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Melanoma: HELP
Articles from Indiana
Based on 140 articles published since 2008

These are the 140 published articles about Melanoma that originated from Indiana during 2008-2019.
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5 · 6
1 Review Optical coherence tomography imaging of melanoma skin cancer. 2019

Rajabi-Estarabadi, Ali / Bittar, Julie M / Zheng, Caiwei / Nascimento, Vanessa / Camacho, Isabella / Feun, Lynn G / Nasiriavanaki, Mohammadreza / Kunz, Michael / Nouri, Keyvan. ·Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA. · Indiana University School of Medicine, Indianapolis, IN, USA. · Georgetown University School of Medicine, Washington, DC, USA. ivc5@georgetown.edu. · Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA. · Department of Biomedical Engineering, Wayne State University, Detroit, MI, USA. · Department of Dermatology, College of Engineering and School of Medicine Wayne State University, Detroit, MI, USA. · Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA. · Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, USA. ·Lasers Med Sci · Pubmed #30539405.

ABSTRACT: No consensus guidelines exist on the use of optical coherence tomography (OCT) for diagnosis of cutaneous melanoma. The objectives of this review are to provide a descriptive review of the literature on characteristics of cutaneous melanomas seen on high-definition OCT (HD-OCT), speckle variance OCT (SV-OCT), and conventional OCT and to compare their diagnostic ability with that of histopathology. A review of PubMed and Google Scholar identified all available literature on OCT in melanoma skin cancer that included all in vivo and ex vivo studies on human or human tissues and excluded all studies on non-human subjects or animal studies. Two hundred nine abstracts were considered for evaluation, 31 abstracts were selected for manuscript review, and 14 abstracts were included that met all criteria. Diagnoses of MIS and MM using HD-OCT and SV-OCT were consistently reported to correlate with histopathology. However, accuracy of diagnosis using conventional OCT varied. Most authors agreed that it was difficult to differentiate MM from benign nevi using conventional OCT. HD-OCT, SV-OCT, and conventional OCT show promise for visualizing cutaneous melanoma. The use of OCT in diagnosis of melanoma is rarely reported in the literature. There is a need to increase and standardize reporting of OCT for diagnosis of cutaneous melanoma.

2 Review Systematic Review of Surgical Treatment and Outcomes After Local Surgery of Primary Cutaneous Melanomas of the Penis and Scrotum. 2018

Bittar, Julie M / Bittar, Peter G / Wan, Marilyn T / Kovell, Robert C / Guzzo, Thomas J / Shin, Thuzar M / Etzkorn, Jeremy R / Sobanko, Joseph F / Miller, Christopher J. ·Indiana University School of Medicine, Indianapolis, Indiana. · Duke University School of Medicine, Durham, North Carolina. · Department of Dermatology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania. · Department of Surgery, Division of Urology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania. ·Dermatol Surg · Pubmed #29985865.

ABSTRACT: BACKGROUND: Few data exist to guide surgical management and counseling about local recurrence after surgery of primary male genital melanoma. OBJECTIVE: To compile all available data on local recurrence rates after surgery of primary cutaneous melanoma of the penis and scrotum. MATERIALS AND METHODS: A systematic review of PubMed, Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS), Excerpta Medica database (EMBASE), and Web of Science identified all surgically treated penile and scrotal melanomas that reported local recurrence status and follow-up time. RESULTS: One hundred twenty-seven melanomas from 74 manuscripts were included. Eighty-six percent of melanomas were located on the penis, and 14% were located on the scrotum. Average follow-up time was 35.7 months. Scrotal melanomas were predominantly treated with organ-sparing surgeries (16/18, 88.9%), whereas penile melanomas were treated more often with amputation (61/109, 56.0%). Overall, local recurrence rate was 15.7% (20/127). Local recurrence rates for penile cases were 18.8% (9/48) after organ-sparing surgery versus 13.1% (8/61) for amputative surgery. Local recurrence rates were 66.7% (4/6) after positive surgical margins versus 10.2% (5/49) after negative surgical margins. CONCLUSION: Local recurrence rates are high after both organ-sparing and amputative surgery of primary cutaneous melanoma of the penis and scrotum. There is a need to standardize reporting for this rare tumor, as more complete data are necessary to develop consensus guidelines for surgical management of male genital melanoma.

3 Review Pigmented onychomatricoma: a rare mimic of subungual melanoma. 2018

Isales, M C / Haugh, A M / Bubley, J / Zarkhin, S / Bertler, D / Hanson, E / Verzi, A E / Brieva, J / Guitart, J / Gerami, P. ·Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. · Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. · Marian University College of Osteopathic Medicine, Indianapolis, IN, USA. · Forefront Dermatology, De Pere, WI, USA. ·Clin Exp Dermatol · Pubmed #29473193.

ABSTRACT: -- No abstract --

4 Review Molecular testing for BRAF mutations to inform melanoma treatment decisions: a move toward precision medicine. 2018

Cheng, Liang / Lopez-Beltran, Antonio / Massari, Francesco / MacLennan, Gregory T / Montironi, Rodolfo. ·Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA. · Unit of Anatomical Pathology, Faculty of Medicine, Cordoba University, Cordoba, Spain. · The Champalimaud Clinical Center, Lisbon, Portugal. · Division of Oncology, S. Orsola-Malpighi Hospital, Bologna, Italy. · Department of Pathology, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, OH, USA. · Institute of Pathological Anatomy and Histopathology, School of Medicine, Polytechnic University of the Marche Region (Ancona), United Hospitals, Ancona, Italy. ·Mod Pathol · Pubmed #29148538.

ABSTRACT: Approximately one-half of advanced (unresectable or metastatic) melanomas harbor a mutation in the BRAF gene, with V600E being the most common mutation. Targeted therapy with BRAF and MEK inhibitors is associated with significant long-term treatment benefit in patients with BRAF V600-mutated melanoma. Therefore, molecular testing for BRAF mutations is a priority in determining the course of therapy. A literature search was performed using MEDLINE/PubMed and scientific congress databases using the terms 'BRAF,' 'mutation,' and 'cancer/tumor.' These results were filtered to include manuscripts that focused on diagnostic tests for determining BRAF mutation status. Numerous BRAF testing methods were identified, including DNA-based companion diagnostic tests and DNA- and protein-based laboratory-developed tests. Herein we review the characteristics of each method and highlight the strengths and weaknesses that should be considered before use and when interpreting results for each patient. Molecular profiling has shown that mutation load increases with melanoma tumor progression and that unique patterns of genetic changes and evolutionary trajectories for different melanoma subtypes can occur. Discordance in the BRAF mutational status between primary and metastatic lesions, as well as intratumoral heterogeneity, is known to occur. Additionally, the development of acquired resistance to combination BRAF and MEK inhibitor therapy is still a formidable obstacle. Therefore, tumor heterogeneity and the development of acquired resistance have important implications for molecular testing and ultimately the treatment of patients with advanced-stage melanoma. Overall, this information may help community oncologists more accurately and effectively interpret results of diagnostic tests within the context of recent data characterizing melanoma tumor progression.

