines state as a class IIa recommendation that "it is reasonable" to choose CABG with left internal mammary artery grafting over PCI in diabetic patients with multivessel disease.

FREEDOM discussant and interventional cardiologist Dr. David O. Williams said that this new study should put an end to the controversy. He predicted the guidelines will be revised to raise CABG from a class IIa recommendation to class I.

"The study is very convincing, and I think the guidelines will eventually come down very strongly on this. And so will payers, by the way – and that’s another group that can exert influence," observed Dr. Williams of Brigham and Women’s Hospital, Boston.

Another discussant, Dr. Alice K. Jacobs, also an interventional cardiologist, said she was impressed by the FREEDOM finding that CABG was superior in all patient subgroups, even in patients with normal left ventricular function.

"Certainly it has been the case that if you had reduced left ventricular function, the needle would swing toward CABG, but now even with normal left ventricular function, patients fare better. That needs to be recognized," said Dr. Jacobs, professor of medicine at Boston University.

"With a diabetic patient who is a candidate for either procedure, one would have to think long and hard about performing PCI at this point," she added.

Interventional cardiologist Dr. Gilles Montalescot of Pitie-Salpétrière University Hospital, Paris, found the demonstrated mortality benefit for CABG in FREEDOM compelling.

"This signal cannot be ignored. There has been some reluctance on the part of interventional cardiologists to send patients who have diabetes to the [operating room] for CABG. We should use these FREEDOM data to convince our colleagues that the way to go is to send our patients for surgery, whatever their SYNTAX score. But I think often the patients, too, have been reluctant to go to the OR," he said.

Dr. Fuster agreed, adding that a key implication of FREEDOM is that when a diabetic patient is scheduled for coronary angiography, a conversation about the study findings needs to occur before the trip to the catheterization laboratory. That way the patient understands in advance that if multivessel disease is found, strong consideration needs to be given to CABG.

Courtesy of Dr. Gilles Montalescot

"To me the crux of the trial is to tell the patient early," Dr. Fuster said.

Persons with diabetes comprise roughly 25% of the nearly 1 million patients who undergo multivessel coronary revascularization each year in the United States.

Simultaneous with Dr. Fuster’s presentation at the AHA meeting, the FREEDOM results were published online in the New England Journal of Medicine (doi:10.1056/NEJMoa1211585).

The FREEDOM trial was funded by the National Heart, Lung, and Blood Institute. Dr. Fuster said he had no relevant financial conflicts. The discussants have received research grants from medical device manufacturers.

LOS ANGELES – Coronary artery bypass graft surgery not only provides better clinical outcomes than percutaneous coronary intervention in diabetic patients with multivessel disease, but it does so in a highly cost-effective manner, according to an economic analysis of the FREEDOM trial.

"The benefits are achieved at an overall cost that represents an attractive use of societal health care resources," Elizabeth A. Magnuson, Sc.D., said at the annual scientific sessions of the American Heart Association.

FREEDOM was a randomized international trial that compared the effectiveness of CABG with percutaneous coronary intervention (PCI) using drug-eluting stents in 1,900 diabetic patients with multivessel coronary artery disease who were candidates for both procedures.

The initial hospitalization for revascularization cost an average of $34,467 in the CABG group, $8,622 more than for PCI-treated patients. But during the next 5 years of follow-up, both repeat revascularizations and mortality were significantly more common in the PCI group.

Based on a conservative model of projected survival that assumed a gradual attenuation of CABG’s clinical benefits over time, bypass surgery was associated with an incremental cost-effectiveness ratio of $8,132 per quality-adjusted year of life (QALY) gained. That’s well below the figure of $50,000 per QALY widely accepted by health policy makers as defining the upper boundary of cost effectiveness, noted Dr. Magnuson, director of health economics and technology assessment at Saint Luke’s Mid-America Heart Institute, Kansas City, Mo.

"Even if we assume no further benefit beyond the trial period and we just captured the life-years lost due to the in-trial death events, we still get very favorable results for CABG, with an incremental cost-effectiveness ratio of roughly $27,000 per QALY," she said.

Discussant Dr. Mark A. Hlatky agreed with Dr. Magnuson that this was a very conservative analysis and said that the actual cost effectiveness of CABG in diabetes patients with multivessel disease might well be even more favorable than she projected.

"The cost-effectiveness results are quite good. This looks like a very economically attractive therapy for patients who have diabetes with multivessel disease," concluded Dr. Hlatky, professor of health research and policy and of cardiovascular medicine at Stanford (Calif.) University.

The study was funded by the National Heart, Lung, and Blood Institute. Dr. Magnuson and Dr. Hlatky reported having no relevant financial conflicts.

