Date of Award

January 2018

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Sean R. Christensen

Abstract

PHOTODYNAMIC THERAPY FOR CUTANEOUS SQUAMOUS CELL CARCINOMA IN-SITU & MUTATION BURDEN ANALYSIS. Yuemei (Amy) Zhang, Mei Zhong, Haifan Lin, and Sean Christensen. Department of Dermatology, Yale University School of Medicine, New Haven, CT.

SCC in-situ (SCCIS), or Bowen’s disease, is a precursor to invasive squamous cell carcinoma (SCC) of the skin. Compared to other available treatment modalities, photodynamic therapy (PDT) may offer comparable efficacy with decreased morbidity and better cosmetic and functional outcomes. This retrospective study analyzes the effectiveness and outcomes of photodynamic therapy with aminolevulinic acid (ALA-PDT) treatment of cutaneous squamous cell carcinoma in-situ (SCCIS) with blue light. Data collection and statistical analysis was performed on the demographics, clinical history, and procedure details of patients who have biopsy-confirmed diagnoses of SCCIS treated initially with PDT. Treated lesions had a complete response rate of 55% (39/71) after initial PDT treatment. 83% (52/63) of lesions had a complete response with 1-2 cycles of PDT. Age and large size (>2 cm) were inversely correlated with complete initial response. The mean disease-free survival was 13.379 months (standard deviation of 2.0 months, C.I. [9.477, 17.280], 41 observations) for lesions receiving 1 PDT treatment, and 13.590 months (standard deviation of 2.3 months, C.I. [9.072, 18.107], 23 observations) for lesions receiving 2 treatments. There was no statistical difference between 1 and 2 PDT treatments in terms of disease-free survival function. Recurrence rates were 12% (4/33) following 1 PDT treatment and 32% (6/19) following 2 PDT treatments. Depending on clinical details, PDT may be an appropriate choice of treatment for SCCIS.

SCCIS and skin cancers arise when cancer-causing mutations develop and accumulate in keratinocytes. The majority of skin cancer cases are attributed to mutations caused by ultraviolet (UV) radiation. Specific UV-induced mutations in tumor-suppressor genes have been documented in normal skin, skin cancer precursors, and SCC lesions. This study aims to develop a system to quantify and characterize the mutations in TP53, Hras, Nras, Kras, CDKN2a, Notch1, Notch2, Notch3, Fat1, Fgfr3, Knstrn, and Braf in clinically and histologically normal skin, and relate this data to level of sun damage using next-generation sequencing. This project is still in process. At this point, primers have been designed to be used in concert with Illumina, Inc.’s extension-ligation system to target a total of 59,547bp within the aforementioned genes, and sequencing of an initial cohort of patient samples has been completed with a total sequence size of 1.54E11bp with 72.26% high-quality sequence. Ongoing work of sequence analysis will quantify the mutation burden in these samples and correlate these results to skin cancer history.

Comments

This thesis is restricted to Yale network users only. It will be made publicly available on 05/29/2021

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