Dermatology Year in Review Part 2: New Treatments

Hensin Tsao, MD, PhD

 

Dermatologists should remember that most basal cell carcinomas (BCCs) are removed by surgery or with radiation or topical therapies. This past year there has been much more data on hedgehog signaling, which is involved in most BCCs.

Hedgehog Pathway

Vismodegib, which targets the hedgehog pathway, has been studied in BCCs. Of note, the hedgehog pathway is also being studied in other cancers, including pancreatic and brain cancer.

Sekulic, et al. published a study in the New England Journal of Medicine looking at the efficacy and safety of Vismodegib in advanced basal-cell carcinoma looking at 33 patients with metastatic basal-cell carcinoma and 63 patients with locally advanced basal-cell carcinoma, the latter of which is more prevalent in the dermatology setting. The primary endpoint of the study was independent review by an outside dermatologist. The study concluded that Vismodegib is associated with tumor responses in patients with locally advanced or metastatic basal-cell carcinoma.

The most commonly reported adverse events (AEs) were muscle spasms, alopecia, and dysgeusia. Other AEs included decrease in weight, fatigue, nausea, decrease in appetite, and diarrhea.

Tang, et al. studied the results of inhibiting the hedgehog pathway in patients with basal-cell nevus syndrome. (New England Journal of Medicine) There were 41 patients in the study; 26 on Vismodegib vs 15 on placebo. The study looked at cessation of new BCC development while on Vismodegib and the decrease in the diameter of existing lesions while on Vismodegib.

The data from this study demonstrate that one can see no new BCCs form while on Vismodegib and a significant decrease in the diameter of existing lesions while on drug. (Of note, there was a significant attrition of use because of the side effects.) Also of importance is the fact that GLI1 levels diminished on patients taking Vismodegib; therefore, indicating that the drug is hitting its target.

Clinical Pearls
  • This small-molecule hedgehog pathway inhibitor is effective for metastatic, advanced and generalized BCCs
    • Represents nice bench-bedside development of a new cancer agent
  • Side effects, recurrences after drug discontinuation, and cost are limiting factors
    • Although FDA-approved, the role of Vismodegib for common BCC settings is unclear given limitations

 

Head Lice

The emergence of resistance to first line antipediculicides complicates the public health problem of head lice. Dermatologists should remember that second-line treatments, such as lindane and malathion, have limitations related to safety; therefore, newer approaches for the treatment of head lice are needed.

David Pariser and colleagues published a large prospective trial in 2012 in the New England Journal of Medicine looking at topical Ivermectin 0.5% for the treatment of head lice. The study found that Ivermectin has a higher success rate versus the control vehicle.

The side effects for Ivermectin were rather tolerable. AEs included pruritus, excoriation, and erythema.

Clinical Pearls
  • Ivermectin targets glutamate channels whereas permethrin targets sodium channels
  • Topical ivermectin achieved a success rate of >90% with single application
    • Similar to oral ivermectin
  • Nit combing not necessary with ivermectin as opposed to permethrin
  • Nice option for permethrin-resistant louse or even as first line
 Targeted Therapy for Melanoma

Although molecular control of melanoma through targeted therapies has shown tremendous success, relapse is still the general rule; therefore, long-term remission will require immune participation in order to have recognition at the immune surveillance level. Often times, the tumor evades the immune system by circumventing immune checkpoints; yet, recent advances in the studies of targeted therapy for melanoma (Anti-PD-1 and Anti-PD-L1 antibodies) have demonstrated positive efficacy in tumor reduction.This new area of research is at the level of the tumor itself. These therapies, currently under trial, both have major potential in clinical practice and patient outcomes.

Data from Topalian et al, published in the New England Journal of Medicine show that the objective response rates are less than 30 percent as defined by the RESIST criteria. Many patients experienced a drop-off of greater than 30 percent tumor reduction using anti-PD-1.  The anti-PD-L1 shows similar results, but not to as great as an extent as that of anti-PD-1.

Clinical Pearls
  • Anti-CTLA4, anti-PD-1 and anti-PD-L1 represents the triumvirate of immune checkpoint therapies
    • Precise molecule and formulation may be important
    • Tremelimumab (another anti-CTLA4 antibody) did not show any significant survival benefit
  • Anti-PD-1 and anti-PD-L1 treatments appear to be less toxic than ipilimumab
  • Combination molecular therapies for acute control and checkpoint therapies for long-term control may be the wave of the future

 

Overcoming Rejection and Cancer

A small study in the New England Journal of Medicine looked at the role Sirolimus (rapamycin) in secondary skin cancer prevention in the transplant population. Rapamycin, which targets the mTOR pathway, blocks the transduction pathway. This action not only prevents the rejection, but can also prevent SCC from developing.

Patients in the study were randomized to either Sirolimus or cyclosporine, tacrolimus. All patients had at least one prior SCC and were stratified by the number of prior SCCs. Overall there was a significant improvement in the probability of survival-free with Sirolimus compared to the calcineurin inhibitor controls. However, when the data is broken down, one can see that the majority of this effect occurred in the sub-population, i.e., patients with only one prior SCC.

Clinical Pearls
  • Sirolimus is an effective suppressor of transplant rejection and has the added benefit of suppressing development of SCCs
  • The medicine’s positive effects must be balanced against a large number of adverse effects
  • It is less effective in patients who have already had more than one SCC
  • This is not the final word in prevention of skin cancer in transplant recipients

Dermatology Year in Review Part 1: New Observations

Hensin Tsao, MD, PhD

Dr Hensin Tsao, Director of the Melanoma Clinic at Massachusetts General Hospital, lead off the 2013 Maui Derm meeting by providing the audience with an overview of some of the top stories in dermatology in 2012-2013.