LOS ANGELES – Coronary artery bypass graft surgery not only provides better clinical outcomes than percutaneous coronary intervention in diabetic patients with multivessel disease, but it does so in a highly cost-effective manner, according to an economic analysis of the FREEDOM trial.

"The benefits are achieved at an overall cost that represents an attractive use of societal health care resources," Elizabeth A. Magnuson, Sc.D., said at the annual scientific sessions of the American Heart Association.

FREEDOM was a randomized international trial that compared the effectiveness of CABG with percutaneous coronary intervention (PCI) using drug-eluting stents in 1,900 diabetic patients with multivessel coronary artery disease who were candidates for both procedures.

The initial hospitalization for revascularization cost an average of $34,467 in the CABG group, $8,622 more than for PCI-treated patients. But during the next 5 years of follow-up, both repeat revascularizations and mortality were significantly more common in the PCI group.

Based on a conservative model of projected survival that assumed a gradual attenuation of CABG’s clinical benefits over time, bypass surgery was associated with an incremental cost-effectiveness ratio of $8,132 per quality-adjusted year of life (QALY) gained. That’s well below the figure of $50,000 per QALY widely accepted by health policy makers as defining the upper boundary of cost effectiveness, noted Dr. Magnuson, director of health economics and technology assessment at Saint Luke’s Mid-America Heart Institute, Kansas City, Mo.

"Even if we assume no further benefit beyond the trial period and we just captured the life-years lost due to the in-trial death events, we still get very favorable results for CABG, with an incremental cost-effectiveness ratio of roughly $27,000 per QALY," she said.

Discussant Dr. Mark A. Hlatky agreed with Dr. Magnuson that this was a very conservative analysis and said that the actual cost effectiveness of CABG in diabetes patients with multivessel disease might well be even more favorable than she projected.

"The cost-effectiveness results are quite good. This looks like a very economically attractive therapy for patients who have diabetes with multivessel disease," concluded Dr. Hlatky, professor of health research and policy and of cardiovascular medicine at Stanford (Calif.) University.

The study was funded by the National Heart, Lung, and Blood Institute. Dr. Magnuson and Dr. Hlatky reported having no relevant financial conflicts.

LOS ANGELES – Coronary artery bypass graft surgery not only provides better clinical outcomes than percutaneous coronary intervention in diabetic patients with multivessel disease, but it does so in a highly cost-effective manner, according to an economic analysis of the FREEDOM trial.

"The benefits are achieved at an overall cost that represents an attractive use of societal health care resources," Elizabeth A. Magnuson, Sc.D., said at the annual scientific sessions of the American Heart Association.

FREEDOM was a randomized international trial that compared the effectiveness of CABG with percutaneous coronary intervention (PCI) using drug-eluting stents in 1,900 diabetic patients with multivessel coronary artery disease who were candidates for both procedures.

The initial hospitalization for revascularization cost an average of $34,467 in the CABG group, $8,622 more than for PCI-treated patients. But during the next 5 years of follow-up, both repeat revascularizations and mortality were significantly more common in the PCI group.

Based on a conservative model of projected survival that assumed a gradual attenuation of CABG’s clinical benefits over time, bypass surgery was associated with an incremental cost-effectiveness ratio of $8,132 per quality-adjusted year of life (QALY) gained. That’s well below the figure of $50,000 per QALY widely accepted by health policy makers as defining the upper boundary of cost effectiveness, noted Dr. Magnuson, director of health economics and technology assessment at Saint Luke’s Mid-America Heart Institute, Kansas City, Mo.

"Even if we assume no further benefit beyond the trial period and we just captured the life-years lost due to the in-trial death events, we still get very favorable results for CABG, with an incremental cost-effectiveness ratio of roughly $27,000 per QALY," she said.

Discussant Dr. Mark A. Hlatky agreed with Dr. Magnuson that this was a very conservative analysis and said that the actual cost effectiveness of CABG in diabetes patients with multivessel disease might well be even more favorable than she projected.

"The cost-effectiveness results are quite good. This looks like a very economically attractive therapy for patients who have diabetes with multivessel disease," concluded Dr. Hlatky, professor of health research and policy and of cardiovascular medicine at Stanford (Calif.) University.

The study was funded by the National Heart, Lung, and Blood Institute. Dr. Magnuson and Dr. Hlatky reported having no relevant financial conflicts.

DENVER – Look for some big changes ahead in the forthcoming update of the Surviving Sepsis Campaign international guidelines.

In the 4 years since the last version of the guidelines came out, major studies have been released that resolved hot debates regarding sepsis management and in some cases overturned established dogma. At the annual American College of Emergency Physicians (ACEP) meeting, emergency physicians deeply involved in crafting the Surviving Sepsis Campaign 2012 guidelines provided a preview of what’s to come.

