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Melanoma: HELP
Articles by David H. Lawson
Based on 40 articles published since 2008
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Between 2008 and 2019, David Lawson wrote the following 40 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Guideline The Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for the treatment of cutaneous melanoma. 2013

Kaufman, Howard L / Kirkwood, John M / Hodi, F Stephen / Agarwala, Sanjiv / Amatruda, Thomas / Bines, Steven D / Clark, Joseph I / Curti, Brendan / Ernstoff, Marc S / Gajewski, Thomas / Gonzalez, Rene / Hyde, Laura Jane / Lawson, David / Lotze, Michael / Lutzky, Jose / Margolin, Kim / McDermott, David F / Morton, Donald / Pavlick, Anna / Richards, Jon M / Sharfman, William / Sondak, Vernon K / Sosman, Jeffrey / Steel, Susan / Tarhini, Ahmad / Thompson, John A / Titze, Jill / Urba, Walter / White, Richard / Atkins, Michael B. ·Rush University Cancer Center, 1725 West Harrison Street, Chicago, IL 60612, USA. ·Nat Rev Clin Oncol · Pubmed #23982524.

ABSTRACT: Immunotherapy is associated with durable clinical benefit in patients with melanoma. The goal of this article is to provide evidence-based consensus recommendations for the use of immunotherapy in the clinical management of patients with high-risk and advanced-stage melanoma in the USA. To achieve this goal, the Society for Immunotherapy of Cancer sponsored a panel of melanoma experts--including physicians, nurses, and patient advocates--to develop a consensus for the clinical application of tumour immunotherapy for patients with melanoma. The Institute of Medicine clinical practice guidelines were used as a basis for this consensus development. A systematic literature search was performed for high-impact studies in English between 1992 and 2012 and was supplemented as appropriate by the panel. This consensus report focuses on issues related to patient selection, toxicity management, clinical end points and sequencing or combination of therapy. The literature review and consensus panel voting and discussion were used to generate recommendations for the use of immunotherapy in patients with melanoma, and to assess and rate the strength of the supporting evidence. From the peer-reviewed literature the consensus panel identified a role for interferon-α2b, pegylated-interferon-α2b, interleukin-2 (IL-2) and ipilimumab in the clinical management of melanoma. Expert recommendations for how to incorporate these agents into the therapeutic approach to melanoma are provided in this consensus statement. Tumour immunotherapy is a useful therapeutic strategy in the management of patients with melanoma and evidence-based consensus recommendations for clinical integration are provided and will be updated as warranted.

2 Review Two heads better than one? Ipilimumab immunotherapy and radiation therapy for melanoma brain metastases. 2015

Patel, Kirtesh R / Lawson, David H / Kudchadkar, Ragini R / Carthon, Bradley C / Oliver, Daniel E / Okwan-Duodu, Derick / Ahmed, Rafi / Khan, Mohammad K. ·Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia (K.R.P., D.O.-D., M.K.K.) · Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia (D.H.L., R.R.K., B.C.C.) · School of Medicine, Emory University, Atlanta, Georgia (D.E.O.) · Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia (R.A.). ·Neuro Oncol · Pubmed #26014049.

ABSTRACT: Melanoma is an aggressive malignancy with a deplorable penchant for spreading to the brain. While focal therapies such as surgery and stereotactic radiosurgery can help provide local control, the majority of patients still develop intracranial progression. Novel therapeutic combinations to improve outcomes for melanoma brain metastases (MBM) are clearly needed. Ipilimumab, the anticytotoxic T-lymphocyte-associated antigen 4 monoclonal antibody, has been shown to improve survival in patients with metastatic melanoma, but many of these trials either excluded or had very few patients with MBM. This article will review the efficacy and limitations of ipilimumab therapy for MBM, describe the current evidence for combining ipilimumab with radiation therapy, illustrate potential mechanisms for synergy, and discuss emerging clinical trials specifically investigating this combination in MBM.

3 Review The emerging role of radiotherapy for desmoplastic melanoma and implications for future research. 2015

Oliver, Daniel E / Patel, Kirtesh R / Parker, Douglas / Delman, Keith A / Lawson, David H / Kudchadkar, Ragini R / Khan, Mohammad K. ·aSchool of Medicine bDepartment of Pathology cDepartment of Dermatology, Emory University dDepartment of Radiation Oncology eDepartment of Surgical Oncology fDepartment of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia, USA. ·Melanoma Res · Pubmed #25588202.

ABSTRACT: The National Comprehensive Cancer Network (NCCN) 2014 guidelines are unclear about the role of radiotherapy in the management of desmoplastic melanoma. The guidelines specify that radiotherapy can be 'considered' for select patients with desmoplastic melanoma with narrow surgical margins. Patient selection criteria, including margins, are not well defined, causing considerable differences in practice patterns across the country. There are also several conflicting reports about the role of radiotherapy in improving postsurgical outcomes when other adverse pathological risks factors, such as increased Clark level, head and neck involvement, perineural invasion, positive margins, or recurrent disease, are also present. Recent data provide further clarification and insights into the role of radiotherapy. Thus, in light of the NCCN guidelines and the recently published series, we critically review the role of radiotherapy for desmoplastic melanoma. In our review, we highlight the published risk factors that predict for increased risk of recurrence after surgery. We also provide a comparison of surgical and radiation outcomes data, and then address areas for further research.

4 Review Role of radiation therapy as immune activator in the era of modern immunotherapy for metastatic malignant melanoma. 2015

Okwan-Duodu, Derick / Pollack, Brian P / Lawson, David / Khan, Mohammad K. ·*Emory University School of Medicine Departments of †Dermatology §Hematology and Oncology ∥Radiation Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta ‡Atlanta Veterans Affairs Medical Center, Decatur, GA. ·Am J Clin Oncol · Pubmed #23648438.

ABSTRACT: Metastatic melanoma is difficult to treat, and often portends a grim prognosis. For patients with cerebral metastases, the prognosis is even more dire. Systemic immunotherapy and targeted agents are emerging as the mainstay of treatment for metastatic melanoma. Although immunotherapy has been shown to prolong relapse-free survival and long-term control of micrometastatic disease, the response rate is suboptimal, prompting the need to optimize and improve therapy. Accumulating evidence suggests that in addition to effective locoregional control, radiation therapy (RT) may induce immune activation and expansion of T lymphocytes recognizing melanocyte-specific antigens including activated cytotoxic T lymphocytes that can potentially kill melanoma cells. In some cases, RT contributes to the clearance of metastatic disease in distant, nonirradiated regions, a bystander phenomenon called the abscopal effect. Here, we evaluate the potential promise of ablative radiation treatment in the era of modern immunotherapy by presenting a patient with metastatic melanoma who remained disease free for over 3 years after an initial diagnosis of advanced metastatic melanoma with brain, subcutaneous tissue, mesenteric, pelvic, and retroperitoneal involvement. The patient failed initial stereotactic radiosurgery, but responded to whole-brain RT in combination with interleukin-2 immunotherapy. Thus, combination RT with immunotherapy may be synergistic by promoting the release and processing of melanoma antigens that can be presented by dendritic cells. This in turn may augment the response to therapies that center on expansion and/or activation of antitumor T cells.

5 Clinical Trial Vemurafenib treatment for patients with locally advanced, unresectable stage IIIC or metastatic melanoma and activating exon 15 BRAF mutations other than V600E. 2017

Hallmeyer, Sigrun / Gonzalez, Rene / Lawson, David H / Cranmer, Lee D / Linette, Gerald P / Puzanov, Igor / Taback, Bret / Cowey, C Lance / Ribas, Antoni / Daniels, Gregory A / Moore, Timothy / Gibney, Geoffrey T / Tawbi, Hussein / Whitman, Eric / Lee, Geraldine / Mun, Yong / Liu, Shiyao / Hamid, Omid. ·aDepartment of Internal Medicine, Advocate Medical Group - Oncology North, Park Ridge, Illinois bMelanoma Research Clinic, University of Colorado Cancer Center, Aurora, Colorado cDepartment of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia dDepartment of Hematology and Oncology, The University of Arizona Cancer Center, Tucson, Arizona eDepartment of Medicine, Washington University School of Medicine, St Louis, Missouri fDepartment of Hematology-Oncology, Vanderbilt University Medical Center, Nashville, Tennessee gDepartment of Surgery, Columbia University Medical Center, New York, New York hDepartment of Medical Oncology, Texas Oncology, Dallas, Texas iDepartment of Medicine, Jonsson Comprehensive Cancer Center at University of California jDepartment of Immuno-Oncology, The Angeles Clinic and Research Institute, Los Angeles kDepartment of Oncology, Moores Cancer Center, University of California, San Diego, La Jolla lGenentech Inc., South San Francisco, California mMid Ohio Oncology and Hematology Inc., Columbus, Ohio nDepartment of Melanoma, Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC oDepartment of Pathology, University of Pittsburgh Cancer Institute and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania pDepartment of Melanoma, Carol G. Simon Cancer Center, Atlantic Health System, Morristown, New Jersey, USA. ·Melanoma Res · Pubmed #29076950.