5 Review Assessing Tumor-Infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method from the International Immuno-Oncology Biomarkers Working Group: Part 2: TILs in Melanoma, Gastrointestinal Tract Carcinomas, Non-Small Cell Lung Carcinoma and Mesothelioma, Endometrial and Ovarian Carcinomas, Squamous Cell Carcinoma of the Head and Neck, Genitourinary Carcinomas, and Primary Brain Tumors. 2017

Hendry, Shona / Salgado, Roberto / Gevaert, Thomas / Russell, Prudence A / John, Tom / Thapa, Bibhusal / Christie, Michael / van de Vijver, Koen / Estrada, M V / Gonzalez-Ericsson, Paula I / Sanders, Melinda / Solomon, Benjamin / Solinas, Cinzia / Van den Eynden, Gert G G M / Allory, Yves / Preusser, Matthias / Hainfellner, Johannes / Pruneri, Giancarlo / Vingiani, Andrea / Demaria, Sandra / Symmans, Fraser / Nuciforo, Paolo / Comerma, Laura / Thompson, E A / Lakhani, Sunil / Kim, Seong-Rim / Schnitt, Stuart / Colpaert, Cecile / Sotiriou, Christos / Scherer, Stefan J / Ignatiadis, Michail / Badve, Sunil / Pierce, Robert H / Viale, Giuseppe / Sirtaine, Nicolas / Penault-Llorca, Frederique / Sugie, Tomohagu / Fineberg, Susan / Paik, Soonmyung / Srinivasan, Ashok / Richardson, Andrea / Wang, Yihong / Chmielik, Ewa / Brock, Jane / Johnson, Douglas B / Balko, Justin / Wienert, Stephan / Bossuyt, Veerle / Michiels, Stefan / Ternes, Nils / Burchardi, Nicole / Luen, Stephen J / Savas, Peter / Klauschen, Frederick / Watson, Peter H / Nelson, Brad H / Criscitiello, Carmen / O'Toole, Sandra / Larsimont, Denis / de Wind, Roland / Curigliano, Giuseppe / André, Fabrice / Lacroix-Triki, Magali / van de Vijver, Mark / Rojo, Federico / Floris, Giuseppe / Bedri, Shahinaz / Sparano, Joseph / Rimm, David / Nielsen, Torsten / Kos, Zuzana / Hewitt, Stephen / Singh, Baljit / Farshid, Gelareh / Loibl, Sibylle / Allison, Kimberly H / Tung, Nadine / Adams, Sylvia / Willard-Gallo, Karen / Horlings, Hugo M / Gandhi, Leena / Moreira, Andre / Hirsch, Fred / Dieci, Maria V / Urbanowicz, Maria / Brcic, Iva / Korski, Konstanty / Gaire, Fabien / Koeppen, Hartmut / Lo, Amy / Giltnane, Jennifer / Rebelatto, Marlon C / Steele, Keith E / Zha, Jiping / Emancipator, Kenneth / Juco, Jonathan W / Denkert, Carsten / Reis-Filho, Jorge / Loi, Sherene / Fox, Stephen B. ·Departments of *Pathology §§§Medical Oncology, Peter MacCallum Cancer Centre, Melbourne †The Sir Peter MacCallum Department of Oncology Departments of **Pathology ∥∥Medicine, University of Melbourne ¶¶Department of Anatomical Pathology, Royal Melbourne Hospital, Parkville #Department of Anatomical Pathology, St Vincent's Hospital Melbourne, Fitzroy ††Department of Medical Oncology, Austin Health ‡‡Olivia Newton-John Cancer Research Institute, Heidelberg §§School of Cancer Medicine, La Trobe University, Bundoora §§§§§Centre for Clinical Research and School of Medicine, The University of Queensland ∥∥∥∥∥Pathology Queensland, Royal Brisbane and Women's Hospital, Brisbane §§§§§§§§§§The Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst ∥∥∥∥∥∥∥∥∥∥Australian Clinical Labs, Bella Vista ‡‡‡‡‡‡‡‡‡‡‡‡Directorate of Surgical Pathology, SA Pathology §§§§§§§§§§§§Discipline of Medicine, Adelaide University, Adelaide, Australia ***********Department of Surgical Oncology, Netherlands Cancer Institute †††††††††††††Department of Pathology ##Divisions of Diagnostic Oncology & Molecular Pathology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, The Netherlands ###Université Paris-Est ****INSERM, UMR 955 ††††Département de pathologie, APHP, Hôpital Henri-Mondor, Créteil ∥∥∥∥∥∥∥∥∥Service de Biostatistique et d'Epidémiologie, Gustave Roussy, CESP, Inserm U1018, Université-Paris Sud, Université Paris-Saclay ¶¶¶¶¶¶¶¶¶¶INSERM Unit U981, and Department of Medical Oncology, Gustave Roussy, Villejuif ##########Faculté de Médecine, Université Paris Sud, Kremlin-Bicêtre †††††††Department of Surgical Pathology and Biopathology, Jean Perrin Comprehensive Cancer Centre ‡‡‡‡‡‡‡University of Auvergne UMR1240, Clermont-Ferrand, France ‡‡‡‡Department of Medicine, Clinical Division of Oncology §§§§Institute of Neurology, Comprehensive Cancer Centre Vienna, Medical University of Vienna, Vienna ††††††††††††††Institute of Pathology, Medical University of Graz, Austria ∥∥∥∥European Institute of Oncology ¶¶¶¶School of Medicine ######Department of Pathology, Istituto Europeo di Oncologia, University of Milan, Milan ¶¶¶¶¶¶¶¶¶¶¶¶¶Department of Surgery, Oncology and Gastroenterology, University of Padova #############Medical Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy †††††Molecular Oncology Group, Vall d'Hebron Institute of Oncology, Barcelona †††††††††††Pathology Department, IIS-Fundacion Jimenez Diaz, UAM, Madrid, Spain §Department of Pathology and TCRU, GZA ¶¶¶Department of Pathology, GZA Ziekenhuizen, Antwerp ∥Laboratory of Experimental Urology, Department of Development and Regeneration, KU Leuven ‡‡‡‡‡‡‡‡‡‡‡Department of Pathology, University Hospital Leuven, Leuven, Belgium ¶Department of Pathology, AZ Klina, Brasschaat ††††††Department of Pathology, GZA Ziekenhuizen, Sint-Augustinus, Wilrijk ∥∥∥Molecular Immunology Unit ‡‡‡‡‡‡Department of Medical Oncology, Institut Jules Bordet, Université Libre de Bruxelles ‡Breast Cancer Translational Research Laboratory/Breast International Group, Institut Jules Bordet **************European Organisation for Research and Treatment of Cancer (EORTC) Headquarters *******Department of Pathology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium §§§§§§§Department of Surgery, Kansai Medical School, Hirakata, Japan #######Severance Biomedical Science Institute and Department of Medical Oncology, Yonsei University College of Medicine, Seoul, South Korea ∥∥∥∥∥∥∥∥Tumor Pathology Department, Maria Sklodowska-Curie Memorial Cancer Center ¶¶¶¶¶¶¶¶Institute of Oncology, Gliwice Branch, Gliwice, Poland ‡‡‡‡‡‡‡‡‡‡‡‡‡‡Pathology and Tissue Analytics, Roche Innovation Centre Munich, Penzberg †††††††††Institute of Pathology, Charité Universitätsmedizin Berlin ‡‡‡‡‡‡‡‡‡VMscope GmbH, Berlin ¶¶¶¶¶¶¶¶¶German Breast Group GmbH, Neu-Isenburg, Germany **********Trev & Joyce Deeley Research Centre, British Columbia Cancer Agency ††††††††††Department of Biochemistry and Microbiology, University of Victoria, Victoria Departments of ‡‡‡‡‡‡‡‡‡‡Medical Genetics #########Pathology and Laboratory Medicine ¶¶¶¶¶¶¶¶¶¶¶Department of Pathology and Laboratory Medicine, Genetic Pathology Evaluation Centre, University of British Columbia, Vancouver, BC ###########Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Canada §§§§§§§§§§§Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Doha, Qatar ‡‡‡‡‡‡‡‡Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center §§§§§§§§Warren Alpert Medical School of Brown University, Providence ¶¶¶¶¶National Surgical Adjuvant Breast and Bowel Project Operations Center/NRG Oncology, Pittsburgh, PA †††Breast Cancer Research Program, Vanderbilt Ingram Cancer Center, Vanderbilt University Departments of ‡‡‡Pathology, Microbiology and Immunology ########Department of Medicine, Vanderbilt University Medical Centre *********Vanderbilt Ingram Cancer Center, Nashville §§§§§§§§§Department of Pathology, Yale University School of Medicine, New Haven ∥∥∥∥∥∥∥∥∥∥∥Department of Oncology, Montefiore Medical Centre, Albert Einstein College of Medicine ∥∥∥∥∥∥∥Montefiore Medical Center ¶¶¶¶¶¶¶The Albert Einstein College of Medicine, Bronx, NY ********Department of Pathology, Brigham and Women's Hospital #####Cancer Research Institute and Department of Pathology, Beth Israel Deaconess Cancer Center ******Harvard Medical School ¶¶¶¶¶¶¶¶¶¶¶¶Division of Hematology-Oncology, Beth Israel Deaconess Medical Center ††††††††Department of Cancer Biology ‡‡‡‡‡‡‡‡‡‡‡‡‡Dana-Farber Cancer Institute, Boston, MA ∥∥∥∥∥∥∥∥∥∥∥∥∥Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO ‡‡‡‡‡Department of Cancer Biology, Mayo Clinic, Jacksonville, FL ∥∥∥∥∥∥Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, IN ¶¶¶¶¶¶Cancer Immunotherapy Trials Network, Central Laboratory and Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA ††††††††††††Department of Pathology, New York University Langone Medical Centre ############New York University Medical School *************Perlmutter Cancer Center §§§§§§§§§§§§§Pulmonary Pathology, New York University Center for Biospecimen Research and Development, New York University ***************Department of Pathology, Memorial Sloan-Kettering Cancer Center ####Departments of Radiation Oncology and Pathology, Weill Cornell Medicine, New York, NY *****Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston, TX ∥∥∥∥∥∥∥∥∥∥∥∥Pathology Department, Stanford University Medical Centre, Stanford ∥∥∥∥∥∥∥∥∥∥∥∥∥∥Department of Pathology, Stanford University, Palo Alto ***Department of Pathology, School of Medicine, University of California, San Diego §§§§§§§§§§§§§§Research Pathology, Genentech Inc., South San Francisco, CA *************Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda ¶¶¶¶¶¶¶¶¶¶¶¶¶¶Translational Sciences, MedImmune, Gaithersberg, MD §§§§§§Academic Medical Innovation, Novartis Pharmaceuticals Corporation, East Hanover ##############Translational Medicine, Merck & Co. Inc., Kenilworth, NJ. ·Adv Anat Pathol · Pubmed #28777143.

