Medicine and Health Sciences Commons^™

Pembrolizumab Versus Placebo As Adjuvant Therapy In Resected Stage Iib Or Iic Melanoma: Outcomes In Histopathologic Subgroups From The Randomized, Double-Blind, Phase 3 Keynote-716 Trial, Dirk Schadendorf, Jason J. Luke, Paolo A. Ascierto, Georgina V. Long, Piotr Rutkowski, Adnan Khattak, Michele Del Vecchio, Luis De La Cruz-Merino, Jacek Mackiewicz, Vanna C. Sileni, John M. Kirkwood, Caroline Robert, Jean-Jacques Grob, Reinhard Dummer, Matteo S. Carlino, Yujie Zhao, Mizuho Kalabis, Clemens Krepler, Alexander Eggermont, Richard A. Scolyer

Research outputs 2022 to 2026

Background Adjuvant pembrolizumab significantly improved recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) versus placebo in the phase 3 KEYNOTE-716 study of resected stage IIB or IIC melanoma. At the prespecified third interim analysis (data cut-off, January 4, 2022), the HR for RFS in the overall population was 0.64 (95% CI, 0.50 to 0.84) and the HR for DMFS was 0.64 (95% CI, 0.47 to 0.88). We present a post hoc analysis of efficacy by subtypes defined by histopathologic characteristics. Methods Patients aged ≥ 12 years with newly diagnosed, resected stage IIB or IIC melanoma were randomly assigned (1:1) to …

Conditional Metastasis Of Uveal Melanoma In 8091 Patients Over Half-Century (51 Years) By Age Group: Assessing The Entire Population And The Extremes Of Age, Carol L. Shields, Annika Samuelson, Glenn Oh, Joseph D. Desimone, Zaynab Sajjadi, Zeynep Bas, Nicholas E Kalafatis, Sara E. Lally, Jerry A. Shields, Philip W. Dockery

Wills Eye Hospital Papers

PURPOSE: To evaluate cumulative incidence of metastasis at specific timepoints after treatment of uveal melanoma in a large cohort of patients and to provide comparison of conditional outcomes in the youngest and oldest cohorts (extremes of age).

METHODS: Retrospective analysis of 8091 consecutive patients with uveal melanoma at a single center over a 51-year period. The patients were categorized by age at presentation (0-29 years [n = 348, 4%], 30-59 years [n = 3859, 48%], 60-79 years [n = 3425, 42%], 80 to 99 years [n = 459, 6%]) and evaluated for nonconditional (from presentation date) and conditional (from specific …

Racial Differences In Perceived Risk And Sunscreen Usage, Rebecca Fliorent, Alicia Podwojniak, Lianne Adolphe, Katharine Milani

Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship

Background Although White individuals have higher incidence of melanoma, clinical outcomes are worse among patients with skin of color. This disparity arises from delayed diagnoses and treatment that are largely due to clinical and sociodemographic factors. Investigating this discrepancy is crucial to decrease melanoma-related mortality rates in minority communities. A survey was used to investigate the presence of racial disparities in perceived sun exposure risks and behaviors. Methods A survey consisting of 16 questions was deployed via social media to assess skin health knowledge. Over 350 responses were recorded, and the extracted data were analyzed using statistical software. Results Of …

Prognostic And Predictive Value Of Metformin In The European Organisation For Research And Treatment Of Cancer 1325/Keynote-054 Phase Iii Trial Of Pembrolizumab Versus Placebo In Resected High-Risk Stage Iii Melanoma, Oliver J. Kennedy, Michal Kicinski, Sara Valpione, Sara Gandini, Stefan Suciu, Christian U. Blank, Georgina V. Long, Victoria G. Atkinson, Stéphane Dalle, Andrew M. Haydon, Andrey Meshcheryakov, Adnan Khattak, Matteo S. Carlino, Shahneen Sandhu, James Larkin, Susana Puig, Paolo A. Ascierto, Piotr Rutkowski, Dirk Schadendorf, Marye Boers-Sonderen, Anna M. Di Giacomo, Alfonsus J. M. Van Der Eertwegh, Jean-Jacques Grob, Ralf Gutzmer, Rahima Jamal, Alexander C. J. Van Akkooi, Caroline Robert, Alexander M. M. Eggermont, Paul Lorigan, Mario Mandala

