Featured – Page 8

Applying Laboratory Breakthroughs to Treat Pediatric Skin Diseases: Part 2

December 12, 2014

Amy Paller, MD, MS

Biologics as Targeted Therapy

Genetic advances are teaching us more about psoriasis as a disease state. The discovery of pathways that influence psoriasis have led to treatments such as TNF alpha inhibitors, interleukin-23 inhibitors, and IL-17 and its receptors. We have also learned that CARD14 mutations are a cause of familial psoriasis/PRP. One of the ways that CARD14 works is through the activation of IL-23 signaling and Th-17 expression, leading to the use of ustekinumab, a commercially available agent that targets IL-12/-23 with success.

Through exome sequencing, we have learned more about generalized pustular psoriasis. There is a deficiency of the interleukin-36 receptor antagonist, DITRA, in hereditary pustular psoriasis (and some cases of “sporadic” generalized pustular psoriasis show mutations in the IL-36R antagonist). This discovery suggests that activated IL-36 (or its related compound, IL-1) may be an important target in pustular psoriasis.

What about alopecia areata? We have learned from some excellent genome-wide association studies (GWAS) that there are several loci that are increased in this disease, one is which is CTLA4. There are ongoing trials of abatacept (CTLA4-Ig initiated) and rixolitinib (JAK 1/2 inhibitor to suppress IL-15 activity), but an early report of JAK1/2 inhibition showed great promise.

Targeting Functional Pathways

We can use systemic administration of small molecule inhibitors to suppress signaling activation. This can be seen with the use of vismodegib in basal cell carcinoma and basal cell carcinoma syndrome (BCNS) (activation of hedgehog signaling) and oral rapamycin in tuberous sclerosis (activation of mTOR signaling). GNAQ mutations cause the majority of blue nevi and 90 percent of cases of Sturge-Weber syndrome and nonsyndromatic portwine stains. GNAQ mutations have now been shown to activate PKC and MAPK but not AKT or mTOR. This observation suggests that an inhibitor of PKC or MAPK signaling might be effective if applied topically. With epidermal nevi, activating mutations have been detected in the genes encoding RAS family members or affecting FGFR3/PI3K/AKT signaling. Differentiating the activated pathway could influence decision-making about the most appropriate inhibitor to apply topically in the future. G13R and Q61R or Q61L Hras mutations in melanocytes cause Spitz nevi and speckled lentiginous nevi, yet another situation in which a targeted inhibitor which blocks Ras signaling might be considered as therapy.

Protein Replacement Therapy

Intradermal or intravenous introduction of recombinant collagen VII into RDEB (recessive dystrophic epidermolysis bullosa) mice leads to the deposition of collagen VII at wound BMZ and decreased skin fragility. Recently, FDA approved a trial of injected collagen VII in patients with RDEB. Future investigations might involve topically applied recombinant collagen VII to wounds or even intravenous delivery to reach mucosal sites as well. Interestingly, studies in mice without epidermolysis bullosa suggest that even normal wounds heal more readily if collagen VII is administered, broadening the potential value of topically delivered collagen VII.

Replacement; however, may not be sufficient. In CHILD syndrome, the cholesterol biosynthetic pathway is blocked, leading to deficiency of cholesterol but also accumulation of toxic metabolites. Application of topical cholesterol to skin is not sufficient, but use of a statin to block both the accumulation of toxic metabolites, as well as replacement of cholesterol leads to dramatic improvement in affected skin using this “pathogenesis-based” therapy.

Summary

New technology has facilitated the advancement in our knowledge about gene function and the effects of gene alteration, including for some of the mosaic disorders. These discoveries have translated into new therapies for patients with genetic disorders and will help with innovative treatment in the future, whether personalized gene-based or pharmacologic therapy. While there are new discoveries to be made, one of the exciting new frontiers involves epigenetics—unraveling how and why genes are turned off with cell and tissue specificity – and then translation this information towards treating human disease.

Infectious Diseases: Update on the Management of Onychomycosis

December 12, 2014

Aditya K. Gupta, MD

Dr Gupta, an expert in the management of nail disorders, discusses clinical advances with regards to the management of onychomycosis.

Factors Affecting Diagnosis

It is very important that we correctly diagnose onychomycosis. For the first time in over twenty years, we are able to use techniques other than light microscopy and culture. Molecular biology can be used to accurately diagnose multiple organisms that may cause onychomycosis. Dr Gupta has learned, through his lab, that often we may have mixed infections of two dermatophytes, a dermatophyte and a non-dermatophyte, or two non-dermatophytes. PCR analysis is more sensitive than culture, so it has a greater ability to identify mixed infections.

Treatment

Oral Therapies

Onychomycosis can be managed with topical therapy, oral therapy, and/or devices, i.e., lasers. In terms of oral therapy, terbinafine is the gold standard. Itraconazole is also indicated for the treatment of onychomycosis and fluconazole can be used off-label.

There are two new oral drugs in development—posaconazole and albaconazole.

It is important to recognize that onychomycosis is a difficult disease to treat, so you should consider the fact that you may need booster therapy or extra treatment around six to nine months from the start of therapy. For example, with terbinafine, giving 250mg per day for four weeks and repeating that at nine months and twelve months.

Topical Therapies

Efinaconazole, a triazole, which was just approved in Canada, has a low MIC for dermatophytes, yeasts and non-dermatophyte molds and relatively low keratin binding to facilitate transungual penetration. With regards to mycological cure and complete cure, data for efinaconazole demonstrated 54 percent and 17 percent cure rates, respectively versus 32 percent and seven percent, respectively with ciclopirox.

Tavaborole, a broad-spectrum benzoxaborole antifungal, has a low molecular weight and low lipophilicity facilitating penetration into the nail plate. At week 52, tavaborole demonstrated a 34 percent mycological cure and an eight percent complete cure as compared to 32 percent and seven percent, respectively with ciclopirox.

We need to recognize that there are differences in the severity and population of participants between the studies looking at the efficacy of efinaconazole and tavaborole; therefore, precluding a head-to-head comparison.

Differences Between Efinaconazole and Tavaborole in Pivotal Phase III Studies

No upper age limit for tavaborole
Nail trim: tavaborole allowed no more than 1mm nail beyond hyponychium
Japan not included in tavaborole study
Efficacy of vehicle for efinaconazole 2x that of tavaborole

Luliconazole is a topical imidazole approved in the United States for the treatment of tinea pedis. There are phase II/III trials currently underway studying its efficacy for onychomycosis.