ABSTRACT: Assessment of the immune response to tumors is growing in importance as the prognostic implications of this response are increasingly recognized, and as immunotherapies are evaluated and implemented in different tumor types. However, many different approaches can be used to assess and describe the immune response, which limits efforts at implementation as a routine clinical biomarker. In part 1 of this review, we have proposed a standardized methodology to assess tumor-infiltrating lymphocytes (TILs) in solid tumors, based on the International Immuno-Oncology Biomarkers Working Group guidelines for invasive breast carcinoma. In part 2 of this review, we discuss the available evidence for the prognostic and predictive value of TILs in common solid tumors, including carcinomas of the lung, gastrointestinal tract, genitourinary system, gynecologic system, and head and neck, as well as primary brain tumors, mesothelioma and melanoma. The particularities and different emphases in TIL assessment in different tumor types are discussed. The standardized methodology we propose can be adapted to different tumor types and may be used as a standard against which other approaches can be compared. Standardization of TIL assessment will help clinicians, researchers and pathologists to conclusively evaluate the utility of this simple biomarker in the current era of immunotherapy.

6 Review Skin cancer prevention practices among malignant melanoma survivors: a systematic review. 2016

Nahar, Vinayak K / Allison Ford, M / Brodell, Robert T / Boyas, Javier F / Jacks, Stephanie K / Biviji-Sharma, Rizwana / Haskins, Mary A / Bass, Martha A. ·Department of Health, Exercise Science and Recreation Management, The University of Mississippi, 215 Turner Center, PO Box 1848, University, MS, 38677, USA. vknahar@go.olemiss.edu. · Department of Dermatology, University of Mississippi Medical Center, 2500 N., State St., Jackson, MS, 39216, USA. vknahar@go.olemiss.edu. · Department of Health, Exercise Science and Recreation Management, The University of Mississippi, 215 Turner Center, PO Box 1848, University, MS, 38677, USA. · Department of Dermatology, University of Mississippi Medical Center, 2500 N., State St., Jackson, MS, 39216, USA. · Department of Pathology, University of Mississippi Medical Center, 2500 N., State St., Jackson, MS, 39216, USA. · Department of Dermatology, University of Rochester School of Medicine and Dentistry, Rochester, NY, 14642, USA. · Department of Social Work, University of Mississippi, 208 Longstreet Hall, PO Box 1848, Oxford, MS, 38677, USA. · Department of Health Policy and Management, Richard M. Fairbanks School of Public Health, Indiana University, IUPUI, 714 N. Senate Ave, Suite 250, Indianapolis, IN, 46202, USA. ·J Cancer Res Clin Oncol · Pubmed #26642962.

ABSTRACT: PURPOSE: This systematic review was conducted to evaluate and summarize the existing literature on prevalence of ultraviolet radiation (UVR) exposure, sun protection, and screening behaviors among individuals diagnosed with malignant melanoma (MM). METHODS: The search was performed in PubMed, CINAHL, PsycINFO, ScienceDirect, EMBASE, and ERIC from inception of each database through July 2014. Studies were included if (1) individuals diagnosed with MM were the primary sample, (2) measured UVR exposure, primary and secondary preventive behaviors, (3) original research communication that constitutes an entire set of empirical data, (4) observational design, and (5) English peer-reviewed. Studies were excluded if (1) all of the inclusion criteria were not met and (2) duplicates, conference abstracts, editorials, news, letters to the editor, comments, reviews, feature articles, white papers, and guidelines. RESULTS: The search resulted in 255 articles that were screened for relevance; however, only 15 articles met all of the inclusion criteria. Most of the studies were cross-sectional (n = 10), used self-administered surveys (n = 8), and were conducted in North America (n = 10). The sample sizes ranged considerably, but were mostly Caucasian (n = 6) and included a higher proportion of women (n = 8). Evidence demonstrated that individuals with MM still engaged in sunbathing, indoor tanning, and reported sunburns. Moreover, survivors reported inadequate levels of both sun protection and skin self-examinations. CONCLUSIONS: The findings highlight the need for intensifying intervention strategies to reduce the risk of new primary MMs in this group. Future research should increase in rigor and include more diverse populations and regions.

7 Review Current applications of molecular genetic technologies to the diagnosis and treatment of cutaneous melanocytic neoplasms. 2013

Zulfiqar, Muhammad / Thompson, Andrew David. ·Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, 350 West 11th Street, Indianapolis, IN 46202-3082, USA. ·Clin Lab Med · Pubmed #24267193.

ABSTRACT: Decades of research have brought knowledge to a point where physicians are beginning to understand human disease processes like oncogenesis on a molecular level. Molecular technologies are now being applied to current clinical settings such as the diagnosis and treatment of cutaneous melanocytic neoplasms. In particular, dermatopathologists are using fluorescence in situ hybridization to aid in the diagnosis of challenging melanocytic neoplasms. Pathologists are working with oncologists to use the sequences of specific genes in melanomas to choose more effective treatments. This article discusses how these technologies are altering the ways in which cutaneous melanocytic neoplasms are diagnosed and treated.

8 Review Towards personalized therapy for patients with malignant melanoma: molecular insights into the biology of BRAF mutations. 2013

Bradish, Joshua R / Montironi, Rodolfo / Lopez-Beltran, Antonio / Post, Kristin M / MacLennan, Gregory T / Cheng, Liang. ·Department of Pathology & Laboratory Medicine, Indiana University School of Medicine, IU Health Pathology Laboratory, 350 W. 11th St, 4th Floor, Indianapolis, IN 46202, USA. ·Future Oncol · Pubmed #23414474.

