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Melanoma: HELP
Articles by William E. Carson
Based on 45 articles published since 2008
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Between 2008 and 2019, W. E. Carson wrote the following 45 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Guideline NCCN Guidelines Insights: Melanoma, Version 3.2016. 2016

Coit, Daniel G / Thompson, John A / Algazi, Alain / Andtbacka, Robert / Bichakjian, Christopher K / Carson, William E / Daniels, Gregory A / DiMaio, Dominick / Fields, Ryan C / Fleming, Martin D / Gastman, Brian / Gonzalez, Rene / Guild, Valerie / Johnson, Douglas / Joseph, Richard W / Lange, Julie R / Martini, Mary C / Materin, Miguel A / Olszanski, Anthony J / Ott, Patrick / Gupta, Aparna Priyanath / Ross, Merrick I / Salama, April K / Skitzki, Joseph / Swetter, Susan M / Tanabe, Kenneth K / Torres-Roca, Javier F / Trisal, Vijay / Urist, Marshall M / McMillian, Nicole / Engh, Anita. ·From Memorial Sloan Kettering Cancer Center; Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance; UCSF Helen Diller Family Comprehensive Cancer Center; Huntsman Cancer Institute at the University of Utah; University of Michigan Comprehensive Cancer Center; The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute; UC San Diego Moores Cancer Center; Fred & Pamela Buffett Cancer Center; Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine; The University of Tennessee Health Science Center; Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute; University of Colorado Cancer Center; Aim at Melanoma; Vanderbilt-Ingram Cancer Center; Mayo Clinic Cancer Center; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; Robert H. Lurie Comprehensive Cancer Center of Northwestern University; Yale Cancer Center/Smilow Cancer Hospital; Fox Chase Cancer Center; Dana-Farber/Brigham and Women's Cancer Center; The University of Texas MD Anderson Cancer Center; Duke Cancer Institute; Roswell Park Cancer Institute; Stanford Cancer Institute; Massachusetts General Hospital Cancer Center; Moffitt Cancer Center; City of Hope Comprehensive Cancer Center; University of Alabama at Birmingham Comprehensive Cancer Center; and National Comprehensive Cancer Network. ·J Natl Compr Canc Netw · Pubmed #27496110.

ABSTRACT: The NCCN Guidelines for Melanoma have been significantly revised over the past few years in response to emerging data on a number of novel agents and treatment regimens. These NCCN Guidelines Insights summarize the data and rationale supporting extensive changes to the recommendations for systemic therapy in patients with metastatic or unresectable melanoma.

2 Guideline Melanoma, Version 2.2016, NCCN Clinical Practice Guidelines in Oncology. 2016

Coit, Daniel G / Thompson, John A / Algazi, Alain / Andtbacka, Robert / Bichakjian, Christopher K / Carson, William E / Daniels, Gregory A / DiMaio, Dominick / Ernstoff, Marc / Fields, Ryan C / Fleming, Martin D / Gonzalez, Rene / Guild, Valerie / Halpern, Allan C / Hodi, F Stephen / Joseph, Richard W / Lange, Julie R / Martini, Mary C / Materin, Miguel A / Olszanski, Anthony J / Ross, Merrick I / Salama, April K / Skitzki, Joseph / Sosman, Jeff / Swetter, Susan M / Tanabe, Kenneth K / Torres-Roca, Javier F / Trisal, Vijay / Urist, Marshall M / McMillian, Nicole / Engh, Anita. · ·J Natl Compr Canc Netw · Pubmed #27059193.

ABSTRACT: This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Melanoma focuses on adjuvant therapy and treatment of in-transit disease, because substantial changes were made to the recommendations for the 2016 update. Depending on the stage of the disease, options for adjuvant therapy now include biochemotherapy and high-dose ipilimumab. Treatment options for in-transit disease now include intralesional injection with talimogene laherparepvec (T-VEC), a new immunotherapy. These additions prompted re-assessment of the data supporting older recommended treatment options for adjuvant therapy and in-transit disease, resulting in extensive revisions to the supporting discussion sections.

3 Guideline Melanoma, version 4.2014. 2014

Coit, Daniel G / Thompson, John A / Andtbacka, Robert / Anker, Christopher J / Bichakjian, Christopher K / Carson, William E / Daniels, Gregory A / Daud, Adil / Dimaio, Dominick / Fleming, Martin D / Gonzalez, Rene / Guild, Valerie / Halpern, Allan C / Hodi, F Stephen / Kelley, Mark C / Khushalani, Nikhil I / Kudchadkar, Ragini R / Lange, Julie R / Martini, Mary C / Olszanski, Anthony J / Ross, Merrick I / Salama, April / Swetter, Susan M / Tanabe, Kenneth K / Trisal, Vijay / Urist, Marshall M / McMillian, Nicole R / Ho, Maria / Anonymous5170793. ·From 1Memorial Sloan-Kettering Cancer Center; 2Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance; 3Huntsman Cancer Institute at the University of Utah; 4University of Michigan Comprehensive Cancer Center; 5The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute; 6UC San Diego Moores Cancer Center; 7UCSF Helen Diller Family Comprehensive Cancer Center; 8Fred & Pamela Buffett Cancer Center at The Nebraska Medical Center; 9St. Jude Children's Research Hospital/The University of Tennessee Health Science Center; 10University of Colorado Cancer Center; 11Aim at Melanoma; 12Dana-Farber/Brigham and Women's Cancer Center; 13Vanderbilt-Ingram Cancer Center; 14Roswell Park Cancer Institute; 15Moffitt Cancer Center; 16The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; 17Robert H. Lurie Comprehensive Cancer Center of Northwestern University; 18Fox Chase Cancer Center; 19The University of Texas MD Anderson Cancer Center; 20Duke Cancer Institute; 21Stanford Cancer Institute; 22Massachusetts General Hospital Cancer Center; 23City of Hope Comprehensive Cancer Center; 24University of Alabama at Birmingham Comprehensive Cancer Center; and 25National Comprehensive Cancer Network. ·J Natl Compr Canc Netw · Pubmed #24812131.

ABSTRACT: The NCCN Guidelines for Melanoma provide multidisciplinary recommendations for the management of patients with melanoma. These NCCN Guidelines Insights highlight notable recent updates. Dabrafenib and trametinib, either as monotherapy (category 1) or combination therapy, have been added as systemic options for patients with unresectable metastatic melanoma harboring BRAF V600 mutations. Controversy continues regarding the value of adjuvant radiation for patients at high risk of nodal relapse. This is reflected in the category 2B designation to consider adjuvant radiation following lymphadenectomy for stage III melanoma with clinically positive nodes or recurrent disease.

4 Guideline Melanoma, version 2.2013: featured updates to the NCCN guidelines. 2013

Coit, Daniel G / Andtbacka, Robert / Anker, Christopher J / Bichakjian, Christopher K / Carson, William E / Daud, Adil / Dimaio, Dominick / Fleming, Martin D / Guild, Valerie / Halpern, Allan C / Hodi, F Stephen / Kelley, Mark C / Khushalani, Nikhil I / Kudchadkar, Ragini R / Lange, Julie R / Lind, Anne / Martini, Mary C / Olszanski, Anthony J / Pruitt, Scott K / Ross, Merrick I / Swetter, Susan M / Tanabe, Kenneth K / Thompson, John A / Trisal, Vijay / Urist, Marshall M / McMillian, Nicole / Ho, Maria / Anonymous4310755. ·Memorial Sloan-Kettering Cancer Center. ·J Natl Compr Canc Netw · Pubmed #23584343.