Among the areas that will see key new recommendations are antibiotic therapy, fluid resuscitation, vasopressors, and lactate monitoring.

• Antibiotics ASAP. The critical importance of getting empiric antibiotics on board within 6 hours after recognizing that a patient has sepsis has been effectively hammered home over the years. But how fast is fast enough? Several recent small studies have reached conflicting conclusions. Now, however, an 800-lb gorilla of a study has provided a definitive answer.

This study, now in press, involved 14,895 patients enrolled in the Surviving Sepsis Campaign’s worldwide database. All had severe sepsis or septic shock, and all received antibiotics within the first 6 hours, explained Dr. Tiffany M. Osborn, a coauthor of the study and of the forthcoming guidelines.

"This was a big question for us. The results strengthen the importance of getting antibiotics started as soon as possible – within the first hour if possible. We found there’s about a 4% increase in mortality for every hour delay. And it’s cumulative: it’s 4% after the first hour, 8% after the second, 12% after the third, and so on," according to Dr. Osborn of Washington University at St. Louis.

A similar time-dependent increase in mortality was observed in patients with severe sepsis as well as in those in septic shock, she added.

• Fluid resuscitation. The initial fluid of choice for resuscitation in severe sepsis and septic shock remains crystalloids, as before. That’s a grade 1A recommendation. What’s brand new is a recommendation to consider adding albumin in the initial fluid resuscitation (grade 2B). This guidance was heavily influenced by a meta-analysis of 17 studies involving close to 2,000 patients that demonstrated a significant protective effect for the use of albumin as an initial resuscitation fluid (Crit. Care Med. 2011;39:386-91).

At this late date, Dr. Osborn said, the guideline panel is strongly leaning toward a recommendation against the use of low-molecular-weight colloids or starches such as hydroxyethyl starch 130/0.42. That would be ground shaking, as synthetic colloids or starches, particularly those of low molecular weight, are a very popular resuscitation fluid both in the United States and abroad. However, recent studies implicate these fluids in increased risks of 90-day mortality and renal failure, compared with the use of Ringer’s lactate.

"Having said this, there are two other trials currently pending. Any month now the results will come out, and we’ll see where we are at that point. But at this time, we’re thinking stay away from low-molecular-weight starches for resuscitation," Dr. Osborn said.

One of the main reasons the Surviving Sepsis Campaign 2012 guidelines won’t actually be published before January 2013 is the guideline panel’s eagerness to see the results of those two studies, she added.

• Vasopressor therapy. The initial target remains, as before, a mean arterial pressure of at least 65 mm Hg. But while the 2008 guidelines recommended either norepinephrine or dopamine as the first-choice vasopressor to correct hypotension in patients not sufficiently responsive to fluid resuscitation, the new guidelines will state that norepinephrine is the preferred agent (grade 1B). That’s a major change. Dopamine has been essentially kicked to the curb in response to multiple studies in the last 4 years implicating it in an increased incidence of arrhythmias and, in some studies, higher mortality.

The final nail in dopamine’s coffin for use in patients with severe sepsis or septic shock was a recent meta-analysis involving five observational and six interventional studies totaling nearly 2,800 patients (Crit. Care Med. 2012;40:725-30).

"Dopamine has actually fallen by the wayside. By far and away, I’m going to choose norepinephrine as the initial vasopressor agent," declared Dr. Michael E. Winters of the University of Maryland, Baltimore.

The new guidelines will suggest that be reserved for highly selected patients: those at very low arrhythmia risk and with a low cardiac output and/or low heart rate (grade 2C), he noted.

Another change in the new guidelines will be a recommendation that epinephrine be added when an additional agent is needed in order to maintain adequate blood pressure (grade 2B).

• Don’t overdo the fluids. "We want to give patients what they need but not more," Dr. Osborn explained. The 2012 guidelines will recommend that physicians use some sort of fluid challenge test while administering fluid boluses. The goal is to keep giving fluid only so long as hemodynamic improvement is seen in response. This can be achieved in a variety of ways, including monitoring change in pulse pressure, stroke volume variation, heart rate, or arterial pressure.

• Lactate clearance. Serum lactate is recognized as an indicator of global organ hypoperfusion and shock. But incorporating lactate clearance as one of the goals of early sepsis therapy has been "a very hot topic," Dr. Winters observed.