ABSTRACT: BRAF mutations have been identified as the most common oncogene mutation in melanomas, especially important in those originating on nonchronically sun-damaged skin. There is a large and continually growing body of evidence regarding the importance of this mutation in targeted therapy for melanoma. In this review, we outline these findings including: molecular pathways used by BRAF, the importance in nonmalignant neoplasms, histologic associations, the relationship of BRAF to KIT and NRAS mutations, and their impact on survival, as well as resistance mechanisms to BRAF inhibitors employed by melanoma. Understanding these topics and how they relate to one another may facilitate the development of new treatments and eventually improve the prognosis for those patients afflicted with this disease.

9 Review Malignant melanoma in transplant patients: a case report and review of the literature. 2012

Sullivan, A Nichole / Bryant, Elizabeth A / Mark, Lawrence A. ·University of Notre Dame, Indiana, USA. ·Cutis · Pubmed #22530331.

ABSTRACT: The clinical course and outcome of malignant melanoma (MM) are well-established for immunocompetent groups; however, they are not well-documented for immunosuppressed populations. Specifically, the influence of immunosuppression may result in poorer outcomes, especially in more advanced cases of melanoma. We report a 67-year-old woman who had previously undergone a kidney and pancreas transplant and presented with American Joint Committee on Cancer (AJCC) stage IIIA melanoma with subsequent rapid demise. As medicine advances with greater numbers of organ transplant recipients, a multi-institutional prospective study for this at-risk population would be greatly beneficial to help characterize the incidence, progression, and prognosis of melanoma in posttransplant immunosuppressed populations.

10 Review Cutaneous malignancy in adolescents. 2011

Turvy, Diane N / Mark, Lawrence A. ·Indiana University School of Medicine, Indianapolis, IN, USA. ·Adolesc Med State Art Rev · Pubmed #21815444.

ABSTRACT: There is compelling epidemiologic evidence that cutaneous malignancies, most notably malignant melanoma and cutaneous T-cell lymphoma, are increasing in incidence. The adolescent population is also affected by this rise in incidence, but can represent both a unique diagnostic and therapeutic challenge. Herein we present up-to-date epidemiology, clinical presentation, risk factors for development, and management options for malignant melanoma, basal cell carcinoma, squamous cell carcinoma, and cutaneous T-cell lymphoma as each pertains to the adolescent population. Prevention in this age group is particularly addressed. One unifying theme that emerges is that a high degree of clinical suspicion and vigilance must be maintained to recognize these entities early on in their presentations.

11 Review Ocular melanocytic neoplasia. 2008

Finn, Michael / Krohne, Sheryl / Stiles, Jean. ·Purdue University. ·Compend Contin Educ Vet · Pubmed #18278744.

ABSTRACT: Tumors of melanocytic origin in ocular tissues are relatively uncommon in dogs and cats, and although many are benign, some have a high potential for metastasis. In addition, even small ocular masses can be significant due to their potential vision-threatening sequelae. Such tumors may occur on the eyelids, on the conjunctival surface, along the limbus, or within the uveal tract. While several similarities exist among these tumors, the prognosis and recommended treatment options vary based on the species affected as well as the location, extent, and histologic characteristics of the tumor. This article reviews the clinical presentation, biologic behavior, and treatment options for eyelid, conjunctival, limbal (epibulbar), and uveal tumors of melanocytic origin in dogs and cats.

12 Clinical Trial Improved survival and tumor control with Interleukin-2 is associated with the development of immune-related adverse events: data from the PROCLAIM 2017

Curti, Brendan / Daniels, Gregory A / McDermott, David F / Clark, Joseph I / Kaufman, Howard L / Logan, Theodore F / Singh, Jatinder / Kaur, Meenu / Luna, Theresa L / Gregory, Nancy / Morse, Michael A / Wong, Michael K K / Dutcher, Janice P. ·Providence Portland Medical Center, 4805 NE Glisan Street, Portland, OR, 97213, USA. · Moores Cancer Center, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA. · Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA, 02215, USA. · Loyola University Medical Center, 2160 S First Avenue, Maywood, IL, 60153, USA. · Rutgers Cancer Center Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ, 08901, USA. · Indiana University Simon Cancer Center, 535 Barnhill Drive, Indianapolis, 46202, USA. · Primary Biostatistical Solutions, 2042 Carnarvon Ct, Victoria, BC, V8R2V3, Canada. · Prometheus Laboratories, 9410 Carroll Park Drive, San Diego, CA, 92121, USA. · Duke University Medical Center, 2301 Erwin Road, Durham, NC, 27705, USA. · MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA. · Cancer Research Foundation of NY, 43 Longview Lane, Chappaqua, NY, 10514, USA. jpd4401@aol.com. ·J Immunother Cancer · Pubmed #29254506.

ABSTRACT: BACKGROUND: Immune related adverse events (irAEs) are associated with immunotherapy for cancer and while results suggest improvement in tumor control and overall survival in those experiencing irAEs, the long-term impact is debated. We evaluated irAE reports related to high dose interleukin-2 therapy (IL-2) documented in the PROCLAIM METHODS: Reports on 1535 patients, including 623 with metastatic melanoma (mM) and 919 with metastatic renal cell cancer (mRCC) (7 patients had both diseases), were queried for irAEs. The timing of the event was categorized as occurring before, during or after IL-2 or related to any checkpoint inhibitor (CPI). mM patients and mRCC patients were analyzed separately. Tumor control [complete + partial response + stable disease (CR + PR + SD) was compared between those experiencing no irAE versus those with the development of irAEs. Survival was analyzed by tumor type related to timing of irAE and IL-2, and in those with or without exposure to CPI. RESULTS: Median follow-up was 3.5+ years (range 1-8+ years), 152 irAEs were reported in 130 patients (8.4% of all PROCLAIM CONCLUSIONS: irAEs following IL-2 therapy are associated with improved tumor control and overall survival. IrAEs resulting from IL-2 and from CPIs are qualitatively different, and likely reflect different mechanisms of action of immune activation and response.

13 Clinical Trial Long-Term Survival after Complete Surgical Resection and Adjuvant Immunotherapy for Distant Melanoma Metastases. 2017

Faries, Mark B / Mozzillo, Nicola / Kashani-Sabet, Mohammed / Thompson, John F / Kelley, Mark C / DeConti, Ronald C / Lee, Jeffrey E / Huth, James F / Wagner, Jeffrey / Dalgleish, Angus / Pertschuk, Daniel / Nardo, Christopher / Stern, Stacey / Elashoff, Robert / Gammon, Guy / Morton, Donald L / Anonymous10680923. ·John Wayne Cancer Institute, Santa Monica, CA, USA. mfaries@theangelesclinic.org. · Istituto Nazionale dei Tumori de Napoli, Naples, Italy. · Mt. Zion Medical Center, University of California, San Francisco, San Francisco, CA, USA. · Royal Prince Alfred Hospital, Sydney, Australia. · Vanderbilt University, Nashville, TN, USA. · H. Lee Moffitt Cancer Center, Tampa, FL, USA. · MD Anderson Cancer Center, Houston, TX, USA. · Southwestern Medical Center at Dallas, University of Texas, Dallas, TX, USA. · Wagner & Associates, Indianapolis, IN, USA. · St. George's Hospital Medical School, London, Great Britain. · CancerVax Corp, Carlsbad, CA, USA. · John Wayne Cancer Institute, Santa Monica, CA, USA. · UCLA Life Sciences, Biomathematics, Los Angeles, CA, USA. ·Ann Surg Oncol · Pubmed #29019177.