ABSTRACT: The NCCN Guidelines for Melanoma provide multidisciplinary recommendations on the clinical management of patients with melanoma. This NCCN Guidelines Insights report highlights notable recent updates. Foremost of these is the exciting addition of the novel agents ipilimumab and vemurafenib for treatment of advanced melanoma. The NCCN panel also included imatinib as a treatment for KIT-mutated tumors and pegylated interferon alfa-2b as an option for adjuvant therapy. Also important are revisions to the initial stratification of early-stage lesions based on the risk of sentinel lymph node metastases, and revised recommendations on the use of sentinel lymph node biopsy for low-risk groups. Finally, the NCCN panel reached clinical consensus on clarifying the role of imaging in the workup of patients with melanoma.

5 Guideline Melanoma. 2012

Coit, Daniel G / Andtbacka, Robert / Anker, Christopher J / Bichakjian, Christopher K / Carson, William E / Daud, Adil / Dilawari, Raza A / Dimaio, Dominick / Guild, Valerie / Halpern, Allan C / Hodi, F Stephen / Kelley, Mark C / Khushalani, Nikhil I / Kudchadkar, Ragini R / Lange, Julie R / Lind, Anne / Martini, Mary C / Olszanski, Anthony J / Pruitt, Scott K / Ross, Merrick I / Swetter, Susan M / Tanabe, Kenneth K / Thompson, John A / Trisal, Vijay / Urist, Marshall M / Anonymous590720. · ·J Natl Compr Canc Netw · Pubmed #22393197.

ABSTRACT: -- No abstract --

6 Review MicroRNA dysregulation in melanoma. 2016

Latchana, Nicholas / Ganju, Akaansha / Howard, J Harrison / Carson, William E. ·Department of Surgery, The Ohio State University, Columbus, OH 43210, USA. Electronic address: Nicholas.Latchana@osumc.edu. · Department of Surgery, The Ohio State University, Columbus, OH 43210, USA. Electronic address: Aganju@neomed.edu. · Department of Surgery, The Ohio State University, Columbus, OH 43210, USA. Electronic address: John.Howard@osumc.edu. · Department of Surgery, The Ohio State University, Columbus, OH 43210, USA; Department of Molecular Virology, Immunology and Medical Genetics, The Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA. Electronic address: William.Carson@osumc.edu. ·Surg Oncol · Pubmed #27566021.

ABSTRACT: Melanoma is the deadliest form of skin cancer. Current challenges facing the management of melanoma include accurate prediction of individuals who will respond to adjuvant therapies as well as early detection of recurrences. These and other challenges have prompted investigation into biomarkers that could be used as diagnostic, prognostic and therapeutic aids. MicroRNAs (miRs) are small 19-22 nucleotide RNA inhibitors of protein translation. Over 800 different miRs are present within cells and importantly miR expression profiles may vary across different cells types and stages of malignancy. Unique expression profiles have been described for malignant melanoma; however, this work has yet to be translated into routine clinical practice. We highlight pertinent studies involving common miRs implicated in the oncogenesis of melanoma including miR-21, miR-125b, miR-150, miR-155, miR-205, and miR-211. In particular, emphasis is placed upon differential expression across different stages of melanoma progression, prognostic implications and potential mechanistic involvement. Focused efforts on inhibition of these miRs could be the most efficient method of translating preclinical endeavors into clinically meaningful applications.

7 Clinical Trial Safety and Activity of Varlilumab, a Novel and First-in-Class Agonist Anti-CD27 Antibody, in Patients With Advanced Solid Tumors. 2017

Burris, Howard A / Infante, Jeffrey R / Ansell, Stephen M / Nemunaitis, John J / Weiss, Geoffrey R / Villalobos, Victor M / Sikic, Branimir I / Taylor, Matthew H / Northfelt, Donald W / Carson, William E / Hawthorne, Thomas R / Davis, Thomas A / Yellin, Michael J / Keler, Tibor / Bullock, Timothy. ·Howard A. Burris and Jeffrey R. Infante, Sarah Cannon Research Institute, Tennessee Oncology, Nashville, TN · Stephen M. Ansell, Mayo Clinic, Rochester, MN · John J. Nemunaitis, Mary Crowley Cancer Research Center, Dallas, TX · Geoffrey R. Weiss and Timothy Bullock, University of Virginia, Charlottesville, VA · Victor M. Villalobos and Branimir I. Sikic, Stanford Cancer Institute, Stanford, CA · Matthew H. Taylor, Oregon Health & Science University, Portland, OR · Donald W. Northfelt, Mayo Clinic, Scottsdale, AZ · William E. Carson III, The Ohio State University, Columbus, OH · Thomas R. Hawthorne, Thomas A. Davis, Michael J. Yellin, and Tibor Keler, Celldex Therapeutics, Hampton, NJ. ·J Clin Oncol · Pubmed #28463630.

ABSTRACT: Purpose CD27, a costimulatory molecule on T cells, induces intracellular signals that mediate cellular activation, proliferation, effector function, and cell survival upon binding to its ligand, CD70. Varlilumab is a novel, first-in-class, agonist CD27 antibody that stimulates the CD27 pathway, which results in T-cell activation and antitumor activity in tumor models. This first-in-human, dose-escalation and expansion study evaluated the safety, pharmacology, and activity of varlilumab in patients with advanced solid tumors. Methods In a 3 + 3 dose-escalation design (n = 25), patients received a single dose of varlilumab (0.1, 0.3, 1.0, 3.0, or 10 mg/kg intravenously) with a 28-day observation, followed by up to five multidose cycles (one dose per week for 4 weeks), depending on tumor response. Expansion cohorts were initiated at 3.0 mg/kg in patients with melanoma (n = 16) and renal cell carcinoma (RCC; n = 15). Primary objectives were to assess the safety and the maximum tolerated and optimal biologic doses of varlilumab. Secondary objectives were to evaluate the pharmacokinetics, pharmacodynamics, and clinical antitumor activity of varlilumab. Results Exposure to varlilumab was linear and dose proportional across dose groups. Only one patient experienced a dose-limiting toxicity-grade 3 transient asymptomatic hyponatremia at the 1.0-mg/kg dose level. Treatment-related adverse events were generally grade 1 or 2 in severity. Evidence of biologic activity consistent with CD27 stimulation-chemokine induction, T-cell stimulation, regulatory T cell depletion-was observed at all dose levels. A patient with metastatic RCC experienced a partial response (78% shrinkage, progression-free survival > 2.3 years). Eight patients experienced stable disease > 3 months, including a patient with metastatic RCC with progression-free survival of > 3.9 years. Conclusion Dose escalation of varlilumab to 10 mg/kg was well tolerated without identification of a maximum tolerated dose. Varlilumab was biologically and clinically active.