Device Therapy—Lasers

There is insufficient data to determine if lasers are fungicidal in onychomycosis, especially as the precise mechanism of action remains unclear. The most likely effect is a selective photothermal effect, although we cannot rule out a photoacoustic, photochemical, or photomechanical effect. Keep in mind that the fungus has to be heated to at least fifty degrees centigrade for at least ten to fifteen minutes or 60 degrees (or even 70 degrees) for shorter periods of time. The aim of selective photothermolysis is the create very high increases in temperature in the fungi while the water content in the dermis and the blood vessels surrounding the nail bed allows for the dissipation of heat to prevent pain and tissue necrosis. The pulse format of the laser is critical for ensuring that heat remains confined and elevated in the fungi, while providing sufficient time for the surrounding tissue to dissipate the heat,

In the United States, the division of the FDA that approves lasers is different from the division that approves anti-fungal treatments. Lasers are indicated for use for the temporary increase of clear nail in patients with onychomycosis—this is quite a different approval as it is a cosmetic approval that does not look for mycological or complete cure. These lasers have not been subject to the same stringent standards that we expect of topical and oral therapies. There have been a number of open, single assignment clinical trials conducted using laser systems; however, randomized, controlled studies are needed to determine if laser is an effective treatment

Prevention of Recurrence and Reinfection

Recurrence rates can be anywhere from 11 to 35 percent or even higher. Remember that fungi can be transmitted to uncontaminated clothing in the wash. It is important to remind patients to wash their clothes and shoes in hot water (greater than 60 degrees) for more than 45 minutes. Ozone can be used to sanitize shoes and sports equipment of dermatophytes, yeasts, and non-dermatophyte molds. Ultraviolet light can also be used to sanitize shoes and reduce fungal burden.

Factors Contributing to Recurrence and Reinfection

The fungus that causes onychomycosis is not just dermatophytes or non-dermatophytes, but mixed infections as well. We have also shown that T. rubrum is not just T. rubum; there are minute-based pair differences that produce different strain types. We have found that strain type switching may contribute to the failure of oral terbinafine.

In summary, terbinafine remains the gold standard for treating onychomycosis. Both continuous and pulsed regimens are beneficial with an optimal pulse regimen of four weeks on, four weeks off and four weeks on. We have found that using this strategy, taking into account the pharmacokinetics of the drug, we can achieve fairly high cure rates. Itraconazole 200mg melt extrusion tablet may lead to better compliance rates versus two 100mg capsules. Don’t forget about booster therapy!

Fluconazole, while off-label in the United States, can be used at 150mg/week for longer than six weeks is also effective. The efficacy for posanoazole and albaconazole is similar, but not superior, to that of terbinafine.

We also have new topicals for onychomycosis—efinaconazole and tavaborole. It remains to see whether or not they will be used as monotherapy or in combination. Perhaps they could be effectively used in patients who fail oral terbinafine. They may also be used to prevent early recurrence of onychomycosis. There are a lot of potentials for the topical therapy.

As dermatologists, we use lasers for many things. We still don’t know enough about the use of lasers for the therapeutic cure of onychomycosis.

Applying Laboratory Breakthroughs to Treat Pediatric Skin Diseases: Part 1

December 9, 2014

Amy Paller, MD, MS

At Maui Derm 2014, Dr Paller discussed how laboratory breakthroughs have enabled us to better treat skin disorders in the pediatric population. These discoveries come from the understanding of disease pathogenesis and our seeking of targeted interventions.

New discoveries and new technologies, e.g., gene sequencing, and analysis of RNA and protein expression, are increasing our understanding of skin disease and aiding in the development of new therapies.

Unraveling the Cause of Monogenetic Disorders

Discoveries from Sanger sequencing revolutionized prenatal diagnoses such as amniocentesis, chorionic villus sampling, and more recently for a limited set of disorders, maternal blood sampling. Preimplantation diagnosis is a technique that utilizes in vitro fertilization to pull out a single egg, extract the DNA, and distinguish whether or not the fertilized egg is normal or not and, thus, implant the eggs that will be normal.

Most dermatologists are familiar with Deep-Sequencing or “next-generation” sequencing technology, which is transforming our understanding of genetic diseases and how we can treat them.

Can next-generation sequencing help patients?

By simultaneously analyzing all candidate genes, we can detect low frequency mutations in known genes, mutations in newly associated genes, and low frequency SNPs in thousands of samples. We can also find genotype-phenotype correlations based on alterations in multiple genes. We can analyze epigenetic changes like methylation at base-pair level, histone modifications and protein-DNA interactions. This may provide us with a greater ability to predict responses to medications and personalized gene therapy.

Technologies in Trials Today

Gene therapy: Ex-vivo cell therapy

Researchers at Stanford are using this technology for recessive dystrophic epidermolysis bullosa (RDEB) in adults. One potential risk of ex vivo gene therapy is that the introduced protein may be viewed by the immune system as foreign, leading to a problem with the creation of autoantibodies. At Stanford, the researchers are only accepting patients (~60% of individuals with RDEB) who have the N-terminal domain of collagen VII—the immunogenic domain. This decreases the chance of the patient developing an autoimmune disorder. In these studies the concern about insertional oncogenesis (ie, that the viral insertion, which is random, could lead to interruption of an important tumor suppressor gene) is mitigated by the fact that any tumor that might developed would be highly visible and easily managed. On question is whether spraying the corrected keratinocytes onto a wound bed could be a substitute for grafting skin; this techniques has been used to introduce normal keratinocytes into graft sites for burn patients (Gerlach et al. Burns 2011;37:e19).

Stem Cell Therapy

Several years ago, the University of Minnesota began pioneering bone marrow transplants on children with RDEB, leading to evidence of incorporation of autologous stem cells, deposition of collagen VII at the dermal-epidermal junction, and some improved healing. Subsequent studies have used newer techniques to decrease the risk to patients and increase efficiency, including extending the therapy to junctional EB (JEB) patients. It is important to note that this procedure still carries a risk with variable success and slow improvement.

Revertant Mosaicism: “Natural” Gene Therapy

This term refers to a spontaneous correction of a loss-of-function mutation, leading to “carrier” phenotype. This has been seen extensively in patients with JEB because of mutations in collagen XVII, but has now been described in several other genetic disorders of the skin. This “natural gene therapy” may lead to expanding a small biopsy of patient cells to introduce as a graft or through use of iPS cells (see below) without requiring immunosuppression because the cells are otherwise the patient’s own cells.

Induced Pluripotent Stem Cells (iPS)

iPS cell technology allows one to take any cell (e.g., keratinocytes, fibroblasts) and de-differentiate it into a stem cell using well-known factors. You can then use other factors that will differentiate it into any type of cell that you want. As noted above, with regards to revertant mosaic areas, you can take those cells directly and turn them into stem cells and give someone back his own cells.