ABSTRACT: BACKGROUND: This phase III study was undertaken to evaluate the efficacy of an allogeneic whole-cell vaccine (Canvaxin™) plus bacillus Calmette-Guerin (BCG) after complete resection of stage IV melanoma. METHODS: After complete resection of ≤5 distant metastases, patients were randomly assigned to BCG+Canvaxin (BCG/Cv) or BCG+placebo (BCG/Pl). The primary endpoint was overall survival (OS); secondary endpoints were disease-free survival (DFS), and immune response measured by skin test (ClinicalTrials.gov identifier: NCT00052156). RESULTS: Beginning in May 1998, 496 patients were randomized. In April 2005, the Data Safety Monitoring Board recommended stopping enrollment due to a low probability of efficacy. At that time, median OS and 5-year OS rate were 38.6 months and 44.9%, respectively, for BCG/Pl versus 31.4 months and 39.6% in the BCG/Cv group (hazard ratio (HR), 1.18; p = 0.250). Follow-up was extended at several trial sites through March 2010. Median OS and 5-year and 10-year survival was 39.1 months, 43.3 and 33.3%, respectively, for BCG/Pl versus 34.9 months, 42.5 and 36.4%, in the BCG/Cv group (HR 1.053; p = 0.696). Median DFS, 5- and 10-year DFS were 7.6 months, 23.8 and 21.7%, respectively, for BCG/Pl versus 8.5 months, 30.0%, and 30.0%, respectively, for the BCG/Cv group (HR 0.882; p = 0.260). Positive DTH skin testing correlated with increased survival. DISCUSSION: In this, the largest study of postsurgical adjuvant therapy for stage IV melanoma reported to date, BCG/Cv did not improve outcomes over BCG/placebo. Favorable long-term survival among study patients suggests that metastasectomy should be considered for selected patients with stage IV melanoma.

14 Clinical Trial Results from an Integrated Safety Analysis of Urelumab, an Agonist Anti-CD137 Monoclonal Antibody. 2017

Segal, Neil H / Logan, Theodore F / Hodi, F Stephen / McDermott, David / Melero, Ignacio / Hamid, Omid / Schmidt, Henrik / Robert, Caroline / Chiarion-Sileni, Vanna / Ascierto, Paolo A / Maio, Michele / Urba, Walter J / Gangadhar, Tara C / Suryawanshi, Satyendra / Neely, Jaclyn / Jure-Kunkel, Maria / Krishnan, Suba / Kohrt, Holbrook / Sznol, Mario / Levy, Ronald. ·Memorial Sloan Kettering Cancer Center, New York, New York. · Indiana University Simon Cancer Center, Indianapolis, Indiana. · Dana-Farber Cancer Institute, Boston, Massachusetts. · Beth Israel Deaconess Medical Center, Boston, Massachusetts. · Clinica Universidad de Navarra, Pamplona, Spain. · The Angeles Clinic and Research Institute, Los Angeles, California. · Aarhus University Hospital, Aarhus, Denmark. · Gustave Roussy and Paris-Sud University Villejuif, Villejuif, France. · Istituto Oncologico Veneto, Padua, Italy. · Istituto Nazionale Tumori Fondazione "G. Pascale," Naples, Italy. · University Hospital of Siena, Siena, Italy. · Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, Oregon. · Abramson Cancer Center of the University of Pennsylvania, Philadelphia, Pennsylvania. · Bristol-Myers Squibb, Princeton, New Jersey. · Stanford University School of Medicine, Stanford, California. · Yale Comprehensive Cancer Center, New Haven, Connecticut. · Stanford University School of Medicine, Stanford, California. levy@stanford.edu. ·Clin Cancer Res · Pubmed #27756788.


15 Clinical Trial Sequential administration of nivolumab and ipilimumab with a planned switch in patients with advanced melanoma (CheckMate 064): an open-label, randomised, phase 2 trial. 2016

Weber, Jeffrey S / Gibney, Geoff / Sullivan, Ryan J / Sosman, Jeffrey A / Slingluff, Craig L / Lawrence, Donald P / Logan, Theodore F / Schuchter, Lynn M / Nair, Suresh / Fecher, Leslie / Buchbinder, Elizabeth I / Berghorn, Elmer / Ruisi, Mary / Kong, George / Jiang, Joel / Horak, Christine / Hodi, F Stephen. ·New York University Langone Medical Center, New York, NY, USA; H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. · H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, USA. · Massachusetts General Hospital, Boston, MA, USA. · Vanderbilt-Ingram Cancer Center, Nashville, TN, USA. · University of Virginia School of Medicine, Charlottesville, VA, USA. · Indiana University Simon Cancer Center, Indianapolis, IN, USA. · University of Pennsylvania, Philadelphia, PA, USA. · Lehigh Valley Health Network, Allentown, PA, USA. · Indiana University Simon Cancer Center, Indianapolis, IN, USA; University of Michigan, Ann Arbor, MI, USA. · Beth Israel Deaconess Medical Center, Boston, MA, USA. · Bristol-Myers Squibb, Princeton, NJ, USA. · Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address: stephen_hodi@dfci.harvard.edu. ·Lancet Oncol · Pubmed #27269740.

ABSTRACT: BACKGROUND: Concurrent administration of the immune checkpoint inhibitors nivolumab and ipilimumab has shown greater efficacy than either agent alone in patients with advanced melanoma, albeit with more high-grade adverse events. We assessed whether sequential administration of nivolumab followed by ipilimumab, or the reverse sequence, could improve safety without compromising efficacy. METHODS: We did this randomised, open-label, phase 2 study at nine academic medical centres in the USA. Eligible patients (aged ≥18 years) with unresectable stage III or IV melanoma (treatment-naive or who had progressed after no more than one previous systemic therapy, with an Eastern Cooperative Oncology Group performance status of 0 or 1) were randomly assigned (1:1) to induction with intravenous nivolumab 3 mg/kg every 2 weeks for six doses followed by a planned switch to intravenous ipilimumab 3 mg/kg every 3 weeks for four doses, or the reverse sequence. Randomisation was done by an independent interactive voice response system with a permuted block schedule (block size four) without stratification factors. After induction, both groups received intravenous nivolumab 3 mg/kg every 2 weeks until progression or unacceptable toxicity. The primary endpoint was treatment-related grade 3-5 adverse events until the end of the induction period (week 25), analysed in the as-treated population. Secondary endpoints were the proportion of patients who achieved a response at week 25 and disease progression at weeks 13 and 25. Overall survival was a prespecified exploratory endpoint. This study is registered with ClinicalTrials.gov, number NCT01783938, and is ongoing but no longer enrolling patients. FINDINGS: Between April 30, 2013, and July 21, 2014, 140 patients were enrolled and randomly assigned to nivolumab followed by ipilimumab (n=70) or to the reverse sequence of ipilimumab followed by nivolumab (n=70), of whom 68 and 70 patients, respectively, received at least one dose of study drug and were included in the analyses. The frequencies of treatment-related grade 3-5 adverse events up to week 25 were similar in the nivolumab followed by ipilimumab group (34 [50%; 95% CI 37·6-62·4] of 68 patients) and in the ipilimumab followed by nivolumab group (30 [43%; 31·1-55·3] of 70 patients). The most common treatment-related grade 3-4 adverse events during the whole study period were colitis (ten [15%]) in the nivolumab followed by ipilimumab group vs 14 [20%] in the reverse sequence group), increased lipase (ten [15%] vs 12 [17%]), and diarrhoea (eight [12%] vs five [7%]). No treatment-related deaths occurred. The proportion of patients with a response at week 25 was higher with nivolumab followed by ipilimumab than with the reverse sequence (28 [41%; 95% CI 29·4-53·8] vs 14 [20%; 11·4-31·3]). Progression was reported in 26 (38%; 95% CI 26·7-50·8) patients in the nivolumab followed by ipilimumab group and 43 (61%; 49·0-72·8) patients in the reverse sequence group at week 13 and in 26 (38%; 26·7-50·8) and 42 (60%; 47·6-71·5) patients at week 25, respectively. After a median follow-up of 19·8 months (IQR 12·8-25·7), median overall survival was not reached in the nivolumab followed by ipilimumab group (95% CI 23·7-not reached), whereas over a median follow-up of 14·7 months (IQR 5·6-23·9) in the ipilimumab followed by nivolumab group, median overall survival was 16·9 months (95% CI 9·2-26·5; HR 0·48 [95% CI 0·29-0·80]). A higher proportion of patients in the nivolumab followed by ipilimumab group achieved 12-month overall survival than in the ipilimumab followed by nivolumab group (76%; 95% CI 64-85 vs 54%; 42-65). INTERPRETATION: Nivolumab followed by ipilimumab appears to be a more clinically beneficial option compared with the reverse sequence, albeit with a higher frequency of adverse events. FUNDING: Bristol-Myers Squibb.