Research outputs 2022 to 2026

Background: Metformin is a commonly prescribed and well-tolerated medication. In laboratory studies, metformin suppresses BRAF wild-type melanoma cells but accelerates the growth of BRAF-mutated cells. This study investigated the prognostic and predictive value of metformin, including with respect to BRAF mutation status, in the European Organisation for Research and Treatment of Cancer 1325/KEYNOTE-054 randomised controlled trial. Methods: Patients with resected high-risk stage IIIA, IIIB, or IIIC melanoma received 200 mg of pembrolizumab (n = 514) or placebo (n = 505) every 3 weeks for twelve months. Pembrolizumab prolonged recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) at approximately 42 months …

Detectable Ctdna At The Time Of Treatment Cessation Of Ipilimumab And Nivolumab For Toxicity Predicts Disease Progression In Advanced Melanoma Patients, Lydia Warburton, Anna Reid, Benhur Amanuel, Leslie Calapre, Michael Millward, Elin Gray

Research outputs 2022 to 2026

Background: Immune checkpoint inhibition (ICI) has led to unprecedented outcomes for melanoma patients but is associated with toxicity. ICI resumption after high grade irAEs poses a significant challenge in the clinical management of melanoma patients and there are no biomarkers that can help identify patients that might benefit from resuming treatment. This study aims to determine if circulating tumor DNA (ctDNA) levels at the time of treatment-limiting irAE could guide treatment decisions in this clinical context. Methods: This is a retrospective exploratory biomarker study from 34 patients treated with combination ICI for stage IV melanoma. Patients had a treatment-limiting toxicity …

Modification Of The Tumor Microenvironment Enhances Anti-Pd-1 Immunotherapy In Metastatic Melanoma, Guilan Shi, Megan Scott, Cathryn G. Mangiamele, Richard Heller

Bioelectrics Publications

Resistance to checkpoint-blockade treatments is a challenge in the clinic. Both primary and acquired resistance have become major obstacles, greatly limiting the long-lasting effects and wide application of blockade therapy. Many patients with metastatic melanoma eventually require further therapy. The absence of T-cell infiltration to the tumor site is a well-accepted contributor limiting immune checkpoint inhibitor efficacy. In this study, we combined intratumoral injection of plasmid IL-12 with electrotransfer and anti-PD-1 in metastatic B16F10 melanoma tumor model to increase tumor-infiltrating lymphocytes and improve therapeutic efficacy. We showed that effective anti-tumor responses required a subset of tumor-infiltrating CD8⁺ and CD4 …

A Small Peptide Increases Drug Delivery In Human Melanoma Cells, Shirley Tong, Shaban Darwish, Hanieh Hossein Nejad Ariani, Kate Alison Lozada, David Salehi, Maris A. Cinelli, Richard B. Silverman, Kamaljit Kaur, Sun Yang

Pharmacy Faculty Articles and Research

Melanoma is the most fatal type of skin cancer and is notoriously resistant to chemotherapies. The response of melanoma to current treatments is difficult to predict. To combat these challenges, in this study, we utilize a small peptide to increase drug delivery to melanoma cells. A peptide library array was designed and screened using a peptide array-whole cell binding assay, which identified KK-11 as a novel human melanoma-targeting peptide. The peptide and its D-amino acid substituted analogue (VPWxEPAYQrFL or D-aa KK-11) were synthesized via a solid-phase strategy. Further studies using FITC-labeled KK-11 demonstrated dose-dependent uptake in human melanoma cells. D-aa …

Prognostic And Predictive Value Of Β-Blockers In The Eortc 1325/Keynote-054 Phase Iii Trial Of Pembrolizumab Versus Placebo In Resected High-Risk Stage Iii Melanoma, Oliver J. Kennedy, Michal Kicinski, Sara Valpione, Sara Gandini, Stefan Suciu, Christian U. Blank, Georgina V. Long, Victoria G. Atkinson, Stéphane Dalle, Andrew M. Haydon, Andrey Meshcheryakov, Adnan Khattak, Matteo S. Carlino, Shahneen Sandhu, James Larkin, Susana Puig, Paolo A. Ascierto, Piotr Rutkowski, Dirk Schadendorf, Rutger Koornstra, Leonel Hernandez-Aya, Anna M. Di Giacomo, Alfonsus J.M. Van Den Eertwegh, Jean Jacques Grob, Ralf Gutzmer, Rahima Jamal, Alexander C.J. Van Akkooi, Caroline Robert, Alexander M. M. Eggermont, Paul Lorigan, Mario Mandala

Research outputs 2022 to 2026

Background:

β-adrenergic receptors are upregulated in melanoma cells and contribute to an immunosuppressive, pro-tumorigenic microenvironment. This study investigated the prognostic and predictive value of β-adrenoreceptor blockade by β-blockers in the EORTC1325/KEYNOTE-054 randomised controlled trial.