ABSTRACT: BRAF mutations are found in ~50% of metastatic melanomas, most commonly in codon V600. Vemurafenib improves progression-free survival and overall survival in patients with advanced BRAF-mutated melanoma. The results of a descriptive study evaluating vemurafenib in patients with advanced melanoma harbouring BRAF mutations other than V600E are reported. Eligible patients with stage IIIC or IV melanoma and non-V600E BRAF mutations received vemurafenib (960 mg, twice daily). End points included investigator-assessed best overall response rate (primary), time to response, duration of response, progression-free survival, overall survival and safety. Planned (V600K vs. non-V600K mutations) subgroup analyses were carried out. Thirty-one patients were enrolled; 13 (42%) had V600K mutations and 18 (58%) had other mutations. Investigator-assessed confirmed that the best overall response rate was 23% (95% confidence interval=10-41%) in the overall population, and was similar between patients with V600K mutations (23%; 95% confidence interval=5-54%) versus other mutations (22%; 95% confidence interval=6-48%). Responses were observed in patients with V600K (n=3), V600E2 (n=1), V600R (n=1), L597S (n=1) and D594G (n=1) mutations. No new safety signals were reported. Vemurafenib showed activity in patients with advanced melanoma with rarer BRAF mutations.

6 Clinical Trial Immune Correlates of GM-CSF and Melanoma Peptide Vaccination in a Randomized Trial for the Adjuvant Therapy of Resected High-Risk Melanoma (E4697). 2017

Butterfield, Lisa H / Zhao, Fengmin / Lee, Sandra / Tarhini, Ahmad A / Margolin, Kim A / White, Richard L / Atkins, Michael B / Cohen, Gary I / Whiteside, Theresa L / Kirkwood, John M / Lawson, David H. ·University of Pittsburgh, Pittsburgh, Pennsylvania. butterfieldl@upmc.edu. · Dana Farber Cancer Institute - ECOG-ACRIN Biostatistics Center, Boston, Massachusetts. · University of Pittsburgh, Pittsburgh, Pennsylvania. · Seattle Cancer Care Alliance, Seattle, Washington. · Levine Cancer Institute, Carolinas Healthcare System, Charlotte, North Carolina. · Beth Israel Deaconess Medical Center, Boston, Massachusetts. · Greater Baltimore Medical Center, Baltimore, Maryland. · Winship Cancer institute of Emory University, Atlanta, Georgia. ·Clin Cancer Res · Pubmed #28536308.

ABSTRACT:

7 Clinical Trial Relationship between physician-adjudicated adverse events and patient-reported health-related quality of life in a phase II clinical trial (NCT01143402) of patients with metastatic uveal melanoma. 2017

Atkinson, Thomas M / Hay, Jennifer L / Shoushtari, Alexander / Li, Yuelin / Paucar, Daniel J / Smith, Sloane C / Kudchadkar, Ragini R / Doyle, Austin / Sosman, Jeffrey A / Quevedo, Jorge Fernando / Milhem, Mohammed M / Joshua, Anthony M / Linette, Gerald P / Gajewski, Thomas F / Lutzky, Jose / Lawson, David H / Lao, Christopher D / Flynn, Patrick J / Albertini, Mark R / Sato, Takami / Lewis, Karl / Marr, Brian / Abramson, David H / Dickson, Mark Andrew / Schwartz, Gary K / Carvajal, Richard D. ·Department of Psychiatry and Behavioral Sciences, Memorial Sloan Kettering Cancer Center, 641 Lexington Ave., 7th Floor, New York, NY, 10022, USA. atkinsot@mskcc.org. · Department of Psychiatry and Behavioral Sciences, Memorial Sloan Kettering Cancer Center, 641 Lexington Ave., 7th Floor, New York, NY, 10022, USA. · Montefiore Medical Center, Albert Einstein Cancer Center, Bronx, NY, USA. · Winship Cancer Institute of Emory University, Atlanta, GA, USA. · Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA. · Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA. · Mayo Clinic, Rochester, MN, USA. · University of Iowa Carver College of Medicine, Iowa City, IA, USA. · Princess Margaret Hospital University Health Network, Toronto, ON, Canada. · Penn Medicine, Philadelphia, PA, USA. · University of Chicago, Chicago, IL, USA. · Mount Sinai Medical Center, Miami Beach, FL, USA. · University of Michigan, Ann Arbor, MI, USA. · Minnesota Oncology, Woodbury, MN, USA. · Univeristy of Wisconsin School of Medicine and Public Health, Madison, WI, USA. · Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, USA. · University of Colorado - Denver, Denver, CO, USA. · Columbia University Medical Center, New York, NY, USA. ·J Cancer Res Clin Oncol · Pubmed #27921276.

ABSTRACT: PURPOSE: Clinical trials commonly use physician-adjudicated adverse event (AE) assessment via the common terminology criteria for adverse events (CTCAE) for decision-making. Patient-reported health-related quality of life (HRQoL) data are becoming more frequent in oncology; however, the relationship between physician-adjudicated AE assessment and HRQoL is understudied. METHODS: Data from a phase II trial (clinicaltrials.gov identifier: NCT01143402) where patients with metastatic uveal melanoma were randomized to receive selumetinib, an oral MEK inhibitor, or chemotherapy were analyzed. Patients reported HRQoL at baseline, after 1 month, and end of treatment (n = 118), whereas physicians adjudicated AEs via CTCAE. Mean HRQoL scores were compared between patient randomization arms, as well as between those patients who did/did not receive dose modifications. RESULTS: Ninety-four percent had a CTCAE grade ≥1 for at least one treatment-associated AE, with 18% undergoing dose modification due to toxicity. Mean HRQoL scores did not significantly differ at each of the three time points. Patient and physician-adjudicated reports of nausea were significantly correlated at the start (r = 0.31, p < 0.01) and end of treatment (r = 0.42, p < 0.05). There were no significant correlations between need for dose modification and HRQoL scores. CONCLUSIONS: Despite the high rate of physician-adjudicated AEs and need for dose modifications with selumetinib, patient-reported HRQoL was not impacted by treatment. Since HRQoL did not differ in the subgroup of patients who received dosage reductions due to AEs, patients may be willing to tolerate select AEs without dose modification (if medically appropriate). More research is needed to determine how to best integrate HRQoL data into clinical trial conduct.

8 Clinical Trial Ipilimumab and Stereotactic Radiosurgery Versus Stereotactic Radiosurgery Alone for Newly Diagnosed Melanoma Brain Metastases. 2017

Patel, Kirtesh R / Shoukat, Sana / Oliver, Daniel E / Chowdhary, Mudit / Rizzo, Monica / Lawson, David H / Khosa, Faisal / Liu, Yuan / Khan, Mohammad K. ·Departments of *Radiation Oncology §Surgery, Division of Surgical Oncology #Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute Departments of †Internal Medicine ∥Hematology and Medical Oncology ¶Radiology, Emory University ‡Emory University School of Medicine, Atlanta, GA. ·Am J Clin Oncol · Pubmed #26017484.