16 Clinical Trial Combination of vemurafenib and cobimetinib in patients with advanced BRAF(V600)-mutated melanoma: a phase 1b study. 2014

Ribas, Antoni / Gonzalez, Rene / Pavlick, Anna / Hamid, Omid / Gajewski, Thomas F / Daud, Adil / Flaherty, Lawrence / Logan, Theodore / Chmielowski, Bartosz / Lewis, Karl / Kee, Damien / Boasberg, Peter / Yin, Ming / Chan, Iris / Musib, Luna / Choong, Nicholas / Puzanov, Igor / McArthur, Grant A. ·Jonsson Comprehensive Cancer Center at University of California, Los Angeles, CA, USA. · University of Colorado Comprehensive Cancer Center, Aurora, CO, USA. · New York University Medical Center, New York, NY, USA. · The Angeles Clinic and Research Institute, Los Angeles, CA, USA. · University of Chicago, Chicago, IL, USA. · Hematology/Oncology Division, University of California, San Francisco, CA, USA. · Karmanos Cancer Institute, Detroit, MI, USA. · Indiana University, Indianapolis, IN, USA. · Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. · Genentech, South San Francisco, CA, USA. · Vanderbilt-Ingram Cancer Center, Nashville, TN, USA. · Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Electronic address: grant.mcarthur@petermac.org. ·Lancet Oncol · Pubmed #25037139.

ABSTRACT: BACKGROUND: Addition of a MEK inhibitor to a BRAF inhibitor enhances tumour growth inhibition, delays acquired resistance, and abrogates paradoxical activation of the MAPK pathway in preclinical models of BRAF-mutated melanoma. We assessed the safety and efficacy of combined BRAF inhibition with vemurafenib and MEK inhibition with cobimetinib in patients with advanced BRAF-mutated melanoma. METHODS: We undertook a phase 1b study in patients with advanced BRAF(V600)-mutated melanoma. We included individuals who had either recently progressed on vemurafenib or never received a BRAF inhibitor. In the dose-escalation phase of our study, patients received vemurafenib 720 mg or 960 mg twice a day continuously and cobimetinib 60 mg, 80 mg, or 100 mg once a day for either 14 days on and 14 days off (14/14), 21 days on and 7 days off (21/7), or continuously (28/0). The primary endpoint was safety of the drug combination and to identify dose-limiting toxic effects and the maximum tolerated dose. Efficacy was a key secondary endpoint. All patients treated with vemurafenib and cobimetinib were included in safety and efficacy analyses (intention-to-treat). The study completed accrual and all analyses are final. This study is registered with ClinicalTrials.gov, number NCT01271803. FINDINGS: 129 patients were treated at ten dosing regimens combining vemurafenib and cobimetinib: 66 had recently progressed on vemurafenib and 63 had never received a BRAF inhibitor. Dose-limiting toxic effects arose in four patients. One patient on a schedule of vemurafenib 960 mg twice a day and cobimetinib 80 mg once a day 14/14 had grade 3 fatigue for more than 7 days; one patient on a schedule of vemurafenib 960 mg twice a day and cobimetinib 60 mg once a day 21/7 had a grade 3 prolongation of QTc; and two patients on a schedule of vemurafenib 960 mg twice a day and cobimetinib 60 mg 28/0 had dose-limiting toxic effects-one developed grade 3 stomatitis and fatigue and one developed arthralgia and myalgia. The maximum tolerated dose was established as vemurafenib 960 mg twice a day in combination with cobimetinib 60 mg 21/7. Across all dosing regimens, the most common adverse events were diarrhoea (83 patients, 64%), non-acneiform rash (77 patients, 60%), liver enzyme abnormalities (64 patients, 50%), fatigue (62 patients, 48%), nausea (58 patients, 45%), and photosensitivity (52 patients, 40%). Most adverse events were mild-to-moderate in severity. The most common grade 3 or 4 adverse events were cutaneous squamous-cell carcinoma (12 patients, 9%; all grade 3), raised amounts of alkaline phosphatase (11 patients, 9%]), and anaemia (nine patients, 7%). Confirmed objective responses were recorded in ten (15%) of 66 patients who had recently progressed on vemurafenib, with a median progression-free survival of 2·8 months (95% CI 2·6-3·4). Confirmed objective responses were noted in 55 (87%) of 63 patients who had never received a BRAF inhibitor, including six (10%) who had a complete response; median progression-free survival was 13·7 months (95% CI 10·1-17·5). INTERPRETATION: The combination of vemurafenib and cobimetinib was safe and tolerable when administered at the respective maximum tolerated doses. The combination has promising antitumour activity and further clinical development is warranted in patients with advanced BRAF(V600)-mutated melanoma, particularly in those who have never received a BRAF inhibitor; confirmatory clinical testing is ongoing. FUNDING: F Hoffmann-La Roche/Genentech.

17 Clinical Trial Adoptive transfer of MART-1 T-cell receptor transgenic lymphocytes and dendritic cell vaccination in patients with metastatic melanoma. 2014

Chodon, Thinle / Comin-Anduix, Begoña / Chmielowski, Bartosz / Koya, Richard C / Wu, Zhongqi / Auerbach, Martin / Ng, Charles / Avramis, Earl / Seja, Elizabeth / Villanueva, Arturo / McCannel, Tara A / Ishiyama, Akira / Czernin, Johannes / Radu, Caius G / Wang, Xiaoyan / Gjertson, David W / Cochran, Alistair J / Cornetta, Kenneth / Wong, Deborah J L / Kaplan-Lefko, Paula / Hamid, Omid / Samlowski, Wolfram / Cohen, Peter A / Daniels, Gregory A / Mukherji, Bijay / Yang, Lili / Zack, Jerome A / Kohn, Donald B / Heath, James R / Glaspy, John A / Witte, Owen N / Baltimore, David / Economou, James S / Ribas, Antoni. ·Authors' Affiliations: Departments of Medicine, Surgery, Pathology and Laboratory Medicine, Microbiology, Immunology and Molecular Genetics, and Molecular and Medical Pharmacology; Jonsson Comprehensive Cancer Center; Department of Ophthalmology, Jules Stein Eye Institute; Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research; Howard Hughes Medical Institute, University of California, Los Angeles (UCLA); The Angeles Clinic Research Institute, Los Angeles; Department of Medicine, University of California San Diego (UCSD) Moores Cancer Center, La Jolla; Divisions of Chemistry and Biology, California Institute of Technology, Pasadena, California; Department of Medical and Molecular Genetics, Indiana University, and the Indiana University Viral Production Facility (IU VPF), Indianapolis, Indiana; Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada; Mayo Clinic Scottsdale, Scottsdale, Arizona; Department of Medicine, University of Connecticut Health Center, Farmington, Connecticut; and Center for Immunology, Roswell Park Cancer Institute, Buffalo, New York. ·Clin Cancer Res · Pubmed #24634374.