8 Clinical Trial Phase III Randomized Study of 4 Weeks of High-Dose Interferon-α-2b in Stage T2bNO, T3a-bNO, T4a-bNO, and T1-4N1a-2a (microscopic) Melanoma: A Trial of the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Research Group (E1697). 2017

Agarwala, Sanjiv S / Lee, Sandra J / Yip, Waiki / Rao, Uma N / Tarhini, Ahmad A / Cohen, Gary I / Reintgen, Douglas S / Evans, Terry L / Brell, Joanna M / Albertini, Mark R / Atkins, Michael B / Dakhil, Shaker R / Conry, Robert M / Sosman, Jeffrey A / Flaherty, Lawrence E / Sondak, Vernon K / Carson, William E / Smylie, Michael G / Pappo, Alberto S / Kefford, Richard F / Kirkwood, John M. ·Sanjiv S. Agarwala, Saint Luke's University Hospital, Easton · Uma N. Rao, Ahmad A. Tarhini, Terry L. Evans, and John M. Kirkwood, University of Pittsburgh Medical Center, Pittsburgh, PA · Sandra J. Lee, and Waiki Yip, Dana Farber Cancer Institute-ECOG-ACRIN Biostatistics Center, Boston, MA · Gary I. Cohen, Greater Baltimore Medical Center, Baltimore, MD · Douglas S. Reintgen, Lakeland Regional Cancer Center, Lakeland · Vernon K. Sondak, H. Lee Moffitt Cancer Center, Tampa, FL · Joanna M. Brell, MetroHealth Medical Center, Cleveland · William E. Carson, The Ohio State University Comprehensive Cancer Center, Columbus, OH · Mark R. Albertini, University of Wisconsin Hospital, Madison, WI · Michael B. Atkins, Georgetown Medical Center, Washington, DC · Shaker R. Dakhil, Cancer Center of Kansas, Wichita, KS · Robert M. Conry, University of Alabama at Birmingham, Birmingham, AL · Jeffrey A. Sosman, Vanderbilt University, Nashville · Alberto S. Pappo, Saint Jude Children's Research Hospital Oncology, Memphis, TN · Lawrence E. Flaherty, Wayne State University/Karmanos Cancer Institute, Detroit, MI · Michael G. Smylie, Cross Cancer Institute, Edmonton, Canada · and Richard F. Kefford, Sydney West Area Health Service, Westmead, Australia. ·J Clin Oncol · Pubmed #28135150.

ABSTRACT: Purpose To test the efficacy of 4 weeks of intravenous (IV) induction with high-dose interferon (IFN) as part of the Eastern Cooperative Oncology Group regimen compared with observation (OBS) in patients with surgically resected intermediate-risk melanoma. Patients and Methods In this intergroup international trial, eligible patients had surgically resected cutaneous melanoma in the following categories: (1) T2bN0, (2) T3a-bN0, (3) T4a-bN0, and (4) T1-4N1a-2a (microscopic). Patients were randomly assigned to receive IFN α-2b at 20 MU/m

9 Clinical Trial Increased visceral to subcutaneous fat ratio is associated with decreased overall survival in patients with metastatic melanoma receiving anti-angiogenic therapy. 2015

Grignol, Valerie P / Smith, Andrew D / Shlapak, Darya / Zhang, Xu / Del Campo, Sara Martin / Carson, William E. ·Division of Surgical Oncology, The Ohio State University, Columbus, OH, USA. · Department of Radiology, University of Mississippi, Jackson, MS, USA. · Center of Biostatistics and Bioinformatics, University of Mississippi, Jackson, MS, USA. · Division of Surgical Oncology, The Ohio State University, Columbus, OH, USA. Electronic address: william.carson@osumc.edu. ·Surg Oncol · Pubmed #26690825.

ABSTRACT: BACKGROUND: Body fat distribution is an emerging prognostic indicator in patients treated with anti-angiogenic (AA) therapy. We sought to evaluate the association of visceral and subcutaneous fat with progression free survival (PFS) and overall survival (OS) in patients with metastatic melanoma treated with AA therapy. METHODS: Stage IV melanoma patients received bevacizumab ± interferon-alpha. Total abdominal fat, visceral fat area (VFA) and subcutaneous fat area (SFA) were measured at L3-L4 on CT images (cm(2)). PFS and OS were estimated by the Kaplan-Meier method. Cox proportional hazards model was used to assess the association of fat and clinical variables with PFS and OS. Prediction accuracy was evaluated using receiver operating characteristic curve with area under the curve (AUC). RESULTS: Forty-two patients were evaluated. Median VFA/SFA and body mass index (BMI) were used to group patients into high and low cohorts. PFS and OS were significantly decreased in patients with high VFA/SFA versus low (PFS, p=0.009; OS, p = 0.007), but not for BMI (PFS, p=0.774; OS, p=0.881). VFA/SFA, LDH and liver metastasis (LM) were predictors of PFS and OS on multivariate analysis. A prognostic score combining VFA/SFA, LDH, and presence or absence of LM had a higher accuracy for predicting PFS at 3 months (AUC 0.759) and OS at 24 months (AUC 0.846) than LDH and LM alone (PFS, AUC 0.705; OS, AUC 0.786). CONCLUSION: Increased VFA/SFA is associated with decreased PFS and OS in patients with metastatic melanoma treated with AA therapy, indicating body fat distribution is an important prognostic factor.

10 Clinical Trial Predicting Overall Survival in Patients With Metastatic Melanoma on Antiangiogenic Therapy and RECIST Stable Disease on Initial Posttherapy Images Using CT Texture Analysis. 2015

Smith, Andrew D / Gray, Mark R / del Campo, Sara Martin / Shlapak, Darya / Ganeshan, Balaji / Zhang, Xu / Carson, William E. ·1 Department of Radiology, University of Mississippi Medical Center, 2500 N State St, Jackson, MS 39216. · 2 Department of Surgery, The Ohio State University Comprehensive Cancer Center, Columbus, OH. · 3 Department of Biomedical Engineering, University College of London, London, UK. ·AJR Am J Roentgenol · Pubmed #26295664.

ABSTRACT: OBJECTIVE: The purpose of this study was to use CT texture analysis to predict overall survival (OS) in patients with metastatic melanoma and stable disease (SD) according to the Response Evaluation Criteria in Solid Tumors (RECIST) on initial posttherapy CT images. MATERIALS AND METHODS: This retrospective study included 42 patients with metastatic melanoma who received bevacizumab therapy in the context of a randomized prospective phase II clinical trial. Target lesions on the baseline and initial posttherapy contrast-enhanced CT examinations were evaluated by CT texture analysis using TexRAD software before and after image filtering in patients with RECIST SD on initial posttherapy images. Cox proportional hazards models were used to assess the associations of CT texture analysis measurements and of other patient factors with OS. The AUC was used to evaluate predictive accuracy. RESULTS: In multivariate analysis (in 23 patients with RECIST SD; median OS, 1.51 years), absolute change in mean positive pixels at spatial scaling filter of 4 mm, change in tumor size, and baseline serum lactate dehydrogenase (LDH) level were predictors of OS (hazard ratio [HR] = 5.05 for decrease in mean positive pixels at spatial scaling filter of 4 mm vs increase, p = 0.007; HR = 4.14 for > 5% increase in tumor size vs otherwise, p = 0.025; and HR = 1.29 for every 100 IU/L increase in baseline LDH level, p = 0.068). A prognostic index containing these three factors was highly accurate for predicting OS at 18 months (AUC = 0.917). CONCLUSION: In patients with metastatic melanoma and RECIST SD on initial post-therapy CT images, a model incorporating CT texture analysis of target lesions, tumor size changes, and baseline LDH levels was highly accurate in predicting OS.