ABSTRACT: BACKGROUND: We compared the safety and efficacy of ipilimumab and stereotactic radiosurgery (SRS) to SRS alone for newly diagnosed melanoma brain metastases (MBM). MATERIALS AND METHODS: We reviewed records of newly diagnosed MBM patients treated with SRS from 2009 to 2013. The primary endpoint of overall survival (OS), and secondary endpoints of local control, distant intracranial failure, and radiation necrosis were compared using Kaplan-Meier method. Univariate and multivariate analysis were performed using the Cox proportional hazards method. RESULTS: Fifty-four consecutive MBM patients were identified, with 20 (37.0%) receiving ipilimumab within 4 months of SRS. Ipilimumab-treated and non-ipilimumab-treated patients had similar baseline characteristics. No difference in symptomatic radiation necrosis or hemorrhage was identified between cohorts. Compared with patients in the nonipilimumab group, 1 year local control (71.4% vs. 92.3%, P=0.40) and intracranial control (12.7% vs. 29.1%, P=0.59) were also statistically similar. The ipilimumab cohort also had no difference in 1-year OS (37.1% vs. 38.5%, P=0.84). Patients administered ipilimumab within 14 days of SRS had higher 1-year (42.9%) and 2-year OS (42.9%) relative to ipilimumab delivered >14 days (33.8%, 16.9%) and SRS alone (38.5%, 25.7%) but these difference were not statistically significant. Univariate analysis and multivariate analysis both confirmed single brain metastasis, controlled primary, and active systemic disease as predictors for OS. CONCLUSIONS: Use of ipilimumab within 4 months of SRS seems to be safe, with no increase in radiation necrosis or hemorrhage; however, our retrospective institutional experience with this treatment regimen was not associated with improved outcomes.

9 Clinical Trial Randomized, Placebo-Controlled, Phase III Trial of Yeast-Derived Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) Versus Peptide Vaccination Versus GM-CSF Plus Peptide Vaccination Versus Placebo in Patients With No Evidence of Disease After Complete Surgical Resection of Locally Advanced and/or Stage IV Melanoma: A Trial of the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Research Group (E4697). 2015

Lawson, David H / Lee, Sandra / Zhao, Fengmin / Tarhini, Ahmad A / Margolin, Kim A / Ernstoff, Marc S / Atkins, Michael B / Cohen, Gary I / Whiteside, Theresa L / Butterfield, Lisa H / Kirkwood, John M. ·David H. Lawson, Winship Cancer Institute of Emory University, Atlanta, GA · Sandra Lee and Fengmin Zhao, Dana-Farber Cancer Institute · Michael B. Atkins, Beth Israel Deaconess Medical Center, Boston, MA · Ahmad A. Tarhini, Theresa L. Whiteside, Lisa H. Butterfield, and John M. Kirkwood, University of Pittsburgh Medical Center, Pittsburgh, PA · Kim A. Margolin, Seattle Cancer Care Alliance, Seattle, WA · Marc S. Ernstoff, Dartmouth-Hitchcock Medical Center, Lebanon, NH · and Gary I. Cohen, Greater Baltimore Medical Center, Baltimore, MD. ·J Clin Oncol · Pubmed #26351350.

ABSTRACT: PURPOSE: We conducted a double-blind, placebo-controlled trial to evaluate the effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) and peptide vaccination (PV) on relapse-free survival (RFS) and overall survival (OS) in patients with resected high-risk melanoma. PATIENTS AND METHODS: Patients with completely resected stage IV or high-risk stage III melanoma were grouped by human leukocyte antigen (HLA) -A2 status. HLA-A2-positive patients were randomly assigned to receive GM-CSF, PV, both, or placebo; HLA-A2-negative patients, GM-CSF or placebo. Treatment lasted for 1 year or until recurrence. Efficacy analyses were conducted in the intent-to-treat population. RESULTS: A total of 815 patients were enrolled. There were no significant improvements in OS (stratified log-rank P = .528; hazard ratio, 0.94; 95% repeated CI, 0.77 to 1.15) or RFS (P = .131; hazard ratio, 0.88; 95% CI, 0.74 to 1.04) in the patients assigned to GM-CSF (n = 408) versus those assigned to placebo (n = 407). The median OS times with GM-CSF versus placebo treatments were 69.6 months (95% CI, 53.4 to 83.5 months) versus 59.3 months (95% CI, 44.4 to 77.3 months); the 5-year OS probability rates were 52.3% (95% CI, 47.3% to 57.1%) versus 49.4% (95% CI, 44.3% to 54.3%), respectively. The median RFS times with GM-CSF versus placebo were 11.4 months (95% CI, 9.4 to 14.8 months) versus 8.8 months (95% CI, 7.5 to 11.2 months); the 5-year RFS probability rates were 31.2% (95% CI, 26.7% to 35.9%) versus 27.0% (95% CI, 22.7% to 31.5%), respectively. Exploratory analyses showed a trend toward improved OS in GM-CSF-treated patients with resected visceral metastases. When survival in HLA-A2-positive patients who received PV versus placebo was compared, RFS and OS were not significantly different. Treatment-related grade 3 or greater adverse events were similar between GM-CSF and placebo groups. CONCLUSION: Neither adjuvant GM-CSF nor PV significantly improved RFS or OS in patients with high-risk resected melanoma. Exploratory analyses suggest that GM-CSF may be beneficial in patients with resected visceral metastases; this observation requires prospective validation.

10 Clinical Trial Effect of selumetinib vs chemotherapy on progression-free survival in uveal melanoma: a randomized clinical trial. 2014

Carvajal, Richard D / Sosman, Jeffrey A / Quevedo, Jorge Fernando / Milhem, Mohammed M / Joshua, Anthony M / Kudchadkar, Ragini R / Linette, Gerald P / Gajewski, Thomas F / Lutzky, Jose / Lawson, David H / Lao, Christopher D / Flynn, Patrick J / Albertini, Mark R / Sato, Takami / Lewis, Karl / Doyle, Austin / Ancell, Kristin / Panageas, Katherine S / Bluth, Mark / Hedvat, Cyrus / Erinjeri, Joseph / Ambrosini, Grazia / Marr, Brian / Abramson, David H / Dickson, Mark Andrew / Wolchok, Jedd D / Chapman, Paul B / Schwartz, Gary K. ·Memorial Sloan-Kettering Cancer Center, New York, New York2Weill Medical College of Cornell University, New York, New York. · Vanderbilt University Medical Center, Department of Hematology-Oncology, Nashville, Tennessee. · Mayo Clinic, Rochester, Minnesota. · University of Iowa Hospital and Clinics, Iowa City. · Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. · H. Lee Moffitt Cancer Center, Tampa, Florida. · Washington University, St Louis, Missouri. · University of Chicago, Chicago, Illinois. · Mount Sinai Comprehensive Cancer Center, Miami Beach, Florida. · Winship Cancer Institute of Emory University, Atlanta, Georgia. · University of Michigan, Ann Arbor. · Metro Minnesota Community Clinical Oncology Program, St Louis Park. · University of Wisconsin, Madison. · Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania. · University of Colorado, Aurora. · Investigational Drug Branch, National Cancer Institute, Rockville, Maryland. · Memorial Sloan-Kettering Cancer Center, New York, New York. ·JAMA · Pubmed #24938562.

ABSTRACT: IMPORTANCE: Uveal melanoma is characterized by mutations in GNAQ and GNA11, resulting in mitogen-activated protein kinase pathway activation. OBJECTIVE: To assess the efficacy of selumetinib, a selective, non-adenosine triphosphate competitive inhibitor of MEK1 and MEK2, in uveal melanoma. DESIGN, SETTING, AND PARTICIPANTS: Randomized, open-label, phase 2 clinical trial comparing selumetinib vs chemotherapy conducted from August 2010 through December 2013 among 120 patients with metastatic uveal melanoma at 15 academic oncology centers in the United States and Canada. INTERVENTIONS: One hundred one patients were randomized in a 1:1 ratio to receive selumetinib, 75 mg orally twice daily on a continual basis (n = 50), or chemotherapy (temozolomide, 150 mg/m2 orally daily for 5 of every 28 days, or dacarbazine, 1000 mg/m2 intravenously every 21 days [investigator choice]; n = 51) until disease progression, death, intolerable adverse effects, or withdrawal of consent. After primary outcome analysis, 19 patients were registered and 18 treated with selumetinib without randomization to complete the planned 120-patient enrollment. Patients in the chemotherapy group could receive selumetinib at the time of radiographic progression. MAIN OUTCOMES AND MEASURES: Progression-free survival, the primary end point, was assessed as of April 22, 2013. Additional end points, including overall survival, response rate, and safety/toxicity, were assessed as of December 31, 2013. RESULTS: Median progression-free survival among patients randomized to chemotherapy was 7 weeks (95% CI, 4.3-8.4 weeks; median treatment duration, 8 weeks; interquartile range [IQR], 4.3-16 weeks) and among those randomized to selumetinib was 15.9 weeks (95% CI, 8.4-21.1 weeks; median treatment duration, 16.1 weeks; IQR, 8.1-25.3 weeks) (hazard ratio, 0.46; 95% CI, 0.30-0.71; P < .001). Median overall survival time was 9.1 months (95% CI, 6.1-11.1 months) with chemotherapy and 11.8 months (95% CI, 9.8-15.7 months) with selumetinib (hazard ratio, 0.66; 95% CI, 0.41-1.06; P = .09). No objective responses were observed with chemotherapy. Forty-nine percent of patients treated with selumetinib achieved tumor regression, with 14% achieving an objective radiographic response to therapy. Treatment-related adverse events were observed in 97% of patients treated with selumetinib, with 37% requiring at least 1 dose reduction. CONCLUSIONS AND RELEVANCE: In this hypothesis-generating study of patients with advanced uveal melanoma, selumetinib compared with chemotherapy resulted in a modestly improved progression-free survival and response rate; however, no improvement in overall survival was observed. Improvement in clinical outcomes was accompanied by a high rate of adverse events. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01143402.