Melanoma

Dermatologists should know that melanoma is the 5th most common cancer in males and the 6th most common cancer in females affecting one in 36 men and one in 55 women.  Most of these numbers are not including melanomas in situ, which would then most likely make the numbers higher. (American Cancer Society 2012)

Unfortunately, melanoma incidence and mortality continue to increase. There is also a disparity in survival among races, i.e., African Americans tend to have a survival disadvantage compared to whites and other races, especially in Stage III.

Another interesting fact is that there are twice as many deaths from melanoma for men than for women; therefore, there is a thought that there is a female survival advantage. Based on the graph below, one can see that the mortality for rate for males, after age 65, really begins to take off.  There appears to be some sort of lethal phenotype associated with melanoma in elderly men, especially in the head and neck. This is a group to whom one should pay particular attention.

A study in the Journal of Clinical Oncology demonstrated a superior outcome of women versus men with Stage I/II cutaneous melanoma. This was based upon a pooled analysis of four European Organization for Research and Treatment of Cancer Phase III trials.

The bulk of the effect appears to come from the tumor thickness (especially in tumors greater than 2 mm). Overall, males seemed to do worse than females.

When the studies are aggregated, almost every study conducted around the world shows a hazard ratio of approximately 0.6 to 0.7. This is consistent across many studies; therefore, this does not show a detection or reporting bias.

Clinical Pearls
  • Melanoma incidence and mortality rates continue to increase
  • There may be a disparity in survival between races
  • There appears to be stronger evidence for a “female advantage” in survival although biologic basis is unclear
    • Unlikely reporting bias since it has been observed worldwide

 

Injection Infection

Another hot topic is that of blood-borne viral infections linked to tattooing. Most of the time it is due to the tattoo artist being substandard in hygiene. Recent studies have demonstrated that M. chelonae infection has been associated with tattoos. Molecular analysis showed M. chelonae was found in 11 clinical isolates and in an unopened bottle of ink. 18 out of 19 patients responded to macrolides and or doxycycline depending on sensitivities. It should be noted that contamination likely occurred before distribution.

For Dermatologists, there appears to be a need for better oversight and record keeping.

Sun Avoidance

Sun avoidance is a crucial component of all skin cancer prevention campaigns. Scientists have begun to study the effects of direct light, diffuse light, and reflected light.  Modeling revealed that a large amount of diffuse UV radiation occurs. Recent studies indicate that direct UV occurs mostly on exposed sites during summer months; reflected irradiation occurs during winter months.

SimuVEX software was utilized to estimate UV from various ambient sources. Diffuse radiation accounted for 75-85% of the annual sun exposure. It is not clear whether or not shading can protect against diffuse light.

Tanning Beds

The WHO has classified sun lamps as a carcinogenic agent. The true morbidity of tanning bed use is an area of intense scrutiny and better estimates are emerging.

The British Medical Journal published a meta-analysis (27 studies) in 2012 looking at cutaneous melanoma and its association with sunbed use.  This study found that there is about an 87% increased risk of melanoma if tanning [beds] are first used before age 35. There is an element of dose-dependence associated with the use. This is becoming a significant public health problem as tanning bed use now contributes to about 10% of melanomas. As expected, the risk of melanoma with tanning bed use is independent of latitude. Public health response is more aggressive these days, but we’re not there yet.

Natural Disaster Dermatology

Murcormycosis is a rare infection caused by molds that are ubiquitous in soil, decaying wood and organic material and if left untreated, it can lead to massive tissue necrosis. Although it usually occurs in immunocompromised patients, the fungus can develop after trauma in the immunocompetent patient.

A 2011 study looked at necrotizing cutaneous murcormycosis after a tornado in Joplin, Missouri.  The study found that of the 13 patients with murcormycosis, five patients died; four out of the six patients were not treated with Amphotericin B and one out of seven patients treated with Amphotericin B died.

What are the risk factors that lead to mortality after infection?

  • Number of wounds that were punctured
  • Rhabdomyolysis
 Clinical Pearls
  • Outbreaks of rare saprophytic infections after catastrophes have been reported
  • All 13 cases had DNA evidence of Apophysomyces trapeziformis
  • Infection needs to be considered early so proper treatment with AmphoB can be instituted
    • Increased number of puncture wounds, early signs of rhabdomyolysis

 

 

 

 

 

Combining Lasers with Toxins and Fillers

Suzanne Kilmer, MD

In this presentation, Dr Kilmer reviewed the techniques for combining the various technologies that are currently available for facial rejuvenation in order to obtain optimal cosmetic improvement for patients.

Dr Kilmer stresses the importance of remembering the 5 Rs:

  • Relax
  • Refill
  • Rejuvenate
  • Resurface
  • Reassess
Relax

It is important to relax the skin with a botulinum toxin to keep both the muscles and the skin from moving as much as it otherwise would. If she is going to laser the skin, the results are improved when the skin/muscles are not moving. Dr Kilmer also uses fillers, in conjunction with the toxins and lasers to fill in lines, tighten up the skin and remove brown/red spots.

Clinical Pearl: Never use toxins, lasers, or any other device that can cause significant swelling on the same day. This can result in the toxin migrating to other places where you do not want it.