11 Clinical Trial Adjuvant vaccine immunotherapy of resected, clinically node-negative melanoma: long-term outcome and impact of HLA class I antigen expression on overall survival. 2014

Carson, William E / Unger, Joseph M / Sosman, Jeffrey A / Flaherty, Lawrence E / Tuthill, Ralph J / Porter, Mark J / Thompson, John A / Kempf, Raymond A / Othus, Megan / Ribas, Antoni / Sondak, Vernon K. ·Division of Surgical Oncology, The Ohio State University, Columbus, Ohio. william.carson@osumc.edu. · SWOG Statistical Center, Seattle, Washington. · Vanderbilt University, Nashville, Tennessee. · Karmanos Cancer Institute, Wayne State University, Detroit, Michigan. · Cleveland Clinic Foundation, Cleveland, Ohio. · Division of Surgical Oncology, The Ohio State University, Columbus, Ohio. · Seattle Cancer Care Alliance, Seattle, Washington. · Los Angeles County Department of Health Services, University of Southern California, Los Angeles, California. · University of California Los Angeles, Los Angeles, California. · H. Lee Moffitt Cancer Center, Tampa, Florida. ·Cancer Immunol Res · Pubmed #24994597.

ABSTRACT: Associations between HLA class I antigen expression and the efficacy of a melanoma vaccine (Melacine; Corixa Corp.) were initially described in stage IV melanoma. Similar associations were observed in S9035, a phase III adjuvant trial evaluating Melacine for 2 years compared with observation in patients with stage II melanoma. This report provides long-term results. The effects of treatment on relapse-free survival (RFS) and overall survival (OS) were evaluated, and prespecified analyses investigated associations between treatment and HLA expression. Multivariable analyses were adjusted for tumor thickness, ulceration and site, method of nodal staging, and sex. P = 0.01 was considered statistically significant in subset analyses to account for multiple comparisons. For the entire study population of 689 patients, there were no significant differences in RFS or OS by treatment arm. HLA serotyping was performed on 553 (80%) patients (vaccine, 294; observation, 259). Among the subpopulation with HLA-A2 and/or HLA-Cw3 serotype, vaccine arm patients (n = 178) had marginally improved RFS (adjusted P = 0.02) and significantly improved OS compared with observation arm patients (n = 145), with 10-year OS of 75% and 63%, respectively [hazard ratio (HR), 0.62; 99% confidence interval (CI), 0.37-1.02; P = 0.01]. There was no impact of HLA-A2 and/or HLA-Cw3 expression on observation arm patients. An analysis of mature data from S9035 indicates a significant OS benefit from adjuvant vaccine therapy for patients with HLA-A2- and/or HLA-Cw3-expressing melanoma. The possibility of interactions between HLA type and outcome should be considered in future immunotherapy trials. Further investigations of melanoma-associated antigens present in Melacine and presented by HLA-A2 and HLA-Cw3 may be warranted.

12 Clinical Trial A phase I study of high-dose interleukin-2 with sorafenib in patients with metastatic renal cell carcinoma and melanoma. 2014

Monk, Paul / Lam, Elaine / Mortazavi, Amir / Kendra, Kari / Lesinski, Gregory B / Mace, Thomas A / Geyer, Susan / Carson, William E / Tahiri, Sanaa / Bhinder, Arvinder / Clinton, Steven K / Olencki, Thomas. ·*Division of Medical Oncology, Comprehensive Cancer Center, The Ohio State University, and Arthur G. James Cancer Hospital and Solove Research Institute, Columbus, OH †Division of Medical Oncology, University of Colorado Denver School of Medicine, Denver, CO. ·J Immunother · Pubmed #24598448.

ABSTRACT: This study was designed to evaluate the safety and feasibility of high-dose interleukin-2 (HD IL-2) followed by sorafenib in patients with metastatic melanoma (MM) and renal cell carcinoma (RCC). Biomarkers relevant to the antitumor effects of IL-2 that may be altered by sorafenib including the percentages of natural T-regulatory cells (Tregs), myeloid-derived suppressor cells (MDSC), and STAT5 phosphorylation (pSTAT5) in T cells were evaluated. We hypothesized that the proposed treatment schedule is feasible and safe and may lead to enhanced tumor response. A phase I dose escalation trial was conducted in patients with either metastatic RCC or MM. HD IL-2 (600,000 IU/kg IV q8h × 8-12 doses) was administered on days 1-5 and 15-19, followed by sorafenib on days 29-82. The sorafenib dose was escalated. The percentage of Tregs, MDSC, and pSTAT5 in T cells were evaluated in peripheral blood by flow cytometry. Twelve of the 18 patients were evaluable for dose-limiting toxicity. No dose-limiting toxicity was observed. The treatment-related toxicity was predictable and did not seem to be additive with this schedule of administration. Partial responses were seen in 3 patients. No significant changes in the percentage of circulating Treg and MDSC were observed, whereas sorafenib did not adversely affect the ability of IL-2 to induce pSTAT5 in T cells. HD IL-2 followed by sorafenib was safe and feasible in patients with MM and RCC and did not adversely affect T-cell signaling through STAT5 in response to IL-2.

13 Clinical Trial A phase I trial of bortezomib and interferon-α-2b in metastatic melanoma. 2014

Markowitz, Joseph / Luedke, Eric A / Grignol, Valerie P / Hade, Erinn M / Paul, Bonnie K / Mundy-Bosse, Bethany L / Brooks, Taylor R / Dao, Thao-Vi / Kondalasula, Sri V / Lesinski, Gregory B / Olencki, Thomas / Kendra, Kari L / Carson, William E. ·Divisions of *Medical Oncology †Surgical Oncology ‡Center for Biostatistics, The Ohio State University, Columbus, OH. ·J Immunother · Pubmed #24316557.

ABSTRACT: The possibility that cytokine administration could enhance the antitumor effects of proteasome inhibition was explored. It was found that coadministration of bortezomib and interferon-α (IFN-α) induced synergistic apoptosis in human melanoma cell lines and prolonged survival in a murine model of melanoma. A phase I study was conducted to determine the tolerability and the maximum tolerated dose of bortezomib when administered in combination with IFN-α-2b to patients with metastatic melanoma. Patients were treated on a 5-week cycle. In week 1 of cycle 1, patients received 5 million U/m(2) IFN-α subcutaneously thrice weekly. During weeks 2-4 of cycle 1, bortezomib was administered intravenously weekly along with IFN-α thrice weekly. There was a treatment break during week 5. After cycle 1, bortezomib was administered in combination with IFN-α. Bortezomib was administered in escalating doses (1.0, 1.3, or 1.6 mg/m) to cohorts of 3 patients. Sixteen patients were treated (8 women, 8 men; median age 59 y). Common grade 3 toxicities included fatigue (5), vomiting (3), and diarrhea (3). Grade 4 toxicities included fatigue (3) and lymphopenia (1). The maximum tolerated dose for bortezomib was 1.3 mg/m(2). One patient had a partial response, and 7 had stable disease. Progression-free survival was 2.5 months, and overall survival was 10.3 months. Bortezomib administration did not augment the ability of IFN-α to induce phosphorylation of STAT1 in circulating immune cells; however, it did lead to reduced plasma levels of proangiogenic cytokines. The combination of bortezomib and IFN-α can be safely administered to melanoma patients.