Improved clarity was provided by a prospective 556-patient quality improvement study by investigators in the Asian Network to Regulate Sepsis Care. Patients who got the primary severe sepsis management bundle of care as recommended in the 2008 Surviving Sepsis Campaign guidelines had an unadjusted mortality of 43.6%. This bundle includes early antibiotic administration, hemodynamic monitoring and support, and achievement of a central venous oxygen saturation level greater than 70% by 6 hours. However, patients who got the bundle plus lactate clearance had a 20.5% mortality rate (Crit. Care 2011;15:R229 [doi:10.1186/cc10469]).

The importance of lactate clearance was further underscored by the findings in the GENESIS Project (Generalized Early Sepsis Intervention Strategies). This quality improvement initiative, conducted at five 5 U.S. community hospitals and six tertiary centers, showed a 42.8% mortality in 1,554 historical controls treated for sepsis before implementation of the Surviving Sepsis Campaign resuscitation bundle. In another 4,801 patients who got the bundle, mortality was significantly lower at 28.8%. And, in those who received the bundle plus lactate clearance, mortality further fell to about 22% (J. Intensive Care Med. 2012 [doi:10.1177/0885066612453025]).

Thus, the coming Surviving Sepsis Campaign 2012 guidelines will suggest that in patients with elevated lactate levels as a marker of hypoperfusion, resuscitation should be targeted at normalizing lactate as rapidly as possible (grade 2C). Having said that, however, a normal lactate doesn’t indicate absence of shock. Other factors, such as the patient’s central venous oxygen saturation level, need to be considered as well, the physicians emphasized.

The Surviving Sepsis Campaign guidelines are sponsored by 27 medical organizations. Among them are the Society of Critical Care Medicine, ACEP, the Society of Hospital Medicine, the American College of Chest Physicians, the American Thoracic Society, the Infectious Diseases Society of America, the Surgical Infection Society, the Pediatric Acute Lung Injury and Sepsis Investigators, and a host of international groups.

Dr. Osborn and Dr. Winter reported having no financial conflicts.

DENVER – Look for some big changes ahead in the forthcoming update of the Surviving Sepsis Campaign international guidelines.

In the 4 years since the last version of the guidelines came out, major studies have been released that resolved hot debates regarding sepsis management and in some cases overturned established dogma. At the annual American College of Emergency Physicians (ACEP) meeting, emergency physicians deeply involved in crafting the Surviving Sepsis Campaign 2012 guidelines provided a preview of what’s to come.

Among the areas that will see key new recommendations are antibiotic therapy, fluid resuscitation, vasopressors, and lactate monitoring.

• Antibiotics ASAP. The critical importance of getting empiric antibiotics on board within 6 hours after recognizing that a patient has sepsis has been effectively hammered home over the years. But how fast is fast enough? Several recent small studies have reached conflicting conclusions. Now, however, an 800-lb gorilla of a study has provided a definitive answer.

This study, now in press, involved 14,895 patients enrolled in the Surviving Sepsis Campaign’s worldwide database. All had severe sepsis or septic shock, and all received antibiotics within the first 6 hours, explained Dr. Tiffany M. Osborn, a coauthor of the study and of the forthcoming guidelines.

"This was a big question for us. The results strengthen the importance of getting antibiotics started as soon as possible – within the first hour if possible. We found there’s about a 4% increase in mortality for every hour delay. And it’s cumulative: it’s 4% after the first hour, 8% after the second, 12% after the third, and so on," according to Dr. Osborn of Washington University at St. Louis.

A similar time-dependent increase in mortality was observed in patients with severe sepsis as well as in those in septic shock, she added.

• Fluid resuscitation. The initial fluid of choice for resuscitation in severe sepsis and septic shock remains crystalloids, as before. That’s a grade 1A recommendation. What’s brand new is a recommendation to consider adding albumin in the initial fluid resuscitation (grade 2B). This guidance was heavily influenced by a meta-analysis of 17 studies involving close to 2,000 patients that demonstrated a significant protective effect for the use of albumin as an initial resuscitation fluid (Crit. Care Med. 2011;39:386-91).

At this late date, Dr. Osborn said, the guideline panel is strongly leaning toward a recommendation against the use of low-molecular-weight colloids or starches such as hydroxyethyl starch 130/0.42. That would be ground shaking, as synthetic colloids or starches, particularly those of low molecular weight, are a very popular resuscitation fluid both in the United States and abroad. However, recent studies implicate these fluids in increased risks of 90-day mortality and renal failure, compared with the use of Ringer’s lactate.

"Having said this, there are two other trials currently pending. Any month now the results will come out, and we’ll see where we are at that point. But at this time, we’re thinking stay away from low-molecular-weight starches for resuscitation," Dr. Osborn said.

One of the main reasons the Surviving Sepsis Campaign 2012 guidelines won’t actually be published before January 2013 is the guideline panel’s eagerness to see the results of those two studies, she added.