ABSTRACT: PURPOSE: It has been demonstrated that large numbers of tumor-specific T cells for adoptive cell transfer (ACT) can be manufactured by retroviral genetic engineering of autologous peripheral blood lymphocytes and expanding them over several weeks. In mouse models, this therapy is optimized when administered with dendritic cell (DC) vaccination. We developed a short 1-week manufacture protocol to determine the feasibility, safety, and antitumor efficacy of this double cell therapy. EXPERIMENTAL DESIGN: A clinical trial (NCT00910650) adoptively transferring MART-1 T-cell receptor (TCR) transgenic lymphocytes together with MART-1 peptide-pulsed DC vaccination in HLA-A2.1 patients with metastatic melanoma. Autologous TCR transgenic cells were manufactured in 6 to 7 days using retroviral vector gene transfer, and reinfused with (n = 10) or without (n = 3) prior cryopreservation. RESULTS: A total of 14 patients with metastatic melanoma were enrolled and 9 of 13 treated patients (69%) showed evidence of tumor regression. Peripheral blood reconstitution with MART-1-specific T cells peaked within 2 weeks of ACT, indicating rapid in vivo expansion. Administration of freshly manufactured TCR transgenic T cells resulted in a higher persistence of MART-1-specific T cells in the blood as compared with cryopreserved. Evidence that DC vaccination could cause further in vivo expansion was only observed with ACT using noncryopreserved T cells. CONCLUSION: Double cell therapy with ACT of TCR-engineered T cells with a very short ex vivo manipulation and DC vaccines is feasible and results in antitumor activity, but improvements are needed to maintain tumor responses.

18 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.).

19 Article Surface Modification of Polymeric Nanoparticles with M2pep Peptide for Drug Delivery to Tumor-Associated Macrophages. 2019

Pang, Liang / Pei, Yihua / Uzunalli, Gozde / Hyun, Hyesun / Lyle, L Tiffany / Yeo, Yoon. ·Department of Industrial and Physical Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana, 47907, USA. · Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China. · Department of Comparative Pathobiology, Purdue University, West Lafayette, Indiana, 47907, USA. · Department of Industrial and Physical Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana, 47907, USA. yyeo@purdue.edu. · Weldon School of Biomedical Engineering, Purdue University, 206 South Martin Jischke Drive, West Lafayette, Indiana, 47907, USA. yyeo@purdue.edu. ·Pharm Res · Pubmed #30859335.

ABSTRACT: PURPOSE: Tumor-associated macrophages (TAMs) with immune-suppressive M2-like phenotype constitute a significant part of tumor and support its growth, thus making an attractive therapeutic target for cancer therapy. To improve the delivery of drugs that control the survival and/or functions of TAMs, we developed nanoparticulate drug carriers with high affinity for TAMs. METHODS: Poly(lactic-co-glycolic acid) nanoparticles were coated with M2pep, a peptide ligand selectively binding to M2-polarized macrophages, via a simple surface modification method based on tannic acid-iron complex. The interactions of M2pep-coated nanoparticles with macrophages of different phenotypes were tested in vitro and in vivo. PLX3397, an inhibitor of the colony stimulating factor-1 (CSF-1)/CSF-1 receptor (CSF-1R) pathway and macrophage survival, was delivered to B16F10 tumors via M2pep-modified PLGA nanoparticles. RESULTS: In bone marrow-derived macrophages polarized to M2 phenotype, M2pep-coated nanoparticles showed greater cellular uptake than those without M2pep. Consistently, M2pep-coated nanoparticles showed relatively high localization of CD206 CONCLUSION: These results support that M2pep-coating can help nanoparticles to interact with M2-like TAMs and facilitate the delivery of drugs that control the tumor-supportive functions of TAMs.

20 Article Extremity nevus count is an independent risk factor for basal cell carcinoma and melanoma, but not squamous cell carcinoma. 2019

Wei, Erin X / Li, Xin / Nan, Hongmei. ·Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. · Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, Indiana. · Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, Indiana; Indiana University Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, Indiana. Electronic address: hnan@iu.edu. ·J Am Acad Dermatol · Pubmed #30713015.

ABSTRACT: BACKGROUND: The presence of nevi portends an increased risk for melanoma. OBJECTIVE: We sought to examine the association between extremity nevus count and the risk of melanoma and keratinocyte cancers. METHODS: We evaluated prospective cohorts of 176,317 women (the Nurses' Health Study, 1986-2012 and the Nurses' Health Study 2, 1989-2013) and 32,383 men (Health Professionals Follow-up Study, 1986-2012). Information on nevus count (none, 1-5, 6-14, ≥15) on the extremity was collected at baseline. RESULTS: There were 1704 incident cases of melanoma, 2296 incident cases of squamous cell carcinoma, and 30,457 incident cases of basal cell carcinoma, with a total of 4,655,043 person-years for melanoma and 4,267,708 person-years for keratinocyte cancers. The presence of an extremity nevus was associated with an increased risk of melanoma in all anatomic areas and increased risk of basal cell carcinoma (BCC). Individuals with ≥15 nevi had the highest risk of melanoma and BCC compared to those without any extremity nevi (melanoma hazard ratio 2.79 [95% confidence interval 2.04-3.83]; BCC HR 1.40 [95% confidence interval 1.32-1.49]). No significant association was observed for squamous cell carcinoma. LIMITATIONS: Limitations of our study included self-reported nevus count and detection bias. CONCLUSIONS: Extremity nevus count is a helpful clinical marker in risk-stratifying individuals for BCC and melanoma on all body sites.

21 Article Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways. 2018

Duffy, David L / Zhu, Gu / Li, Xin / Sanna, Marianna / Iles, Mark M / Jacobs, Leonie C / Evans, David M / Yazar, Seyhan / Beesley, Jonathan / Law, Matthew H / Kraft, Peter / Visconti, Alessia / Taylor, John C / Liu, Fan / Wright, Margaret J / Henders, Anjali K / Bowdler, Lisa / Glass, Dan / Ikram, M Arfan / Uitterlinden, André G / Madden, Pamela A / Heath, Andrew C / Nelson, Elliot C / Green, Adele C / Chanock, Stephen / Barrett, Jennifer H / Brown, Matthew A / Hayward, Nicholas K / MacGregor, Stuart / Sturm, Richard A / Hewitt, Alex W / Anonymous2901124 / Kayser, Manfred / Hunter, David J / Newton Bishop, Julia A / Spector, Timothy D / Montgomery, Grant W / Mackey, David A / Smith, George Davey / Nijsten, Tamar E / Bishop, D Timothy / Bataille, Veronique / Falchi, Mario / Han, Jiali / Martin, Nicholas G. ·QIMR Berghofer Medical Research Institute, Brisbane, Australia. David.Duffy@qimrberghofer.edu.au. · QIMR Berghofer Medical Research Institute, Brisbane, Australia. · Department of Epidemiology, Richard M. Fairbanks School of Public Health, Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, IN, 63110, USA. · Department of Twin Research & Genetic Epidemiology, St Thomas Hospital Campus, Kings College, London, UK. · Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK. · Department of Dermatology, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands. · MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK. · University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia. · Centre for Ophthalmology and Vision Science, University of Western Australia and the Lions Eye Institute, Perth, Australia. · Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, 02115, MA, USA. · Department of Genetic Identification, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands. · Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia. · Department of Epidemiology, Erasmus MC, Rotterdam, Netherlands. · Department of Internal Medicine, Erasmus MC, Rotterdam, Netherlands. · Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA. · Molecular Oncology Group, CRUK Manchester Institute, University of Manchester, Manchester, UK. · Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA. · Dermatology Research Centre, University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia. ·Nat Commun · Pubmed #30429480.

ABSTRACT: The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk. Here we report a meta-analysis of 11 nevus GWAS from Australia, Netherlands, UK, and USA comprising 52,506 individuals. We confirm known loci including MTAP, PLA2G6, and IRF4, and detect novel SNPs in KITLG and a region of 9q32. In a bivariate analysis combining the nevus results with a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A, CYP1B1, PPARGC1B, HDAC4, FAM208B, DOCK8, and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1, reached a suggestive level. Overall, we conclude that most nevus genes affect melanoma risk (KITLG an exception), while many melanoma risk loci do not alter nevus count. For example, variants in TERC and OBFC1 affect both traits, but other telomere length maintenance genes seem to affect melanoma risk only. Our findings implicate multiple pathways in nevogenesis.