11 Clinical Trial A single-arm, open-label, expanded access study of vemurafenib in patients with metastatic melanoma in the United States. 2014

Flaherty, Lawrence / Hamid, Omid / Linette, Gerald / Schuchter, Lynn / Hallmeyer, Sigrun / Gonzalez, Rene / Cowey, C Lance / Pavlick, Anna / Kudrik, Fred / Curti, Brendan / Lawson, David / Chapman, Paul B / Margolin, Kim / Ribas, Antoni / McDermott, David / Flaherty, Keith / Cranmer, Lee / Hodi, F Stephen / Day, Bann-Mo / Linke, Rolf / Hainsworth, John. ·From the *Karmanos Cancer Center, Wayne State University, Detroit, MI; †The Angeles Clinic and Research Institute, Los Angeles, CA; ‡Washington University, St Louis, MO; §University of Pennsylvania, Philadelphia, PA; ∥Oncology Specialists S.C., Park Ridge, IL; ¶University of Colorado Cancer Center, Aurora, CO; #Baylor Sammons Cancer Center, Texas Oncology, PA, Dallas, TX; **NYU Medical Center, New York, NY; ††South Carolina Oncology Associates, Columbia, SC; ‡‡Providence Portland Medical Center, Portland, OR; §§Winship Cancer Institute, Emory University, Atlanta, GA; ∥∥Memorial Sloan Kettering Cancer Center, New York, NY; ¶¶Seattle Cancer Care Alliance, Seattle, WA; ##UCLA School of Medicine, Los Angeles, CA; ***Beth Israel Deaconess Medical Center and †††Massachusetts General Hospital, Boston, MA; ‡‡‡University of Arizona Cancer Center, Tucson, AZ; §§§Dana Farber Cancer Institute, Boston, MA; ∥∥∥Genentech, San Francisco, CA; ¶¶¶The SFJ Pharma Group, Pleasanton, CA; and ###Sarah Cannon Research Institute, Nashville, TN. ·Cancer J · Pubmed #24445759.

ABSTRACT: PURPOSE: This open-label, multicenter study was designed to allow access to vemurafenib for patients with metastatic melanoma, bridging the time between end of enrollment in the phase III registration trial (December 2010) and commercial availability following US Food and Drug Administration approval of vemurafenib for the treatment of unresectable or metastatic BRAF-mutated melanoma (August 2011). PATIENTS AND METHODS: Eligible patients had metastatic melanoma with a BRAF mutation (detected by the cobas 4800 BRAF V600 Mutation Test). Unlike previous vemurafenib trials, patients with poor performance status (PS) and treated brain metastases were permitted. Enrolled patients received oral vemurafenib 960 mg twice daily. RESULTS: Of 374 patients enrolled at 29 US sites (December 2010 to October 2011), 371 patients received vemurafenib and were followed up for a median of 2.8 months (the study had a prespecified end upon vemurafenib approval and commercial availability). At baseline, most patients (75%) had stage M1c disease, and 19% had an Eastern Cooperative Oncology Group PS of 2 or 3; 72% of patients had received prior systemic therapy for metastatic melanoma, 27% received prior ipilimumab, and 29% radiotherapy for prior brain metastases. Because reassessment data to confirm response were not available for most patients, point estimates of objective response rate (ORR) are reported. Among 241 efficacy-evaluable patients, the ORR was 54% (median time to response, 1.9 months). The ORR in non-central nervous system sites in patients with previously treated brain metastases (n = 68) was 53%. The ORR in prior ipilimumab-treated patients (n = 68) was 52%. For patients with PS of 0 or 1 (n = 210) and 2 or 3 (n = 31), the ORRs were 55%, and 42%, respectively. The safety profile observed was consistent with that reported in previous studies. The number of patients with grade 3 or 4 treatment-related adverse events was higher in patients with PS 2 or 3 than in those with PS 0 or 1 (10% vs. 5%, respectively). Adverse events requiring a dose reduction (at least 1 level) occurred in 11% of patients, and 9 patients (2%) experienced events leading to vemurafenib withdrawal, including 2 with repeated QT interval prolongation. DISCUSSION: This study confirmed the established rapid and high tumor response rate achievable with vemurafenib in BRAF mutation-positive metastatic melanoma. Several groups not included in previous studies, including patients with previously treated brain metastases, Eastern Cooperative Oncology Group PS 2 to 3, or previous ipilimumab treatment had benefitted from vemurafenib similar to the overall population. No new safety signals were detected.

12 Clinical Trial Safety profile and pharmacokinetic analyses of the anti-CTLA4 antibody tremelimumab administered as a one hour infusion. 2012

Ribas, Antoni / Chesney, Jason A / Gordon, Michael S / Abernethy, Amy P / Logan, Theodore F / Lawson, David H / Chmielowksi, Bartosz / Glaspy, John A / Lewis, Karl / Huang, Bo / Wang, Erjian / Hsyu, Poe-Hirr / Gomez-Navarro, Jesus / Gerhardt, Diana / Marshall, Margaret A / Gonzalez, Rene. ·Division of Hematology-Oncology, 11-934 Factor Building, Jonsson Comprehensive Cancer Center at the University of California Los Angeles, Los Angeles, CA 90095-1782, USA. aribas@mednet.ucla.edu ·J Transl Med · Pubmed #23171508.

ABSTRACT: BACKGROUND: CTLA4 blocking monoclonal antibodies provide a low frequency but durable tumor responses in patients with metastatic melanoma, which led to the regulatory approval of ipilimumab based on two randomized clinical trials with overall survival advantage. The similarly fully human anti-CTLA4 antibody tremelimumab had been developed in the clinic at a fixed rate infusion, resulting in very prolonged infusion times. A new formulation of tremelimumab allowed testing a shorter infusion time. METHODS: A phase 1 multi-center study to establish the safety and tolerability of administering tremelimumab as a 1-hour infusion to patients with metastatic melanoma. Secondary endpoints included pharmacokinetic and clinical effects of tremelimumab. RESULTS: No grade 3 or greater infusion-related adverse events or other adverse events preventing the administration of the full tremelimumab dose were noted in 44 treated patients. The overall side effect profile was consistent with prior experiences with anti-CTLA4 antibodies. Objective tumor responses were noted in 11% of evaluable patients with metastatic melanoma, which is also consistent with the prior experience with CTLA4 antagonistic antibodies. CONCLUSIONS: This study did not identify any safety concerns when tremelimumab was administered as a 1-hour infusion. These data support further clinical testing of the 1-hour infusion of tremelimumab. (Clinical trial registration number NCT00585000).

13 Clinical Trial Prognostic value of 18f-fluorodeoxyglucose positron emission tomography-computed tomography in predicting survival in patients with unresectable metastatic melanoma to the liver undergoing yttrium-90 radioembolization. 2012

Piduru, Sarat M / Schuster, David M / Barron, Bruce J / Dhanasekaran, Renumathy / Lawson, David H / Kim, Hyun S. ·Department of Radiology and Imaging Sciences, Emory University School of Medicine, 1364 Clifton Road NE, Atlanta, GA 30323, USA. ·J Vasc Interv Radiol · Pubmed #22609292.