Methods:

Patients with resected stage IIIA, IIIB or IIIC melanoma and regional lymphadenectomy received 200 mg of adjuvant pembrolizumab (n = 514) or placebo (n = 505) every three weeks for one year or until recurrence or unacceptable toxicity. At a median follow-up of 3 years, pembrolizumab prolonged recurrence-free survival (RFS) compared to placebo (hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.47–0.68). β-blocker use was …

Gut Microbiota Diversity And Composition In Predicting Immunotherapy Response And Immunotherapy-Related Colitis In Melanoma Patients: A Systematic Review, Oliver Oey, Yu-Yang Liu, Angela F. Sunjaya, Daniel M. Simadibrata, Muhammad A. Khattak, Elin Gray

Research outputs 2022 to 2026

Background: Gut microbiome (GM) composition and diversity have recently been studied as a biomarker of response to immune checkpoint blockade therapy (ICB) and of ICB-related colitis. Aim: To conduct a systematic review on the role of GM composition and diversity in predicting response and colitis in patients with melanoma treated with ICB. Methods: The review protocol was registered in PROSPERO: CRD42021228018. From a total of 300 studies, nine studies met inclusion criteria. Two studies were phase I clinical trials, while the remainder were prospective observational studies. All but one study has moderate risk of bias. In addition, we conducted a …

Associations Of Physical Activity And Exercise With Health-Related Outcomes In Patients With Melanoma During And After Treatment: A Systematic Review, Brendan J. Crosby, Pedro Lopez, Daniel A. Galvao, Robert U. Newton, Dennis Taaffe, Tarek M. Meniawy, Lydia Warburton, Muhammad A. Khattak, Elin S. Gray, Favil Singh

Research outputs 2014 to 2021

Purpose:

Although exercise medicine is recommended to counter treatment-related side-effects and improve health-related outcomes of patients affected by different cancers, no specific recommendations exist for patients with melanoma. As a result, we systematically examined the current evidence regarding the effects of physical activity and exercise on objectively-measured and patient-reported outcomes among patients with melanoma.

Methods:

Searches were conducted in PubMed, CINAHL, EMBASE, SPORTDiscus, and Web of Science databases. This review included published data involving physical activity or exercise and objectively-measured or patient-reported outcomes of patients with cutaneous melanoma. The quality of included studies was assessed using …

Circulating Tumor Dna Reflects Uveal Melanoma Responses To Protein Kinase C Inhibition, John J. Park, Russell J. Diefenbach, Natalie Byrne, Georgina V. Long, Richard A. Scolyer, Elin S. Gray, Matteo S. Carlino, Helen Rizos

Research outputs 2014 to 2021

The prognosis for patients with UM is poor, and recent clinical trials have failed to prolong overall survival (OS) of these patients. Over 95% of UM harbor activating driver mutations, and this allows for the investigation of ctDNA. In this study, we investigated the value of ctDNA for adaptive clinical trial design in metastatic UM. Longitudinal plasma samples were analyzed for ctDNA in 17 metastatic UM patients treated with PKCi-based therapy in a phase 1 clinical trial setting. Plasma ctDNA was assessed using digital droplet PCR (ddPCR) and a custom melanoma gene panel for targeted next generation sequencing (NGS). Baseline …

The Prognostic Impact Of Circulating Tumour Dna In Melanoma Patients Treated With Systemic Therapies—Beyond Braf Mutant Detection, Gabriela Marsavela, Peter A. Johansson, Michelle R. Pereira, Ashleigh C. Mcevoy, Anna L. Reid, Cleo Robinson, Lydia Warburton, Muhammad A. Khattak, Tarek M. Meniawy, Benhur Amanuel, Michael Millward, Nicholas K. Hayward, Melanie R. Ziman, Elin S. Gray, Leslie Calapre

Research outputs 2014 to 2021

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. In this study, we evaluated the predictive value of circulating tumour DNA (ctDNA) to inform therapeutic outcomes in metastatic melanoma patients receiving systemic therapies. We analysed 142 plasma samples from metastatic melanoma patients prior to commencement of systemic therapy: 70 were treated with BRAF/MEK inhibitors and 72 with immunotherapies. Patient-specific droplet digital polymerase chain reaction assays were designed for ctDNA detection. Plasma ctDNA was detected in 56% of patients prior to first-line anti-PD1 and/or anti-CTLA-4 treatment. The detection rate in the immunotherapy cohort was comparably lower than those with BRAF inhibitors …