Refill-Restore Volume Loss

When using dermal fillers, the objective is to restore volume based on a patient’s specific needs. Fillers can be placed in various areas locally such as the nasolabial folds, marionette lines, deep glabellar rhytids, tear troughs, scars, and the nasal bridge. Fillers can also be used globally in the cheeks and temples.  It is important to remember that there may be a lag time resulting in delayed gratification. It is very important to keep in mind that one can’t massage post poly-L-lactic acid (Sculptra) in areas where Botulinum toxin was placed.

Rejuvenation

There are various approaches to rejuvenation. These include:

  • Vascular approach (more specific?)
    • Stimulated by injury to microvasculature, which initiates cascade of events.
  • Pigment approach
    • Targeting melanin can remove pigmented lesions and may also improve textural changes.
  • Thermal approach
    • Non specific heating leads to injury response/wound healing and possible collagen tightening.
  • Fractional approach
    • Nonablative and ablative
Resurface

Dermatologists can resurface the skin with the chemical or mechanical removal of the epidermis. Devices that be used for resurfacing can be both selective and nonselective.

Combination Treatment

Best order

  • Start with toxins to stop movement and relax muscles.
    • Relax frown, smile and lip lines when doing facial rejuvenation
    • Relax DAOs and neck bands when doing fillers, tightening or resurfacing
      • May need less filler and patients are happy sooner with tightening devices
  • Then filler or laser depending on a patient’s specific needs (and ability for downtime)
    • Never do toxins and lasers that cause swelling at the same time because toxins can migrate.
  • Typically end with filler if still needed after toxins and laser
    • Sometimes the combination will diminish the need for filler
    • If able to tell that will need volume, can do before or at same time as laser

Caveats of Combining Treatments

  • Toxin with Filler
    • Can’t massage post poly-L-lactic acid (Sculptra) in areas where Botulinum toxin was placed
  • Toxin with Laser
    • Can’t do toxin same day as Fractional lasers – swelling can lead to migration
    • Can do botulinum toxin with PDL, IPL, CoolTouch, SmoothBeam, Thermage, Titan
  • Filler with Laser
    • Can do filler same day but do first if doing fractional as swelling can mask need for filler.
  • Fractional with RF tightening
    • Same day – do Thermage 1st because need intact skin but when you do the fractional laser the skin may still be sensitive

Combining Fractional with other Devices

  • Fractional laser with other lasers/txs
    • Lentigines – pre-tx QS lasers, KTPs, etc
    • AKs – LN2
    • Sebaceous hyperplasia, nevi – 1450 nm
    • Vascular lesions – PDL, KTP, Alex
    • Downtime from other treatment is simultaneous and shortened
  • Fractional resurfacing with ablative resurfacing
    • Almost always do fully ablative to upper eyelids
      • More tightening/more predictable – do inner canthi
    • Can ablate/sculpt edges of scars, upper lip lines and elevated lesions
  • Ablative fractional and nonablative fractional resurfacing
    • Nonablative fractional to face, ablative to neck for more tightening /crepiness – useful for those with hx ablative resurfacing/chemical peels/dermabrasion

Other combination treatment includes fat loss and tightening, fractionated RF + QS/KTP/PDL and, fractionated US + QS/KTP/PDL.

Reassess

Remember that combination treatment may minimize the need for other treatments and may increase the interval for maintenance. It is extremely important to assess whether or not the patient’s needs have been met. Ask yourself and the patient if new things have become noticeable now that the initial needs have been met? And remember, with time, additional needs may become apparent.

Summary

  • Botox, fillers and lasers can all be used synergistically to minimize the signs of sun damage and aging.
  • Expertise in technique, use of the best possible modalities, and watching for and treating any possible complications will produce the best results.
  • Combining these modalities may obviate the need for more invasive procedures, such as facelift

 

Fractionated Laser Technologies

Sandy Tsao, MD

There is a lot of information out there and our patients are coming to us with questions about the various devices. Remember, there isn’t one clear-cut way to manage your patients.

What’s the rationale for fractional resurfacing?
  • Safer for non-facial areas; beard area
  • Safer for darker skin phonotypes
  • Efficacy greater compared with other non-ablative technologies
  • Safer side effect profile c/w ablative devices
  • Recovery time markedly reduced
  • No permanent lines of demarcation to date
  • Non-ablative and ablative devices

There are a variety of fractional technologies for rejuvenation currently available to the practicing dermatologist.

The Goal of Thermal Injury

Thermal injury is thought to be key for tissue repair. Heat-induced inflammation results in immediate collagen shrinkage and tissue contraction and subsequent fibroblast stimulation.  There is a zone of irreversible thermal damage and associated inflammation must heal before re-epithelialization begins. Prolonged inflammation due to infection, hypersensitivity, or extensive thermal damage due to vigorous treatment can result in complications.

How does fractional resurfacing work?
  • One pulse produces one MTZ
  • Thermally induced coagulation, not vaporization
  • Columnar shape
  • Diameters are variable
  • 1:5 width to depth ratio
  • 5-48% total skin coverage – each treatment

It is important to remember to match treatment depth with the indication.

Pigment-Superficial to mid dermis

Mild rhytids- Mid reticular dermis

Moderate rhytids – Deep reticular dermis

Surgical scars and acne scars- Deep remodeling

 Fractional non-ablative laser treatment in a cross section of human tissue demonstrated complete re-epithelialization within 24 hours. There was clear collagen denaturation from the papillary dermis into the mid reticular dermis. Healing occurs from viable tissues. Zones of spared tissue contain clusters of epidermal stem cells and Transit Amplifying (TA) cells.

Ablative Fractional Resurfacing

These work like the nonablative devices; however, you lose the epidermis.