ABSTRACT: PURPOSE: To investigate the prognostic value of (18)F-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT) in predicting survival in patients with unresectable metastatic melanoma to the liver undergoing yttrium-90 ((90)Y) radioembolization. MATERIALS AND METHODS: A retrospective review of 12 patients with unresectable hepatic melanoma metastases (5 patients with cutaneous metastases, 7 patients with ocular metastases) who underwent (18)F-FDG PET-CT before (90)Y was performed. Metabolically significant tumors, defined as having a long-axis diameter ≥ 1 cm and maximum standardized uptake value (SUV(max)) ≥ 2.5, were identified on (18)F-FDG PET-CT. SUV(max), glycolytic activity, and volume were determined for each tumor. Overall SUV(max), total tumor glycolytic activity (TGA), total metabolic tumor volume (MTV), and metabolic tumor burden (MTB) based on percentage of liver involvement (MTV/total liver volume) were calculated. Kaplan-Meier method, life-table analysis, and Cox proportional hazards model were used for statistical analysis. RESULTS: Median SUV(max) was 10.9 (range, 4.6-15.3), median TGA was 377.0 SUV/cm(3) (range, 53.6-20,393.4 SUV/cm(3)), median MTV was 85.4 cm(3) (range, 11.5-2,504.1 cm(3)), and median MTB was 5.5% (range, 0.1%-54.0%). MTB was found to be a significant negative prognostic marker of survival on univariate (P = .020) and multivariate (P = .018) analyses accounting for age and duration from metastatic diagnosis to first (90)Y treatment. A 60th percentile MTB of 7.0% (hazard ratio, 5.704; P = .040) was a statistically significant cutoff. Median survivals from first (90)Y treatment in patients with MTB < 7.0% and ≥ 7.0% were 10.8 months (95% confidence interval [CI], 6.8-14.8) and 4.7 months (95% CI, 1.6-7.8), respectively. SUV(max) (P = .422), TGA (P = .064), and MTV (P = .065) were not found to be statistically significant. CONCLUSIONS: MTB based on (18)F-FDG PET-CT performed before treatment was found to be a negative prognostic factor for patient survival after (90)Y radioembolization for unresectable metastatic melanoma to liver.

14 Clinical Trial gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. 2011

Schwartzentruber, Douglas J / Lawson, David H / Richards, Jon M / Conry, Robert M / Miller, Donald M / Treisman, Jonathan / Gailani, Fawaz / Riley, Lee / Conlon, Kevin / Pockaj, Barbara / Kendra, Kari L / White, Richard L / Gonzalez, Rene / Kuzel, Timothy M / Curti, Brendan / Leming, Phillip D / Whitman, Eric D / Balkissoon, Jai / Reintgen, Douglas S / Kaufman, Howard / Marincola, Francesco M / Merino, Maria J / Rosenberg, Steven A / Choyke, Peter / Vena, Don / Hwu, Patrick. ·Indiana University Health Goshen Center for Cancer Care, Goshen, IN 46526, USA. dschwart@iuhealth.org ·N Engl J Med · Pubmed #21631324.

ABSTRACT: BACKGROUND: Stimulating an immune response against cancer with the use of vaccines remains a challenge. We hypothesized that combining a melanoma vaccine with interleukin-2, an immune activating agent, could improve outcomes. In a previous phase 2 study, patients with metastatic melanoma receiving high-dose interleukin-2 plus the gp100:209-217(210M) peptide vaccine had a higher rate of response than the rate that is expected among patients who are treated with interleukin-2 alone. METHODS: We conducted a randomized, phase 3 trial involving 185 patients at 21 centers. Eligibility criteria included stage IV or locally advanced stage III cutaneous melanoma, expression of HLA*A0201, an absence of brain metastases, and suitability for high-dose interleukin-2 therapy. Patients were randomly assigned to receive interleukin-2 alone (720,000 IU per kilogram of body weight per dose) or gp100:209-217(210M) plus incomplete Freund's adjuvant (Montanide ISA-51) once per cycle, followed by interleukin-2. The primary end point was clinical response. Secondary end points included toxic effects and progression-free survival. RESULTS: The treatment groups were well balanced with respect to baseline characteristics and received a similar amount of interleukin-2 per cycle. The toxic effects were consistent with those expected with interleukin-2 therapy. The vaccine-interleukin-2 group, as compared with the interleukin-2-only group, had a significant improvement in centrally verified overall clinical response (16% vs. 6%, P=0.03), as well as longer progression-free survival (2.2 months; 95% confidence interval [CI], 1.7 to 3.9 vs. 1.6 months; 95% CI, 1.5 to 1.8; P=0.008). The median overall survival was also longer in the vaccine-interleukin-2 group than in the interleukin-2-only group (17.8 months; 95% CI, 11.9 to 25.8 vs. 11.1 months; 95% CI, 8.7 to 16.3; P=0.06). CONCLUSIONS: In patients with advanced melanoma, the response rate was higher and progression-free survival longer with vaccine and interleukin-2 than with interleukin-2 alone. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00019682.).

15 Clinical Trial A multi-center phase II evaluation of the small molecule survivin suppressor YM155 in patients with unresectable stage III or IV melanoma. 2011

Lewis, Karl D / Samlowski, Wolfram / Ward, John / Catlett, Joseph / Cranmer, Lee / Kirkwood, John / Lawson, David / Whitman, Eric / Gonzalez, Rene. ·University of Colorado Health Sciences Center, Aurora, CO, USA. karl.lewis@ucdenver.edu ·Invest New Drugs · Pubmed #19830389.

ABSTRACT: METHODS: This was an open-label, multi-center, study of YM155 monotherapy in subjects with unresectable stage III or IV melanoma. Thirty-four chemotherapy naïve subjects were treated with YM155 at a dose of 4.8 mg/m(2)/day administered by continuous infusion for 168-hours (7 days) followed by a 14-day rest period, for up to 6 cycles or until disease progression. RESULTS: One subject had a partial response to treatment seen at cycle two and lasting through cycle eight. Median progression-free survival was 1.3 months (95% CI; 1.3-2.7). Median overall survival was 9.9 months (95% CI; 7.0-14.5). Overall, YM155 was well tolerated with the most common (>20%) adverse events reported as fatigue, nausea, pyrexia, headache, arthralgia and back pain. Only four subjects required dose reductions. CONCLUSIONS: YM155 was well tolerated in subjects with advanced melanoma; however, the pre-specified primary end-point for efficacy which required two responders in 29 evaluable subjects was not achieved.

16 Clinical Trial Phase II, randomized, controlled, double-blinded trial of weekly elesclomol plus paclitaxel versus paclitaxel alone for stage IV metastatic melanoma. 2009

O'Day, Steven / Gonzalez, Rene / Lawson, David / Weber, Robert / Hutchins, Laura / Anderson, Clay / Haddad, Jonathan / Kong, Steven / Williams, Anthony / Jacobson, Eric. ·Angeles Clinic and Research Institute, Santa Monica, CA 90404, USA. soday@theangelesclinic.org ·J Clin Oncol · Pubmed #19826135.

ABSTRACT: PURPOSE: Elesclomol is a novel, small-molecule, oxidative stress inducer believed to exert selective cytotoxicity by increasing intracellular concentrations of reactive oxygen species, which results in cell death via mitochondrial apoptosis. We evaluated whether the addition of elesclomol to weekly paclitaxel could improve efficacy in patients with stage IV metastatic melanoma. PATIENTS AND METHODS: We randomly assigned patients with metastatic melanoma, measurable disease, and one or fewer prior chemotherapy regimens to elesclomol 213 mg/m(2) plus paclitaxel 80 mg/m(2) (E + P) or to paclitaxel 80 mg/m(2) alone at a 2:1 ratio; regimens were given as a 1-hour intravenous infusion weekly, during 3 of every 4 weeks until disease progression per Response Evaluation Criteria in Solid Tumors or death occurred. Patients who experienced progression were unblended, and patients on paclitaxel alone were permitted to cross over to E + P. The primary efficacy end point was progression-free survival (PFS); secondary end points were response rate (RR), toxicity, and overall survival (OS; analyzed post hoc). RESULTS: At 21 US sites, 53 patients were randomly assigned to E + P, and 28 patients were randomly assigned to paclitaxel. The addition of elesclomol to paclitaxel yielded a doubling of median PFS (112 v 56 days) and a 41.7% risk reduction for disease progression/death (hazard ratio, 0.583; P = .035). Respective RRs for the E + P and paclitaxel groups were 15% and 3%; median OS was 11.9 v 7.8 months. Of patients on paclitaxel alone, 19 (68%) of 28 crossed over to E + P after they experienced progression. Weekly E + P was well tolerated. CONCLUSION: E + P resulted in a statistically significant doubling of median PFS, with an acceptable toxicity profile and encouraging OS. A multinational, phase III trial (SYMMETRY) of E + P compared with paclitaxel alone in metastatic melanoma has closed.