Thermal Analysis Of Infrared Irradiation-Assisted Nanosecond-Pulsed Tumor Ablation, James Hornef, Chelsea M. Edelblute, Karl H. Schoenbach, Richard Heller, Siqi Guo, Chunqi Jiang

Bioelectrics Publications

Nanosecond Pulsed Electric Fields (nsPEF) have the potential to treat a variety of cancer types including melanoma, pancreatic and lung squamous cancers. Recent studies show that nsPEF-based cancer therapy may be improved further with the assistance of moderate heating of the target. A feedbacklooped heating system, utilizing a 980-nm fiber optic laser, was integrated into nsPEF electrodes for tumor ablation. The laser beam profile was determined to be Gaussian using a knife-edge technique. Thermal properties of the biological target were evaluated based on the treatment area, penetration depth and thermal distribution due to laser irradiation with or without nsPEF. Synergistic …

Biological Pathway Involvement In Melanoma Heterogeneity And Drug-Induced Resistance, Sarah V. Pack

STAR Program Research Presentations

Tumors develop resistance to numerous drug therapies, and this remains a major obstacle in treating many types of non-surgical cancers. Melanoma provides a good model system for studying drug resistance in cancer due to its high propensity to incur resistance after a significant initial response to a drug. Genes that are highly expressed in melanoma cancer cells have been studied, but in order to further understand the collective function of these highly expressed genes we must analyze gene sets, or pathways. A single gene’s function is rarely independent of other genes, and pathway analysis takes this into account.

Our objective …

The Immunosuppressive Role Of Edn3/Ednrb Signaling In The Melanoma Microenvironment, Juliano Tiburcio De Freitas

FIU Electronic Theses and Dissertations

Endothelins are cytokines ubiquitously expressed in the microenvironment of several tumors. In melanoma is not clear whether stromal cells respond to the endothelin present in the microenvironment. To address this question, I generated tumors derived from different murine melanoma cell lines (B16F10, YUMM1.7, YUMMER1.7) in a transgenic mouse that overexpresses endothelin 3 (Edn3) by keratinocytes in the skin (K5-Edn3). Tumors from all the cell lines grew larger and were more aggressive when Edn3 was overexpressed in the skin. In tumors derived from YUMM1.7-GFP cells, very few tumorigenic cells expressed the Edn3 receptor, Endothelin receptor b (Ednrb) suggesting an …

Micromelanomas Identified With Time-Lapse Total Body Photography And Dermoscopy, Elizabeth D. Drugge, Elgida R. Volpicelli, Rebecca M. Sarac, Sophie R. Strang, Dirk M. Elston, Rhett J. Drugge

NYMC Faculty Publications

No abstract provided.

Skin Cancer: Causes, Prevention, And Treatment, Lauren Queen

Senior Honors Theses

The purpose of this thesis is to analyze the causes, prevention, and treatment of skin cancer. Skin cancers are defined as either malignant or benign cells that typically arise from excessive exposure to UV radiation. Arguably, skin cancer is a type of cancer that can most easily be prevented; prevention of skin cancer is relatively simple, but often ignored. An important aspect in discussing the epidemiology of skin cancer is understanding the treatments that are available, as well as the prevention methods that can be implemented in every day practice. It is estimated that one in five Americans will develop …

New Malignancies After Squamous Cell Carcinoma And Melanomas: A Population-Based Study From Norway, Trude E. Robsahm, Margaret R. Karagas, Judy R. Rees, Astri Syse

Dartmouth Scholarship

Skin cancer survivors experience an increased risk for subsequent malignancies but the associated risk factors are poorly understood. This study examined the risk of a new primary cancer following an initial skin cancer and assessed risk factors associated with second primary cancers.

Comparative Study Of Long-And Short-Pulsed Electric Fields For Treating Melanoma In An In Vivo Mouse Model, Xinhua Chen, Xinmei Chen, Karl H. Schoenbach, Shusen Zheng, R. James Swanson

Bioelectrics Publications

A mouse melanoma model was set up with green fluorescent protein (GFP) expression in vivo. With the same energy, long- (1 ms) and short- (300 ns) pulsed electric fields were delivered to two melanomas injected into the same mouse. The tumor growth and green fluorescence were followed up to compare the different treatment efficacy of long and short pulses. After two days post treatment, short pulse-treated tumors showed a significantly lower tumor volume compared with long pulse-treated tumors (n=8, p