  • Ablative tissue coagulation with loss of stratum corneum
  • Multiple microthermal zones of injury surrounded by viable tissue
  • Resurfacing with replacement of skin in 5-7 days
  • More thermal damage with longer healing time
  • Immediate and delayed therapeutic benefits greater
    • Epidermal and dermal coagulation for resurfacing
    • Collagen denaturation for tissue remodeling

 

The downside to laser treatment can be the downtime associated with the procedures and patients should be aware of this. Estimated downtimes are:

Microlaser peel– 7 days peeling, 2 weeks of a pink hue

Fractionated non-ablative

1410nm- 1 day of mild erythema and edema

1550nm- 2-3 days of erythema and edema

1927nm- 4-5 days of erythema and edema

2940nm- 7 days of erythema and edema. 2 weeks of pink hue

Fractionated ablative– 7 days of erythema and edema; 4-6 weeks of pink hue

Ablative– 14 days of erythema and edema; 2-3 months of pink hue

Laser Treatment of the Periorbital Region

When treating  around the eyes with laser therapy, less aggressive treatment is needed. When treating the lids, a metal protective lens is necessary. For lens placement, use alcaine anesthesia and erythromycin. Be sure to use particular caution in patients with prior surgical history.

Darker Skin Types
  • Less is more (Fluence, density, passes)
  • Consider a laser test site
  • Stress the need for strict photoprotection
  • Discuss the increased risk of PIH
  • Consider pre-treatment use of retin-a or hydroquinones
  • Use caution with ablative fractional devices

Charities and Laser Treatment

Michael Gold, MD

There are many charities throughout the world that are providing laser treatment for scars due to injuries and/or accidents to those who cannot afford the treatment.

The Wounded Warrior Project, here in the United States, is providing laser treatment to our wounded troops. This effort is really helping to improve the quality of life of veterans.

 

 

Targeting Vascular Lesions

Stuart Nelson, MD, PhD

There are a variety of different “optical technologies” that can be used to treat vascular skin lesions. These technologies include: pulsed green or yellow light, intense pulsed light, alexandrite, diode, Nd:YAG and dual devices such as combined pulsed dye + Nd:YAG. Dermatologists should remember that a variety of vascular skin lesions are amenable to laser therapy such as angiomas, adenoma sebaceum, angiokeratomas, blue rubber bleb nevus, ecchymosis, poikiloderma, rosacea, scars, telangiectasias, vascular malformations and warts.  Therapies are based on the concept of selective photothermolysis (Anderson and Parrish, 1983). Wavelengths of light highly absorbed by targeted hemoglobin with thermal injury confined to the vessel and immediate perivascular area.

Clinical Pearls
  • Epidermal melanin is a competing chromophore for many of the wavelengths used to treat vascular lesions. Epidermal cooling is essential, particularly for the treatment of lesions in patients with darker skin phototypes.
  • Short pulse durations (< 6 ms) can cause purpura and should be used cautiously for the treatment of facial vascular lesions, particularly in men.
  • Facial telangiectasia are easy to treat by pulsed green or yellow light or intense pulsed light and the operator should see an immediate response (vessel disappearance or collapse). Pick one, understand treatment endpoints and then perfect your technique.
  • Paradoxically, scars respond much better to lowerenergy densities.
  • Nd:YAG lasers can be used to treat linear arborizing telangiectasia of the lower extremities with pulse durations of 10-100 ms (depending on vessel diameter), energy densities of 50- 200 J/cm2 delivered on small spots (2-3 mm). Also consider “endovenous” approaches.

 

Treatment of port wine stains by pulsed dye laser remains the standard of care. Caveats for treatment include: 1) begin treatment as early as possible and treat aggressively; 2) due to blood vessel size heterogeneity, multiple wavelengths and pulse durations should be used; and 3) maintenance treatments helpful to maintain result. Many lesions that respond well initially to treatment may reach a response plateau. Such lesions may also be treated with a deeper penetrating 755 nm alexandrite laser.  The pulsed dye laser is effective for treating superficial hemangiomas. The risk/benefit ratio is favorable and, at least for symptomatic lesions (e.g., bleeding/ulcerating) and those that cause functional impairment (e.g., periorbital), laser therapy is appropriate. Caveats for therapy include: 1) lesions <3 mm thick; 2) low energy densities (<5 J/cm2) with large spot sizes; 3) epidermal cooling essential; and 4) repeat treatments every 2-4 weeks.

 

Lasers: Safety and Complications

Key Safety Pearls

Omar Ibrahimi, MD, PhD
  • Lasers are extremely powerful methods for delivery of light. A basic understanding of laser safety is mandatory for anyone operating a laser
  • The major risks associated with laser use in dermatology include: eye injury, infectious hazards, medication overdoses, fire, and electrical shock
  • Lasers in the visible light and near infrared range are absorbed by melanin and can damage the retina (can cause blindness)
  • Lasers in the mid-far infrared range are absorbed by water and can damage the cornea
  • Use of appropriate eye goggles can minimize the risk of eye damage (remember that eyewear is wavelength-specific)
  • There are risks with topical anesthesia

Complications with Lasers

Matt Avram, MD, JD

As dermatologists, here are some clinical pearls to keep in mind with regards to lasers:

  • Practice good common sense
  • Know your limits
  • Examine the patient in the same day, if possible. If you are uncertain as to what is happening, consult a colleague
  • Do not abandon or avoid a patient with a poor outcome or side effect
What are some of the common reasons for litigations with laser treatment?

Dr Avram and colleagues revied 1,601 cases. They found that 75% of physicians in low-risk specialties will face a malpractice claim by age 65. Of the cases that were reviewed, they found 182 unique legal claims involving injury from a cutaneous laser treatment. These cases were mainly in California, New York, and Texas.