Many genetic diseases are dominant negative disorders, i.e., a genetic change in one allele is enough to disrupt function. Small interfering RNA (siRNA) is an approach to suppress the express of a target gene and has already been described in a human trial as a viable means to suppress gene expression and lead to clearance in pachyonychia congenita (Leachman et al. Mol Ther. 2010;18:442). siRNA specifically directed against the KRT6a mutation in a patient was injected into a tiny area of the plantar keratoderma using a left-right, double-blind analysis. Despite clear improvement, the injections were very painful, emphasizing the need for improved techniques for the delivery of genetic material through the epidermal barrier. Protrusion array devices utilize microneedles, often dissolvable, as a painless way to deliver genetic material or protein through the barrier. New creams that can be applied to the skin, including with the use of nanotechnology, are also under development as a means to deliver siRNA. TALENs and CRISPrs induce site-specific, double-stranded DNA breaks, then allow homologous-directed repair with the normal sequence. Although early in development, these techniques hold the promise of delivery of the normal sequence without the risk of random insertional oncogenesis.

Proteomic arrays (amino acid sequences encoded by mass spectrometry) and phosphoarrays (screens for activated proteins.) allow us to look at proteins directly and are great for drug discovery. ELISA assays have also become more sensitive. These technologies are allowing us to understand the specific pathways that are impacted in disease, leading to the possibility of targeted erapies for our patients with skin disease. With a better understanding of genes, we can develop newer therapies based on the pathways that they affect.

Melanoma Clinic: Lunch, Lesions, and Lessons: Part 4

December 5, 2014

Hensin Tsao, MD, PhD

Ilona Frieden, MD

Philip LeBoit, MD

Keith Flaherty, MD

Case Study

An 11 year-old boy presents to your office with his parents for the evaluation of a pigmented band on the right thumb. What would you do next?

Photo and follow up in 6 months
Reassure and continue careful surveillance at home
Perform an matrix biopsy with local anesthesia
Matrix biopsy under general anesthesia

Melanonychia Management

Melanonychia is not rare; however, nail melanoma in children is rare. The pre-test probability of a benign outcome is high. Most of the time we can photograph and follow the patient over time. In an unscientific perusal of cases at UCSF, Dr Frieden found that the majority of the patients were of Asian descent. Occasionally, a biopsy is performed. In a 20-year cohort, there were no melanoma deaths in childhood from nail melanoma.

Special Sites and Concepts of “Mino”

Special sites, such as the nail, scalp, oral and genitalia, require careful scrutiny and some pathologists appear to have a better handle regarding the appearance of melanocytic lesions. The usual rules, both clinically and pathologically, often times do not apply. Definite cases of nail melanoma in childhood have been reported and there have been issues in the pathology of nail melanocytic biopsies. Richert and colleagues conducted a retrospective cohort of 30 biopsied lesions in Belgium. Seven out of the 30 patients were age 20 or younger and none of them had melanoma. (Richert B, et al. J Am Acad Dermatol. 2013;69(1):96-140.) A 2008 review article reported two cases of nail melanoma in children with skin type 3 and 4 in a 14 year-old and a 6 year-old. Both were diagnosed with having melanoma in situ (MIS) with onset of melanonychia less than one year of age. There were eight other reported cases in the literature with six diagnosed as MIS. Two had lymph node disease and neither presented as melanonychia. (Iorrizzo et al. Dermatol Surg. 2008;34:974-8)

“Struck by lightening versus severe bike accident?” Dr Frieden thinks about nail melanoma in terms of risk assessment. In general, we would not worry about being struck by lightening. It doesn’t mean it doesn’t happen, but it is extraordinarily rare.

Infectious Diseases Update: Part 1: Interesting ID Literature

November 23, 2014

Ted Rosen, MD

In this presentation, Dr Rosen provides us with new information on infectious diseases that has recently appeared in the literature.

MRSA

A study in the International Journal of Antimicrobial Agents states that minocycline is often forgotten but preferred to trimethoprim-sulfamethoxazole or doxycycline for the treatment of community-acquired methicillin-resistant Staphylococcus aureus skin (MRSA) and soft-tissue infections. (Cunha B. Int J Antimicrob Agents. 2013;42:497). They point out that there is about a thirty percent discrepancy in discordance between the in vitro antibacterial testing and actual clinical effectiveness when it comes to the tetracycline family, this is less so with minocycline.

When treating MRSA, remember that incision and drainage is the most important intervention, if possible. CA-MRSA can be either modestly or severely virulent depending upon the presence or absence of PVL (Panton-Valentine leukocidin).

Typically we have some choices in treatment. We tend to leave linezolid for the last resort and clindamycin often has inducible resistance so we’re left with doxycycline, TMP-SMX, and minocycline. Cunha and his colleagues point out that second only to TMP-SMX, minocycline is the best in tissue penetrability and is equivalent to linezolid in predictable efficacy. Nationwide, only one to two percent of MRSA are resistant to linezolid and minocycline; however, up to twelve percent are resistant to doxycycline.

Because there is a generic minocycline available, the cost issues are largely negated. There are other issues such as hypersensitivity reactions and rare autoimmune phenomena. The authors feel, from a microbiological standpoint, minocycline is a preferred drug.

Herpes

We now have some new therapies available for the treatment of herpes. Herpotherm utilizes thermotherapy for genital herpes. A prospective study conducted in Russia evaluated 32 women. Twenty-one patients received thermotherapy plus acyclovir and ten received thermotherapy alone. Treatment was initiated with the first objective sign of HSV-2. Within one day, symptoms were gone or almost gone, with or without acyclovir as concomitant therapy demonstrating that thermotherapy is beneficial for genital herpes. Although exposure id of short duration (seconds), patients should be warned to expect some discomfort.

Topical zinc sulfate in-vitro inhibits the growth of HSV. Mahajan and colleagues tried various concentrations of zinc sulfate on 100 clinical and Tzanck verified men with genital HSV over a six-month period. They had a very specific treatment protocol:

Q5d x 1 mo
Then Q10d x 2 mo
Then Q15d x 3 mo

Of note, all of the patients had nine or more recurrences per year, i.e., frequent outbreaks of genital HSV. Here’s what the authors found:

4% Zinc sulfate is a cheap, non-toxic therapy that is easy to use and may be a viable treatment for hard to manage HSV-2. The key is to apply this when there is an outbreak and as it heals, patients should continue to follow the protocol. (Mahajan BB. Indian J Sex Transm Dis. 2013;34:32-34.)

