Faculty Bibliography

Cutaneous squamous cell carcinoma (cSCC) causes approximately 10,000 deaths annually in the U. S. Current therapies are largely ineffective against metastatic and locally advanced cSCC. There is a need to identify novel, effective, and less toxic small molecule cSCC therapeutics. We developed a 3-dimensional bioprinted skin (3DBPS) model of cSCC tumors together with a microscopy assay to test chemotherapeutic effects in tissue. The full thickness SCC tissue model was validated using hematoxylin and eosin (H&E) and immunohistochemical histological staining, confocal microscopy, and cDNA microarray analysis. A nondestructive, 3D fluorescence confocal imaging assay with tdTomato-labeled A431 SCC and ZsGreen-labeled keratinocytes was developed to test efficacy and general toxicity of chemotherapeutics. Fluorescence-derived imaging biomarkers indicated that 50% of cancer cells were killed in the tissue after 1μM 5-Fluorouracil 48-hour treatment, compared to a baseline of 12% for untreated controls. The imaging biomarkers also showed that normal keratinocytes were less affected by treatment (11% killed) than the untreated tissue, which had no significant killing effect. Data showed that 5-Fluorouracil selectively killed cSCC cells more than keratinocytes. Our 3DBPS assay platform provides cellular-level measurement of cell viability and can be adapted to achieve nondestructive high-throughput screening (HTS) in bio-fabricated tissues.

T-cell landscape differences between cutaneous squamous cell carcinoma (cSCC) tumors in immune competent (SCC in IC) and immunocompromised organ transplant recipients (TSCC in OTR) are unclear. We developed an analytical method to define tumor infiltrating lymphocyte (TIL) phenotype in cSCC from immune competent and immune suppressed patients using single-cell TCR sequencing and gene expression data. TSCC exhibits reduced proportions of cytotoxic and naïve TILs and similar numbers of regulatory TILs. Fewer, more heterogeneous TCR clonotypes are observed in TIL from OTR. Most TCR sequences for top ten clonotypes correspond to known antigens, while 24% correspond to putative neoantigens. OTR show increased cSCC events over 12 months possibly due to reduced cytotoxic T-cells. Our novel method of barcoding CD8+ T-cells is the first providing gene expression and TCR sequences in cSCC. Knowledge regarding putative antigens recognized by TCRs with phenotypic function of T-cells bearing those TCRs could facilitate personalized cSCC treatments.

There have been several significant advances in cancer treatment in the last decade that are applicable to the treatment of melanoma and advanced nonmelanoma skin cancers. Among these are the development of immune checkpoint inhibitors targeting the programmed death protein-1 (PD-1)/programmed death legand-1 (PDL-1) axis, as well as targeted inhibitors of the BRAF/MEK signaling cascade in melanoma, and the hedgehog signaling pathway in basal cell carcinoma (BCC). These immune-based and targeted therapies have dramatically changed the treatment options for locally advanced and metastatic melanoma, Merkel's cell carcinoma, cutaneous squamous cell carcinoma (cSCC), and BCC. In this article, we will briefly review the currently approved targeted and immunotherapy-based treatments for locally advanced and metastatic melanoma, Merkel's cell carcinoma, and cSCC and discuss various combinations of approved therapies, as well as emerging therapeutic candidates that are currently in clinical trials, including novel checkpoint inhibitors in development, intratumoral oncolytic agents (viral and nonviral), and various immune-based therapies such as toll-like receptor (TLR) agonists, adoptive T-cell therapy, T-cell costimulation, and innate immune cell therapy. For advanced BCC, we will discuss trials investigating the currently approved smoothened (SMO) inhibitors for neoadjuvant use, emerging SMO inhibitors in development, topical SMO inhibitors, alternative targets in the hedgehog signaling pathway, and the use of anti-PD-1 agents for advanced BCC both alone and in combination with SMO inhibitors.

BACKGROUND:Opioid overprescribing is a major contributor to the opioid crisis. The lack of procedure-specific guidelines contributes to the vast differences in prescribing practices. OBJECTIVE:Create opioid-prescribing consensus guidelines for common dermatologic procedures. METHODS:We utilized a four-step modified Delphi method to conduct a systematic discussion among a panel of providers in the fields of general dermatology, dermatologic surgery, and cosmetics/phlebology to develop opioid-prescribing guidelines for some of the most common dermatologic procedural scenarios. Guidelines were developed for opioid-naïve patients undergoing routine procedures. Opioid tablets were defined as oxycodone 5-mg oral equivalents. RESULTS:Postoperative pain after most uncomplicated procedures (76%) can be adequately managed with acetaminophen and/or ibuprofen. Group consensus identified no specific dermatological scenario that routinely requires more than 15 oxycodone 5-mg oral equivalents to manage postoperative pain. Group consensus found that 23 percent of the procedural scenarios routinely require 1-10 opioid tablets, while only one routinely requires 1-15 opioid tablets. LIMITATIONS/CONCLUSIONS:These recommendations are based on expert consensus in lieu of quality evidence-based outcomes research. These recommendations must be individualized to accommodate patients' comorbidities. CONCLUSIONS:Procedure-specific opioid-prescribing guidelines may serve as a foundation to produce effective and responsible postoperative pain management strategies after dermatologic interventions.

The International Immunosuppression and Transplant Skin Cancer Collaborative (ITSCC) is an organization of more than 500 physicians and scientists focused on the treatment of cutaneous malignancies following solid organ transplantation and in other forms of immunosuppression. It is well known that solid organ transplant recipients (SOTRs) have an approximate 100-fold increase in the risk of developing skin cancer with consensus guidelines recommending these patients be managed as high risk for local recurrence and metastasis associated with poor outcomes. In September 2018, ITSCC and its European counterpart, the Skin Care in Organ Transplant Patients-Europe (SCOPE), held their biennial scientific retreat in Essex, MA to discuss novel findings in the pathogenesis of cutaneous malignancy including new treatment and prevention strategies in this at risk population for significant morbidity and mortality from their cutaneous disease. This meeting report is a summary of the novel findings discussed.

BACKGROUND:Skin cancer is the most common malignancy affecting solid organ transplant recipients (SOTR), and SOTR experience an increased skin cancer-associated in morbidity and mortality. There are no formal multidisciplinary guidelines for skin cancer screening after transplant, and current practices are widely variable. METHODS:We conducted three rounds of Delphi-method surveys with a panel of 84 U.S. dermatologists and transplant physicians to establish skin cancer screening recommendations for SOTR. RESULTS:The transplant team should risk stratify SOTR for screening, and dermatologists should perform skin cancer screening by full body skin examination. SOTR with a history of skin cancer should continue regular follow-up with dermatology for skin cancer surveillance post-transplant. High-risk patients include thoracic organ recipients, SOTR age 50 and above, and male SOTR. High-risk Caucasian patients should be screened within 2 years after transplant, all Caucasian, Asian, Hispanic, and high-risk African American patients should be screened within 5 years after transplant. No consensus was reached regarding screening for low-risk African American SOTR. CONCLUSION/CONCLUSIONS:We propose a standardized approach to skin cancer screening in SOTR based on multi-disciplinary expert consensus. These guidelines prioritize and emphasize the need for screening for SOTR at greatest risk for skin cancer.