Most common litigated procedures
  • Hair removal
  • Rejuvenation
  • Leg veins
Most common injuries
  • Burn
  • Scar
  • Pigmentation
Most common reasons for litigation
  • Negligence
  • Informed consent
  • Fraud

In 50% of the cases, the courts ruled in favor of the plaintiffs.

Common Complications with Laser Treatment
  • Hypopigmentation
  • Pigmented lesions
  • Scarring

Remember that lasers can be an effective treatment for

  • Lentigines
  • Ephelides
  • Nevus of Ota/Ito

They should NOT be utilized for

  • Atypical nevi
  • Lentigo maligna
  • Melanoma

*When in doubt-perform a biopsy

 In Summary
  • Use common sense
  • If you can’t recognize or treat the condition- don’t use a laser
  • If you’re uncertain, call an experienced colleague

 

 

Introduction to Lasers and Light

Victor Ross, MD

“To understand laser tissue interactions and heat transfer is to understand laser medicine.” It’s important that Dermatologists understand how lasers work and how they interact with the skin. Electromagnetic radiation is energy. To best understand lasers, one should be familiar with the definitions that are associated with their use, i.e., fluence, pulse width, spot size and incident light. LASER is defined as Light Amplification by the Stimulated Emission of Radiation. It is a means to direct light in a focal, monochromatic way.  Why do we need to know how and why lasers work? This way, if something goes wrong, you have a basic troubleshooting guide. Non-familiarity with the device is probably the number one reason that complications occur.

Clinical Pearls
  • Check beam profile
  • Don’t forget that parts on the laser can break (mirrors, lamps, etc)
  • Lots of different technologies exist
  • Lots of different scanners available to enhance lasers
  • Understand aesthetic laser wavelengths
  • Understand pulse width
  • The majority of laser interactions are thermal
  • Cool the epidermis before the laser pulse comes down
  • Pulse duration is very important You can’t use long pulses with tattoos
  • We have a lot of cooling devices now available
  • Use short pulses to resurface
There are three basic targets for skin and lasers:
  • Water
  • Blood
  • Melanin
Three important considerations
  • Photon migration in tissue
  • Temperature increase as a response of chromophore absorption
  • Response of chromophore to temperature-time combination (generally speaking, the higher the temperature, the less time to heat the target)
What is selective photothermolysis?

Site-specific, thermally mediated injury to pigmented targets; Only gets hot with the right wavelength and the right pulsewidth.

Physical Characteristics We can Exploit (e.g. scar)
  • Hyperemia
  • Hyper-pigmentation
  • Exophytic nature
  • Hyper-metabolism
  • Inflammation

Photomodulation- Can we rejuvenate without heat?

Maybe some day we will see this, it’s not quite ready at this point.

Fillers: Part 3

Managing Complications

Joel Cohen, MD

In this presentation, Dr Cohen reviews the complications that can occur when utilizing fillers and best practices on how to manage these various complications. Dermatologists use fillers across the world, millions of times per year, and most of the time, everything is fine; but understanding the complications and how to manage them is imperative for dermatologists.

Clinicians should be aware that there are new filler agents and new indications for the agents currently available, so it is important to understand these products and recognize what can potentially go wrong when using them in patients.

Filler complications include:

  • Superficial injection
  • Vascular compromise
  • Bruising
  • Sensitivity
  • Granuloma
Superficial Injection

When injecting the peri-ocular area, it is critical that dermatologists understand the anatomy and how to inject these areas.  When Dr Cohen injects these areas, he defines them by either “infra-orbital hollow” or “tear trough”.

Approach to Infra-Orbital Hollow injection

Dr Cohen uses anesthetic eye drops, a jaeger retractor to protect the globe, and a 32-gauge needle above the level of the muscle. He discusses the importance of the 32-gauge needle, as he believes it slows down the injection. This is an off-label usage of an HA injection and should be done very superficially.  It is also important to avoid superficial nodules.

Injecting the Tear Trough

Dr Cohen injects very deep, below the muscle on the level of the periosteum. An anterior approach may help to lessen bleeding encounters.

Persistent Swelling

Persistent swelling has been documented across the board with various fillers. It is important to remember that this is an off-label area and dermatologists choose their agents based on personal preferences.  Experts are not sure if the swelling is related to etiology, e.g., Botox a few weeks prior. Treatment for persistent swelling includes time, massage, caffeine, oral HCTZ, and hyaluronidase.   Hyaluronidase can be helpful for an area that was superficially injected (very localized).

When injecting the glabella, you would want to see a little bleeding, you do not want to see it blanche. Seeing a blanche means that you have compromised a blood vessel and this is an emergency.

Botulinum toxin, in combination with fillers, may provide a better, more durable response.

Vascular Compromise and Necrosis

The glabella is an area at significant risk for impending necrosis. Vascular compromise and necrosis, albeit rare, are caused by compression and intravascular injection.  In 2006, Dr Cohen and colleagues published a prevention and treatment protocol for injection necrosis of the glabella (Derm Surg, Feb 2006).

Understanding the facial arteries is of great importance for dermatologists who do soft tissue augmentation.

If you see a blanche, immediately stop the procedure. With some warm tap water gauze, try to tap the area and the warmth will facilitate vasodilation. If you have nitro paste in your office, you can apply that as well along with giving your patient aspirin to manage the headache associated with nitro paste.