Flat Warts

A study by Li and colleagues, published in the Journal of the European Academy of Dermatology and Venereology evaluated photodynamic therapy with five percent, ten percent, and twenty percent aminolevulinic acid (ALA) in the treatment of generalized recalcitrant facial verruca plana. This was a prospective study of 55 adult patients with bilateral facial flat warts. The two sides of the patient’s faces were randomized to receive ALA 5 percent, 10 percent or 20 percent. There was no placebo control. Patients were irradiated with a 633-nm red light in two 7.5- minute sessions, separated by 30 minutes of non-exposure. This was repeated three times, every two weeks. This study demonstrated that ALA 10 and 20 percent were most efficacious for the treatment of generalized recalcitrant facial verruca plana. In the United States, we have Levulan Kerastick (20% ALA-d). (Li Q, et al. J Eur Acad Dermatol Venereol. 2013 Nov 25. [Epub ahead of print])

Onychomycosis in Psoriatic Patients

A systematic review by Klaassen and colleagues analyzed the literature with regards to the prevalence of onychomycosis in patients with nail psoriasis. They looked at over 700 studies out of which they chose ten based on their criteria. The authors found that an average of 18 percent of psoriasis patients with nail dystrophy have concurrent onychomycosis. There was no shift from dermatophytes to saprophytes or yeast in these studies. Because psoriasis is treated with immunosuppressive agents, this may aggravate any concurrent fungal infection. (Klaassen KMG, et al. J Eur Acad Dermatol Venereol. 2013 Aug 19)

Take Home Message: It is important that we check for fungal disease in patients with psoriasis nail dystrophy before instituting therapy.

Atypical Mycobacteria/Nontuberculous Mycobacteria

In a case series and epidemiologic study, Falsey and colleagues looked at cutaneous inoculation of nontuberculous mycobacteria during professional tattooing. How does this happen? One to four weeks after the tattoo is placed, it may itch or hurt and there are monomorphous crusted papules or postules that are confined to the tattoo area. At first blanche, we might look at this and think it’s bacterial, but it turns out that it is Mycobacterium either abcessus or chelonae. Clarithromycin, minocycline and ciprofloxacin are all viable treatment options; however, the authors strongly recommend that you send off one the papules for culture and sensitivity because the sensitivities vary widely. Why does this happen? Because the atypical mycobacteria are found as a contaminant in the tattoo ink or sometimes the non-sterile water used to dilute the ink (especially when outsourced from China). (Falsey R, et al. Clin Infect Dis. 2013;57(6):e143-147.)

Take Home Message: Think NTM in new tattoo lesions

Herpes Zoster

Wang and colleagues conducted a population-based retrospective cohort study looking at herpes zoster infection and acute coronary syndrome (ACS), i.e., any event that suddenly decreases blood flow to the heart muscle (heart attack, unstable angina). This study included 59,958 patients with herpes zoster compared to an age/sex- matched cohort of 231,832 non-zoster patients. The authors found that acute coronary syndrome was associated with herpes zoster 25 percent more commonly. This was statistically significant (p=.0001) at both three months and one year after the herpes zoster was resolved. (Wang CC, et al. Br J Dermatol. Dec 6, 2013. e-pub ahead of print)

Take Home Message: Warn zoster patients about the risk of ACS and review symptoms of ACS.

Flood-related Skin Diseases

Flood, one of the most common natural disasters, has contributed to many public health problems. A study conducted in Thailand identified the following flood-related dermatological disorders:

Irritant contact dermatitis
Webspace tinea pedis
Webspace mixed infection
Cellulitis (S. pyogenes, Aeromonas)
Gas gangrene (clostridium)
Fasciitis (Vibrio spp)
Traumatic wounds (check cuts for lacerations, punctures, serious digital injuries)
Insect bites and stings (mosquito, fire ant, centipede)
Animal bites (stray dogs/cats, snakes)
Aggravation of pre-existing skin disease due to psychic trauma (psoriasis, atopy/eczema, alopecia areata, urticaria, vitiligo)

Functional Facial Anatomy: A Primer

November 23, 2014

Sandy Tsao, MD

Where are the safe areas to inject? What can we do in certain areas that we cannot do in others? In order to answer these questions, we need to understand the basic facial anatomy.

Remember that it only takes one complication to understand how significant the facial anatomy can be. As the neuromodulators change and as we become more knowledgeable about treatments, we have a better perspective. When we’re talking about facial anatomy, we’re thinking about the muscles of facial expression that run from the skull to the skin. These muscles are innervated by the facial nerve and are sphincters and dilators of the eyes, nose and mouth. It is key to understand that the wrinkles that we’re seeing are actually perpendicular to the action of the muscle. This is very important for us when we’re thinking about where the lines are and how we would like to get rid of them.

The facial skeleton is composed of fourteen stationary bones and the mandible. These fourteen bones form the basic shape of the face and are responsible for providing attachments for muscles that make the jaw move and control facial expression.

The facial nerve divides into five terminal branches for muscles of facial expression:

Temporal
Zygomatic
Buccal
Marginal mandibular
Cervical

If you’re ever cutting or injecting into any of these areas, it is critical to think about the insertions and the direction of these nerves.

The skin of the face is supplied by the trigeminal nerve (V), except for the small area over the angle of the mandible and the parotid gland that is supplied by the great auricular nerve (C2 and 3). The trigeminal nerve (V) divides into three major divisions—the ophthalmic (V), maxillary (V₂), and mandibular (V₃) nerves.

The arterial supply comes from the common carotid artery and it will innervate and branch thoroughly throughout the scalp and the facial structures and drain via the jugular nerve. Why is this significant? Every time we inject, there is always the potential for a hematoma, a bruise or an injury. Understanding where that vasculature is and where the drainage spots are is helpful to minimize side effects.

Muscles

The Temporoparietalis is key to us because of the temporal nerve. This muscle allows us to raise our ears, widen our eyes, and retract our temples. This can be an ideal place to add a filler; however, it is critical to understand that the temporal nerve is a little deeper. Across the face we have the Frontalis muscle that allows us to raise the eyebrows, widen the eyes, and furrow the forehead. We often take advantage of this to minimize and soften the horizontal lines across the face.

In direct opposition are the depressor muscles of the upper face, which include the Corrugator muscles. These muscles interdigitate with the frontalis; they actually displace the brow inferomedially creating the frown. The Corrugator muscles work in conjunction with the Depressor Supercilii that causes medial brow frowning. Last not but not least is the Procerus muscle—a very important muscle because it not only displaces the brow medially, but also creates the horizontal bands that many patients are interested in improving.

Clinical Pearl-When you are influencing one set of muscles, almost always there is another muscle that is acting against it.