14 Clinical Trial Metastatic melanoma: lactate dehydrogenase levels and CT imaging findings of tumor devascularization allow accurate prediction of survival in patients treated with bevacizumab. 2014

Gray, Mark R / Martin del Campo, Sara / Zhang, Xu / Zhang, Haowei / Souza, Frederico F / Carson, William E / Smith, Andrew D. ·From the Department of Radiology, University of Mississippi Medical Center, 2500 N State St, Jackson, MS 39216. ·Radiology · Pubmed #24072776.

ABSTRACT: PURPOSE: To predict survival in patients with metastatic melanoma by evaluating a combination of serum lactate dehydrogenase (LDH) level and initial computed tomographic (CT) findings of tumor devascularization after antiangiogenic therapy. MATERIALS AND METHODS: Consent was waived for this institutional review board-approved, retrospective, secondary analysis. Forty-four patients with metastatic melanoma received bevacizumab therapy in a randomized prospective phase II trial. Target lesions on the initial posttherapy CT images were evaluated by using Response Evaluation Criteria in Solid Tumors, the Choi criteria, and Morphology, Attenuation, Size, and Structure (MASS) criteria. Cox proportional hazards models were used to assess the association of baseline clinical variables including serum LDH and imaging findings with progression-free and overall survival. The receiver operating characteristic curve with area under the curve (AUC) was used to evaluate accuracy. RESULTS: In multivariate analysis, a high baseline serum LDH level was associated with decreased progression-free survival (hazard ratio = 1.29 for each increase of 100 IU/L; P = .002) and overall survival (hazard ratio = 1.44 for each increase of 100 IU/L; P = .001). Evaluation with MASS criteria of the first CT examination after therapy strongly predicted progression-free (P < .001) and overall (P < .001) survival. Baseline serum LDH level was moderately accurate for predicting progression-free survival at 9 months (AUC = 0.793) and overall survival at 18 months (AUC = 0.689). The combination of baseline serum LDH levels and evaluation with MASS criteria at the first CT examination after therapy had significantly higher accuracy for predicting progression-free survival at 9 months (AUC = 0.969) and overall survival at 18 months (AUC = 0.813) than did baseline serum LDH levels alone for prediction of progression-free survival (P = .020). CONCLUSION: A combination of baseline serum LDH levels and evaluation with MASS criteria at the first CT examination after bevacizumab therapy had the highest accuracy for predicting survival in patients with metastatic melanoma.

15 Clinical Trial BEAM: a randomized phase II study evaluating the activity of bevacizumab in combination with carboplatin plus paclitaxel in patients with previously untreated advanced melanoma. 2012

Kim, Kevin B / Sosman, Jeffrey A / Fruehauf, John P / Linette, Gerald P / Markovic, Svetomir N / McDermott, David F / Weber, Jeffrey S / Nguyen, Hoa / Cheverton, Peter / Chen, Daniel / Peterson, Amy C / Carson, William E / O'Day, Steven J. ·The University of Texas MD Anderson Cancer Center, Houston, TX, USA. ·J Clin Oncol · Pubmed #22124101.

ABSTRACT: PURPOSE: Metastatic melanoma, a highly vascularized tumor with strong expression of vascular endothelial growth factor, has an overall poor prognosis. We conducted a placebo-controlled, double-blind phase II study of carboplatin plus paclitaxel with or without bevacizumab in patients with previously untreated metastatic melanoma. PATIENTS AND METHODS: Patients were randomly assigned in a two-to-one ratio to carboplatin (area under the curve, 5) plus paclitaxel (175 mg/m(2)) and bevacizumab (15 mg/kg; CPB) or placebo (CP) administered intravenously once every 3 weeks. Progression-free survival (PFS) was the primary end point. Secondary end points included overall survival (OS) and safety. RESULTS: Two hundred fourteen patients (73% with M1c disease) were randomly assigned. With a median follow-up of 13 months, median PFS was 4.2 months for the CP arm (n = 71) and 5.6 months for the CPB arm (n = 143; hazard ratio [HR], 0.78; P = .1414). Overall response rates were 16.4% and 25.5%, respectively (P = .1577). With 13-month follow-up, median OS was 8.6 months in the CP arm versus 12.3 months in the CPB arm (HR, 0.67; P = .0366), whereas in an evaluation 4 months later, it was 9.2 versus 12.3 months, respectively (HR, 0.79; P = .1916). In patients with elevated serum lactate dehydrogenase (n = 84), median PFS and OS were longer in the CPB arm (PFS: 4.4 v 2.7 months; HR, 0.62; OS: 8.5 v 7.5 months; HR, 0.52). No new safety signals were observed. CONCLUSION: The study did not meet the primary objective of statistically significant improvement in PFS with the addition of bevacizumab to carboplatin plus paclitaxel. A larger phase III study will be necessary to determine whether there is benefit to the addition of bevacizumab to carboplatin plus paclitaxel in this disease setting.

16 Clinical Trial A phase 2 trial of bevacizumab and high-dose interferon alpha 2B in metastatic melanoma. 2011

Grignol, Valerie P / Olencki, Thomas / Relekar, Kiran / Taylor, Cynthia / Kibler, Amanda / Kefauver, Cheryl / Wei, Lai / Walker, Michael J / Chen, Helen X / Kendra, Kari / Carson, William E. ·Division of Surgical Oncology, The Ohio State University, Columbus, OH 43210, USA. ·J Immunother · Pubmed #21654521.

ABSTRACT: Bevacizumab is a humanized recombinant monoclonal antibody that neutralizes vascular endothelial growth factor, an agent with proangiogenic effects in melanoma. Interferon alpha (IFN-α) has antiangiogenic properties through its ability to downregulate basic-fibroblast growth factor levels. We hypothesized that the coadministration of these agents would lead to tumor regression. Patients with metastatic melanoma received bevacizumab 15 mg/kg intravenously on day 1 of the 2-week cycle. IFN-α was administered thrice weekly at 5 MU/m subcutaneously during cycle 1 and was increased to 10 MU/m during cycle 2. Patients were restaged every 6 cycles. Patients with stable disease or a response continued with therapy. Baseline serum vascular endothelial growth factor and fibroblast growth factor were measured. Twenty-five patients were accrued. Mean age was 58.4 years. Eleven patients required IFN-α dose reductions due to toxicity. Common grade 3 toxicities associated with IFN-α included fatigue and myalgia. Bevacizumab administration was associated with grade 2-3 proteinuria in 6 patients. Grade 4 adverse events were pulmonary embolus (1), myocardial infarction (1), and stroke (1). Six patients had a partial response, and 5 patients exhibited stable disease that lasted more than 24 weeks (range: 30 to 122 wk). Median progression-free survival and overall survival were 4.8 and 17 months, respectively. Significantly lower fibroblast growth factor levels were observed in patients with a partial response compared to those with stable or progressive disease (P=0.040). Administration of bevacizumab with IFN led to a clinical response in 24% of patients with stage IV melanoma and stabilization of disease in another 20% of patients. This regimen has activity in advanced melanoma.