Understanding the vessels and patterns is important not only to dermatologists, but to patients and office staff as well. Hyaluronidase with multiple stabs and perhaps into the adjacent artery has been demonstrated as a novel treatment for impending necrosis. It is very important as a healthcare provider to intervene immediately and NOT “wait and see what happens” in the cases of impending necrosis.

Scars

Fillers can be for postsurgical depressed scars on the ears, nose, and cheeks. Dr Cohen and colleagues published various case reports in 2008 on the use of fillers for postsurgical depressed scars after skin cancer reconstruction. The use of hyaluronic acid and calcium hydroxylapatite has proven successful to fill and blend these scars.

Bruising

Bruising may occur regardless of the injection site. The injection pattern is extremely important and it is critical that dermatologists understand the various approaches to injection. There are some things that patients can do to reduce bruising, such as avoiding aspirin. Patients on anticoagulants also have to be managed. There are vitamins that can potentially interfere with bleeding; so again, something to keep in mind.  Clinicians need to be realistic with their patients, so they can expect some bruising and/or swelling which may last up to ten days. It is  important to communicate with patients prior to the procedure.

Cannulas

There are two cannulas available in the US. Dr Cohen uses cannulas in the hands, cheeks, infra orbital, and décolleté. They seem to decrease bruising along with potentially decreasing pain in some areas.

What about the legal issues?

Dr. Matthew Avram MD, JD, one of the faculty members in the audience, commented on the legal issues surrounding complications involving dermal fillers. According to Dr. Avram: “Regarding the use of fillers, there is a standard of care regarding complications of vascular occlusions, which include some of the following issues:
– Office staff should be informed regarding potential side effects/symptoms (Suspicion Index); therefore, recognizing possible complications
-Consent forms should include, but not be limited to the possibility of:

  • Scars
  • Ulceration
  • Blindness
  • Discoloration of skin

Physicians should also ensure that adequate “on-site” aid is available, i.e., Nitropaste, hyaluronidase, etc…

With regards to the use of toxins:
Actually, it is quite amazing that among the millions injections that have been utilized over the past decade, we found only two reported cases involving the use of botulinum toxins for aesthetic purposes.”

 Summary

In conclusion, there are a variety of fillers available for patients. It is important that dermatologists understand the anatomy of the face in order to optimize injection results and minimize potential complications. If there is a complication make sure that your staff who answers the patient’s phone call has a high index of suspicion regarding complications and act when necessary to bring the patient to the office on an urgent basis.

 

Fillers: Part 2

Update on Fillers

Michael Gold, MD

Recently, Dr Gold published an article on an International Perspective on Fillers. In Europe, Restylane is a very large family of products. It is made by a company called Q-Med who is now owned by Galderma. Before the merger, Q-Med licensed all of the products to Medicis (now owned by Valeant).  In the US, we have four Juverderm products. In Europe, they  have various versions of Juvederm. We’re hoping to see Voluma by the end of 2013.

There are three Belotero products available outside the US. (Soft, Balance, and Intense.) We have the Balance product here in the US. Remember the term CPM that takes the cross-linking one step further, giving the product a longer duration. There are many fillers in Europe (150 companies) and Asia out there, but they may not be on the radar in the United States.

Atlean is often referred to as a second generation Sculptra. There is some hope that we may see Atlean in the US.

Anteis makes three products using the CPM technology as well. In the US, we will never see the Anteis products (because they are Belotero). In the rest of the world, where Merz doesn’t have the distribution rights, we will see the Anteis products—they are exactly the same and show some very nice results. Anteis also has another product, Modelis, which does some very deep filling. The Anteis Injection System reduces erythema and swelling and provides a significant improvement in injection technique. Dr Gold has used this in Europe and finds it easy to use and patients seem to do well.

Emervel is a product owned by Galderma. There are five Emervel products marketed in Europe without lidocaine, and four with lidocaine. These products are going to be marketed by Valeant because of the Q-Med agreement. There are two of them pending with the FDA (with lidocaine).

Summary
  • Europe has more fillers than the United States
  • FDA is more stringent
  • Costly to bring products to market

 

The China Filler Market

There are lots of counterfeit fillers. Doctors are buying this stuff and injecting it into patients and this is a real problem. “Don’t buy fake products.” We have great companies with great products. We need to embrace the new technology and treat patients with these new options.

Fillers: Part 1

Kent Remington, MD

Dr Remington began the filler session with a discussion on facial reflation and the concept of aesthetics. For many years, we focused on the old aesthetic rule of “if it ain’t broke, don’t fix it.” The new rule in aesthetics is “if it ain’t broke, break it, then fix it and make it better.”

Dr Remington presented the audience with some key pearls and takeaway messages from his clinical experience.

**It is extremely important that dermatologists focus on the face in great detail as patients are paying for great results. One of Dr Remington’s biggest challenges is getting is patients to look at their entire face, as opposed to focusing on what they choose to see; therefore, missing a lot of things. “We look with our eyes and see with our brains.” By understanding and seeing everything about each patient, the outcomes can be better. It’s all about harmony and symmetry.

What do we need to think about in detail?

  • Genetics
  • Age group
  • Personality and lifestyle
  • Attention to details

Overall, faces are all about genetics, which are all about biology, which is all about physiology, which is all about physics, which is all about math; therefore, every face has a mathematical transformation. Dr. Remington presented a series of cases in which he used numerous fillers and neuromodulators to achieve an overall “reflation “of the face. In doing so he stated that it is not about the number of cc’s of material injected but more about what is needed to create a “wow”.

As dermatologists, we need to take a more comprehensive approach.  Instead of just injecting a specific area, step back and see what the patient really needs.

Where are we now?