The Transverse Nasalis muscle is a muscle is that interdigitates with the opposite muscle as well as the Procerus muscle. This is the muscle that allows for depression of the cartiginous part of the nose as well as drawing the ala toward the septum. This muscle is what we refer to as the “bunny lines.” We want to be very careful with injections here because too low of injections can infect the smile lines. This is one muscle into which we directly inject and try to keep on the higher edge of the muscular complex.

The Orbicularis Oculi is muscle that has two parts—palpebral and orbital. It has two components, each of which need to be thought about because influence of one portion may influence another part of the muscle. This muscle helps us to open and close our eyes, allowing us to form tears. When we’re addressing this muscle, we’re generally dealing with the orbital aspect of the muscle. When injected correctly, this can provide softening of the crow’s feet. If you inject the Orbicularis Oculi too deeply, you can infect the smile by influencing either the Zygomatic Major or Minor or even the Labii Inferioris Superior.

Clinical Pearl-It is pertinent to understand your endpoints because you will have migration of the neuromodulators over a three- to four-month period of time.

Levator Muscles of the Mouth

The Zygomaticus Major helps to raise the angle of the mouth superiorly and posteriorly and helps our mouths smile or laugh. The Zygomaticus Minor runs medially to the Zygomaticus Major and allows the upper lip to displace superiorly and deepens the nasolabial furrow allowing us to make an expression of contempt.

What about the rest of the mouth? The Depressor Labii Inferioris displaces the lower lip inferiorly and slightly laterally. The consequences of which will allow for displacement of the skin downward and lateral pull to the mouth and potentially an uneven smile if the Mentalis muscle is injected to superiorly. The Risorius muscle is one of our elevators and as a consequence it displaces the skin of the cheek posteriorly, it stretches the lower lip, and displaces the corners of the cheek downward and lateral and we see a nice grin.

The Levator Labii Superioris Alaeque Nasi is an important to muscle to know because it dilates the nose and actually raises the upper lip. The Levator Labii Superioris muscle is responsible for raising the upper lip. This is one of the muscles that we like to target when we’re trying to get less of a grin. When a neuromodulator is placed into these muscles, you can see less “gummy” show in the upper lip.

The Orbicularis Oris is also a very critical muscle. It is quite large and has a number of insertions into it. This muscle helps to bring the lips together and protrude forward. The Buccinator muscle merges with the upper and lower lip muscles and helps to compress cheeks against the teeth along with tensing and contracting the cheeks for a nice pucker. Injection into the vertical Rhytids will allow for some softening of the lines created by that muscular action.

The Depressor Anguli Oris helps as a depressor muscle. It depresses the angle of the mouth resulting in an expression of grief. This muscle is often times sought after as a muscle either to relax by a neuromodulator or to uplift by dermal filler. The Mentalis elevates and protrudes the lower lip allowing for an expression of doubt. This is a critical area to avoid surrounding muscles so that the smile itself is not influenced.

The Platysma muscle is a large muscle that helps to shape not only the lower face, but also heavily influences our neck musculature. It results in the depression of the lower jaw, displaces the lower lip inferiorly, and allows for an expression of horror or fright.

Conclusions

In conclusion, knowledge of the facial muscles is paramount in procedures affecting facial animation. We must understand the relationship of facial muscles and associated nerves and vessels as well as the relationship of muscles and planes throughout the face.

MauiDerm News Editor-Judy Seraphine

Melanoma Clinic: Lunch, Lesions, and Lessons: Part 3

November 5, 2014

Hensin Tsao, MD, PhD

Ilona Frieden

Philip LeBoit, MD

Keith Flaherty, MD

Case Study

A forty year-old woman presents to her PCP with a lesion that she had removed near her left knee (cryotherapy) about one year ago. She thinks something is returning. “It is a tiny miniscule nodule that appears to be a scar.” This appears to be a dermatological issue and “she wants to see her old dermatologist to have it rechecked.” What is an appropriate next step for the physician?

Refer and document
Refer and follow-up with phone call in 1 m
Refer and call the local dermatologist
Refer and follow up with letters until lesion is removed

If you have a general concern, three certified letters can be a good approach. It is extremely important to follow-through and maintain good communication so that you are not held liable.

Seven months later, the patient returns to the PCP with her parents. She was diagnosed with an invasive melanoma. She didn’t see the dermatologist, whom she was supposed to see last spring, until just recently. The patient was referred to Massachusetts General Hospital.

Melanoma on the left knee showed NMM; 7.5mm thick, ulceration 0.4mm, 12 mits/mm²; no microsatellites. She underwent wide resection and sentinel lymph node biopsy (0/8). One year after the diagnosis, she returns for a follow-up and informs you that she wants to become pregnant. She is now 41 years old and she had a miscarriage several years ago. This scenario is not uncommon and Dr Tsao has had referrals regarding this situation.

What do you tell a 41 year-old woman with a stage IIc (life expectancy 30-50%) melanoma about pregnancy?

Fine to become pregnant
Wait at least 2 years
Wait at least 5 years
Wait at least 10 years

Dr Flaherty comments that the fundamental question that we don’t have a great answer to is whether or not every instance of microscopic metastatic disease would ultimately manifest as overt metastatic disease with time. Or, are there patients who can live chronically, i.e., forever with microscopic disease? We do know of late relapses with melanoma. Dr Flaherty tends to tell patients the suggestion that microscopic metastatic disease will convert to macroscopic metastatic disease and the worst that could happen, in the pregnancy setting, is that you could influence the conversion, in other words, it could happen sooner. It is also important to discuss where patients are on the risk curve. The risk of occurrence falls with time.

The risk of relapse after 10 years is actually not clear because high-risk lesions should have relapsed by then while thin relapses continue to emerge. There are differences in the kinetics of relapse between a thin melanoma and a thick melanoma. The bigger the tumor, the more aggressive it is. If the patient survives to year five or ten, it is less likely that something will happen. In fact, there might be a cross over point, probably around year 10, whereby if you had a thick tumor and you’re still alive, the likelihood of it recurring is quite low.

Pregnancy and Melanoma

There are many case control series of melanoma during pregnancy versus not during pregnancy. A 2008 study found no evidence that pregnancy worsens the prognosis. (Cancer Causes Control. 2008;5:437) Some studies suggest that melanoma during pregnancy may be slightly thicker but survival is not altered that much.

The patient visits with a high-risk obstetrician who clears her to become pregnant. Three months later, she finds out that she is pregnant. How do you follow a pregnant person with a history of melanoma?

Routine post-melanoma surveillance
Routine surveillance with total body photography
Increased surveillance every three months
Increased surveillance with total body photography

Total body photography could be a viable option. There is really no literature on dermoscopy in pregnancy. These patients should be followed very carefully. Regarding post-melanoma surveillance, you don’t need to necessarily change your practice because of pregnancy. There are no great studies that convincingly demonstrate a higher risk of relapse during pregnancy. This is highly anecdotal, yet it is very compelling and memorable when it happens.