17 Clinical Trial A pilot study of bevacizumab and interferon-α2b in ocular melanoma. 2011

Guenterberg, Kristan D / Grignol, Valerie P / Relekar, Kiran V / Varker, Kimberly A / Chen, Helen X / Kendra, Kari L / Olencki, Thomas E / Carson, William E. ·Division of Surgical Oncology, The Ohio State University, Columbus, Ohio 43210, USA. ·Am J Clin Oncol · Pubmed #20458209.

ABSTRACT: OBJECTIVES: We hypothesized that administration of bevacizumab, a monoclonal antibody that neutralizes vascular endothelial growth factor, in combination with high-dose interferon-alpha2b (IFN-α2b), an inhibitor of basic fibroblast growth factor, would have clinical activity in patients with metastatic ocular melanoma. METHODS: Patients with metastatic ocular melanoma received bevacizumab (15 mg/kg intravenously every 2 weeks) plus IFN-α2b (5 MU/m subcutaneously 3 times weekly for 2 weeks followed by a dose of 10 MU/m subcutaneously thereafter). Patients exhibiting a clinical response or stabilization of disease were treated until disease progression. RESULTS: In this pilot study, 5 patients were treated (3 men, 2 women) with a mean age of 63.8 years (range, 53-71 years). Overall, the regimen was well-tolerated. The following adverse events were noted: grade 3 dyspnea (2 patients), grade 3 and 4 fatigue (2), grade 3 muscle weakness (1), grade 3 anorexia (1), grade 1 and 2 proteinuria (2), and grade 3 diarrhea (1). All adverse events resolved with a treatment holiday or dose reduction. One patient had reduction in tumor burden of 23% by Response Evaluation Criteria in Solid Tumors criteria and 2 patients had stabilization of disease lasting 28 and 36 weeks, respectively. Two patients failed to respond and progressed after 6 and 7 weeks of therapy. CONCLUSION: Bevacizumab and IFN-α2b were well tolerated in this patient population, and clinical activity was observed. Further study of high-dose IFN-α2b in combination with bevacizumab in this setting is warranted.

18 Article Alterations in patient plasma microRNA expression profiles following resection of metastatic melanoma. 2018

Latchana, Nicholas / DiVincenzo, Mallory J / Regan, Kelly / Abrams, Zachary / Zhang, Xiaoli / Jacob, Naduparambil K / Gru, Alejandro A / Fadda, Paolo / Markowitz, Joseph / Howard, J Harrison / Carson, William E. ·Department of General Surgery, University of Toronto, Toronto, Canada. · Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio. · Medical Scientist Training Program and Biomedical Sciences Graduate Program, The Ohio State University, Columbus, Ohio. · Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio. · Department of Radiation Oncology, The Ohio State University, Columbus, Ohio. · Department of Pathology, University of Virginia, Charlottesville, Virginia. · Department of Molecular Virology, Immunology and Medical Genetics, The Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, The Ohio State University, Columbus, Ohio. · Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida. · Department of Surgery, The Ohio State University, Columbus, Ohio. ·J Surg Oncol · Pubmed #30132912.

ABSTRACT: BACKGROUND AND OBJECTIVES: MicroRNAs (miRs) are noncoding RNAs that regulate protein translation and melanoma progression. Changes in plasma miR expression following surgical resection of metastatic melanoma are under-investigated. We hypothesize differences in miR expression exist following complete surgical resection of metastatic melanoma. METHODS: Blood collection pre- and post-surgical resection was performed in six individuals with solitary melanoma metastases. miR expression in extracted RNA was quantified using the NanoString nCounter Digital Analyzer. RESULTS: Pre- and post-surgical plasma samples contained 216 miRs with expression above baseline. Comparison of postsurgical to preresection samples revealed differential expression of 25 miRs: miR-let-7a, miR-let7g, miR-15a, miR-16, miR-22, miR-30b, miR-126, miR-140, miR-145, miR-148a, miR-150-5p, miR-191, miR-378i, miR-449c, miR-494, miR-513b, miR-548aa, miR-571, miR-587, miR-891b, miR-1260a, miR 1268a, miR-1976, miR-4268, miR-4454 (P < 0.05). Utilizing P < 0.0046 as a cutoff to control for one false positive among the 216 miRs revealed that postsurgical melanoma plasma samples had upregulation of miR-1260a (P = 0.0007) and downregulation of miR-150-5p (P = 0.0026) relative to pre-surgical samples. CONCLUSIONS: Differential expression of miR-150-5p and miR-1260a is present in plasma following surgical resection of metastatic melanoma in this small sample (n = 6) of melanoma patients. Therefore, further investigation of these plasma miRs as noninvasive biomarkers for melanoma is warranted.

19 Article Analysis of MLN4924 (pevonedistat) as a potential therapeutic agent in malignant melanoma. 2018

Olaverria Salavaggione, Gonzalo N / Duggan, Megan C / Carson, William E. ·Department of Surgery, Comprehensive Cancer Center. · Department of Surgery, Biomedical Sciences Graduate Program. · Department of Surgery, Division of Surgical Oncology, The Ohio State University, Columbus, Ohio, USA. ·Melanoma Res · Pubmed #30020196.

ABSTRACT: The NEDD8 pathway is a known activator of the ubiquitin-protease system, a complex that is partially responsible for the degradation of proteins involved in cell-cycle regulation and neoplastic growth. In this study, we evaluated the antitumor potential of MLN4924 (pevonedistat), a potent NEDD8 inhibitor. We hypothesized that MLN4924 treatment induces apoptosis in human melanoma cells. A375 and Mel39 BRAF V600E mutant melanoma cell lines were treated in vitro with MLN4924 alone or in combination with interferon-α (IFN-α) or vemurafenib - therapeutic agents utilized on melanoma patients. Annexin/propidium iodine flow cytometry analysis showed that treatment with MLN4924 for 72 h induced apoptosis in A375 and Mel39 melanoma cells with an IC50 of 1200 and 143 nmol/l, respectively. Combination therapy of A375 cells with 10 U/ml IFN-α and 1200 nmol/l MLN4924 led to a significant increase in cell death (78.2±3.7%) compared with single-agent treatment by IFN-α (17.5±2.5%) or MLN4924 (50.7±1.0%; P<0.005). Treatment of A375 cells with 1 μmol/l vemurafenib had a notable effect on cell viability. However, the addition of MLN4924 to vemurafenib had an inhibitory effect on apoptosis. Results from MTS proliferation assays indicate that MLN4924 has antiproliferative effects on melanoma cells in vitro, with the addition of IFN-α further inhibiting proliferation. Pretreatment with MLN4924 led to A375 cell sensitization to vemurafenib treatment and immunoblot analysis of MLN4924-treated cells revealed cleavage of caspase-3, caspase-7, caspase-9, and poly-ADP-ribose polymerase. These results show that MLN4924 does have an efficacy in treating melanoma in vitro alone or in combination with IFN-α, and thus it may have potential use in patients with advanced melanoma.

20 Article Diffusion mapping of drug targets on disease signaling network elements reveals drug combination strategies. 2018

Xu, Jielin / Regan-Fendt, Kelly / Deng, Siyuan / Carson, William E / Payne, Philip R O / Li, Fuhai. ·Department of Biomedical Informatics, The Ohio State University, Columbus, OH 43210, U.S.A., Jielin.Xu@osumc.edu. ·Pac Symp Biocomput · Pubmed #29218872.