Wm. Philip Werschler, MD

In this presentation, Dr Werschler provided the audience an overview of the fillers currently available on the market by class and by product, and how they can best be utilized in clinical practice.

How did we get here today?

Beginning in 1981, bovine collagen was introduced to the US marketplace. As people began to get their winkles and fold augmented to look younger they discovered that unfortunately, the duration of collagen was only three months or so, thus the market for collagen injections never grew to meet expectations   It was subsequently withdrawn from the market. In December, 2003, the US FDA approved Restylane (Hyaluronic Acid), which revolutionized the dermal filler market. With Restylane physicians a dermal filler that had a duration of over 6 months, required no pre-treatment skin testing, was easy to use,  could be stored at room temperature and had a modest cost.  With Restylane we had the introduction of a viable product for the emerging, if nascent, dermal filler market.

Radiesse is a novel “next-generation” filler that was approved in 2006 by the FDA for the correction of wrinkles and folds (such as Nasolabial Folds), and for the correction of HIV-associated lipoatrophy. Radiesse is termed a “stimulatory” or “collagen-stimulator” product.  This differs from the previous generation “replacement” space occupying materials collagen and hyaluronic acid.  With the addition of collagen stimulation, the duration of effect of Radiesse was extended to 9-18 months.

On the same day that Radiesse was approved, the FDA also approved the first and only “permanent” dermal filler, Artefill (collagen + PMMA).  Artefill consists of bovine collagen in combination with polymethmethacrylate spheres.   As these spheres are non-biodegradable, they represent a permanent placement into the tissue.  Well tolerated with an excellent safety profile, Artefill does require pre-treatment skin testing because of the bovine collagen present. Special handling includes refrigeration, and collagen stimulation gradually anchors the PMMA spheres into place typically after 2-3 treatments.

In 2007/2008 Hyaluronic Acid plus manufacturer added lidocaine was FDA approved for the hyaluronic acids, Juvederm, Restylane and Perlane. Similarly, the FDA approved the mixing of lidocaine and Radiesse by the injector at the time of use.  These approvals resulted in greater patient comfort during injection and further expanded the dermal filler marketplace. Stabilized Porcine Collagen came onto the market briefly during this time, however due to problems with patient tolerance and complications, the manufacturer withdrew the product and it is no longer available.

In 2009, the FDA approved Sculptra, poly-L -lactic acid, for aesthetic use (it received FDA approval in 2004 for HIV associated facial lipoatrophy).  A pure collagen stimulator, Sculptra, is technically is not a dermal filler, however; it is best thought of in this category.  Sculptra is routinely mixed with lidocaine and sterile water for injection, requires 3-5 injections sessions to gradually grow new collagen leading to the clinical effect developing over a period of three to six months.  Duration is a 2+ years effect based on extensive clinical trials and experience.

More recently, an advanced technology hyaluronic acid, Belotero, and  an autologous cultured dermal fibroblast  (LAVIV)  were approved. Belotero is a “cohesive polydensified matrix” hyaluronic acid that possesses different tissue integration properties than previous generation products.  The net clinical result is that the product may be injected more superficially than other HAs without risk of the Tindall or Rayleigh effect tinting the skin blue.

Laviv, is not a dermal filler but instead uses a patients own fibroblasts which are harvested from a punch biopsy, grown in a lab and then injected into the patient.  The injected fibroblast then produce native collagen in the patient’s skin  This process includes harvesting tissue from the patient (post-auricular) and sending it to a processing laboratory which then amplifies the cell count and returns a viable culture for re-injection. The first FDA approved tissue therapy for aesthetics, Laviv, presents a multitude of intriguing possibilities in the future.

Ever since fillers first came onto the market, experts have been trying to develop a methodology to differentiate one from another. There are many ways  to do so:

  • Chemical components
  • Duration of action
  • Natural/Synthetic
  • MOA
    • Replacement Filler or Bio-Stimulatory/collagen stimulator

Remember that fillers exist in two primary categories:

  • Volume Replacement
  • Collagen Stimulation

When you use the above descriptive methodology, you can see that collagen and hyaluronic acids are replacement fillers and PLLA and LAVIV are bio-stimulatory. And notably, CaHA and PMMA are blends of both MOAs.

There are many ways to categorize fillers within a class.

Volume Replacement

Hyaluronic Acid

HAs have a very simple chemical structure and is identical in all species and tissues; thus it is non-immunogenic. It is found in all vertebrates and synthesized by some bacteria. The identical structure of HA from all sources makes it an ideal substance for use as a biomaterial in health and medicine.  HAs are highly hydrophilic; therefore, they absorb water, i.e., their principal method of giving a volumizing effect. They are also rapidly metabolized in vivo.

Gel Mass Sizing

In addition to crosslinking, manufacturers use other techniques to improve HA filler properties.  For example, Medicis uses a process that creates specific sizes and shapes to form granular consistency gels Restylane® and Perlane®.

In creating the JUVÉDERM® family of products, Allergan uses Hylacross™ Technology to create random sizes and shapes that form a smooth cohesive gel. Beletero, which is rather new to the market, uses another technology (CPM) to achieve unique properties.

Hyaluronic acids can be used virtually everywhere for anything and everything and they are the most versatile of all of the filler products. These fillers may be ideal for novice patients because they have an  “eraser” (hyaluronidase), which can be injected to make the product dissolve, if so desired for either aesthetic effect or for treatment of necrosis. . This is a unique feature of this category.

New Approaches to Fillers: Pure Neocollagenesis

PLLA

Through a variety of mechanisms of action, they stimulate fibroblasts to make collagen.