At week 17 of her pregnancy, she noticed a small, firm nodule within her melanoma scar. Wedge biopsy showed recurrence of melanoma with neurotropism. Wide resection cleared recurrence and a skin graft was placed.

Management of Melanoma Recurrence During Pregnancy

There are treatment options; however, there are no data for metastatic disease during pregnancy. With regards to immunotherapy, high-dose IL-2, which is a physiologic stress, poses a theoretical risk of abruption (in the setting of hypotension). Ipilimumab is likely the first-line choice. Looking at targeted therapy, BRAF inhibitors showed no risk of teratogenicity in limited preclinical studies and MEK inhibitors are theoretically of greater concern; however, that may not be the case in combination with BRAF inhibitors. Chemotherapy is rarely an attractive first-line option in any case.

Package Inserts

Vemurafenib
- Pregnancy Category D
- Vemurafenib can cause fetal harm when administered to a pregnant woman based on its mechanism of action
Iplimumab
- Pregnancy Category C
- Use ipilimumab during pregnancy only if the potential benefit justifies the potential risk to the fetus.

The patient received XRT to the left knee graft area with shielding of the fetus to prevent radiation crossover. At 36 weeks, she underwent a Caesarian section. A histological examination of the placenta did not reveal melanoma. (There have been reports of metastases to the placenta or fetus) One month after delivery she noticed two subcutaneous nodules in the mid-calf distal to the scar site. A biopsy showed metastatic melanoma consistent with in-transit disease. PET/CT showed multiple left lower leg FDG avid nodules, but no visceral metastases. Both radiologically and clinically, she’s beginning to develop at a faster pace.

What would you recommend now?

Isolated limb perfusion
Targeted removal of individual lesions
Genotyping with anti-BRAF agent if BRAF+
Systemic treatment with IL-2 or immune checkpoint antibody

In-Transit Metastases

We lack high-level evidence for the optimal approach in this case. According to the NCCN guidelines, enrollment in a clinical trial is the preferred approach. Options for local therapy include complete surgical excision, intralesional injection (BCG, IFN, IL-2), local ablation therapy, topical imiquimod for superficial dermal lesions, and consideration of palliative XRT for unresectable disease. Isolated limb infusions/perfusions with melphalan could be considered as a regional therapy option as well as the use of systemic therapy. Systemic used to be considered as bottom of the list; however, it is being utilized more and more.

The issue with regional therapy is that it has no impact on disease elsewhere. With regards to intralesional therapy, Weide and colleagues found a high response rate after intratumoral treatment with IL-2 in a phase two study of 51 patients with metastatic melanoma. The 2-year survival rate was 77 percent for patients with stage IIIB/IIIC disease. Efficacy and survival did not differ between patients who had greater than or equal to 20 lesions and patients who had less than 20 lesions. (Weide B, et al. Cancer. 2010;116(17):4139-4146.)

Alexander and colleagues analyzed factors that influenced the outcome in patients with in-transit malignant melanoma undergoing isolated limb perfusion using modern treatment parameters. Between May 1992 and February 2005, 91 patients underwent a 90-minute hyperthermic ILP. There were 62 complete responses (69%) and 23 partial responses (26%) in 90 assessable patients.

The patient underwent isolated limb perfusion with melphalan but unfortunately continued to progress. She continued to progress through multiple experimental treatments over the ensuing year and she expired six years after her initial diagnosis.

Pregnancy and Melanoma-Take Home Points

Pregnancy does not appear to compromise survival
- “Wait time” considerations include:
  - Potential treatment complications during pregnancy
  - Age of patient and desire for children
  - Personal outlook (e.g. religion, “abandoning” children)
  - Availability of oocyte cryopreservation
- Risk extinction is more obvious for thicker tumors
Bottom line (not scientifically based)
- For patients with multiple DN- watch q3m’s during pregnancy
- For MIS and thin melanomas- OK to start (need discussion)
- For melanomas >1mm- wait 2 yrs unless age is major concern
Discussion (Push/pull model)
Push information-
- There is the chance of relapse and death (estimate prognosis)
- Come to an agreement on a course of action
- There is a tiny chance of transplacental metastasis
- Pregnancy per se does not appear to influence outcome- gestation cannot be an instrument of guilt or regret
- Need partnership with high-risk OB and possibly early consult with medical oncology
- Patients should probably be monitored more frequently
- Inform patient about possibility of additional biopsies during pregnancy
- Inform patient about oocyte cryopreservation
Pull information (warning: takes time and may be difficult emotionally)-
- Does the patient understand the implications of relapse during pregnancy (including the possibility of termination)?
- What are the plans should baby survive but mother does not?
  - Discussion becomes more concrete and intense as relapse risk increases
  - Wait time is meant to clarify this risk a bit
  - May need social work to help through these conversations

MauiDerm News Editor-Judy Seraphine

Update in Cutaneous T-cell Lymphoma (CTCL)

October 26, 2014

Alain H. Rook, MD

At MauiDerm 2014, Dr Rook provided the audience with an update on CTCL, a challenging disease in the field of dermatology. Dr Rook, one of the world’s leading authorities on CTCL, is a professor at the Perelman School of Medicine at the University of Pennsylvania.

There is one scenario that unfortunately occurs all too often with patients who present with erythroderma—you must be absolutely sure of the diagnosis before you administer therapies (anti-TNF agents, ustekinumab, cyclosporine, etc) that will blunt the immune response. This is extremely important because you do not want to administer these agents in patients with CTCL as they can lead to rapid disease progression.

Diagnosis of Erythroderma

In an erythrodermic patient, dermatologists should be aware that a single biopsy is inadequate in up to fifty percent of cases due to the absence of critical diagnostic features.

What do we look for in a biopsy?

When looking at a biopsy, we look for well-known epidermotropic morphology. We also look for clusters of cells. Another critical finding is the lining up of some large lymphocytes at the dermal/epidermal junction. The malignant T-cells are being recruited towards the epidermis by chemokines, with the “sentinel sign” a characteristic that is more often found in erythroderma than is epidermotropism. We also need to look for large atypical cells in the dermis occasionally in association with eosiniphils. Eosiniphilia, together with erythroderma, should not equal pityriasis rubra pilaris or psoriasis, but is more characteristic of erythroderma associated with either atopic dermatitis or cutaneous T-cell lymphoma (CTCL).

