Dermatology Year in Review Part 3: New Insights

Hensin Tsao, MD, PhD

 

Mosaics

In the world of dermatology, we are filled with hamartomatous “overgrowth” syndromes. Many, however, are de novo so the genetic mechanism is unclear. Often times, segments or large quadrants of the body are affected clinically suggesting somatic mosaicism.

Two studies in 2012, that complimented some earlier studies, looked at somatic mosaic mutations of these various overgrowth syndromes. In the first study, megacephaly was a feature in all three cases. Patients may have nevus flammeus. The blood/saliva from all patients was subjected to total exome resequencing, which is a technology that is really hitting medicine right now. In effect, total exome resequencing is looking at all of the coding sequence of one’s genome (exome) and in doing so, trying to find the mutation that may be responsible for the phenotype that you see. In the first study, megacephaly was a feature in all three cases. Patients may have nevus flammeus.

The three genes that were found were the AKT3, PIK3R2, and PIK3CA.

Clinical Pearls
  • Germline and mosaic versions of cancer mutations lead to developmental and hamartomatous conditions
  • As sequencing technologies improve, the mechanism of new syndromes will emerge
  • Interesting that these patients may not be more susceptible to cancer overall
 Looking Ahead
  • Between biologics and small molecule inhibitors, we are in a new therapeutic renaissance
    • The mechanism-to-medicine bridge is finally open
  • NextGen sequencing will help define rare hereditary and mosaic genodermatoses
  • Health care economics, not science, is the wild card

 

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