• Vasopressor therapy. The initial target remains, as before, a mean arterial pressure of at least 65 mm Hg. But while the 2008 guidelines recommended either norepinephrine or dopamine as the first-choice vasopressor to correct hypotension in patients not sufficiently responsive to fluid resuscitation, the new guidelines will state that norepinephrine is the preferred agent (grade 1B). That’s a major change. Dopamine has been essentially kicked to the curb in response to multiple studies in the last 4 years implicating it in an increased incidence of arrhythmias and, in some studies, higher mortality.

The final nail in dopamine’s coffin for use in patients with severe sepsis or septic shock was a recent meta-analysis involving five observational and six interventional studies totaling nearly 2,800 patients (Crit. Care Med. 2012;40:725-30).

"Dopamine has actually fallen by the wayside. By far and away, I’m going to choose norepinephrine as the initial vasopressor agent," declared Dr. Michael E. Winters of the University of Maryland, Baltimore.

The new guidelines will suggest that be reserved for highly selected patients: those at very low arrhythmia risk and with a low cardiac output and/or low heart rate (grade 2C), he noted.

Another change in the new guidelines will be a recommendation that epinephrine be added when an additional agent is needed in order to maintain adequate blood pressure (grade 2B).

• Don’t overdo the fluids. "We want to give patients what they need but not more," Dr. Osborn explained. The 2012 guidelines will recommend that physicians use some sort of fluid challenge test while administering fluid boluses. The goal is to keep giving fluid only so long as hemodynamic improvement is seen in response. This can be achieved in a variety of ways, including monitoring change in pulse pressure, stroke volume variation, heart rate, or arterial pressure.

• Lactate clearance. Serum lactate is recognized as an indicator of global organ hypoperfusion and shock. But incorporating lactate clearance as one of the goals of early sepsis therapy has been "a very hot topic," Dr. Winters observed.

Improved clarity was provided by a prospective 556-patient quality improvement study by investigators in the Asian Network to Regulate Sepsis Care. Patients who got the primary severe sepsis management bundle of care as recommended in the 2008 Surviving Sepsis Campaign guidelines had an unadjusted mortality of 43.6%. This bundle includes early antibiotic administration, hemodynamic monitoring and support, and achievement of a central venous oxygen saturation level greater than 70% by 6 hours. However, patients who got the bundle plus lactate clearance had a 20.5% mortality rate (Crit. Care 2011;15:R229 [doi:10.1186/cc10469]).

The importance of lactate clearance was further underscored by the findings in the GENESIS Project (Generalized Early Sepsis Intervention Strategies). This quality improvement initiative, conducted at five 5 U.S. community hospitals and six tertiary centers, showed a 42.8% mortality in 1,554 historical controls treated for sepsis before implementation of the Surviving Sepsis Campaign resuscitation bundle. In another 4,801 patients who got the bundle, mortality was significantly lower at 28.8%. And, in those who received the bundle plus lactate clearance, mortality further fell to about 22% (J. Intensive Care Med. 2012 [doi:10.1177/0885066612453025]).

Thus, the coming Surviving Sepsis Campaign 2012 guidelines will suggest that in patients with elevated lactate levels as a marker of hypoperfusion, resuscitation should be targeted at normalizing lactate as rapidly as possible (grade 2C). Having said that, however, a normal lactate doesn’t indicate absence of shock. Other factors, such as the patient’s central venous oxygen saturation level, need to be considered as well, the physicians emphasized.

The Surviving Sepsis Campaign guidelines are sponsored by 27 medical organizations. Among them are the Society of Critical Care Medicine, ACEP, the Society of Hospital Medicine, the American College of Chest Physicians, the American Thoracic Society, the Infectious Diseases Society of America, the Surgical Infection Society, the Pediatric Acute Lung Injury and Sepsis Investigators, and a host of international groups.

Dr. Osborn and Dr. Winter reported having no financial conflicts.

DENVER – Look for some big changes ahead in the forthcoming update of the Surviving Sepsis Campaign international guidelines.

In the 4 years since the last version of the guidelines came out, major studies have been released that resolved hot debates regarding sepsis management and in some cases overturned established dogma. At the annual American College of Emergency Physicians (ACEP) meeting, emergency physicians deeply involved in crafting the Surviving Sepsis Campaign 2012 guidelines provided a preview of what’s to come.

Among the areas that will see key new recommendations are antibiotic therapy, fluid resuscitation, vasopressors, and lactate monitoring.

• Antibiotics ASAP. The critical importance of getting empiric antibiotics on board within 6 hours after recognizing that a patient has sepsis has been effectively hammered home over the years. But how fast is fast enough? Several recent small studies have reached conflicting conclusions. Now, however, an 800-lb gorilla of a study has provided a definitive answer.

