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LIVE BLOG: New Applications of Systemic Immunomodulators in Dermatology

In this live blog from the 11th Annual SDPA conference in Atlanta, Dr. Neal Bhatia spoke on New Applications of Systemic Immunomodulators in Dermatology. Below are some highlights of his lecture.

 

What are the risks for the Immunosuppressed patient?

  • 40% of transplant recipients experience premalignant skin tumors within the first 5 years of immunosuppression
    • More frequently aggressive histological subtypes and uncommon clinical morphologies
    • 5-8%mortality rate in organ transplant patients 
    • AK/SCC including Bowen’s>>BCC
  • HPV, UVA/B, and multiple factors augment the risks

Stockfleth E, Ulrich C, Meyer T, Christophers E. “Epithelial malignancies in organ transplant patients: clinical presentation and new methods of treatment,” Recent Results Cancer Res. 2002;160:251-8.

NMSC and Renal Transplants

  • Biphasic increase in skin cancer incidence based on age at transplantation.
  • Steady increase in risk for older RTRs (age 50+ years) from year 2
  • Increased risk in younger RTRs age < 50
    • Occurred later but much more significantly
    • Reaching 200 times the risk for an age-matched nontransplanted population by year 6
  • Male RTRs were at particular risk of invasive SCC at sun-exposed sites such as the scalp and the external ear.
  • Risk of malignant melanoma and Kaposi sarcoma were also increased relative to the nontransplanted population.

NMSC and Liver Transplants

– Two dermatologists, 100 consecutive patients

  • Mean age at transplantation= 42.5 years
  • Average time since transplantation was 5.5 years (range 0.75-16 years)

– Primary objective: assess lesion types

– Secondary determinations:

– Duration of transplant

– The type of immunosuppression involved

– The degree of sun exposure

  • 4 pts with skin cancer, 7 total lesions 
    • 1 SCC, 6 BCC 
    • Infections: Fungal 19%, viral 2%, bacterial 5%
  • Immunosuppressivetherapy: cyclosporinA, azathioprine and prednisolone
    • 35% of LTR pts on Triple-drug
    • 48% dual therapy (tacrolimus and prednisolone) 
    • 17% monotherapy (tacrolimus)
  • Higher percentages on less suppression and shorter treatment durations-?less cancer

Increased Risks with Myeloid CA… and a bad sign as well

Where does SCC begin from AK? 

Indicators of progression from AK to SCC

  • Dysregulation of p53—uncontrolled cell proliferaton
  • Expression of p16 oncogene
  • Inducible Expression of Fas (CD 95) ligand
  • TRAIL—Tumor necrosis factor-Related Apoptosis Inducing Ligand
    • Associated with significant processing of initiator caspase-8 and effector caspase-3.

Risk Factors for NMSC

  • General risk factors1 
    • Age
    • Skin type 
    • Sun exposure 
    • History of prior NMSC
  • OTR-related risk factors
    • Immunosuppression 
      • Level of immunosuppression is directly related to NMSC incidence 
      • Transplanted organ: kidney (highest) > liver > heart (lowest)
  • HPV infection 
    • HPV is more prevalent among immunosuppressed patients

HPV and AKs

  • HPV 21 closest subtype linked to progression of AKs—90% of AKs and SCC
    • HPV 5 and 8 less prevalent 
    • Vaccine potential?
  • E6 and E7 proteins essential
    • E6 binds and Inactivates p53 and BAK
    • anti-apoptotic effect of the E6 protein in HPV proposed as a tumor inducing factor
    • Inactivation of p53 slows DNA repair

Should we use the HPV Vaccine for Chemoprevention?

What about switching immunosuppressive therapy?

When to Consider Chemoprevention for NMSC

  • Two primary systemic strategies 
    • Oral retinoids 
    • Reduction of immunosuppression
  • Balance morbidity and inconvenience of surgery and risk of progression vs adverse effects of systemic therapy
    • Tumor burden 
    • Risk of metastasis 
    • Morbidity and inconvenience
  • In high-risk patients, the benefits of systemic chemoprevention outweigh the adverse effects
  • Augments, does not completely replace surgical therapy

Systemic Chemoprevention for AK

Original Study in Transplant Patients

Acitretin for all High-Risk Cancer Patients

Isotretinoin for NMSC Chemoprevention

Polypodium leucotomos

  • An aquatic fern originating in Central America
    • Adapted to life on land using natural protective mechanisms against UV
    • Extract is obtained from selected plants
  • Used for centuries by native Americans as an anti-inflammatory agent

Impact of photodamage by

Polypodium leucotomos

  • UV-irradiated skin
  • Induction of ROS
  • Lipidperoxidation
  • Overall decrease in dendritic cells
  • Increase TNF release

Polypodium leucotomos

  • Neutralize ROS
  • Protect membranes
  • Undo UV suppression of dendritic cells
  • Inhibit TNF release
  • Suppress hypersensitivity
  • Restore hypersensitivity response

PDT and Chemoprevention

  • Most data for OTR patients
  • PDT treatments every 4-8 weeks for 2 years 
    • 79% reduction of SCC in 1 year, 95% in 2 years 
    • Derm Surg 2010, 36:652
  • PDT treatments x 2 one week apart 
    • Reduced AK recurrences in 6 months 
    • BJD 2010, 162:171

Blue vs. Red

MAL and Transplant Patients

Reduction in the Incidence of Squamous Cell Carcinoma in Solid Organ Transplant Recipients Treated with Cyclic Photodynamic Therapy. 

Comparison between Cryotherapy, Topical 5-FU, and Topical Imiquimod

  • Krawtchenko N, Roewert-Huber J, Ulrich M, Mann I, Sterry W, Stockfleth E.
  • British Journal of Dermatology. 2007;157(s2):34-40.
  • A randomized study of topical 5% imiquimod vs. topical 5-fluorouracil vs. cryosurgery in immunocompetent patients with actinic keratoses: a comparison of clinical and histological outcomes including 1-year follow-up

 

Image: Admean