ABSTRACT: The emergence of drug resistance to traditional chemotherapy and newer targeted therapies in cancer patients is a major clinical challenge. Reactivation of the same or compensatory signaling pathways is a common class of drug resistance mechanisms. Employing drug combinations that inhibit multiple modules of reactivated signaling pathways is a promising strategy to overcome and prevent the onset of drug resistance. However, with thousands of available FDA-approved and investigational compounds, it is infeasible to experimentally screen millions of possible drug combinations with limited resources. Therefore, computational approaches are needed to constrain the search space and prioritize synergistic drug combinations for preclinical studies. In this study, we propose a novel approach for predicting drug combinations through investigating potential effects of drug targets on disease signaling network. We first construct a disease signaling network by integrating gene expression data with disease-associated driver genes. Individual drugs that can partially perturb the disease signaling network are then selected based on a drug-disease network "impact matrix", which is calculated using network diffusion distance from drug targets to signaling network elements. The selected drugs are subsequently clustered into communities (subgroups), which are proposed to share similar mechanisms of action. Finally, drug combinations are ranked according to maximal impact on signaling sub-networks from distinct mechanism-based communities. Our method is advantageous compared to other approaches in that it does not require large amounts drug dose response data, drug-induced "omics" profiles or clinical efficacy data, which are not often readily available. We validate our approach using a BRAF-mutant melanoma signaling network and combinatorial in vitro drug screening data, and report drug combinations with diverse mechanisms of action and opportunities for drug repositioning.

21 Article Identification of NRAS isoform 2 overexpression as a mechanism facilitating BRAF inhibitor resistance in malignant melanoma. 2017

Duggan, Megan C / Stiff, Andrew R / Bainazar, Maryam / Regan, Kelly / Olaverria Salavaggione, Gonzalo N / Maharry, Sophia / Blachly, James S / Krischak, Madison / Walker, Christopher J / Latchana, Nicholas / Tridandapani, Susheela / de la Chapelle, Albert / Eisfeld, Ann-Kathrin / Carson, William E. ·Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210. · Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH 43210. · Division of Surgical Oncology, The Ohio State University, Columbus, OH 43210. · Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210; Albert.delaChapelle@osumc.edu ann-kathrin.eisfeld@osumc.edu william.carson@osumc.edu. · Division of Surgical Oncology, The Ohio State University, Columbus, OH 43210 Albert.delaChapelle@osumc.edu ann-kathrin.eisfeld@osumc.edu william.carson@osumc.edu. ·Proc Natl Acad Sci U S A · Pubmed #28827320.

ABSTRACT: Activating mutations in BRAF are found in 50% of melanomas and although treatment with BRAF inhibitors (BRAFi) is effective, resistance often develops. We now show that recently discovered NRAS isoform 2 is up-regulated in the setting of BRAF inhibitor resistance in melanoma, in both cell lines and patient tumor tissues. When isoform 2 was overexpressed in BRAF mutant melanoma cell lines, melanoma cell proliferation and in vivo tumor growth were significantly increased in the presence of BRAFi treatment. shRNA-mediated knockdown of isoform 2 in BRAFi resistant cells restored sensitivity to BRAFi compared with controls. Signaling analysis indicated decreased mitogen-activated protein kinase (MAPK) pathway signaling and increased phosphoinositol-3-kinase (PI3K) pathway signaling in isoform 2 overexpressing cells compared with isoform 1 overexpressing cells. Immunoprecipitation of isoform 2 validated a binding affinity of this isoform to both PI3K and BRAF/RAF1. The addition of an AKT inhibitor to BRAFi treatment resulted in a partial restoration of BRAFi sensitivity in cells expressing high levels of isoform 2. NRAS isoform 2 may contribute to resistance to BRAFi by facilitating PI3K pathway activation.

22 Article Classification of Indeterminate Melanocytic Lesions by MicroRNA Profiling. 2017

Latchana, Nicholas / Del Campo, Sara E Martin / Grignol, Valerie P / Clark, Jennifer R / Albert, Scott P / Zhang, Jie / Wei, Lai / Aldrink, Jennifer H / Nicol, Kathleen K / Ranalli, Mark A / Peters, Sara B / Gru, Alejandro / Trihka, Prashant / Payne, Philip R O / Howard, J Harrison / Carson, William E. ·Department of Surgery, The Ohio State University, Columbus, OH, USA. · Department of Internal Medicine, Indiana University School of Medicine, Indianapolis, IN, USA. · Department of Surgery, Upstate University Hospital, Syracuse, NY, USA. · Department of Biomedical Informatics, The Ohio State University, Columbus, OH, USA. · Department of Pediatric Surgery, Nationwide Children's Hospital, Columbus, OH, USA. · Department of Pathology, Nationwide Children's Hospital, Columbus, OH, USA. · Department of Hematology/Oncology, Nationwide Children's Hospital, Columbus, OH, USA. · Department of Pathology, The Ohio State University, Columbus, OH, USA. · Department of Pathology, University of Virginia, Charlottesville, VA, USA. · Department of Molecular Virology, Immunology and Medical Genetics, The Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, The Ohio State University, Columbus, OH, USA. · Institute of Informatics, Washington University, St. Louis, MO, USA. · Department of Surgery, The Ohio State University, Columbus, OH, USA. William.Carson@osumc.edu. · Department of Molecular Virology, Immunology and Medical Genetics, The Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, The Ohio State University, Columbus, OH, USA. William.Carson@osumc.edu. ·Ann Surg Oncol · Pubmed #27469124.

ABSTRACT: PURPOSE: Identification of indeterminate melanocytic skin lesions capable of neoplastic progression is suboptimal and may potentially result in unnecessary morbidity from surgery. MicroRNAs (miRs) may be useful in classifying indeterminate Spitz tumors as having high or low risk for malignant behavior. METHODS: RNA was extracted from paraffin-embedded tissues of benign nevi, benign Spitz tumors, indeterminate Spitz tumors, and Spitzoid melanomas in adults (n = 62) and children (n = 28). The expression profile of 12 miRs in adults (6 miRs in children) was analyzed by real-time polymerase chain reaction. RESULTS: Benign Spitz lesions were characterized by decreased expression of miR-125b and miR-211, and upregulation of miR-22, compared with benign nevi (p < 0.05). A comparison of Spitzoid melanomas to benign nevi revealed overexpression of miR-21, miR-150, and miR-155 in the malignant primaries (p < 0.05). In adults, Spitzoid melanomas exhibited upregulation of miR-21, miR-150, and miR-155 compared with indeterminate Spitz lesions. Indeterminate Spitz lesions with low-risk pathologic features had lower miR-21 and miR-155 expression compared with Spitzoid melanoma tumors in adults (p < 0.05), while pathologic high-risk indeterminate Spitz lesions had increased levels of miR-200c expression compared with low-risk indeterminate lesions (p < 0.05). Pediatric Spitzoid melanomas exhibited increased miR-21 expression compared with indeterminate Spitz lesions (p < 0.05). Moreover, miR-155 expression was increased in indeterminate lesions with mitotic counts >1 and depth of invasion >1 mm, suggesting miR-155 expression is associated with histological characteristics. CONCLUSIONS: miR expression profiles can be measured in indeterminate Spitz tumors and correlate with markers of malignant potential.