17 Clinical Trial Temozolomide, thalidomide, and whole brain radiation therapy for patients with brain metastasis from metastatic melanoma: a phase II Cytokine Working Group study. 2008

Atkins, Michael B / Sosman, Jeffrey A / Agarwala, Sanjiv / Logan, Theodore / Clark, Joseph I / Ernstoff, Marc S / Lawson, David / Dutcher, Janice P / Weiss, Geoffrey / Curti, Brendan / Margolin, Kim A. ·Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA. Matkins@bidmc.harvard.edu ·Cancer · Pubmed #18792064.

ABSTRACT: BACKGROUND: The combination of temozolomide (TMZ) and thalidomide was reported to produce a high response rate, including shrinkage of brain metastases, in patients with metastatic melanoma. The authors tested the efficacy of a regimen including TMZ, thalidomide, and whole brain radiation therapy (WBRT) in patients with brain (CNS) metastases from melanoma. METHODS: Patients with melanoma, CNS metastases documented by magnetic resonance imaging, and no prior systemic chemotherapy received WBRT, 30 Gray in 10 fractions, Days 1 to 5 and 8 to 12; TMZ, 75 mg/m(2)/day, Weeks 1 to 6; and thalidomide, 100 mg/day, Weeks 1 to 4, then escalated by 100 mg/day at Weeks 5, 7, and 9 as tolerated to a maximum of 400 mg/day. CNS and systemic tumor response was assessed at Week 10. Patients without CNS or clinically significant systemic disease progression received additional cycles of TMZ at 10-week intervals. RESULTS: Thirty-nine patients received treatment, and 3 exhibited CNS response (1 complete response, 2 partial responses) (response rate, 7.6%; 95% confidence interval, 0.7%-16.1%), all unconfirmed by repeat imaging. Seven patients had stable CNS disease at 10 weeks. No patient exhibited a systemic response. Only 4 patients received 2 cycles of therapy, and just 1 received 3. Median time to progression was 7 weeks, and median overall survival was 4 months. Grade 3-4 side effects included deep venous thrombosis (3), pulmonary embolism (1), and CNS events (12). Eighteen (45%) patients required admission for side effects (7) and/or symptomatic disease progression (11). CONCLUSIONS: The efficacy of TMZ, thalidomide, and WBRT in the treatment of CNS metastatic melanoma is low. Other treatment approaches should be considered for this patient population.

18 Article T cell receptor sequencing of activated CD8 T cells in the blood identifies tumor-infiltrating clones that expand after PD-1 therapy and radiation in a melanoma patient. 2018

Wieland, Andreas / Kamphorst, Alice O / Adsay, N Volkan / Masor, Jonathan J / Sarmiento, Juan / Nasti, Tahseen H / Darko, Sam / Douek, Daniel C / Xue, Yue / Curran, Walter J / Lawson, David H / Ahmed, Rafi. ·Department of Microbiology and Immunology, Emory Vaccine Center, Winship Cancer Institute, Emory University School of Medicine, 1510 Clifton Road, Rm G209, Atlanta, GA, 30322, USA. · Department of Oncological Sciences and Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. · Laboratory Medicine, Department of Pathology, Emory University School of Medicine, Atlanta, GA, 30322, USA. · Koç University Hospital, 34010, Istanbul, Turkey. · Division of General Medicine and Geriatrics, Department of Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA. · Department of Surgery, Emory University School of Medicine, Atlanta, GA, 30322, USA. · Human Immunology Section, Vaccine Research Center, National Institutes of Health, Bethesda, MD, 20892, USA. · Department of Radiation Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, 30322, USA. · Department of Hematology and Medical Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, 30322, GA, USA. · Department of Microbiology and Immunology, Emory Vaccine Center, Winship Cancer Institute, Emory University School of Medicine, 1510 Clifton Road, Rm G209, Atlanta, GA, 30322, USA. rahmed@emory.edu. ·Cancer Immunol Immunother · Pubmed #30167863.

ABSTRACT: PD-1-targeted therapy has dramatically changed advanced cancer treatment. However, many questions remain, including specificity of T cells activated by PD-1 therapy and how peripheral blood analysis correlates to effects at tumor sites. In this study, we utilized TCR sequencing to dissect the composition of peripheral blood CD8 T cells activated upon therapy, comparing it with tumor-infiltrating lymphocytes. We report on a nonagenarian melanoma patient who showed a prominent increase in peripheral blood Ki-67 + CD8 T cells following brain stereotactic radiation and anti-PD-1 immunotherapy. Proliferating CD8 T cells exhibited an effector-like phenotype with expression of CD38, HLA-DR and Granzyme B, as well as expression of the positive costimulatory molecules CD28 and CD27. TCR sequencing of peripheral blood CD8 T cells revealed a highly oligoclonal repertoire at baseline with one clonotype accounting for 30%. However, the majority of dominant clones-including a previously identified cytomegalovirus-reactive clone-did not expand following treatment. In contrast, expanding clones were present at low frequencies in the peripheral blood but were enriched in a previously resected liver metastasis. The patient has so far remained recurrence-free for 36 months, and several CD8 T cell clones that expanded after treatment were maintained at elevated levels for at least 8 months. Our data show that even in a nonagenarian individual with oligoclonal expansion of CD8 T cells, we can identify activation of tumor-infiltrating CD8 T cell clones in peripheral blood following anti-PD-1-based immunotherapies.

19 Article The Dietary Supplement Chondroitin-4-Sulfate Exhibits Oncogene-Specific Pro-tumor Effects on BRAF V600E Melanoma Cells. 2018

Lin, Ruiting / Xia, Siyuan / Shan, Changliang / Chen, Dong / Liu, Yijie / Gao, Xue / Wang, Mei / Kang, Hee-Bum / Pan, Yaozhu / Liu, Shuangping / Chung, Young Rock / Abdel-Wahab, Omar / Merghoub, Taha / Rossi, Michael / Kudchadkar, Ragini R / Lawson, David H / Khuri, Fadlo R / Lonial, Sagar / Chen, Jing. ·Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, GA 30322, USA. · The First Affiliated Hospital, Biomedical Translational Research Institute, Guangdong Province Key Laboratory of Molecular Immunology and Antibody Engineering, Jinan University, Guangzhou 510632, China. · Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, GA 30322, USA; General Hospital of Lanzhou Military Region, Lanzhou 730050, China. · Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, GA 30322, USA; Department of Pathology, Medical College, Dalian University, Dalian 116622, China. · Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. · Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: jchen@emory.edu. ·Mol Cell · Pubmed #29547721.

ABSTRACT: Dietary supplements such as vitamins and minerals are widely used in the hope of improving health but may have unidentified risks and side effects. In particular, a pathogenic link between dietary supplements and specific oncogenes remains unknown. Here we report that chondroitin-4-sulfate (CHSA), a natural glycosaminoglycan approved as a dietary supplement used for osteoarthritis, selectively promotes the tumor growth potential of BRAF V600E-expressing human melanoma cells in patient- and cell line-derived xenograft mice and confers resistance to BRAF inhibitors. Mechanistically, chondroitin sulfate glucuronyltransferase (CSGlcA-T) signals through its product CHSA to enhance casein kinase 2 (CK2)-PTEN binding and consequent phosphorylation and inhibition of PTEN, which requires CHSA chains and is essential to sustain AKT activation in BRAF V600E-expressing melanoma cells. However, this CHSA-dependent PTEN inhibition is dispensable in cancer cells expressing mutant NRAS or PI3KCA, which directly activate the PI3K-AKT pathway. These results suggest that dietary supplements may exhibit oncogene-dependent pro-tumor effects.