This study, now in press, involved 14,895 patients enrolled in the Surviving Sepsis Campaign’s worldwide database. All had severe sepsis or septic shock, and all received antibiotics within the first 6 hours, explained Dr. Tiffany M. Osborn, a coauthor of the study and of the forthcoming guidelines.

"This was a big question for us. The results strengthen the importance of getting antibiotics started as soon as possible – within the first hour if possible. We found there’s about a 4% increase in mortality for every hour delay. And it’s cumulative: it’s 4% after the first hour, 8% after the second, 12% after the third, and so on," according to Dr. Osborn of Washington University at St. Louis.

A similar time-dependent increase in mortality was observed in patients with severe sepsis as well as in those in septic shock, she added.

• Fluid resuscitation. The initial fluid of choice for resuscitation in severe sepsis and septic shock remains crystalloids, as before. That’s a grade 1A recommendation. What’s brand new is a recommendation to consider adding albumin in the initial fluid resuscitation (grade 2B). This guidance was heavily influenced by a meta-analysis of 17 studies involving close to 2,000 patients that demonstrated a significant protective effect for the use of albumin as an initial resuscitation fluid (Crit. Care Med. 2011;39:386-91).

At this late date, Dr. Osborn said, the guideline panel is strongly leaning toward a recommendation against the use of low-molecular-weight colloids or starches such as hydroxyethyl starch 130/0.42. That would be ground shaking, as synthetic colloids or starches, particularly those of low molecular weight, are a very popular resuscitation fluid both in the United States and abroad. However, recent studies implicate these fluids in increased risks of 90-day mortality and renal failure, compared with the use of Ringer’s lactate.

"Having said this, there are two other trials currently pending. Any month now the results will come out, and we’ll see where we are at that point. But at this time, we’re thinking stay away from low-molecular-weight starches for resuscitation," Dr. Osborn said.

One of the main reasons the Surviving Sepsis Campaign 2012 guidelines won’t actually be published before January 2013 is the guideline panel’s eagerness to see the results of those two studies, she added.

• Vasopressor therapy. The initial target remains, as before, a mean arterial pressure of at least 65 mm Hg. But while the 2008 guidelines recommended either norepinephrine or dopamine as the first-choice vasopressor to correct hypotension in patients not sufficiently responsive to fluid resuscitation, the new guidelines will state that norepinephrine is the preferred agent (grade 1B). That’s a major change. Dopamine has been essentially kicked to the curb in response to multiple studies in the last 4 years implicating it in an increased incidence of arrhythmias and, in some studies, higher mortality.

The final nail in dopamine’s coffin for use in patients with severe sepsis or septic shock was a recent meta-analysis involving five observational and six interventional studies totaling nearly 2,800 patients (Crit. Care Med. 2012;40:725-30).

"Dopamine has actually fallen by the wayside. By far and away, I’m going to choose norepinephrine as the initial vasopressor agent," declared Dr. Michael E. Winters of the University of Maryland, Baltimore.

The new guidelines will suggest that be reserved for highly selected patients: those at very low arrhythmia risk and with a low cardiac output and/or low heart rate (grade 2C), he noted.

Another change in the new guidelines will be a recommendation that epinephrine be added when an additional agent is needed in order to maintain adequate blood pressure (grade 2B).

• Don’t overdo the fluids. "We want to give patients what they need but not more," Dr. Osborn explained. The 2012 guidelines will recommend that physicians use some sort of fluid challenge test while administering fluid boluses. The goal is to keep giving fluid only so long as hemodynamic improvement is seen in response. This can be achieved in a variety of ways, including monitoring change in pulse pressure, stroke volume variation, heart rate, or arterial pressure.

• Lactate clearance. Serum lactate is recognized as an indicator of global organ hypoperfusion and shock. But incorporating lactate clearance as one of the goals of early sepsis therapy has been "a very hot topic," Dr. Winters observed.

Improved clarity was provided by a prospective 556-patient quality improvement study by investigators in the Asian Network to Regulate Sepsis Care. Patients who got the primary severe sepsis management bundle of care as recommended in the 2008 Surviving Sepsis Campaign guidelines had an unadjusted mortality of 43.6%. This bundle includes early antibiotic administration, hemodynamic monitoring and support, and achievement of a central venous oxygen saturation level greater than 70% by 6 hours. However, patients who got the bundle plus lactate clearance had a 20.5% mortality rate (Crit. Care 2011;15:R229 [doi:10.1186/cc10469]).