23 Article The combination of MLN2238 (ixazomib) with interferon-alpha results in enhanced cell death in melanoma. 2016

Suarez-Kelly, Lorena P / Kemper, Gregory M / Duggan, Megan C / Stiff, Andrew / Noel, Tiffany C / Markowitz, Joseph / Luedke, Eric A / Yildiz, Vedat O / Yu, Lianbo / Jaime-Ramirez, Alena Cristina / Karpa, Volodymyr / Zhang, Xiaoli / Carson, William E. ·The Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, The Ohio State University, Columbus, OH, USA. · Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH, USA. · Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus OH, USA. · Division of Surgical Oncology, Department of Surgery, The Ohio State University, Columbus OH, USA. · Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University, Columbus, OH, USA. ·Oncotarget · Pubmed #27783987.

ABSTRACT: The ubiquitin-proteasome signaling pathway is critical for cell cycle regulation and neoplastic growth. Proteasome inhibition can activate apoptotic pathways. Bortezomib, a selective proteasome inhibitor, has anti-melanoma activity. MLN2238 (ixazomib), an oral proteasome inhibitor, has improved pharmacotherapeutic parameters compared to bortezomib. Interferon-alpha (IFN-α), an immune boosting agent, is FDA-approved for treatment of melanoma. In this study in vitro and in vivo evaluation of the antitumor potential of ixazomib and combination treatments with ixazomib and IFN-α were performed. Apoptosis induced by ixazomib was first observed at 12 hours and was maximal at 48 hours with similar levels of cell death compared to bortezomib. IFN-α alone had little effect on cell viability in vitro. However, the combination of ixazomib with IFN-α significantly enhanced ixazomib's ability to induce apoptotic cell death in BRAF V600E mutant and BRAF wild-type human melanoma tumor cells. The combination of ixazomib and IFN-α also enhanced inhibition of cell proliferation in BRAF V600E mutant melanoma tumor cells; however, this was not seen in BRAF wild-type cells. Ixazomib-induced apoptosis was associated with processing of the pro-apoptotic proteins procaspase-3, -7, -8, and -9, and cleavage of poly-ADP-ribose polymerase (PARP). In an in vivo xenograft model of human melanoma, combination treatment with IFN-α-2b and ixazomib demonstrated a significant reduction in tumor volume when compared to vehicle (p = 0.005) and single therapy ixazomib (p = 0.017) and IFN-α-2b (p = 0.036). These pre-clinical results support further evaluation of combination treatment with ixazomib and IFN-α for the treatment of advanced BRAF V600E mutant melanoma.

24 Article A Critical Role for CD200R Signaling in Limiting the Growth and Metastasis of CD200+ Melanoma. 2016

Liu, Jin-Qing / Talebian, Fatemeh / Wu, Lisha / Liu, Zhihao / Li, Ming-Song / Wu, Laichu / Zhu, Jianmin / Markowitz, Joseph / Carson, William E / Basu, Sujit / Bai, Xue-Feng. ·Department of Pathology and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210; · Department of Pathology and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210; Department of Gastroenterology, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; · Department of Gastroenterology, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; · Davis Medical Research Center, Columbus, OH 43210; and. · Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China. · Department of Pathology and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210; Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China Xue-Feng.Bai@osumc.edu. ·J Immunol · Pubmed #27385779.

ABSTRACT: CD200 is a cell surface glycoprotein that functions through engaging CD200R on cells of the myeloid lineage and inhibits their functions. Expression of CD200 was implicated in a variety of human cancer cells, including melanoma cells; however, its roles in tumor growth and immunity are not clearly understood. In this study, we used CD200R-deficient mice and the B16 tumor model to evaluate this issue. We found that CD200R-deficient mice exhibited accelerated growth of CD200(+), but not CD200(-), B16 tumors. Strikingly, CD200R-deficient mice receiving CD200(+) B16 cells i.v. exhibited massive tumor growth in multiple organs, including liver, lung, kidney, and peritoneal cavity, whereas the growth of the same tumors in wild-type mice was limited. CD200(+) tumors grown in CD200R-deficient mice contained higher numbers of CD11b(+)Ly6C(+) myeloid cells, exhibited increased expression of VEGF and HIF1α genes with increased angiogenesis, and showed significantly reduced infiltration of CD4(+) and CD8(+) T cells, presumably as the result of reduced expression of T cell chemokines, such as CXCL9 and CXCL16. The liver from CD200R-deficient mice, under metastatic growth of CD200(+) tumors, contained significantly increased numbers of CD11b(+)Gr1(-) myeloid cells and Foxp3(+) regulatory T cells and reduced numbers of NK cells. Liver T cells also had a reduced capacity to produce IFN-γ or TNF-α. Taken together, we revealed a critical role for CD200R signaling in limiting the growth and metastasis of CD200(+) tumors. Thus, targeting CD200R signaling may potentially interfere with the metastatic growth of CD200(+) tumors, like melanoma.

25 Article Folate-conjugated immunoglobulin targets melanoma tumor cells for NK cell effector functions. 2016

Skinner, Cassandra C / McMichael, Elizabeth L / Jaime-Ramirez, Alena C / Abrams, Zachary B / Lee, Robert J / Carson, William E. ·aDepartment of Surgery, Division of Surgical Oncology Departments of bNeurosurgery cBiomedical Informatics dMolecular Virology, Immunology, and Medical Genetics eBiomedical Sciences Graduate Program, College of Medicine fCollege of Pharmacy, Arthur G. James Comprehensive Cancer Center and Solove Research Institute, The Ohio State University, Columbus, Ohio, USA. ·Melanoma Res · Pubmed #27035691.

ABSTRACT: The folate receptor (FR) is overexpressed on the vascular side of cancerous cells including those of the breast, ovaries, testes, and cervix. We hypothesized that a folate-conjugated immunoglobulin (F-IgG) would bind to the FR that is overexpressed on melanoma tumor cells to target these cells for lysis by natural killer (NK) cells. Folate receptor expression was confirmed in the Mel-39 (human melanoma) cell line by flow cytometry and immunoblot analysis using KB (human oral epithelial) and F01 (human melanoma) as a positive and a negative control, respectively. FR-positive and FR-negative cell lines were treated with F-IgG or control immunoglobulin G in the presence or absence of cytokines to determine NK cell ability to lyse FR-positive cell lines. NK cell activation was significantly upregulated and lysis of Mel 39 tumor cells increased following treatment with F-IgG compared with control immunoglobulin G at all effector : target (E : T) ratios (P<0.01). This trend further increased by NK cell stimulation with the activating cytokine interleukin-12. NK cell production of cytokines such as interferon-gamma, macrophage inflammatory protein 1α, and regulated on activation normal T-cell expressed and secreted (RANTES) was also significantly increased in response to costimulation with interleukin-12 stimulation and F-IgG-coated Mel 39 target cells compared with controls (P<0.01). In contrast, F-IgG did not bind to the FR-negative cell line F01 and had no significant effect on NK cell lysis or cytokine production. This research indicates the potential use of F-IgG for its ability to induce an immune response from NK cells against FR-positive melanoma tumor cells, which can be further increased by the addition of cytokines.

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