20 Article Performance of a prognostic 31-gene expression profile in an independent cohort of 523 cutaneous melanoma patients. 2018

Zager, Jonathan S / Gastman, Brian R / Leachman, Sancy / Gonzalez, Rene C / Fleming, Martin D / Ferris, Laura K / Ho, Jonhan / Miller, Alexander R / Cook, Robert W / Covington, Kyle R / Meldi-Plasseraud, Kristen / Middlebrook, Brooke / Kaminester, Lewis H / Greisinger, Anthony / Estrada, Sarah I / Pariser, David M / Cranmer, Lee D / Messina, Jane L / Vetto, John T / Wayne, Jeffrey D / Delman, Keith A / Lawson, David H / Gerami, Pedram. ·Department of Cutaneous Oncology, Moffitt Cancer Center, 10920 N. McKinley Drive room 4123, Tampa, FL, 33612, USA. · Department of Plastic Surgery, Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, Cleveland, OH, 44195, USA. · Department of Dermatology, Knight Cancer Institute, Oregon Health & Science University, 3303 S.W. Bond Avenue, Portland, OR, 97239, USA. · Department of Medical Oncology, University of Colorado School of Medicine, 12801 E. 17th Avenue, Aurora, CO, 80045, USA. · Department of Surgical Oncology, The University of Tennessee Health Science Center, 910 Madison, Suite 303, Memphis, TN, 38163, USA. · Department of Dermatology, University of Pittsburgh Medical Center, 3601 Fifth Avenue, Pittsburgh, PA, 15213, USA. · Department of Pathology, University of Pittsburgh Medical Center, 3708 Fifth Avenue, Suite 500.94, Pittsburgh, PA, 15213, USA. · START Center for Cancer Care, 4383 Medical Drive, San Antonio, TX, 78229, USA. · Castle Biosciences, Inc., 820 S. Friendswood Drive, Suite 201, Friendswood, TX, 77546, USA. · Dermatology North Palm Beach, 840 U.S. Highway Number One, North Palm Beach, FL, 33408, USA. · Research & Development, Kelsey Research Foundation, 5615 Kirby Drive, Suite 660, Houston, TX, 77005, USA. · Affiliated Dermatology, 20401 North 73rd Street, Suite 230, Scottsdale, AZ, 85255, USA. · Pariser Dermatology Specialists, Virginia Clinical Research, Inc., 6160 Kempsville Circle, Suite 200A, Norfolk, VA, 23502, USA. · Eastern Virginia Medical School, P.O. Box 1980, Norfolk, VA, 23501-1980, USA. · Department of Sarcoma Medical Oncology, Seattle Cancer Care Alliance, 825 Eastlake Avenue E, Seattle, WA, 98109, USA. · Department of Anatomic Pathology, Moffitt Cancer Center, 10920 N. McKinley Drive, Tampa, FL, 33612, USA. · Division of Surgical Oncology, Knight Cancer Institute, Oregon Health & Science University, 3303 S.W. Bond Avenue, Portland, OR, 97239, USA. · Department of Surgical Oncology, Northwestern University Feinberg School of Medicine, 251 East Huron Street, Chicago, IL, 60611, USA. · Department of Dermatology, Northwestern University Feinberg School of Medicine, 676 North St. Clair Street, Suite 1600, Chicago, IL, 60611, USA. · Skin Cancer Institute, Northwestern University, Lurie Comprehensive Cancer Center, 420 East Superior Street, Chicago, IL, 60611, USA. · Department of Surgery, Emory University Winship Cancer Institute, 1364 Clifton Road NE, Atlanta, GA, 30322, USA. · Department of Hematology and Medical Oncology, Emory University Winship Cancer Institute, 550 Peachtree Street NE, Atlanta, GA, 30308, USA. · Skin Cancer Institute, Northwestern University, Lurie Comprehensive Cancer Center, 420 East Superior Street, Chicago, IL, 60611, USA. pgerami1@nm.org. · Departments of Dermatology and Pathology, Northwestern University Feinberg School of Medicine, 676 North St. Clair Street, Arkes 1600, Chicago, IL, 60611, USA. pgerami1@nm.org. ·BMC Cancer · Pubmed #29402264.

ABSTRACT: BACKGROUND: The heterogeneous behavior of patients with melanoma makes prognostication challenging. To address this, a gene expression profile (GEP) test to predict metastatic risk was previously developed. This study evaluates the GEP's prognostic accuracy in an independent cohort of cutaneous melanoma patients. METHODS: This multi-center study analyzed primary melanoma tumors from 523 patients, using the GEP to classify patients as Class 1 (low risk) and Class 2 (high risk). Molecular classification was correlated to clinical outcome and assessed along with AJCC v7 staging criteria. Primary endpoints were recurrence-free (RFS) and distant metastasis-free (DMFS) survival. RESULTS: The 5-year RFS rates for Class 1 and Class 2 were 88% and 52%, respectively, and DMFS rates were 93% versus 60%, respectively (P < 0.001). The GEP was a significant predictor of RFS and DMFS in univariate analysis (hazard ratio [HR] = 5.4 and 6.6, respectively, P < 0.001 for each), along with Breslow thickness, ulceration, mitotic rate, and sentinel lymph node (SLN) status (P < 0.001 for each). GEP, tumor thickness and SLN status were significant predictors of RFS and DMFS in a multivariate model that also included ulceration and mitotic rate (RFS HR = 2.1, 1.2, and 2.5, respectively, P < 0.001 for each; and DMFS HR = 2.7, 1.3 and 3.0, respectively, P < 0.01 for each). CONCLUSIONS: The GEP test is an objective predictor of metastatic risk and provides additional independent prognostic information to traditional staging to help estimate an individual's risk for recurrence. The assay identified 70% of stage I and II patients who ultimately developed distant metastasis. Its role in consideration of patients for adjuvant therapy should be examined prospectively.

21 Article HMG-CoA synthase 1 is a synthetic lethal partner of BRAF 2017

Zhao, Liang / Fan, Jun / Xia, Siyuan / Pan, Yaozhu / Liu, Shuangping / Qian, Guoqing / Qian, Zhiyu / Kang, Hee-Bum / Arbiser, Jack L / Pollack, Brian P / Kudchadkar, Ragini R / Lawson, David H / Rossi, Michael / Abdel-Wahab, Omar / Merghoub, Taha / Khoury, Hanna J / Khuri, Fadlo R / Boise, Lawrence H / Lonial, Sagar / Chen, Fangping / Chen, Jing / Lin, Ruiting. ·From the Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322. · the Department of Hematology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China. · the Department of Radiation Oncology, Emory University School of Medicine, Atlanta, Georgia 30322. · the Department of Dermatology, Emory University School of Medicine, Atlanta, Georgia 30322. · the Atlanta Veterans Administration Medical Center, Decatur, Georgia 30033. · the Memorial Sloan-Kettering Cancer Center, New York, NY 10065, and. · the Department of Hematology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China hope058@163.com. · From the Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, jchen@emory.edu. ·J Biol Chem · Pubmed #28468827.

ABSTRACT: Contributions of metabolic changes to cancer development and maintenance have received increasing attention in recent years. Although many human cancers share similar metabolic alterations, it remains unclear whether oncogene-specific metabolic alterations are required for tumor development. Using an RNAi-based screen targeting the majority of the known metabolic proteins, we recently found that oncogenic BRAF

22 Article Prevention of Dietary-Fat-Fueled Ketogenesis Attenuates BRAF V600E Tumor Growth. 2017

Xia, Siyuan / Lin, Ruiting / Jin, Lingtao / Zhao, Liang / Kang, Hee-Bum / Pan, Yaozhu / Liu, Shuangping / Qian, Guoqing / Qian, Zhiyu / Konstantakou, Evmorfia / Zhang, Baotong / Dong, Jin-Tang / Chung, Young Rock / Abdel-Wahab, Omar / Merghoub, Taha / Zhou, Lu / Kudchadkar, Ragini R / Lawson, David H / Khoury, Hanna J / Khuri, Fadlo R / Boise, Lawrence H / Lonial, Sagar / Lee, Benjamin H / Pollack, Brian P / Arbiser, Jack L / Fan, Jun / Lei, Qun-Ying / Chen, Jing. ·Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, School of Medicine, Emory University, Atlanta, GA 30322, USA. · Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. · Cancer Metabolism Laboratory, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China. · Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA. · Department of Dermatology, Emory University, Atlanta, GA 30322, USA; Atlanta Veterans Administration Medical Center, Atlanta, GA 30322, USA. · Department of Radiation Oncology, Winship Cancer Institute of Emory, School of Medicine, Emory University, Atlanta, GA 30322, USA. Electronic address: jfan3@emory.edu. · Cancer Metabolism Laboratory, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China. Electronic address: qlei@fudan.edu.cn. · Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, School of Medicine, Emory University, Atlanta, GA 30322, USA. Electronic address: jchen@emory.edu. ·Cell Metab · Pubmed #28089569.