The importance of lactate clearance was further underscored by the findings in the GENESIS Project (Generalized Early Sepsis Intervention Strategies). This quality improvement initiative, conducted at five 5 U.S. community hospitals and six tertiary centers, showed a 42.8% mortality in 1,554 historical controls treated for sepsis before implementation of the Surviving Sepsis Campaign resuscitation bundle. In another 4,801 patients who got the bundle, mortality was significantly lower at 28.8%. And, in those who received the bundle plus lactate clearance, mortality further fell to about 22% (J. Intensive Care Med. 2012 [doi:10.1177/0885066612453025]).

Thus, the coming Surviving Sepsis Campaign 2012 guidelines will suggest that in patients with elevated lactate levels as a marker of hypoperfusion, resuscitation should be targeted at normalizing lactate as rapidly as possible (grade 2C). Having said that, however, a normal lactate doesn’t indicate absence of shock. Other factors, such as the patient’s central venous oxygen saturation level, need to be considered as well, the physicians emphasized.

The Surviving Sepsis Campaign guidelines are sponsored by 27 medical organizations. Among them are the Society of Critical Care Medicine, ACEP, the Society of Hospital Medicine, the American College of Chest Physicians, the American Thoracic Society, the Infectious Diseases Society of America, the Surgical Infection Society, the Pediatric Acute Lung Injury and Sepsis Investigators, and a host of international groups.

Dr. Osborn and Dr. Winter reported having no financial conflicts.

PRAGUE – Everolimus significantly improved the skin lesions of tuberous sclerosis complex in two phase-III clinical trials, Dr. Sergiusz Jozwiak reported at the annual congress of the European Academy of Dermatology and Venereology.

Tuberous sclerosis is a genetic disorder characterized by the growth of numerous nonmalignant tumors in various organs including the brain, kidneys, heart, and skin.

The most devastating skin lesions associated with tuberous sclerosis complex are facial angiofibromas. Hypopigmented spots are also common, said Dr. Jozwiak, a pediatric neurologist at the Children’s Memorial Health Institute of Warsaw.

In the first study, Examining Everolimus in a Study of Tuberous Sclerosis Complex (EXIST-1), about 100 patients with subependymal giant cell astrocytoma (SEGA) were randomized 2:1 to receive everolimus or placebo. In EXIST-2, approximately 100 patients with renal angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis were randomized to receive either everolimus or placebo. EXIST-1 participants averaged about 8 years of age; those in EXIST-2 had an average age of 30 years.

Both studies met their primary end points, with favorable effects documented in patients with SEGA and renal angiomyolipoma. This led the Food and Drug Administration to approve everolimus (Afinitor), an oral inhibitor of the mammalian target of rapamycin (mTOR), for the treatment of both conditions.

Dr. Jozwiak reported on the skin lesion response to everolimus, a prespecified secondary end point in EXIST-1 and -2.

Close to 95% of all participants – 224 subjects in the two trials – had skin lesions at baseline. Of those on everolimus, 42% in EXIST-1 and 26% in EXIST-2 had significant improvements in their skin lesions, compared with 11% and 0%, respectively, of those on placebo.

The skin response was partial in all cases as judged on a 7-point scale, but the response, when it occurred, was durable: All patients with a partial response to everolimus maintained that response at last follow-up, ranging from 2 to 20 months. Thus, the median duration of skin response has yet to be determined, Dr. Jozwiak noted.

Mouth ulcers were the most common and troublesome everolimus side effect, seen intermittently in 70% of the patients in the two phase-III trials. The side effect was managed by temporary reductions in dosing or suspension of therapy for a week.

"We were able to reinstitute full-dose therapy in all patients," he said.

There were no other serious treatment-related adverse events. The incidence of infections was similar in the everolimus and placebo arms of the studies.

Everolimus was dosed starting at 4.5 mg/m² per day, with a target trough level of 5-15 ng/mL in EXIST-1. In EXIST-2, which was limited to an adult patient population, the drug was dosed at 10 mg/day.

The EXIST trials were sponsored by Novartis. Dr. Jozwiak is a consultant to the company.

PRAGUE – Everolimus significantly improved the skin lesions of tuberous sclerosis complex in two phase-III clinical trials, Dr. Sergiusz Jozwiak reported at the annual congress of the European Academy of Dermatology and Venereology.

Tuberous sclerosis is a genetic disorder characterized by the growth of numerous nonmalignant tumors in various organs including the brain, kidneys, heart, and skin.

The most devastating skin lesions associated with tuberous sclerosis complex are facial angiofibromas. Hypopigmented spots are also common, said Dr. Jozwiak, a pediatric neurologist at the Children’s Memorial Health Institute of Warsaw.