In up to fifty percent of cases, there is a high frequency of non-diagnostic histology in Sezary syndrome, the leukemic variant of CTCL. Published studies have observed chronic dermatitis in 33 percent of biopsies from Sezary syndrome and no evidence of CTCL in 25 percent of biopsies from these patients. “Non-specific cutaneous histopathologic findings are common in Sezary syndrome.” (Trotter MJ. J Cut Pathol. 1997)

In addition, we like to study both the skin and the blood and determine if there is a dominant T-cell clone. In particular, if you see matching clones in the skin and blood, that’s usually typical of CTCL, but not always. Autoimmunity can be associated with dominant clones; however, you typically do not see the identical clone in the skin and blood in a patient with autoimmune disease. This is much more characteristic of CTCL or a T-cell lymphoma.

Flow cytometry is absolutely critical to perform on an erythrodermic patient in whom you would like to rule out CTCL. Prior to about ten years ago, the gold standard was looking for the loss of CD7 on CD4 T-cells that is known to occur in about 50 percent of leukemic patients. Now, we typically look for loss of CD26, occurring in greater than 90 percent of leukemic patients in our experience. This is important because in more than 80 percent of active erythrodermic CTCL cases, you will see active peripheral blood involvement or leukemia. This is a critical test to perform in a highly skilled laboratory. Many of the public laboratories that are not associated with academic programs do not monitor for loss of CD26.

Flow Cytometry

More useful than Sezary prep
Confirms presence of blood disease
CD4+/CD7- or CD4+/CD26-
False positive increase in CD4+/CD26- T-cells in atopic dermatitis
> 20% circulating lymphocytes that are CD4+/CD26- highly suggestive of Sezary syndrome

Don’t forget about physical examination, i.e., palpate lymph nodes.

It’s important to remember that when you’re treating Sezary syndrome, you should NOT use:

Cyclosporine
Azathioprine
Mycophenylate mofetil
Anti-tumor necrosis factor agents
Anti-IL-12/23

The reason that we cannot use the therapies mentioned above is because the cellular immune response is absolutely critical for these patients. Combined immune potentiators for advanced CTCL have been shown to produce high response rates. These include combinations of interferons, bexarotene (or an RAR specific retinoid), GM-CSF, and photopheresis. We also attempt to debulk the skin with PUVA or total skin electron beam.

It is noteworthy that a 2011 paper demonstrated that psoralen plus UVA light can be associated with the clearing of peripheral blood disease in advanced CTCL. (Raphael BA, et al. JAAD.2011;65(1):212-214.) In fact, three out of the five patients presented in this series cleared their blood when PUVA was added to their regimen. And we certainly can accomplish the same in the majority of patients who receive full dose total skin electron beam.

Why is the skin involved in T-cell lymphoma?

Malignant T-cells are very high expressors of cutaneous lymphoid antigen (CLA). When the cutaneous endothelium is activated by interferon gamma or tumor necrosis factor, you observe upregulation of E-Selectin. The cells then begin to adhere and roll very slowly. The malignant cells are also very high expressers of CCR4; this is important because CCR4 is the chemokine receptor for CCL17 (TARC) which is manufactured in the epidermis and which is responsible for attracting the cells into the skin.

Phase I trial data demonstrate that KW-0761, an anti-CCR4 monoclonal antibody with enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) currently in phase III trials for leukemic forms of CTCL, is both efficacious and safe.

Treatment of CTCL

Alemtuzumab, which is particularly useful for leukemic CTCL in the absence of bulky nodal disease, targets CD52 on T-cells, B-cells, and monocytes, which at high dose, causes patients to become severly immunodepressed. In 2007, Maria Bernengo published a clinical protocol for the use of low-dose alemtuzumab.

3 mg days 1 and 3
10 mg days 5 and 7
Continue 10 mg every other day until Sezary count < 1000/ mm³
Monitor Sezary count Q2 weeks for one month then Q month
If Sezary count exceeds 2000/ mm³ resume treatment
High response rates of non-transformed disease
Low infection rates

Alemtuzumab is extremely effective at this dose and Dr Rook has never seen a serious or life-threatening infection at his institution. But, nevertheless, patients still require prophylaxis against PCP, fungal infection, and against reactivation of Herpes and varicella zoster.

Histone deacetylase inhibitors are very effective for advanced disease, particularly romidepsin. Romidepsin is a parenteral agent that produces responses in advanced disease in about fifty percent for both tumor stage disease and refractory Sezary syndrome. It is generally pretty well tolerated unless the patient has serious cardiovascular disease. While vorinostat is easier to administer because it is oral, patients don’t tend to like it because of unpleasant side effects including diarrhea and fatigue.

Brentuximab vedotin is an agent that is likely to be useful for large-cell transformation and is under investigation. It is currently FDA-approved for CD30-positive lymphomas, ALCL, and relapsed Hodgkin’s disease. This drug is a fusion protein that contains an antibody directed at CD30. This is important because CD30 gets upregulated in large-cell transformation. Appended to it is monomethyl auristatin, a tubulin toxin. In view of its affinity for CD30, brentuximab can be administered to patients with refractory large-cell transformation. Adverse effects can include peripheral neuropathy.

Early Disease

This is the typical arciform distribution of early disease. The fact that we can see clearing in the center is highly suggestive that the host immune response is playing a role in keeping this somewhat under control. The survival rate of patients with stage 1a disease when treated is similar to that of the general population. It is important to note that patients who present with plaques have a worse prognosis than patients who present with patches, these patients need to be treated vigorously and immediately.

Treatment of Stage T1 (patches or plaques on less than 10 percent of the skin surface area)

Potent Topical Steroids
Nitrogen Mustard (0.01-0.04% ointment)
Carmustine (0.03-0.04% ointment)
Narrowband UVB
PUVA
Topical Retinoids (Bexarotene, Tazarotene)
Imiquimod

A novel mechlorethamine 0.016% gel (Valchlor) was FDA-approved in 2013 for the treatment of CTCL. Dr Rook advises that this compound be used with caution because it can be irritating. When using a topical chemotherapeutic, Dr Rook prefers to use it nightly in an effort to avoid drug resistance. However, because Valchlor is irritating, the recommendations are to use it every other night and perhaps in conjunction with topical steroids to prevent/reduce irritation.

Interferon Alpha and Antitumor Effects

Interferon activates anti-tumor cytolytic cells and inhibits the growth of malignant T-cells. It also inhibits the production of Th2 cytokines. We have also found that response rates are greater when used in combination with PUVA, retinoids, photopheresis, and/or interferon gamma. In order to minimize the side effects of interferon, Dr Rook utilizes a low-dose interferon. Nevertheless, there is a dose related effect with higher doses being more efficacious but are less well tolerated.