PLLA was first approved for HIV-related facial lipoatrophy in the United Sates in 2004 and the aesthetic approval was received in 2009.  It is the only approved pure collagen stimulator currently available in the US; therefore, it is considered “stimulatory” and “biodegradable” in classification. PLLA is indicated for the correction of nasolabial folds. Of note, Dermik aesthetics, a division of Sanofi-Aventis, recently sold the product to Valeant Pharmaceuticals Intl. based in Canada.

What is the composition of PLLA?

  • Poly-L-lactic acid
  • Sodium  carboxymethylcellulose (CMC)
  • Non-pyrogenic mannitol
  • Sterile water (added) for injection (USP)
  • Lidocaine (optional—most dermatologists and plastic surgeons add lidocaine for patient comfort)

Sculptra is composed of microparticles of PLLA, a biocompatible, biodegradable, synthetic polymer from the alpha-hydroxy-acid family.  It is derived from natural components, it is a crystalline, amorphous mixture with microparticles averaging 40 to 63 μm in size. The slow resorption of PLLA after implantation is due to the high molecular weight (140,000 Daltons) of the polymer and the irregular crystalline shape of the microparticles.

Lactic acid can be converted through polymerization to a variety of polymers, including poly-L-lactic acid. Many of these polymers, including polylactic acid, have been used for many years in medical devices and sutures, including absorbable sealants, flow restrictors, fixation systems, suture anchors/absorbable sutures, fixation screws, and tissue regeneration.

Investigator evaluations throughout the study confirmed that improvements in facial appearance with Sculptra Aesthetic achieved improvement in WAS. 100% of patients improved at week 3; 88.7% at month 13; and 86.3% at month 25.

How long does it last? Sculptra may last two to three years. It is important to remember that it is difficult to establish exact duration of the product because of one’s natural course of aging.

Where is it used?

Poly-L-lactic acid treatment primarily to add volume, and as such is used to thicken dermis and to stimulate collagen growth in the pre-periosteal plane.  Placement may include the temporal hollows, across the zygomata, in the mid face, nasolabial folds, labiomental sulcus, pre-jowl sulcus, mandibular sweep, angle and for genioplasty.  Sculptra is not recommended for use in areas of concentric movement such as the lips and eyelids.  In terms of adding volume, this is a great way to go.

Personalized Dermal Technology

LaViv is an innovative technology to isolate, purify, and regenerate a patient’s own fibroblast cells for re-injection.

Fibroblast cells produce collagen and play key role in the continued health of skin. Collagen provides firmness and structure to the skin and is essential in supporting the dermis.. As skin ages, fibroblast cells decrease and the collagen matrix that provide the skin its structure breaks down.

This is a way to restore the equilibrium.  LaViv is the first autologous cell therapy for use in aesthetics filed with the FDA. There is strict release testing on each clinical lot to ensure performance and safety including:

  • Collagen content testing results must achieve specification for each prepped injection, indicating cells are biologically active and produce collagen
  • Cell suspension must consist of at least 98% fibroblasts prior to release
  • Cells in suspension must achieve a viability level of at least 85%
New Approaches to Fillers: Volume Replacement + NeoCollagenesis

Calcium Hydroxylapatite (CaHa)-Radiesse

CaHa is best used for facial contouring. It’s mechanism of action is to serve as a filler material initially (particles + gel) then provide long term benefit through natural collagen integration in and around the particles. The result is a long lasting, but not permanent correction augmentation that feels like the patient’s own tissue.

The advantages of Radiesse include immediate site-specific correction in one to two sessions and strong structural tissue support with no Tyndall effect. CaHa is malleable up to two weeks and has a long duration of nine to 18 months. No pretreatment testing is required, it is also cost-effective and does not migrate or obscure radiographic studies and it doesn’t ossify in the skin. Radiesse received approval in the United Sates in 2006 for both HIV and aesthetic use and is the only approved biodegradable dual collagen stimulator and replacement filler currently available in the US. When utilizing Radiesse, no skin or allergy testing is needed and there is no special handling. The product is available in 0.3, 0.8 and 1.5 mL and recently approved 3.0 mL syringes through Merz Aesthetics.

Where is it used?

CaHA is used most everywhere; however, it is not ideally used in the lips or the eyelids. Some people do use the product in those areas; however, Dr Werschler does not recommend it.

PMMA Dermal Filler-Artefill

Artefill was approved in the United Sates in 2006 and is the only approved PMMA-enhanced dermal filler currently available in the US. It is indicated for the correction of nasolabial folds. Suneva Medical acquired (ARTES) Artefill in 2009 and is currently manufacturing, selling, and distributing Artefill in the US.

Conclusions

Injectables are: Facial Shaping Agents

  • They can enhance natural features
  • They can rejuvenate fading youth
  • They can restore aged, facial features
  • They can even improve natural beauty
  • Each product has features that result in certain benefits in clinical use
  • They are not all alike!

 

What’s new since last year?

  • Belotero is “back” on market
  • Valeant owns Medicis, Dermik
  • Still waiting FDA approval for Allergan’s Voluma
  • Artiste injection pump now available
  • 2013 is still young!

 

Clinical Pearls
  • Use filling agents appropriate to the requirements of the job
  • Not all products are created equal – understand the differences!
  • Some areas are more difficult to correct than others  (e.g. lips and tear troughs) so master the basic indications first such as NLF
  • Evaluate and approach filling from a multi-step progression:
    • Volume, shape, contour, wrinkle, line and crinkle filling
    • Product duration claims are a slippery slope- be careful with those and be conservative with your ranges
    • Under-promise and over deliver