In the first study, Examining Everolimus in a Study of Tuberous Sclerosis Complex (EXIST-1), about 100 patients with subependymal giant cell astrocytoma (SEGA) were randomized 2:1 to receive everolimus or placebo. In EXIST-2, approximately 100 patients with renal angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis were randomized to receive either everolimus or placebo. EXIST-1 participants averaged about 8 years of age; those in EXIST-2 had an average age of 30 years.

Both studies met their primary end points, with favorable effects documented in patients with SEGA and renal angiomyolipoma. This led the Food and Drug Administration to approve everolimus (Afinitor), an oral inhibitor of the mammalian target of rapamycin (mTOR), for the treatment of both conditions.

Dr. Jozwiak reported on the skin lesion response to everolimus, a prespecified secondary end point in EXIST-1 and -2.

Close to 95% of all participants – 224 subjects in the two trials – had skin lesions at baseline. Of those on everolimus, 42% in EXIST-1 and 26% in EXIST-2 had significant improvements in their skin lesions, compared with 11% and 0%, respectively, of those on placebo.

The skin response was partial in all cases as judged on a 7-point scale, but the response, when it occurred, was durable: All patients with a partial response to everolimus maintained that response at last follow-up, ranging from 2 to 20 months. Thus, the median duration of skin response has yet to be determined, Dr. Jozwiak noted.

Mouth ulcers were the most common and troublesome everolimus side effect, seen intermittently in 70% of the patients in the two phase-III trials. The side effect was managed by temporary reductions in dosing or suspension of therapy for a week.

"We were able to reinstitute full-dose therapy in all patients," he said.

There were no other serious treatment-related adverse events. The incidence of infections was similar in the everolimus and placebo arms of the studies.

Everolimus was dosed starting at 4.5 mg/m² per day, with a target trough level of 5-15 ng/mL in EXIST-1. In EXIST-2, which was limited to an adult patient population, the drug was dosed at 10 mg/day.

The EXIST trials were sponsored by Novartis. Dr. Jozwiak is a consultant to the company.

PRAGUE – Everolimus significantly improved the skin lesions of tuberous sclerosis complex in two phase-III clinical trials, Dr. Sergiusz Jozwiak reported at the annual congress of the European Academy of Dermatology and Venereology.

Tuberous sclerosis is a genetic disorder characterized by the growth of numerous nonmalignant tumors in various organs including the brain, kidneys, heart, and skin.

The most devastating skin lesions associated with tuberous sclerosis complex are facial angiofibromas. Hypopigmented spots are also common, said Dr. Jozwiak, a pediatric neurologist at the Children’s Memorial Health Institute of Warsaw.

In the first study, Examining Everolimus in a Study of Tuberous Sclerosis Complex (EXIST-1), about 100 patients with subependymal giant cell astrocytoma (SEGA) were randomized 2:1 to receive everolimus or placebo. In EXIST-2, approximately 100 patients with renal angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis were randomized to receive either everolimus or placebo. EXIST-1 participants averaged about 8 years of age; those in EXIST-2 had an average age of 30 years.

Both studies met their primary end points, with favorable effects documented in patients with SEGA and renal angiomyolipoma. This led the Food and Drug Administration to approve everolimus (Afinitor), an oral inhibitor of the mammalian target of rapamycin (mTOR), for the treatment of both conditions.

Dr. Jozwiak reported on the skin lesion response to everolimus, a prespecified secondary end point in EXIST-1 and -2.

Close to 95% of all participants – 224 subjects in the two trials – had skin lesions at baseline. Of those on everolimus, 42% in EXIST-1 and 26% in EXIST-2 had significant improvements in their skin lesions, compared with 11% and 0%, respectively, of those on placebo.

The skin response was partial in all cases as judged on a 7-point scale, but the response, when it occurred, was durable: All patients with a partial response to everolimus maintained that response at last follow-up, ranging from 2 to 20 months. Thus, the median duration of skin response has yet to be determined, Dr. Jozwiak noted.

Mouth ulcers were the most common and troublesome everolimus side effect, seen intermittently in 70% of the patients in the two phase-III trials. The side effect was managed by temporary reductions in dosing or suspension of therapy for a week.

"We were able to reinstitute full-dose therapy in all patients," he said.

There were no other serious treatment-related adverse events. The incidence of infections was similar in the everolimus and placebo arms of the studies.

Everolimus was dosed starting at 4.5 mg/m² per day, with a target trough level of 5-15 ng/mL in EXIST-1. In EXIST-2, which was limited to an adult patient population, the drug was dosed at 10 mg/day.

The EXIST trials were sponsored by Novartis. Dr. Jozwiak is a consultant to the company.