Treatment Protocol

Initial Dose 5-2.5 million Units SQ 3 x per week
Increase to: 5-7.5 million Units SQ 4-5 x per week
Typical Dose: 5-5 million Units SQ every other day

Bexarotene

Bexarotene induces apoptosis of malignant T-cells. Keep in mind that not all patients will respond; there is only about a forty percent response rate due to the likely reason that the critical RXR receptors may not be expressed at the cell surface of the malignant population in all patients. Dr Rook recommends using bexarotene in combination with interferon, PUVA, and/or photopheresis in an effort to prevent resistance. If you are treating patients using bexarotene, they will require intensive control of hyperlipidemia, i.e, use of a statin and/or other lipid-lowering drugs. Bexartone also produces central hypothyroidism by suppressing TSH so thyroid function should be measured with free T4 (not TSH). Bexarotene may be more difficult to use in diabetics and patients with hyperlipidemia.

Imidazoquinolines

These particular drugs are powerful Toll-like receptor agonists and are therapeutically active for CTCL. Many patients may not respond to imiquimod. Dr Rook prefers to use the Zyclara Pump (3.75% Imiquimod) as it is easier to control the amount dispensed as well as easy to spread.

Resiquimod, a combined TLR 7 and 8 agonist, is at the first stages of the pipeline. It has a bioavailability ten times greater than imiquimod and potency up to 100 times greater than imiquimod. A one-gram application induces a systemic interferon alpha response. Dr Rook is conducting a phase 1 trial with resiquimod and has found that patients get systemic absorption, activation of circulating antigen-presenting cells, and widespread clinical responses. This appears to be a very exciting drug that clears treated lesions and induces the resolution of distant lesions.

MauiDerm News Editor-Judy Seraphine

Melanoma Clinic: Lunch, Lesions and Lessions: Part 2

October 26, 2014

Part 2

Hensin Tsao, MD, PhD

Keith Flaherty, MD

Ilona Frieden

Philip LeBoit, MD

Case 2

In early August of 2007, a 47 year-old patient presented to her PCP with concerns of an atypical appearing lesion on the left lower leg. She was referred to a dermatologist. On August 14^th, the biopsy showed 0.97 mm, Level IV, SSM, four mitoses, and non-ulcerated. A wide excision was performed and there was no residual melanoma and no further surgery was recommended. ‎In April of 2009, the patient noted a small cutaneous mass in scar line on the lower left leg. In June, the patient underwent wide local excision and sentinel lymph node biopsy. The results showed two out of three positive sentinel nodes, the largest metastasis was 4mm; and (+) extracapsular extension. On July 29, 2009, she underwent (L) inguinal LND and sartorius muscle transposition flap. Zero out of seven nodes (including Cloquet’s node) were negative. There were a total of two out of ten positive nodes. She received adjuvant interferon. Unfortunately, two years later, a PET-CT showed an increase in the number of FDG avid lesions in the leg and inguinal and pelvic adenopathy. She’s now considering systemic treatment.

What specimen should be used for determining the patient’s BRAF status?

Primary melanoma FFPE
Primary melanoma FFPE and blood DNA for comparison
Sentinel lymph node metastasis
Soft tissue metastasis from leg

The general guidelines are to take the most recent evidence of advanced disease. Concordance is very important. Do you know that the lesion in the lung is identical to the lesion that presented five years ago according to its genotype?

SNaPshot panel reveals BRAF WT, NRAS and Q61R mutation. On March 21, 2011, she received high-dose IL-2 therapy. In June of 2011, the PET/CT revealed increased FDG uptake in pre-existing left leg subcutaneous nodules and an increase in size as well as FDG uptake in bilateral inguinal lymph nodes. In August, she enrolled in a clinical trial of bevacizumab and ipilimumab. A CT C/A/P performed in April of 2012 revealed an increase in the size of the largest lung mestastasis (15mm to 20mm) and a new 1.6cm liver metastasis. MRI of the brain was negative. June 8, 2012 was her first day on 10-017, a phase 1 study of a CDK4/6 dual inhibitor. By the end of the July, CT C/A/P revealed disease progression in the lung and a new, solitary brain metastatsis measuring 4mm; the disease burden was otherwise relatively stable. In August, she underwent stereotactic radiation to the solitary, 4mm brain mestastasis. October 23, 2012 was cycle one/day one of BKM120/MEK162 trial # 11-308. She remained stable for four months.

One of our greatest challenges is that NRAS is not something that we can target with a drug. Indirect strategies; however, may work.

MEK inhibitors in NRAS-mutant melanoma have some efficacy. It’s not comparable to what a MEK inhibitor or BRAF inhibitor can do in BRAF-mutant cancer, but it is certainly a suggestion that may perturb these tumors.

Acne: Clinical Pearls

October 8, 2014

James Treat, MD

Dr James Treat provides us with an outline on the management of pediatric acne…

Acne Type and Age of Onset

Neonatal: Birth to ≤6 wk
Infantile: 6 wk to ≤1 y
Mid-childhood: 1 y to <7 y
Preadolescent: ≥7 to ≤12 y or menarche in girls
Adolescent: ≥12 to ≤19 y or after menarche in girls

Neonatal Acne:

Benign, self-limited, asymptomatic eruption of erythematous papules and pustules; no comedones
- Typically localized to cheeks, forehead, and scalp
  - But: can extend into scalp and onto the shoulders (Neonatal Cephalic Pustulosis)

Infantile Acne:

Clinical: Typically starts at around 3-6 months of age up (as young as 6 weeks) and usually lasts 6-12 months

Clinically this looks like adolescent acne:
- Comedones, inflammatory papules and nodules
Scarring potential
Harbinger for later acne
Most Infantile acne is NOT associated with an endocrinopathy

BUT if on exam you see:

Excess Growth
Advancement of Tanner Stage
Cliteromegaly or enlarged testciles.

THEN: Hormonal workup, consider endocrine evaluation

FSH, LH, DHEAS, Free and Total Testosterone, 17 OH Progesteterone , androstendione, and Bone Age

Mid-Childhood Acne

Starts between 1 and 7 years of age.

Clinically this looks like adolescent acne:

Comedones, inflammatory papules and nodules
Scarring potential
Harbinger for later acne
This is not an age when there is normal androgen production so acne at this age requires a workup.
Clinical exam:
- Excess Growth
- Advancement of Tanner Stage
- Cliteromegaly or enlarged testciles.

Hormonal workup and endocrine evaluation

FSH, LH, DHEAS, Free and Total Testosterone, 17 OH Progesterone, androstenedione and Bone Age

Treatment (off label): same as adolescent acne except NO tetracycline derivatives

Topical retinoids and Benzoyl Peroxide products often enough
Systemic choices: erythromycin derivatives, isotretinoin