22 Article Single-cell RNA-seq analysis identifies markers of resistance to targeted BRAF inhibitors in melanoma cell populations. 2018

Ho, Yu-Jui / Anaparthy, Naishitha / Molik, David / Mathew, Grinu / Aicher, Toby / Patel, Ami / Hicks, James / Hammell, Molly Gale. ·Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA. · Department of Molecular and Cellular Biology, Stony Brook University, Stony Brook, New York 11794, USA. · Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana 46556, USA. · Middlebury College, Middlebury, Vermont 05753, USA. · Mount Sinai Health System, New York, New York 10003, USA. · Department of Biological Science, University of Southern California, Los Angeles, California 90089, USA. ·Genome Res · Pubmed #30061114.

ABSTRACT: Single-cell RNA-seq's (scRNA-seq) unprecedented cellular resolution at a genome-wide scale enables us to address questions about cellular heterogeneity that are inaccessible using methods that average over bulk tissue extracts. However, scRNA-seq data sets also present additional challenges such as high transcript dropout rates, stochastic transcription events, and complex population substructures. Here, we present a

23 Article Characterization of Thermally Activated Metalloenediyne Cytotoxicity in Human Melanoma Cells. 2018

Keller, Eric J / Porter, Meghan / Garrett, Joy E / Varie, Meredith / Wang, Haiyan / Pollok, Karen E / Turchi, John J / Zaleski, Jeffrey M / Dynlacht, Joseph R. ·Departments of a   Radiation Oncology. · d   Department of Chemistry, Indiana University, Bloomington, Indiana. · b   Pediatrics. · c   Medicine, Indiana University School of Medicine, Indianapolis, Indiana. ·Radiat Res · Pubmed #29763378.

ABSTRACT: Enediynes are a highly cytotoxic class of compounds. However, metallation of these compounds may modulate their activation, and thus their cytotoxicity. We previously demonstrated that cytotoxicity of two different metalloenediynes, including (Z)-N,N'-bis[1-pyridyl-2-yl-meth-(E)-ylidene]octa-4-ene-2,6-diyne-1,8-diamine] (PyED), is potentiated when the compounds are administered to HeLa cells during hyperthermia treatment at concentrations that are minimally or not cytotoxic at 37°C. In this study, we further characterized the concentration, time and temperature dependence of cytotoxicity of PyED on human U-1 melanoma cells. We also investigated the potential mechanisms by which PyED cytotoxicity is enhanced during hyperthermia treatment. Cell killing with PyED was dependent on concentration, temperature during treatment and time of exposure. Potentiation of cytotoxicity was observed when cells were treated with PyED at temperatures ≥39.5°C, and enhancement of cell killing increased with temperature and with increasing time at a given temperature. All cells treated with PyED were shown to have DNA damage, but substantially more damage was observed in cells treated with PyED during heating. DNA repair was also inhibited in cells treated with the drug during hyperthermia. Thus, potentiation of PyED cytotoxicity by hyperthermia may be due to enhancement of drug-induced DNA lesions, and/or the inhibition of repair of sublethal DNA damage. While the selective thermal activation of PyED supports the potential clinical utility of metalloenediynes as cancer thermochemotherapeutic agents, therapeutic gain could be optimized by identifying compounds that produce minimal toxicity at 37°C but which become activated and show enhancement of cytotoxicity within a tumor subjected to localized hyperthermic or thermal ablative treatment, or which might act as bifunctional agents. We thus also describe the development and initial characterization of a novel cofactor complex of PyED, platinated PyED (Pt-PyED). Pt-PyED binds to DNA-like cisplatin, and much like PyED, cytotoxicity is greatly enhanced after treatment with the drug at elevated temperatures. However, in contrast to PyED, Pt-PyED is only minimally cytotoxic at 37°C, at concentrations at which cytotoxicity is enhanced by hyperthermia. Further development of cisplatin-based enediynes may result in compounds which, when activated, will possess multiple DNA binding modalities similar to cisplatin, but produce less side effects in tissues at normothermic temperatures.

24 Article Genome-wide association study in 176,678 Europeans reveals genetic loci for tanning response to sun exposure. 2018

Visconti, Alessia / Duffy, David L / Liu, Fan / Zhu, Gu / Wu, Wenting / Chen, Yan / Hysi, Pirro G / Zeng, Changqing / Sanna, Marianna / Iles, Mark M / Kanetsky, Peter A / Demenais, Florence / Hamer, Merel A / Uitterlinden, Andre G / Ikram, M Arfan / Nijsten, Tamar / Martin, Nicholas G / Kayser, Manfred / Spector, Tim D / Han, Jiali / Bataille, Veronique / Falchi, Mario. ·Department of Twin Research and Genetic Epidemiology, King's College London, London, SE1 7EH, UK. · QIMR Berghofer Medical Research Institute, Brisbane, 4029, Australia. · CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China. · University of Chinese Academy of Sciences, Beijing, 100049, China. · Department of Genetic Identification, Erasmus MC University Medical Center Rotterdam, Rotterdam, 3000 CA, The Netherlands. · Department of Epidemiology, Richard M. Fairbanks School of Public Health, Melvin & Bren Simon Cancer Center, Indiana University, Indianapolis, 46202, IN, USA. · Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, LS9 7TF, UK. · Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, 33612, FL, USA. · INSERM, UMR 946, Genetic Variation and Human Diseases Unit, Paris, 75010, France. · Institut Universitaire d'Hématologie, Université Paris Diderot, Sorbonne Paris Cité, Paris, 75010, France. · Department of Dermatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, 3000 CA, The Netherlands. · Department of Internal Medicine, Erasmus MC University Medical Center Rotterdam, Rotterdam, 3000 CA, The Netherlands. · Department of Epidemiology, Erasmus MC University Medical Center Rotterdam, Rotterdam, 3000 CA, The Netherlands. · Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, 02115, MA, USA. · Department of Dermatology, West Herts NHS Trust, Herts, HP2 4AD, UK. · Department of Twin Research and Genetic Epidemiology, King's College London, London, SE1 7EH, UK. mario.falchi@kcl.ac.uk. ·Nat Commun · Pubmed #29739929.

ABSTRACT: The skin's tendency to sunburn rather than tan is a major risk factor for skin cancer. Here we report a large genome-wide association study of ease of skin tanning in 176,678 subjects of European ancestry. We identify significant association with tanning ability at 20 loci. We confirm previously identified associations at six of these loci, and report 14 novel loci, of which ten have never been associated with pigmentation-related phenotypes. Our results also suggest that variants at the AHR/AGR3 locus, previously associated with cutaneous malignant melanoma the underlying mechanism of which is poorly understood, might act on disease risk through modulation of tanning ability.

25 Article A geometric approach to characterize the functional identity of single cells. 2018

Mohammadi, Shahin / Ravindra, Vikram / Gleich, David F / Grama, Ananth. ·Computer Science and Artificial Intelligence Laboratory, MIT, Cambridge, MA, 02139, USA. mohammadi@broadinstitute.org. · Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. mohammadi@broadinstitute.org. · Department of Computer Science, Purdue University, West Lafayette, IN, 47907, USA. · Department of Computer Science, Purdue University, West Lafayette, IN, 47907, USA. ayg@purdue.cs.edu. ·Nat Commun · Pubmed #29666373.

ABSTRACT: Single-cell transcriptomic data has the potential to radically redefine our view of cell-type identity. Cells that were previously believed to be homogeneous are now clearly distinguishable in terms of their expression phenotype. Methods for automatically characterizing the functional identity of cells, and their associated properties, can be used to uncover processes involved in lineage differentiation as well as sub-typing cancer cells. They can also be used to suggest personalized therapies based on molecular signatures associated with pathology. We develop a new method, called ACTION, to infer the functional identity of cells from their transcriptional profile, classify them based on their dominant function, and reconstruct regulatory networks that are responsible for mediating their identity. Using ACTION, we identify novel Melanoma subtypes with differential survival rates and therapeutic responses, for which we provide biomarkers along with their underlying regulatory networks.