ABSTRACT: Lifestyle factors, including diet, play an important role in the survival of cancer patients. However, the molecular mechanisms underlying pathogenic links between diet and particular oncogenic mutations in human cancers remain unclear. We recently reported that the ketone body acetoacetate selectively enhances BRAF V600E mutant-dependent MEK1 activation in human cancers. Here we show that a high-fat ketogenic diet increased serum levels of acetoacetate, leading to enhanced tumor growth potential of BRAF V600E-expressing human melanoma cells in xenograft mice. Treatment with hypolipidemic agents to lower circulating acetoacetate levels or an inhibitory homolog of acetoacetate, dehydroacetic acid, to antagonize acetoacetate-BRAF V600E binding attenuated BRAF V600E tumor growth. These findings reveal a signaling basis underlying a pathogenic role of dietary fat in BRAF V600E-expressing melanoma, providing insights into the design of conceptualized "precision diets" that may prevent or delay tumor progression based on an individual's specific oncogenic mutation profile.

23 Article Selective Internal Yttrium-90 Radioembolization Therapy (90Y-SIRT) Versus Best Supportive Care in Patients With Unresectable Metastatic Melanoma to the Liver Refractory to Systemic Therapy: Safety and Efficacy Cohort Study. 2017

Xing, Minzhi / Prajapati, Hasmukh J / Dhanasekaran, Renumathy / Lawson, David H / Kokabi, Nima / Eaton, Bree R / Kim, Hyun S. ·*Division of Interventional Radiology, Department of Radiology, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA †Interventional Radiology and Image-guided Medicine, Department of Radiology and Imaging Sciences Departments of ‡Hematology and Medical Oncology §Radiation Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA. ·Am J Clin Oncol · Pubmed #25089529.

ABSTRACT: OBJECTIVES: To investigate survival, efficacy, and safety of selective internal yttrium-90 radioembolization therapy (Y-SIRT) in patients with unresectable metastatic melanoma (MM) to liver refractory to systemic therapy. METHODS: An IRB-approved retrospective review of 58 patients diagnosed with unresectable MM to the liver, refractory to systemic therapy, between February 2003 and March 2012 was conducted. Of these, 28 received resin-based Y-SIRT (group A), and 30 patients received best supportive care (group B). Survival was calculated using the Kaplan-Meier method and Cox proportional hazard models. RESULTS: Groups A and B were similar for the Child-Pugh class, ECOG scores, age, sex, and race. Median overall survival (OS) from diagnosis of primary melanoma in groups A and B were 119.9 and 26.1 months, respectively (P<0.001). Median OS from hepatic metastasis in groups A and B were 19.9 and 4.8 months, respectively (P<0.0001). In group A, median OS from hepatic metastasis in the Child-Pugh A, B, and C patients was 37.7, 4.2, and 3.6 months, respectively (P<0.001). In group B, median OS from hepatic metastasis in the Child-Pugh A, B, and C patients was 7.8, 4.2, and 1.9 months, respectively (P=0.04). Within group A, median OS from first Y-SIRT was 10.1 months; median OS of the Child-Pugh A, B, and C patients from first Y-SIRT was 10.3, 1.2, and 0.9 months, respectively (P=0.04). Median OS from first Y-SIRT was significantly greater in the absence of diffuse (>10) liver metastases (15.1 vs. 4.7 mo, P=0.02), and in the absence of extrahepatic metastases (21.3 vs. 8.6 mo, P<0.001). Common clinical toxicities following Y-SIRT included abdominal pain (17.9%), fatigue (14.3%), and self-limiting grade III bilirubin toxicity (10.7%). CONCLUSION: For patients with unresectable MM to the liver refractory to systemic therapy, resin-based Y was associated with longer survival from liver metastases than best supportive care. Child-Pugh A patients with <10 metastatic lesions and absence of extrahepatic metastases demonstrated greatest survival following Y-SIRT.

24 Article Exogenous IL-2 Induces FoxP3+ Th17 Cells In Vivo in Melanoma Patients. 2016

Diller, Maggie L / Kudchadkar, Ragini R / Delman, Keith A / Lawson, David H / Ford, Mandy L. ·Departments of *Surgery †Hematology and Medical Oncology ‡Surgical Oncology, Winship Cancer Institute §Emory Transplant Center, Emory University, Atlanta, GA. ·J Immunother · Pubmed #27741090.

ABSTRACT: Th17 cells represent a distinct subset of CD4 effector T cells with potent pathogenic qualities, capable of directly mediating tumor cell destruction. IL-2 has frequently been shown to have a negative effect on Th17 differentiation while supporting regulatory T-cell (FoxP3CD4, TREG) growth and development in both in vitro models and in vivo animal models. We investigated the effect of in vivo IL-2 on both the Th17 and FoxP3CD4 T-cell compartments in a human model of cancer. High-dose IL-2 (HDIL-2) was administered at a dose of 720,000 IU/kg to patients with melanoma (n=7) and peripheral blood was collected at baseline and at 24, 48, 72, and 96 hours posttreatment. Peripheral blood mononuclear cells (PBMCs) were isolated and subjected to intracellular cytokine and extracellular receptor staining for flow cytometry. We report that HDIL-2 increased both frequencies and absolute numbers of Th17 cells on day 4 of treatment. The administration of HDIL-2 to patients with melanoma increased IL-6 production by peripheral immune cells, a cytokine vital in the downregulation of FoxP3 expression and expansion of the Th17-cell population. Furthermore, we demonstrated that FoxP3CD4 T cells express IL-17 in patients with melanoma undergoing HDIL-2 therapy. Taken together, our findings indicate that HDIL-2 combined with the conditions of malignancy create an immune environment supportive of Th17 differentiation and that expansion of this compartment may occur through the transdifferentiation of IL-17-secreting FoxP3CD4 T cells.

25 Article The influence of postoperative lymph node radiation therapy on overall survival of patients with stage III melanoma, a National Cancer Database analysis. 2016

Danish, Hasan H / Patel, Kirtesh R / Switchenko, Jeffrey M / Gillespie, Theresa W / Jhaveri, Jaymin / Chowdhary, Mudit / Abugideiri, Mustafa / Delman, Keith A / Lawson, David H / Khan, Mohammad K. ·aDepartment of Radiation Oncology bBiostatistics and Bioinformatics Shared Resource cDepartment of Surgery, Division of Surgical Oncology dDepartment of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia, USA. ·Melanoma Res · Pubmed #27575390.

ABSTRACT: Recently, TROG 02.01 results showed that in stage III melanoma patients with nodal metastasis, adjuvant radiation to lymph node basin after nodal dissection improves lymph node field relapse without an overall survival (OS) benefit. However, this trial was neither designed nor powered to detect an OS difference. In the present study, we analyzed patients in the National Cancer Database (NCDB) with stage III melanoma with pathologically involved nodes and compared survival outcomes of adjuvant radiation and no-radiation cohorts. Inclusion criteria were as follows: age at least 18 years; diagnosed 2003-2011; surgery to regional lymph nodes; pathologically involved lymph nodes; and American Joint Committee on Cancer stage (IIIA-C). We used propensity score matching analysis to compare the OS of patients with similar baseline demographic, clinical, and pathologic characteristics who received adjuvant radiation and no adjuvant radiation. Overall, 912 patients were analyzed with an average age at diagnosis of 54.4 years and a median follow-up time of 5.5 years. In this cohort, the 5-year OS was 69.0, 51.1, and 30.6% for stage IIIA, IIIB, and IIIC, respectively. On propensity score-adjusted multivariate analysis, we found that adjuvant radiation had no statistically significant impact on OS (hazard ratio: 1.09, 95% confidence interval: 0.75-1.58, P=0.640). Furthermore, age older than 60 years, number of nodes, increasing pathologic stage, and absence of immunotherapy correlated with worse OS. In this NCDB analysis, we found that the adjuvant radiotherapy for node-positive, stage III melanoma patients did not improve OS. This is consistent with TROG 02.01; however, there may be patient selection bias not accounted for by the NCDB.

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